Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-12-11
2001-03-06
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S277000
Reexamination Certificate
active
06197775
ABSTRACT:
This application is a 371 of International Application No. PCT/JP96/01631 filed Jun. 14, 1996.
1. Technical Field
The present invention relates to novel phosphonate nucleotide derivatives. More specifically, it relates to novel phosphonate nucleotide derivatives which have antiviral activity and are useful as active ingredients of medicaments.
2. Background Art
Viral infectious diseases are recognized as a major medical problem, and to achieve therapeutic treatment of these diseases, it has been attempted to develop medicaments having antiviral activity and not exhibiting growth inhibitory activity on healthy cellular systems. For example, a class of phosphonate nucleotides has been intensively studied recently as compounds having selective toxicity against viruses. More specifically, it has been reported that 9-(2-phosphonylmethoxy)ethyladenine (PMEA), 9-(2-phosphonylmethoxy)ethyl-2,6-diaminopurine (PMDAP) and the like are effective against herpes simplex viruses type-1 and type-2 (HSV-1 and HSV-2), human immunodeficiency virus (HIV), and human hepatitis B virus (HBV) (Yokota et al., Antimicrob. Agents Chemother., 35, 394 (1991); and Votruba et al. Mol. Pharmacol., 32, 524 (1987)).
However, these known phosphonate nucleotides may possibly have toxicity to a living body, including myeloid cell growth inhibition as a typical example, and mutagenicity, and their problems have been pointed out from a viewpoint of safety (Antiviral Research, 16, 77 (1991)). In addition, these compounds have insufficient oral absorbability (DeClercq et al., Antimicrob. Agents Chemother., 33, 185 (1989)), and accordingly, parenteral administration such as intravenous injection or intramuscular injection is unavoidably applied in order to obtain an essential blood concentration for exhibiting efficacy. Therapeutic treatment by parenteral administration cannot be applied to patients other than inpatients, and such method is undesired for treatment of diseases such as AIDS or hepatitis B virus infectious disease which require long-term therapy.
On the other hand, the inventors of the present invention found that specific ester derivatives of phosphonate nucleotides have antiviral activity and high oral absorbability (European Patent Publication No. 632,048). Howver, the derivatives have not yet been clinically developed.
DISCLOSURE OF THE INVENTION
The inventors of the present invention conducted intensive researches to solve the foregoing problems, and a result, they found that a specific class of phosphonate nucleotides having novel chemical structures have higher antiviral activity compared to compounds already reported, and that they are safer to a living body and have high oral absorbability. The present invention was achieved on the basis of these findings.
The present invention thus provides phosphonate nucleotide derivatives represented by the following general formula (I) and salts thereof, and hydrates and solvates thereof:
In the above formula, R
1
represents hydrogen atom, a C
1
-C
6
alkyl group, or a C
7
-C
10
aralkyl group; R
2
represents a C
1
-C
6
alkyl group, a C
7
-C
10
aralkyl group, or phenyl group, R
3
and R
4
each independently represent hydrogen atom, a C
1
-C
6
alkyl group, an acyloxymethyl group, an acylthioethyl group, or an ethyl group substituted with one or more halogen atoms; R
5
represents hydrogen atom, a C
1
-C
4
alkyl group, a C
1
-C
4
hydroxyalkyl group, or a C
1
-C
4
alkyl group substituted with one or more halogen atoms; and X represents —CH— or nitrogen atom.
According to further embodiments of the present invention, there are provided medicaments comprising the above substances; pharmaceutical compositions and antiviral agents comprising the above substances as an active ingredient. In addition, there are also provided uses of the above substances for the manufacture of pharmaceutical compositions having antiviral activity, and methods for treatment of viral infectious diseases comprising the step of administering a therapeutically effective amount of the above substance to a patient.
BEST MODE FOR CARRYING OUT THE INVENTION
In the phosphonate nucleotide derivatives of the above general formula (I), examples of the C
1
-C
6
alkyl group represented by R
1
, R
2
, R
3
, and R
4
include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group or the like.
Examples of the C
7
-C
10
aralkyl group represented by R
1
and R
2
include, for example, benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group or the like.
In particular, hydrogen atom and a C
1
-C
4
alkyl group are preferred as R
1
, and a C
1
-C
4
alkyl group, benzyl group, and phenyl group are preferred as R
2
. As R
2
, a C
1
-C
4
alkyl group and phenyl group are particularly preferred. The C
1
-C
4
alkyl group represented by R
5
may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group or the like.
The acyloxymethyl group represented by R
3
and R
4
may be, for example, acetyloxymethyl group, propionyloxymethyl group, butyryloxymethyl group, isobutyryloxymethyl group, valeryloxymethyl group, isovaleryloxymethyl group, pivaloyloxymethyl group or the like.
The acylthioethyl group represented by R
3
and R
4
may be, for example, acetylthioethyl group, propionylthioethyl group, butyrylthioethyl group, isobutyrylthioethyl group, valerylthioethyl group, isovalerylthioethyl group, pivaloylthioethyl group or the like.
In the ethyl group substituted with one or more halogen atoms represented by R
3
and R
4
, the halogen atom includes fluorine atom, chlorine atom, bromine atom, and iodine atom. Examples of the ethyl group substituted with one or more halogen atoms include 1-fluoroethyl group, 2-fluoroethyl group, 1-chloroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 2,2-dibromoethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, 2,2,2-tribromoethyl group and the like. In particular, ethyl groups substituted at the 2-position are preferred, and fluorine atom is preferred as the halogen atom.
As R
3
and R
4
, a C
1
-C
6
alkyl group or an ethyl group substituted with one or more halogen atoms are preferred, and 2,2,2-trifluoroethyl group is particularly preferred.
Examples of the C
1
-C
4
hydroxyalkyl group represented by R
5
include hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group and the like.
In the C
1
-C
4
alkyl group substituted with one or more halogen atoms represented by R
5
, examples of the halogen atom include fluorine atom and chlorine atoms or the like, and examples of the C
1
-C
4
alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group or the like. Examples of the C
1
-C
4
alkyl group substituted with one or more halogen atoms include fluoromethyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, chloroethyl group, fluoropropyl group, chloropropyl group, fluorobutyl group, chlorobutyl group and the like.
Hydrogen atom or a C
1
-C
4
alkyl group is preferred as R
5
.
The compounds of the present invention are characterized in that they have higher antiviral activity compared to a compound disclosed in European Patent Publication No. 632,048, which is derived by the replacement of the amino group at the 6-position of purine ring with a substituted amino group, and that they are safer to living bodies and can achieve higher oral absorbability. Among the compounds of the present invention, its has been found that those having phenyl group as R
2
are characterized to have lower toxicity compared to those having an alkyl group or aralkyl group as R
2
, and those having an alkyl group as R
5
are characterized to have l
Inoue Naoko
Kamiya Naohiro
Sekiya Kouichi
Takashima Hideaki
Ubasawa Masaru
Mitsubishi Chemical Corporation
Shah Mukund J.
Truong Tamthom N.
Wenderoth , Lind & Ponack, L.L.P.
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