Phosphonate nucleotide compound

Details Phosphonate nucleotide compound Phosphonate nucleotide compound

2002-11-04

2004-07-27

Berch, Mark L. (Department: 1624)

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

06767900

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel phosphonate nucleotide compound. More specifically, the present invention relates to a phosphonate nucleotide compound, salts thereof, and hydrates and solvates thereof, which have an anti-viral activity and are useful as a medicament.
BACKGROUND ART
Infectious viral diseases are recognized as a medically important problem, and for the purpose of treating such diseases, the development of an agent having an anti-viral activity and having no growth inhibiting activity against a normal cell system, has been studied. For example, phosphonate nucleotides are being actively studied as selective anti-viral agents. 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 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.,32, 524 (1987)).
However, these known phosphonate nucleotide analogues have problems regarding safety, since there is a possibility that they show toxicity such as bone marrow cell growth inhibition and mutagenicity in organisms (Antiviral Research, 16, 77 (1991)). Furthermore, since these compounds do not have oral absorbency (De Clercq et al., Antimicrob. Agents Chemother., 33, 185 (1989)), they have a problem that methods for administration is limited to parenteral administration such as an intravenous injection and an intramuscular injection, in order to obtain a blood level necessary for exerting an effect. Treatment by parenteral administration is difficult for patients other than inpatients, and therefore has not been a preferable treatment for AIDS patients, hepatitis B virus patients and the like who need a long-term treatment.
The present inventors have previously found that certain ester derivatives of phosphonate nucleotide show high oral absorbency (EP632048), and further found an anti-viral agent having no toxicity such as bone marrow cell growth inhibition and mutagenicity by altering a base portion thereof to a specific structure (EP785208). However, such an anti-viral agent is not yet in actual use.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide an anti-viral agent having no toxicity such as bone marrow cell growth inhibition and mutagenicity. Furthermore, another object of the present invention is to provide a low-cost anti-viral agent obtained by a small number of steps of manufacturing process.
Through intensive studies directed towards the above objects, the present inventors have found that certain 2-amino-6-arylthiopurinephosphonate, which is not specifically disclosed in the aforementioned EP632048 and EP785208, have a high anti-viral activity, and also that these compounds have advantages that they can be synthesized more economically and simply and is more excellent in terms of safety than previously known compounds, thereby completing the present invention.
Thus, the present invention provides a phosphonate nucleotide compound represented by the following formula (I) or a salt thereof, or a hydrate or solvate thereof:
wherein,
R′ is a hydroxyl group; each of R
2
and R
3
is independently a hydrogen atom, 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
is 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 is CH or a nitrogen atom.
Moreover, another aspect of the present invention provides a pharmaceutical composition, which comprises a substance selected from the group consisting of the above compound and salt thereof, and hydrate and solvate thereof, and a pharmacologically acceptable pharmaceutical additive; and an anti-viral agent, which comprises, as an active ingredient, a substance selected from the group consisting of the above compound and salt thereof, and hydrate and solvate thereof. A further aspect of the present invention provides a use of a substance selected from the group consisting of the above compound and salt thereof, and hydrate and solvate thereof for production of the above pharmaceutical composition; and a method for treating virus infection diseases, said method comprising a step of administrating to mammals such as a human, an effective amount of a substance selected from the group consisting of the above compound and salt thereof, and hydrate and a solvate thereof.
THE BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is described in detail below.
In the phosphonate nucleotide compound of the above formula (I), examples of a C
1
-C
22
alkyl group represented by R
2
and R
3
include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an icosyl group, a henicosyl group, and a docosyl group.
Examples of an acyloxymethyl group represented by R
2
and R
3
include an acetyloxymethyl group, a propionyloxymethyl group, a butyryloxymethyl group, an isobutyryloxymethyl group, a valeryloxymethyl group, an isovaleryloxymethyl group, and a pivaloyloxymethyl group.
Examples of an acylthioethyl group represented by R
2
and R
3
include an acetylthioethyl group, a propionylthioethyl group, a butyrylthioethyl group, an isobutyrylthioethyl group, a valerylthioethyl group, an isovalerylthioethyl group, and a pivaloylthioethyl group.
In an ethyl group substituted by one or more halogen atoms represented by R
2
and R
3
, the type of the halogen atom may be any of a fluorine, chlorine, bromine or iodine atom. Examples of an ethyl group substituted by one or more halogen atoms include a 1-fluoroethyl group, a 2-fluoroethyl group, a 1-chloroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 2,2-dibromoethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, and a 2,2,2-tribromoethyl group. It is particularly preferable that 2-position of an ethyl group is substituted, and the preferred halogen atom is a fluorine atom. At least one of R
2
and R
3
is preferably an ethyl group substituted by one or more halogen atoms, particularly preferably a 2,2,2-trifluoroethyl group.
Examples of a C
1
-C
4
alkyl group represented by R
4
include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Examples of a C
1
-C
4
hydroxyalkyl group represented by R
4
include a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 1-hydroxybutyl group, a 2-hydroxybutyl group, a 3-hydroxybutyl group, and a 4-hydroxybutyl group. Examples of a C
1
-C
4
alkyl group substituted by one or more halogen atoms represented by R
4
include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group to which a halogen atom(s) such as a fluorine atom or a chlorine atom is bound. Specific examples of such groups include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a chloroethyl group, a fluoropropyl group, a chloropropyl group, a fluorobutyl group, and a chlorobutyl group.
The first condition for the preferred compound of the present invention is that each of R
2
and R
3
is independently a hydrogen atom, a C
1
-C
22
alkyl group, or an ethyl group substituted by one or more halogen atoms. The second condition for the preferred compound of t

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