Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1997-06-20
1999-08-10
Jones, Dwayne C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
564308, 564307, A01N 3302
Patent
active
059360003
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The subject invention is directed toward 2-aminoindan analogs that selectively bind to the dopamine D3 receptor in vitro. The dopamine D3 receptor was recently cloned by Sokoloff et al., (Nature, 347, 146 (1990)). It was hypothesized that this receptor subtype is of importance for the action of anti-psychotics. Interestingly, this receptor shows a high abundance in brain regions associated with emotional and cognitive functions.
Compounds with this profile may be useful in treating CNS disorders, e.g. schizophrenia, mania, depression, geriatric disorders, drug abuse and addiction, Parkinson's disease, anxiety disorders, sleep disorders, circadian rhythm disorders and dementia.
Information Disclosure Statement
Arneric, S. P. et al., Neuropharmacol., 21, 885 (1982) describes indan analogs compared with other dopamine agonists. Compounds with 5,6 substitution were found to be inactive in this model of food intake.
Arneric, S. P. et al., Arch. Int. Pharmocodyn. Ther., 257, 263 (1982) describes 2-aminotetralin and 2-aminoindan analogs where the 5,6 dimethoxy substituted compound is again disclosed as inactive agents in an assay to evaluate contractions in vascular smooth muscle.
Bhatnagar, R. K. et al., Pharmacol., Biochem. Behav., 17(Suppl. 1), 11 (1982) discusses SAR studies of various structural entities including aminoindans which interact with dopamine receptors. The 5,6 dimethoxy indans are disclosed as inactive compounds.
Cannon, J. G. et al., J. Med. Chem., 25, 858 (1982) describes 4,7-dimethoxy-2 aminoindans and their dopaminergic and cardiovascular actions.
Cannon, J. G. et al., J. Med. Chem., 25, 1442 (1982) discloses the synthesis of the 5,6 di-methoxy and di-hydroxy indans and also some biology which shows they are devoid of dopamine receptor activity.
Cannon, J. G. et al., J. Med. Chem., 27, 186 (1984) describes the synthesis of N-alkylated derivatives of 2-amino-4,6-dihydroxyindans.
Cannon, J. G. et al., J. Med. Chem., 28, 515 (1985) describes the resolution of the 4-hydroxy aminoindan.
Cannon, J. G. et al., J. Med. Chem., 29, 2016 (1986) describes the ortho OH/methyl, hydroxymethyl, formyl or carboxy derivatives of 2-aminoindans
Hacksell, U. et al., J. Med. Chem., 24, 429 (1981) describes the synthesis of monophenolic 2-aminoindans as central dopamine receptor stimulants.
Ma, S. et al., J. Pharmacol. Exp. Ther., 256, 751 (1991) describes dopaminergic structure activity relationships of 2-aminoindans with mainly di-substitution in the 4,5 positions.
Nichols, D. E. et al., J. Med. Chem., 33, 703 (1990) describes nonneurotoxic tetralin and indan analogues of 3,4 (methylenedioxy)amphetamine.
PCT Patent Publication No. WO90/07490 describes 2-aminotetralins and 2-aminoindans with aromatic substitution with an OCH.sub.3 or OH in conjunction with a Br group.
European Patent 88302599.1 filed Mar. 24, 1988 discloses antiarrhythmic aminoindanes having a bicyclic structure and methyl group on the amine not disclosed in the subject invention.
U.S. Pat. No. 4,132,737 discloses trifluoromethyl substituted 1-aminoindanes whereas the subject invention is 2-aminoindanes; and U.S. Pat. No. 5,225,596 discloses substituted tetralins although not as substituted herein.
SUMMARY OF THE INVENTION
In one aspect the subject invention is directed toward compounds and pharmaceutically acceptable salts of Formula I: ##STR1## wherein R.sub.1 and R.sub.2 are independently H, C.sub.1-8 alkyl, or C.sub.1-8 alkylAryl; SO.sub.2 NR.sub.1 R.sub.2, SO.sub.2 CH.sub.3, halogen, OSO.sub.2 CF.sub.3, SCH.sub.3 or OCH.sub.3 ; Aryl; and -C.sub.8 alkylAryl.
In another aspect the subject invention is directed toward compounds and pharmaceutically acceptable salts of Formula I, above, including racemic mixtures and as both enantiomers. Preferred are structures of Formula I where R.sub.1 and R.sub.2 are independently H and a lower alkyl (C.sub.1-8 alkyl); and Y is CONR.sub.1 R.sub.2, SO.sub.2 NR.sub.1 R.sub.2, SO.sub.2 CH.sub.3 (where R.sub.1 and R.sub.2 are independently H and a lower alkyl).
In yet another aspe
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Leiby Jeffrey A.
Romero Arthur G.
Corneglio Donald L.
Jones Dwayne C.
Pharmacia & Upjohn Company
Stein Bruce
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