Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-25
2003-04-29
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...
C514S321000, C514S300000, C546S277400, C546S197000, C546S113000
Reexamination Certificate
active
06555560
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 wouldt 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
3
, R
4
, R
5
and R
7
are, independently, 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;
R
2
and R
6
are hydrogen or alkyl of 1 to 6 carbon atoms;
Z is CR
7
or N;
X is O, S, H
2
or F
2
;
the dotted lines at a and b represent independently optional double bonds; 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, hydroxy, halo, cyano, trifluoromethyl, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms. In still more preferred embodiments of the present invention, R
1
is hydrogen, halo and methoxy.
In other embodiments of the invention R
2
is preferably hydrogen or lower alkyl. R
2
is still more preferably hydrogen.
R
3
, R
4
, and R
5
are preferably independently selected from hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of one to six carbon atoms, and alkoxy of one to six carbon atoms in some embodiments of the invention. Still more preferably R
3
, R
4
, and R
5
are preferably independently selected from hydrogen, cyano and halogen.
R
6
is preferably hydrogen or lower alkyl.
X is preferably O or H
2
.
Of the compounds of Formula I, still more preferred are those in which R
1
is hydrogen, hydroxy, halo, cyano, trifluoromethyl, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms; R
2
is hydrogen, methyl or ethyl; R
3
, R
4
, and R
5
are preferably independently selected from hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of one to six carbon atoms, and alkoxy of one to six carbon atoms, Z is CR
7
, R
7
is hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms; n is an integer 0 or 1; and R
6
and the dotted lines are defined as above.
Most preferred are those examples in which R
1
is hydrogen, halo or methoxy, R
2
and R
6
are hydrogen, R
3
, R
4
, and R
5
are preferably independently selected from hydrogen, halo and cyano, Z is CR
7
, R
7
is hydrogen, halo or cyano, n is 0 and the dotted line in the azaheterocycle represents a double bond.
This invention relates to both the R and S stereoisomers of the aminomethyl-1,4,5-trioxa-phenanthrene, 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 aminomethyl-1,4,5-trioxa-phenanthrene 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 prepared 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.
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
.
Carboalkoxy as used herein refers to the group R—O—C(═O)— where R is an alkyl group of 1 to 5 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 compounds of the present invention are:
3-[4-(5-fluoro-1-H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2,3-dihydro-7-H-pyrano[2,3-f][1,4]benzodioxin-7-one;
5-fluoro-3-[1,2,3,6-tetrahydro-1-[(2,3,8,9-tetrahydro-7H-pyrano[2,3-f][1,4]-benzodioxin-2-yl)methyl]-4-pyridinyl]-1H-indole;
3-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2,3,6,7-tetrahydro-1,4,5-trioxa-phenanthren-8-one; and
3-{1-(2,3
Stack Gary P.
Tran Megan
Barrett Rebecca R.
Fan Jane
Wyeth
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