Hydroxy and polyhydroxy derivatives of coumarin, preparation...

Details Hydroxy and polyhydroxy derivatives of coumarin, preparation... Hydroxy and polyhydroxy derivatives of coumarin, preparation...

2000-01-03

2001-09-18

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C549S284000, C549S285000, C549S286000, C549S399000, C549S400000, C549S402000

Reexamination Certificate

active

06291518

ABSTRACT:

TECHNICAL FIELD
IPC: C07D 311/04
In investigations in the field of finding novel compounds having antiviral action against HIV-1 and HIV-2 viruses causing AIDS disease, some derivatives of 4-hydroxycoumarin, e.g. phenoprocoumon, showed a significant action (H. I. Skulnick et al.,
J. Med. Chem
. 40 (1997) 1149). This invention gave a strong push to further investigations of novel hydroxycoumarin derivatives, which resulted in the synthesis of 3,3′, 3″, 3′″-(1,4-dimethylenephenyl)tetrakis[4-hydroxycoumarin] having the activity IC
50
=1.5 &mgr;M (H. Zhao et al.,
J. Med. Chem
. 40 (1997) 242).
It should especially be pointed out that derivatives of hydroxycoumarin may be used as oral non-peptide inhibitors of HIV-1 protease and integrase and some of the said derivatives have reached the first phase and the second phase of clinical trials.
On the basis of their earlier experiences the present inventors have prepared a series of novel hydroxy and polyhydroxy derivatives of coumarin in order to find still more active preparations with expressed action against HIV-1 and HIV-2 viruses.
The present invention relates to novel hydroxy and polyhydroxy derivatives of coumarin fused with dialdehydes and aldehyde acids of the general formulae I, II, III and IV:
wherein
R
1
=R
2
=4-hydroxycoumarin;
R
1
=R
2
=4,7-dihydroxycoumarin;
R
1
=R
2
=4,5,7-trihydroxycoumarin;
R
1
=4-hydroxycoumarin, R
2
=—CH(OH)CH
3
.
Objects of the invention are also processes for the preparation of hydroxy and polyhydroxy derivatives of coumarin fused with dialdehydes and aldehyde acids, and the antiviral action thereof.
According to the present invention novel hydroxy and polyhydroxy derivatives of coumarin fused with dialdehydes and aldehyde acids of the general formulae I, II, III and IV are prepared starting from hydroxy- and polyhydroxycoumarin of the formula V
wherein
R
1
=OH, R
2
=R
3
=H;
R
1
=R
3
=OH, R
2
=H;
R
1
=R
2
=R
3
=OH,
by condensation reactions in ethanol or in glacial acetic acid wits dialdehydes and aldehyde acids of the formulae VI, VII, VIII and IX:
Novel hydroxy and polyhydroxy derivatives of coumarin according to the present invention exhibit antiviral action against HIV-1 virus.
The invention is illustrated by the following Examples, which in no way limit the scope thereof.


REFERENCES:
patent: 6100409 (2000-08-01), Trkovnik et al.
Zhao et al, Chem. Alo. vol. 126 No. 98847, (1997), “Coumarin-Based Inhibitors of HIV Integrase”, 1997.

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