Antiviral 2,4-pyrimidinedione derivatives and process for...

Details Antiviral 2,4-pyrimidinedione derivatives and process for... Antiviral 2,4-pyrimidinedione derivatives and process for...

2001-08-10

2004-03-30

Rotman, Alan L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S274000, C544S300000, C544S301000, C544S302000, C544S303000, C544S304000, C544S309000, C544S310000, C544S311000, C544S312000, C544S313000, C544S314000

Reexamination Certificate

active

06713486

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel pyrimidinedione derivatives, which are useful as an antiviral agent, particularly for treating acquired immunodeficiency syndrome (AIDS), a process for the preparation thereof and 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), Ziagen, Nevirapine, Sustiva, Delavirdine, Indinavir, Ritonavir, Viracept, Saquinavir and Agenerase 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, there have been reported 2,4-pyrimidinedione derivatives having 1-alkoxymethyl substituents {
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);
J. Med. Chem
., 42, 4500 (1999); EP 0,449,726 A1; EP 0,420,763 A2; U.S. Pat. No. 5,278,167; U.S. Pat. No. 5,318,972; U.S. Pat. No. 5,461,060; WO95/18109 A1; and U.S. Pat. No. 5,112,835}; 1-allyl or propargyl substituents (U.S. Pat. No. 5,747,500); and 1-cyclopentenylmethylene substituents (U.S. Pat. No. 5,922,727). Although these compounds exhibit improved activity against human immunodeficiency virus (HIV), there exists a need to develope non-toxic compounds having even higher potency against both wild-type and mutant HIV.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the present invention to provide a novel compound having superior antiviral activity against both wild-type and mutant HIV-1 as well as 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 is provided a novel 2,4-pyrimidinedione compound of formula(I) or a pharmaceutically acceptable salt thereof:
wherein:
R
1
is a C
6-10
aryl or C
3-10
heteroaryl group optionally having one or more substituents selected from the group consisting of halogen, C
1-6
alkyl, C
1-6
alkyl substituted with one or more halogen atoms, C
3-6
cycloalkyl, cyano, nitro, hydroxy, thiohydroxy, azido, C
1-6
alkoxy, oximino, C
1-3
alkyloximino, O—(C
1-6
alkyl)-substituted oximino, C
1-6
alkylcarbonyl, C
3-6
cycloalkylcarbonyl, hydroxymethyl, azidomethyl, C
1-6
alkoxymethyl, C
1-6
acyloxymethyl, carbamoyloxymethyl, aminomethyl, N—(C
1-3
alkyl)aminomethyl, N,N-di(C
1-3
alkyl)aminomethyl, carboxy, C
1-6
alkoxycarbonyl, aziridine, amino, hydroxyethylamino, cyclopropylamino, C
1-6
alkylamino, di(C
1-6
alkyl)amino, trifluoroacetamido, C
1-6
acylamido, carbamoyl, hydroxyethylcarbamoyl, cyclopropylcarbamoyl, C
1-6
alkylcarbamoyl, di(C
1-6
alkyl)carbamoyl, aminocarbamoyl, dimethylaminocarbamoyl, hydrazino, 1,1-dimethylhydrazino, imidazolyl, triazolyl and tetrazolyl; a tetrahydropyridyl or piperidyl group optionally substituted with a c
1-6
alkyl or c
1-6
alkoxycarbonyl group; a tetrahydropyranyl group; or a tetrahydrofuryl group;
R
2
is hydrogen, halogen, nitro, cyano, C
1-3
alkoxycarbonyl, C
1-3
alkylamino, di(C
1-3
alkyl)amino, C
1-3
alkylcarbamoyl, di(C
1-3
alkyl)carbamoyl, C
1-6
alkyl, C
3-6
cycloalkyl or benzyl;
R
3
and R
4
are each independently hydrogen, halogen, hydroxy, cyano, nitro, amino, acetamido, trifluoroacetamido, azido, C
1-3
alkyl, C
1-3
alkyl substituted with one or more halogen atoms, C
1-3
alkoxycarbonyl, carbamoyl, C
1-3
alkylcarbamoyl, di(C
1-3
alkyl)carbamoyl or C
1-3
alkoxy;
A is O or S; and
Z is O, S, C═O, NH or CH
2
.
DETAILED DESCRIPTION OF THE INVENTION
Among the compounds of formula(I) of the present invention, the preferred are those wherein R
1
is a phenyl, pyridyl or N-oxopyridyl group optionally having one or more substituents as listed in formula(I).
The 2,4-pyrimidinedione compound of formula(I) may be prepared by coupling a compound of formula(II) with a compound of formula(III), as shown in the Reaction Scheme A:
wherein:
R
1
, R
2
, R
3
, R
4
, A and Z have the same meanings as defined in formula(I) above;
Z′ is same as Z with the proviso that when A is oxygen, it can be a acetamido group; and
Y is a suitable leaving group, e.g., halogen, methanesulfonyl, toluenesulfonyl or trifluoromethanesulfonyl.
In Reaction Scheme A, the above reaction may be conducted in a solvent in the presence of a base at a temperature ranging from −10 to 100° C., wherein the molar ratio of the compound of formula(II) to the compound of formula(III) may range from 1:0.8 to 1:1.2. Representative examples of the base include lithium hydride, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate and the like. Suitable for use in this reaction is a polar solvent such as acetonitrile, hexamethylphosphoramide (HMPA), dimethylsulfoxide (DMSO) and dimethylformamide(DMF).
The compounds of formula(II) may in some cases be prepared in accordance with the procedure disclosed in U.S. Pat. No. 5,747,500. Alternatively, the compounds of formula(II) may be advantageously prepared in some special cases by the procedure illustrated in Reaction Scheme B:
In accordance with the method (i) in Reaction Scheme B, a compound of formula(IV) which may be prepared by way of a known method disclosed in, e.g.,
Ber
., 52B, 869 (1919) and
J. Med. Chem
., 7, 808 (1964), is subjected to a coupling reaction with an arylformamide derivative in a polar solvent, e.g., dimethylformamide, in the presence of a strong base, e.g., sodium hydride, under a nitrogen atmosphere to provide a compound of formula(V) (Step (a)). The compound of formula (V) is reacted with sodium methoxide in methanol to give a compound of formula(VI) (Step (b)). Then, the compound of formula(VI) is demethylated and acetylated by the action of acetylbromide to provide a compound of formula(II-a) (Step (c)).
In the method (ii) of Reaction Scheme B, the compound of formula (IV) is reacted with a arylacetonitrile derivative in a polar solvent, e.g., dimethylformamide, in the presence of a base, e.g., sodium hydride, to provide a compound of formula(VII) (Step (d)), which is reacted with sodium methoxide in methanol to give a compound of formula(VIII) (Step (e)). Thereafter, the compound of formula(VIII) is reacted with a base, e.g., sodium hydride, in a polar solvent, e.g., dimethylformamide, in the presence of oxygen to provide a compound of formula(IX) (Step (f)), which is hydrolyzed with an acid, e.g., hydrochloric acid, to provide a compound of formula(II-b) (Step (g)).
Each of the compounds of formula(II-a) and (II-b) may be converted to one of the compounds of formula(II) containing various substituents via further reactions.
In this regard, in accordance with another aspect of the present invention, there is provided a compound of formula(II):
wherein:
R′
2
is ethyl or isopropyl;
R′
3
is nitro, amino, acetamido, trifluoroacetamido or C
1-3
alkoxycarbonyl;
R′
4
is methyl or halogen; and
Z″ is C═O, NH or acetamido.
Exemplary compounds of formula(I) of the present invention which can be prepared in accordance with the methods described above are listed in the following Table 1:
TABLE 1
Comp.
A
Z
R
1
R
2
R
3
R
4
 1
O
C═O
Isopropyl
CH
3
CH
3

 2
O
C═O
Isopropyl
CH
3
CH
3

 3
O
C═O
Isopropyl
CH
3
CH
3

 4
O
C═O
Ethyl
CH
3
CH
3

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