Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-20
2003-10-14
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S126000, C546S124000, C546S112000, C514S299000
Reexamination Certificate
active
06632824
ABSTRACT:
BACKGROUND OF INVENTION
The present invention relates to aryl-8-azabicyclo[3.2.1]octane and aryl-8-azabicyclo[3.2.1]oct-2-ene derivatives having pharmacological activity, and to their use in the treatment of diseases affected by disorders of the serotonin affected neurological systems, such as depression and anxiety.
Pharmaceuticals which enhance serotonergic neurotransmission are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affection drugs operated through a variety of physiological functions which endowed them with several side effect liabilities. The more currently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier (5-HT-T).
The present invention relates to a new class of molecules which have the ability to act at the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
Some of the present molecules have a second activity as partial agonists/inhibitors of the serotonin 1
A
receptor (5-HT
1A
). Since SSRIs require several weeks before a full therapeutic effect is seen, their mechanism of action can't solely be explained by the inhibition of 5-HT-T. It is believed that this delayed effect is due to the involvement of 5-HT
1A
autoreceptors. It has been previously suggested (Artigas et al.
TiPs,
1993, 14, 262) that the efficacy of reuptake inhibitors may be attenuated by the activation of 5-HT
1A
receptors which results in the reduced firing rate of 5-HT neurons. Repeated SSRI administration, causing desensitization of 5-HT
1A
receptors, is postulated to be required before the antidepressant effect of these compounds is seen. Support for desensitization of 5-HT
1A
in humans is shown by an obsessive-compulsive disorder (OCD) study (Lesch et al.
Psychopharm.
1991, 105, 415), where patients given repeated treatment with SSRIs developed tolerance to the hypothermic response induced by the administration of the 5-HT
1A
antagonist ipsapirone. Thus a dual SSRI/5-HT
1A
antagonists should provide antidepressant activity with a rapid onset of action. Studies using a combination of an SSRI (fluoxetine) and a 5-HT
1A
antagonists (pindolol) appear to support this hypothesis (Artigas et. al.
Arch. Gen. Psychiat.
1994, 51, 248 and Perez et al.
Arch. Gen. Psychiat
1999, 56, 375).
Aryloxyalkyl amines have previously been shown to effect 5-HT-reuptake. U.S. Pat. No. 5,614,523 (Audia et al.) discloses a series of indoloxyethylpiperazines which affect the 5-HT
1A
and 5-HT-T receptors. U.S. Pat. No. 5,627,196 (Audia et al.) discloses a series of indoloxyethyltetrahydropyridines and indolyoxyethylpiperidinols which affect the 5-HT
1A
and 5-HT-T receptors. U.S. Pat. No. 5,741,789 (Hibschman et al.) teaches a series of quinolinoxyethylpiperidines which affect the 5-HT
1A
and 5-HT-T receptors. U.S. Pat. No. 5,789,402 (Audia et al.) discloses a series of indoloxyethylpiperidines which affect the 5-HT
1A
and 5-HT-T receptors. The current invention differs from the these patents in that the 8-azabicyclo[3.2.1]octane and 8-azabicyclo[3.2.1]oct-2-ene ring structures are used instead of the corresponding piperidines/tetrahydropyridines.
8-Azabicyclo[3.2.1]octanes and 8-azabicyclo[3.2.1]oct-2-enes have previously been shown to effect 5-HT-T reuptake. WO 9713770 (Moldt et al.) teaches a series of phenyl tropenes which affect the 5-HT-T receptor. WO 9716451 (Scheel-Krügger et al.) discloses a series of fused tropane derivatives which act as neurotransmitter reuptake inhibitors. WO 9965492 (Audia et al.) provides a series of aryl tropenes/tropanes that affect the 5-HT-T receptor in. The current invention differs from these references in that an aryloxy alkyl chain has been attached to the aryl 8-azabicyclo[3.2.1]octane and aryl 8-azabicyclo[3.2.1]oct-2-ene structures.
SUMMARY OF THE INVENTION
The present invention comprises compounds represented by the formula I:
wherein:
A is an optional residue which combines with the carbon atoms to which it is attached to complete a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, dioxinyl, pyrrolyl, imidazolyl, pyridinyl, pyridazynyl or pyrimidinyl group;
X is NH, O or S;
n is an integer from 0 to 3;
Ar
1
is phenyl or pyridyl substituted with 0-2 substituents selected from the group consisting of C
1
-C
3
alkyl, C
1
-C
3
alkoxy, halo, cyano, nitro, trifluoromethyl, difluoromethyl, hydroxyl, and trifluoromethoxy groups and combinations thereof;
Ar
2
is indolyl, benzimidazolyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, benzyl, benzofuryl, or benzothienyl, substituted with 0-2 C
1
-C
3
alkyl, C
1
-C
3
alkoxy, halo, cyano, nitro, trifluoromethyl, difluoromethyl, hydroxyl, or trifluoromethoxy groups;
and all crystalline forms and pharmaceutically acceptable salts thereof.
The present invention further comprises a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier.
The present invention also comprises methods of making and using the compounds and formulations of this invention, which methods are described in further detail below.
DETAILED DESCRIPTION
A preferred aspect of this invention comprises compounds of formula I wherein:
A is a residue which combines with the carbon atoms to which it is attached to complete a cyclopentyl, cyclohexyl, pyrrolyl, or pyridinyl, group
X is an NH, O or S moiety
n is 1-2;
Ar
1
is a phenyl group substituted with 0-2 substituents selected from C
1
-C
3
alkyl, C
1
-C
3
alkoxy, halo, cyano, trifluoromethyl, hydroxyl, and trifluoromethoxy groups and combinations thereof;
Ar
2
is indolyl, phenyl, naphthyl, benzofuryl, or benzothienyl, substituted with 0-2 C
1
-C
3
alkoxy, halo, cyano, nitro, trifluoromethyl, difluoromethyl, hydroxyl, or trifluoromethoxy groups;
and all crystalline forms and pharmaceutically acceptable salts thereof.
More preferred compounds of this invention are compounds of formula I wherein:
A is a residue which combines with the carbon atoms to which it is attached to complete a pyrrolyl, or pyridinyl, group
X is an NH, or O moiety
n is 1;
Ar
1
is phenyl substituted with 0-2 groups selected from C
1
-C
3
alkoxy, halo, trifluoromethyl, trifluoromethoxy, and combinations thereof;
Ar
2
is indolyl, naphthyl, benzofuryl, or benzothienyl, substituted with 0-2 halo, cyano, trifluoromethyl, difluoromethyl, hydroxyl, or trifluoromethoxy groups;
and all crystalline forms and pharmaceutically acceptable salts thereof.
In this specification, the term alkyl, whether used alone or as part of another group, includes straight and branched chain alkyl groups containing from 1 to 3 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, are encompassed by the term alkyl. The alkyl group may be substituted or unsubstituted. The aforementioned number of carbon atoms in the alkyl group refers to carbon backbone and does not include carbon atoms of substituents, such as alkoxy substitutions and the like.
Alkoxy, whether used alone or as part of another group include straight and branched chain alkoxy groups containing from 1 to 3 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy, are encompassed by the term alkoxy. The alkoxy group may be substituted or unsubstituted. The aforementioned number of carbon atoms in the alkoxy group does not include carbon atoms of substituents, such as alkyl substitutions and the like.
Halogen or halo as used herein means chlorine, bromine, iodine and fluorine.
Highly preferred compounds of the present invention include:
4-[2-(3-Naphthalen-2-yl-8-aza-bicyclo[3.2.1]oct-2-en-8-yl)-ethoxy]-1H-indole or a pharmaceutically acceptable salt thereof;
3-{8-[2-(1H-Indol-4-yloxy)ethyl]-8-azabicyclo[3.
Aulakh Charanjit S.
Hild Kimberly R.
Mazzarese Joseph M.
Wyeth
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