Antiviral guanine derivatives

Details Antiviral guanine derivatives Antiviral guanine derivatives

1994-12-15

2003-06-03

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen bonded directly to ring carbon of the purine ring...

Reexamination Certificate

active

06573378

ABSTRACT:

The present invention relates to compounds having antiviral activity, processes for their preparation and pharmaceutical compositions containing them.
The compound 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine of formula (A)
is disclosed in Synthetic Communications, 2(6), 345-351 (1972) but no pharmaceutical activity has been indicated for the compound in this or any other published document. We have repeated the synthesis of the compound as described in the above publication, and have shown that the product is a mixture of the compound of formula (A), its monobenzyl ether and its dibenzyl ether, this mixture having a melting point and uv spectrum in agreement with those reported in the publication for the supposedly ‘pure’ compound of formula (A). Our analysis of the product produced by the above synthesis showed that it contained 45-50% by weight of the compound of formula (A), 45-50% by weight of the monobenzyl ether and 5% or less by weight of the dibenzyl ether.
By different synthetic routes, we have prepared the compound of formula (A) in a substantially pure form and have found that it has anti-viral activity. This activity is also shown by certain derivatives of the compound of formula (A).
According to the present invention there is provided a compound of formula (I)
or a salt, phosphate ester or acyl derivative thereof, in which X represents chlorine, straight or branched chain C
1-6
alkoxy, preferably methoxy, phenoxy, phenyl C
1-6
alkoxy, —NH
2
, —OH or —SH with the proviso that, when X is —OH, the compound of formula (I) is in a purity state of greater than 50% by weight of pure compound.
The term ‘acyl derivative’ is used herein to include any derivative of the compounds of formula (I) in which one or more acyl groups are present. Such derivatives include biological precursors of the compounds of formula (I) in addition to those derivatives which are per se biologically active.
Examples of acyl derivatives of the compounds of formula (I) are those wherein one or both of the hydrogens in the acyclic OH groups, and/or one of the hydrogen atoms in the —NH
2
group, are replaced by
wherein R is hydrogen or an alkyl, aryl, aralkyl or heterocyclyl group.
Examples of alkyl groups R include straight and branched chain groups containing up to 18 carbon atoms, preferably up to 6 carbon atoms. Particular examples are methyl, ethyl, t-butyl and pentyl.
Examples of aryl groups R include phenyl optionally substituted with up to five preferably up to three groups.
Examples of aralkyl groups R include phenyl-C
1-6
alkyl groups such as benzyl.
Examples of heterocyclyl groups R include single or fused rings containing one or two hetero-atoms in each ring, selected from oxygen, nitrogen and sulphur.
Examples of phosphate esters of the compounds of formula (I) include those where one or both of the acyclic —OH groups are replaced by
or salts thereof, or where the two —OH groups are replaced by a bridging
group
Salts, phosphate esters and acyl derivatives of the compounds of formula (I) are preferably pharmaceutically acceptable, but non-pharmaceutically acceptable compounds are also within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable compounds.
The compounds of formula (I) are defined herein as including tautomers of formula (I), wherein the —OH and —SH substituents are replaced by ═O and ═S substituents respectively.
A particular group of compounds of the invention are those of formula (II)
or pharmaceutically acceptable salts thereof, in which X is as defined in formula (I), and each of R
1
, R
2
and R
3
represents hydrogen or an acyl group of formula
in which R
4
is C
1-18
alkyl or imidazolyl, or R
1
or R
2
represents a phosphate ester group of formula
or R
1
and R
2
together represent a
bridging group.
Subject to the aforementioned purity proviso in relation to compounds of the invention, a preferred compound of the present invention is the compound of formula (A)
or a salt or acyl derivative therof.
In a further aspect of the invention there is provided a compound of formula (A) in a purity state of greater than 60% preferably greater than 80% more preferably greater than 90% and particularly preferably more than 95% by weight of pure compound.
In yet a further aspect of the invention, there is provided an isolated, substantially completely pure compound of formula (A), or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula (A) in crystalline form having a melting point of 275-277° C.
The compounds of the present invention have antiviral activity, and are potentially useful in the treatment of infections caused by herpes viruses, such as herpes simplex type 1, herpes simplex type 2 and varicella zoster viruses.
Accordingly, the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt, phosphate ester or acyl derivative thereof, for use as an active therapeutic substance, and in particular for use in the treatment of viral infections. In this aspect of the invention, the compounds of formula (I) are not subject to the aforementioned purity proviso.
Examples of pharmaceutically acceptable salts of the compounds of formula (I) are those formed with organic bases, preferably with amines such as ethanolamines or diamines; and alkali metals, such as sodium and potassium; and acid addition salts formed with a pharmaceutically acceptable acid such as hydrochloric acid, orthophosphoric acid and sulphuric acid.
The compound of formula (A) or a salt thereof may be prepared by converting the group X in a compound of formula (III).
in which X, excluding —OH, is as defined in formula (I); R
a
and R
b
, which may be the same or different, are each hydrogen or O— protecting groups, preferably acyl groups; and Y is chlorine or —NHR
c
, in which R
c
is hydrogen or acyl, to an —OH group by means of hydrolysis, preferably acid hydrolysis, when X is other than NH
2
, or, when X is —NH
2
, by means of a deaminase reaction, or when Y is chlorine and X is —OH, converting Y to a —NH
2
group by reaction with ammonia under pressure in accordance with known methods, and subsequently, if desired, converting the compound of formula (A) to a salt thereof by treatment with an acid or base.
Acyl groups R
a
, R
b
and R
c
may be those of formula
as hereinbefore defined.
Examples of groups R
a
and R
b
in formula (III) are acetyl and cyclic acetal such as isopropylidene. R
c
is preferably acetyl or hydrogen.
A preferred process for preparing the compound of formula (A) comprises treating a compound of formula (III) in which X is chlorine, Y is —NH
2
and R
a
and R
b
are each acetyl, with aqueous mineral acid, preferably hydrochloric acid.
Compounds of formulae (III) when each of R
a
, R
b
and R
c
is hydrogen or acyl, are themselves compounds of the invention, having the additional utility as intermediates for the preparation of the compound of formula (A).
In a further aspect of the invention, compounds of formula (I) or acyl derivatives thereof, together with, compounds of formula (III), may be prepared by treating a compound of formula (IV).
in which X is as defined in formula (I) and Y is as defined in formula (III), with a compound of formula (V)
in which R
a
and R
b
are as defined in formula (III) and Z is a leaving group such as Cl, Br, or I, preferably Br.
Compounds of formula (IV) are either known compounds or can be made from known compounds by known methods.
Compounds of formula (V) in which Z is bromine may be prepared by brominating a compound of formula (VI).
preferably by treatment with carbon tetrabromide and triphenylphosphine in an organic, aprotic solvent, such as dimethylformamide.
Compounds of formula (V) in which Z is Cl or I may be prepared in an analogous manner.
Compounds of formula (VI) in which R
a
and R
b
are identical may be prepared according to the following schematic process.
Acyl derivatives of compounds of formula (I) may also be prepared by acylating an optionally prote

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