Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1999-06-17
2001-02-27
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C544S244000
Reexamination Certificate
active
06194398
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATION
This application is a 371 of PCT/JP97/02819 Aug. 12, 1997.
TECHNICAL FIELD
This invention relates to novel phosphonate nucleotide compounds, more particularly, it relates to novel phosphonate nucleotide compounds which have antiviral activity and are useful as medicaments, their salts, their hydrates or their solvates.
BACKGROUND ART
Infectious viral diseases are recognized as an important medical problem and, with the aim of treating such diseases, attempts have been made to develop a drug which has antiviral activity but has no activity to inhibit growth of normal cell lines. For example, extensive studies have been conducted on phosphonate nucleotides as selective antiviral agents. Illustratively, it has been reported that 9-(2-phosphonylmethoxy)ethyladenine (PMEA), 9-(2-phosphonylmethoxy)ethyl-2,6-diaminopurine (PMDAP) and the like compounds are effective against herpes simplex virus 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); Votruba et al.,
Mol. Pharmacol
., 3, 524 (1987)).
However, these known phosphonate nucleotides have a problem in terms of safety such as a possibility of causing toxicity and mutagenicity, typically including bone marrow cell growth inhibition, in the living body (
Antiviral Research
, 16, 77 (1991)), and, since these compounds do not have oral absorption ability (De Clercq et al.,
Antimicrob. Agents Chemother
., 33, 185 (1989)), their route of administration is limited to intravenous injection, intramuscular injection and the like parenteral administration in order to obtain enough blood levels for exerting their effects. Since the treatment by parenteral administration is difficult to apply to outpatients, such a method is not suitable for the treatment of AIDS, hepatitis B and the like diseases which require long-term therapy.
On the other hand, the inventors of the present invention have previously found that specified ester derivatives of a phosphonate nucleotide show high oral absorption ability (EP 632048), but they have not been put into practical use yet.
DISCLOSURE OF THE INVENTION
The present invention contemplates providing novel compounds which show high antiviral activity and higher safety for the living body in comparison with the compounds so far proposed, simultaneously having high oral absorption ability.
The present invention relates to phosphonate nucleotide compounds represented by formula (I):
(in the above formula (I), R
1
represents a C
1
-C
6
alkyl group or a C
7
-C
10
aralkyl group, each of R
2
and R
3
independently represents a hydrogen atom (with the proviso that R
2
and R
3
are not hydrogen atoms at the same time), a C
1
-C
22
alkyl group, an acyloxymethyl group, an acylthioethyl group or an ethyl group substituted by one or more halogen atoms, R
4
represents a 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 by one or more halogen atoms and X represents a carbon atom or a nitrogen atom), a salt thereof, a hydrate thereof or a solvate thereof, as well as a pharmaceutical composition and an antiviral agent each of which comprises these compounds.
BEST MODE OF CARRYING OUT THE INVENTION
The following describes the present invention in detail.
In the phosphonate nucleotide derivatives represented by the just described formula (I), examples of the C
1
-C6 alkyl group defined by R
1
include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like groups.
Examples of the C
7
-C
10
aralkyl group defined by R
1
include benzyl, phenetyl, phenylpropyl, phenylbutyl and the like groups.
According to the present invention, preferred is a compound in which R
1
is the just described C
1
-C
6
alkyl group or benzyl group, more preferably a C
1
-C
6
alkyl group.
Examples of the C
1
-C
22
alkyl group defined by R
2
and R
3
include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl and the like groups.
Examples of the acyloxymethyl group of R
2
and R
3
include acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, isovaleryloxymethyl, pivaloyloxymethyl and the like groups.
Examples of the acylthioethyl group of R
2
and R
3
include acetylthioethyl, propionylthioethyl, butyrylthioethyl, isobutyrylthioethyl, valerylthioethyl, isovalerylthioethyl, pivaloylthioethyl and the like groups.
With regard to the ethyl group of R
2
and R
3
substituted by one or more halogen atoms, examples of the halogen atom include fluorine, chlorine, bromine, iodine and the like atoms, and examples of the ethyl group substituted by one or more halogen atoms include 1-fluoroethyl, 2-fluoroethyl, 1-chloroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2-dibromoethy, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl and the like groups, wherein it is particularly desirable that the 2-position of ethyl group is substituted, and fluorine atom is desirable as the halogen atom.
It is desirable that at least one of R
2
and R
3
is an ethyl group substituted by one or more halogen atoms, particularly 2,2,2-trifluoroethyl group.
Examples of the C
1
-C
4
alkyl group of R4 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like groups.
Examples of the C
1
-C
4
hydroxyalkyl group of R
4
include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl and the like groups.
With regard to the C
1
-C
4
alkyl group of R
4
substituted by one or more halogen atoms, examples of the halogen atom include fluorine, chlorine and the like atoms, examples of the C
1
-C
4
alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like groups, and examples of the C
1
-C
4
alkyl group substituted by one or more halogen atoms include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, chloroethyl, fluoropropyl, chloropropyl, fluorobutyl, chlorobutyl and the like groups.
According to the present invention, a compound in which R
4
is hydrogen atom is desirable.
Also, according to the present invention, a compound in which X is carbon atom is desirable.
The phosphonate nucleotide compound of the present invention represented by the aforementioned formula (I) can form a pharmaceutically acceptable salt. With regard to illustrative examples of such a salt, it can form lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt and the like metal salts or ammonium salt, methylaimonium salt, dimethylanmonium salt, trimethylammonium salt, dicyclohexylammonium salt and the like ammonium salts when an acidic group is present, and it can form hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like mineral acid salts or methanesulfonate, benzenesulfonate, paratoluenesulfonate, acetate, propionate, tartarate, fumarate, maleate, malate, oxalate, succinate, citrate, benzoate, mandelate, cinnamate, lactate and the like organic acid salts when a basic group is present.
In addition, the phosphonate nucleotide compound of the present invention represented by the aforementioned formula (I) or salts thereof can exist in the form of hydrates or solvates, and these hydrates and solvates are also included in the present invention. Examples of the solvent capable of forming solvates include methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride and the like.
Illustrative examples of the compound of the present invention are shown in Table 1 below. In the table, Me means methyl group, Et means ethyl group, n-Pr means n-propyl group, i-Pr means isopropyl group, n-Bu means n-butyl group, i-Bu means iso
Kamiya Naohiro
Sekiya Kouichi
Takashima Hideaki
Ubasawa Masaru
Ueda Naoko
Berch Mark L.
McKenzie Thomas
Mitsubishi Chemical Corporation
Sughrue Mion Zinn Macpeak & Seas, PLLC
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