Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-04
2003-12-23
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
06667322
ABSTRACT:
Major depressive disorder affects an estimated 340 million people worldwide. According to the World Health Organization, depression is the fourth greatest public health problem. If left untreated, the effects of depression can be devastating, robbing people of the energy or motivation to perform everyday activities and, in some cases, leading to suicide. Symptoms of the disorder include feelings of sadness or emptiness, lack of interest or pleasure in nearly all activities, and feelings of worthlessness or inappropriate guilt. In addition to the personal costs of depression, the disorder also results in more than $40 billion in annual costs in the United States alone, due to premature death, lost productivity, and absenteeism.
Selective serotonin reuptake inhibitors (SSRIs) have had 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.
SSRIs work by blocking the neuronal reuptake of serotonin, which tends to increase the concentration of serotonin in the synaptic space, and thus increase the activation of postsynaptic serotonin receptors. However, although a single dose of an SSRI can inhibit the neuronal serotonin transporter and thus 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 acutely. Over time, the somatodendritic autoreceptors become desensitized, allowing the full effect of the SSRI to be expressed in the forebrain. This time period corresponds to the latency for the onset of antidepressant activity [Perez, V., et al.,
The Lancet,
349:1594-1597 (1997)].
A 5-HT
1A
agonist or partial agonist acts directly on postsynaptic serotonin receptors to increase serotonergic neurotransmission during the latency period for the SSRI effect. Accordingly, the 5-HT
1A
partial agonists buspirone and gepirone [Feiger, A.,
Psychopharmacol. Bull.,
32(4), 659-665 (1996), Wilcox, C.,
Psychopharmacol. Bull.,
32(3), 335-342 (1996)] and the 5-HT
1A
agonist flesinoxan [Grof, P.,
International clinical Psychopharmacology,
8(3), 167-72 (1993)] have shown efficacy in clinical trials for the treatment of depression. Furthermore, such agents would also stimulate the somatodendritic autoreceptors, thus hastening their desensitization and decreasing the SSRI latency period. An agent with a dual mechanism of antidepressant action would be expected to have greater efficacy and thus reduce the number of patients refractory to treatment. Indeed, buspirone augmentation has been shown to produce marked clinical improvement in patients initally unresponsive to standard antidepressant therapy [Dimitriou, E.,
J. Clinical Psychopharmacol.,
18(6), 465-469 (1998)].
Thus, it is highly desirable to provide improved compounds which both inhibit serotonin reuptake and which are agonists or partial agonists 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
and R
2
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; or R
1
and R
2
, taken together, form methylenedioxy, ethylenedioxy or propylenedioxy;
R
3
, R
4
, R
5
and R
7
are independently selected from hydrogen, halo, cyano, carboxamido, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms;
R
6
is hydrogen or alkyl of 1 to 6 carbon atoms;
X is CR
7
or N;
the dotted lines at a and b independently represent optional double bonds; and
n is an integer 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
In some preferred embodiments of the invention R
1
and R
2
are independently hydrogen, halo, cyano, carboxamido, trifluoromethyl, amino, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms. More preferably, one of R
1
and R
2
is alkoxy of 1 to 6 carbon atoms or together R
1
and R
2
form methylenedioxy, ethylenedioxy or propylenedioxy. One of R
1
and R
2
is still more preferably alkoxy of 1 to 3 carbon atoms.
In some preferred embodiments of the invention R
3
, R
4
and R
5
are independently selected from hydrogen, halo, cyano, alkyl of one to six carbon atoms, and alkoxy of one to six carbon atoms. Still more preferably R
3
, R
4
and R
5
are independently selected from hydrogen, halogen and cyano.
R
6
is preferably hydrogen or lower alkyl.
X is preferably CR
7
. When X is CR
7
, then R
7
is preferably hydrogen, halo, cyano, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms and more preferably hydrogen, halogen or cyano.
Of the compounds of Formula I, some preferred members are those in which R
1
and R
2
are, independently, hydrogen, halo, cyano, carboxamido, trifluoromethyl, amino, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms; R
3
, R
4
, R
5
and R
7
are independently selected from hydrogen, halo, cyano, 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
, X and the dotted line are defined as above.
More preferred compounds are those of Formula I in which R
1
is alkoxy of one to six carbon atoms and is attached to position 8 of a chroman moiety, R
2
and R
6
are hydrogen, R
3
, R
4
, R
5
and R
7
are independently selected from hydrogen, halo or cyano, X is CR
7
, 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 2-aminomethyl-chromans and chromenes, 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-chromans and chromenes is not indicated, is intended to embrace the individual R and S enantiomers as well as mixtures of the two.
In some embodiments of the present invention the R 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 corresonding 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 as 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 Da
Gross Jonathan Laird
Mewshaw Richard Eric
Stack Gary Paul
Fan Jane
Woodcock & Washburn LLP
Wyeth
LandOfFree
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