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European Patent Office
_„.
Office
europeen des brevets
EUROPEAN
©
MM II II II Ml I Ml II II Ml I II I II
© Publication number:
PATENT
Date of publication of patent specification: 18.03.92
_ _
0 2 0 5_ 8 2 6
B1
SPECIFICATION
Int. CI.5: A61 K 3 1 / 6 7 5
©
© Application number: 86105776.8
@ Date of filing: 25.04.86
© Phosphonylmethoxyalkyl adenines for the treatment of virus diseases.
©
©
Priority: 25.04.85 CS 3018/85
@ Date of publication of application:
30.12.86 Bulletin 86/52
©
Publication of the grant of the patent:
18.03.92 Bulletin 92/12
©
Designated Contracting States:
AT BE CH DE FR GB IT LI LU NL SE
©
References cited:
FR-A- 2 539 132
Proprietor: Ceskoslovenska Akademle VED
p/a Center of Discoveries and Inventions
P.O. Box 80
CS-16070 Praha(CS)
©
Inventor: de Clercq, Erik
p/a Rega Instltuut Mlnderbroedersstraat 10
B-3000 Leuven(BE)
Inventor: Holy, Antonln Institute of Organic
Chem. and
Blochem. Czechoslovak Academy of Sclences
CS-16610 Praha(CS)
Inventor: Rosenberg, Ivan Institute of Organic
Chem. and
Blochem. Czechoslovak Academy of Sclences
CS-16610 Praha(CS)
©
Representative: Bruin, Cornells Wlllem et al
Octrooibureau Arnold & Sledsma Sweelinckplein 1
NL-2517 GK The Hague(NL)
PROCEEDINGS 8TH SYMPOSIUM MED.
CHEM., vol. 1, 1985, pages 241-242; E.J. REIST
et al.: "Nucleotide analogs as antiviral
agents"
00
CO
CM
00
m
o
CM
Proprietor: Stichting REGA V.Z.W.
Mlnderbroedersstraat 10
B-3000 Leuven(BE)
NATURE, vol. 272, 20th April 1978, pages
694-696, Macmillan Journals Ltd; L. CARRASCO: "Membrane leaklness after viral Infectlon and a new approach to the development of antiviral agents"
JOURNAL OF MEDICAL CHEMISTRY, vol. 28,
no. 3, 1985, pages 282-287, American Chemlcal Society; E. DE CLERCQ et al.:
"Broad-spectrum antiviral agents"
Note: Within nine months from the publication of the mention of the grant of the European patent, any person
may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition
shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee
has been paid (Art. 99(1) European patent convention).
Rank Xerox (UK) Business Services
EP 0 205 826 B1
NATURE, vol. 323, 2nd October 1986, pages
464-467; E. DE CLERCQ et al.: "A novel selective broad-spectrum antl-DNA virus agent"
ANTIVIRAL RESEARCH, vol. 4, 1984, pages
119-133, Elsevier Science publishers B.V.; E.
DE CLERCQ et al.: "Broad-spectrum antiviral
activity of adenosine analogues"
2
EP 0 205 826 B1
Description
5
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25
This invention relates to a novel therapeutical agent for virus diseases and to its preparation.
It is known that certain substituted alkyl derivatives of adenine exhibit a marked antiviral activity. Such
adenine derivatives are: 9-(S)-(2,3-dihydroxypropyl)adenine as disclosed in U.S. - A - 4.230.708, Deritadenine as disclosed by Holy et al. in Coll. Czech. Chem. Comm., 47, 1392-1407 (1982) and 3-(adenin9-yl)-2-hydroxypropanoic acid esters as disclosed in U.S. - A - 4.605.658.
Although these adenine derivatives have been indicated as broad-spectrum antiviral agents, it appears
that their antiviral activity is directed predominantly against RNA-viruses such as measles, parainfluenza and
vesicular stomatitis virus and further only against a single DNA-virus, viz. vaccinia virus. Their activity
against the majority of DNA-viruses such as herpes simplex and herpes zoster, however, is rather minimal
or totally absent.
Therefore, there is a need for antiviral adenine derivatives having their antiviral activity directed
predominantly against DNA-viruses and a primary object of the invention is to provide adenine derivatives
and therapeutic compositions having such activity.
In accordance with the invention, it has now been found that certain phosphonylmethoxyalkyl adenines
exhibit a marked antiviral activity against several DNA-viruses such as vaccinia and herpes viruses, while
being ineffective against the majority of RNA-viruses and having a low toxicity for host cells. This is
surprising since antiviral activities are shown only by a limited number of adenine derivatives and since it
could not be expected that the introduction of a phosphonylmethoxy group would induce such a drastic shift
in antiviral activity.
The phosphonylmethoxyalkyladenines of the present invention can be represented by the following
general formula (I)
NH,
30
40
45
50
55
wherein R1 is methylene, -CH(OH)-CH2- or - CH-CH2OH and R2 is a hydroxyl group and in some cases R1
and R2 are linked with each other to form a cyclic ester group. They can be used in the form of free acids
or in the form of salts such as alkalimetal, ammonium or amine salts.
Most of the compounds of formula (I), except those wherein R1 is methylene, will have an asymmetric
carbon atom and will exist in more than one enantiomeric form. It should be noted that in that case, only the
(S)-form of the compounds and also the racemic or (RS) form will show sufficient antiviral activity. The best
antiviral activity among the compounds of formula (I) is shown by (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-adenine.
It should be noted that most of the derivatives of formula (I) were already disclosed in GB-A-2 134 907
where the intended use is for sterilizing insects. Therefore, the compounds as such and their chemical
syntheses are not a part of the present invention.
Further, antivirally active phosphonyl-alkyloxymethyl-adenines were suggested on page 9 of WO-A84/04748 (EP-A-0 145 739) without, however, being exemplified therein.
Moreover, a few antivirally active phosphonyl derivatives of guanine were disclosed in the literature.
Thus, an in vitro antiherpes activity of 9-(3-phosphono-1-propyloxymethyl)-guanine and of 9-(3ethylphosphono-1-propyloxymethyl)-guanine was disclosed in the examples of WO-A-84/04748 and by
Reist et al. in "Proceedings 78th Symp. Med. Chem. 1, pp. 241-242 (1985).
An antivirally active phosphonyl derivative of guanidine indicated as GppCH2p was disclosed by L.
Carrosco, Nature 272, pp. 694-696 (1978).
The derivatives of formula (I) can be prepared in genealong at least two routes, viz. (A) condensation of
a 9-(hydroxyalkyl)-adenine with chloromethanephosphonylchloride followed by alkaline hydrolysis (GB-A-2
134 907) and (B) condensation
of a 9-(hydroxyalkyl)-adenine
with p-toluenesulphonylox3
EP 0 205 826 B1
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25
30
35
40
45
50
55
ymethylenephosphoric acid diester followed by removal of the ester groups with trimethyliodosilane.
Racemic mixtures can be separated into their components either before or after the preparation and if the
product is a free acid, it can be converted to a salt by reaction with an alkali metal, ammonia or with
amines.
As stated before, the derivatives of formula (I) have a low toxicity for host cells. The cytotoxic effect of
these derivatives on tissue culture cells is only observed at concentrations higher than 100 or 200 or 400
M.g/ml, i.e. at concentrations which are substantially higher than the active virostatic concentrations
(compare Table 2 below). Further, the derivatives of formula (I) are ineffective in tissue culture cells infected
with the majority of RNA-viruses such as reoviruses, rhabdoviruses, paramyxoviruses, enteroviruses. Some
of the derivatives are very active, however, against Moloney murine sarcoma virus, a retrovirus which
induces sarcomatous tumors in mice (compare Table 3) and, therefore, these derivatives may be expected
to be effective against retroviruses in general. The principal target of the compounds of formula (I) is formed
by DNA-viruses like vaccinia viruses and herpes simplex virus. All such compounds inhibit the replication of
several strains of herpes simplex viruses of types 1 and 2 (compare Table 4). When compared to known
compounds used in therapeutic compositions for the treatment of diseases caused by herpes viruses, such
as acyclovir, (E)-5-(2-bromovinyl)-2'-deoxyuridine, and 5-iodo-2'-deoxyuridine, the compounds of formula (I)
are less potent; however, they lack the disadvantages of such compounds, viz. the low solubility of
acyclovir, the mutagenic, teratogenic, embryotoxic and carcinogenic potential of 5-iodo-2'-deoxyuridine. An
important and substantial feature of the compounds of formula (I) is their effect on those herpes virus strains
which are deficient in thymidine kinase inducing activity (TK~-strains). Thymidine kinase is essential for the
activity of acyclovir and (E)-5-(2-bromovinyl)-2'-deoxyuridine, which are thus inactive against TK~herpes
viruses (Prusoff et al., pages 1-27 in: "Targets for the Design of Antiviral Agents", Eds. De Clercq and
Walker, Plenum Press, New York and London, 1984). To the contrary, the compounds of formula (I) have a
distinct activity against TK~ herpes viruses (compare table 4). The compounds of formula (I) can therefore
be used in the therapy of diseases caused by TK~herpes virus strains and, furthermore, they may be useful
in combination with acyclovir and other known compounds.
The antiviral activity of the derivatives of formula (I) is entirely novel and unexpected. It is known that
phosphoric acid esters of antivirally active nucleoside analogues such as adenine arabinoside, 5-ethyl-uracil
arabinoside, acyclovir, 5-iodo-2'-deoxyuridine and (E)-5-2-bromovinyl)-2'deoxyuridine, are also effective as
antiviral agents. These esters merely act, however, as prodrugs and even before they have the opportunity
to enter the cells, they are hydrolyzed to release the free nucleoside analogues. The compounds of formula
(I) are equally polar as the above phosphoric acid esters. They can penetrate, however, as such into the
cells and hence produce the desired biological effects without any hydrolysis.
Therapeutic compositions containing compounds of formula (I) as an active ingredient for treating virus
diseases in human and veterinary practice may take the form of powders, suspensions, solutions, sprays,
emulsions, unguents or creams and may be used for local application (lesions of skin, mucosa, eye, etc.)
for intranasal, rectal, vaginal and also for oral or parenteral (intravenous, intradermal, intramuscular,
intrathecal etc.) administration. Such compositions may be prepared by combining (e.g. mixing, dissolving
etc.) the active compound of formula (I) in the form of a free acid or a salt with pharmaceutically acceptable
excipients of neutral character (such as aqueous or non-aqueous solvents, stabilizers, emulsifiers, detergents, additives), and further, if necessary, with dyes and aromatizers. The concentration of the active
ingredient in the therapeutic composition may vary widely between 0.1 percent and 100 percent, dependent
on the character of the disease and the mode of administration. Further, the dose of the active ingredient to
be administered may vary between 0.1 mg and 100 mg per kg of body weight.
The antiviral activity of the compounds of formula (I) is documented by the following examples which in
no way limit their use. The following abbreviations are used in the examples and tables:
MCC - minimum compound concentration which brings about a microscopically detectable change in cell
morphofology;
MIC50 - minimum compound concentration which will cause a 50% inhibition of the cytopathic effect of the
virus;
ID50 - concentration of compound which causes a 50% decrease of incorporation of precursors labeled with
tritium (3H);
dThd - 2'-deoxythymidine; Urd - uridine; Leu - L-leucine.
Cell lines: PRK - primary tissue culture rabbit kidney cells; Vera B and Vera Flow - continuous lines of
African green monkey kidney cells; HeLa - continuous line of human cervical carcinoma cells; MO continuous murine embryonic cell line.
Designation of compounds of formula (I): No. 1: (RS)-9-(2(3)hydroxy-3(2)-phosphonylmethoxypropyl)adenine.
4
EP 0 205 826 B1
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2: (RS)-9-(2-hydroxy-3-phosphonylmethoxypropyl)-adenine.
3: ( S)-9-(2-hydroxy-3-phosphonylmethoxypropyl)-adenine.
4: (S) -9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine.
5: 2',3'-cyclic O-phosphonylymethyl ether of (RS)-9-(2,3-dihydroxypropyl)adenine.
6: 9-(2-phosphonylmethoxyethyl)adenine.
Designation of the other compounds:
(S)- DHPA, 9-(S)-(2,3-dihydroxypropyl)adenine; ACV, aclycovir; BVDU, (E)-5-(2-bromovinyl)-2'-deoxyuridine;
IDU, 5-iodo-2'-deoxyuridine.
Compounds nos. 1-6 have been prepared as follows: compound no. 1 (a mixture of isomers) was
prepared by reaction of (RS)-9-(2,3-dihydroxypropyl)adenine with chloromethylphosphonyl dichloride followed by an alkaline treatment. Compound no. 2 was isolated from compound no. 1 by chromatographic
separation. Compounds nos. 3 and 4 were prepared by reaction of (S)-9-(2,3-dihydroxypropyl)adenine with
chloromethylphosphonyl dichloride followed by an alkaline treatment and by chromatographic separation on
an ion exchange resin. Compound no. 5, a mixture of isomers, was synthesized by cyclization of compound
no. 1 with N,N-dicyclocarbodiimide.
Compound no. 6 was prepared by reaction of 9-(2-hydroxyethyl)adenine with diethyl p-toluene sulfonyloxymethane phosphonate followed by cleavage of the ester groups.
Some physical data obtained by paper chromatography and electrophoresis are given in Table 1.
No.
No.
No.
No.
No.
Table 1
20
Compound
No.
No.
No.
No.
No.
No.
1
2
3
4
5
6
Rf
Eup
k
0.10
0.10
0.10
0.10
0.38
0.15
0.82
0.82
0.82
0.82
0.47
0.82
2.37 + 2.63
2.63
2.63
2.37
3.00 + 3.45
2.31
The Rf values were obtained by paper chromatography in 2-propanol-conc. aqueous ammonia-water
(7:1:2, vol/vol). The values of Eup were obtained by paper electrophoresis (20V/cm) at pH 7.5 and show the
mobility related to uridine 3-phosphate. The k-values were obtained by HPLC on Separon six RPS (5/u.m) (4
x 200 mm, 0.7 ml/min.) in 5 vol. % methanol in 0.05 mol/l triethylammonium hydrogen carbonate at pH 7.5.
The detection was at 254 nm.
k = (tr-t0)/t0 when tr is the retention time and t0 is the hold-up time.
Example 1
Determination of cytotoxicity and antimetabolic activity of compounds of formula (I) in tissue cultures.
Primary rabbit kidney cell cultures were incubated in Petri dishes with solutions of compounds of
formula (I) at increasing concentrations (1-400 u.g/ml) in Eagle's minimum essential medium for 72 h; the
morphological changes of the cells in the individual dishes were evaluated microscopically. The minimum
cytotoxic concentration (MCC) shown in table 2 is the lowest concentration of the compound at which
morphological changes of the cells were observed under the experimental conditions used.
For the determination of the antimetabolic effects of the compounds of formula (I), the primary rabbit
kidney cell cultures in Eagle's culture medium were incubated in the presence of increasing concentrations
of the compounds and a fixed amount of radiolabeled precursor (37.1 03Bq (1 u.Ci) per dish,
(3H-methyl)dThd 1110.109 Bq/mmol (30 Ci/mmol),
(3H-11,21)dUrd 999.1 09 Bq/mmol (27 Ci/mmol),
(3H-5)Urd 1110.109 Bq/mmol (30 Ci/mmol),
(3H-4,5)Leu 1739.1 09 Bq/mmol (47 Ci/mmol).
The concentration of the labeled precursor was determined as described earlier (De Clercq et al, Biochem.
Pharmac. 24, 523 (1975)). The ID5o values of the compounds of formula (I) which cause a 50 % decrease
of the incorporation of the precursor compared to controls not containing the compound are listed in table 2.
It is obvious from these values that none of the compounds of formula (I) shows a marked cytotoxicity and
that only compounds nos. 4 and 6 specifically affect the incorporation of 2'-deoxyuridine into cells at a
5
EP 0 205 826 B1
concentration of about 100 ug/ml.
Example 2
5
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Determination of antiviral effect of compounds of formula (I) in tissue cultures.
The cell cultures were infected with 100-fold the virus dose required for infection of half of the cells
(100 CCID5o). 1 hour after infection, the cells were further incubated in the presence of Eagle's medium
containing increasing concentrations of the compound of formula (I). Using a series of compounds assayed
at different concentrations, the minimum compound concentration necessary to produce a 50 % inhibition of
the cytophatic effect of the virus (MIC50) was determined by the method of Rosenthal and Schechmaister
("Tissue Culture", Pergamon Press, New York, p. 510, 1973). From the data presented in Table 3, it is clear
that compounds of formula (I) efficiently inhibit vaccinia virus, herpes simplex virus type 1 and 2 and
Moloney sarcoma virus.
Example 3
Determination of the antiviral effect of compounds of formula (I) on herpes viruses.
20
25
The experiment was carried out as described under Example 2 with primary rabbit kidney (PRK) cells
infected by 100 CCID50 of various strains of herpes simplex virus of type 1 and 2, and with human
embryonic lung (HEL) cells infected with 20 PFU (plaque-formation units) of various strains of varicella
zoster virus and cytomegalovirus. The evaluation of the effect of compounds of formula (I) is given in
Tables 4 and 5. These data show that all the compounds were active against the cited viruses, including the
TK~-mutants. In this respect, compound no. 4 was the most effective one.
Example 4
30
35
40
Effects of compounds of formula (I) on the multiplication (yield) of herpes simplex virus type 1 and vaccinia
virus.
The primary rabbit kidney cells cultures (PRK) were infected with a virus dose of 1045 PFU/0.5ml(PFU
being one unit of plaque formation) of herpes simplex virus type 1 (strain KOS) or vaccinia virus, as
described under example 2. The cells were subsequently exposed to compound (I) (at 100 u.g/ml) in
Eagle's culture medium.
The virus yield was determined after 1, 24, 48 and 72 h by determining the number of plaques in PRK
cells. The data listed in table 6 show that all compounds tested (nos. 1,2,4,5,6) decreased the yield of
herpes simplex virus type 1 (KOS) and vaccinia virus by 10,000 to 100,000-fold as determined at either 1, 2
or 3 days after virus infection.
Table 2
Cytotoxic and antimetabolic effects of compounds of formula I on PRK cells
Compound
55
No. 1
No. 2
No. 3
No. 4
No. 5
No. 6
(S)-DHPA
MCC (ug/ml)
^100
>400
^200
^200
>400
^200
>400
ID5o (ug/ml)
dThd
dUrd
Urd
Leu
250
280
>400
297
^390
242
350
230
>400
>400
74
^360
114
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
6
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7
EP 0 205 826 B1
Table 4
Effect of compounds of formula I on individual
simplex virus (HSV-l.HSV-2) in PRK c e l l s
of herpes
strains
MIC5Q (ug/ml)
Compound
HSV-2 ( s t r a i n )
HSV-1 (strain)
KOS
F
Mclntyre
TK
TK
B2006
196
Lyons
7-20
15-70
7-15
10-15
10-15
10-15
30-150
70-150
30-100
1-3
1-3
G
CHOI
7-20
No. 1
20-30
30
15-30
7
No. 2
2-10
10-15
10-15
-
No. 3
70-150
150
70-150
-
No. 4
1
1-3
1-3
1
1
No. 5
30
30
30
-
7
30
15
15
No. 6
15-30
30
—
3
7
7
15
15
0.2
0.1
0.2
70
20
0.07
0.02
0.02
> 200
70
2
0.2
0.2
ACV
BVDU 0.02
0.2
IDU
7
30-40
Table
of
Effect
virus
compound
(VZV)
and
no.
4 on
7
70
2
0.2
5
individual
strains
in
(CMV)
cytomegalovirus
0.07
0.07
0.2
-
1
MIC5Q
of
varicella-zoster
HEL c e l l s
(jag/ml)
Compound
VZV
YS
No.
Oka
(strain)
CMV ( s t r a i n )
TK
TK
YSR
07-1
Davis
AD
169
0.004
0.004
0.004
0.004
0.3
0.3
ACV
0.2
0.3
20
4
20
30
BVDU
0.006
0.007 >400
> 400
300
200
4
8
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Table 6
Effect of selected compounds of formula (I) (100 u.g/ml) on multiplication of herpes simplex virus type 1
(HSV-1) (strain KOS) and vaccinia virus (W) in PRK cell cultures
Titer of HSV-1 (logi o PFU/ml)
Compound
No. 1
No. 2
No. 4
No. 5
No. 6
Control
(S)-DHPA
Titer of W (logi oPFU/ml)a'b
1h
24 h
48 h
72 h
1h
24 h
48 h
72 h
< 1.3
1.3
1.3
3.3
<1.3
<1.3
<1.3
<1.3
6.7
6.5
4.0
<1.3(<6.0)
<1.3(4.3)
2.8 (6.04)
3.34 (6.36)
6.5
6.9
3.9
7.0
6.9
1.7
2.2
1.6
2.7
2.0
1.7
2.2
1.8
6.1
4.7
1.2
2.0 (<1. 3)
<1 .3 (<1 .3)
<1 .3 (<1 .3)
5.54
6.5
5.2
1.5
1.8
1.5
6.3
5.5
aAverage of two determinations.
bThe values in parentheses were obtained at a compound concentration of 10 u.g/ml.
20
25
Claims
Claims for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE
1.
A therapeutic composition for use in the treatment of virus diseases, which comprises as an active
ingredient a phosphonylmethoxyalkyladenine of the following general formula (I)
30
(I)
35
wherein R1 is methylene, -CH(OH)-CH2- or CH-CH2OH and R2 is a hydroxyl group, and, wherein, when
R1 is different from methylene, R1 and R2 may be linked with each other to form a cyclic ester group,
said adenine derivative being in (RS) or (S) form when R1 is different from methylene and further being
in the form of a free acid or a salt thereof.
40
45
50
2.
The composition as claimed in claim 1, comprising (S)-9-hydroxy-2-phosphonylmethoxypropyl)adenine
as an active ingredient.
3.
Use of compounds of formula (I) for the manufacture of a therapeutic composition against virus
diseases.
Claims for the following Contracting State : AT
1.
A method of manufacturing a therapeutic composition for use in the treatment of virus diseases, which
comprises the step of incorporating therein as an active ingredient a phosphonylmethoxyalkyladenine of
the following general formula (I)
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EP 0 205 826 B1
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wherein R1 is methylene, -CH(OH)-CH2- or CH-CH2OH and R2 is a hydroxyl group, and, wherein, when
R1 is different from methylene, R1 and R2 may be linked with each other to form a cyclic ester group,
said adenine derivative being in (RS) or (S) form when R1 is different from methylene and further being
in the form of a free acid or a salt thereof.
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2.
The method as claimed in claim 1, comprising the step of incorporating (S)-9-hydroxy-2-phosphonylmethoxypropyl)adenine therein as an active ingredient.
3.
Use of compounds of formula (I) for the manufacture of a therapeutic composition against virus
diseases.
Revendicatlons
Revendicatlons pour les Etats contractants suivants : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE
1.
Composition therapeutique destinee a etre utilisee dans le traitement de maladies virales, qui comprend, en tant qu'ingredient actif, une phosphonylmethoxyalkyladenine representee par la formule
generale (I) suivante :
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CH2(R )-OCII2P-OH
dans laquelle :
- R1 represente methylene, -CH(OH)-CH2- ou CH-CH2OH ; et
- R2 represente un groupe hydroxyle ; et
dans laquelle, lorsque R1 est different de methylene, R1 et R2 peuvent etre lies I'un a I'autre pour
former un groupe ester cyclique,
ledit derive d'adenine se presentant sous la forme (RS) ou (S) lorsque R1 est different de methylene, et
se presentant en outre sous la forme d'un acide libre ou d'un sel de celui-ci.
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2.
Composition selon la revendication 1, comprenant, en tant qu'ingredient actif, la (S)-(hydroxy-3
phosphonylmethoxy-2 propyl)-9 adenine.
3.
Utilisation des composes de la formule (I) pour la fabrication d'une composition therapeutique pour
lutter contre les maladies virales.
Revendicatlons pour PEtat contractant sulvant : AT
1.
Procede de fabrication d'une composition therapeutique destinee a etre utilisee dans le traitement de
maladies virales, qui comprend I'etape consistant a incorporer a celle-ci en tant qu'ingredient actif, une
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EP 0 205 826 B1
phosphonylmethoxyalkyladenine representee par la formule generale (I) suivante:
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dans laquelle:
- R1 represente methylene, -CH(OH)-CH2- ou CH-CH2OH; et
- R2 represente un groupe hydroxyle; et
dans laquelle, lorsque R1 est different de methylene, R1 et R2 peuvent etre lies I'un a I'autre pour
former un groupe ester cyclique,
ledit derive d'adenine se presentant sous la forme (RS) ou (S) lorsque R1 est different de methylene, et
se presentant en outre sous la forme d'un acide libre ou d'un sel de celui-ci.
is
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2.
Procede selon la revendication 1, comprenant I'etape consistant a incorporer a celle-ci, en tant
qu'ingredient actif, la (S)-(hydroxy-3-phosphonylmethoxy-2 propyl)-9 adenine.
3.
Utilisation des composes de la formule (I) pour la fabrication d'une composition therapeutique pour
lutter contre les maladies virales.
Patentanspruche
Patentanspruche fur folgende Vertragsstaaten : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE
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1.
Therapeutische Zusammensetzung zur Verwendung bei der Behandlung von Viruserkrankungen, die als
aktiven Bestandteil ein Phosphonylmethoxyalkyladenin der folgenden allgemeinen Formel (I) enthalt
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worin R1 Methylen, -CH(OH)-CH2- oder -CH-CH2OH ist und R1 eine Hydroxylgruppe ist, und worin,
wenn R1 von Methylen verschieden ist, R1 und R2 miteinander unter Bildung einer cyklischen
Estergruppierung verbunden sein konnen, wobei das Adenin-Derivat in der (RS) oder (S)-Form vorliegt,
wenn R1 von Methylen verschieden ist, und ferner in Form einer freien Saure oder eines Salzes davon.
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2.
Zusammensetzung nach Anspruch 1, dadurch gekennzeichnet, da/S sie (S)-9-(3-Hydroxy-2-phosphonylmethoxypropyl)-adenin als aktiven Bestandteil enthalt.
3.
Verwendung der Verbindungen der Formel (I) zur Herstellung einer therapeutischen Zusammensetzung
gegen Viruserkrankungen.
Patentanspruche fur folgenden Vertragsstaat : AT
1.
Verfahren zur Herstellung einer therapeutischen Zusammensetzung zur Verwendung bei der Behandlung von Viruserkrankungen, dadurch gekennzeichnet, dass man darin als aktiver Bestandteil ein
Phosphonylmethoxyalkyladenin der folgenden allgemeinen Formel (I) aufnimmt,
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EP 0 205 826 B1
worin R1 Methylen, -CH(OH)-CH2- oder -CH-CH2OH ist und R2 eine Hydroxylgruppe ist, und worin,
wenn R1 von Methylen verschieden ist, R1 und R2 miteinander unter Bildung einer cyklischen
Estergruppierung verbunden sein konnen, wobei das Adenin-Derivat in der (RS) oder (S)-Form vorliegt,
wenn R1 von Methylen verschieden ist, und ferner in Form einer freien Saure oder eines Salzes davon.
Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass man darin (S)-9-(3-Hydroxy-2-phosphonylmethoxypropyl)-adenin als aktiver Bestandteil aufnimmt.
Verwendung der Verbindungen der Formel (I) zur Herstellung einer therapeutischen Zusammensetzung
gegen Viruserkrankungen.
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