CA1340856C - N-phosphonylmethoxyalkyl pyrimidines and purines and therapeutic application thereof - Google Patents
N-phosphonylmethoxyalkyl pyrimidines and purines and therapeutic application thereofInfo
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- CA1340856C CA1340856C CA000542404A CA542404A CA1340856C CA 1340856 C CA1340856 C CA 1340856C CA 000542404 A CA000542404 A CA 000542404A CA 542404 A CA542404 A CA 542404A CA 1340856 C CA1340856 C CA 1340856C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
Abstract
Disclosed are N-(2-phosphonylmethoxyethyl) and N-(3-hydroxy-2-phosphonylmethoxypropyl) derivatives of pyrimidine and purine bases, easily accessible from such heterocyclic bases and their N-(2-hydroxyethyl) or N-(2,3-dihydroxypropyl) derivatives. Most of the compounds exhibit a marked antiviral activity against DNA-viruses and can be used in therapeutic antiviral compositions.
Description
13408~~
N-Phosphonylmethoxyalkyl pyrimidines and purines and therapeutic application thereof This invention relates to N-phoaphonylmethoxy-alkyl derivatives of pyrimidine and purine bases and to antivirally active therapeutic compositions containing the same.
S Some substituted N-alkyl derivatives of hetero-cyGlic bases exhibit important biological effects. Among them are e.g. theophylline derivatives like Diprophyllin and Proxyphyllin (registered trademarks) which have a broncho-dilatory effect. Further examples are guanine derivatives such as e.g. 9-(2-hydroxyethoxymethyl)guanine (Acyclovir), 9-(1,3-dihydroxy -2-propoxymethyl)guanine (DHPG), and 9-(4-hydroxybutyl)guanine (HBG), as well as adenine derivatives such as e.g. 9-(S)-(2,3-dihydroxypropyl)adenine (DHPA), 3-(adenin-9-yl)-2-hydroxypropanoic acid (AHPA) and esters thereof, all of which have an antiviral effect. A review of antiviral adenine and guanine derivatives is given in M.J. Harnden (Ed), Approaches to Antiviral Agents:
Macmillan, London 1985, pp. 101-134. Significant biological effects have also been found for erythro-9-(2-hydroxynonyl) adenine (EHNA), 1-(2-hydroxyethoxymethyl)-5-benzyluracil and 1-(1,3-dihydroxy-2-propoxymethyl)-5-benzyluracil which are specific inhibitors of catabolic enzymes and which may therefore have a potential application in the chemotherapy of metabolic or malignant diseases.
Most of these compounds can be regarded as acyclic analogues of nucleo~ides in which the nucleoside - 2 - ~ 3 4-U'8.5 ~
sugar moiety is replaced by a substituted carbon chain bearing hydroxy groups. In the living organism, such nucleoside analogues are usually converted to phosphate eaters (nucleotide analogues) which may then act as active S antimetabolites.
Attempts to use the nucleoside analogues in phosphate ester form as therapeutic agents have not been particularly successfull because such esters are readily dephosphorylated in the organism. On the other hand, better results have been shown by a few phosphonylalkyl derivatives of nucleoside analogues. Thus, it is known that 9-(1r,1-phosphonylalkyl)hypoxanthines inhibit purine nucleoside phosphorylase, an important target enzyme in the therapy of metabolic and malignant diseases (C. E. Nakamura et al., Siochem. Pharmacol. _35, 133-136 (1986)). Further, an antiviral effect of 9-(phosphonylalkoxymethyl)purines has been reported (WO 84.04748).
Thi$ group of compounds further Comprises two extraordinari-ly important derivatives, viz. 9-(8)-(2-phosphonylmethoxy-3-hydroxypropyl)adenine (HPMPA) as disclosed in GB-A-2.134.907, and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) as disclosed in EP-A-0 205 826, Hoth these compounds are very potent antiviral agenta~ acting specifically against DNA viruses.
DNA viruses such as e.g. herpes viruses (herpes simplex, herpes zoster, cytomegalo viruses, Epstein-Barx virus). pox viruses and adenoviruses, can inflict serious diseases. Some of these diseases have so far been treated with Acyclovir and DHPG (D. S.
freestone: Antiviral Res. _15, 307-324 (1985)) but the application thereof is limited by a low water-solubility and by side-effects. Further, the effect of Acyclovir and DHPG is dependent on the presence of a specific viral enzyme, thymidine kinase. This means that those strafns or mutants of the above viruses that are devoid of this enzyme are not sensitive to the antivirals mentioned.
The phosphonylalkyl derivatives HPMPA and PMEA are effective even In those cases where the above mentioned drugs fail.
During further investigations, it has now been found that the antiviral effect of N-phosphonylalkyl S derivatives is not limited to adenine-based derivatives like HPMPA and PMEA but that the effect is also present in N-phosphonylmethoxyalkyl derivatives of other pyrimidine and purine bases such as cytosine, uracil, thymidine, guanine, hypoxanthine and the like. The present invention is based 70 upon this finding.
The derivatives in question can be represented by the following general formula I
i5 B-CHZ-CH-OCH2P(0)(OH)z (I~
R
wherein R is a hydrogen atom or a hydroxymethyl group and B
20 is a uracil-1-yl, uracil-3-yl, thymin-1-yl, thymin-3-yl, cytosin-1-yl or cytosin-3-yl residue optionally carrying at least one substituent selected from methyl, methoxy, halo, hydroxy, amino, hydroxylamino, hydrazino, thio and methylthio, a guanin-3-yl, guanin-7-yl, guanin-9-yl, 25 hypoxanthin-3-yl, hypoxanthin-7-yl, hypoxanthin-9-yl, xanthin-3-yl, xanthin-7-yl, xanthin-9-yl, purin-3-yl, purin-7-yl or purin-9-yl residue optionally carrying at least one of said substituents, a residue of adenine carrying at least one of said substituents, or an aza, 30 deaza, deoxy or deamino analogue of any of said residues optionally carrying one or more of said substituents, as well as salts of such N-phosphonylmethoxyalkyl derivatives with alkalimetals, ammonia or amines.
-3a-~~~~856 The derivatives of formula I and their salts arE
new compounds which can be prepared easily from hetero-cyclic bases and their N-(2-hydroxyethyl) or N-(2.3' dihydroxypropyl) derivatives. Most of them exhibit a marked antiviral activity against DNA viruses and can therefore be incorporated in therapeutic compositions far the treatment of virus diseases while others can be converted into active compounds by chemcial transformation. Therefore, the invention relates to the N-phosphonylmethoxyalkyl derivatives and their chemical synthesis, as well ag to therapeutic compositions containing the same.
It should be noted that B in general formula I
can represent a great variety of heterocyclic base residues.
Thus, H may be a residue from natural pyrimidine bases such as e.g. cytosine, uracil, thymidine, or a residue from purine bases such as e.g. adenine, guanine, hypoxanthine, xanthine, purine itself, or the like. The ring system of such - ~ -heterocyclic bases may Carry one or more substituents such as e.g, alkyl, alkoxy, hydroxyl, amino, hydroxylamino, hydrazino, thio, alkylthio and the like, Further, the ring system may be a modified ring system such as an aza, deaza, deoxy or deamino analogue of a pyrimidine or purine base. The heterocyclic bases may be bonded in any position to the remainder of the molecule;
thus, pyrimidine bases may be bonded in 7-position or 3-position while purine bases may be bonded in 3-position, ~-position or 9-~poe.ition, Further, it should be noted that the N-phosphonyl-methoxyalkyl derivatives of unsubstituted adenine (HPMPA and PMEA) are excluded from the definition of general formula I because they have been disclosed earlier.
The antiviral effect of the derivatives of general formula I can be utilized for the therapy of viral diseases, e.g. diseases caused by DNA viruses. An important characteristic of the derivatives of general formula I is their antiviral effect against those DNA viruses which are resistant to AcyClovir or DHPG, e.g. against TK~ mutants of herpes viruses, Contrary to antiviral nucleoside analogues like Acyclovir, DHFG, HBG, DHPA, AHPA and esters of AHPA, the antiviral effect of the derivatives of formula I is not limited to a specific heterocycliC base. This fact indicates a completely different mechanism of action of compounds of general formula I which is supported also by their effect against strains and mutants resistant to other antiviral agents, Just like the already mentioned adenine derivatives (HPMPA, PMLA) the cytosine and guanine derivatives of formula z are highly effective against TK- mutants of herpes virus type 1 and 2 and vaCCinia virus. Moreover, the cytosine compounds of formula I may be more easily accessible than the adenine derivatives (HPMPA, PMEA).
Therapeutic Compositions according to this invention which contain derivatives of general formula I as an active ingredient, may be applied in the form of powders, suspensions, solutions, sprays, emUls~ions, pastes, ofntments, etc., and Can be used for parenteral administration - I~~08~
(intravenous, intradermal, intramuscular, intrathecal, etc,) as well as for oral, rectal, intravaginal or intranasal administration or topical applications. Such compositions can be prepared by mixing or dissolving the salt ar the tree acid of the derivative of general formula I with pharmaceut~,cally acceptable carriers, stabilizers, solvents, wetting agents, additives, etc, used for such purposes. According to the requirements and the administration form, such compositions may contain the derivatives of formula I in different Concentrations, from 0,1% up to 100% by weight, Further, the dose of the active ingredient to be administered may vary between 0.1 mg and 100 mg per kg of body-weight.
Compounds of general formula I, wherein R is a hydrogen atom (i.e. 2-phosphonylmethoxyethyl derivatives of pyrimidine or purine bases) Can be prepared by reacting a compound of general formula II
8-CH2CH20H (II) wherein B has the same meaning as in formula I, with diesters of p-tolueneaulfonyloxymethanephoaphonic acid and subsequent reaction with trimethylhalogenosilanes.
They can also be prepared by reacting an alkali metal salt of the pyrimidine or purine bags with diesters of Z-bromoethoxy-methanephasphonic acid of general formula III
SrCH2CH20GH2P(0)(OC2H5)~ (III) to give an intermediate of general formula IV
H-CH2CH20CHZP(0)(OC2H5)2 (IV) wherein 9 has the same meaning as in formula I, followed 3S by treatment with trimethylhalogenosilanes.
Compounds of general formula I, wherein R is a hydroxymethyl group, i.e. N-(3-hydroxy-2-phosphonylmethoxy-- 6 - 13~.0~5~
propyl) derivatives of pyrimidine and purine bases, contain one a9ymmetric Carbon atom. Both the enantiomeric forms as well as the racemates can be prepared From compounds of general formula V
B-CH2CH(OH)CH20H (V) wherein H has the same meaning as in formula I. The Compounds of formula V are accessible from the corresponding pyrimidine and purine bases by a number of synthetic routes (A. Holy:
Collect. Czechoslov. Chem. Commun. 40, 187 (1975)= ibid 43, 3103 (1978)). They can be converted into compounds of formula I by reacting specifically protected derivatives of Compounds of formula V, which contain a Free 2-hydroxy group, with the above mentioned diesters of p-toluenesulfonyloxymethanephosphonic acid and subsequent cleavage with trimethylhalogenosilanes. A more advantageous method, however, comprises reacting unprotected compounds of formula V with chloromethanephosphonyl dichloride of formula VI
C1CH2P(0)C12 (VI) either in pyridine or to advantage in triethyl phosphate, followed by isomerization of the resulting 2'-0-chloro-methanephosphonyl esters of the compounds of formula V to 3'-0-chloromethanephosphonyl esters of the same compounds by treatment fn a mineral acid or water. The resulting compounds are represented by general formula VII
B-CH2-;H-CH20P(0)(OH)CH2C1 (VII) OH
wherein H has the same meaning as in formula I. Treatment o~
compounds of formula VII with aqueous alkali metal hydroxides affords compounds of formula I (wherein R is a hydroxymethyl group) in practically quantit&tive yields.
!I
- ~.~~~8~6 Further compounds of general formula I can be prepared by chemical transformation of the heterocyclic based thus, e.g, the reaction of uracil derivatives (formula, I, wherein 6 is utacil-1-yi) with bromine or iodine affords compounds of formula I wherein B is 5-halogenouracil-i-y1T
treatment of adenine derivatives (HPMPA, PMEA) with nitrous acid of amyl nitrite leads to compounds of formula I wherein H is a hypoxanthin--9-yl moiety, and a similar deamination of guanine derivatives gives compounds of formula I wherein i~ B is a xanthin-9-yl moiety. Also substitution et the purine base, e.g, with chlorine, in the pre-formed skeleton of compounds of general formula I leads to the corresponding N-phosphonylmethoxyalkyl-8-halogenoputines. On the other hand, compounds of general formula I wherein 8 is a i5 2-methylthioadenin-9-yl group, can be transformed into HPMPA
or PMEA by a desulfuration reaction, e.g, with Raney nickel.
The transformation of the heterocyclic ring can be utilized particularly in such cases where the reaction conditions in the preparation of 20 compounds of formula I from the heterocyclic base do not afford the desired isomer (hypoxanthine, xanthine) or lead to destruction of the heterocyclic base (mafnly due to the use of strong alkalis fn the reaction of the intermediate of formula VII). Halogen-substituted derivatives of the 25 pyrimidfne or purine series can also serve as starting compounds for further transformation of the heterocyclic base.
The derivatives of general formula I ace acids of medium strength. They can be easily purified by 30 chromatography on anion exchange resins (such as Dowex I;
Sephadex A-25; DEAF cellulose etc.), preferably fn volatile organic acids, (e.g. acetic acid or formic acid) or in volatile neutral buffers (e. g, ttiethylammonium hydrogen carbonate). Some of the compounds according to the invention 35 (particularly those with basic heterocyclic moieties) Can be stored as free acids which, however, may be sparingly soluble in water. Higher solubility is achieved by conversion of the free acids into their better soluble * T ra de Ma rk - a - 13~08J~
salts, particularly salts from alkali meta~.s (sodium, lithium and the like), ammonia or amines. This conversion can be effected by neutralisation with the corresponding bases or by ion-exchange. Further, a certain type of salt can be converted to another type of salt by ion-exchange, The compounds of general formula I can be easily characterized by their ultraviolet absorption spectra, by paper chromatography, high performance liquid chromatography (HPLC) or by paper electrophoresis; at the same time, these methods can serve as homogeneity criteria.
The antiviral activity of Compounds of general formula I is determined by measurement of their inhibitory effect on virus-induced cytopathogenicity. To this end, suitable cells such as e,g, primary rabbit kidney cells (PRK-cells) are previously infected with the corresponding virus and then cultivated in a medium Containing various concentrations of the compound$ of general formula T. The compounds are regarded as significantly active if an effect is observed at a cancentration not exceeding 100 ~g/ml of medium without changing markedly the cell morphology in the control (virus-unfnfeGted) culture of the same cells under the same conditions.
A survey of the effect of compounds of foxmula I
on some representative viruses is given in Table I. The preparation of the compounds is described in the Examples and their characteristics are given in Table 2, without limiting in any way either the structure of the compounder or their antiviral effects.
Exam le 1 Determination of the antiviral activity of compounds of general formula I in cell Culture.
Confluent monolayers of PRK-cells cultured in Eagle's minimum essential medium (EMEM) in the wells of a ~5 microtiter tray are inoculated with 100 CCI0g0 of a test virus far one hour (1 CCZDgO represents the amount of _ g _ 13~08~~
virus required for infection of 508 of the cells under the prevailing conditions?. Then, the virus solution i~
removed and the cells are washed with EMEM and cultivated in solutions of EMEM containing various concentrations (wt/vol) of the test compounds. The cytopathogenic eFfect (CPE) of the virus in these ce~.l cultures is evaluated at the time when the same virus has reached a CPE of 1008 in a control culture, i.e. a culture where the cells are Cultivated in EMLM without test compounds, The antiviral effect is obtained from a series of measurements at various concentrations of the test compounds and is expressed as MIC50 (ug/ml), i.e, the minimum concentration of the test compound which reduces the CPE of the virus to 50~. The resulting values with test compounds of general formula I are combined in Table 1, where NA means:
inactive, HSV means: herpes virus, and W means: vaccinia virus. Table 1 has a special Column for values of MCC50, i.e.
the lowest concentration of the te8t compound effecting observable morphological changes in 508 of the cultured cells not infected with the virus.
1 c~n a I 1 3~
1 og .
1 > O a f~ N Q O n 1 h a r~ ~s I
> n O
I ( ( 1 I
~) r N ( 1 1 1 1 ~ I t 1 x >1 ~ O n h O I O n O h n ~
1 ff7 ~ O ct H ~ 1 1 1 Y
Z: p~ N
h- cn i 1 I I
I .-f vp 1 1 1 1 o O O r~ O O h h ~ n o x f~ 1 1 ~
1 > 0 O -i N 1 N
Y ~
1 Z +' 1 1 1 I-m N
f .-.. 1 1 I
N
cn 1 i 1 1 1 ? O O n O O Q N n r~ O O
1 (>7 1 n N h N N 1 N t ~ 1 >~
Z
J
1 ..~ ~ 1 1 1 ~ Q ,'1n C O ~ N p N n .-r 1 > mn n N N 1 I r 0~
N ..a .i 1 z 1 1 I I
-I N 1 I 1 i .-1 > ~ N 4 ~ O ~ ~ N O Q 1 0 1 t 1 ~ I I 1 1 .-. 1 1 1 1 w ( 1 1 1 N I
O
1' .r 1 1 1 1 w p .-rN O n N N O N -~ O
I
C
1 > 1 h h n 1 1 1 H
tn a I x 1 1 I I
~
1 1 , 1 1 O 1 t 1 1 1 Wi ~ N n C ~ n N O N n O
1 c~ I h n 1 ~ 1 .--Z .-1 N
a I 1 i O 1 1 1 ~ N N n O n a N 1 O 1 1 O n ca cn 1 > 1 n N ~ i t 1 O
cn Y
1 = 1 1 t I
..~
~ ~ ~
~ ~ ~ ~, Q 1 1 I
1 1 ( I
~ ~
i 1 d 0 ~ ~ 1 p 1 1 N N N N N N N
1 1 z z z x z r 1 z 1 1 ~ ~ i ~i U ~ ~ = ~
a ~ I 1 1 1 1 - . . -. . . .
1 1 . . . , (n N 1 fn 1 1 (n N fn Ln tY
I r ... ... ,... 1 t 1 r ~1 r~
1 1 ?~ ~ .-~ 1 1 1 t N
1 1 1 ~~ ..
C
1 1 Q1 O Gt11 I WI 1 rl G ~ (n >~O
I 1 rl ~ 1 1 C 1 -rl -r.~tr ~ ~~.1 H
.-v H ~
1 t .-t>>C O c0 .-1C .i .-11 .1 1 >
> 7 O
7 1 41 G -t ~ m ~. >- T O
t 1 ( -1~ ~.d >-O1t b ~ 1 ~ I 1 E 1 Q1 ~C
p~ .-~11 <C N ~ Q1 IDd ~ 01 O
1 ~ O
1 i 1 C O a0 O 1 Q ~ I 1 1 1 L 1 C .1C 1. 4. C C C C m .rl ~r1 'p 1 1 .~ Uir1 'O "O ~.1rl~.rr~1 .~ 1 1 I
l- L i O ~ T ~ C ~ ~ G C N
~ ~ ro ~ 1 C ~N 1 , 1 w Z Z ~ 1 d 0.
'C7 1 N I
1 1 F~ (aN ~ l0 C9 N c~1 Q 1 W 1 ., - 11 -13~085~
Example 2 Preparation of compounds of general formula I (R a H).
A solution of diethyl 2-bromoethoxymethanephos-phonate (2.75 g; 10 mmol) in dimethylformamide (10 ml) is added dropwise at 80oC during 2-3 hours under exclusion of moisture to a stirred solution of the sodium salt of a pyrimidine or purine base (prepared from 10 mmol of the base and 0.24 g (10 mmol) of sodium hydride in 80 ml of dimethylformamide). After stirring at 80oC for 3-5 hours, the solvent is evaporated at 13 Pa and the residue is extracted with boiling chloroform (400-500 ml). The extract is Concentrated in vacuo and subjected to chromatography on a column of silica gel (200 ml), using gradient elution with ethanol-chloroform. This affords a chromatographically homogeneous compound of formula IV which can be crystallised from a mixture of ethyl acetate (or ethanol) and light petroleum. The product is treated with trimethylbromosilane (2.4 ml) fn aGetonitrile (40 ml) for 16 hours at room temperature. The solvent is evaporated at 2 kPa, the residue fs dissolved in 10% triethylamine solution in 50% (vol/vol) aqueous acetonitrile and after 30 minutes the ~olvent is again evaporated at 2 kPa. The residue is subjected to chromatography on a column of 8ephadex A-25 (HC03; 150 ml) wing a linear gradient (2 litres total) of 0.02~O.a mol/liter of triethylammonium hydrogen carbonate, pH 7.5, as an elution agent. The main UV-absorbing fraction containing the desired compound is concentrated and the buffer therein is removed by repeated co-distillation with methanol (all evaporations are effected at 2 kPa). The residue is dissolved into water (20 ml) and applied onto a column of Dowex 50 X 8 (Na+; 50 ml) and eluted with water. The UV-absorbing eluate is concentrated and the product therein is precipitated from methanol with ether, The resulting sodium salt of compound I (R = H) is isolated in 80-90% yield (from compound V), Compounds of general formula I prepared in this .;!:
1~~0~~~
,Z -way are listed in table 2.
Example 3 Preparation of compounds of general formula I (R ~ H).
A pyrimfdine or purine base (10 mmol) is converted to its sodium salt and reacted with diethyl 2-bromoethoxymethanephosphonate in the same way as in Example 2. The solvent is evaporated at 13 Pa. Instead of using an extraction with chloroform, the intermediate of formula IV is heated with 1 mol/liter sodium hydroxide (50 ml) at 80oC for 8 hours. After neutralization with a ration exchange resin (H+-form), the mixture is made alkaline with triethylamine, filtered and concentrated at 2 kPa whereupon the residue is dried at ,3 Pa over phosphorus pentoxide. Thereafter, the product is reacted with trimethylbromosilane and worked up in the same way as in Example 2.
Compounds of general formula I, prepared in this way, are listed in Table 2.
Example 4 Preparation of compounds of general formula I (R = CH20H).
Chloromethanephosphonyl dichloride (0.40 ml) is added to a stirred mixture of the N-(2,3-dihydroxypropyl) derivative V and triethylphosphate (10 ml). After stirring for 16 hours in a stoppered flask, ether (80 ml) is added thereto and the resulting precipitate is filtered, washed with ether and dried at 13 Pa. A solution of this material in water (20m1) is refluxed for 8 hours, neutralized with >rriethylamine and concentrated at 2 kPa. The residue ig dissolved in water (1.5 ml) and 0.3 ml portions of this solution ate applied onto a column (8 x 500 mm) of octadecyl-silica gel (e. g. separon*
SIX C18, 7 u), equilibrated with 0.05 mol/liter ttiethylammonium hydrogen carbonate, pH 7.5. The column is wnshed with the same buffer until the salts are removed and then with a step-wise gradient of methanol in the same buffer (usually up to 10 vol%), elution rate 2 ml/min. The combined eluates, containing compound VII are stripped of solvent at 2 kPa and heated with 2 mol/liter sodium hydroxide (10 ml) to * Trade Mark ~3~08~6 80oC. The mixture is neutralized with a cation exchanger (in H+-form), filtered and concentrated at 2 kPa. The residue is worked up in the same way as in Example 2 and affords the sodium salt of compound I (R ~ CH20H) in 50-60 8 yield (from compound V).
Compounds of general formula I prepared in this way are listed in Table 2, Exam~le_5 Preparation of compounds of general formula I (R ~ CH20H).
The reaction is carried out as described in Example 4, After refluxing the reaction intermediate in aqueous solution, the content o~ compound VII is determined by HPLC (usually more than 80~ of the isomer mixture). The mixture is neutralized with sodium hydroxide and concentrated at 2 kPa and the residue is heated to 80oC with 2 mol/liter sodium hydroxide (20 ml) .~vr 10 hours. The solution is neutralized with a cation,exchange resin (H*-~orm)~made alkaline with triethylamine, filtered and evaporated at 2 kPa. The crude product is purified by chromatography on Sephadex A-Z5 as described in Example 2, affording a product which contains more than 808 of the sodium salt o~ compound I
(R ~ CH20H).
Example 6 To a solution of the sodium salt of 9-(2-phosphonylmethaxy-ethyl)adenine (4 mmol) in 80~ acetic acid (50 ml) is added 3-methylbutyl nitrite (4 ml). After standing in a stoppered flask ~or 72 hours at room temperature, the solvent is evaporated at 2 kPa and the residue ig repeatedly co--distilled with water to remove traces of acetic acid. The residue is dissolved into water (10 ml), applied onto a column (200 ml) of a Cation-exchange resin (e.g. Dowex SO X 8) (H+-form) and eluted with water until. a drop in UV absorption occurs. The eluate is evaporated at 2 kPa, the residue is codigtilled with ethanol, crystallized from ethanol-ether - - 13~.08~~
- 1a -(10 ml : 50 ml), filtered, washed with ether and'dried at 13 Pa. Yield : 0.93 g (90%) of 9-(2-phosphonylmethoxyethyl)hypo-xanthine (free acid), not melting up to 260oC.
Example 7 Bromine (0.5 ml) fa added to a stirred solution of the sodium salt of 9-(S)-(3-hydroxy-2-phosphonylmethoxy-propyl)adenine (2 mmol) in 1 mol/liter sodium acetate, pH
N-Phosphonylmethoxyalkyl pyrimidines and purines and therapeutic application thereof This invention relates to N-phoaphonylmethoxy-alkyl derivatives of pyrimidine and purine bases and to antivirally active therapeutic compositions containing the same.
S Some substituted N-alkyl derivatives of hetero-cyGlic bases exhibit important biological effects. Among them are e.g. theophylline derivatives like Diprophyllin and Proxyphyllin (registered trademarks) which have a broncho-dilatory effect. Further examples are guanine derivatives such as e.g. 9-(2-hydroxyethoxymethyl)guanine (Acyclovir), 9-(1,3-dihydroxy -2-propoxymethyl)guanine (DHPG), and 9-(4-hydroxybutyl)guanine (HBG), as well as adenine derivatives such as e.g. 9-(S)-(2,3-dihydroxypropyl)adenine (DHPA), 3-(adenin-9-yl)-2-hydroxypropanoic acid (AHPA) and esters thereof, all of which have an antiviral effect. A review of antiviral adenine and guanine derivatives is given in M.J. Harnden (Ed), Approaches to Antiviral Agents:
Macmillan, London 1985, pp. 101-134. Significant biological effects have also been found for erythro-9-(2-hydroxynonyl) adenine (EHNA), 1-(2-hydroxyethoxymethyl)-5-benzyluracil and 1-(1,3-dihydroxy-2-propoxymethyl)-5-benzyluracil which are specific inhibitors of catabolic enzymes and which may therefore have a potential application in the chemotherapy of metabolic or malignant diseases.
Most of these compounds can be regarded as acyclic analogues of nucleo~ides in which the nucleoside - 2 - ~ 3 4-U'8.5 ~
sugar moiety is replaced by a substituted carbon chain bearing hydroxy groups. In the living organism, such nucleoside analogues are usually converted to phosphate eaters (nucleotide analogues) which may then act as active S antimetabolites.
Attempts to use the nucleoside analogues in phosphate ester form as therapeutic agents have not been particularly successfull because such esters are readily dephosphorylated in the organism. On the other hand, better results have been shown by a few phosphonylalkyl derivatives of nucleoside analogues. Thus, it is known that 9-(1r,1-phosphonylalkyl)hypoxanthines inhibit purine nucleoside phosphorylase, an important target enzyme in the therapy of metabolic and malignant diseases (C. E. Nakamura et al., Siochem. Pharmacol. _35, 133-136 (1986)). Further, an antiviral effect of 9-(phosphonylalkoxymethyl)purines has been reported (WO 84.04748).
Thi$ group of compounds further Comprises two extraordinari-ly important derivatives, viz. 9-(8)-(2-phosphonylmethoxy-3-hydroxypropyl)adenine (HPMPA) as disclosed in GB-A-2.134.907, and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) as disclosed in EP-A-0 205 826, Hoth these compounds are very potent antiviral agenta~ acting specifically against DNA viruses.
DNA viruses such as e.g. herpes viruses (herpes simplex, herpes zoster, cytomegalo viruses, Epstein-Barx virus). pox viruses and adenoviruses, can inflict serious diseases. Some of these diseases have so far been treated with Acyclovir and DHPG (D. S.
freestone: Antiviral Res. _15, 307-324 (1985)) but the application thereof is limited by a low water-solubility and by side-effects. Further, the effect of Acyclovir and DHPG is dependent on the presence of a specific viral enzyme, thymidine kinase. This means that those strafns or mutants of the above viruses that are devoid of this enzyme are not sensitive to the antivirals mentioned.
The phosphonylalkyl derivatives HPMPA and PMEA are effective even In those cases where the above mentioned drugs fail.
During further investigations, it has now been found that the antiviral effect of N-phosphonylalkyl S derivatives is not limited to adenine-based derivatives like HPMPA and PMEA but that the effect is also present in N-phosphonylmethoxyalkyl derivatives of other pyrimidine and purine bases such as cytosine, uracil, thymidine, guanine, hypoxanthine and the like. The present invention is based 70 upon this finding.
The derivatives in question can be represented by the following general formula I
i5 B-CHZ-CH-OCH2P(0)(OH)z (I~
R
wherein R is a hydrogen atom or a hydroxymethyl group and B
20 is a uracil-1-yl, uracil-3-yl, thymin-1-yl, thymin-3-yl, cytosin-1-yl or cytosin-3-yl residue optionally carrying at least one substituent selected from methyl, methoxy, halo, hydroxy, amino, hydroxylamino, hydrazino, thio and methylthio, a guanin-3-yl, guanin-7-yl, guanin-9-yl, 25 hypoxanthin-3-yl, hypoxanthin-7-yl, hypoxanthin-9-yl, xanthin-3-yl, xanthin-7-yl, xanthin-9-yl, purin-3-yl, purin-7-yl or purin-9-yl residue optionally carrying at least one of said substituents, a residue of adenine carrying at least one of said substituents, or an aza, 30 deaza, deoxy or deamino analogue of any of said residues optionally carrying one or more of said substituents, as well as salts of such N-phosphonylmethoxyalkyl derivatives with alkalimetals, ammonia or amines.
-3a-~~~~856 The derivatives of formula I and their salts arE
new compounds which can be prepared easily from hetero-cyclic bases and their N-(2-hydroxyethyl) or N-(2.3' dihydroxypropyl) derivatives. Most of them exhibit a marked antiviral activity against DNA viruses and can therefore be incorporated in therapeutic compositions far the treatment of virus diseases while others can be converted into active compounds by chemcial transformation. Therefore, the invention relates to the N-phosphonylmethoxyalkyl derivatives and their chemical synthesis, as well ag to therapeutic compositions containing the same.
It should be noted that B in general formula I
can represent a great variety of heterocyclic base residues.
Thus, H may be a residue from natural pyrimidine bases such as e.g. cytosine, uracil, thymidine, or a residue from purine bases such as e.g. adenine, guanine, hypoxanthine, xanthine, purine itself, or the like. The ring system of such - ~ -heterocyclic bases may Carry one or more substituents such as e.g, alkyl, alkoxy, hydroxyl, amino, hydroxylamino, hydrazino, thio, alkylthio and the like, Further, the ring system may be a modified ring system such as an aza, deaza, deoxy or deamino analogue of a pyrimidine or purine base. The heterocyclic bases may be bonded in any position to the remainder of the molecule;
thus, pyrimidine bases may be bonded in 7-position or 3-position while purine bases may be bonded in 3-position, ~-position or 9-~poe.ition, Further, it should be noted that the N-phosphonyl-methoxyalkyl derivatives of unsubstituted adenine (HPMPA and PMEA) are excluded from the definition of general formula I because they have been disclosed earlier.
The antiviral effect of the derivatives of general formula I can be utilized for the therapy of viral diseases, e.g. diseases caused by DNA viruses. An important characteristic of the derivatives of general formula I is their antiviral effect against those DNA viruses which are resistant to AcyClovir or DHPG, e.g. against TK~ mutants of herpes viruses, Contrary to antiviral nucleoside analogues like Acyclovir, DHFG, HBG, DHPA, AHPA and esters of AHPA, the antiviral effect of the derivatives of formula I is not limited to a specific heterocycliC base. This fact indicates a completely different mechanism of action of compounds of general formula I which is supported also by their effect against strains and mutants resistant to other antiviral agents, Just like the already mentioned adenine derivatives (HPMPA, PMLA) the cytosine and guanine derivatives of formula z are highly effective against TK- mutants of herpes virus type 1 and 2 and vaCCinia virus. Moreover, the cytosine compounds of formula I may be more easily accessible than the adenine derivatives (HPMPA, PMEA).
Therapeutic Compositions according to this invention which contain derivatives of general formula I as an active ingredient, may be applied in the form of powders, suspensions, solutions, sprays, emUls~ions, pastes, ofntments, etc., and Can be used for parenteral administration - I~~08~
(intravenous, intradermal, intramuscular, intrathecal, etc,) as well as for oral, rectal, intravaginal or intranasal administration or topical applications. Such compositions can be prepared by mixing or dissolving the salt ar the tree acid of the derivative of general formula I with pharmaceut~,cally acceptable carriers, stabilizers, solvents, wetting agents, additives, etc, used for such purposes. According to the requirements and the administration form, such compositions may contain the derivatives of formula I in different Concentrations, from 0,1% up to 100% by weight, Further, the dose of the active ingredient to be administered may vary between 0.1 mg and 100 mg per kg of body-weight.
Compounds of general formula I, wherein R is a hydrogen atom (i.e. 2-phosphonylmethoxyethyl derivatives of pyrimidine or purine bases) Can be prepared by reacting a compound of general formula II
8-CH2CH20H (II) wherein B has the same meaning as in formula I, with diesters of p-tolueneaulfonyloxymethanephoaphonic acid and subsequent reaction with trimethylhalogenosilanes.
They can also be prepared by reacting an alkali metal salt of the pyrimidine or purine bags with diesters of Z-bromoethoxy-methanephasphonic acid of general formula III
SrCH2CH20GH2P(0)(OC2H5)~ (III) to give an intermediate of general formula IV
H-CH2CH20CHZP(0)(OC2H5)2 (IV) wherein 9 has the same meaning as in formula I, followed 3S by treatment with trimethylhalogenosilanes.
Compounds of general formula I, wherein R is a hydroxymethyl group, i.e. N-(3-hydroxy-2-phosphonylmethoxy-- 6 - 13~.0~5~
propyl) derivatives of pyrimidine and purine bases, contain one a9ymmetric Carbon atom. Both the enantiomeric forms as well as the racemates can be prepared From compounds of general formula V
B-CH2CH(OH)CH20H (V) wherein H has the same meaning as in formula I. The Compounds of formula V are accessible from the corresponding pyrimidine and purine bases by a number of synthetic routes (A. Holy:
Collect. Czechoslov. Chem. Commun. 40, 187 (1975)= ibid 43, 3103 (1978)). They can be converted into compounds of formula I by reacting specifically protected derivatives of Compounds of formula V, which contain a Free 2-hydroxy group, with the above mentioned diesters of p-toluenesulfonyloxymethanephosphonic acid and subsequent cleavage with trimethylhalogenosilanes. A more advantageous method, however, comprises reacting unprotected compounds of formula V with chloromethanephosphonyl dichloride of formula VI
C1CH2P(0)C12 (VI) either in pyridine or to advantage in triethyl phosphate, followed by isomerization of the resulting 2'-0-chloro-methanephosphonyl esters of the compounds of formula V to 3'-0-chloromethanephosphonyl esters of the same compounds by treatment fn a mineral acid or water. The resulting compounds are represented by general formula VII
B-CH2-;H-CH20P(0)(OH)CH2C1 (VII) OH
wherein H has the same meaning as in formula I. Treatment o~
compounds of formula VII with aqueous alkali metal hydroxides affords compounds of formula I (wherein R is a hydroxymethyl group) in practically quantit&tive yields.
!I
- ~.~~~8~6 Further compounds of general formula I can be prepared by chemical transformation of the heterocyclic based thus, e.g, the reaction of uracil derivatives (formula, I, wherein 6 is utacil-1-yi) with bromine or iodine affords compounds of formula I wherein B is 5-halogenouracil-i-y1T
treatment of adenine derivatives (HPMPA, PMEA) with nitrous acid of amyl nitrite leads to compounds of formula I wherein H is a hypoxanthin--9-yl moiety, and a similar deamination of guanine derivatives gives compounds of formula I wherein i~ B is a xanthin-9-yl moiety. Also substitution et the purine base, e.g, with chlorine, in the pre-formed skeleton of compounds of general formula I leads to the corresponding N-phosphonylmethoxyalkyl-8-halogenoputines. On the other hand, compounds of general formula I wherein 8 is a i5 2-methylthioadenin-9-yl group, can be transformed into HPMPA
or PMEA by a desulfuration reaction, e.g, with Raney nickel.
The transformation of the heterocyclic ring can be utilized particularly in such cases where the reaction conditions in the preparation of 20 compounds of formula I from the heterocyclic base do not afford the desired isomer (hypoxanthine, xanthine) or lead to destruction of the heterocyclic base (mafnly due to the use of strong alkalis fn the reaction of the intermediate of formula VII). Halogen-substituted derivatives of the 25 pyrimidfne or purine series can also serve as starting compounds for further transformation of the heterocyclic base.
The derivatives of general formula I ace acids of medium strength. They can be easily purified by 30 chromatography on anion exchange resins (such as Dowex I;
Sephadex A-25; DEAF cellulose etc.), preferably fn volatile organic acids, (e.g. acetic acid or formic acid) or in volatile neutral buffers (e. g, ttiethylammonium hydrogen carbonate). Some of the compounds according to the invention 35 (particularly those with basic heterocyclic moieties) Can be stored as free acids which, however, may be sparingly soluble in water. Higher solubility is achieved by conversion of the free acids into their better soluble * T ra de Ma rk - a - 13~08J~
salts, particularly salts from alkali meta~.s (sodium, lithium and the like), ammonia or amines. This conversion can be effected by neutralisation with the corresponding bases or by ion-exchange. Further, a certain type of salt can be converted to another type of salt by ion-exchange, The compounds of general formula I can be easily characterized by their ultraviolet absorption spectra, by paper chromatography, high performance liquid chromatography (HPLC) or by paper electrophoresis; at the same time, these methods can serve as homogeneity criteria.
The antiviral activity of Compounds of general formula I is determined by measurement of their inhibitory effect on virus-induced cytopathogenicity. To this end, suitable cells such as e,g, primary rabbit kidney cells (PRK-cells) are previously infected with the corresponding virus and then cultivated in a medium Containing various concentrations of the compound$ of general formula T. The compounds are regarded as significantly active if an effect is observed at a cancentration not exceeding 100 ~g/ml of medium without changing markedly the cell morphology in the control (virus-unfnfeGted) culture of the same cells under the same conditions.
A survey of the effect of compounds of foxmula I
on some representative viruses is given in Table I. The preparation of the compounds is described in the Examples and their characteristics are given in Table 2, without limiting in any way either the structure of the compounder or their antiviral effects.
Exam le 1 Determination of the antiviral activity of compounds of general formula I in cell Culture.
Confluent monolayers of PRK-cells cultured in Eagle's minimum essential medium (EMEM) in the wells of a ~5 microtiter tray are inoculated with 100 CCI0g0 of a test virus far one hour (1 CCZDgO represents the amount of _ g _ 13~08~~
virus required for infection of 508 of the cells under the prevailing conditions?. Then, the virus solution i~
removed and the cells are washed with EMEM and cultivated in solutions of EMEM containing various concentrations (wt/vol) of the test compounds. The cytopathogenic eFfect (CPE) of the virus in these ce~.l cultures is evaluated at the time when the same virus has reached a CPE of 1008 in a control culture, i.e. a culture where the cells are Cultivated in EMLM without test compounds, The antiviral effect is obtained from a series of measurements at various concentrations of the test compounds and is expressed as MIC50 (ug/ml), i.e, the minimum concentration of the test compound which reduces the CPE of the virus to 50~. The resulting values with test compounds of general formula I are combined in Table 1, where NA means:
inactive, HSV means: herpes virus, and W means: vaccinia virus. Table 1 has a special Column for values of MCC50, i.e.
the lowest concentration of the te8t compound effecting observable morphological changes in 508 of the cultured cells not infected with the virus.
1 c~n a I 1 3~
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1 > O a f~ N Q O n 1 h a r~ ~s I
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h- cn i 1 I I
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Example 2 Preparation of compounds of general formula I (R a H).
A solution of diethyl 2-bromoethoxymethanephos-phonate (2.75 g; 10 mmol) in dimethylformamide (10 ml) is added dropwise at 80oC during 2-3 hours under exclusion of moisture to a stirred solution of the sodium salt of a pyrimidine or purine base (prepared from 10 mmol of the base and 0.24 g (10 mmol) of sodium hydride in 80 ml of dimethylformamide). After stirring at 80oC for 3-5 hours, the solvent is evaporated at 13 Pa and the residue is extracted with boiling chloroform (400-500 ml). The extract is Concentrated in vacuo and subjected to chromatography on a column of silica gel (200 ml), using gradient elution with ethanol-chloroform. This affords a chromatographically homogeneous compound of formula IV which can be crystallised from a mixture of ethyl acetate (or ethanol) and light petroleum. The product is treated with trimethylbromosilane (2.4 ml) fn aGetonitrile (40 ml) for 16 hours at room temperature. The solvent is evaporated at 2 kPa, the residue fs dissolved in 10% triethylamine solution in 50% (vol/vol) aqueous acetonitrile and after 30 minutes the ~olvent is again evaporated at 2 kPa. The residue is subjected to chromatography on a column of 8ephadex A-25 (HC03; 150 ml) wing a linear gradient (2 litres total) of 0.02~O.a mol/liter of triethylammonium hydrogen carbonate, pH 7.5, as an elution agent. The main UV-absorbing fraction containing the desired compound is concentrated and the buffer therein is removed by repeated co-distillation with methanol (all evaporations are effected at 2 kPa). The residue is dissolved into water (20 ml) and applied onto a column of Dowex 50 X 8 (Na+; 50 ml) and eluted with water. The UV-absorbing eluate is concentrated and the product therein is precipitated from methanol with ether, The resulting sodium salt of compound I (R = H) is isolated in 80-90% yield (from compound V), Compounds of general formula I prepared in this .;!:
1~~0~~~
,Z -way are listed in table 2.
Example 3 Preparation of compounds of general formula I (R ~ H).
A pyrimfdine or purine base (10 mmol) is converted to its sodium salt and reacted with diethyl 2-bromoethoxymethanephosphonate in the same way as in Example 2. The solvent is evaporated at 13 Pa. Instead of using an extraction with chloroform, the intermediate of formula IV is heated with 1 mol/liter sodium hydroxide (50 ml) at 80oC for 8 hours. After neutralization with a ration exchange resin (H+-form), the mixture is made alkaline with triethylamine, filtered and concentrated at 2 kPa whereupon the residue is dried at ,3 Pa over phosphorus pentoxide. Thereafter, the product is reacted with trimethylbromosilane and worked up in the same way as in Example 2.
Compounds of general formula I, prepared in this way, are listed in Table 2.
Example 4 Preparation of compounds of general formula I (R = CH20H).
Chloromethanephosphonyl dichloride (0.40 ml) is added to a stirred mixture of the N-(2,3-dihydroxypropyl) derivative V and triethylphosphate (10 ml). After stirring for 16 hours in a stoppered flask, ether (80 ml) is added thereto and the resulting precipitate is filtered, washed with ether and dried at 13 Pa. A solution of this material in water (20m1) is refluxed for 8 hours, neutralized with >rriethylamine and concentrated at 2 kPa. The residue ig dissolved in water (1.5 ml) and 0.3 ml portions of this solution ate applied onto a column (8 x 500 mm) of octadecyl-silica gel (e. g. separon*
SIX C18, 7 u), equilibrated with 0.05 mol/liter ttiethylammonium hydrogen carbonate, pH 7.5. The column is wnshed with the same buffer until the salts are removed and then with a step-wise gradient of methanol in the same buffer (usually up to 10 vol%), elution rate 2 ml/min. The combined eluates, containing compound VII are stripped of solvent at 2 kPa and heated with 2 mol/liter sodium hydroxide (10 ml) to * Trade Mark ~3~08~6 80oC. The mixture is neutralized with a cation exchanger (in H+-form), filtered and concentrated at 2 kPa. The residue is worked up in the same way as in Example 2 and affords the sodium salt of compound I (R ~ CH20H) in 50-60 8 yield (from compound V).
Compounds of general formula I prepared in this way are listed in Table 2, Exam~le_5 Preparation of compounds of general formula I (R ~ CH20H).
The reaction is carried out as described in Example 4, After refluxing the reaction intermediate in aqueous solution, the content o~ compound VII is determined by HPLC (usually more than 80~ of the isomer mixture). The mixture is neutralized with sodium hydroxide and concentrated at 2 kPa and the residue is heated to 80oC with 2 mol/liter sodium hydroxide (20 ml) .~vr 10 hours. The solution is neutralized with a cation,exchange resin (H*-~orm)~made alkaline with triethylamine, filtered and evaporated at 2 kPa. The crude product is purified by chromatography on Sephadex A-Z5 as described in Example 2, affording a product which contains more than 808 of the sodium salt o~ compound I
(R ~ CH20H).
Example 6 To a solution of the sodium salt of 9-(2-phosphonylmethaxy-ethyl)adenine (4 mmol) in 80~ acetic acid (50 ml) is added 3-methylbutyl nitrite (4 ml). After standing in a stoppered flask ~or 72 hours at room temperature, the solvent is evaporated at 2 kPa and the residue ig repeatedly co--distilled with water to remove traces of acetic acid. The residue is dissolved into water (10 ml), applied onto a column (200 ml) of a Cation-exchange resin (e.g. Dowex SO X 8) (H+-form) and eluted with water until. a drop in UV absorption occurs. The eluate is evaporated at 2 kPa, the residue is codigtilled with ethanol, crystallized from ethanol-ether - - 13~.08~~
- 1a -(10 ml : 50 ml), filtered, washed with ether and'dried at 13 Pa. Yield : 0.93 g (90%) of 9-(2-phosphonylmethoxyethyl)hypo-xanthine (free acid), not melting up to 260oC.
Example 7 Bromine (0.5 ml) fa added to a stirred solution of the sodium salt of 9-(S)-(3-hydroxy-2-phosphonylmethoxy-propyl)adenine (2 mmol) in 1 mol/liter sodium acetate, pH
4.0 (40 ml). After stirring at room temperature for two days, the mixture is decolorized with a saturated solution of sodium hydrogen sulfite and the whole solution is applied onto a column of a ration exchange resin (e.g. Dowex 50 X 8) (Hf-form; 150 ml). After washing the column with water until a drop in conductivity and UV-absorption is reached, the product is eluted with 2% (voI) aqueous ammonia. The ammonia~containing UV-absorbing eluate is concentrated at 2 kPa and the residue is taken up in water and filtered thtvugh a column o~ octadecyl-silica gel (80 ml). The UV-absorbing eluate is again concentrated at 2 kPa, dissolved into water, (5 ml) and applied onto a column of Dowex 50 X 8 (Na+-form;
50 ml). The column is washed with water, the UV-absorbing eluate is concentrated at 2 kPa, the residue is co-distilled with ethanol, mixed with ethanol (10 ml) and ether (100 ml) and collected on a filter. Xield: 55~ of sodium salt of 9-(Sj~(3-hydroxy-2-phosphonylmethoxypropyl)-8-bromoadenine which (according to HPLC analysis) contains less than 0.5%
of the starting compound.
Example B
The sodium salt of 9-(RS)-(3-hydroxy-2-phos-phonylmethoxypropyl)-2-methylthioadenine (2.0 gj is added to moist Raney nickel (7 g) in 0.2 mol/liter sodium hydroxide (25 ml). After stirring tinder reflux for 72 hours, the hot mixture is filtered through Celite which is then washed with boiling water (100 ml) and the filtrate is neutralized with a ration-exchanger (H+-form). According to HPLC analysis, the product contains 75-808 of the reaction product. After * Trade Mark concentration, the residue ie dissolved in water (10 ml) and applied onto a column of octadecyl-sil ks gel (20 u, 1B0 ml) in 0.05 mol/liter triethylammonium hydrogen carbonate, pH
7.5. The product is eluted with the same buffer, elution rate 1 ml/min, Fractions 20 ml, monitored by BPLC (see Table 2). The product~containing fractions are combined, and concentrated at 2 kPa and the product is converted to the sodium salt of (RS)-HPMPA as described in Example 2s yield:
Several compounds of general formula I as prepared with the method of one of the Examples are listed in Table 2. The 6th column gives RF values obtained by paper chromatography in 2-propanol -concentrated aqueous ammonia - water (7:1:2). The 7th column gives values for the HPLC elution constant on a Z00 x 4 mm RPS C18 (5u) column in 0.05 mol/liter triethylammonium hydrogen carbonate, pH 7.5, containing 5 vol$ of methanol. The Constant is defined as k ~ (kR-k0)/k0, where kR is the retention time of the compound in minutes and k0 is the hold-up time of the~column in minutes. The last column of Table 2 gives values of the electraphvretical mobility (50 V/cm) in 0.05 mol/1 triethylammonium hydrogen carbonate, pH 7.5, on a paper Whatmari No. 3MM, related to uridine 3'-phosphate. In the column of HPLC
elution constants, some values have been marked for denoting different methanol contents: in the values marked With (e), (f) and (g), the eluent contained 0 voI%, 15 vol% and 7.5 vol$ of methanol respectively.
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w w , , w w w w w , .. w w w v o Q o 0 0 0 0 0 0 0 0 0 0 0 0 o a o 0 In u7 tn N ~ 4 m ~ O In u7 C7 n N n O v N
cD ~D n r~ a~ n n n n ~ aD ct ~D w ~t ~ :a ~c n ao v v In d ~ v v v c n ~ ~ u~ ~n a ~r ID
in fA N tn U7 U7 cn U7 N (n Cfi U7 In tn N
fn ~ ~ ~ t!7 ~ ~ ~ fn Q; ~ U'1 tY IY
x x i z z s r r = x r r r s x br o ~ 0 0 0 ~ ~ 0 0 0 0 0 N N~ NO N N N N N N N N N N N N N N
z x a~ x = x r x r x r x r r r x s x x U U U U U U U U U U U U U U U U U U U
?--1 I Q) p . Q1 I rl C ~
r1 1 ?~C .-.dJi r1( r-1! .-11. QI
c ,-I,.,1 rl ~'-> C ? Q~C O l ?~
a~~ 1 1 ~..,~1 1 a~ a c N ( ?. 1 ~ 0101 I C Q7 C ~ O rr1 1 C 'D I 1 (JlC!I 'If0 C L
C (~Ql ..at9 C G I 'OG C c0 r1 ~
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U r-1.~ ..1~ G p7~ C C fp C ~ c0 c0 O
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01v 'O 'Li? ? 1 1 1 1 N 1 I 1 1 t r~
f--v 'L ~ r Z N N N N O Cp C!J1'~tD ~DlD C
Q C1 .G
C ~
E c r1 ~
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~ X
cD
N
Z
50 ml). The column is washed with water, the UV-absorbing eluate is concentrated at 2 kPa, the residue is co-distilled with ethanol, mixed with ethanol (10 ml) and ether (100 ml) and collected on a filter. Xield: 55~ of sodium salt of 9-(Sj~(3-hydroxy-2-phosphonylmethoxypropyl)-8-bromoadenine which (according to HPLC analysis) contains less than 0.5%
of the starting compound.
Example B
The sodium salt of 9-(RS)-(3-hydroxy-2-phos-phonylmethoxypropyl)-2-methylthioadenine (2.0 gj is added to moist Raney nickel (7 g) in 0.2 mol/liter sodium hydroxide (25 ml). After stirring tinder reflux for 72 hours, the hot mixture is filtered through Celite which is then washed with boiling water (100 ml) and the filtrate is neutralized with a ration-exchanger (H+-form). According to HPLC analysis, the product contains 75-808 of the reaction product. After * Trade Mark concentration, the residue ie dissolved in water (10 ml) and applied onto a column of octadecyl-sil ks gel (20 u, 1B0 ml) in 0.05 mol/liter triethylammonium hydrogen carbonate, pH
7.5. The product is eluted with the same buffer, elution rate 1 ml/min, Fractions 20 ml, monitored by BPLC (see Table 2). The product~containing fractions are combined, and concentrated at 2 kPa and the product is converted to the sodium salt of (RS)-HPMPA as described in Example 2s yield:
Several compounds of general formula I as prepared with the method of one of the Examples are listed in Table 2. The 6th column gives RF values obtained by paper chromatography in 2-propanol -concentrated aqueous ammonia - water (7:1:2). The 7th column gives values for the HPLC elution constant on a Z00 x 4 mm RPS C18 (5u) column in 0.05 mol/liter triethylammonium hydrogen carbonate, pH 7.5, containing 5 vol$ of methanol. The Constant is defined as k ~ (kR-k0)/k0, where kR is the retention time of the compound in minutes and k0 is the hold-up time of the~column in minutes. The last column of Table 2 gives values of the electraphvretical mobility (50 V/cm) in 0.05 mol/1 triethylammonium hydrogen carbonate, pH 7.5, on a paper Whatmari No. 3MM, related to uridine 3'-phosphate. In the column of HPLC
elution constants, some values have been marked for denoting different methanol contents: in the values marked With (e), (f) and (g), the eluent contained 0 voI%, 15 vol% and 7.5 vol$ of methanol respectively.
* Trade Mark ".. ,1 I , , cJ N v r N ;mn ~ ao In ao tn N a~ co co ca c. 1 cn a n n r' n n n n n n r~ ~ ~ n n a~ O n n .
1 u,~ 1 p O O O O O O O O O O O ~~ O O O Q ~ O O
r; N ~n t0 cfJ rt N N I~ N t0 ~ a1 N ~~ II7 tA n O
N c~7 WD n u7 et Qt ~~ n N ~ n N c~ a0 N
w . . . . w . . . . . . . . v w 1 ~c 1 0 0 0 ~ o o N o N o o M ~ 0 0 0 0 0 0 0 t 1 I I
O n n N ch N of tD n N ~ ~ c"~ ao n. u7 .--~ r'~
1 1 ~ c'? N r'1 ~ :'J :.t O N M N ~ N N N N N
.
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a k I .
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a oU
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x x x z x = z r = r z r ~r N N N N N N N
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.
T
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r1 G .1 t G t0 C ~ C l_ N N .-r ..4 .C G p pl 1 ~ 1 ..~ rr N v.r rr X ~rl rl O -~'1 'O ~ t0 ~rl N r ~t p C o C t. ~- 01 N v O CI 6 .-.1 C C
.L~ 1 1 rt1 ~ '~ F cD Q_ G? ~ m ~ x ~ t~. T ~ L
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1~4~~~~
of u7 tn p O In c~ o N co O O n ~~ ~ ~ o cv n r~ n cz~ ~ cD ~ n ~ n o n ao r r n d O O O O O O C? O ~~ Q O O O O O ~' C ~'' O w V- '~- Q1 C~. 1J1 r7 N N ~ O n n. u7 O ~7 ~D 1l Q V ID
n (~ :f7 n n C7 ~-1 0~ ~ ID ~i ~ ~-t QI
r . . , . . 1 r , N N ...r p O ~ Q C? o d t.0 In ~ O O ~-r 'w~ O
N N N CD QJ n N cr7 O tI7 ('7 t0 GO tl7 ID ~-t ~ i'~ Cfl N N N N N N C7 N Q N ~ N ~ N '~'r '~'~ ~ N
w w , , w w w w w , .. w w w v o Q o 0 0 0 0 0 0 0 0 0 0 0 0 o a o 0 In u7 tn N ~ 4 m ~ O In u7 C7 n N n O v N
cD ~D n r~ a~ n n n n ~ aD ct ~D w ~t ~ :a ~c n ao v v In d ~ v v v c n ~ ~ u~ ~n a ~r ID
in fA N tn U7 U7 cn U7 N (n Cfi U7 In tn N
fn ~ ~ ~ t!7 ~ ~ ~ fn Q; ~ U'1 tY IY
x x i z z s r r = x r r r s x br o ~ 0 0 0 ~ ~ 0 0 0 0 0 N N~ NO N N N N N N N N N N N N N N
z x a~ x = x r x r x r x r r r x s x x U U U U U U U U U U U U U U U U U U U
?--1 I Q) p . Q1 I rl C ~
r1 1 ?~C .-.dJi r1( r-1! .-11. QI
c ,-I,.,1 rl ~'-> C ? Q~C O l ?~
a~~ 1 1 ~..,~1 1 a~ a c N ( ?. 1 ~ 0101 I C Q7 C ~ O rr1 1 C 'D I 1 (JlC!I 'If0 C L
C (~Ql ..at9 C G I 'OG C c0 r1 ~
C O ..~r~ G ~r1Q)N ~' Q-C '7.
U r-1.~ ..1~ G p7~ C C fp C ~ c0 c0 O
? 5. ~...i.~ 't3dC C7~ .1 O W t ~~ C ri -v 1 1 1 1 t S. ~0~ ~ 'O .-1 'O ~'CO '~ rlL 1 ,,,,...1,..1Ip~ L ca x 1 x N 7 ~-N I 1 ' C C ~ ?~ O O 7- O O <9 O IDC1 :l1 C C ~ ItIN t C C G 7 6 L N ~- L O 1 N rl il rl K YC a.'N w1rl t O t~f0 ~ 'O~ CIt w ~ ~ a a ~ ~ ~ a~ a m z ~ i ~ h I
01v 'O 'Li? ? 1 1 1 1 N 1 I 1 1 t r~
f--v 'L ~ r Z N N N N O Cp C!J1'~tD ~DlD C
Q C1 .G
C ~
E c r1 ~
..1 cs ~ ~.
~ X
cD
N
Z
Claims (29)
1. 9-(3-hydroxy-2-phosphono methoxypropyl) guanine.
2. 9-(2-phosphonomethoxy)ethyl) guanine.
3. A pharmaceutical composition for antiviral use comprising an effective antiviral amount of 9-(2-(phosphonomethoxy)ethyl) guanine in admixture with a pharmaceutically acceptable carrier.
4. The use of 9-(2-(phosphonomethoxy)ethyl) guanine as an antiviral agent.
5. 1-(3-hydroxy-2-(phosphonomethoxy) propyl) cytosine.
6. A pharmaceutical composition for antiviral use comprising an effective antiviral amount of 1-(3-hydroxy-2-(phosphonomethoxy) propyl) cytosine in admixture with a pharmaceutically acceptable carrier.
7. The use of 1-(3-hydroxy-2-(phosphonomethoxy) propyl) cytosine as an antiviral agent.
8. N-phosphonylmethoxyalkyl derivatives of pyrimidine and purine bases of the general formula I
wherein R is a hydrogen atom or a hydroxymethyl group, and B is (a) pyrimidin-1-yl, pyrimidin-3-yl, purin-3-yl, purin-7-yl or purin-9-yl, optionally carrying at least one substituent selected from methyl, halo, methoxy, hydroxy, oxo, amino, hydroxylamino, hydrazine, thio and alkylthio, or (b) the aza or deaza ring analogue of the groups defined in (a) above, or B is N6-dimethylamino adenine, with unsubstituted adenin-9-yl being excluded; the phosphodiesters thereof; and the salts thereof with alkali metals, ammonia or amines.
wherein R is a hydrogen atom or a hydroxymethyl group, and B is (a) pyrimidin-1-yl, pyrimidin-3-yl, purin-3-yl, purin-7-yl or purin-9-yl, optionally carrying at least one substituent selected from methyl, halo, methoxy, hydroxy, oxo, amino, hydroxylamino, hydrazine, thio and alkylthio, or (b) the aza or deaza ring analogue of the groups defined in (a) above, or B is N6-dimethylamino adenine, with unsubstituted adenin-9-yl being excluded; the phosphodiesters thereof; and the salts thereof with alkali metals, ammonia or amines.
9. N-phosphonylmethoxyalkyl derivatives of formula I according to claim 8, wherein the residues B are aza or deaza uracil, thymine, cytosine, guanine, adenine, hypoxanthine or xanthine.
10. N-phosphonylmethoxyalkyl derivatives of formula I according to claim 8, wherein the residue B is 6-methylpurin-3-yl, 6-methylpurin-7-yl or 6-methylpurin-9-yl.
11. N-phosphonylmethoxyalkyl derivatives of formula I according to claim 8, wherein the substituent B is substituted with at least one of a methyl, amino, bromo, fluoro, hydroxy or a thio group.
12. N-phosphonylmethoxyalkyl derivatives of formula I according to claim 9, wherein the substituent B is substituted with at least one of a methyl, amino, bromo, fluoro, hydroxy or a thio group.
13. N-phosphonylmethoxyalkyl derivatives of formula I according to claim 10, wherein the substituent B is substituted with at least one of a methyl, amino, bromo, fluoro, hydroxy or a thin group.
14. N-phosphonylmethoxyalkyl derivatives of formula I according to claim 8, wherein B is Uracil-1-yl, Thymin-1-yl, Cytosin-1-yl, 6-Methylpurin-9-yl, Hypoxanthin-9-yl, 2-Aminoadenin-9-yl, 8-Bromoadenin-9-yl, 2-Aminopurin-9-yl, 6-Hydroazinopurin-9-yl, 7-Deaza-8-azaadenin-9-yl, 7-Deaza-8-azahypoxanthin-9-yl, 5-Methylcytosin-1-yl, 5-Fluorouracil-1-yl, Guanin-7-yl, Adenin-3-yl, Hypoxanthin-9-yl, 2-Methyladenin-9-yl, 2-Methylthioadenin-9-yl, N6-Dimethyladenin-9-yl, 8-Hydroxyadenin-9-yl, 6-Hydroxylaminopurin-9-yl, 6-Thiopurin-9-yl, Purin-9-yl, or Xanthin-9-yl.
15. N-phosphonylmethoxyalkyl derivatives of formula I according to any one of claims 8, 9, 10, 11, 12, 13 and 14 representing the following combinations of R and B and having the indicated C2 configuration:
B R
Uracil-1-yl H
Thymin-1-yl H
Cytosin-1-yl H
6-Methylpurin-9-yl H
Hypoxanthin-9-yl H
2-Aminoadenin-9-yl H
8-Bromoadenin-9-yl H
2-Aminopurin-9-yl H
6-Hydrazinopurin-9-yl H
7-Deaza-8-azaadenin-9-yl H
7-Deaza-8-azahypoxanthin-9-yl H
Uracil-1-yl (RS)-CH2OH
Cytosin-1-yl (S)-CH2OH
5-Methylcytosin-1-yl (S)-CH2OH
Thymin-1-yl (S)-CH2OH
5-Fluorouracil-1-yl (RS)-CH2OH
Guanin-7-yl (RS)-CH2OH
Adenin-3-yl (RS)-CH2OH
Hypoxanthin-9-yl (RS)-CH2OH
Hypoxanthin-9-yl (S)-CH2OH
2-Methyladenin-9-yl (RS)-CH2OH
2-Methylthioadenin-9-yl (RS)-CH2OH
2-Aminoadenin-9-yl (RS)-CH2OH
2-Aminoadenin-9-yl (S)-CH2OH
2-Aminopurin-9-yl (RS)-CH2OH
N6-Dimethyladenin-9-yl (RS)-CH2OH
8-Bromoadenin-9-yl (S)-CH2OH
8-Hydroxyadenin-9-yl (RS)-CH2OH
7-Deaza-8-azaadenin-9-yl (RS)-CH2OH
6-Hydroxylaminopurin-9-yl (RS)-CH2OH
6-Hydrazinopurin-9-yl (RS)-CH2OH
6-Thiopurin-9-yl (RS)-CH2OH
Purin-9-yl (RS)-CH2OH
Xanthin-9-yl (RS)-CH2OH
B R
Uracil-1-yl H
Thymin-1-yl H
Cytosin-1-yl H
6-Methylpurin-9-yl H
Hypoxanthin-9-yl H
2-Aminoadenin-9-yl H
8-Bromoadenin-9-yl H
2-Aminopurin-9-yl H
6-Hydrazinopurin-9-yl H
7-Deaza-8-azaadenin-9-yl H
7-Deaza-8-azahypoxanthin-9-yl H
Uracil-1-yl (RS)-CH2OH
Cytosin-1-yl (S)-CH2OH
5-Methylcytosin-1-yl (S)-CH2OH
Thymin-1-yl (S)-CH2OH
5-Fluorouracil-1-yl (RS)-CH2OH
Guanin-7-yl (RS)-CH2OH
Adenin-3-yl (RS)-CH2OH
Hypoxanthin-9-yl (RS)-CH2OH
Hypoxanthin-9-yl (S)-CH2OH
2-Methyladenin-9-yl (RS)-CH2OH
2-Methylthioadenin-9-yl (RS)-CH2OH
2-Aminoadenin-9-yl (RS)-CH2OH
2-Aminoadenin-9-yl (S)-CH2OH
2-Aminopurin-9-yl (RS)-CH2OH
N6-Dimethyladenin-9-yl (RS)-CH2OH
8-Bromoadenin-9-yl (S)-CH2OH
8-Hydroxyadenin-9-yl (RS)-CH2OH
7-Deaza-8-azaadenin-9-yl (RS)-CH2OH
6-Hydroxylaminopurin-9-yl (RS)-CH2OH
6-Hydrazinopurin-9-yl (RS)-CH2OH
6-Thiopurin-9-yl (RS)-CH2OH
Purin-9-yl (RS)-CH2OH
Xanthin-9-yl (RS)-CH2OH
16. Methods for preparing the N-phosphonylmethoxyalkyl derivatives of formula I
according to any one of claims 8, 9, 10, 11, 12, 13, and 14 wherein R is a hydrogen atom, characterized by:
(A) - reaction of N-(2-hydroxyethyl) derivatives of the corresponding heterocyclic bases having the formula II
B-CH2CH2-OH (II) wherein B is as in formula I of claim 8, with diesters of p-toluenesulfonyloxymethane-phosphonic acid, and - cleavage with a trimethylhalogenosilane, or (B) - reaction of an alkali metal salt of the heterocyclic bases corresponding to B as in formula I of claim 8, with diesters of 2-bromoethoxymethanephosphonic acid of the general formula III
Br-CH2CH2OCH2P(O)(OC2H5) 2 (III) to give intermediates of the general formula IV
B-CH2CH2OCH2P(O)(OC2H5) 2 (IV) and - treatment with a trimethylhalogenosilane.
according to any one of claims 8, 9, 10, 11, 12, 13, and 14 wherein R is a hydrogen atom, characterized by:
(A) - reaction of N-(2-hydroxyethyl) derivatives of the corresponding heterocyclic bases having the formula II
B-CH2CH2-OH (II) wherein B is as in formula I of claim 8, with diesters of p-toluenesulfonyloxymethane-phosphonic acid, and - cleavage with a trimethylhalogenosilane, or (B) - reaction of an alkali metal salt of the heterocyclic bases corresponding to B as in formula I of claim 8, with diesters of 2-bromoethoxymethanephosphonic acid of the general formula III
Br-CH2CH2OCH2P(O)(OC2H5) 2 (III) to give intermediates of the general formula IV
B-CH2CH2OCH2P(O)(OC2H5) 2 (IV) and - treatment with a trimethylhalogenosilane.
17. Methods for preparing the N-phosphonylmethoxyalkyl derivatives of formula I
according to any one of claims 8, 9, 10, 11, 12, 13, and 14, wherein R is a hyroxymethyl group, characterized by:
(A) - reaction of a protected N-(2,3-dihydroxypropyl) derivative of the heterocyclic bases of the general formula V
B-CH2CH(OH)CH2-OH (V) wherein B is as in formula I of claim 8, and having a free 2-hydroxy group with diesters of p-toluenesulfonyloxymethanephosphonic acid and - cleavage with a trimethylhalogenosilane, or (B) - reaction of unprotected compounds of formula V with chloromethanephosphonyl dichloride of the formula VI
C1-CH2P(O)Cl2 (VI) isomerization of the formed 2'-0-chloromethanephosphonyl esters of the compounds of formula V in a mineral acid or in water to the corresponding 3'-0-chloromethanephosphonyl esters of the general formula VII
- treatment of the compounds of formula VII with an aqueous alkali metal hydroxide.
according to any one of claims 8, 9, 10, 11, 12, 13, and 14, wherein R is a hyroxymethyl group, characterized by:
(A) - reaction of a protected N-(2,3-dihydroxypropyl) derivative of the heterocyclic bases of the general formula V
B-CH2CH(OH)CH2-OH (V) wherein B is as in formula I of claim 8, and having a free 2-hydroxy group with diesters of p-toluenesulfonyloxymethanephosphonic acid and - cleavage with a trimethylhalogenosilane, or (B) - reaction of unprotected compounds of formula V with chloromethanephosphonyl dichloride of the formula VI
C1-CH2P(O)Cl2 (VI) isomerization of the formed 2'-0-chloromethanephosphonyl esters of the compounds of formula V in a mineral acid or in water to the corresponding 3'-0-chloromethanephosphonyl esters of the general formula VII
- treatment of the compounds of formula VII with an aqueous alkali metal hydroxide.
18. Methods for preparing N-phosphonylmethoxyalkyl derivatives of formula I
according to any one of claims 8, 9, 10, 11, 12, 13, and 14, characterized in that:
A - for preparing compounds of formula I wherein B is 5-halogenouracil-1-yl, a uracil-1-yl derivative of formula I is halogenated;
B - for preparing compounds of formula I wherein B is a hypoxanthin-9-yl moiety, a corresponding adenine derivative is deaminated with nitrous acid or amyl nitrite;
C - for preparing compounds of formula I wherein B is a xanthin-9-yl moiety, a corresponding guanine derivative is deaminted with nitrous acid or amyl nitrite, and D - for preparing compounds of formula I wherein B is an 8-halogenopurine, the corresponding purine base is halogenated.
according to any one of claims 8, 9, 10, 11, 12, 13, and 14, characterized in that:
A - for preparing compounds of formula I wherein B is 5-halogenouracil-1-yl, a uracil-1-yl derivative of formula I is halogenated;
B - for preparing compounds of formula I wherein B is a hypoxanthin-9-yl moiety, a corresponding adenine derivative is deaminated with nitrous acid or amyl nitrite;
C - for preparing compounds of formula I wherein B is a xanthin-9-yl moiety, a corresponding guanine derivative is deaminted with nitrous acid or amyl nitrite, and D - for preparing compounds of formula I wherein B is an 8-halogenopurine, the corresponding purine base is halogenated.
19. The method of claim 18 wherein, in process A, halogenation is carried out using bromine or iodine.
20. The method of claim 18 wherein, in process B, the adenine derivative is 9-(2-phosphonomethoxy)ethyl)adenine.
21. The method of claim 18 wherein in process D, halogenation is carried out using chlorine.
22. Pharmaceutical compositions exhibiting antiviral activity characterized in that they comprise at least one N-phosphonylmethoxyalkyl derivative of formula I of any one of claims 1, 2, 5, 8, 9, 10, 11, 12, 13, and 14, as active ingredient in a concentration of from 0.01 to 100 % by weight.
23. The use of the N-phosphonylmethoxyalkyl derivatives of formula I according to any one of claims 8, 9, 10, 11, 12, 13, and 14, for the treatment of virus diseases.
24. The use of claim 23 wherein the virus is a DNA virus.
25. The compound of claim 8 wherein B is 2-aminoadenine and R is H.
26. The compound of claim 8 wherein B is 2-aminoadenine and R is CH2OH.
27. The compound of claim 5 in the (S) configuration.
28. Compounds represented by general formula (VII) wherein B is (a) pyrimidin-1-yl, pyrimidin-3-yl, purin-3-yl, purin-7-yl, or purin-9-yl optionally carrying at least one substituent selected from methyl, halo, methoxy, hydroxy, amino, hydroxylamino, hydrazino, thio and alkylthio, or the aza or deaza analogue of the groups defined in (a) above, or B is N6-dimethylamino adenine; with unsubstituted adenin-9-yl being excluded;
and the salts thereof with alkali metals, ammonia or amines.
and the salts thereof with alkali metals, ammonia or amines.
29. The use of the 9-(-3-hydroxy-2-phosphono methoxypropyl) guanine as an antiviral agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CSPV-5469-86 | 1986-07-18 | ||
| CS865469A CS264222B1 (en) | 1986-07-18 | 1986-07-18 | N-phosphonylmethoxyalkylderivatives of bases of pytimidine and purine and method of use them |
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|---|---|
| CA1340856C true CA1340856C (en) | 1999-12-21 |
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ID=5399635
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000542404A Expired - Lifetime CA1340856C (en) | 1986-07-18 | 1987-07-17 | N-phosphonylmethoxyalkyl pyrimidines and purines and therapeutic application thereof |
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| Country | Link |
|---|---|
| US (3) | US5142051A (en) |
| EP (1) | EP0253412B1 (en) |
| JP (1) | JPH0822866B2 (en) |
| KR (1) | KR950004179B1 (en) |
| AT (1) | ATE57932T1 (en) |
| AU (1) | AU600002B2 (en) |
| CA (1) | CA1340856C (en) |
| CS (1) | CS264222B1 (en) |
| DE (2) | DE19775085I2 (en) |
| DK (1) | DK170646B1 (en) |
| EG (1) | EG18273A (en) |
| ES (1) | ES2036194T3 (en) |
| FI (1) | FI86856C (en) |
| GR (1) | GR3002534T3 (en) |
| IE (1) | IE60117B1 (en) |
| IL (1) | IL83235A (en) |
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| NL (1) | NL970036I2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CS264222B1 (en) * | 1986-07-18 | 1989-06-13 | Holy Antonin | N-phosphonylmethoxyalkylderivatives of bases of pytimidine and purine and method of use them |
| NZ222553A (en) * | 1986-11-18 | 1991-07-26 | Bristol Myers Co | Phosphonomethoxyalkylene purine and pyrimidine derivatives and pharmaceutical compositions |
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- 1986-07-18 CS CS865469A patent/CS264222B1/en not_active IP Right Cessation
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1987
- 1987-07-16 NZ NZ221100A patent/NZ221100A/en unknown
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- 1987-07-17 US US07/074,900 patent/US5142051A/en not_active Expired - Lifetime
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- 1987-07-17 DK DK373487A patent/DK170646B1/en not_active IP Right Cessation
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- 1987-07-19 EG EG42/87A patent/EG18273A/en active
- 1987-07-20 PT PT85354A patent/PT85354B/en unknown
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1990
- 1990-11-19 GR GR90400937T patent/GR3002534T3/en unknown
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1994
- 1994-10-11 US US08/320,591 patent/US5641763A/en not_active Expired - Lifetime
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- 1995-03-28 US US08/412,398 patent/US5869467A/en not_active Expired - Lifetime
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