8-aza-bicyclo[3.2.1]octan-3-ol derivatives of...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C546S126000, C546S125000, C544S335000, C544S180000, C544S182000, C544S333000, C514S256000, C514S241000, C514S242000

Reexamination Certificate

active

06656951

ABSTRACT:

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. Novel 5-HT
1A
antagonists would be desirable for these and other uses.
DESCRIPTION OF INVENTION
In accordance with this invention, there is provided a group of novel agents which affect diseases of the central nervous system having the structural formula:
wherein
R
1
is a straight-chained alkyl of 1 to 6 carbon atoms, or a branched chain alkyl of 3 to 8 carbon atoms; and
R
2
is phenyl, naphthyl, anthracyl, phenanthryl, pyridyl, pyrimidyl, triazinyl, furyl, pyrrolyl, pyrazolyl, indolyl, imidazolyl, benzofuryl, benzothienyl, oxazolyl, or thiazolyl, each optionally substituted with 0 to 3 substituents selected from straight-chain alkyl of 1 to 6 carbon atoms, branched-chain alkyl of 3 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms, mono- or dialkylamino in which each alkyl group has 1 to 6 carbon atoms, nitro, halo, amino, cyano, trifluoromethyl, trifluoromethoxy, and hydroxy; or a pharmaceutically acceptable salt thereof.
R
1
is preferably straight chain alkyl of 1 to 3 carbon atoms or a branched chain alkyl of 3 to 6 carbon atoms. Still more preferably, R
1
is straight chain alkyl of 1 to 2 carbon atoms.
In some embodiments of the present invention R
2
is phenyl, naphthyl, pyridyl, pyrimidyl, furyl, pyrrolyl, pyrazolyl, indolyl, imidazolyl, benzofuryl, or benzothienyl; each optionally substituted with 1 to 3 substituents the same or different selected from straight-chain alkyl of 1 to 3 carbon atoms, branched-chain alkyl of 3 to 6 carbon atoms, alkoxy of 1 to 3 carbon atoms, mono- or di-alkylamino in which each alkyl group has 1 to 3 carbon atoms, nitro, amino, cyano, halogen, trifluoromethyl, trifluoromethoxy, or hydroxy.
In other embodiments of the invention R
2
is phenyl, naphthyl, pyridyl, pyrrolyl, indolyl, or benzothienyl; each optionally substituted with 1 to 3 substituents the same or different selected from nitro, amino, cyano, halogen, trifluoromethyl, trifluoromethoxy, or hydroxy. R
2
is more preferably phenyl, naphthyl, benzothienyl, or pyridyl, each optionally substituted with 1 to 3 substituents the same or different selected from nitro, amino, cyano, halogen, trifluoromethyl, trifluoromethoxy, or hydroxy. In still more preferred embodiments of the invention R
2
is trifluoromethylphenyl or methoxyphenyl.
In some aspects of this invention the R
1
O substituent to the 1,4-benzodioxan nucleus is at the 8-position. Examples of R
2
are phenyl, naphthyl, pyridyl, pyrimidyl, furyl, pyrrolyl, pyrazolyl, indolyl, imidazolyl, benzofuryl, or benzothienyl, optionally substituted with 0 to 3 substituents selected from straight-chain alkyl of 1 to 3 carbon atoms, branched-chain alkyl of 3 to 6 carbon atoms, alkoxy of 1 to 3 carbon atoms, mono- or dialkylamino in which each alkyl group has from 1 to 3 carbon atoms, nitro, amino, cyano, halogen, trifluoromethyl, trifluoromethoxy, or hydroxy.
In still other aspects of the invention the R
1
O substituent to the 1,4-benzodioxan nucleus is at the 8-position, R
1
is a straight-chained alkyl of 1 to 2 carbon atoms, and R
2
is a phenyl, naphthyl, pyridyl, pyrrolyl, indolyl, or benzothienyl group optionally substituted with nitro, amino, cyano, halogen, trifluoromethyl, trifluoromethoxy or hydroxy.
It is understood that the definition of the compounds of formula I, when R
1
and R
2
contain asymmetric carbons, encompass all possible stereoisomers and mixtures thereof which possess the activity discussed below. This invention relates to both the R and S stereoisomers of the 2-aminomethyl-2,3-dihydro-1,4-benzodioxan, 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 2-aminomethyl-2,3-dihydro-1,4-benzodioxan 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 stereoisomer 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, NY, 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.
Alkoxy as used herein refers to the group R—O— where R is an alkyl group of 1 to 6 carbon atoms.
Halogen (or halo) as used herein refers to chlorine, bromine, fluorine and iodine.
Pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids.
Specific examples of the present invention include:
(S)-8-(8-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol;
(S)-8-(8-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-phenyl-8-aza-bicyclo[3.2.1]octan-3-ol;
(S)-3-Benzo[b]thiophen-3-yl-8-(8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-aza-bicyclo[3.2.1]octan-3-ol;
8-{[(2S)-8-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl]methyl)-3-pyridin-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol;
8-{[(2S)-8-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl]methyl)-3-(3-trifluoromethyl-phenyl)-8-aza-bicyclo[3.2.1]octan-3-ol;
8-{[(2S)-8-Methoxy-2,3-dihydro-1,4-benzodioxin-2-yl]methyl}-3-(2-methoxyphenyl)-8-azabicyclo[3.2.1]octan-3-ol;
8-{[(2S)-8-Methoxy-2,3-dihydro-1,4-benzodioxin-2-yl]methyl}-3-[3-(trifluoromethyl)phenyl]-8-azabic

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