NO874782L - Guanine. - Google Patents

Description

This invention relates to the production of substituted

9-(1 or 3-monoacyloxy- or 1,3-diacyloxy-2-propoxymethyl)-purine derivatives and pharmaceutically acceptable acid addition salts thereof useful as antiviral agents. The compounds can be used in pharmaceutical preparations together with a suitable non-toxic carrier, and the preparation is suitable for combating viral infections.

Viral infections are very widespread and cause a number of different symptoms. Some viral infections are easily fought with the help of the body's defense mechanism, but when this defense mechanism is weakened, these infections can lead to perma-

nent damage, e.g. blindness and even death. One such virus family that can cause serious infections is the herpes virus group.

The agents that are currently used to treat viral infections are in many cases ineffective or, if they are effective, they must be used in large and/or continuous doses that entail serious side effects and/or toxicity.

There is therefore a need for an effective antivirus that

is effective at lower dosages than what is used with the current agents, so that the chance of possible side effects and toxicity is reduced.

US Patent 4,199,574 describes compounds with the gene

real formula:

where X is sulfur or oxygen, <p>} is hydrogen, halogen, hydroxy, alkoxy, azide, thio, alkylthio, amino, alkylamino or dialkylamino; R is hydrogen, halogen, alkylthio, acylamino, amino or azide; R<3> is hydrogen, linear or branched or cyclic alkyl, hydroxyalkyl, benzyloxyalkyl or phenyl; R<4> is hydrogen, hydroxy or alkyl; R5 is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzyloxy, benzoyl-

oxy, benzoyloxymethyl, sulfamoyloxy, phosphate, carboxy-propiamyloxy, linear or cyclic acyloxy having from 1 to 8 carbon atoms, e.g. acetoxy or a substituted carbamoyl group with the formula NHCO-Z, where Z is alkyl, aryl or aralkyl optionally substituted with one or more of the groups sulfonyl, amino, carbamoyl or halogen; R<6>is hydrogen or alkyl, provided that when X is oxygen and R<2>, R<3>, R<4> and R^ are hydrogen, R<1> is not amino or methylamino when R<5> is hydrogen or hydroxy, or a salt thereof.

The class of compounds represented by the above formula, and the pharmaceutically acceptable acid addition salts thereof, are said to exhibit antiviral activity. See also Tetrahydron Letters, 21, 327-330 (1980), US Patent No. 4,294,831 and US Patent No. 4,347,360.

It has now been found that substituted 9-(1 or 3-monoacyloxy- or 1,3-diacyloxy-2-propoxymethyl)purines and their salts are particularly active antiviral agents.

According to the invention, compounds are produced with the formula:

and the acid addition salts, preferably the pharmaceutically acceptable acid addition salts thereof, where R<1>is hydrogen or -C(0)R<7>where R<7>is hydrogen, alkyl with 1-19 carbon atoms, hydroxyalkyl with 1-8 carbon atoms, alkoxyalkyl of 2-9 carbon atoms, alkenyl of 2-19 carbon atoms, phenyl, 1-adamantyl, 2-carboxyethyl or carboxymethyl, and the pharmaceutically acceptable alkali metal salts thereof; 7 11R is -C(0)R where R is as defined above; R is hydrogen, halogen, thio, lower alkylthio with 1-6 carbon atoms, azido, NR<9>R10 where R<9> and R<10> independently of each other are hydrogen or lower alkyl with 1-6 carbon atoms, or -NHC (0)R<8>wherein R<8>is hydrogen, alkyl of 1-19 carbon atoms or 1-adamantyl; and (a) R<6> is hydrogen, halogen, lower alkoxy of 1-6 carbon atoms, azido. thio, lower alkylthio with 1-6 carbon atoms,

9 lo 9 10 r

-NR R where R and R are as indicated above, or -NHC (0)R

8 4 S

where R is as defined above, and R together with R is a single bond; or (b) R^ together with R<6> is a keto group, and R<4> is halogen. The new compounds produced according to the invention can be used in pharmaceutical preparations together with a suitable carrier such as an antiviral agent.

Viral infections can be treated by administering a compound developed according to the invention or a preparation containing it.

The new compounds of formulas IXa and XIV (below) where A is hydrogen are useful as intermediates and as antiviral agents.

The compounds of formula I can be prepared by esterification of a compound of formula X or XIV below.

Unless otherwise stated, the following designations have the meanings given below.

The term "alkyl" refers to a linear or branched monovalent substituent consisting only of carbon and hydrogen, containing no unsaturation and having 1-19 carbon atoms. Examples of alkyl are methyl, etui, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, iso-hexyl, 2-methyl-2-propyl , n-octyl, n-decyl, n-tetradecyl and n-nonadecyl. The term "lower alkyl" refers to alkyl groups as defined above, but containing 1-6 carbon atoms. The term "alkenyl" refers to a linear or branched monovalent substituent consisting only of carbon and hydrogen, containing one or more double bonds and having 2-19 carbon atoms. Examples of "alkenyl" are propenyl, pentenyl, heptenyl, dodecenyl, dodecadieny1, pentadecenyl and pentadecadienyl. The term "1-adamantyl" refers to the following ring structure:

"Lower Alkoxy" refers to "lower alkyl-O-" where "lower alkyl" is as defined above. Examples of "Lower Alkoxy"

are methoxy, ethoxy, i-butoxy and n-hexyloxy. The term "Alkoxyalkyl" denotes the alkyl-O-alkyl wherein alkyl is as defined above and the alkyl is a divalent alkyl group. Examples of "alkoxyalkyl" are methoxymethyl, i-propoxymethyl, n-octanyloxymethyl and ethoxypropyl. The term "lower alkylthio" refers to "lower alkyl-S-" where "lower alkyl" is as defined above. Examples of "lower alkylthio" are methylthio, n-propylthio and n-pentylthio. "Ten" refers to -SH. "Amino" refers to -NH2. "Azido" refers to N3. "Halogen" refers to fluorine, chlorine and bromine. "2-carboxyethyl" refers to HOOCCH2CH2-.

"Pharmaceutically acceptable acid addition salts" refers to those salts which have the biological action and properties of the free compound and are not biologically or otherwise undesirable. Suitable acids for salt formation are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like, and organic acids such as trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like.

"Pharmaceutically acceptable alkali metal salts" refers

to the metal salts of the free carboxy group in the carboxyethyl group. Examples of alkali metals are sodium and potassium. 1 2 Compounds of formula (I) where R is hydrogen and R is C(0)R 7 contain an asymmetric carbon atom. These compounds can therefore be prepared in any optically active form, or as a racemic mixture. Unless otherwise indicated, all of the monoesters of formula (I) described herein are in racemic form. However, the invention is not limited to the racemic form, but also includes the preparation of the individual optical isomers of the monoesters of formula (I). 5 6

It should be understood that the definition of R together with R

as keto includes the tautomeric hydroxy form, for practical reasons the keto form will be used to represent both tautomeric forms.

A preferred group of compounds of formula (I) is that where R<3> is amino, R<4> is hydrogen and R<5> together with R<6> is keto (compounds of formula Ia below). Another preferred group of compounds of formula (I) is that where R 3 is amino and R 6 is hydrogen, thio or NH 2 , and R<4> together with R<5> is a bond. A preferred subgroup within these groups is that where R<1>and R<2>are both -C(0)R</>. A more preferred subgroup is that where R is alkyl with 1-5 carbon atoms, it being particularly preferred that R<7> is methyl or ethyl. Another preferred subgroup among these groups is the one where R^ is hydrogen and R 2 is -C(0)R 7. A more preferred subgroup within this subgroup is the one where R<7> is alkyl of 1-5 carbon atoms, as it is particularly preferred that R<7> is methyl or ethyl.

The compounds of formula (I) and their pharmaceutically acceptable salts show potent antiviral activity when administered to warm-blooded and cold-blooded animals, particularly mammals, birds and fish, but especially humans. For example, the compounds produced according to the invention show very good activity against Herpes Simplex virus I and II and related virus types such as cytomegalovirus, Epstein-Barr virus and varicella Zoster virus as well as viral hepatitis such as hepatitis B. Compounds of formula (I) where R1 and R<2> is -C(0)R<7> where R<7> is ethyl, i.e. the dipropanoester, exhibits properties that make it particularly suitable for the treatment of viral infections. This ester is more soluble in aqueous solutions than what would be expected on the basis of the solubility of the nearby homologues, so that the dipropane ester is particularly suitable for parenteral administration. Moreover, the dipropanoate is more readily available biologically.

Pharmaceutical preparations, both for veterinary use and for humans, containing the compounds prepared according to the invention, which are suitable for antiviral use, are prepared by methods and contain excipients that are well known in the art. A generally recognized work concerning such methods and components is Remington's Pharmaceutical Sciences by E.W. Martin, (Mark Publ. Co., 15th Ed., 1975). Liposomes can also be used in pharmaceutical preparations together with the compounds of formula (I), using known methods [e.g. as described in F. Szoka Jr., et al., Ann. Fox. Biophys, Bioeng. 9:467-508

(1980), S.E. Schullery et al, Biochemistry 19;3919-3923 (1980) and G. Gregoriadin et al, "Liposomes in Biological Systems", John Wiley and Sons (1980)].

The compounds produced according to the invention can be administered parenterally (eg by intravenous, subcutaneous, intraperitoneal or intramuscular injection), orally, locally, rectally or intranasally.

The preparations are administered orally or parenterally in doses, calculated as the free base, of approx. 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg body weight for mammals, and is used for humans in a unit dose form that is administered 1 to 5 times a day in an amount of 1-500 mg per unit dose. For oral administration, fine powders or granules may contain diluents, dispersants and/or surfactants, and may be prepared in a beverage, in water or in a syrup; in capsules or sachets in the dry state or in a non-aqueous solution or suspension, where the suspending agent may be present; in tablets where binders and lubricants may be present; in a suspension in water or a syrup; or in an aerosol. When it is desirable or necessary, flavourings, preservatives, suspending agents, thickening agents or emulsifying agents may be present. Tablets and granules are preferred, and these can be coated. The amount of compound of formula (I) in the preparation can vary from 0.1% by weight to 99% by weight or more of the compound based on the total preparation weight, and approx. 1% by weight to 99.9% by weight excipient. Preferably, the compound is present in an amount of 10-95% by weight.

For parenteral administration or for administration as drops, such as eye infections, the compounds can be prepared in aqueous solution in a concentration from approx. 0.1 to 10%, especially from approx. 0.1 to 7 1. The solution may contain antioxidants, buffers and other suitable additives.

Alternatively for infections of the eye or other external tissues, e.g. the mouth and the skin, the preparations are preferably applied to the infected part of the patient's body locally as an ointment, cream, aerosol or powder, preferably in an ointment or cream. The compounds can be prepared in an ointment, e.g. with a water-soluble ointment base, or in a cream, e.g. with an oil-in-water cream base, in a concentration from approx. 0.01 to 10%, preferably 0.1 to 7%, particularly preferred approx. 3.0% weight/volume. In addition, viral infections can be treated using systems with prolonged release of the drug as described in US patent 4,217,898.

For aerosol administration, the active ingredient is supplied in finely divided form together with a surfactant and a propellant. Typical percentage amounts of active ingredient are 0.01 to 20% by weight, preferably 0.04 to 1.0%.

Surfactants must of course be non-toxic and are preferably soluble in the propellant. Representative examples of such agents are the esters or partial esters of fatty acids containing from 6-22 carbon atoms, such as caproic acid, octanoic acid, lauric acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, oleostearic acid and oleic acid with an aliphatic polyhydric alcohol or its cyclic anhydride such as ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol (sorbitan esters sold under the trademark "Spans") and the polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed Esters, such as mixed or natural glycerides, can be used. The preferred surfactants are oleates or sorbitan, e.g. those sold under the trade names "Arlacel C" (sorbitan sesquioleate), "Span 80" (sorbitan monooleate) and "Span 85" (sorbitan trioleate). The surfactant can make up 0.1-20% by weight of the preparation, preferably 0.25-5%.

The rest of the preparation is usually propellant. Liquefied propellants are typically gases at ambient conditions and are condensed under pressure. Among suitable liquefied propellants are the lower alkanes containing up to 5 carbon atoms, such as butane and propane, and preferably fluorinated or fluorochlorinated alkanes, such as those sold under the trademark "Freon". Mixtures of the above can also be used.

When producing the aerosol, a container equipped is filled

with a suitable valve, with the suitable propellant, containing the finely divided active ingredient and surfactant. The components are thus held at elevated pressure until they are released by means of the valve.

The compounds produced according to the invention, or

preparations containing these are also useful for treating mammals other than humans, birds, e.g. chickens and turkeys, and cold-blooded animals, e.g. fish. For example, the compounds produced according to the invention and preparations containing them can exhibit antiviral activity against the following non-human viruses:

Sciruid herpesvirus 1

Cavlid herpesvirus 1

Lagomorph herpesvirus 1

Phasianid herpesvirus 1

Phasianid herpesvirus 2 (Marek's disease)

Turkey herpes virus 1

Anatid herpesvirus 1

Catfish herpes virus 1

Equid herpes virus 3

Bovid herpesvirus 1

Bovid herpesvirus 2

Bovid herpesvirus 3

Bovid herpesvirus 4

Pig herpesvirus 1

Pig herpesvirus 2

Murid herpesvirus 1

Cebid herpes virus 1

Cebid herpesvirus 2

Tupaiid herpesvirus 1

Canine herpes virus 1

Feline herpes virus 1

Equid herpes virus 1

Equid herpesvirus 2

Avian viral diseases such as Marek's disease and the like are prevented and/or treated using the compounds produced according to the invention, by methods well known in veterinary medicine, e.g. by injecting the preparation containing the compound into the birds, or by adding the compound produced according to the invention to the feed or drinking water.

Fish that are in a confined area, such as a pond, aquarium or holding tank, can also be treated for viral infections such as herpes-like viruses, e.g. "channel catfish virus" (CCV), herpes virus salomones, Nerka virus and the like by adding the compound directly to the water in the pond, aquarium or storage tank or by incorporating the compounds into the feed.

The exact form of administration for the compounds and preparations will necessarily depend on the needs of the individual being treated, the type of treatment and of course the judgment of the doctor who carries out the treatment.

The compounds of formula (I) can be prepared from the compounds of formula (X) (below) and the compounds of formula (XIV) where A is hydrogen (below), which are prepared according to reaction nucleus Ib. The intermediate product of formula (V) used in reaction core Ib is produced according to reaction core Ia. (Pages 10,11 and 12) .

In reaction core Ia, the compound with formula (III) is prepared by adding epichlorohydrin (II) dropwise to a solution of an alkali metal salt, preferably the sodium salt, of optionally substituted benzyl alcohol in a solvent such as dimethylformamide, dimethylacetamide, hexamethylphosphoramide, dimethylsulfoxide, sulfolane, tetrahydrofuran and dioxane, at a temperature of approx. Q to 100°C, preferably approx. 15-40°C. The reaction mixture is stirred for approx. 10 to 24 hours, preferably for approx. 12 to 18 hours, at a temperature of approx. 0 to 100°C, preferably from approx. 20 to 50°C.

The compound of formula (III) is chloromethylated to a compound of formula (IV) by bubbling dry hydrogen chloride gas into a solution of the compound and paraformaldehyde dissolved in a halogenated hydrocarbon solvent1 such as dichloroethane, chloroform, dichloromethane or 1,1,2-trichloroethane cooled to a temperature of approx. 0 to 25°C, preferably at a temperature of approx. 0°C. The hydrogen chloride gas is added over 30 minutes to 3 hours, preferably over 1 to 2 hours, until the paraformaldehyde has dissolved. The solution is kept at a temperature from approx. 0 to 10°C for approx. 12 to 48 hours, preferably from approx. 0 to 5°C for approx. 16 to 24 hours.

The compound of formula (V) is prepared by reacting an alkali metal acetate such as sodium acetate, with the compound of formula (IV) dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dimethylacetamide, hexamethylphosphoramide, dimethylsulfoxide, sulfolane, and dioxane at a temperature of approx. 0 to 45°C, preferably from 0 to 25°C. The solution is stirred from approx. 5 to approx. 24 hours, preferably from approx. 10 to approx. 18 hours at a temperature from approx. 10 to approx. 30°C, preferably at a temperature from approx. 15 to 25°C.

According to the reaction core Ib, a compound of formula (VII) is prepared by heating guanine (VI) with acetic acid

where A is hydrogen or acetyl, and R<3> and R^ are as indicated in the following table:

hydride, undiluted, at reflux temperature for approx. 10 to 24 hours, preferably for approx. 12 to 18 hours.

N 2,9-diacetylguanine of formula (VII) is reacted with a compound of formula (V) to form a compound of formula (VIII), undiluted or in a solvent, such as dioxane, sulfolane or the like, in the presence of a catalytic amount of an acid such as bis(p-nitrophenyl)phosphate, toluenesulfonic acid, methylphosphonic acid or dichloroacetic acid, preferably bis-(p-nitrophenyl)phosphate at a temperature of approx. 75 to 200°C, preferably at approx. 110 to 180°C. The reaction is usually carried out using 0.8 to 1.2 mol of the compound of formula (V) to 1 mol of the compound of formula (VII).

The protecting benzyl groups are removed from the compound of formula (VIII) by catalytic hydrogenation to form a compound of formula (IX). A catalyst such as palladium-on-charcoal, in a slurry, is added to a solution of the compound of formula (VIII) dissolved in a solvent such as aqueous methanol. Hydrogen is added to the solution at a pressure of 1 to 14 atmospheres, preferably at a pressure of 2 to 5.5 atmospheres.

The compound of formula (X) is prepared by deacetylation of the compound of formula (IX) with a base such as ammonia dissolved in an alcohol such as methanol. A solution of the compound of formula (IX) and the base is stirred for approx. 5 to 36 hours, preferably for approx. 10 to 24 hours, at a temperature from approx. 10 to 30°C, preferably at a temperature from approx. 15 to 25°C.

The compound of formula (X) can be esterified to the diacetate of formula (XI) by reacting the compound of formula (X) with an excess of acetic anhydride, either undiluted or in a solvent such as dimethylformamide, dimethylacetamide and the like, at room temperature for two to three days .

The compound of formula (XII) can be prepared by reacting the compound of formula (XI) with phosphorus oxychloride according to the method described in J. Org. Che., 28:945, 1963. The compound of formula (XI) is added to a solution of phosphorus oxychloride in N,N-diethylaniline at room temperature. The suspension is heated under reflux for 2 to 30 minutes, preferably for 2 to 5 minutes. Excess phosphorus oxychloride is removed, and the product is recovered in the usual way, such as extraction with an organic solvent followed by chromatography.

The compound of formula (XII) can be further chlorinated by

to form the diazo salt with sodium nitrite in hydrochloric acid as described in J. Org. Chem. 31:3258, 1966. To the compound of formula (XII) in aqueous hydrochloric acid is added sodium nitrite in water at 0 to 5°C. The solution is diluted with water, and excess hydrochloric acid is neutralized with aqueous ammonia, and a compound of formula (XIII) is recovered by well-known methods, such as extraction with an organic solvent followed by chromatography.

Compounds of formula (XIV) can be prepared from compounds of formula (XII) and (XIII) by well-known methods. See e.g. "Heterocyclic Compounds - Fused Pyrimidines Part II Purines, Ed. D.J. Brown (1971) Wiley-Interscience" and US Patent No. 4,199,574, to which reference should be made. See the above table for compounds of formula (XlV)a-j.

The compound of formula (XlVb) where A is hydrogen, can be prepared by reacting a compound of formula (XII) with thiourea dissolved in a solvent such as isopropanol, with heating under reflux for 1 to 2 hours. The formed thiourea adduct is decomposed with alkali such as aqueous ammonia, so that the thio compound is obtained. The reaction also leads to hydrolysis of the ester groups.

Compounds of formula (XlVa) where A is hydrogen and R

is lower alkyl, is prepared from a compound of formula (XII) by treatment with an alcoholic solution of the appropriate alkali metal alkoxide such as sodium methoxide, in methanol at room temperature or with gentle heating.

Various compounds of formula (XIV) can be prepared from the compound of formula (XIII). The compound of formula (XIVc) where A is acetyl, is prepared e.g. by treating the compound of formula (XIII) with sodium azide in a solvent such as ethanol-water, dimethylformamide, hexamethylphosphoramide and the like. The reaction component is heated for 2 to 24 hours at 80 to 200°C. The compound of formula (XlVb) where A is hydrogen is prepared by hydrogenating a compound of formula (XIVc) using e.g. a palladium-on-charcoal catalyst.

The compound of formula (XIII) is converted into compound

sen of formula (XlVe) where A is hydrogen, by heating the compound of formula (XIII) and ammonia dissolved in methanol in a bomb for 16 to 24 hours at 85 to 110°C. The above compound can be further ammoniated by heating the compound of formula (XlVe) dissolved in liquid ammonia in a bomb for 24 to 48 hours at 110 to 150°C to form a compound of formula (XlVd) where A is hydrogen.

Another method of preparing a compound of formula (XlVd) is by treating the compound of formula (XlVe) with hydrazine and then with a cold solution of sodium nitrite to form a compound of formula (Xivf) where A is hydrogen, as in is in turn hydrogenated to the compound of formula (XlVd) using e.g. a palladium-on-wood-charcoal catalyst.

The amino groups in the compounds of formula (XIV) where R<3> and/or R^ is amino, can be alkylated to the secondary or tertiary amines by treatment with an alkyl halide such as methyl iodide. A preferred method for producing the above-mentioned alkylated amino compounds is by reacting a compound of formula (XIII) or (XlVe) with an alkyl or dialkylamine.

Compounds of formula (IXa) where R g is different from methyl can be prepared by protecting the hydroxy groups of a compound of formula (IX) with a trityl protecting agent as defined below, deacetylating the amino nitrogen, reacting the deacetylated compound with the appropriate acid chloride and removal of the protective gurps with glacial acetic acid:water.

The compounds of formula (XIV) where A is acetyl, can be hydrolysed by well-known methods, such as by acid or basic hydrolysis.

Compounds of the formulas (XlVg) and (XlVh) can be prepared by hydrogenation of the compounds of the formulas (XII) and (XlVe), respectively, using a hydrogenation catalyst such as palladium in the presence of a base such as magnesium dioxide.

Compounds of formula (XlVi) where A is hydrogen are prepared by reacting a compound of formula (XlVh) with sodium nitrite in acetic acid to form the 6-keto compound, which in turn is chlorinated with a chlorinating agent such as phosphoryl chloride, phosphorus pentachloride and the like by known methods . The 6-chloro intermediate is treated with thiourea as described above.

Compounds with formula (XlVj) can e.g. is prepared by reacting a compound of formula (XlVe) with methanolic hydrogen sulphide-ammonium carbonate as described in J. Org. Chem., 39(9):1256, 1974, or with sodium kercaptide in dimethylformamide as described in J.Med.Chem., 16(12):1381, 1973.

Compounds of formula (XIV) where R<3> or R is thio can be alkylated with an alkyl halide such as an alkyl iodide in a solvent such as an alkanol at room temperature.

The following compounds with formula (XIV) where A is hydrogen, can e.g. is prepared by one or a combination of the methods described above: 2-amino-6-methoxy-9-(1,3-dihydroxy-2-propoxymethyl)-purine;

2-methylamino-6-ethoxy-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-amino-6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine, m.p. 155-157°C;

2-n-butylamino-6-6io-9-(1,3-dihydroxy-2-propoxymethyl)-purine;

2-amino-6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl)-purine;

2-dimethylamino-6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2,6-diazido-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2,6-diamino-9-(1,3-dihydroxy-2-propoxymethyl)purine,

m.p. 174-180°C;

2-methylamino-6-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2,6-di(methylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-chloro-2-amino-9-(1,3-dihydroxy-2-propoxymethyl)-purine, m.p. 197.5-198.5°C;

2-chloro-6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-azido-6-ethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-methylamino-9-(o,3-dihydroxy-2-propoxymethyl)-

purine;

2-dimethylamino-9-(1,3-dihydroxy-2-propoxynethyl)-

purine;

6-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-dimethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl)purine; and 6-amino-2-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine.

Diesters of formula (I) can be prepared by esterification methods known per se. For example, diesters of formula (I) where R<7> is lower alkyl can be prepared by reacting compounds of formula (X) and (XIV) where A is hydrogen with an excess of the appropriate acid anhydride, either undiluted or in a solvent such such as dimethylformamide, dimethylacetamide, N-methylpyrrolidine and the like. The reaction components are stirred for 1 to 5 days, preferably for 2 to 3 days at 0 to 50°C, preferably at room temperature in the presence of a catalyst, e.g. 4-Dimethylaminopyridine. Compounds of formula (X) or (XIV) and the acid anhydride are used in molar ratios of approx. 1:10-100.

The acid anhydrides are readily available, or if they are not readily available, they can be prepared by methods known per se, e.g. by heating the acid in the presence of acetic anhydride or acetyl chloride.

The diesters of formula (I) where R<7> is hydrogen can be prepared by the method described above using the mixed anhydride of formic acid and acetic acid, which can be prepared by reacting formic acid with acetic anhydride, undiluted, at 0 to 40°C.

Another method for preparing the diesters of formula (I) for all meanings of R<7> is first to treat compounds of formula (XI) or (XIV) where A is acetyl and R<3> and/or R<6 >is amino, with a trityl protecting agent

such as triphenylmethyl chloride (trityl chloride), 4-methoxyphenyldi-

phenylmethyl chloride (monomethoxytrityl chloride) and the like. The trityl protection rails are easily available from e.g. Aldrich Chemical Co. The reaction components in a solvent such as dimethylformamide, pyridine and the like with a catalyst, e.g. 4-dimethylpyridine, is heated at 40 to 70°C, preferably at 45 to 60°C for 8 to 24 hours, preferably for 12 to 18 hours. The amino-protected compound is isolated in the usual manner such as crystallization, and the acetate groups are hydrolysed with a base such as an alkali metal hydroxide, e.g. sodium hydroxide and potassium hydroxide, or with ammonium hydroxide. The dihydroxy compound and a catalyst such as 4-dimethylaminopyridine in pyridine are added dropwise to the appropriate acid chloride either undiluted or in a solvent such as methylene chloride, dichloroethane and the like. The reaction components are stirred at room temperature for 10 to 24 hours, preferably from 12 to 18 hours. The product is isolated by well-known methods such as chromatography. The amino protecting groups are removed by treatment with an organic acid such as glacial acetic acid, trifluoroacetic acid and the like with heating from 60 to 100°C, preferably from 60 to 80°C for 1 to 12 hours, preferably from 1 to 5 hours. The product is isolated by chromatography or crystallization.

The amino group(s) in the above-described compound of formula (XI) and (XIV) can also be protected by reacting the compounds with the acetal of N,N-dimethylformamide which is available from, among others Aldrich Chemical Co., and then proceed as described above.

The acid chlorides are readily available, or if they are not

are readily available, they can be prepared by reacting the appropriate acid with a chlorinating agent such as phosphorus trichloride, phosphorus pentachloride or thionyl chloride under known reactions sb et inge Iser.

Diesters of formula (I) where R<3> is amino, R<5> together with

R<6>is keto and R<4>is hydrogen and R<7>is alkyl with 7-19 carbon atoms, alkenyl with 7-19 carbon atoms, 2-methyl-2-propyl, 1-adamantyl or phenyl, can also be prepared by esterification with the appropriate acid chloride. The acid chloride dissolved in a solvent such as methylene chloride, dichloroethane and the like is added to a compound of formula (IX) dissolved in a solvent such as pyridine, lutidines and the like. The reaction components are stirred for 9 to 24 hours, preferably 16 to 24 hours at 15 to 50°C, preferably at room temperature. The amino group is deacetylated by treatment with an alcoholic solution of a base such as a methanol solution of ammonium hydroxide.

Another method for the preparation of diesters of formula (I) where R7 is alkyl of 7 to 19 carbon atoms is the reaction of compounds of formulas (X) or (XIV) where A is hydrogen, with the condensation product of dicyclohexylcarbodiimide, available from Aldrich Chemical Co ., and the appropriate carboxylic acid. The carboxylic acid in a molar excess of dicyclohexylcarbodiimide is added to the above compounds dissolved in a solvent such as dimethylformamide, dimethylacetamide and the like. The solution is stirred with heating from 35 to 75°C, preferably from 40 to 60°C for 16 to 72 hours., preferably for 24 to 60 hours. The diesters of formula (I) are isolated by precipitation.

Diesters and monoesters of formula (I) where R 7 is hydroxyalkyl are prepared by first protecting the hydroxy group in the hydroxy acid with a benzyl group, reacting the protected acid with a trityl-protected compound of formula (X) or (XIV) as described below, where A is hydrogen, and removing the benzyl group by catalytic hydrogenation followed by removal of the trityl group(s) as described above.

The monoester of formula (I) can be prepared by reacting compounds of formula (X) or (XIV) where A is hydrogen, with a trityl protecting group as defined above. The protecting group reacts with the amino nitrogen if this is present and a hydroxy group. The unprotected hydroxy group is esterified using an acid chloride using the method described above. The protecting groups are removed as described above.

The following examples shall serve to further illustrate the invention, and it shall be understood that they must not be taken as a limitation, but only as an illustration.

MANUFACTURE I

Preparation of 1,3-di-O-benzylglycerol

Sodium hydride (100 g (50% dispersion in mineral oil),

2.08 mol) was washed twice with 1 liter of hexane and then dried under nitroa. Triturated dimethylformamide (1.5 liters) was

added. Benzyl alcohol (400 ml) was then added at such a rate that the temperature was kept below 50°C. The addition took 2 hours. Epichlorohydrin (92.5 g, 1 mol) was then added dropwise over half an hour with ice cooling to keep the temperature below 40°C. The solution was then stirred for 16 hours at 21°C and then for 2.5 hours at 50°C. The dimethylformamide was then removed by evaporation under reduced pressure. The oily residue was dissolved in 2.5 l of diethyl ether. The organic solution was washed with 2 L of water, 2 L of 2% hydrochloric acid, 2 L of 1% sodium bicarbonate and 1 L of salt solution, dried over sodium sulfate and concentrated to a brown oil. Distillation gave 147.8 g of 1,3-di-O-benzylglycerol (bp. 170-180°C/ 1 torr).

MANUFACTURE II

Preparation of 1,3-di-O-benzyl-2-Q-chloro-methylglycerol

Dry hydrogen chloride gas was bubbled for 1.5 h in a solution of 1,3-di-O-benzylglycerol from Preparation I (15 g, 55 mmol) and paraformaldehyde (3.3 g, 110 mmol) in 175 mL of 1,2- dichloroethane at 0°C. The solution was then stored in a closed flask for 21 hours at 4°C. Then the solution was dried over magnesium sulfate by heating to 21°C and was then filtered and concentrated to give 17.5 g of 1,3-di-O-benzyl-2-O-chloromethyl-glycerol.

MANUFACTURE III

Preparation of 2-O-acetoxymethyl-1,3-di-O-benzylglycerol

To a solution of 1,3-di-0-benzyl-2-0-chloromethylglycerol from Preparation II (17.5 g, 55 mmol) in 400 ml of dimethylformamide at 0°C under a drying tube was added sodium acetate (6 g). The solution was then heated to 21°C and stirred magnetically for 15 hours. The solvent was removed by evaporation under reduced pressure, and the oily residue was dissolved in 450 g of diethyl ether. The ether solution was washed once with 750 mL of water, twice with 250 mL of water, and once with 250 mL of brine, dried over sodium sulfate, and concentrated to give 19 g of 2-O-acetoxymethyl-1,3-di-O -benzylglycerol as an oil.

PRODUCTION IV

Preparation of N 2,9-diacetylguanine

Guanine (20 g, 0.132 mol) was mixed with 300 ml of acetic anhydride, and the mixture was heated under reflux for 16 hours. The mixture was cooled, and excess acetic anhydride was removed by evaporation under reduced pressure. The residue was recrystallized from dimethylsulfoxide to give

25.6 g of N 2,9-diacetylguanine.

PRODUCTION V

A. Preparation of N 2-acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine

N 2,9-diacetylguanine from Preparation IV (15.61 g, 66 mmol), 2-O-acetoxymethyl-1,3-di-O-benzylglycerol from Preparation III (19 g, 55 mmol), and bis(p- nitrophenyl)phosphate (0.5 g) was stirred together with 150 ml of diethyl ether. The solvent was removed by evaporation, and the residue was heated in a 175°C oil bath for 1.5 hours under a stream of nitrogen. Column chromatography eluting with 1:9 methanol/methylene chloride followed by recrystallization from ethyl acetate gave 4.76 g of N 2-acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine, m.p. 145-146°C.

B. Preparation of N 2-acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine

To a solution of N 2-acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine (4.62 g, 9.67 mmol) in 150 ml of methanol plus 40 ml of water was added 20% palladium hydroxide-on- charcoal as a slurry in 10 ml of water. The mixture was hydrogenated at

a Parr hydrogenator at 4 atmospheres of hydrogen pressure for 38 hours and was then filtered through celite and concentrated to a white solid. Recrystallization from methanol/ethyl acetate gave 1.4 g of N 2-acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine, m.p. 205-208°C.

The mother liquor was further reduced by 10% on 1 ladium-on-charcoal

(1 g) in 150 mL methanol plus 50 mL water at 4 atmospheres for 47 hours. The total yield of N<2->acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine was 2.11 g.

C. Preparation of 9-(1,3-dihydroxy-2-propoxymethyl)guanine

N -acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine

(721.9 mg, 2.4 mmol) was stirred with 50 ml of methanolic ammonia-

solution (methanol saturated with ammonia at 0°C) for 17 hours at 21°C. The solution was concentrated to a white solid and the residue recrystallized from water or methanol to give 582.3 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, m.p. 2 50°C.

EXAMPLE 1

9-(1,3-diacetyloxy-2-propoxymethyl)guanine

(Compound where R<1> and R<2> are acetyl, R<3> is amino, R<4>

is hydrogen and R and R is keto)

A mixture of 3.00 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, 300 mg of 4-dimethylaminopyridine, and 100 ml of acetic anhydride was stirred vigorously for 3 days at room temperature. The acetic anhydride was removed by evaporation under reduced pressure and the residue recrystallized from methanol to give 3.62 g of 9-(1,3-diacetyloxy-2-propoxymethyl)guanine, mp 237-239°.

EXAMPLE 2

9-(1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethylguanine (Compound where R<1>and R<2>are 2,2-dimethylpropanoyl, R<3>is amino, R<4> is hydrogen, and R"* and R^ are keto)

A mixture of 1.306 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, 150 mg of 4-dimethylaminopyridine and 50 ml of 2,2-dimethylpropanoic anhydride and dry dimethylformamide (75 ml) was stirred vigorously for 2 days. The dimethylformamide was removed by evaporation under reduced pressure, and 200 ml of ethyl ether was added to the residue. After cooling to 0°C, the precipitate was isolated by filtration and recrystallized from methanol to give 1.83 g of 9-(1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl)guanine, m.p. 230-232°.

Using the method according to example 1 or 2, using the appropriate acid anhydride instead of acetic anhydride or 2,2-dimethylpropanoic anhydride, and using a compound of formula (X) or the appropriate compound of formula (XIV) where A is hydrogen, produced e.g. the following compounds similarly: 2-amino-6-methoxy-9-(1,3-diacetyloxy-2-propoxymethyl)-purine;

2-methylamino-6-ethoxy-9-(1,3-dipropanoyloxy-2-propoxymethyl)purine;

2-amino-6-thio-9-(1,3-di-acetyloxy-2-propoxymethyl)-purine, m.p. 235-236°C;

2-n-butylamino-6-thio-9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)purine;

2-amino-6-methylthio-9-[1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl]purine;

2-dimethylamino-6-methylthio-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2,6-diazido-9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)-purine;

2,6-diamino-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2-methylamino-6-amino-9-(1,3-dipropanoyloxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1,3-di-n-butanoyloxy-2-propoxymethyl)purine;

2,6-di(methylamino)-9-[1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl]purine;

6-chloro-2-amino-9-[1,3-diacetyloxy-2-propoxymethyl]-purine, m.p. 122-123°C;

2-chloro-6-methylamino-9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)purine;

2-azido-6-ethylamino-9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)purine;

2-amino-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]-purine;

2-methylamino-9-(1,3-dipropanoyloxy-2-propoxymethyl)-purine;

2-dimethylamino-9-(1,3-di-n-butanoyloxy-2-propoxymethyl)-purine;

6-amino-9-[1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl] purine;

6-methylamino-9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)purine;

6-dimethylamino-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

6-thio-9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)purine;

6-methylthio-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

9-(1,3-dipropanoyloxy-2-propoxymethyl)guanine,

m.p. 191-193°C;

9-(1,3-di-n-butanoyloxy-2-propoxymethyl)guanine,

m.p. 19 9-201°C;

9-1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl]guanine;

9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)guanine,

m.p. 193-198°C;

9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)guanine,

m.p. 179-181°C;

9-[1,3-di-(4-methylpentanoyloxy)-2-propoxymethyl]-guanine, m.p. 185.5-186.5°C;

9-1,3-di-methoxyacetyloxy-2-propoxymethyl)guanine,

m.p. 183-185°C; and

9- 11,3-di-(3-carboxypropanoyloxy)-2-propoxymethyl]-guanine, mp 140-144°C.

EXAMPLE 3

9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine

To 50 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine in 5 ml of N,N-dimethylformamide were added 290 mg of dicyclohexylcarbodiimide and 300 mg of -n-hexadecanoic acid, and the solution was stirred at 50°C for 50 hours. The solution was then precipitated in ice water. The water was extracted with methylene chloride (3 times). The combined methylene chloride extracts were concentrated, then purified on preparative silica gel plates which were developed in 1:9 methanol:methylene chloride to give 140 mg of 9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine, m.p. 150-154°C.

By proceeding as in the above example, using the appropriate carboxylic acid instead of n-hexadecanoic acid, and using a compound of formula (X) or compounds of formula (XIV) where A is hydrogen, e.g. similarly, the following compounds: 2-amino-6-methoxy-9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)-purine;

2-amino-6-chloro-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)-purine;

2-amino-6-thio-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;

2-n-butylamino-6-thio-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;

2-amino-6-methylthio-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;

2-dimethylamino-6-methylthio-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;

2,6-diazido-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)purine;

2,6-diamino-9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)purine;

2-methylamino-6-amino-9-(1,3-di-n-nonanoyloxy-2-propoxymethyl)purine;

2-amino-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;

2,6-di(methylamino)-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;

2-chloro-6-amino-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;

2-chloro-6-methylamino-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;

2-azido-6-ethylamino-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;

6-amino-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)-purine;

2-methylamino-9-(1,3-n-eicosanoyloxy-2-propoxymethyl)purine;

2-dimethylamino-9-(1,3-di-n-nonanoyloxy-2-propoxymethyl)purine;

2-amino-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;

6-methylamino-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;

6-dimethylamino-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;

6-thio-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;

6-methylthio-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;

9-(1,3-di-n-nonanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine, m.p. 165-166°C;

9-(1,3-di-n-decanoyloxy-2-propoxymethyl)guanine, m.p. 158-160°C;

9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)guanine, m.p. 162-164°C;

9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)guanine, m.p. 137-140°C;

9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)guanine; and 9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)guanine.

EXAMPLE 4

A. N 2~( 4- methoxyphenyldiphenylmethyl)- 9-( 1, 3- diacetoxy-2- propoxymethyl) guanine

A solution of 3.3 g of 9-(1,3-diacetoxy-2-propoxymethyl)-guanine, 7.0 g of 4-methoxyphenyldiphenylmethyl chloride, 7.0 ml of triethylamine and 300 mg of 4-dimethylaminopyridine in 50 ml of dry dimethylformamide was heated with magnetic stirring at 50°C for 15 hours. Methanol (5 mL) was added. The solution was then concentrated under reduced pressure to a brown oil which was chromatographed over silica gel eluting with 1:12 methanol/methylene chloride to give an oil. The oil was crystallized from ethyl acetate:hexane to give 5.42 g of N 2-(4-methoxyphenyldiphenylmethyl)-9-(1,3-diacetoxy-2-propoxymethyl)guanine, m.p. 139-141°.

Triphenylmethyl chloride can be used in place of 4-methoxyphenyldiphenylmethyl chloride in part A above to prepare the corresponding triphenylmethyl-protected compounds.

By proceeding as in part A above, using the appropriate compound of formula (XIV) where A is acetyl, e.g. the following compounds: 2-(4-methoxyphenyldiphenylmethylamino)-6-methoxy-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2-(4-Methoxyphenyldiphenylmethylamino)-6-thio-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2-(4-Methoxyphenyldiphenylmethylamino)-6-methylthio-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2-methylamino-6-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2-(4-Methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

6-chloro-2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2-(4-Methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)purine; and

6-(4-Methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)purine.

B. N 2-(4-Methoxyphenyldiphenylmethyl)-9-(1,3-dihydroxy-2-propoxymethyl)guanine

A solution of 4.0 g of N 2-(4-methoxyphenyldiphenyl-methyl)-9-(1,3-diacetoxy-2-propoxymethyl)guanine in 100 ml of methanol plus 20 ml of concentrated ammonium hydroxide was stirred magnetically at 22°C for 16 hours and then at 50°C for 2.5 hours. A further 10 ml of ammonium hydroxide was then added and the solution was stirred for a further 2.5 hours at 50°C. Then the solution was concentrated under reduced pressure and the remaining solid was recrystallized from methanol:ethyl acetate to give 3.5 g of N 2-(4-methoxyphenyldiphenylmethyl)-9-(1,3-dihydroxy-2-propoxymethyl)guanine, m.p. 148-151°C.

By proceeding as in part B above, the compounds prepared in part A can be similarly hydrolyzed to the following compounds: 2-(4-methoxyphenyldiphenylmethylamino)-6-methoxy-9-(1,3-dihydroxy-2-propoxymethyl) purine;

2-(4-Methoxyphenyldiphenylmethylamino)-6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-methylamino-6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-chloro-2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine; and

6-(4-Methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine.

C. N 2-(4-Methoxyphenyldiphenylmethyl)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine

To a magnetically stirred solution of 1.05 g of N<2->(4-methoxy enyldiphenylmethyl)-9-(1,3-dihydroxy-2-propoxymethyl)guanine and 25 mg of 4-dimethylaminopyridine in 30 ml of dry pyridine was added

dropwise a solution of 1.2 g of n-octanoyl chloride in 10 ml of methylene chloride. After 15 hours, 1.5 ml of water was added, and the solution was concentrated under reduced pressure. The residue was chromatographed over silica gel eluting with 1:9 methanol:methylene chloride to give a white solid which was recrystallized from ethyl acetate:hexane to give N 2-(4-methoxyphenyldiphenylmethyl)-9-(1,3-dyne-octanoyloxy- 2-propoxymethyl)guanine.

By proceeding as in part C above, the compounds from part B can be esterified to the following compounds in a similar way: 2-(4-methoxyphenyldiphenylmethylamino)-6-methoxy-9-(1,3-di-n-butanoyloxy-2 -propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-thio-9-11,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2-(4-Methoxyphenyldiphenylmethylamino)-6-thio-9-(1,3-di-n-octanoyloxy-(2-propoxymethyl)-purine;

2-(4-Methoxyphenyldiphenylmethylamino-6-thio-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;

2-(4-Methoxyphenyldiphenylmethylamino)-6-methylthio-9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]-purine;

2-methylamino-6-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-methylamino-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;

6-chloro-2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-tt-octadecanoyllocyl-2-propoxymethyl)purine;

2-(4-Methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2-(4-Methoxyphenyldiphenylmethylamino)-9-11,3-di-

(1-adamantylcarboxy)-2-propoxymethyl]purine;

6-(4-Methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;

N 2-(4-Methoxyphenyldiphenylmethyl)-9-(1,3-dipropanoyloxy-2-propoxymethyl)guanine;

N 2-(4-Methoxyphenyldiphenylmethyl)-9-(1,3-di-n-butanoyloxy-2-propoxymethyl)guanine;

N 2-(4-Methoxyphenyldiphenylmethyl)-9-(1,3-di-(2-methyl-propanoyloxy)-2-propoxymethyl)guanine;

N 2-(4-Methoxyphenyldiphenylmethyl)-9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)guanine;

N 2-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl)guanine;

N 2-(4-Methoxyphenyldiphenylmethyl)-9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)guanine;

N 2-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)guanine;

N 2-(4-Methoxyphenyldiphenylmethyl)-9-(1,3-d-n-decanoyloxy-2-propoxymethyl)guanine;

N 2-(4-Methoxyphenyldiphenylmethyl)-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)guanine;

N 2-(4-Methoxyphenyldiphenylmethyl)-9-(1,3-di-n-tetradecanoyl-oxy-2-propoxymethyl)guanine;

N 2-(4-Methoxyphenyldiphenylmethyl)-9-(1,3-di-n-hexadecanoyl-oxy-2-propoxymethyl)guanine clear oil;

N 2-(4-Methoxyphenyldiphenylmethyl)-9-(1,3-di-n-octadecanoyl-oxy-2-propoxymethyl)guanine;

N2-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)guanine; and

N2-(4-methoxyphenyldiphenyl)-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]guanine; m.p. 20l-203°C;

N2-(4-methoxyphenyldiphenyl)-9-[1,3-di-(benzyloxyacetyloxy)-2-propoxymethyl]guanine;

N2-(4-methoxyphenyldiphenyl)-9-[1,3-di-(3-benzyloxy-propanoyloxy)-2-propoxymethyl]guanine; and

N2-(4-Methoxyphenyldiphenyl)-9-[1,3-di-(4-benzyloxy-butanoyloxy)-2-propoxymethyl]guanine.

D. 9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine

A solution of 0.969 g of N 2-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine in 40 ml of glacial acetic acid plus 10 ml of water was stirred at 75°C for 3 hours. The solution was then concentrated and the residue chromatographed over silica gel, eluting with 1:15 methanol:methylene chloride to give a white solid. The product was recrystallized from methanol to give 0.385 g of 9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine, m.p. 165-166°C.

By proceeding as in part D above, using the compounds from part C, the following compounds can be similarly prepared: 2-amino-6-methoxy-9-(1,3-di-n-butanoyloxy-2- propoxymethyl (purine;

2-amino-6-thio-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2-amino-6-thio-9-1,3-di-n-octanoyloxy-2-propoxymethyl ]purine;

2-amino-6-thio-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;

2-amino-6-methylthio-9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)purine;

2,6-di-amino-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)-purine;

2,6-di-amino-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;

2,6-diamino-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2,6-di-amino-9-1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;

2-methylamino-6-amino-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;

2-chloro-6-amino-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)purine;

2-amino-9-(1,3-di-octanoyloxy-2-propoxymethyl)purine;

2-amino-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2-amino-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl] purine;

6-amino-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;

9-(1,3-dipropanoyloxy-2-propoxymethyl)guanine,

m.p. 191-193°C;

9-11,3-di-n-butanoyloxy-2-propoxymethyl)guanine m.p. 199-201°C;

9-[1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl]guanine;

9-1,3-di-n-pentanoyloxy-2-propoxymethylguanine, m.p. 193-198°C;

9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]-guanine, m.p. 230-232°C;

9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)guanine m.p. 179-181°C;

9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-decanoyloxy-2-propoxymethyl)guanine, m.p. 158-160°C;

9-1,3-di-n-dodecanoyloxy-2-propoxymethyl)guanine, m.p. 162-164°C;

9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)guanine, m.p. 137-140°C;

9 - (1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine, mp 150-154°C; 9 - (1,3-di-n-octadecanoyloxy-2-propoxymethyl)guanine; 9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)guanine; 9-[1,3-di-(1-adamantylcarboxy)-2-propoxynrethyl]guanine, m.p. 283-285°C; 9-1,3-di-(2-butenoyloxy)-2-propoxymethyl]guanine; 9 - [1,3-di-(4-octenoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(9-dodecenoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(cis-9-hexadeconoyloxy)-2-propoxymethyl]-guanine;

9-[1,3-di-(cis-9-octadecenoyloxy)-2-propoxymethyl]-guanine;

9-[1,3-di-(9,12-octadecadienoyloxy)-2-propoxymethyl]-guanine; and

9-[1,3-di-(9,12,15-octadecatrianoyloxy)-2-propoxymethyl]guanine.

By catalytically removing the benzyl group and then leaving

forward as in part D of the above example, e.g. in a similar way the following compounds: 9-[1,3-di-(hydroxyacetyloxy)-2-propoxymethyl]guanine,•

9-[1,3-di-(3-hydroxypropanoyloxy)-2-propoxymethyl]-guanine; and

9-[1,3-di-(4-hydroxybutanoyloxy)-2-propoxymethyl]-guanine.

EXAMPLE 5

To 0.26 g of N 2-acetyl-9-(1,3-dihydroxy-2-propoxymethyl)-guanine from Preparation V, part B and 10 mg of 4-dimethylaminopyridine in a solution of 7 ml of pyridine was added 0.764 g of adamantane- carboxylic acid chloride as a solution in 3 ml of methylene chloride. The solution was magnetically stirred for 18 hours at 21°C, and then 1 ml of water was added. After stirring for one additional hour, the solution was concentrated, and the residue was treated for 16 hours with 10 ml of methanol containing 1 ml of concentrated ammonium hydroxide. The solution was concentrated and the residue triturated with methanol to give 0.277 g of 9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]guanine, m.p. 283-285°C.

By proceeding as above, using the appropriate acid chloride and the appropriate compound of formula (IX) or (XIV) where A is hydrogen, prepare in a similar manner, e.g. the following compounds: 2-amino-6-methoxy-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2-amino-6-thio-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)-purine;

2-amino-6-methylthio-9-(1,3-di-n-decanoyloxy-2-peroxymethyl)purine;

2,6-diamino-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)-purine;

2-methylamino-6-amino-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;

2-chloro-6-amino-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)purine;

2-amino-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;

6-amino-9-[1,3-di-(4-octenoyloxy)-2-propoxymethyl]-purine;

9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]-guanine;

9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-decanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)guanine;

9-[1,3-di-(4-octenoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(9-dodecanoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(cis-9-hexadecenoyloxy)-2-propoxymethyl]-guanine;

9-[1,3-di-(cis-9-octadecenoyloxy)-2-propoxymethyl]-guanine;

9-1,3-di-(9,12-octadecadienoyloxy)-2-propoxymethyl]-guanine;

9-1,3-di-(9,12-15-octadecatrienoyloxy)-2-propoxymethyl]guanine; and

9-(1,3-dibenzoyloxy-2-propoxymethyl)guanine, m.p. 242-243°C.

EXAMPLE 6

A- N 2- ( 4- methoxyphenyldiphenylmethyl)- 9-[ 1- hydroxy-3-(4- methoxyphenyldiphenylmethoxy)- 2- propoxymethyl 1 - guanine

To 2 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine in N,N-dimethylformamide (50 ml) were added 6.33 g of 4-methoxyphenyldiphenylmethyl chloride, 20 mg of N,N-dimethylaminopyridine and 10 ml of triethylamine . The reaction mixture was stirred at 50-60°C for 60 hours and was then precipitated in ice water (900 mL). The precipitate was isolated by filtration, and the product was recrystallized from ethanol. The somewhat impure product was further purified by column chromatography on silica gel eluting with 1:9 methanol .-methylene chloride to give 3.5 g of N<2->(4-methoxyphenyldiphenylmethyl)-9-L1-hydroxy-3-( 4-methoxy-phenyldiphenylmethoxy)-2-propoxymethyl]-guanine after recrystallization from methanol, m.p. 159-161°C.

By proceeding as in Part A above, applying

the appropriate compounds of formula (XIV) where A is hydrogen instead of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, and using the appropriate amount of 4-methoxyphenyldiphenylmethyl chloride, are prepared, e.g. similarly, the following compounds: 2-(4-methoxyphenyldiphenylmethylamino)-6-methoxy-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]-purine;

2-(4-Methoxyphenyldiphenylmethylamino)-6-thio-9-11-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-(4-Methoxyphenyldiphenylmethylamino)-6-methylthio-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-methylamino-6-(4-methoxyphenyldiphenylmethylamino)-9-[1-hydroxy-3-(4-methylphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-(4-Methoxyphenyldiphenylmethylamino)-6-methylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-chloro-6-(4-methoxyphenyldiphenylmethylamino)-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-(4-Methoxyphenyldiphenylmethylamino)-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethylamino)-2-propoxymethyl]purine;

6-(4-Methoxyphenyldiphenylmethylamino)-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-methylamino-6-ethoxy-9-[1-hydroxy-3-(4-methoxyphenyl-diphenylmethoxy)-2-propoxymethyl]purine;

2-n-butylamino-6-thio-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-dimethylamino-6-methylthio-9-11-hydroxy-3-(4-methoxy-phenyldiphenylmethoxy)-2-propoxymethyl]purine;

2,6-diazido-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-3-hydroxy-2-propoxymethyl]purine;

2,6-di(methylamino)-9-[1-hydroxy-3-(4-methoxyphenyldi-phenylmethoxy)-2-propoxymethyl]purine;

2-chloro-6-methylamino-9-[1-hydroxy-3-(4-methoxyphenyldi-phenylmethoxy)-2-propoxymethyl]purine;

2-azido-6-ethylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-dimethylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

6-methylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

6-dimethylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

6-thio-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-3-hydroxy-2-propoxymethyl]purine; and

6-methylthio-9-[1-hydroxy-3-(4-methoxyphenyldiphenyl-methoxy)-3-hydroxy-2-propoxymethyl]purine.

B. 9-(l-n-hexadecanoyloxy-3-hydroxy-2-propoxymethyl)-guanine

To a stirred mixture of 3 g of n-hexadecanoyl chloride in pyridine (50 ml) was added 1.5 g of N 2-(4-methoxyphenyldiphenylmethyl)-9-[hydroxy-3-(4-methoxyphenyldiphenylmethoxy-2-propoxymethyl]- guanine. The reaction mixture was stirred for 48 hours at 50-60°C and then precipitated in ice water (500 mL). The resulting precipitate was treated with 80% acetic acid (aqueous) at 80°C for one hour. The acetic acid was evaporated under reduced pressure, and the residue was chromatographed on a silica gel column eluting with 1-9 methanol:methylene chloride to give 0.45 g of 9-(1-n-hexadecanoyloxy-3-hydroxy-2-propoxymethyl)guanine after recrystallization from methanol, mp 226 -227°C.

By proceeding as in part B above, using the appropriate acid chloride instead of n-hexadecanoyl chloride, e.g. similarly, the following compounds: 2-amino-6-methoxy-9-(1-acetyloxy-3-hydroxy-2-propoxymethyl)purine;

2-amino-6-thio-9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxymethyl]purine;

2-amino-6-methylthio-9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxymethyl]purine;

2,6-diamino-9-[1-(2-methylpropanoyloxy)-3-hydroxy-2-propoxymethyl]purine;

2-methylamino-6-amino-9-(1-n-pentanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1-n-hexanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-chloro-6-amino-9-(1-n-heptanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-amino-9-(1-n-octanoyloxy-3-hydroxy-2-propoxymethyl)-purine;

6-amino-9-(1-n-decanoyloxy-3-hydroxy-2-propoxymethyl)-purine;

2-methylamino-9-(1-n-dodecanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-n-butylamino-6-thio-9-(1-n-tetradecanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-dimethylamino-6-methylamino-9-(1-n-hexadecanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2,6-diaziodi-9-(1-octadecanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2,6-di(methylamino-9-(1-n-eicosanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-chloro-6-methylamino-9-(1-acetyloxy-3-hydroxy-2-propoxymethyl)purine;

2-azido-6-ethylamino-9-(1-propanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-dimethylamino-9-(1-n-butanoyloxy-3-hydroxy-2-propoxymethyl)purine; ■

6-methylamino-9-[1-(2-methylpropanoyloxy)-3-hydroxy-2-propoxymethyl[purine;

6-dimethylamino-9-(1-n-pentanoyloxy-3-hydroxy-2-propoxymethyl)purine;

6-thio-9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxymethyl]purine;

6-methylthio-9-(1-n-hexanoyloxy-3-hydroxy-2-propoxymethyl)purine;

9-(1-acetyloxy-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-butanoyloxy-3-hydroxy-2-propoxymethyl)guanine;

9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-[1-(2-methylpropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-(1-n-pentanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-hexanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-heptanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-octanoyloxy)-3-hydroxy-2-propoxymethyl)guanine, m.p. 215.5-217.5°C;

9- r (1-n-decanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-dodecanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-tetradecanoyloxy)-3-hydroxy-2-propoxymethyl)-guanine;

9-(1-n-octadecanoyloxy)-3-hydroxy-2-propoxymethyl)-guanine;

9-(1-n-eicosanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-methoxyacetyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-[1-(1-adamantylcarboxy)-3-hydroxy-2-propoxymethyl]-guanine;

9-(1-benzoyloxy-3-hydroxy-2-propoxymethyl)guanine;

9-[1-(2-butenoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-LI-(4-octenoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-[1-(9-dodecenoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-1-(cis-9-hexadecenoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-LI-(9,12-octadecadienoyloxy)-3-hydroxy-2-propoxymethyl ] guanine;

9-[1-(9,12,15-octadecatrionoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-1-(2-butenoyloxy)-3-hydroxy-2-propoxymethyl]guanine; and

9-[1-(3-carboxypropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine, m.p. 191-192°C.

By removing the benzyl group catalytically and then proceeding as above, e.g. in a similar way the following compounds: 9-(1-hydroxyacetyloxy-3-hydroxy-2-propoxymethyl)guanine;

9-[1-(3-hydroxypropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine; and

9-[1-(4-hydroxybutanoyloxy)-3-hydroxy-2-propoxymethyl]guanine.

EXAMPLE 7

A double stoichiometric excess of 3% hydrogen chloride

in methanol is added to a solution of 1,0 and 9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine in 20 ml of methanol. Diethyl ether is added until precipitation is complete. The product is filtered, washed with ether, air dried and recrystallized to give 9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine hydrochloride.

In a similar way, all the compounds of formula I

in free base form is converted to the acid addition salts by treatment with the appropriate acid, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like.

EXAMPLE 8

1.0 g of 9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine-HCl suspended in 50 ml of ether is stirred with a double stoichiometric excess of dilute aqueous potassium carbonate solution until the salt is completely dissolved. The organic layer is then separated, washed twice with water, dried over magnesium sulfate and evaporated to give 9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine as the free base.

Alkali metal salts of mono- and diesters of formula I, in particular where R<7> is 1-adamantyl or 2-methyl-2-propyl, can be prepared according to the following example.

EXAMPLE 9

This example illustrates the preparation of representative pharmaceutical preparations containing an active compound of formula (I) such as 9-[1,3-di-(2,2-dimethylpropanoyloxy-2-propoxymethyl]guanine).

All the above ingredients, except water, are mixed and heated at 60°C with stirring. A sufficient amount of water at 60°C is added with vigorous stirring to give 100 g of cream preparation which is then cooled to room temperature.

The following preparation is suitable for intraperitoneal and intramuscular injection.

The active compound is dissolved in propylene glycol, polyethylene glycol 400 and "Tween" 80. A sufficient amount

0.9% saline is then added with stirring to give 100 ml of the IP or IM solution which is filtered through a 0.2 µm membrane filter and packaged under sterile conditions.

The following preparation is suitable for intravenous injection.

The active compound is added to a solution of polysorbate 80 and propylene glycol or polyethylene glycol 400 in 20 ml of water and mixed. The resulting solution is diluted with water to 100 ml and filtered through the appropriate 0.2 mm membrane filter.

The above ingredients are mixed and granulated using methanol as solvent. The preparation is then dried and formed into tablets (containing 200 mg of active compound) with a suitable tableting machine.

EXAMPLE 10

The very good antiviral activity of the compounds produced according to the invention is illustrated by the following investigation: Herpes simplex virus 2 strain G for infection is produced in HEp-2 cell cultures. Viruses are adsorbed for 1 hour, fresh medium is placed on the cells, and they are incubated at 35°C until all cells are infected. The cell suspension is frozen at -70°C, thawed and centrifuged to remove cell debris. The liquid on top is divided into portions and stored frozen in wood

-70°C until they are to be used. A 10~<6>,<7> dilution of the liquid

at the top gives a 50% cell culture infectious dose (CCID- ) i

-3 7

HEp-2 cells, and a 10' dilution gives a 50% lethal infection (LC,-q) in mice.

Groups of 20 female Swiss Webster mice (15-17 g) are infected intraperineally using 0.2 ml of EMEM containing 10 LCg0pr. mice of viruses. Mice infected with 10°'^ more or less virus than the 10 2LC^Q infection serve as a strength control to ensure that the model is working correctly.

Treatment with the test compounds begins 6 hours after infection. The mice, divided into groups of 20, receive the compounds administered subcutaneously in saline at a dose of 20 mg/kg.

One group of 20 mice is used as a control group and receives saline administered subcutaneously. The treatment is repeated 24, 48, 72 and 96 hours after infection.

The compounds produced according to the invention show antiviral activity in this test as illustrated in the following table.

EXAMPLE 11

Acute toxicity study in mice.

Groups of 5 male Swiss mice (Simonsen) weighing approx. 25 g was given subcutaneously the compounds indicated in the following table. As indicated, the sample material was only given on day 1, and the mice were observed daily for mortality for 21 days.

Claims (1)

Guanine derivatives, characterized by the formula: where R is hydrogen, halogen, thio, lower alkylthio with 1-6 carbon atoms, azido or NR^r <IO> where R <9> and R^-O independently of each other are hydrogen or lower alkyl with 1-6 carbon atoms; and r <6> is hydrogen, halogen, lower alkoxy of 1-6 carbon atoms, azido, thio, lower alkylthio of 1-6 carbon atoms or -NR<9> r10 where <R9>Q g Rio is as indicated above; with the proviso that when R<3> is hydrogen, R<6> is not NH2 or chlorine, or by the formula: .where R 1 is hydrogen, alkyl of 1-19 carbon atoms or 1-adamantyl.