Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reissue Patent
1997-10-23
2003-02-04
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S274000, C544S309000, C544S310000, C544S311000, C544S312000, C544S313000, C544S314000, C544S317000
Reissue Patent
active
RE037979
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel 6-substituted acyclopyrimidine derivatives and antiviral agents containing the derivative as the active ingredients.
BACKGROUND OF THE INVENTION
Infectious diseases caused by human acquired immunodeficiency virus (HIV), which is a type of retrovirus, have recently become a serious social problem. A compound of 3′-deoxy-3′-azidothymidine is known as a nucleoside compound used in the clinical treatment for diseases caused by HIV-infection. However, this compound has side-effects since it also exhibits considerable strong toxicity in the host cells.
Although some 2′,3′-dideoxyribonucleosides are known as nucleoside compounds exhibiting an anti-viral activity, it is still necessary to develop a substance possessing a higher activity and lower toxicity to the host cell (Hiroaki Mitsuya, Bodily Defense, Vol. 4, pp.213-223 (1987)).
On the other hand, various acyclonucleoside compounds have been synthesized since Acyclovir (acycloguanosine) was developed as an antiviral substance effective against herpes virus (C. K. Chu and S. J. Culter, J. Heterocyclic Chem., 23, p.289 (1986)). However, no acyclonucleoside compound having a sufficient activity especially against retroviruses has yet been discovered.
We have focussed our attention on 6-substituted acyclopyrimidine nucleoside compounds and have synthesized various novel 6-substituted acyclopyrimidine nucleoside derivatives and screened those compounds to detect effective antiviral agents, especially to the retrovirus, in order to provide antiviral agents exhibiting an effective activity particularly against retroviruses.
Some 6-substituted acyclopyrimidine nucleoside compounds such as 6-fluoro substituted derivatives, 6-alkylamino substituted derivatives (DD-A-232492) and 6-methyl substituted derivatives (C. A. 107, 129717w (1987)) are known; however, the antiviral activity of these compounds has not been described.
As a result of our researches for compounds exhibiting an effective antiviral activity, particularly anti-retroviral activity, we found that specific 6-substituted pyrimidine nucleoside compounds according to the invention satisfy the above demand to achieve the present invention.
SUMMARY OF THE INVENTION
The present invention concerns 6-substituted acyclopyrimidine nucleoside derivatives represented by the following general formula I;
wherein R
1
represents a hydrogen atom, halogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, arylcarbonylalkyl, arylthio or aralkyl group;
R
2
represents an arylthio, alkylthio, cycloalkylthio, arylsulfinyl, alkylsulfinyl, cycloalkylsulfinyl, alkenyl, alkynyl, aralkyl, arylcarbonyl, arylcarbonylalkyl or aryloxy group, those groups optionally substituted by one or more of substituents selected from a halogen atom, alkyl, halogenated alkyl, alkoxy, hydroxyl, nitro, amino, cyano and acyl groups;
R
3
represents a hydrogen atom, methyl, branched alkyl or —CH
2
—Z—(CH
2
)
n
—R
5
group where R
5
represents a hydrogen atom, halogen atom, hydroxyl, heterocyclic carbonyloxy, formyloxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, aralkylcarbonyloxy, arylcarbonyloxy, azido, alkoxycarbonyloxy, N-alkylcarbamoyloxy, N-arylcarbamoyloxy, alkoxy, aralkyloxy, branched alkyl, cycloalkyl or aryl group, the alkoxycarbonyloxy to aryl groups mentioned above as R
5
optionally substituted by one or more substituents selected from a halogen atom, aryl, alkyl, alkoxy and halogenated alkyl groups, Z represents an oxygen, sulfur atom or methylene group, and n represents 0 or an integer of 1 to 5,
R
4
represents a hydrogen atom, alkyl or aralkyl group,
X and Y represent an oxygen or sulfur atom independently, provided that when R
4
and Z represent a hydrogen atom and oxygen atom respectively R
5
does not represent a hydroxyl group, or the following general formula I′;
wherein R
1
, R
2
, R
3
and Y have the same meanings as defined for the formula I above, pharmaceutically acceptable salts thereof and antiviral agents containing the derivative or the salt thereof as an active ingredient.
DETAILED DESCRIPTION OF THE INVENTION
The 6-substituted acyclopyrimidine nucleoside derivatives according to the invention are represented by the general formula I or I′.
The group of R
1
represents a hydrogen atom; halogen atom such as chlorine, iodine, bromine and fluorine; alkyl group such as methyl, ethyl, n-propyl, i-propyl and n-butyl; cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; alkenyl group such as vinyl, propenyl, butenyl, phenylvinyl, bromovinyl, cyanovinyl, alkoxycarbonylvinyl and carbamoylvinyl; alkynyl group such as ethynyl, propynyl and phenylethynyl; alkylcarbonyl group such as acetyl, propionyl, and i-butyryl; arylcarbonyl group such as benzoyl and naphthoyl; arylcarbonylalkyl group such as phenacyl; arylthio group such as phenylthio, tolylthio and naphthylthio; or aralkyl group such as benzyl.
The group of R
2
represents an arylthio group such as phenylthio and naphthylthio; alkylthio group such as methylthio, ethylthio, propylthio, butylthio and pentylthio; cycloalkylthio group such as cyclopentylthio, cyclohexylthio and cycloheptylthio; arylsulfinyl group such as phenylsulfinyl; alkylsulfinyl group such as methylsulfinyl, ethylsulfinyl and butylsulfinyl; cycloalkylsulfinyl group such as cyclopentylsulfinyl and cyclohexylsulfinyl; alkenyl group such as vinyl, propenyl and phenylvinyl; alkynyl group such as ethynyl, propynyl and phenylethynyl; aralkyl group such as benzyl; arylcarbonyl group such as benzoyl; arylcarbonylalkyl group such as phenacyl; or aryloxy group such as phenoxy, and those groups may be optionally substituted by one or more of substituents selected from a halogen atom such as chlorine, bromine, fluorine and iodine, alkyl group such as methyl, ethyl, propyl, butyl and pentyl, a halogenated alkyl group such as trifluoromethyl, alkoxy group such as methoxy, ethoxy, propoxy and butoxy, hydroxyl group, nitro group, amino group, cyano group and acyl group such as acetyl.
The group of R
3
represents a hydrogen atom, methyl group, branched alkyl group such as i-propyl and t-butyl or —CH
2
—Z—(CH
2
)
n
—R
5
group where R
5
represents a hydrogen atom; halogen atom such as fluorine, chlorine, iodine and bromine; hydroxyl group; heterocyclic carbonyloxy group such as nicotinoyloxy; formyloxy group; optionally branched alkylcarbonyloxy group such as acetoxy, propyonyloxy, n-butyryloxy, i-butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy and decanoyloxy; cycloalkylcarbonyloxy group such as cyclohexylcarbonyloxy; aralkylcarbonyloxy group such as benzylcarbonyloxy; arylcarbonyloxy group such as benzoyloxy, toluoylcarbonyloxy and naphthoylcarbonyloxy group; azido group; alkoxycarbonyloxy group such as methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, i-propoxycarbonyloxy, n-butoxycarbonyloxy and t-butoxycarbonyloxy group, optionally substituted by one or more substituents selected from a halogen atom such as fluorine, chlorine, bromine and iodine, aryl group such as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenated alkyl group such as trifluoromethyl; N-alkylcarbamoyloxy group such as N-methylcarbamoyloxy, N-ethylcarbamoyloxy, N-propylcarbamoyloxy, N-butylcarbamoyloxy and N-pentylcarbamoyloxy, optionally substituted by one or more substituents selected from a halogen atom such as fluorine, chlorine, bromine and iodine, aryl group such as phenyl, toluyl and naphthyl, alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, alkoxy group such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy and halogenated alkyl group such as trifluoromethyl; N-arylcarbamoyloxy group such as N-phenylcarbamoyloxy and N-tolylcarbamoyloxy, optionally substituted by one or more substituents selected from a halogen atom such as fluorine, chlorine, bromine and iodine,
Baba Masanori
DeClercq Erik Desiré
Miyasaka Tadashi
Tanaka Hiromichi
Ubasawa Masaru
Coleman Brenda
Conlin David G.
Dike, Bronstein, Roberts & Cushman/Edwards & Angell
Mitsubishi Chemical Corporation
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