Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-25
2004-08-24
Wilson, James O. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S256000, C514S304000, C544S180000, C544S333000, C546S126000
Reexamination Certificate
active
06780860
ABSTRACT:
BACKGROUND OF THE INVENTION
Recent studies with the selective 5-HT
1A
antagonist WAY-100635 have confirmed a role for 5-HT
1A
receptors in learning and memory. Carli et. al. (Neuropharmacology (1999), 38(8), 1165-1173) demonstrated that WAY-100635 prevented the impairment of spatial learning caused by intrahippocampal injection of 3-[(R)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP), a competitive NMDA receptor antagonist, in a two-platform spatial discrimination task. Boast et al. (Neurobiol. Learn. Mem. (1999), 71(3) 259-271) found that WAY-100635 significantly reduced the cognitive impairment induced by the non-competitive NMDA antagonist MK801, as determined by the performance of rats trained on a delayed nonmatching to sample radial arm maze task. Menesis et. al. (Neurobiol. Learn. Mem. (1999), 71(2) 207-218) showed that post-training administration of WAY-100635 reversed the learning deficit induced by scopolamine, a cholinergic antagonist, in an autoshaping learning task. New and novel 5-HT
1A
antagonists would be useful for these and other uses.
DESCRIPTION OF THE INVENTION
In accordance with this invention, there is provided a group of novel 5-HT
1A
antagonists of the formula I:
wherein
R
1
is hydrogen, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
X—Y—Z is N═C(R
2
)—O, N═C(R
2
)—NH or NH—C(R
2
)═CH;
R
2
is hydrogen, halo, trifluoromethyl, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atoms or alkyl of one to six carbon atoms; and
R
3
is phenyl, naphthyl, anthracyl, phenanthryl, pyridyl, pyrimidyl, triazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, indolyl, imidazolyl, benzofuryl, benzothienyl, oxazolyl, or thiazolyl, each optionally substituted with from one to three substituents selected from hydroxy, halo, trifluoromethyl, cyano, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atoms and alkyl of one to six carbon atoms;
or a pharmaceutically acceptable salt thereof.
In some embodiments of the present invention X—Y—Z is N═C(R
2
)—O.
R
1
is preferably hydrogen, halo, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms. In more preferred embodiments, R
1
is hydrogen, trifluoromethyl, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms.
In some embodiments of the present invention R
2
is preferably hydrogen, trifluoromethyl, amino, mono- or dialkylamino in which each alkyl group has one to six carbon atoms, or alkyl of 1 to 6 carbon atoms, R
2
is more preferably hydrogen, trifluoromethyl, or alkyl of one to six carbon atoms. R
2
is still more preferably hydrogen or alkyl of one to six carbon atoms and still more preferably alkyl from 1 to 3 carbon atoms.
In other embodiments of the present invention R
3
is phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, pyrazolyl, indolyl, imidazolyl, benzofuryl, or benzothienyl, each optionally substituted with from one to three substituents selected from hydroxy, halo, trifluoromethyl, cyano, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atoms and alkyl of one to six carbon atoms. R
3
is more preferably phenyl, naphthyl, pyridyl, pyrrolyl, indolyl, or benzothienyl, each optionally substituted with from one to three substituents selected from halo, trifluoromethyl, cyano, alkoxy of one to six carbon atoms and alkyl of one to six carbon atoms R
3
is preferably phenyl or naphthyl, each optionally substituted with from one to three substituents selected from halo, trifluoromethyl, cyano, alkoxy of one to six carbon atoms and alkyl of one to six carbon atoms.
Still more preferred compounds are those in which R
1
is hydrogen, halo, trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has one to six carbon atoms; R
2
is hydrogen, trifluoromethyl, amino, mono- or di-alkylamino in which each alkyl group has one to six carbon atoms, or alkyl of one to six carbon atom; and R
3
is phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, pyrazolyl, indolyl, imidazolyl, benzofuryl, or benzothienyl, each optionally substituted with from one to three substituents selected from hydroxy, halo, trifluoromethyl, cyano, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkoxy of one to six carbon atoms and alkyl of one to six carbon atoms.
Most preferred are those in which R
1
is hydrogen, halo, trifluoromethyl, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms; R
2
is hydrogen, trifluoromethyl or alkyl of one to six carbon atom; and R
3
is phenyl, naphthyl, pyridyl, pyrrolyl, indolyl, or benzothienyl, each optionally substituted with from one to three substituents selected from halo, trifluoromethyl, cyano, alkoxy of one to six carbon atoms and alkyl of one to six carbon atoms.
This invention relates to both the R and S stereoisomers of the 8-aminomethyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene, as well as to mixtures of the R and S stereoisomers. Throughout this application, the name of the product of this invention, where the absolute configuration of the 8-aminomethyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene is not indicated, is intended to embrace the individual R and S enantiomers as well as mixtures of the two. In some preferred embodiments of the present invention the S isomer is preferred.
Where a stereoisomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of the corresponding enantiomer refers to a compound which is isolated or separated via separation techniques or prepared free of the corresponding enantiomer. Substantially free, as used herein means that the compound is made up of a significantly greater proportion of one stereoisomer. In preferred embodiments the compound is made up of at least about 90% by weight of a preferred stereoisomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of a preferred stereoisomer. Preferred stereoisomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or by methods described herein. See, for example, Jacques, et. al.,
Enantiomers, Racemates and Resolutions
(Wiley Interscience, New York, 1981); Wilen, S. H., et. al.,
Tetrahedron
33:2725 (1977); Eliel, E. L.
Stereochemistry of Carbon Compounds
(McGraw-Hill, N.Y., 1962); Wilen, S. H.
Tables of Resolving Agents and Optical Resolutions
p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).
Alkyl as used herein refers to an aliphatic hydrocarbon chain and includes straight and branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl having 1 to 3 carbon atoms.
Alkanamido as used herein refers to the group R—C(═O)—NH— where R is an alkyl group of 1 to 5 carbon atoms.
Alkanoyloxy as used herein refers to the group R—C(═O)—O— where R is an alkyl group of 1 to 5 carbon atoms.
Alkanesulfonamido as used herein refers to the group R—S(O)
2
—NH— where R is an alkyl group of 1 to 6 carbon atoms.
Alkoxy as used herein refers to the group R—O— where R is an alkyl group of 1 to 6 carbon atoms.
Carboxamido, as used herein refers to the group —CO—NH
2
.
Carboal
Gilbert Adam M.
Stack Gary P.
Tran Megan
McKenzie Thomas
Wilson James O.
Woodcock & Washburn LLP
Wyeth
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