Naphthothiazolone derivatives active on the D.sub.3 dopaminergic

Details Naphthothiazolone derivatives active on the D.sub.3 dopaminergic Naphthothiazolone derivatives active on the D.sub.3 dopaminergic

1999-12-06

2000-08-22

Stockton, Laura L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

206223, 206569, 206570, 424 165, 548150, A61K 31428, A61K 5108, C07D27784

Patent

active

061073180

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to 4,5,6,7-tetrahydro-naphthothiazolone derivatives selectively active on the D.sub.3 dopaminergic receptor.
The D.sub.3 dopaminergic receptor was cloned for the first time by Sokoloff et al. (Nature. 347. 146. 1990), and is abundant in the cerebral areas connected to the emotional and cognitive functions.
The patent application WO 96/23760 (in the name of Pharmacia & Upjohn) describes 2-aminoindanes with selective activity for the D.sub.3 receptor.
The D.sub.3 -antagonists are said to have a potential use as antipsychotics. e.g. in the therapy of schizophrenia, schizo-emotional diseases, psychotic depression, manias. The pathologies which may be treated with the D.sub.3 -receptor agonists include dyskinesia, such as Parkinson's disease, neuroleptic parkinsonism and late dyskinesia, and also depression, anxiety, memory failure, sexual disorders, drug addiction (e.g. from cocaine).
The patent application EP 0 186 087 (in the name of Karl Thomae GmbH) discloses tetrahydrobenzothiazoies N-substituted on both the rings useful as D.sub.2 and D.sub.3 receptor agonists, and thus useful in the treatment of schizophrenia and Parkinson's disease One of these compounds, 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole, is further claimed in the patent application WO 96/18395 (in the name of Up-john/Boehringer Ingelheim) as endowed with neuroprotective effect.
We have now found a new class of compounds endowed with selective activity on the D.sub.3 doparninergic receptors as antagonists, agonists or partial agonists.
Therefore the present invention relates to compounds of formula I ##STR3## wherein n is an integer comprised between 2 and 6. R.sub.1 is a methyl group or a group ##STR4## wherein R.sub.2, R.sub.3 and R.sub.4 are independently hydrogen, hydroxy, methoxy, methylsulfonyl, or one of R.sub.2, R.sub.3 and R.sub.4 together with another one of the three substituents forms a --O--CH.sub.2 --O-- bridge;
The compounds of formula I have at least an asymmetric centre, marked by an asterisk, and may therefore be in form of stereoisomers.
Object of the present inventions are the compounds of formula I in form of stereoisomeric mixture and also as single stereoisomers.
The compounds of formula I are active on the D.sub.3 dopamineraic receptors also by oral route. They are therapeutically useful in the treatment of psychotic diseases, such as schizophrenia, dyskinesia, such as Parkinson's disease, of depression, anxiety, memory diseases, sexual disorders and drug addiction.
Preferred compounds of formula I are the ones wherein the carbon atom marked by an asterisk has the S configuration.
Pharmaceutically acceptable salts of the compounds of formula I are salts with organic and inorganic acids such as, e.g., hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, acetic, benzoic, maleic, fumaric, succinic, citric, aspartic, methansulfonic and 3,7-di-t.butylnaphthalen-1,5-disulfonic (dibudinic acid).
The preparation of the compounds of formula I is effected according to methods known by the skilled in the art. For example, a compound formula II ##STR5## or a salt thereof is duly protected on the amino group, for example with diterbutylcarbonate, phthalic anhydride or trifluoroacetic anhydride; the hydroxy group is then turned into a polyfluoroalkylsultonyioxy group (R.sub.f SO.sub.2 O--) such as, for example, trifluoromethylsulfonyloxy, thereby yielding a compound of formula III ##STR6## wherein R.sub.f is a lower polyfluoroalkiyl group and PG a protecting group, which is nitrated for example with nitric acid or other nitrating agzents such as ammonium nitrate/trifluoroacetic anhydride or nitroniurn tetrafluoroborane, to give a compound of formula IV ##STR7## wherein R.sub.f and PG are as defined above. The nitro group of the compound of formula IV is reduced to amino by hydrogenation in the presence of a catalyst made of a metal such as palladium, platinum, nickel, rhodium and ruthenium; in the meantime the polfluoroalkylsulfonyioxy group is reduced, thus obtaining a com

REFERENCES:
patent: 5639770 (1997-06-01), Chihiro et al.

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