1-(dimethylamino)ethyl-substituted 6H-benzo[C]chromen-6-ones against senile dementia
This invention relates to novel (±)1-(Dimethylamino)ethyl substituted 6H-benzo[c]chromen-6-one compounds which are useful as pharmaceutical compositions.
1. A compound having the following formula I or a pharmaceutically acceptable salt thereof as a racemic mixture or a single enantiomer
wherein:
R 1 is —CH(CH 3 )N(CH 3 ) 2 in racemic form or a single enantiomer;
R 2 is selected from —H, —OH, —OCH 3 or —OCON(CH 3 )(C 2 H 5 );
R 3 is selected from —H, a halogen, an alkyl, or an alkoxy group and can be in any position
and positions of R 1 and R 2 are interchangeable.
2. The compound according to claim 1 having the following formula II or a pharmaceutically acceptable salt thereof as a racemic mixture or a single enantiomer
wherein:
R 1 is —CH(CH 3 )N(CH 3 ) 2 in racemic form or a single enantiomer;
R 2 is selected from —H, —OH, —OCH 3 or —OCON(CH 3 )(C 2 H 5 );
R 3 is H;
and positions of R 1 and R 2 are interchangeable.
3. The compound according to claim 1 , which is (R)-3-(1-(dimethylamino)ethyl)-6H-benzo[c]chromen-6-one.
4. The compound according to claim 1 , which is (S)-3-(1-(dimethylamino)ethyl)-6H-benzo[c]chromen-6-one.
5. The compound according to claim 1 , which is (R)-3-(1-(dimethylamino)ethyl)-1-methoxy-6H-benzo[c]chromen-6-one.
6. The compound according to claim 1 , which is (S)-3-(1-(dimethylamino)ethyl)-1-methoxy-6H-benzo[c]chromen-6-one.
7. The compound according to claim 1 , which is (R)-1-(1-(dimethylamino)ethyl)-3-methoxy-6H-benzo[c]chromen-6-one.
8. The compound according to claim 1 , which is (S)-1-(1-(dimethylamino)ethyl)-3-methoxy-6H-benzo[c]chromen-6-one.
9. The compound according to claim 1 , which is (R)-3-(1-(dimethylamino)ethyl)-1-hydroxy-6H-benzo[c]chromen-6-one.
10. The compound according to claim 1 , which is (S)-3-(1-(dimethylamino)ethyl)-1-hydroxy-6H-benzo[c]chromen-6-one.
11. The compound according to claim 1 , which is (R)-1-(1-(dimethylamino)ethyl)-3-hydroxy-6H-benzo[c]chromen-6-one.
12. The compound according to claim 1 , which is (S)-1-(1-(dimethylamino)ethyl)-3-hydroxy-6H-benzo[c]chromen-6-one.
13. The compound according to claim 1 , which is (R)-3-(1-(dimethylamino)ethyl)-6-oxo-6H-benzo[c]chromen-1-yl ethyl(methyl)carbamate.
14. The compound according to claim 1 , which is (S)-3-(1-(dimethylamino)ethyl)-6-oxo-6H-benzo[c]chromen-1-yl ethyl(methyl)carbamate.
15. The compound according to claim 1 , which is (R)-1-(1-(dimethylamino)ethyl)-6-oxo-6H-benzo[c]chromen-3-yl ethyl(methyl)carbamate.
16. The compound according to claim 1 , which is (S)-1-(1-(dimethylamino)ethyl)-6-oxo-6H-benzo[c]chromen-3-yl ethyl(methyl)carbamate.
17. A method of treating a disease due to acetylcholinesterase and/or butyrylcholinesterase activity, said method comprising administering a compound having the formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease is senile dementia.
18. A process for the preparation of formula II or a pharmaceutically acceptable salt thereof as a racemic mixture or a single enantiomer,
wherein;
R 1 is —CH(CH 3 )N(CH 3 ) 2 in racemic form or a single enantiomer;
R 2 is selected from —H, —OH, —OCH 3 or —OCON(CH 3 )(C 2 H 5 );
R 3 is H;
and positions of R 1 and R 2 are interchangeable;
said method comprising reacting a (1-(dimethylamino)ethyl)-substituted-phenol compound of formula III in racemic form or a single enantiomer,
wherein R 4 is selected from —H or —OCH 3 , with a 2-halobenzoic acid compound
in the presence of polyphosphoric acid to form an ester intermediate of formula IV,
wherein R 4 is as described above and X is a halogen, and reacting the ester intermediate of formula IV in racemic form or a single enantiomer with PdCl 2 (PPh 3 ) 2
in the presence of NaOAc in dimethylacetamide to obtain the compound of formula V,
wherein R 1 and R 4 are as described above; and treating the compound of formula V with a hydrolyzing agent to obtain the compound of formula II wherein R 2 is OH; and treating the compound of formula V with a carbamoyl halide compound to obtain the compound of formula II wherein R 2 is —OCON(CH 3 )(C 2 H 5 ).
19. The method of claim 17 , wherein said compound is (±)-3-(1-(dimethylamino)ethyl)-6-oxo-6H-benzo[c]chromen-1-ylethyl(methyl)carbamate.