Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-23
2003-06-03
Fan, Jane (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S300000, C514S322000, C546S273100, C546S199000, C546S113000
Reexamination Certificate
active
06573283
ABSTRACT:
BACKGROUND OF THE INVENTION
Major depression is a serious health problem affecting more than 5% of the population, with a life-time prevalence of 15-20%.
Selective serotonin reuptake inhibitors have produced significant success in treating depression and related illnesses and have become among the most prescribed drugs. They nonetheless have a slow onset of action, often taking several weeks to produce their full therapeutic effect. Furthermore, they are effective in fewer than two-thirds of patients.
Serotonin selective reuptake inhibitors (SSRIs) are well known for the treatment of depression and other conditions. SSRIs work by blocking the neuronal reuptake of serotonin, thereby increasing the concentration of serotonin in the synaptic space, and thus increasing the activation of postsynaptic serotonin receptors.
However, although a single dose of an SSRI can inhibit the neuronal serotonin transporter which would be expected to increase synaptic serotonin, long-term treatment is required before clinical improvement is achieved.
It has been suggested that the SSRIs increase the serotonin levels in the vicinity of the serotonergic cell bodies and that the excess serotonin activates somatodendritic autoreceptors, 5-HT
1A
receptors, causing a decrease in serotonin release in major forebrain areas. This negative feedback limits the increment of synaptic serotonin that can be induced by antidepressants.
A 5-HT
1A
antagonist would limit the negative feedback and should improve the efficacy of the serotonin reuptake mechanism. (Perez, V., et al.,
The Lancet,
349:1594-1597 (1997)). Such a combination therapy would be expected to speed up the effect of the serotonin reuptake inhibitor.
Thus, it is highly desirable to provide improved compounds which both inhibit serotonin reuptake and which are antagonists of the 5-HT
1A
receptor.
DESCRIPTION OF THE INVENTION
In accordance with this invention, there is provided a group of novel compounds of the formula:
wherein
R
1
, R
2
, R
3
, R
4
, R
5
and R
8
are independently hydrogen, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, pentafluoroethyl, 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;
R
6
and R
7
are, independently, hydrogen or alkyl of 1 to 6 carbon atoms;
A dotted line represents an optional double bond;
Z is CR
8
or N; and
n is an integer 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
In some preferred embodiments of the present invention, R
1
is hydrogen, halo, cyano, trifluoromethyl, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms, and more preferably R
1
is hydrogen.
In other embodiments of the invention R
2
is hydrogen, halo, trifluoromethyl, pentafluoroethyl, 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 more preferably hydrogen, trifluoromethyl, pentafluoroethyl or lower alkyl.
In still other embodiments of the invention R
3
, R
4
and R
5
are independently selected from hydrogen, halo, cyano, carboxamido, alkyl of one to six carbon atoms, and alkoxy of one to six carbon atoms. R
3
, R
4
and R
5
are more preferably independently selected from hydrogen, cyano and halogen, and most preferably hydrogen or halogen.
Where Z is CR
8
, R
8
is preferably hydrogen, halo, cyano, carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms, more preferably hydrogen, cyano or halogen and most preferably hydrogen or halogen.
R
6
is preferably hydrogen in some embodiments of the invention.
R
7
is preferably hydrogen or lower alkyl in other embodiments of the invention.
In other preferred embodiments n is preferably 0 or 1 and most preferably 0.
The optional double bond is preferably present in still other preferred embodiments of the invention.
Of the compounds of Formula I, still more preferred are compounds in which R
1
is hydrogen, halogen, cyano, trifluoromethyl, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms; R
2
is hydrogen, halogen, trifluoromethyl, pentafluoroethyl, 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
3
, R
4
and R
5
are independently selected from hydrogen, halogen, cyano, carboxamido, alkyl of one to six carbon atoms, and alkoxy of one to six carbon atoms; n is an integer 0 or 1.
Still more preferred are those compounds in which R
1
is hydrogen, halogen, cyano, trifluoromethyl, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms; R
2
is hydrogen, trifluoromethyl, pentafluoroethyl, or alkyl of one to six carbon atoms, R
3
, R
4
and R
5
are independently selected from hydrogen, halogen and cyano, R
6
and R
7
are hydrogen, n is 0 and the dotted line represents a double bond.
In still more preferred embodiments of the present invention R
1
is hydrogen, R
2
is trifluoromethyl, pentafluoroethyl, or lower alkyl, R
3
, R
4
and R
5
are independently selected from hydrogen and halogen, R
6
is hydrogen, R
7
is hydrogen or lower alkyl, Z is CR
8
, R
8
is hydrogen or halo, n is 0, and the optional double bond is present.
This invention relates to both the R and S stereoisomers of the 8-aminomethyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-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-3H-6,9-dioxa-1,3-diaza-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, 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).
It is further recognized that tautomers of the claimed compounds may exist, for instance, when R
7
is hydrogen the imidazole may exist in either of two tautomeric forms. The claims in this application, either for the title compounds or intermediates, are intended to embrace both of the tautomers, as well as mixtures of the two.
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.
Alkanoyl
Barrett Rebecca R
Fan Jane
Wyeth
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