NOVEL DERIVATIVES OF GUANINE

Abstract: Novel antiviral compounds of the formula wherein R₁ is hydrogen, R₂ is hydrogen, fluoro, methoxy or methylthio and R₃ is hydrogen, hydroxy or mercapto; with the provisos that when R₃ is hydrogen then R₂ is methoxy or methylthio and that when R₃ is hydroxy then R₂ is fluoro, methoxy or methylthio; and with the further proviso that R₁ can also be methoxy or fluoro when R₂ is methoxy or fluoro; and physiologically acceptable salts or optical isomers thereof, methods for their preparation, pharmaceutical compositions containing the compounds, and use of said compounds in the treatment of virus infections.

Description: NOVEL DERIVATIVES OF GUANINE I DESCRIPTION Field of the Invention The present invention relates to novel derivatives of guanine, methods for their preparation, novel pharmaceutical compositions and use of said compounds in the treatment of virus infections, such as herpes virus infections, which can cause various diseases in an animal or human host, including both common infections and neoplastic diseases, i.e. cancer. Background of the Invention The effects of viruses on bodily functions is the end result of changes occurring at the cellular and subcellular levels. The pathogenic changes at the cellular level are different for different combinations of viruses and host cells. While some viruses cause a general destruction (killing) of certain cells, other may transform cells to a neoplastic state. Important common viral infections are herpes dermatitis (including herpes labialis), herpes keratitis, herpes genitalis, herpes zoster, herpes encephalitis, infections mononucleosis and cytomegalovirus infections all of which are caused by viruses belonging to the herpesvirus group. Other important viral diseases are influenza A and B which are caused by influenza A and B virus respectively. Another important common viral disease is viral hepatitis and especially hepatitis B virus infections are widely spread. Effective and selective antiviral agents are needed for the treatment of these diseases as well as for other diseases caused by viruses. Several different viruses of both DNA and RNA type have been shown to cause tumors in animals. The effect of cancerogenic chemicals can on animals result in activation of latent tumor viruses. It is possible that tumor viruses are involved in human tumors. The most likely human cases known today are leucemias, sarcomas, breast carcinomas, Burkitt lymphomas, nasopharyngeal carcinomas and cervical cancers where RNA tumor viruses and herpes viruses are indicated. This makes the search for selective inhibitors of tumorogenic viruses and their functions an important undertaking in the efforts to treat cancer. Prior Art The compound 9-(4-hydroxybutyl)-guanine is disclosed in Chem. Pharm. Bull. 17 (1969) 1268-1270 and in Agr. Biol. Chem., 37 (1973) 2037-2043. However, no antiviral or other pharmacological activity has been disclosed for said compound. US 4 199 574 discloses a broad class of substituted purines of the formula EMI2.1 wherein X is oxygen or sulphur; R1 is hydrogen, halogen, hydroxy, alkoxy, azide, thio, alkylthio, amino, alkylamino, or dialkylamino; 3 R2 is hydrogen, halogen, alkylthio, acylamino, amino or azide; R3 is hydrogen, straight or branch chain or cyclic alkyl, hydroxyalkyl, benzyloxyalkyl, or phenyl; R4 is hydrogen, hydroxy or alkyl; RS is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzyloxy, benzoyloxy, benzoyloxymethyl, sulphamoyloxy, phosphate carboxypropionyloxy, straight chain or cyclic acyloxy having from 1 to 8 carbon atoms e.g., acetoxy or substituted carbamoyl group of formula NHCO-Z wherein Z is alkyl, aryl or aralkyl optionally substituted by one or more of sulphonyl, amino, carbamoyl or halogen; R6 is hydrogen or alkyl, provided that when X is oxygen and R2, R3, R4 and R6 are hydrogen, R1 is not amino or methylamino when R5 is hydrogen or hydroxy. These compounds are asserted to possess antiviral activity against various classes of DNA and RNA viruses. 9-(2-hydroxyethoxymethyl)guanine ad 2-amino-9-(2hydroxyethoxymethyl)adenine are mentioned as examples of expecially active compounds. Disclosure of Invention The present invention relates to the novel antiviral compound of the formula EMI3.1 wherein R1 is hydrogen, R2 is hydrogen, fluoro, methoxy or methylthio and R3 is hydrogen, hydroxy or mercapto; with the provisos that when R3 is hydrogen then R2 is methoxy or methylthio and that when R3 is hydroxy then R2 is fluoro, methoxy or methylthio; and with the further proviso that R1 can also be methoxy or fluoro when R2 is methoxy or fluoro; and physiologically acceptable salts or optical isomers thereof. It has been found that such compound exerts an antiviral effect aninhibits certain viral functions including tumorogenic functions and the multiplication of viruses. The invention thus provides a compound, and physiologicalAy acceptable salts thereof, which compounds are useful in therapeutic and/or prophylactic treatment of viral diseases and which may be useful in therapeutic and/or prophylactic treatment of cancer caused by viruses. An.effective selective antiviral agent with acceptable side effects should have a selective inhibiting effect on a specific viral function of the virus to be combated. It is, therefore, one object of the present invention to provide a novel method for combating virus infections using an antiviral agent which exerts a selective inhibiting effect on viral functions but which exerts only a negligible inhibiting'effect on functions of the host cells. The invention also relates to novel pharmaceutical compositions containing the antiviral agents. Although the present invention relates broadly to a novel method for combating virus infections in animals and man, and compounds to be used at such treatment, it will be particularly useful in the treatment of herpesvirus infections. An especially important area of use for the compounds of the present invention is in the treatment of herpesvirus infections. Among the herpesviruses may be mentioned Herpes simplex type 1 and 2, varicella (Herpes zoster), virus causing infectious mononucleosis (i.e. Epstein-Barr virus) and cytomegalovirus. Imrortant diseases caused by rrpesviruses are herpes dermatitis1 (including herpes lanielis), herpes genl tclis, herpes keratitis, herpes encephalitis and herpes voter. Another possible area of use for the compounds of the present invention are in the treatment of cancer and tumors, particularly those caused by viruses. This effect may be obtained in different ways, i.e. by inhibiting the transformation of virus-infected cells to a neoplastic statE, by inhibiting the spread of viruses from tran-sformed cells to other normal cells and by arresting the growth of virustransformed cells. A further area of use for the compounds of the present invention is in the inhibition of transformed cells due to the presence in these cells of specific herpesvirus enzymes like thymidine kinase. Possible areas of use for the compounds of the present invention with respect to cancer chemotherapy are treatment of leukemias, iymphomas including Burkitt lymphomas and Hodgkin's disease, sarcomas, breast carcinoma, nasopharyngeal carcinomas and cervical cancers in which viruses are indicated. Other possible areas of use for the compounds of the present invention with respect to cancer chemotherapy are treatment of multiple myeloma and cancer of the lungs (and bronchus), the stomach, the liver, the colon, the bladder, the lips, the bones, the kidneys, the ovary, the prostate, the pancreas, the skin (melanoma), the rectum, the salivary glands, the mouth, the esophagus, the testis, the brain (and cranial meninges), the thyroid gland, thE gallbladder (and ducts), the nose, the larynx, connective tissues, the penis, the vulvas, the vagina, the corpus uteri and the tongue. The invention furthermore provides A. A method for the treatment of diseases caused by viruses in animals including man, comprising administering to an animal so infected a therapeutically Effective amount of a compound of the formula I or a physiologically acceptable salt thereof. B. h method for inhibiting the multiplication of viru±,in particular herpesviruses, in animals including man, by administering to an animal'in need of such treatment a compound of the formula I. or a physiologically acceptable salt thereof in an amount sufficient for inhibiting said multiplication. C. A method for the treatment of virus induced neoplastic diseases in animals including man, by inhibiting the growth of cells expressing viral functions,- characterized by administering to an animal so infected a therapeutically effective amount of a compound of the formula or a physiologically acceptable salt thereof. D. A method for inhibiting the growth of virus-transformed cells in animals including man, characterized by administering to an animal in need of such treatment a compound of the formula I or a physiologically acceptable salt thereof in an amount sufficient for inhibiting said growth. E. A method for the treatment of virus-induced neoplastic diseases in animals including man, by inhibiting the multiplication of tumor viruses, characterized by administering to an animal in need of such treatment a compound of the formula I or a physiologically acceptable salt thereof in an amount sufficient for inhibiting such multiplication. F. A method for the treatment of neoplastic diseases in animals including man, characterized by administering to an animal a therapeutically effective amount of a compound of the formula I or a physiologically acceptable salt thereof. The invention also relates to the use of a compound of the formula I or a physiologically acceptable salt thereof, in each of the above given methods A, B, C, D, E and F. As stated previously the compound of the present invention has the formula EMI7.1 wherein R1 is hydrogen, R2 is hydrogen, fluoro, methoxy or methylthio and R3 is hydrogen, hydroxy or mercapto; with the provisos that when R3 is hydrogen then R2 is methoxy or methylthio and that when R3 is hydroxy then R2 is fl-uoro, methoxy or methylthio; and with the further proviso that R1 can also be methoxy or fluoro when R2 is methoxy or fluoro; including physiologically acceptable salts and optical isomers thereof. Preferred subgroups of said compounds in accordance with the invention are those wherein: (I) R3 is selected from hydrogen and hydroxy, R1 is selected from hydrogen, fluoro and methoxy and R2 is selected from fluoro, methoxy and methylthio, with the provisos that when R1 is hydrogen and R2 is fluoro then R3 is hydroxy and that when R1 is fluoro or methoxy then R2 is also fluoro or methoxy; or (II) R3 is hydrogen, R1 is selected from hydrogen, fluoro and methoxy and R2 is selected from hydrogen, fluoro, methoxy and methylthio, with the proviso that when R1 is fluoro or methoxy then R2 is also fluoro or methoxy; or (III) R1 and R2 are the same or different and are selected from hydrogen and fluoro, and R3 is selected from hydrogen and hydroxy, with the proviso that when R1 is hydrogen and R2 is fluoro then R3 is hydroxy; or (IV) R1 is selected from hydrogen and fluoro, R2 is selected from hydrogen, fluoro, methoxy and methylthio and R3 is selected from hydrogen and hydroxy, with the provisos that when R1 is hydrogen and R2 is fluoro then R3 is hydroxy and with the further proviso that when R1 is fluoro then R2 is fluoro or methoxy; or (V) R1 is selected from hydrogen, fluoro and methoxy, R2 is selected from hydrogen, fluoro, methoxy and methylthio and R3 is selected from hydrogen and hydroxy, with the provisos that when R1 is hydrogen and R2 is fluoro then R3 is hydroxy and that when R1 is fluoro or methoxy then R2 is also fluoro or methoxy; ; or (VI) R1 is selected from hydrogen and fluoro, R2 is selected from hydrogen, fluoro, methoxy and methylthio and R3 is selected from hydrogen and mercapto, with the provisos that when R1 and R2 are both hydrogen then R3 is mercapto; and that when R1 is fluoro then R2 is fluoro or methoxy; or (VII) R3 is selected from hydrogen and mercapto, R1 is selected from hydrogen, fluoro and methoxy and R2 is selected from hydrogen, fluoro, methoxy and methylthio, with the provisos that when R1 is hydrogen and R2 is hydrogen and fluoro then R3 is mercapto and that when R1 is fluoro or methoxy then R2 is also fluoro or methoxy; or (VIII) R1 and R2 are the same or different and are selected from hydrogen and fluoro and R3 is selected from hydrogen, hydroxy and mercapto with the provisos that when R1 and R2 are both hydrogen then R3 is mercapto and that when R1 is hydrogen and R2 is fluoro then R3 is selected from hydroxy or mercapto; or (IX) Rl and R2 are the same or different and are selected from hydro gen, fluoro and methoxy and R3 is selected from hydrogen, hydroxy and mercapto, with the proviso that when Rl and R2 are both hydrogen then R3 is me rcapto; or (X) R1 is hydrogen, R2 is selected from hydrogen, methoxy and methyl thio- and R3 is selected from hydrogen, hydroxy and mercapto, with the proviso that when R1 and R2 are both hydrogen, then R3 is mercapto; or (XI) R1 is hydrogen, R2 is selected from hydrogen, fluoro, methoxy and methylthio and R3 is selected from hydrogen, hydroxy and mercapto, with the provisos that when R2 is fluoro then R3 is selected from hydroxy and mercapto and that when R1 and R2 are both hydrogen then R3 is mercapto; or (XII) R1 is hydrogen, R2 is selected from hydrogen and fluoro and R3 is selected from hydrogen, hydroxy and mercapto, with the provisos that when R2 is hydrogen then R3 is mercapto and that when R2 is fluoro then R3 is selected from hydroxy and mercapto; or (XIII) R1 is hydrogen, R2 is selected from hydrogen, fluoro, methoxy and methylthio and R3 is selected from hydrogen, hydroxy and mercapto, with the provisos that when R2 is hydrogen or hydroxy then R3 is mercapto and that when R2 is fluoro then R3 is selected from hydroxy and mercapto. The provisos in the definition for the groups R1, R2 and R3 above mean that the following specific compounds, including salts and optical isomers thereof, constitute part of the present invention: EMI10.1 The compounds of the formula I contain one or two asymmetric centers. Accordingly, they exist in two or four optical forms, respectively, and all such forms as well as the diastereomeric isomers constitute a further aspect of the invention. Methods of Preparation The compounds of the invention may be obtained by one of the following methods A-D constituting a further aspect of the invention. A. Condensing an acyclic side chain, where the functional groups may optionally be protected, to the N-9 position of a guanine derivative, followed by removal of the protecting groups, through one or more chemical reactions. EMI11.1 EMI12.1 wherein R1 and R2 has the meaning given above, X is a group such as chlorine, bromine, iodine or a group OS02Rlo where R10 is alkyl containing 1-8 carbon atoms, fluorinated alkyl containing 1-8 carbon atoms such as trifluoromethyl, alkylaryl such as benzyl or aryl. Y is hydrogen or a quarternary ammonium ion such as for example tetrabutylammonium. R5 is R3 as defined above, or OR6 or SR6 where R6 is hydrogen or a hydroxyl protecting group of which a great variety is known to those skilled in the art and are described for example in "Protective Groups in Organic Chemistry" (T.W. Greene, Wiley 1981), "Methoden der Organischen Chemie" (Houben-Weyl)" VI/Ib, or in "Comprehensive Organic Chemistry" (D.H.R. Barton and W.D. Ollis eds., 1979) Vol. 1, p. 623-629. Just some examples of R6 are acyl groups such as acetyl or benzoyl, alkoxy carbonyl or aryloxycarbonyl groups, silyl groups such as for example tert.-butyl dimethylsilyl, alkylaryl such as benzyl and triarylmethyl, or S02R10 where R10 is as defined above. R5 and OR6 may together form an epoxide when R3 is OH and R5 and OR6 may additionally form a cyclic derivative such as for example a carbonate ester or carbonate thioester or the corresponding orthoacid cyclic derivatives or cyclic acetal type compounds. R7 is hydroxyl, chlorine, bromine, iodine, thiol, thioeter, S02R10 where Rlo is as defined above; or an oxygen derivative OR12 where R12 is alkyl, alkylaryl such as benzyl, substituted silyl, phosphoryl diester, phosphinothioyl or S02R10 where R10 is as defined above. R8 and Rg are the same or different and are R11 where R11 is hydrogen or an amine protecting group known to those skilled in the art and described for example in "Protective Groups in Organic Chemistry" (T.W. Greene, Wiley 1981), "Methoden der Organischen Chemie (Houben Weyl)" XI/1 p. 1005 cont., or in "Comprehensive Organic Chemistry" (D.H.R. Barton and W.D. Ollis eds., 1979) Vol. 2, p. 49-52. Some examples of R11 are acyl groups, alkoxycarbonyl or aryloxycarbonyl groups, or silyl groups. The condensation is preferably conducted in an organic solvent such as for example dimethylformamide, ethanol, acetonitrile or dichloromethane, at- a temperature of between 0 C and 100 C for 1 hour to 3 days in the presence of a base (when Y is H) such as for example potassium carbonate. After condensation, the compounds are hydrolyzed at 0-1000C for 1-24 hours with acid or base such as for example acetic acid, hydrochloric acid (1-35%) in water, sodium hydroxide (1-20%) in water, ammonia (1-25%) in water or methanol, or hydrogenated with hydrogen gas in an organic solvent such as for example ethanol or dimethylformamide over a metal catalyst for 1-24 hours at a pressure of 0.1-5 MPa. B 1. By substitution reactions on a guanine N-9 derivatized 4-carbon side-chain. EMI13.1 EMI14.1 R6, R8 and R9 are as defined above. R53 is R1, iodine or OS02Rlo, R14 is R2, iodine or OS02Rlo, R15 is R3, iodine or OSO,R10 where R1, R2, R3 and R10 are as defined above. The substitution reactions are performed in an organic solvent such as dimethylformamide, ethanol, acetonitrile or dichloromethane at a temperature of between 0 C and 100 C for 1-24 hours and the substituting reagent will be hydrogen fluoride, methanol, methane thiol, water, ammonia or hydrogen sulfide or their respective ions or ion pairs. When R6, R8 and Rg are not hydrogen then in a following reaction step R8 and Rg are removed according to method A. B 2. By reduction of an ester group to an alcohol. EMI14.2 EMI15.1 R1, R2, R5, R7, R8, Rg and R10 are as defined above. The reduction may be performed by hydrogen gas or hydrogen generated in situ, with a metal as catalyst or with a hydride reducing agent in an organic solvent. C 1. Pyrimidine ring closure to the guanine base of a substituted imidazole derivative EMI15.2 wherein R1, R2, R5 and R6 are as defined above, Z is NH2 or alkoxy i.e. C0Z is an amide or ester group and R16 is NH2, or guanidine. The ring closure may be performed by known methods, the principles of which are given for example in "Comprehensive Organic Chemistry" p. 505-508 (1979, vol. 4, D.H.R. Barton and W.D. Ollis eds.). The ring closure is performed in an organic solvent at a temperature from 50 to 250"C with or without the addition of a reagent such as for example guanidine. When R6 is not H and R5 is not R3, then the side chain protecting groups are removed in a following reaction step according to method A. C 2. Imidazole ring closure, to the guanine base, of a substituted pyrimidine derivative. EMI16.1 wherein R1, R2, R5 and R6 are as defined above and R17 is nitroso, nitro, amino, or an amino derivative such as formic amide (-NH-CHO) or amino ortho ester EMI17.1 The ring closure may be peformed by known methods, the principles of which are given for example in "Comprehensive Organic Chemistry" p. 499-504 (1979, Vol. 4, D.H.R. Barton and W.D. Ollis eds.). The ring closure may be performed in an organic solvent such as for example formic acid, formamide, orthoformate ester at a temperature from 50 to 2500C for 1/2 hour to 10 hours. When R17 is nitroso or nitro, these groups first have to be reduced to amino groups by known methods. When R6 is not H and R5 is not R3, then the side chain protecting groups are removed in a following reaction step according to method A. D. Substitution in the pyrimidine ring of a purine to the formation of a guanine ring EMI17.2 R1, R2, R5, R6 and Hal have the meaning given above and R18 is hydroxyl or amino. The halogen atoms are substituted by ammonia in an organic solvent such as methanol, from normal to higher pressure at room temperature to 100 C for 1 to 25 hours or by an azide ion followed by hydrogenation by known methods. When R18 is amino the amino group can be substituted to a hydroxyl function by selective diazotization with nitrite in a solvent such as acetic acid at a temperature from 0 C to 500C for 1-24 hours, or enzymatically with adenosinedeaminase in water at a pH from 6 to 9 from 1 to 48 hours. When R6 is not hydrogen and R5 is not R3, then the side chain protecting groups are removed in a following reaction step according to method A. The described methods A-D may be used to give mixtures of diastereomers and optical isomers, or in appropriate cases a single diastereomer or a single optical isomer. Additionally a single optical isomer may be obtained from the optical mixtures by methods known per se. The starting materials in the above methods A-D are either known compounds or can be prepared by methods known to those skilled in the art. Salts Physiologically acceptable salts of compounds of the invention are prepared by methods known in the art. The salts are novel compounds and comprise a further aspect of the invention. Metal salts can be prepared by reacting a metal hydroxide with a compound of the invention. Examples of metal salts which can be prepared in this way are salts containing Li, Na and K. A less soluble metal salt can be precipitated from a solution of a more soluble salt by addition of a suitable metal compound. Acid salts can be prepared by reacting a compound of the invention with an acid as HC1, HBr, H2S04, or an organic sulphonic acid. Pharmaceutical compositions Pharmaceutical compositions of the compounds of the invention constitute a further aspect of the invention. In clinical practice the compounds of the invention may be administered locally or systemically. They will normally be administered topically, orally, intranasally, by injection or by inhalation in the form of a pharmaceutical composition comprising the active ingredient in the form of the original compound or optionally in the form of a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier which may be a solid, semi-solid or liquid diluent or an ingestible capsule, and such compositions comprise a further aspect of the invention. The compound may also be used without carrier material. As examples of pharmaceutical compositions may be mentioned tablets, drops, such as nasal drops, eye drops, preparations for topical application such as ointments, jellies, creams and suspensions, aerosols for inhalation, nasal spray, liposomes etc. Usually the active substance will comprise between 0.01 and 99, or between 0.1 and 99% by weight of the composition, for example between 0.5 and 20% for compositions intended for injection and between 0.1 and 50% for compositions intended for oral administration. The compositions are preferably in dosage unit form. Further, they are preferably provided in sterilized form. To produce pharmaceutical compositions in the form of dosage units for oral application containing a compound of the invention the active ingredient may be mixed with a solid, pulverulent carrier, for example lactose, saccharose, sorbitol, mannitol, a starch such as potato starch, corn starch, amylopectin, laminaria powder or citrus pulp powder, a cellulose derivative or gelatine and- also may include lubricants such as magnesium or calcium stearate or a Carbowaxe or other polyethylene glycol waxes and compressed to form tablets or cores for drawees. If drags are required, the cores may be coated for example with concentrated sugar solutions which may contain gum arabic, talc and/or titianium dioxide, or alternatively with a film forming agent dissolved in easily volatile organic solvents or mixtures of organic solvents. Dyestuffs can be added to these coatings, for example, to distinguish between different contents of active substance. For the preparation of soft gelatine capsules consisting of gelatine and, for example, glycerol and a plasticizer, or similar closed capsules, the active substance may be admixed with a CarbowaxX or a suitable oil as e.g. sesame oil, olive oil, or arachis oil. Hard gelatine capsules may contain granulates of the active substance with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starches (for example potato starch, corn starch or amylopectin), cellulose derivatives or gelatine, and may also include magnesium stearate or stearic acid as lubricants. By using several layers of the active drug, separated by slowly dissolving coatings sustained release tablets are obtained. Another way of preparing sustained release tablets is to divide the dose of the active drug into granules with coatings of different thicknesses and compress the granules into tablets together with the carrier substance. The active substance can also be incorporated in slowly dissolving tablets made for instance of fat and wax substances or evenly distributed in a tablet of an insoluble substance such as a physiologically inert plastic substance. Liquid compositions for oral application may be in the form of elixirs, syrups or suspensions, for example solutions containing from about 0.1% to 20% by weight of active substance, sugar and a mixture of ethanol, water, glycerol, propylene glycol and optionally aroma, saccharine and/or carboxymethylcellulose as a dispersing agent. For parenteral application by injection compositions may comprise an aqueous solution of the active drug or a physiologically acceptable salt thereof, desirably in a concentration of 0.05-10%, and optionally also a stabilizing agent and/or buffer substances in aqueous solution. Dosage units of the solution may advantageously be enclosed in ampoules. For topical application, especially for the treatment of herpesvirus infections on skin, genitals and in mouth and eyes the compositions are suitably in the form of a solution, ointment, gel, suspension, cream or the like. The amount of active substance may vary, for example between 0.05-20% by weight of the active substance. Such compositions for topical application may be prepared in known manner by mixing the active substance with known carrier materials such as isopropanol, glycerol, paraffin, stearyl alcohol, polyethylene glycol, etc. The pharmaceutically acceptable carrier may also include a known chemical absorption promoter. Examples of absorption promoters are e.g. dimethylacetamide (US 3,472,931, trichloroethanol or trifluoroethanol (US 3,891,757), certain alcohols and mixtures thereof (GB 1,001,949). The dosage at which the active ingredients are administered may vary within a wide range and will depend on various factors such as for example the severity of the infection, the age of the patient, etc., and may have to be individually adjusted. As a possible range for the amount of the compounds of the invention which may be administered per day may be mentioned from about 0.1 mg to about 2000 mg or from about 1 mg to about 2000 mg, or preferably from 1 mg to about 2000 mg for topical administration, from 50 mg to about 2000 mg or from 100 to about 1000 mg for oral administration and from 10 mg to about 2000 mg or from 50 to about 500 mg for injection. In severe cases it may be necessary to increase these doses 5-fold to 10-fold. In less severe cases it may be sufficient to use up to 500 or 1000 mg. The pharmaceutical compositions containing the active ingredients may suitably be formulated so that they provide doses within these ranges either as single dosage units or as multiple dosage units. Thus, it has been found according to the invention that the compounds of the formula I and the physiologically acceptable salts thereof can be used to inhibit herpesvirus multiplication. The compounds of the formula I and physiologically acceptable salts thereof are useful in therapeutic and/or prophylactic treatment of virus infections. A preferred aspect of the invention is the use of the compounds of the formula I or a physiologically acceptable salt thereof, in the treatment of herpesvirus infections. Working Examples The following examples illustrate the preparation of compounds according to the invention. Example 1. 9-(4-hydroxy-2,2-dimethoxybutyl)guanine EMI23.1 A small amount of 9-(2-oxo-4-hydroxybutyl)guanine (1.0 mg) was dissolved in dry methanol (2.5 ml) and molecular sieve 3A (0.5 g) was added. The stirred solution was treated with hydrogen chloride saturated methanol (5 drops) and kept at room temperature for 24 h. Molecular sieve 5 (0.5 g) was added and the solution was stirred for a few minutes. The reaction mixture was filtered and the filtrate was evaporated to dryness. The product was analyzed by reverse phase high performance liquid chromatography (Waters HPLC, radial pak column RP-18 8x100 mm, watermethanol 7:3, 2 m-l/min). The relative retention times for the starting material and the desired product were 2.13 and 4.95 respectively. 9-(2-oxo-4-hydroxybutyl)guanine used as a starting material was prepared as follows: a) 3-Hydroxybutyl o-chlorobenzoate EMI23.2 Butan 1,3-diol (1.0 g) was dissolved in pyridine (50 ml) and cooled to OOC. Ortho-chlorobenzoylchloride (1.9 g) was added with stirring. The reaction mixture was kept at 0 C for 1 hour and then at room temperature over night. The solution was poured with stirring into ice-water (--00 ml). After stirring for 15 min the aqueous mixture was extracted with chloroform. The combined chloroform extracts were washed with ice-cold 0.25 M aqueous sulfuric acid, saturated aqueous sodium hydrogen carbonate and water. The dried solution (sodium sulfate) was concentrated to a syrup and purified by silica gel column chromatography (toluene-ethyl acetate 1:1) to yield chromatographically pure 3-hydroxybutyl o-chlorobenzoate (1.92 g) RF: 0.56, TLC in the same solvent. NMR (CDCl3): 1.24 (3H,d,-CH3), 1.63-2.10 (2H,m,-CH2-), 3.69-4.23 (lH,m, -CH-), 4.29-4.66 (2H,m,-CH2-) OH 7.13-7.52 (3H,m, aromatic protons), 7.63-7.92 (lH,m, aromatic proton). b) 3-Oxobutyl o-chlorobenzoate EMI24.1 Pyridinium chlorochromate adsorbed to aluminium oxide (33 g, 32.8 mmol) (CrO3tC5H5N HCl prepared according to Yu-Shia Cheng et al., Synthesis, March 1980) was added to 3-hydroxybutyl o-chlorobenzoate (1.8 g, 7.8 mmol; prepared according to a)) in n-hexane (100 ml). After stirring at room temperature over night the solid was filtered and the filtrate evaporated to dryness to give 1.21 g of 3-oxobutyl o-chlorobenzoate (TLC toluene-ethyl acetate 1:1, Rf 0.74). 1H NMR (CDCl3): 62.21 (3H,s-CH3), 2.81 (2H, triplet -COCH2-) 4.54 (2H, triplet -CH2O-), 7.0-7.45 (3H,m, aromatic protons) 7.45-7.84 (lH,m, aromatic proton). c) 4-Bromo-3-oxcbutyl o-chlorobenzoate EMI25.1 3-Oxobutyl o-chlorobenzoate (670 mg, 2.96 mmol; prepared according to b)) was dissolved in anhydrous methanol (10 ml). The solution was stirred and cooled in an icebath, and bromine (0.15 ml, 2.96 mmol) was added rapidly. The reaction mixture was kept at +5"C for 18 h. Water (7 ml) and concentrated sulfuric acid (0.6 ml) were added and the mixture was stirred at room temperature over night. Water (10 ml) was added to the solution and the aqueous mixture was extracted with chloroform. The combined chloroform extracts were washed with saturated aqueous sodium hydrogen carbonate and water. The dried solution (sodium sulfate) was concentrated to a syrup and purified by silica gel column chromatography (toluen-e-ethyl acetate 16:1) to yield pure 4-bromo-3-oxobutyl o-chlorobenzoate 385 mg (TLC in the same solvent Rf 0.40). 1H NMR (CDC13): t 3.12 (2H, triplet COCH2), 3.87 (2H, singlet EMI25.2 4.57 (2H, triplet -CH20), 7.12-7.48 (3H,m, aromatic protons), 7.48-7.81 (1H, aromatic proton). d) 4-(2-Amino-6-chloropurin-9-yl )-3-oxobutyl o-chlorobenzoate EMI25.3 2-Amino-6-chloropurine (36.6 mg, 0.216 mmol) and anhydrous potassium carbonate (30.0 mg, 0.216 mmol) were mixed with dimethylformamide (7 ml). The mixture was cooled in an icebath and 4-bromo-3-oxobutyl o-chlorobenzoate (66 mg, 0.216 mmol; prepared according to c)) in dimethylformamide (1 ml) was added. After stirring at room temperature for 18 h, the mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by preparative silica gel layer chromatography (chloroform-methanol 6:1) to yield pure 4-(2-amino-6-chloropurin-9-yl) -3-oxobutyl o-chlorobenzoate (18 mg). TLC in the same solvent, Rf: 0.40. NMR (DMSO-d6): 63,15 (2H, triplet-COCK2-), 4.26 (2H, triplet, -CH20-) 5.09 (2H, singlet -NCH2-CO-), 6.96 (2H, singlet, NH2 purine residue) 7.437.63 (3H,m, aromatic protons), 7.83-7.95 (lH,m, aromatic proton), 8.06 (lH,s,H-8, purine). e) 9-(2-Oxo-4-hydroxybutyl )guanine EMI26.1 4-(2-Amino-6-chloropurin-9-yl )-3-oxobutyl o-chlorobenzoate (18 mg; prepared according to d)) was dissolved in 1M hydrochloric acid (20 ml) and refluxed for three hours. The solution was made alkaline with diluted ammoniumhydroxide and evaporated to dryness. The residue was purified by preparative HPLC on a reverse phase column (p Bondapack C18 methanolwater 1:3), followed by chromatography on a Biogel P-2 column eluated with water. The residue, 5.4 mg, was a white solid which gave a single peak on HPLC (same solvent system as above). NMR (DMSO-d6): L3.1 (2H, triplet, -COCH2-), 4.1 (2H, -NCH2CO-), 4.3 (2H, triplet, -CH20-), 6.6 (2H, singlet, NH2, purine residue), 7.7 (1H, singlet H-8, purine). Example 2. 9-(3-Mercapto-4-hydroxybutyl )guanine EMI27.1 9-(3-Mercapto-4-t- butyldimethylsilyloxybutyl)guanine was dissolved in 80% acetic acid and heated on a steam bath for 1 hour. The solution was made alkaline with aqueous ammonia and concentrated. The residue was purified by preparative HPLC on a reverse phase column (u Bondapack C18 methanol-water 10:90) to give a single peak. The starting compound, 9-(3-mercapto-4-t-butyidimethylsilyloxybutyl)gua- nine was prepared as follows: a) 4-Bromo-2-hydroxybutyric acid ethyl ester EMI27.2 2-Hydroxybutyrolactone, GB 688.253 [CA 48 p. 3996 (1954)], (5.1 g) was dissolved in 10 ml ethanol and the solution was saturated with hydrogen bromide at 0 C. After standing at room temperature during 66 hours, the solvent was evaporated at a low pressure. The residue was mixed with ice-water and the mixture neutralized with 10% aqueous sodium carbonate. The mixture was then extracted several times with dimethyl ether and the combined ether extracts washed with saturated, aqueous sodium sulphate and dried over anhydrous sodium sulphate. After evaporation of the solvent, the residue was distilled at 1,6 kPa. The fraction boiling at 109-112"C weighing 3.79 g was used in b) below. b) 4-(2-Amino-6-chloropurin-9-yl )-2-hydroxybutyric acid ethyl ester EMI28.1 2-Amino-6-chloropurine (0.509 g, 3.00 mmole), 4-bromo-2-hydroxybutyric acid ethyl ester (0.633 g, 3.00 mmole; prepared according to a) and anhydrous potassium carbonate (0.415 g, 3.00 mmole) were mixed with 10 ml of dimethyl formamide and the mixture stirred at room temperature during 65 hours. The mixture was then filtered and the filtrate evaporated at a pressure of 0.01 kPa. The crystalline residue was triturated with 8 ml of chloroform and the undissolved material filtered off and washed with 2 ml of chloroform. The material obtained was then triturated with 5 ml of water and the undissolved material filtered off and washed with 2 ml of water. Recrystallization from 11 ml of ethanol gave 0.360 g product. M.P. 163-4"C (uncorr.) UV spectrum(ethanol): > max (nm) 311, 248. Analyses - Found: C 43.90; H 4.78; Cl 11.72; N 23.52; 0 15.90%. Calculated for C11H14C1N503: C 44.08; H 4.71; C1 11.83; N 23.37; 0 16.01%. c) 4-(2-Amino-1 ,6-dihydro-6-oxopurin-9-yl )-2-hydroxybutyric acid EMI28.2 4-(2-Amino-6-chloropurin-9-yl )-2-hydroxybutyric acid ethyl ester (1.40 g, 4.67 mmole; prepared according to b) in 100 ml of 1M aqueous hydrochloric acid was refluxed during 2.5 h. The solution was then evaporated at a pressure of about 1.3 kPa. Water (25 ml) was added to the residue and the solution evaporated again. This procedure was repeated 4 times. The residue was triturated with 150 ml of acetone and the semi-solid material filtered off to yield 1.38 g. This crude product (1.27 g) was partly dissolved in 5 ml of water, the solution was filtered and the undissolved material washed with 2.5 ml water. The pH of the filtrate was then adjusted to 6-7 with solid sodium bicarbonate. The water solution obtained was filtered and undissolved material washed with 7.5 ml water. 0.4 ml of acetic acid was then added to the filtrate. After cooling to 0 C, the precipitate was filtered off and washed with 3 ml of water. Recrystallization from 75 ml of water gave 0.68 g product. M.p. > 250 C (dec.). UV spectrum(0.lM hydrochloric acid): nm) 279, 254; UV spectnul(O.lM-sodium hydroxide): Xmax(nm) 269, 256 (info.). Analyses - Found: C 42.63; H 4.41; N 27.74; 0 25.30%. Calculated for CgHllN504: C 42.69; H 4.38; N 27.66; 0 25.27. d) 4-(2-Amino-l ,6-dihydro-6-oxopurin-9-yl )-2-hydroxybutyric acid ethyl ester EMI29.1 4-(2-Amino-l ,6-dihydro-6-oxopurin-9-yl )-2-hydroxybutyric acid (2.00 g, 7.9 mmole; prepared according to c)) was mixed with 500 ml of ethanol. The mixture was saturated with hydrogen chloride gas, first without cooling and then with cooling in ice-water. The total addition time was about 15 minutes. The mixture was then slowly warmed to room temperature and allowed to stand over night. After evaporation of the solvent, the residue was treated three times each with 25 ml of ethanol, the solvent being reevaporated after each treatment. The residue was then dissolved in 12 ml of water and the pH adjusted to 6-7 with saturated aqueous sodium bicarbonate. The precipitate was filtered off, washed with 2 ml of water and dried in vacuo to yield 1.60 g. Recrystallization from ethanol gave a pure product, m.p. 161-3"C (a sample for analysis had m.p. 162-3oC). Analyses - Found: C 46.96; H 5.35; N 24.77; 0 22.60%. Calculated for C11H15N504: C 46.97; H 5.38; N 24.90; 0 22.75%. e) 9-(3,4-Dihydroxybutyl )guanine EMI30.1 To a suspension of ethyl 4-(2-amino-1,6-dihydro-6-oxopurin-9-yl)-2- hydroxybutyrate (prepared according to d)) in isopropanol was added an excess of sodium borohydride and the mixture was refluxed over night (at least 8 hours). Hydrochloric acid was added until a clear solution was obtained (neutral pH). After removal of the solvent the residue was dissolved in a minimum amount of boiling water and kept at 0 C for a couple of hours. The solid was filtered off. The filtrate was evaporated at reduced pressure and the residue dissolved in hydrochloric acid (1 mol/litre) and adsorbed on a cation exchange resin (Dowex 50 W, H+-form). The resin was washed with water and then eluted with 5% ammonium hydroxide. The eluent was evaporated to give a crystalline solid which was recrystallized from water to afford colourless needles. M.p. 260-10C (dec.) (uncorrected) UV spectrum (hydrochloric acid 0.01 mol/litre): AmaX(nm) 277, 253 (E=11500) M.S.: 11.2 a J. (int): 239 (M+, 0.13), 222 (0.19), 221 (0.11), 152 (0.43), 151 (0.56), 44 (1.0). f) 9-(4-t-Butyldimethyl silyloxy-3-hydroxybutyl) guanine EMI30.2 A mixture of 9-(3,4-dihydroxybutyl)guanine (66 mg, 0.276 mmol; prepared according to e)), t-butyidimethylchlorsilane (80 mg, 0.53 mmol), and imidazole (55 mg, 0.81 mmol) in 3.5 ml of dry dimethylformamide was stirred at room temperature for 2h, and the solvent was evaporated in vacuo. The semi-solid residue was triturated with a little diethyl ether and aqueous sodium hydrogencarbonate solution, washed with water and dried in vacuo to yield 89 mg of a crude product. Chromatography (15 g of silica gel, chloroform-methanol 5:1 by volume) afforded 68 mg of mono-TBDMSi derivative. M.p. 235.5-240.5"C. 1H NMR (DMSO-d6): s0.02 (s, 6H) Si(CH3)2; 0.85 (s, 9H) C(CH3)3; 1.55-1.8 and 1.9-2.1 (2m, 2H) -C-CH2, 3.35-3.6 (m, 3H) CHCH2; 4.0-4.1 (m, 2H) NCH2; 6.3 (broad s, 2H) NH2; 7.6 (s, 1H) H8. 13C NMR (DMSO-d6): The 13C NMR spectrum was in agreement with the postulated structure. A downfield shift of C-4 from 65.925 [in 9-(3,4-dihydroxybutyI)guanine] to 67.336 ppm was observed. g) 9-(3-Thioacetyl-4-t-butyidimethylsilyloxybutyl)guanine EMI31.1 Diisopropylazodicarboxylate (75 mg, 0.37 mmol; cf. R.P. Volante, Tetrahedron letters vol. 22, No. 33, pp 3119-3122, 1981) was added to a solution of triphenylphosphine (97.6 mg, 0.37 mmol) in dimethylformamide (2 ml) at 0 C. The mixture was stirred at 0 C for 30 min, 9-(3-hydroxy-4-t-butyldimethylsilyloxybutyl)guanine (50 mg, 0.16 mmol; prepared according to f)) in dimethylformamide (2 ml) and thioacetic acid in 1 ml dimethylformamide (28 mg, 0.37 mmol) was added dropwise and the solution was stirred at 0 C for 1 h, at 20"C over night and at 800C for 4 hours. The solution was concentrated and puri fied by preparative thin layer chromatography (elution with chloroformmethanol 5:1) -to yield 10 mg of 9-(3-thioacetyl-4-t-butyldimethyl- silyloxybutyl)guanine. Rf 0.38 (chloroform- methanol 8:1). 1K NMR (DMSO-d6): s0.02 (s, 6H) (CH3)2Si; 0.85 (s, 9H) C(CH3)3; 2.3 (s, 3H) CH3COS; 4.0 (AB quartet, 2H) NCH2, 6.4 (s, 2H) H2N; 7.7 (s, 2K) H8. h) 9-(3-Mercapto-4-t-butyidimethylsilyloxybutyl)guanine EMI32.1 9-(3-Thioacetyl-4-t-butyldimethylsilyloxybutyl)guanine (10 mg; prepared according to g)) was dissolved in methanol (10 ml), saturated with ammonia and kept at room temperature for 1 h. Thin layer chromatography (chloroform-methanol --5:1-) showed the absence of starting material and the solution was concentrated to give 9-(3-mercapto-4-t-butyidimethylsilyl- oxybutyl)guanine. Rf = 0.32 (chloroform-methanol 5:1). Mass spectrometry revealed the presence of a sulfhydryl group. The following examples illustrate the preparation of pharmaceutical compositions of the invention. The wording "active substance" denotes a compound according to the present invention or a salt thereof. Tablets Each tablet contains: Active substance 20.0 mg Maize starch 25.0 mg Lactose 190.0 mg Gelatin 1.5 mg Talc 12.0 mg Magnesium stearate 1.5 mg 250.0 mg Suppositories Each suppository contains: Active substance 20.0 mg Ascorbyl palmitate 1.0 mg Suppository base (Imhausen H or WitepsolH) ad 2000.0 mg Syrup Active substance 0.200 g Liquid glucose 30.0 g Sucrose 50.0 g Ascorbic acid 0.1 g Sodium pyrosulfite 0.01 g Disodium edetate 0.01 g Orange essence 0.025 g Certified colour + 0.015 g Purified water ad 100.0 g Injection solution Active substance 3.000 mg Sodium pyrosulfite 0.500 mg Di sodium edetate 0.100 mg Sodium chloride 8.500 mg Sterile water for injection ad 1.00 ml Sublingual tablets Active substance 5.0 mg Lactose 85.0 ing Talc 5.0 mg Agar 5.0 mg 100.0 mg Jelly Active substance 1.0 g <RTI ID=34.2> Methocele 4.0 g Methyl paraoxybenzoate 0.12 g Propyl paraoxybenzoate 0.05 g Sodium hydroxide and hydrochloric acid to pH 6.7 Distilled water ad 100.0 ml Ointment I Active substance 1.0 g Cetyltrimethylammoniumbromide 0.6 g Stearyl alcohol 2.25 g Cetanol 6.75 g Liquid paraffine 17.0 g Glycerol 12.0 g Hydrochloric acid to pH 6.5 Distilled water ad 100.0 g Ointment II Active substance 3.0 g Polyethylene glycol 1500 50.0 g Polyethylene glycol 4000 15.0 g Propylene glycol ad 100.0 g Ointment III Active substance 3.0 g Sorbitan monoleate 5.0 g Petrolatum ad 100.0 g Ointment IV Active substance 5.0 g Adeps lane 20.0 g Tweeny 60 4.0 g Spans 40 2.0 g Paraffin, liquid 4.0 g Propylene glycol 5.0 g Hydrochloric acid to pH 6.5-8 Sterile water ad 100.0 g Ointment V Active substance 5.0 g Adeps lane 20.0 g Tweeny 60 4.0 g Spans 40 2.0 g Paraffin, liquid 4.0 g Propylene glycol 5.0 g Boric acid 2.0 g Sodium hydroxide to pH 6.5-8 Sterile water ad 100.0 g Eye drops I Active substance 0.1 g Disodium edetate 0.10 g Sodium chloride for isotonia q.s. Hydrochloric acid to pH 6.5-8 Methocele 65 HG 4000 0.65 g Sterile water ad 100.0 ml Eye drops II Active substance 0.3 g Di sodium edetate 0.10 g Sodium chloride for isotonia q.s. Hydrochloric acid to pH 6.5-8 Methocelo 65 HG 4000 0.65 g Sterile water ad 100.0 ml Eye drops III Active substance 0.2 g Di sodium edetate 0.1 g Sodium chloride for isotonia q.s. Boric acid 0.1 g Methocels 65 HG 4000 0.65 g Sterile water ad 100.0 ml Eye ointment I Active substance 3.0 g Paraffin oil 19.0 g Petrolatum 78.0 g Cream Active substance 3.0 9 ArlatonO 4.0 g Cetanol 2.0 g Stearic acid 2.0 g Paraffin oil 2.0 g Propylene glycol 2.0 g Glycerol 1.5 g Methyl-p-hydroxybenzoate 0.06 g Propyl-p-hydroxybenzoate 0.03 g Sodium hydroxide 0.002 g Hydrochloric acid 2M to pH 8.0 (water phase) Distilled water to 100.0 9 Jelly Active substance 3.0 g Methocel 2.45 g Glycerol 10.0 g Tweeny 0.10 g Methyl-p-hydroxybenzoate 0.06 g Propyl-p-hydroxybenzoate 0.03 g Sodium hydroxide 0.002 g Hydrochloric acid 2M to pH 8.0 Distilled water to 100.0 g Tablets Each tablet contains: : Active substance 100.0 mg Starch 60.0 mg Lactose 190.0 mg Polyvinylpyrrolidone 5.0 mg Magnesium stearate 5.0 mg 360.0 mg Example 3. rac. threo-9-(3,4-Dihydroxy-2-fluorobutyl)guanine EMI39.1 A solution of rac. threo-4-(2-amino-6-chloropurin-9-yl) -3-fluoro-O,O-isopropylidenebutane-1 ,2-diol 483 ing) in 1 ml of 2 M hydrochloric acid was kept at 100 C for 2 h and then evaporated to dryness in vacuum. The residue was dissolved in 10 ml of water and the solution neutralized by addition of weak anion exchange resin (OH form), heated to boiling and filtered warm. Upon cooling 42 mg (62%) of white crystals were obtained. Mp. ca. 2770C. UV spectrum, lambda-max (nm): 0.01 M HCl 253 (276) H2 (pH 7) 251 (270 infl.) 0.01 M NaOH 266 (255 infl.). 13C NMR, 50.10 MHz (DMSO-d6): ppm 157.02 (C6); 153.84 (C2); 151.57 (C4); 137.93 (C8); 116.69 (C5); 92.49, 88.94 178 P 178 Hz, CHF); 70.56, 70.18 (Jc-c-F 18.3 Hz,CHO); 61.52, 61.42 (JC-C-C-F 4e9 Hz, CH2O); 44.23, 43.76 (JC-C-F 23.2 Hz, NCH2). The starting compound rac. threo-4-(2-amino-6-chloropurin-9yl)-3-fluoro-0,0-isopropylidenebutane-l,2-diol was prepared as follows a) rac. lr2-Dideoxy-l-bromo-2-fluoro-3,4-0-isopropylidene- threitol EMI39.2 This compound was synthesized in 45% yield from rac. 2-deoxy -2-fluoro-3,4-O-isopropylidenethreitol (R. Cherry and P. W. Kent, J. Chem. Soc. 1962, 2507-09) by the method of R. Barner et al., Helv. Chim. Acta 64,' 926 (1981). 13C NMR (CDCl3): ppm 110.46 (C(CH3)2); 92.90, 89.25 183 Hz, CHF); 75.26, 74.87 (JC-C-F 19.5 Hz, CRO); 65.12, 65.00 (J-C-C-F 6.1 Hz, CH20); 29.58, 29.05 (JC-C-F 27 Hz, CH2Br); 26.17, 25.47 (C(CH3)2). b) rac. threo-4-(2-Amino-6-chloropurin-9-yl)-3-fluoro-0,0- isopropylidenebutane-l, 2-diol EMI40.1 A mixture of rac. 1,2-dideoxy-1-bromo-2-fluoro-3,4-O- -isopropylidenethreitol (325 ing, 1.43 mmol), 2-amino-6- -chloropurine (300 mg, 1.77 mmol), finely ground, anhydrous potassium carbonate (244 mg, 1.77 mmol), and sodium iodide (120 mg) in 5 ml of dry dimethylformamide was stirred at room temperature for 70 h. After addition of water (10 ml) the mixture was washed with 3x10 ml of n-hexane and then extracted with 3x10 ml of dichloromethane. The CH2Cl2 extracts were dried (MgSO4) and evaporated in vacuum. Flash chromatography (silica gel, chloroform-methanol 15:1) afforded 164 mg (44%) of rac. threo-4-(2-amino-6-chloropurin-9-yl)-3-fluoro-O,O-isopropylidenebutane-1,2-diol. 13C NMR (CDCl3): ppm 159.40 (C2); 153.81, 151.21 (C6-C4); 142.76 (C8); 110.36 (C(CH3)2); 90.81, 87.18 (JC-F 182 Hz, CHF); 74.51, 74.12 (JC-C-F 19.5 Hz, CHO); 64.71, 64.61 (JC,C-C-F 4.9 Hz, CH2O); 44.64, 44.18 (JC-C-F 23 Hz, NCH2); 25.91, 25.18 (C(CH3)2). Example 4. rac. erythro-9- (3, 4-Dihydroxy-2-methoxybutyl) guanine EMI41.1 A solution of rac. erythro-4-(2-amino-6-chloropurin-9-yl) -3-methoxy-O,O-isopropylidenebutane-1 ,2-diol (15 mg) in 1 ml of 1 M hydrochloric acid was kept at 100 C for 1 h and then evaporated in vacuum, reevaporated with 3x1 ml of water and the residue dissolved in 1 ml of water1 neutralized with aqueous ammonia and cooled to yield 11 mg of white crystals. 13C NMR, 50.10 MHz (DMSO-d6): ppm 156.90 (C6); 153.79 (C2); 151.55 (C4); 138.22 (C8); 116.40 (cos); 80.01 (CHOCH3); 71.45 (CHOH); 62.76 (CH2OH); 57.90 (OCH3); 43.13 (NCH2). The starting compound rac. erythro-4-(2-amino-6-chloropurin-9 yl)-3-methoxy-0,0-isopropylidenebutane-l,2-diol was prepared as follows: a) rac. 2-0-methyl-l,3,4-tribenzoylerythritol EMI41.2 rac. 1,2,4-o-Tribenzoylerythritol (690 mg, 1.59 mmol), methyl iodide (0.30 ml, 4.76 mmol), and silver oxide (737 mg, 3.18 mmol) were stirred in 16 ml of dimethylformamide at room temperature for 24 h. The mixture was filtered through Celite and evaporated in vacuum. Flash chromatography (silica gel, n-hexane-ethyl acetate 4:1) afforded 230 mg of pure rac. 2-0-methyl-7,3,4-tribenzoylerythritol. 3C NMR (CDCl3): ppm 166.09, 166.02, 165.41 (carbonyls); 133.18, 133.01, 129.65, 129.58, 128.34 (phenyl); 78.16 (CH-OCH3); 71.13 (CH-OCOC6H5); 63.10, 62.59 (2 CH2); 58.77 (OCH3) b) rac. 2-0-Methylerythritol EMI42.1 rac. 2-O-Methyl-1,3,4-tribenzoylerythritol (230 mg, 0.51 mmol) and sodium methoxide (15 mg) were stirred in 5 ml of anhydrous methanol at room temperature for 70 skin. and then evaporated to dryness. The residue was dissolved in water, washed twice with carbon tetrachloride and evaporated to yield 69 mg of product. 13C NMR (CD3OD): ppm 83.79 (CH-OCH3); 72.82 (CHOH); 64.55, 61.63 (2 CH2); 58.67 (OCR3). c) rac. 2-0-Methyl-3,4-0-isopropylidenerythritol EMI42.2 A solution of rac. 2-O-methylerythritol (69 mg, 0.39 mmol) and 3 drops of 70% perchloric acid in 5 ml of acetone was stirred at room temperature for 2.5 h, neutralized with saturated aqueous sodium bicarbonate and.evaporated, dissolved in ethyl acetate, washed with a small volyme of brine, dried (Na2SO4), and evaporated to afford the isopropylidene derivative in quantitative yield. 13C NMR (CDC13): ppm 109.24 (C(CH3)2); 82.05 (CH-OCH3); 75.70 (CHO); 66.89 (CH2O); 61.20 (CH2OH); 58.38 (OCH3); 26.61, 25.20 (C(CH3)2). d) rac. 1-Deoxy-1-bromo-2-0-methyl-3,4-0-isopropylidenery- thritol EMI43.1 This compound was synthesized in 39% yield from rac. 2-0-methyl-3,4-0-iSopropylidenerythritol as described for example 3 a). 13C NMR (CDCl3): ppm 109.66 (C(CH3)2); 80.64 (±H-OCH3); 75.75 (CHO); 66.87 (CH2O); 58.09 (OCH3); 32.28 (CH2Br); 26.90, 25.27 (C(CH3)2). e) rac. erythro-4-( 2-Amino-6-chloropurin-9-yl)-3-methoxy-0,0- isopropylidenebutane-1,2-diol EMI43.2 This compound was synthesized in 34% yield essentially as described for example 3b)with reaction temperature 900C for 5 h. 13C NMR {CDCl3): ppm 159.28 (C2); 143.62 (C8); 110.00 (C(CH3)2); 80.83 (CH-OCH3); 75.21 (CHO); 66.99 (CH2O); 58.97 (OCH3); 43.79 (NCR2); 26.76, 25.13 lC(CH3)2).

Claims: CLAIMS 1. A compound of the formula EMI44.1 wherein R1 is hydrogen, R2 is hydrogen, fluoro, methoxy or methylthio and R3 is hydrogen, hydroxy or mercapto; with the provisos that when R3 is hydrogen then R2 is methoxy or methylthio and that when R3 is hydroxy then R2 is fluoro, methoxy or methylthio; and with the further proviso that R1 can also be methoxy or fluoro when R2 is methoxy or fluoro; and physiologically acceptable salts or optical isomers thereof. 2. A compound according to claim 1 wherein in the formula I R3 is hydroxy, R1 is selected from hydrogen, fluoro and methoxy and R2 is selected from fluoro, methoxy and methylthio, with the proviso that when R1 is fluoro or methoxy then R2 is also fluoro or methoxy; and physiologically acceptable salts or optical isomers thereof. 3. A compound according to claim 1 wherein in the formula I R1 is hydrogen, R2 is hydrogen and R3 is mercapto; and physiologically acceptable salts or optical isomers thereof. 4. A compound according to claim 1 wherein in the formula I R1 is hydrogen, R2 is fluoro and R3 is hydroxy; and physiologically acceptable salts or optical isomers thereof. 5. A compound according to claim 1 wherein in the formula I R1 is hydrogen, R2 is methoxy and R3 is hydroxy; and physiologically acceptable salts or optical isomers thereof. 6. A compound according to claim 1 wherein in the formula I R1 and R2 are methoxy and R3 is hydrogen; and physiologically acceptable salts or optical isomers thereof. 7. A compound according to claim 1. wherein in the formula I R1 and R2 are methoxy and R3 is hydroxy; and physiologically acceptable salts or optical isomers thereof. 8. A pharmaceutical composition comprising as an active ingredient a compound of the formula EMI45.1 wherein R1 is hydrogen, R2 is hydrogen, fluoro, methoxy or methylthio and R3 is hydrogen, hydroxy or mercapto; with the provisos that when R3 is hydrogen then R2 is-methoxy or methylthio and that when R3 is hydroxy then R2 is fluoro, methoxy or methylthio; and with the further proviso that R1 can also be methoxy or fluoro when R2 is methoxy or fluoro; or a physiologically acceptable salt or an optical isomer thereof; in conjunction with a pharmaceutically acceptable carrier. 9. A pharmaceutical composition according to claim 8 designed for systemic administration. 10. A pharmaceutical composition according to claim 8 designed for topical administration. 11. A compound according to any of claims 1-7 for use in the treatment of virus infections. 12. A compound according to claim il for use in the treatment of herpes virus infections. 13. A compound according to any of claims 1-7 for use in the treatment of neoplastic diseases. 14. -A method for the preparation of a compound of the formula EMI46.1 wherein R1 is hydrogen, R2 is hydrogen, fluoro, methoxy or methylthio and R3 is hydrogen, hydroxy or mercapto; with the proviso that when R3 is hydrogen then R2 is methoxy or methylthio and that when R3 is hydroxy then R2 is fluoro, methoxy or methylthio; and with the further proviso that R1 can also be methoxy or fluoro when R2 is methoxy or fluoro; or a physiologically acceptable salt or an optical isomer, comprising A. Condensing an acyclic side chain of the formula EMI46.2 to the N-9 position of a guanine derivative of the formula; EMI46.3 followed by removal of possible protecting groups, in which formulas R1 and R2 has the meaning given above, X is a group such as chlorine, bromine, iodine or a group OS02R10 where Rlo is alkyl containing 1-8 carbon atoms, fluorinated alkyl containing 1-8 carbon atoms, alkylaryl or aryl; Y is hydrogen or a quarternary ammonium ion; R5 is R3 as defined above, or OR6 or SR6 where R6 is hydrogen or a hydroxyl protecting group; R5 and OR6 may optionally together form an epoxide when R3 is OH, or R5 and OR6 may optionally form a cyclic derivative such as a carbonate ester, carbonate thioester or the corresponding orthoacid cyclic derivatives or cyclic acetal type compounds; R7 is hydroxyl, chlorine, bromine, iodine, thiol, thioether, S02R10 where R, is as defined above; or an oxygen derivative OR12 where R12 is alkyl, alkylaryl, substituted silyl, phosphoryl diester, phosphinothioyl or SO2R10 where R10 is as defined above; R8 and R9 are the same or different and are R11 where Rll is hydrogen or an amine protecting group; or Bl. Substituting groups in a compound of the formula EMI47.1 followed by removal of possible protecting groups, in which formula R6, R8 and R9 are as defined above; R13 is R1, iodine or OS02Rlo; R14 is R2, iodine or OSO2R10; R15 is R3, iodine or 0SO2R10; and R1, R2, R3 and R10 are as defined above; or 32. Reducing the ester group to an alcohol in a compound of the forr:iula EMI48.1 followed by removal of possible protecting groups, in which formula R1, R2, R5, R7, R8, R9 and R10 are as defined above; or C1. Ring closure of a compound of the formula EMI48.2 followed by removal of possible protecting groups, in which formula R1,-R2, R5 and R6 are as defined above, Z is NH2 or an alkoxy group, and R16 is NH2 or guanidine; or C2. Ring closure of a compound of the formula EMI48.3 followed by removal of possible protecting groups, in which formula R1, R2, R5 and R6 are as defined above, and R17 is nitro, nitro, amino, formic amide or amino ortho ester; or D. Substitution in the pyrimidine ring of a compound of the formula EMI49.1 followed by removal of possible protecting groups, in which formula R1, R2, R5 and R6 have the meaning given above, Hal is fluoro, chloro, bromo or iodine, R18 is hydroxyl or amino, whereby when R18 is amino the amino group is converted to a hydroxyl function; to the formation of a compound of the formula I, whereupon optionally a base obtained is converted to a pharmaceutically acceptable salt or a salt obtained is converted to the base or to a different, pharmaceutically acceptable salt, and optionally an isomeric mixture obtained is separated into a pure enantiomeric isomer. 15. A method according to claim 14 for the preparation of a compound of any of claims 2-7.

Inventors: EKLIND, KARIN INGEBORG, GOTTHAMMAR, KRISTINA BIRGITTA, HAGBERG, CURT-ERIK, JOHANSSON, KARL NILS-GUNNAR, KOVACS, ZSUZSANNA MARIA ILONA, NOREN, JAN-OLOF, STENING, GORAN BERTIL, Norèn, Jan-Olof, Stening, Göran Bertil
Applicants: ASTRA LAKEMEDEL AKTIEBOLAG
Application year: 1983
Main classification: C07D473
IPC codes: C07D473, A61K31, C07F7, C07D317, C07C43