Antiviral 2,4-pyrimidinedione derivatives and process for the pr

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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544314, A61K 31513, C07D23954

Patent

active

061368156

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to novel pyrimidinedione derivatives having 6-aryloxy or 6-arylcarbonyl substituents, which are useful as an antiviral agent, particularly for treating acquired immunodeficiency syndrome (AIDS), and pharmaceutically acceptable salts thereof. The present invention also relates to a process for the preparation of such derivatives and to a pharmaceutical composition containing same as an active ingredient.


DESCRIPTION OF THE PRIOR ART

Various compounds such as AZT (3'-azido-3'-deoxythymidine), DDC (2',3'-dideoxycytidine), DDI (2',3'-dideoxyinosine), D4T (3'-deoxy-2',3'-didehydrothymidine) 3TC(lamivudine), Nevirapine, Indinavir, Ritonavir and Saquinavir have been reported to have the ability, albeit limited, to inhibit the reproduction of AIDS virus. However, they are also known to cause undesirable side effects due to their toxicity as well as to induce the mutation of the virus, thereby increasing the resistance of the virus.
In order to minimize such problems, therefore, many attempts have been made. For example, 2,4-pyrimidinedione derivatives substituted with an alkoxymethyl group on the N-1 position thereof have been reported in J. Med. Chem., 35, 4713 (1992); J. Med. Chem., 35, 337 (1992); J. Med. Chem., 34, 1508 (1991); J. Med. Chem., 34, 1394 (1991); J. Med. Chem., 34, 349 (1991); Molecular Pharm., 39, 805 (1991); Tet. Lett., 35, 4531 (1994); J. Med. Chem., 38, 2860 (1995); Nucleosides and Nucleotides, 14, 575 (1995); J. Med. Chem., 39, 2427 (1996); EP 0,449,726 A1; EP 0,420,763 A2; U.S. Pat. No. 5,318,972; and WO95/18109 A1 to have improved activity against human immunodeficiency virus (HIV), while exhibiting lower toxicity. However, needs have continued to exist for compounds having higher potency against HIV while exhibiting a much lower toxicity.


SUMMARY OF THE INVENTION

Accordingly, it is a primary object of the present invention to provide a novel compound having both superior antiviral activity against HIV and reduced toxicity.
It is another object of the present invention to provide a pharmaceutical composition containing same.
It is a further object of the present invention to provide a process for the preparation of said novel compound.
In accordance with one aspect of the present invention, there are provided a novel 2,4-pyrimidinedione compound of formula(I) and pharmaceutically acceptable salts thereof: ##STR2## wherein: R.sup.1 is hydrogen or a C.sub.1-10 alkyl group optionally having a substituent selected from the group consisting of aryl, hydroxy, C.sub.1-10 alkoxy and C.sub.2-5 alkylcarbonyloxy groups; substituent;


DETAILED DESCRIPTION OF THE INVENTION

Among the compounds of formula(I) of the present invention, the preferred are those wherein R.sup.1 is methyl, hydroxymethyl, acetoxymethyl or phenyl.
Among the preferred compounds of the present invention, the more preferred are those wherein R.sup.2 is ethyl or isopropyl.
Among the more preferred compounds of the present invention, the most preferred are those wherein R.sup.3 and R.sup.4 are each hydrogen or methyl.
The 2,4-pyrimidinedione compound of formula(I) may be prepared by silylating a compound of formula(II) to give a compound of formula(III) and coupling the compound of formula(III) with a compound of formula(IV), as shown in the following Reaction Scheme A: ##STR3## wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4 and A have the same meanings as defined in formula(I) above; and
In Reaction Scheme A, the silylation of the compound of formula(II) may be conducted under a conventional silylation condition. Preferably, it may be carried out by refluxing the compound and 1,1,1,3,3,3-hexamethyldisilazane, which is used as a solvent and as a silylating agent, for 2 to 24 hours in the presence of a catalyst, e.g., chlorotrimethylsilane.
The reaction between the compound of formula(III) and the compound of formula(IV) may be conducted in the absence or presence of a Lewis acid at a temperature ranging from -20 to 100.degree. C. Preferably, it may be carried out by stirring t

REFERENCES:
patent: 5112835 (1992-05-01), Miyasaka et al.

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