NOVEL DERIVATIVES OF GUANINE

Abstract: Antivirally active compounds of formula (I), wherein m is 1 or 2, n is 1 or 2, whereby m is 1 when n is 2 and m is 2 when n is 1, Ra is (CH2)pOH, NHCONH2 or CORa, Ra is hydrogen, hydroxy or amino, p is 1 to 4, Rb and Rb are independently selected from hydrogen or (CH2)pOH, with the proviso that at least one of Rb or Rb is hydrogen; or Rb and Rb together constitute an additional carbon-carbon bond to form an alkyne; or a physiologically acceptable salt, geometric or optical isomer thereof; processes for preparation of said compounds, pharmaceutical preparations containing the compounds, methods for treatment of virus infections and the medical use of the compounds.

Description: Novel Derivatives of Guanine Description !§l< 2f_th§_Indention The present invention relates to novel derivatives of guanine, methods for their preparation, novel pharmaceutical compositions and to a method for selectively combating viruses, such as herpes viruses, etc., which can cause various diseases in animals including man. Such diseases in¬ clude both common infections and neoplastic diseases, i.e. cancer. §?!$9!22 θ^_2f--: §-l!]ϊ?0ϊi20 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 virus¬ es and host cells. While some viruses cause a general destruction (kill¬ ing) of certain cells, other may transform cells to a neoplastic state. Important common viral infections are herpes dermatitis (including herp- es labialis), herpes keratitis, herpes genitalis, herpes zoster, herpes encephalitis, infectious 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 leukemias, 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. By the following references are guanine derivatives previously described Synthetic Communications 2 (6), 345-351 (1972), US Patent 4 199 574, US Patent 4355 032, European Patent Application 82401571.3 (publication number 74306) and the European Patent Application 81850250.2 (publica¬ tion number 55239); the latter discloses antiviral compounds of the formula wherein R, and R« might be selected from hydrogen, hydroxy and fluoro. Disclosure of Invention The present invention relates to the novel compounds of the formula wherein A is (CH c)m-CiH-(Cr ά nOH (Aa) or K CH 2 -C=C—CH 2 0H (Ab) wherein m is 1 or 2, n is 1 or 2, whereby is 1 when n is 2 and is 2 when n is 1, Ra' is (CH,.) n p0H, NHCONH, <- or CORα" , R" is hydrogen, hydroxy or amino, 3 p is 1 to 4, R' and R" are independently selected from hydrogen or (CFL)-OH, with the proviso that at least one of R' or R" is hydrogen; or R and R" together constitute an additional carbon-carbon bond to form an alkyne; with the additional proviso that when m is 2 and n is 1 and R' is (CH ? ) OH then p is 2 to 4; or a p a physiologically acceptable salt, geometric or optical isomer thereof. The invention also relates to a novel method for combating virus infec¬ tions in animals and man, compounds for use at such treatment and novel pharmaceutical preparations containing a compound of the formula I, whereby when A is Aa, also R' is CH ? 0H is included in the formula I, a ^ as an active ingredient within the antiviral area. Said compound is described in the prior art as a chemical compound. It has now been found that the compounds of the invention exert an anti¬ viral effect and inhibit certain viral functions including tumorogenic functions and the multiplication of viruses. It has also been found that the compounds of the invention have especial¬ ly high affinity to viral thy idine kinase, which is ery important for antiviral activity when the compounds are used in cells with a high level of thymidine. The invention thus provides compounds, geometric isomers and physiologi¬ cally acceptable salts thereof, which compounds are useful in therapeut¬ ic 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 func¬ tions of the host cells. An especially important area of use for the compounds of the present invention is in the treatment of herpesvirus infections. Among the her- pesviruses may be mentioned Herpes simplex type 1 and 2, varicella (Herp¬ es zoster), virus causing infectious mononucleosis (i.e. Epstein-Barr virus) and cytomegalovirus. Important diseases caused by herpesviruses are herpes dermatitis (including herpes labialis), herpes genitalis, herpes keratitis, herpes encephalitis and herpes zoster. Another possible area of use for the compounds of the present invention is in the treatment of cancer and tumors, particularly those caused by viruses. This effect may be obtained in different ways, i.e. by in- hibiting the transformation of virus-infected cells to a neoplastic state, by ' inhibiting the spread of viruses from transformed 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, lymphomas including Burkitt lymphomas and Hodgkin's disease, sarcomas, breast carcinoma, nasopharyngeal carcinomas and cervical cancers in which vir¬ uses 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 thera¬ peutically effective amount of a compound of the formula I or a physio- logically acceptable salt thereof. B. A method for inhibiting the multiplication of virus, 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 physiological - ly 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 I 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 virus¬ es, characterized by administering to an animal in need of such treat¬ ment 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 includ¬ ing 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 including the compound, wherein R' is CH OH when m is 2 and n is 1 or a ^ a physiologically acceptable salt thereof, in each of the above given methods A, B, C, D, E and F. As stated previously the novel compounds of the present invention have either the formul *a wherein is 1 or 2 and n is 1 or 2, whereby m is 1 when n is 2 and m is 2 when n is 1, R' is (CH ) OH, NHC0NH or COR", wherein R" is hydro- gen, hydroxy or amino and where p is 1 to 4 with the additional proviso that when m is 2 and n is i and R' is (CH,) ' OH then p is 2 to 4; or a physiologically acceptable salt or optical isomer thereof; or the formula HN I III H 2 N " N 1 CH —C—C —CH,0H 2 I ! 2 R R b wherein R' and R" are independently selected from hydrogen or (CH 2 ) OH, where p is 1 to 4, with the proviso that at least one of R' and R is hydrogen, or R and R together constitute an additional carbon-carbon bond to form an alkyne; or a physiologically acceptable salt or geometric isomer thereof. The proviso in the definition for m, n and R' above mean that the follow¬ ing specific compounds, including salts and optical iso ers thereof, constitute part of the present invention: C00H C0NH 2 CHO NHC0NH 2 CH 2 CH 2 0H CH 2 CH 2 CH 2 0H CH 2 CH 2 CH 2 CH 2 OH C00H C0NH 2 CHO NHC0NH 2 CH 2 0H CH 2 CH 2 0H CH 2 CH 2 CH 2 0H CH 2 CH 2 CH 2 CH 2 0H The compounds of the formula II contain one asymmetric center when R' and (CH 2 ) OH are different. Accordingly, they exist in two optical forms, which constitute a further aspect of the invention. The following specific compounds, including salts and geometric isomers thereof, constitute a further part of the present invention: R b . R b H H CH 2 0H H CH 2 CH 2 0H H CH 2 CH 2 CH 2 0H H CH 2 CH 2 CH 2 CH 2 0H CH 2 0H H CH 2 CH 2 0H H CH 2 CH 2 CH 2 0H H CH 2 CH 2 CH 2 CH 2 0H H When R£ is not CH 2 0H, the compound exists as two geometric isomers, which constitutes a further aspect of the invention. The present invention comprises the following compounds; •[4-hydroxy-2-(hydroxymethyl )butyl ]guanine, ■ [4-hydroxy-3-carboxybutyl Iguanine, •[hydroxy-3-carbamoylbutyl ]guanine, ■ [4-hydroxy-3-formylbutyl ]guanine, -[4-hydroxy-3-ureidobutyl ]guanine, [5-hydroxy-3-(hydroxymethyl )pentyl Iguanine, [6-hydroxy-3-(hydroxymethyl )hexyl Iguanine, [4-hydroxy-2-carboxybutyl Iguanine, [4-hydroxy-2-carbamoylbutyl ]guanine, [4-hydroxy-2-formylbutyl Iguanine, ■ [4-hydroxy-2-ureidobutyl Iguanine, 9-[ 4-hydroxy-2- (hydroxyethyl ) butyl Iguani ne, 9-[ 5-hydroxy-2- ( hydroxyethyl )pentyl ] guanine, 9-[6-hydroxy-2-(hydroxyethyl )hexyl Iguanine, 9-[4-hydroxy-3-(hydroxymethyl ) -2-butenyl ] guani ne, 9-(4-hydroxy-2-butenyl )guani ne, ci s-9- (4-hydroxy-2-butenyl )guani ne, 9-(4-hydroxy-2-butynyl ) guanine . A preferred sub-group of compounds of the invention is obtained when R' is (CH 2 ) p 0H such as hydroxymethyl or hydroxyethyl . Further preferred compounds of the invention are 9-[4-hydroxy-3-(hydroxy¬ methyl )-2-butenyl ]guanine and cis-9-(4-hydroxy-2-butenyl )guanine. The compound of formula III, wherein R and R form a bond has antiviral activity and said compound may also act as an intermediate for compounds of formula III, wherein R^ and R are hydrogen atoms. Methods of Preparation The compounds of the invention may be obtained by one of the following methods A-N 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 chemi cal reactions. wherein m, n and R' are as defined above in the formula I. X, and Y a a are generally selected from groups being able to react with each other for the formation of an optionally protected compound of the formula I. X is e.g. a group such as chloro, bromo, iodo, or a group 0S0 R 7 where R 7 is alkyl containing 1-8 carbon atoms, fluorinated alkyl containing 1-8 carbon atoms such as trifluoromethyl , arylalkyl such as benzyl, or aryl. Y is e.g. hydrogen or a quaternary ammonium ion such as tetra- butylammonium. R is hydrogen or a protecting group of which a great variety is known to those skilled in the art (see for example "Protect¬ ive Groups in Organic Chemistry", T.W. Greene, Wiley 1981; "Methoden der Organischen Che ie", Houben-Weyl Vl/lb; and "Comprehensive Organic Chemistry", D.H.R. Barton and W.D. Ollis eds., 1979, Vol 1. p. 623-629). Some examples of R- are acyl groups such as acetyl or benzoyl , alkoxy- carbonyl or aryloxycarbonyl groups, silyl groups such as for example tert.-butyldimethylsilyl , arylalkyl such as benzyl and triarylmethyl , or S0 2 R 7 where R 7 is as defined above. R 2a is R' as defined above in formula I, or may be CN, C00Rg a , CH(0R 9a ) 2 . CH(SRg a ) 2 , NHC0NHR ga or (CH 2 ) 0Rg a , where p is as defined above, R ga is substituted silyl or as defined above for R 7 and R g is as defined above for R_ , or Rg and R g may additionally together with R, form a divalent group, that is a cyclic derivative such as for example a lactone or another cyclic ester, orthoacid, acetal, ether or silyl type compound. Rg is hydroxy, chloro, bromo, iodo, mercapto, alkylthio containing 1-8 carbon atoms, S0 2 R 7 as defined or an oxygen derivative OR-, Q where R^ is alkyl, arylalkyl such as benzyl, substituted silyl, phos- phoryl diester, phosphinothioyl or S0 2 R 7 where R 7 is as defined. R. and Rg a are the same or different and are R, as defined. The condensation is preferably conducted in an organic solvent such as for example di ethylformamide, ethanol, acetonitrile or dichloro- methane, 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 0-100°C 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 organ¬ ic solvent such as for example ethanol or dimethylformamide over a metal catalyst for 1-24 hours at a pressure of 100 to 5000 kPa (1-50 atmos¬ pheres). When R 2 is CH(SR g ) 2 , the hydrolysis may be performed with a reagent such as mercuric chloride in a separate step. B. Condensing an unsaturated side chain, where the functional groups may optionally be protected, to the N-9 position of a guanine derivative with base catalysis, followed by reduction and/or removal of protecting groups Εa R 4a' R 5a and R 6a are as defined above, R ]4a is CN, C0NH 2 or C00Rg a and R 15a is C00R 8a or CH 2 0R 9a' where R 8a and R 9a are as defined above and may additionally together form a divalent group, that is a cyclic deriva¬ tive such as for example a lactone or another cyclic ester, orthoacid, acetal, ether or silyl type compound, and R lga is C0NH 2 , COOH or CH 2 0H. The condensation is preferentially conducted in an organic solvent such ad for example dimethylformamide, ethanol, acetonitrile or dichloro- methane, at a temperature of between 0°C and 100°C for 1 hour to 3 days in the presence of a base catalyst such as for example potassium carbon¬ ate, sodium methoxide, sodium hydride or tetrabutylammonium hydroxide. C. Reduction or selective reduction of derivatized or activated carboxy¬ lic acid groups, followed by removal of protecting groups. m, n, R 3a , R 4a , R 5a and R 6a are^s defined above, R ]la is R ga as defined above or a group such as (CH 3 ) 2 N=CH0- in an activated carboxylic acid derivative, R £a is R 2a or a group (CH 2 ) p . 1 C0R 11a , where R 2a , R llfi and p are as defined above and R ]3a is R a or R ]2a as defined above. The reduction may be performed by hydrogen gas or hydrogen generated in situ, with a metal as catalyst or, preferentially, a hydrid reducing agent in an organic solvent. D. Pyrimidine ring closure to the guanine base of a substituted imida¬ zole derivative nORo.a wherein , n, R 2 and R 3 are as defined above, Z is NH 2 or alkoxy i.e. COZ is an amide or ester group and R-,-, is NH~ or guanidino. 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° with or without the addition of a reagent such as for example guanidine. When R 2 and R- are not R' and hydrogen, respective¬ ly, the side chain protecting groups are removed in a subsequent reaction step according to method A. E. Imidazole ring closure, to the guanine base, of a substituted pyrimi' dine derivative wherein , n, R_ and R~ are as defined above and R-,g is nitroso, nitro, amino, or an amino derivative such as formylamino (-NH-CH0) or ortho ester amino e.g. ). The ring closure may be performed 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 250°C for 1/2 hour to 10 hours. When R. Q is nitroso or nitro, these groups first have to be reduced to amino groups by known methods. When R« and R 9 are not R' and hydrogen, respectively, the side chain protecting groups are removed in a subsequent reaction step according to method A. F. Substitution in the pyrimidine ring of a purine for the formation of a guanine ring m, n, R« and R. are as defined above, R,g is chloro, bromo, iodo, hydroxy or amino and R 2Q is fluoro, chloro, bromo, iodo or amino. When ?0 a ^ s not a ^ o i is 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 R-ig is amino it can be substituted to a hydroxy! function by selective diazotization with nitrite in a solvent such as acetic acid at a temperature from 0°C to 50°C for 1-24 hours and when Rng is a halogen atom it may additionally be hydrolyzed to hydrox 1 according to method A. G. 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 chemi- cal reactions. 6b CH 2 - C " ^==C ■■ - -CH 2 0H wherein Rύ and Rύ' are as defined above in the formula I. X. and Y are generally selected from groups being able to react with each other for the formation of an optionally protected compound of the formula I. X. is e.g. a group such as chloro, bromo, iodo, or a group 0S0 2 Rg where Rg. is alkyl containing 1-8 carbon atoms, fluorinated alkyl containing 1-8 carbon atoms such as trifluoromethyl , arylalkyl such as benzyl, or aryl. Y is e.g. hydrogen or a quaternary ammonium ion such as tetra- butylammonium. R 3 , is hydrogen or a hydroxy protecting group of which a great variety is known to those skilled in the art (see for example "Protective Groups in Organic Chemistry", T.W. Greene, Wiley 1981; "Methoden der Organischen Chemie", Houben-Weyl Vl/lb; and "Comprehensive Organic Chemistry", D.H.R. Barton and W.D. Ollis eds., 1979, Vol. 1. p. 623-629). Some examples of R,. are acyl groups such as acetyl or benzoyl , alkoxy- carbonyl or aryloxycarbonyl groups, silyl groups such as for example tert.-butyldimethyls lyl , arylalkyl such as benzyl and triarylmethyl , or SOp g where R g . is as defined above. R 2 . is R and R 7 . is R" as defined above in formula I, or both may be (CH„) ORg. , where p is 1 to 4 and R g , is as defined for R-. , and R g . and R 3b are the same or different and may additionally together form a divalent group, that is a cyclic derivative such as for example a carbonate ester, thiocarbonate ester or the corresponding orthoacid cyclic derivatives or cyclic acetal type compounds. R g , is hydroxy, chloro, bromo, iodo, mercapto, alkylthio containing 1-8 carbon atoms, S0 2 R 8b wnere R 8b is as de" i ned or an oxygen derivative 0R-. Q . where R-ι Q . is alkyl, arylalkyl such as benzyl, substituted silyl, phosphoryl diester, phosphinothioyl or SO Rg, where R g . is as defined. Rg. and . Rg b are the same or different and are R.,, as defined. The condensation is preferably conducted in an organic solvent such as for example dimethylformamide, ethanol, acetonitrile or dichloro- methane, 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 0-100°C 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. H. Condensing an unsaturated side chain, where the functional groups may optionally be protected, to the N-9 position of a guanine derivative with metal catalysis, followed by removal of the protecting groups, through one or more chemical reactions. .'N HN • N i ! b ! b CH 2 —C ~ —C CH 2 0H R b' R b' R 2b' R 4b' 5b' R 6b anc ' R 7b are as e ^ " ' ne above. The condensation is preferably conducted in an organic solvent such as for example dimethylformamide, ethanol, acetonitrile or dichloro- methane, at a temperature of between 0°C and 100°C for 1 hour to 3 days in the presence of a metal catalyst, such as for example tetrakis(tri- phenylphosphine)palladium(O). BADORIGI AL ' J. Reduction of derivatized or activated carboxylic acid groups to alco¬ hol, followed by removal of protecting groups. 15 ned above. R,,. is R β . as defined in an activated carboxylic acid derivative. R , ,, , is R 7b or (CHp) •, C0R ιih as de"frined above, R, 7b is R 2b or (CH.) -I C0R llb as defined above, and R,, b and R, 2b or R,, b and 20 R 17b may additionally together form a divalent group, that is a cyclic derivative such as for example a lactone or another cyclic ester, orthoacid, acetal, ether or silyl type compound. The reduction may be performed by hydrogen gas or hydrogen generated 25 in situ, with a metal as catalyst or, preferentially, a hydride reducing agent in an organic solvent. K. Partial reduction of the triple bond of a compound of the formula -CH 2 0R 3b wherein R, and Rg b are moval 3b' R4, Rς b as defined above, followed by re b of the optional protecting groups to yield AL —CH-CH OH The reduction is performed according to known methods, such as for ex¬ ample by hydrogen gas with a metal as catalyst to yield the cis isomer. or with sodium metal dissolved in liquid ammonia to yield the trans isomer. L. Pyrimidine ring closure to the guanine base of a substituted imida¬ zole derivative. wherein R 2b , R 3b and R 7b are as defined above, Z is NH 2 or alkoxy i.e. COZ is an amide or ester group and R-, 3b is NH~ or guanidino. 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° with or without the addition of a reagent such as for example guanidine. When R 3b is not hydrogen, R 2b is not R and R 7b is not R", the side chain protecting groups are removed in a subsequent reaction step according to method G. M. Imidazole ring closure, to the guanine base, of a substituted pyrimi 5 dine derivative. k 14b HN -> 10 H £ N- 15 HN ' -> H 2 N N-- R 2b R 7b CH 2 —C---—C-CH 2 0R 3b 20 wherein R 2b , R 3b and R 7b are as defined above and R-,» b is nitroso, nitro, amino, or an amino derivative such as formylamino (-NH-CH0) or ortho ester amino 25 0C 2 H 5 (e.g. -NH-CH ). The ring closure may be performed by known methods 0C 2 H 5 (the principles of which are given for example in "Comprehensive Organic 30 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 250°C for 1/2 hour to 10 hours. When R 14b is nitroso or 35 nitro, these groups first have to be reduced to amino groups by known methods. When R 3b is not hydrogen, R 2b is no R' and R 7b is not R b , the side chain protecting groups are removed in a subsequent reaction step according to method G. ^ N. Substitution in the pyrimidine ring of a purine for the formation of a guanine ring. CH 2 C- ~ C-CH 2 0R 3b R 2b' 3b and R 7b are as de ^ 'ined above, R , 5b is chloro, bromo, iodo, hydroxy or amino and R, gb is fluoro, chloro, bromo, iodo, or amino. When R, fib is not amino it is 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 R-, 5b is amino it can be substituted to a hydroxy! function by selective diazotization with nitrite in a solvent such as acetic acid at a temperature from 0°C to 50°C for 1-24 hours and when R^ b is a halogen atom it may additionally be hydrolyzed to hydroxy! according to method G. The described methods A-F may be used to give mixtures of optical isomers, or in appropriate cases a single optical isomer. Additionally a single optical isomer may be obtained from the racemic mixtures by methods known per se. The described methods G-N may be used to give mixtures of geometric isomers, or in appropriate cases a single geometric isomer. Additionally a single geometric isomer may be obtained from the isomeric mixtures by methods known per se. The starting materials in the above methods A-N are either known com¬ pounds or can be prepared by methods known to those skilled in the art. These groups of new compounds can be prepared in a way known per se. Salts Physiologically acceptable salts of compounds of the invention are pre¬ pared by methods known in the art. The salts are novel compounds and 10 comprise a further aspect of the invention. Metal salts can be prepared by treating 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 solu¬ tion of a more soluble salt by addition of a suitable metal compound. 15 Acid salts can be prepared by treating a compound of the invention with an acid such as HC1 , HBr, H 2 S0 4 , or an organic sulphonic acid. Pharmaceutical preparations 20 Pharmaceutical preparations of the compounds of the formula I wherein A is (CH 2 ) m CH-(CH 2 ) n OH (Aa) or R a 30 CH 2 -C=C—CH 2 0H ' (Ab) R b R b wherein m is 1 or 2, 35 n is 1 or 2, whereby m is 1 when n is 2 and m is 2 when n is 1, R a is ( CH 2 ) p 0H ' NHC0NH 2 or COR^', R a is hydrogen, hydroxy or amino, p is 1 to 4, Ri and R.' is independently selected from hydrogen or (CH 2 ) OH, with the proviso that at least one of Rl or Rύ' is hydrogen; or Rύ and R b together constitute an additional carbon-carbon bond to form an alkyne; or a physiologically acceptable salt, geo- metric or optical isomer thereof,with a pharmaceutically accept¬ able carrier, constitute a further aspect of the invention. The compounds of the invention can be administered systemically or local¬ ly and will in clinical practice normally be administered topically, orally, intranasally, by injection, by infusion, or by inhalation in the form of a pharmaceutical preparation comprising the active in¬ gredient 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 preparations com¬ prise a further aspect of the invention. The compounds may also be used without carrier material. As examples of pharmaceutical preparations may be mentioned tablets, solutions, 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 preparation, for example between 0.5 and 20% for preparations intended for injection and between 0.1 and 50% for preparations intended for oral administration. The preparations are preferably in dosage unit form. Further, they are preferably provided in sterilized form. To produce pharmaceutical preparations in the form of dosage unit for oral application containing a compound of the invention the active in¬ gredient may be mixed with a solid, pulverulent carrier, for example lactose, saccharose, sorbitol, mannitol, a starch such as potato starch, corn starch, amylopectin, la inaria powder or citrus pulp powder, a cellulose derivative or gelatine and also may include lubricants such as magnesium or calcium stearate or a Carbowax ® or other polyethylene glycol waxes and compressed to form tablets or cores for dragees. If dragees are required, the cores may be coated for example with concen¬ trated sugar solutions which may contain gum arabic, talc and/or titan¬ ium dioxide, or alternatively with a film forming agent dissolved in easily volatile organic solvents or mixtures of organic solvents. Dye- stuffs can be added to these coatings, for example, to distinguish be¬ tween different contents of active substance. For the preparation of soft gelatine capsules consisting of gelatine and, for example, glycerol 5 and a plasticizer, or similar closed capsules, the active substance may be admixed with a Carbowax ® 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 lac¬ tose, saccharose, sorbitol, mannitol, starches (for example potato 10 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 dis¬ solving coatings sustained release tablets are obtained. Another way 15 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 tab¬ lets made for instance of fat and wax substances or evenly distributed 20 in a tablet of an insoluble substance such as physiologically inert plastic substance. Liquid preparations for oral application may be in the form of elixirs, syrups or suspensions, for example solutions containing from about 0.1% 25 to 20% by weight of active substance, sugar and a mixture of ethanol, water, glycerol, propylene glycol and optionally aroma, saccharine and/or carboxy ethylcellulose as a dispersing agent. For parenteral application by injection preparations may comprise an 30 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. 35 For topical application, especially for the treatment of herpesvirus infections on skin, genitals and in mouth and eyes the preparations are suitably in the form of a solution, ointment, gel, suspension, cream or the like. The amount of active substance may vary, for example be- r tween 0.05-20% by weight of the active substance. Such preparations for topical application may be prepared in known manner by mixing the active substance with known carrier materials such as isopropanol, gly¬ cerol, paraffin, stearyl alcohol, polyethylene glycol, polypropylen glycol, etc. The pharmaceutically acceptable carrier may also include a known chemical absorption promoter. Examples of absorption promoters are e.g. dimethylacetamide (U.S. Pat. No. 3,472,931), trichloroethanol or trifluoroethanol (U.S. Pat. No. 3,891,757), certain alcohols and mixtures thereof (British Pat. No. 1,001,949). It may also contain deter- gents to facilitate the penetration of the active substance into the skin. The dosage at which the active ingredients are administered may vary within a wide range and will depend on various factors such as for exa p- le 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, 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 a compound of the formula I including the compound, wherein R' is CH 2 0H when is 2 and n is 1; 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. 10 Example 1. 9-[4-hydroxy-2-(hydroxymethyl )butyl Iguanine (Method C) A suspension of sodium borohydride (135 mg, 3.57 mmol) and dried lithium bromide (220 mg, 2.53 mmol) in 4 ml of dried and distilled diglyme was stirred at room temperature for 1/2 h. After addition of dimethyl 2-(2- -amino-6-chloropurin-9-ylmethyl )succinate (215 mg, 0.656 mmol) and 3 25 drops of trimethyl borate the mixture was stirred at room temperature over-night and then kept at 100°C for 5h. The solvent was evaporated in vacuum and the residue dissolved in 10 ml of 70% formic acid in water and kept at 50°C over-night. The mixture was evaporated to dryness in vacuum, dissolved in water, neutralized with sodium hydrogen carbonate 30 and evaporated in vacuum. Chromatography (silica gel, ethyl acetate + methanol + water 4+3+1 parts of volume) and recrystallization from water afforded 99 mg of 9-[4-hydroxy-2-(hydroxymethyl )butyl Iguanine. The compound was purified by preparative HPLC (Porasil C-,g reversed- phase column; methanol + water 20+80) to yield a pure product after 35 recrystallization from water. M.p. 235°C. UV spectrum, λ, mav (nm): 0.01 M HC1 253 (277) H 2 0 (pH 7) 252 ( 270 infl.) øfl 0.01 M NaOH 268 ( 256 infl.) ] H NMR (DMSO-dg): 0^1. 3 (m, 2H) CH 2 CH 2 0H; 2.09 (m, 1H) CH; 3.34 (d, 2H) CHCH 2 0H; 3 ~ 47 (t, 2H) CHgCH^QH; 3.96 (ABX sys¬ tem, 2H) ~ NCH 2 ; 6.25 (broad s, 2H) H 2 ; 7.59 (s, 1H) H 8 ; 10.4 (broad s, 1H) NH. The starting compound, dimethyl 2-(2-amino-6-ch1oropurin-9-y1methyl )- succinate was prepared as follows: (Method B) H COOCH, 2 3 CH 3 A mixture of 2-amino-6-chloropurine (4.07 g, 0.024 mol ), dimethyl ita- conate (5.00 g, 0.032 mol), and sodium hydride (55% in oil, 0.2 g) in 50 ml of dry dimethylformamide was stirred at room temperature for 3 days. About 50 ml of water was added and the mixture was washed with n-hexane (2x50 ml) and then extracted with 2x50 ml of dichloromethane. The combined CH 2 C1 2 extracts were washed with 2x20 ml of water, dried with magnesium sulfate, and evaporated in vacuum. Treatment with ether and drying afforded a white crystalline product. Chromatography (silica gel, chloroform + methanol 15+1) yielded 5.54 g (71%) or recrystalliza¬ tion (MeOH-H 2 0) yielded 5.15-g (66.1%) of dimethyl 2-(2-amino-6-chloro- purin-9-ylmethyl)succinate. U ■>V spectrum in EtOH,A.max„ (nm): 310 (247). ! NMR (CDC1 3 ) d2.67 (dd, 2H) CH 2 C00; 3.46 (m, 1H) CH; 3.70 (2s, 2x3H) 0CH 3 ; 4.42 (ABX system, J qem =14 Hz, 2H) NCH 2 ; 5.35 (broad s, 2H) NH £ ; 7.79 (s, 1H) H 8 . Example 2. 9-[4-Hydroxy-3-(hydroxymethyl )butyl Iguanine (Method A) 10 A mixture of 2-amino-6-chloropurine (1.275 g, 7.5 mmol) and potassium carbonate (0.69 g, 5 mmol) in dry dimethylformamide (30 ml) was sonicat¬ ed for 15 min., benzyl 2-benzyloxymethyl-4-bromobutyl ether (1.82 g, 5 mmol) was added, and the mixture was sonicated for 4h and then stirred over-night. After evaporation in vacuum the residue was extracted with 15 3x50 ml of chloroform and the extracts were evaporated to dryness in * vacuum. Chromatography (silica gel, chloroform + methanol 20+1 by volume) afforded 0.58 g (26%) of pure compound 4-(2-amino-6-chloropurin-9-yl )-2- benzyloxymethylbutyl benzyl ether. A small sample of said compound was recrystallized from toluene. M,p. 108.5-109.5°C. 20 ] H NMR (CDC1 3 ): cfl.96 (m, 3H) N-C-CH^CH.; 3.48 (ABX system, 4H) (CH(CH 2 0) 2 ; 4.13 (t,2H) NCH 2 ; 4.46 (s, 4H) 0CH 2 Ph; 5.49 (s, 2H) NH 2 ; 7.30 (m, 10H) phenyl ; 7.6 * 9 (s, 1H) Hg. Deprotection A solution of 4-(2-amino-6-chloropurin-9-yl )-2-benzyloxymethylbutyl benzyl ether (0.904 g, 2 mmol) in 25 ml of 80% aqueous formic acid was 35 kept at 100°C for Ih, palladium catalyst (10% on carbon, 0.40 g) was added, and the mixture was hydrogenated at room temperature and atmosphe¬ ric pressure with efficient stirring for 45 min. After evaporation in vacuum to dryness the residue was heated to boiling with 50 ml of water, J> 1 ml of concentrated aqueous ammonia was added, the solution was boiled gently for a short while and then evaporated to dryness. Recrystalliza¬ tion from water afforded 0.23 g (45%) of 9-[4-hydroxy-3-(hydroxymethyl )- butyl Iguanine. M.p. 252-262°C (decomposition, slow heating) or 264-265° (fast immersion of the capillary). ] H NMR (DMSO-dg): ' 1.51 (m, 1H) CH; 1.76 (q, 2H) N-C-CH 2 ; 3.42 (ABX system, 4H) 2CH 2 0; 4.02 (t, 2H) NCH 2 ; 6.29 (broad s, 2H) NH 2 ; 7,64 (s, 1H) H 8 ; 1.0.3 (broad s, 1H) NH. UV, ' max (nm): ethanol 255 c 12300 (^270 infl.) 1 M HC1 253 .11300, 279 1 M NaOH 268 (257 infl.) The starting compound, benzyl 2-benzyloxymethyl-4-bromobutyl ether was prepared as follows: a) Diethyl (2,2-dimethoxyethyl )ma!onate CH 3 Q C00CH 2 -CH 3 CH-CH 2 -CH CH 3 0 C00CH 2 -CH 3 Diethyl malonate (168.18 g, 1.05 mol) was added to a solution of sodium ethoxide (from 23.0 g, 1.00 mol of sodium) in 500 ml of dry ethanol at 50°C during 45 min. Bro oacetaldehyde dimethylacetal (74.2 g, T.06 mol) was added at the same temperature during 45 min. and the mixture was refluxed over-night. Ethanol was evaporated in vacuum, and the resi¬ due was dissolved in 200 ml of water and extracted with 3x300 ml of ether. The extracts were dried (MgSO , evaporated, and distilled in vacuum to give 115.0 g (46%) of the title compound. B.p. 97-101°C (0.6 mm Hg) . ] H NMR (CDC1 3 ): i ' l.30 (t, =7Hz, 6H) 2C-CH 3 ; 2.20 (dd, =5Hz and 7Hz, 2H) CH-CH 2 ; 3.35 (s, 6H) 20CH 3 ; 3.44 (t, 1H) C0CHC0; 4.20 (q, J=7Hz, 4H) 20CH 2 ; 4.42 (t, J=5Hz, 1H) O-CH-0. *t> a ' '< b) 4,4-Dimethoxy-2-(hydroxymethyl)butanol Diethyl (2,2-dimethoxyethyl)malonate (115.0 g, 0.46 mol) was added to a suspension of lithium aluminum hydride (38.0 g, 1.00 mol) in 400 ml of dry ether at a rate to maintain a gentle reflux. After stirring for 15 min. 40 ml of water, 40 ml of 15% aqueous NaOH, and 120 ml of water were added and stirring was continued until a white suspension was ob- • tained. The inorganic salts were filtered off and extracted with several 200 ml portions of tetrahydrofuran (THF). The combined organic extracts were evaporated and distilled twice in vacuum to yield 50.23 g (66.5%) of the title compound. B.p. 116-125° (0.02 mm Hg). ] H NMR (CDC1 3 ): cf1.6-2.1 (m, 3H) CH 2 -CH; 3.35 (s, 6H) 20CH 3 ; 3.67 (d, 4H) 2CH £ 0; 4.48 (t, J=5Hz, 1H) O-CH-0. c) Benzyl 2-(benzyloxymethyl)-4,4-dimethoxybutyl ether Sodium hydride (55% in oil, 32.72 g, 0 ^ .75 mol) was washed twice with n-hexane and suspended in 200 ml of THF. 4,4-Dimethoxy-2-(hydroxymethyl)- butanol (49.26 g, 0.3 mol) was added dropwise to maintain a gentle evolu¬ tion of hydrogen gas. Then benzyl chloride (94.94 g, 0.45 mol) was added during 30 min. and the mixture was refluxed over-night, cooled, diluted with 50 ml of ethanol, and evaporated in vacuum. The residue was suspend¬ ed in about 200 ml of water and extracted with 3x100 ml of ether. The combined organic extracts were dried (MgSQ and distilled in vacuum. The " title compound (94.34 g, 91%) was obtained at 197-200°C (0.01 mm Hg). r ] H NMR (CDC1 3 ): l.67 (diffuse t, 2H) CHCH 2 CH; 2.02 ( , 1H) CH; 3.23 (s, 6H) 20CH 3 ; 3.46 (d, 4H) 2CH 2 0; 4.43 (s, 4H) 20CH 2 Ph; 4.43 (t, 1H) 0-CH-O; 7.27 (broad s, 10H), phenyl . d) 4-Benzy1oxy-3-benzyloxymethylbutan-l-o1 A mixture of benzyl 2-benzyloxymethyl-4,4-dimethoxybutyl ether (51.62 g, 0.15 mol), acetic acid (70 ml), water (30 ml), and THF (100 ml) was refluxed for 2h and then evaporated in vacuum. The residue was dissolved in ether and the solution washed with aqueous potassium carbonate solu¬ tion and water, dried (MgSO , and evaporated in vacuum. The residue of crude 4-benzyloxy-3-benzyloxymethylbutanal (quantitative yield) was dissolved in 100 ml of THF and added during 30 min. to a- suspension of lithium aluminum hydride (7.6 g, 0.20 mol) in 100 ml of THF. Then 8 ml of water, 8 ml of 15% aqueous NaOH and 24 ml of water were added and the mixture was stirred until a white, sandy suspension was ob¬ tained. The inorganic salts were filtered off and washed with several portions of THF. The combined extracts were evaporated in vacuum to yield 41.93 g (93%) of the title compound. ] H NMR (CDC1 3 ): cf1.66 (q, 2H) CH^CH^; 2.05 ( , 1H) CH; 3.0 (t, 1H) OH; 3.46 (d, 4H) CHΪCH^O)^ 3.64 (q, 2H) CH^OH; 4.47 (s, 4H) 2 0CH 2 Ph; 7.30 (m, 10H) phenyl. e) Benzyl 2-benzyloxymethyl-4-bromobutyl ether A solution of 4-benzyloxy-3-benzyloxymethylbutan-1-ol (41.75 g, 139 mmol) in 150 ml of dry dichloromethane was cooled in ice-water bath. Triphenylphosphine (42.0 g, 160 mmol) was added with stirring and then N-bromosuccinimide (26.0 g, 146 mmol) in portions during 15 min. After Ih at room temperature ether (400 ml) was added and the precipitated triphenylphosphine oxide filtered off. The solution was concentrated in vacuum to a small volume, and more ether was added to extract the product from precipitated triphenylphosphine oxide. Finally, this ex¬ traction-precipitation step was repeated with light petroleum to give, after evaporation, 33.55 g (66%) of crude title compound. ] H NMR (CDC1 3 ): cTl.98 (q, 2H) Br-C-CH 2 ; 2.15 (m, IH) CH; 3.45 (t, 2H) 10 BrCH 2 ; 3.47 ( , 4H) CH(CH 2 0) 2 ; 4.47 (s, 4H) 20CH 2 Ph; 7.30 (m, 10H) phenyl . Example 3. 9-[4-hydroxy-2-(hydroxymethyl )butyl jguanine (Method C) Dimethyl 2-(2-amino-6-chloropurin-9-ylmethyl )succinate (8.00 g, 0.0244 mol) was dissolved in 200 ml of tert. butanol at 50°C, lithium borohyd¬ 25 ride (2.66 g, 0.122 mol) was added in portions, and the mixture was stirred for Ih. Then 100 ml of water was added and the stirring was continued over-night, the inorganic salts were filtered off and the solution was evaporated to dryness in vacuum. The residue was found to contain 78 mole-% of 2-amino-6-tert.butoxy-9-[4-hydroxy-2(hydroxy¬ 30 methyl )butyl ]purine together with the 6-chloro compound. ] H NMR (DMSO-d.): ςfl.10 (s, 9H) C(CH, 3)',3; ! 1.38 (m, 2H) CH CH 0H; 2.14 _2°' ( , IH) CH; 3.34 (d, 2H) CHCH 2 0H; 3.45 (diffuse t, 2H) CH 2 CH 2 0H; 4.06 (t, ABX system, 2H) NCH 2 ; 4.5 {very broad s) OH; 6.77 (s, 2H) NH 2 ; 8.08 (s, IH) H8. 35 13 C NMR (DMSO-dg): < 31.41, C(CH 3 ) 3 ; 31.92, CHgCHgOH; 37.88, CH; 45.01, NCH 2 ; 58.72 and 61.3, 2CH 2 0H; 66.65, C(CH 3 ) 3 ; 123.59, C5; 143.91, C8; 149.53, C6; 154.59, C4; 159.87, C2. r Qegrotectign A solution of crude 2-amino-6-tert.butoxy-9-[4-hydroxy-2-(hydroxymethyl ) • butyl]purine (436 mg, 1.41 mmol) in 6 ml of 50% aqueous formic acid was kept at 100°C for 3h and then evaporated to dryness in vacuum, more water was added and the mixture was lyophilized. The residue was kept at 100°C for 2h with 10 ml of 2M aqueous ammonia. The ammonia was re¬ moved by a stream of nitrogen gas, the solution was heated to boiling, a small amount of solid matter was removed, and the filtrate was cooled in the refrigerator to afford 208 mg of crystalline 9-[4-hydroxy-2-(hyd- roxymethyl )butyl Iguanine. 13 C NMR (DMSO-dg): cf31.80, CH^OH; 38.17, CH; 44.35, NCH 2 ; 58.80 and 60.94, 2CH 2 0H; 116.64, C5; 138.05, C8; 151.57, C4; 153.57, C2; 156.92, C6. Example 4. Preparation of 4-(2-Amino-l ,6-dihydro-6-oxopurin-9-yl )-2- -hydroxymethyl utyric acid (Method A) 2-Amino-6-chloropurine (3.37 g, 19.9 mmol), 4-bromo-2-hydroxymethylbutyr¬ ic acid ethyl ester (4.49 g, 19.9 mmol) and anhydrous potassium carbon¬ ate (2.75 g, 19.9 mmol) were mixed with 50 ml of dimethylformamide and the mixture was stirred at room temperature during 92 hours. The mixture was then filtered and the filtrate evaporated. The residue was extracted with 3x50 ml fchloroform and the combined extracts were evaporated. Flash chromatography (silica gel, chloroform-methanol 10:1) and two re- crystallizations from water afforded 0.995 g of the 4-(2-amino-6-chloro- purin-9-yl )-2-hydroxymethylbutyric acid ethyl ester. 13 C NMR (CDC1 3 ): ppm 173.56, 159.40, 153.81, 151.16, 142.38, 124.89, 62.61, 61.11, 45.08, 41.91, 28.46 and 14.16. Degrotection 4-(2-Amino-6-chloropurin-9-yl )-2-hydroxymethylbutyric acid ethyl ester (0.80 g) in 50 ml IM hydrochloric acid was refluxed during 3 hours and then evaporated in vacuum, re-evaporated with 3x10 ml of water and the residue dissolved in 5 ml of water. The pH was then adjusted to 6-7 with solid sodiumbicarbonate. The solution obtained was filtered and the pH was adjusted to 4 with acetic acid. After cooling to 0°C the precipitate was filtered off and washed with water. Recrystallization from water gave 0.43 g of 4-(2-amino-l ,6-dihydro-6-oxopurin-9-yl )2- hydroxymethylbutyric acid. 13 C NMR (DMS0-dg): ppm 174.80 (C=0), 157.09 (C6), 153.64 (C2), 151.38 (C4), 137.49 (C8), 116.84 (C5), 62.15 (CH 2 0H), 45.59 (CH), 41.33 (NCH 2 ) and 28.66 ( -CH 2 -CH 2 ). The starting compound, ;brorrø;2;hγd^ox^meth^^ acid ethyl ester was prepared as follows: 2-Hydroxymethylbutyrolactone [G. Claesson et al . Arkiv for kemi Z__\, 173 (1967)], (3.0 g) was dissolved in 20 ml ethanol and the solution was saturated with hydrogen bromide at 0°C. After standing at 0°C during 0.5 hour, 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 diethyl ether and the combined ether extracts were washed with saturated, aqueous sodium chloride and dried over anhydrous sodium sulphate. After evaporation of the solvent, the residue was dissolved in 25 ml chloro- form and filtered. Evaporation of the solvent yielded 4.59 g of the compound 4-bromo-2-hydroxymethylbutyric acid ethyl ether. 13 C NMR (CDC1 3 ): ppm 174.14, 62.54, 61.08, 46.02, 31.45, 38.89 and 14.26. Example 5. 9-[4-Hydroxy-2-(hydroxymethyl)butyl ]guanine hydrochloride 9-[4-Hydroxy-2-(hydroxymethyl)butyl ]guanine (46 mg; Example 1) was dis¬ solved in 0.4 ml of 1 M aqueous hydrochloric acid and the solution was lyophilized (0.1 mm Hg) over-night. The residue (53 mg, quantitive yield) was dissolved in a few drops of warm ethanol and precipitated with several volumes of tetrahydrofuran to yield a white, crystalline product. M.p.~85°C (d). ] H NMR (D 2 0): 61.61 (m, * 2H) CH 2 CH 2 0H; 1.87 (m, IH); 2.31 (septet, IH) CH; 3.57 (d, 2H) CHCH 2 0H; 3.72 Tdiffuse q) CH 2 CH 2 0H; 4.32 (m, 2H) CH 2 ; 4.90 (s) HD0; 8.96 (s ~ TlH) Hg. Example 6. 9-[4-Hydroxy-3-(hydroxymethyl )-2-buteπyl Jguanine (Method A) Crude 1-benzyloxy-2-benzyloxymethylbut-3-en-2-ol (1.42 g, 3.16 mmol) in 10 ml of CH ? C1 2 was added to 0.71 g thionyl chloride (6 mmol) and 2 drops of DMF in 10 ml of CH^Cl 2 , and the solution was stirred for 0.5 h and evaporated in vacuum. Toluene was added and the mixture was evaporated in vacuum to yield crude 1-benzyloxy-2-benzyloxymethyl-4- -chlorobut-2-ene. A mixture of 1.61 g 2-amino-6-chloropurine (9.5 mmol) and 1.31 g finely ground anhydrous 2 C0 3 (9.5 mmol) in 50 ml of dry dimethylformamide (DMF) was kept at 100°C for 5 min. and cooled. At 10°C the crude 1-ben¬ zyloxy-2-benzyloxymethyl-4-chlorobut-2-ene in 25 ml of dry DMF was added with stirring during 4 h. After 2 days at room temperature the mixture was evaporated in vacuum, the residue was extracted with 2x25 ml of chloroform and the extract evaporated to dryness. Chromatography (silica gel,- CHCl 3 +MeOH 19+1) afforded 0.25 g (18%) of 4-(2-amino-6-chloropurin- -9-yl )-l-benzyloxy-2-benzyloxymethyl-2-butene (TLC on silica gel, CHC + MeOH 13+1 parts by volume Rf 0.62). ] H NMR (CDC1 3 -CD 3 0D): cf4.05 and 4.19 (2s, 2x2H) =C(CH 2 0) 2 ; 4.49 and 4.55 (2s, 2x2H) benzylic CH 2 ; 4.70 (d, 2H) N-CH 2 ; 5.85 (t, IH) CH=; 6.2 (broad s, 2H) NH 2 ; 7.3 (broad s, 10H) phenyl; 7.49 (s, IH) Hg. Degrotection A solution of 4-(2-amino-6-chloropurin-9-yl )-l-benzyloxy-2-benzyloxy¬ methyl-2-butene (148 mg, 0.329 mmol), 1.8 ml of trifluoroacetic acid and 0.2 ml of water in a sealed ampoule was kept at 110°C for 17 h. After cooling the mixture was diluted with 2 ml of water, heated to boiling for one minute, and evaporated to dryness in vacuum, dissolved in water and re-evaporated. Chromatography (silica gel, ethyl acetate + methanol + water 70+20+10 parts of volume) afforded 34 mg (41%) of 9-[4-hydroxy-3-(hydroxymethy )-2-butenyl ]guanine. ] H NMR (DMS0-d 6 ): cf3.96 and 4.10 (2d, 2x2H) = C(CH 2 0) 2 ; 4.68 (d, 2H) N-CH 2 ; 4.83 (2t, 2H) 20H; 5.60 (t, IH) CH=; 6.50 (broad s, 2H) H 2 ; 7.66 (s, IH) H 8 ; 10.6 (broad s, IH) NH. The starting compound ^-Benzyl_oxy 2;benzyl_oxymethylbut-3-en-2-ol , was prepared as follows: HO .CH 2 0CH 2 CgH 5 CH 2 == CH v CH 2 0CH 2 C 6 H 5 A solution of 4.0 g vinyl bromide (37.4 mmol) in 8 ml of dry tetrahydro- furan (THF) was added to 0.94 g Mg (38.7 mmol) in 3 ml of THF under N 2 at about 60°C and the mixture was refluxed (C0 2 -ethanol condenser) for 1 h). A solution of 7.4 g (27.4 mmol) of 1 ,3-bis(benzyloxy)-propan-2-one (Araki Y. et al . , J. Chem. Soc, Perkin Trans. 1, 1981, 19) in 25 ml of THF was added dropwise at 10°C and the mixture was stirred at ambient temperature for 2 h. Then 8 ml of a 20% aqueous NH 1 solution was added and the organic phase was evaporated, dissolved in ether, dried with MgS0 4 , and evaporated in vacuum to give 7.90 g of 1-benzyloxy-2-benzyl- oxymethylbut-3-en-2-ol as a crude oil. ] H NMR (CDC1 3 ): cf2.67 (s, IH) OH; 3.50 (s, 4H) C(CH 2 0) 2 ; 4.55 (s, 4H) 20CH 2 Ph; 5.0-6.3 (m, 3H) CH 2 =CH; .7.32 (broad s, 10H) phenyl. Example 7. cis-9-(4-Hydroxy-2-butenyl )guanine (Method B) 2-Amino-6-chToropurine (3.4 g), butadiene monoepoxide (1.65 g) and tetra- kis (triphenylphosphine)palladiu (0) (1.0 g) in dry dimethylformamide (75 ml) were stirred under a nitrogen atmosphere and heated at 60°C for 45 minutes. The solvent was evaporated in vacuum (0.1 mm Hg) and the residue was triturated with hot chloroform (4x50 ml). The combined chloroform solutions were concentrated (25 ml volume) and diluted with ether (100 ml). The gummy precipitate was collected, dried and triturated with hot 1 ,2-dimethoxyethane (3x50 ml). The combined solutions were evaporated in vacuum (0.1 mm Hg) to give a crude mixture (4 g) which was separated on a column of silica gel (500 g) eluted with chloroform + methanol 10+1 (800 ml) followed by chloroform + methanol 8+1. Frac¬ tions of about 15 ml were collected and the compound cis-4-(2-Amino-6- chloropurin-9-yl )-2-buten-l-ol was obtained as a minor product (0.2 g) in fractions 74-78. M.p. 160-165°C. UV (nm): 0.1 M HC1 241, 315 0.1 M NaOH 246, 308 H NMR (DMS0-d 6 ): cf .20 (t, J 5.4Hz, 2H) CH 2 0; 4.76 (d, J 6.8Hz, 2H) NCH 2' 5.54-5.83 (m, 2H) CH=CH; 6.69 (s, 2H) NH ; 8.06 (s, IH) H Q§Brotection cis-4-(2-Amino-6-chloropurin-9-yl )-2-buten-l-ol (50 mg) in formic acid- water 7+3 (5 ml) was heated at 45°C under a nitrogen atmosphere for 20 hours. The solvent was evaporated in vacuum and the residue was dried. Water (0.5 ml) was added and the solution was neutralized with aqueous ammonia. The precipitate was filtered, washed with water, ethanol and ether, and dried to give the compound cis-9-(4-hydroxy-2- -butenyl )guanine (40 mg). ] H NMR (DMSO-dg): cf4.15 (diffuse t, 2H) CH 2 0; 4.65-4.90 (ABX system, 2H) NCH 2 ; 5.75 (m, 2H) CH=CH; 6.52 (broad s, 2H) NH 2 7.66 (s, IH) Hg. Example 8. 9-(4-hydroxy-2-butynyl )guanine (Method A) N-Bromosuccinimide (1.78 g, 10 mmol) was added in portions to a stirred suspension of 2-butyn-l ,4-diol (2.50 g, 30 mmol) and triphenylphosphine (2.62 g, 10 mmol) in 20 ml of dichloromethane at room temperature. After 1 h, the unreacted butyndiol was removed by filtration. The solution was evaporated in vacuum to small volume, dissolved in 20 ml of dry dimethylformamide (DMF) and added to a suspension of 2-amino-6-chloro- purine (1.70 g, 10 mmol) and finely ground anhydrous K 2 C0 3 (2.07 g, 15 mmol) in 75 ml of dry DMF, stirred at 0°C. The stirring was continued at room temperature for 3 days. Then the mixture was evaporated in vacuum to dryness. Chromatography (silica gel, CHC1-, + MeOH 7+1) afforded 467 mg (20%; after recrystallization from water to remove 2-butyn-l ,4-diol ) of 4-(2-amino-6-chloropurin-9ryl )-2-butyn-l-ol (TLC on silica gel, CHC1 3 + MeOH 5+1; R f 0.57). ] H NMR (DMS0-d 6 ): cf 4.10 (dt, 2H) CH 2 0; 4.96 (t, J=2.0Hz, 2H) NCH 2 ; 5.12 (t, J=5.9Hz, IH) OH; 6.89 (broad s, 2H) NH 2 ; 8.17 (s, IH) Hg. 13 C NMR (DMSO-dg): ςf 32.79 (NCH 2 ); 49.07 (CH 2 0); 7.7.80 and 85.19 (C=C); 123.43 (C5); 142.43 (C8); 149.82 (C6); 153.69 (C4); 160.01 (C2). Deprotection A solution of 4-(2-amino-6-chloropurin-9-yl )-2-butyn-l-ol (140 mg, 0.59 mmol) in 2 ml of 50% aqueous formic acid was kept at 80° for 6 h and then evaporated to dryness in vacuum. The residue was dissolved in 2 ml of water - cone, aqueous ammonia 1+1 and the solution kept at 80° for 1 h and then evaporated in vacuum to dryness. Recrystallization from water afforded 90 mg (70%) of 9-(4-hydroxy-2-butynyl )guanine. ] H NMR (DMSO-dg): of4.09 (m, 2H) CH 2 0; 4.84 (t, J=2.0Hz, 2H) NCH 2 ; 5.11 (t, J=6.0Hz, IH) OH; 6.44 (broad s, 2H) NH 2 ; 7.73 (s, IH) Hg. 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 10 Maize starch 25.0 mg Lactose 190.0 mg Gelatin 1.5 mg Talc 12.0 mg Magnesium stearate 1.5 mg 15 250.0 mg Suppositories Each suppository contains: 20 Active substance 20.0 mg Ascorbyl palmitate ' 1.0 mg Suppository base (Imhausen H or Witepsol ® H)ad 2000.0 mg 25 Syrup Acti ve substance 0.200 g Liqui d gl ucose 30.0 g 30 Sucrose 50.0 g Ascorbi c aci d 0.1 g Sodium pyrosul fi te 0.01 g Di sodi um edetate 0.01 g Orange essence 0.025 g 35 Certi fi ed col our 0.015 g Purifi ed water ad 100.0 g r jf Injection solution Active substance 3.000 mg Sodium pyrosulfite 0.500 mg Disodium 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 mg Talc 5.0 mg Agar 5.0 mg 100.0 mg Jelly Active substance 1.0 g Methocel ® 4.0 g Methyl p-hydroxybenzoate 0.12 g Propyl p-hydroxybenzoate 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 Paraffin, liquid 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 . g Polyethylene glycol 4000 15 g Propylene glycol ad 100 g Ointment III Active substance 3.0 g Sorb tan monoleate 5.0 g Petroleum ad 100 g Ointment IV Active substance 5 g Adeps lanae 20 g Tween ® 60 4 g Span ® 40 2 g Paraffin, liquid 4 g Propylene glycol 5 g Hydrochloric acid to pH 6.5- ■ 8 Sterile water ad 100 g Ointment V Active substance 5 g Adeps lanae 20 g Tween ® 60 4 g Span ® 40 2 g Paraffin, liquid 4 g Propylene glycol 5 g Boric acid 2 g Sodium hydroxide to pH 6.5-8 Sterile water ad 100 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 Methocel ® 65 HG 4000 0.65 Sterile water ad 100 ml Eye drops II Active substance 0.3 g Disodium edetate 0.10 g Sodium chloride for isotonia q.s. Hydrochloric acid to pH 6.5-8.0 Methocel ® 65 HG 4000 0.65 Sterile water ad 100 ml Eye drops III Active substance 0.2 g Disodium edetate 0.1 g Sodium chloride for isotonia q.s. Boric acid 0.1 g Methocel ® HG 4000 0.65 g Sterile water ad 100 ml Eye ointment I Active substance 5 g Paraffin oil 19 g Petrolatum 76 g Cream • Active substance 3.0 9 Arlaton ® 4.0 g 5 Cetanol 2.0 g Stearic acid 2.0 g Paraffin oil 2.0 g Propylene glycol 2.0 g Glycerol 1 .5 g 10 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) 15 Distilled water to 100 g Jelly Active substance 3.0 g 20 Methocel ® 2.45 g Glycerol 0.0 g Tween ® 0.10 g Methyl p-hydroxybenzoate 0.06 g Propyl p-hydroxybenzoate 0.03 g 25 Sodium hydroxide 0.002 g Hydrochloric acid 2M to pH 8.0 Distilled water to 100 g Tablets 30 Each tablet contains: Active substance 100.0 mg Starch 60.0 mg 35 Lactose 190.0 mg Polyvinylpyrrolidone 5.0 mg Magnesium stearate 5.0 mg 360.0 mg jj_ψV . Biological tests The inhibiting effect of compounds of the invention on herpesvirus was tested using the methods described below. The cellular toxicity of the compounds on host cell functions was also tested. In the following the compound 9-[4-hydroxy-2-(hydroxymethyl )butyl Iguani¬ ne (base) is denoted VSA 671, the compound 9-[4-hydroxy-3-(hydroxymeth¬ yl )butyl Iguanine (base) is denoted VIS 873, the compound cis-9-(4-hyd- roxy-2-butenyl )guanine (base) is denoted VSA 151 and the compound 9-[4- -hydroxy-3-(hydroxymethyl )-2-butenyl ]guanine (base) is denoted VSA 668, Herpes simplex type 1 virus is denoted HSV-1, Herpes simplex type 2 virus is denoted HSV-2 and Varicella zoster virus is- denoted VZV. I. Inhibition of virus multiplication in cell cultures The inhibition of HSV-1 (strain C42) by VSA 671, VIS 873, VSA 151 and VSA 668 has ' been measured in a plaque reduction assay in Vero (Green Monkey Kidney) cells and in HEL (human embryonic lung) cells as describ- ed by Ejercito et al . , J. Gen. Virol. 2 357 (1968). The effect on VZV (several strains) multiplication in HL (human lung fibroblast) cells by VSA 671 was determined by measuring the formation of late antigens by the ELISA technique as described by B. Wahren et al . , J. Virological methods 6, 141-149 (1983). The results are shown in Table 1. Table 1. Inhibition of herpesvirus multiplication by VSA 671, VIS 873, VSA 151 and VSA 668. HSV-1 VZV in Vero cells in HEL cells in HL cells Compound Inhibition (%)/Conc. .(μM) ID 50 (μM) ID 50 (μM) VSA 671 90/l 0.2 1.3-2.5 VIS 873 >90/l 0.4 VSA 151 >90/10 0.6 VSA 668 >90/25 II. Affinity of VSA 671, VIS 873, VSA 151 and VSA 668 for herpesvirus- induced thymidine kinase Inhibition constants (K..) showing the affinity for HSV-1 thymidine kin- ase was determined according to the method of A. Larsson et al., Anti- microb. Agents Chemother. 23, 664 (1983). The inhibition constants are shown in Table 2. Table 2. Inhibition constants of VSA 671, VIS 873, VSA 151 and VSA 668 for HSV-1 thymidine kinase. Compound (μM) V VSSAA 6 67711 0.6 VIS 873 1.5 VSA 151 7 VSA 668 . 25 A high affinity for the viral thymidine kinase is an advantage for anti¬ viral activity under conditions when the compounds have to compete with thymidine. VSA 671 has an affinity close to that of the natural sub¬ strate, thymidine (K 0.42 μM). III. Cellular toxicity VSA 671, VIS 873, VSA 151 and VSA 668 were tested for cellular toxicity on human embryonic cells as described by K. Stenberg [Biochemical Pharma- cology 30, 1005-1008 (1980)]. All compounds showed low cellular toxi¬ city (Table 3) at concentrations that inhibit herpesvirus multiplication to more than 90% (see Table 1). Table 3. Cellular toxicity of VSA 671, VIS 873, VSA 151 and VSA 668, expressed as percent reduction in cell growth (Flow 1000) after 48 h of incubation. Cone. Compound Percent reduction in cell (μM) growth 200 VSA 671 18 200 VIS 873 7 200 VSA 151 0 200 VSA 668 0 IV. Animal experiments a) Experiments on cutaneous herpesvirus infection on guinea pigs were carried out as previously described by S. Alenius and B. Oberg [Archives of Virology 58, 277-288 (1978)]. The experiments showed that VIS 873 had a therapeutic effect on cutaneous herpesvirus infections when appli- ed topically as shown in Table 4. Thirty μl of solution or solvent was added topically 3 times per day for 4 days starting 24 h post inocula¬ tion. Table 4. Therapeutic effect on cutaneous herpesvirus infection Cone, of VIS 873 in Percent reduction in dimethylsulfoxide cumulative score as o, compared to placebo 0 treatment 2.5 36 b) Treatment of a "systemic" HSV-1 or HSV-2 infection in mice with VSA 671 or VIS 873 i.p. was carried out as described in A. Larsson et al ., Antimicrob. Agents Chemother. 23, 664-670 (1983). Mice were infected with 10 pfu (pl que-forming units) HSV-1 (C42) or 10 pfu HSV-2 (strain 91075) i.p., and treatment was started 1 h after infection. Treatment consisted of two daily i.p. doses of either nucleo- side analog, dissolved in phosphate-buffered saline, for 5 days. Cumula¬ tive mortality (treated vs. untreated animals) was determined during the course of the experiment, i.e. 21 days. The results are shown in Table 5. Table 5. Antiviral effect of VIS 873 and VSA 671 on systemic (i.p.) HSV-1 and HSV-2 infections in mice. Compound Dose Virus Cumulative mortality {%) (treated/untreated) VSA 671 25 mg/kg HSV-1 30/90 50 " 30/90 25 " HSV-2 40/90 50 " 30/90 VIS 873 5 mg/kg HSV-1 30/80 10 0/80 5 II " HSV-2 70/90 10 20/90 25 0/90 50 10/100 Best mode of carrying out the invention Among the compounds of the present invention according to formula I, the compounds 9-[4-hydroxy-3-(hydroxymethyl )butyl ]guanine, 9-[4-hydroxy- -(2-hydroxymethyl )butyl ]guanine and cis-9-(4-hydroxy-2-butenyl )guanine and their use for the treatment of herpesvirus infections represent the best mode known at present. The compound 9-[4-hydroxy-2- -( ydroxymethyl )butyl ]guan ne has shown a very good effect against varciella zoster virus multipl cation.

Claims: 49 CLAIMS 1. A compound of the formula wherein A is (CH ) -CH-(CH ) OH (Aa) 2 m i 2 n or CH -C=C-CH OH (Ab) 2 i i 2 R b R S wherein m is 1 or 2, n is 1 or 2, whereby m is 1 when n is 2 and m is 2 when n is 1 R' is (CH OH, NHCONH, or COR" a -. p ά a R" is hydrogen, hydroxy or amino, a p is 1 to 4, R! and R are independently selected from hydrogen or (CH„) OH, with the proviso that at least one of Rύ or R is hydrogen; or R! and R together constitute an additional carbon-carbon bond to form an alkyne; and with the additional proviso that when is 2 and n is 1 and R' is (CH ? ) OH then p is 2 to 4; or a physiologically acceptable salt, geometric .or optical isomer thereof. A compound of the formula wherein m is 1 or 2 and n is 1 or 2, whereby m is 1 when n is 2 and m is 2 when n is 1, Ra • is (CH pOH, NHCONH, <- or COR", wherein Rα" is hydrogen, hydroxy or amino and where p is 1 to 4 with the proviso that when m is 2 and n is 1 and Ra' is (CH,)_p0H then p is 2 to 4; or a physio- logically acceptable salt or optical isomer thereof. 3. A compound of the formula wherein R. ' and R. " are independently selected from hydrogen or (CH 2 ) OH, where p is 1 to 4, with the proviso that at least one of R. ' and R. " is hydrogen, or R, ' and R. " together constitute an additional carbon-carbon bond to form an alkyne; or a physiologically acceptable salt or geometric isomer thereof. 4. A compound according to the claims 1 and 3, wherein in the formulas I and III R. ' or R. " are hydroxymethyl. 5. A compound according to the claims 1 and 3 having the formula 9-[4- -hydroxy-3-(hydroxymethyl )-2-butenyl ]guanine. 6. A compound according to the claims 1 and 3 having the formula 9-(4- -hydroxy-2-butenyl )guanine. 7. A compound according to claim 6 having the formula cis-9-(4-hydroxy- -2-butenyl )guanine. 8. A compound according to the claims 1 and 3 having the formula 9-(4- -hydroxy-2-butynyl )guanine. 9. A compound according to the claims 1 or 2, wherein in the formulas I and II R ■ is CH 2 0H or CH 2 CH 2 0H. 10. A compound according to the claims 1 and 2 having the formula 9-[4- -hydroxy-2-(hydroxymethyl)butyl ]guanine. 11. A compound according to claims 1 and 2 having the formula 9-[4-hyd- roxy-2-(hydroxyethyl)butyl ]guanine. 12. A compound according to one of the claims 1-2 and 9-11 in the form of an optical isomer thereof. 13. A compound according to one of the claims 1 and 3-6 in the form of a geometric isomer thereof. 14. A compound according to one of the claims 1-13 in the form of a physiologically acceptable salt thereof. 15. A pharmaceutical preparation comprising as an active ingredient a compound of the formula wherein A is (CH,2)m-CiH-(CH 2'n OH (Aa) or CH,-C=C-CH,0H (Ab) 2 I I 2 R b R b' wherein m is 1 or 2, n is 1 or 2, whereby m is 1 when n is 2 and m is 2 when n is 1 Ra' is (CH, c)pOH, NHCONH, or CORa", Ra" is hydrogen, hydroxy or amino, p is 1 to 4, R' and RjJ are independently selected from hydrogen or (CH 2 ) OH, with the proviso that at least one of R or RjJ is hydrogen; or R ■ and RjJ together constitute an additional carbon-carbon bond to form an alkyne; or a physiologically acceptable salt, geometric or optical isomer thereof, in conjunction with a pharmaceutically acceptable carrier. 16. A pharmaceutical preparation comprising as an active ingredient a compound of the formula R a wherein is 1 or 2 and n is 1 or 2, whereby m is 1 when n is 2 and m is 2 when n is 1, Ra' is (CH, c)pOH, NHCONH,_. or CORa" wherein Ra" is hydrogen, hydroxy or amino and where p is 1 to 4; or a physiologically acceptable salt or optical isomer thereof, in conjunction with a pharma¬ ceutically acceptable carrier. 17. A pharmaceutical preparation comprising as an active ingredient a compound of the formula wherein R and RjJ are independently selected from hydrogen or (CH OH, where p is 1 to 4, with the proviso that at least one of R' and RjJ is hydrogen, or R and RjJ together constitute an additional carbon-carbon bond to form an alkyne; or a physiologically acceptable salt or geo¬ metric isomer thereof, in conjunction with a pharmaceutically acceptable carrier. 18. A pharmaceutical preparation according to the claims 15-17 designed for systemic administration. 19. A pharmaceutical preparation according to the claims 15-17 designed for topical administration. 20. A method for the treatment of virus infections in an animal or human host in need of treatment, comprising administering a therapeutically effective amount of a compound of the formula wherein A is (CH,2)m-CIH-(CH,2) n n OH (Aa) or R' a CH,-C=CH-CH,OH (Ab) I I R b R b' wherein m is 1 or 2, n is 1 or 2, whereby m is 1 when n is 2 and m is 2 when n is 1, Ra' is (CH,.)p0H, NHCONH,. or CORa" R" is hydrogen, hydroxy or amino, p is 1 to 4, R' and RjJ are independently selected from hydrogen or (CH ? ) OH. with the proviso that at least one of R' or RjJ is hydrogen; or Ri and RjJ together constitute an additional carbon-carbon bond to form an alkyne; or a physiologically acceptable salt, geometric or optical isomer thereof. 21. A method for the treatment of virus infections in an animal or human host in need of treatment, comprising administering a therapeutically effective amount of a compound of the formula wherein m is 1 or 2 and n is 1 or 2, whereby m is 1 when n is 2 and m is 2 when n is 1, Ra' is (CH,.)pOH, NHCONH,_. or CORα", wherein Ra" is hydro- gen, hydroxy or amino and where p is 1 to 4; or a physiologically accept¬ able salt or optical isomer thereof. 22. A method for the treatment of virus infections in an animal or human- host in need of treatment, comprising administering a therapeutically effective amount of a compound of the formula wherein Rl and RjJ are independently selected from hydrogen or (CH ? ) OH, where p is 1 to 4, with the proviso that at least one of Rl and RjJ is hydrogen, or R' and RjJ together constitute an additional carbon-carbon bond to form an alkyne; or a physiologically acceptable salt or geometric isomer thereof. 23. A method according to the claims 20-22 for the treatment of infections caused by herpesviruses. 24. A method according to the claims 20-21 for the treatment of infections caused by varicella (Herpes zoster) virus. 25. A method according to claim 23 for the treatment of infections caused by Herpes simplex type 1 and 2 virus. 26. A compound of the formula wherein A is wherein is 1 or 2, n is 1 or 2, whereby m is 1 when n is 2 and m is 2 when n is 1 Ra' is (CH, L)pOH, NHCONH, L. or CORa" Rα" is hydrogen, hydroxy or amino, p is 1 to 4, Rύ and RjJ are independently selected from hydrogen or (CH ) OH with the proviso that at least one of Rύ or RjJ is hydrogen; or Rύ and RjJ together constitute an additional carbon-carbon bond to form an alkyne; or a physiologically acceptable salt, geometric or -optical isomer thereof, for use in the treatment of virus infections. 27. A compound of the formula R a wherein m is 1 or 2 and n is 1 or 2, whereby m is 1 when n is 2 and m is 2 when n is 1, Ra' is (CH,.)pOH, NHCONH, C or COR a" wherein Rα" is hydro- gen, hydroxy or amino and where p is 1 to 4; or a physiologically accept¬ able salt or optical isomer thereof for use in the treatment of virus infections. 28. A compound of the formula wherein Rύ and RjJ are independently selected from hydrogen or (CH 2 ) OH, where p is 1 to 4, with the proviso that at least one of Rύ and RjJ is hydrogen, or Rύ and RjJ together constitute an additional carbon-carbon bond to form an alkyne; or a physiologically acceptable salt or geomet¬ ric isomer thereof, for use in the treatment of virus infections. 29. A compound according to the claims 26-27 for use in the treatment of varicella (Herpes zoster). 30. A compound according to the claims 26-28 for use in the treatment of Herpes simplex type 1 and 2. 31. A process for preparing a compound of the formula wherein A is (CH, ,2)m--CCrHH.--((CCHH,,2))nO(H (Aa) or wherein m i s 1 or 2, n is 1 or 2, whereby m is 1 when n is 2 and m is 2 when n is 1 Ra' is (CH c,)pOH, NHCONH, or COR a" R" is hydrogen, hydroxy or amino, a p is 1 to 4, R; and RjJ are independently selected from hydrogen or (CH O with the proviso that at least one of Rύ or RjJ is hydrogen; o R' and RjJ together constitute an additional carbon-carbon bond to form an alkyne, and with the additional proviso that when m is 2 and n is 1 and Ra' is (CH,2)pOH then p is 2 to 4; or a physiologically acceptable salt, geometric or optical isomer thereof, by: for the preparation of a compound of the formula I wherein A is Aa: A. Condensation of a compound of the formula R ,22aa X a -(CH 2 ) m -CH-(CH 2 ) n -OR 3a . to the N-9 position of a guanine derivative of the formula followed by removal of optional protecting groups, in which formulas R', m and n have the.meaning given above; is a leaving group such as chloro, bromo, iodo or 0S0 2 R 7 where R-, is alkyl, fluorinated alkyl arylalkyl or aryl; Y is hydrogen or a quaternary ammonium ion; R, is hydrogen or a protecting group such as acyl, alkoxycarbonyl, arylcarbo- nyl, silyl or S0 2 R 7a ; R 2a is R fl as defined above or CN, C00R« , CH(0R 9a ) 2 , CH(SR 9a ) 2 , NHC0NHR 9a , or (CHg) 0R ga , where p is as defined above; Rg a is substituted silyl or a group R 7 as defined above; R g is a group R 3 as defined above or R g and R g together with R 3 form a divalent group, that is a cyclic derivative such as lactone, cyclic ester, orthoacid, acetal, ether or silyl type compound; R. and R ς are defined as group R 3a above; R ga is a leaving group such as the group X defined above, OH or OR-, Qa , where R. j0 is alkyl, arylalkyl,, S0 2 R 7a' subs tituted silyl, phosphoryl diester or phosphinothioyl ; B. Condensation of a compound of the formula to the N-9 position of a guanine derivative of the formula followed by removal of optional protecting groups, in which formulas R 4a' R 5a and R 6a are as defiπed under A, R,. is CN, C0NH 2 or COORg and R,- is COORg or CH 2 0R g , where Rg and R g are as defined under A; C. Reduction of derivatized or activated carboxylic acid groups in a compound of the formula followed by removal of optional protecting groups, in which formula m, n, R 2 R. R 5 and Rg are as defined under A, R,, is a group Rg or a group (CH 3 )„ N=CH0- and R, ? is a group R ? or a group (CH,2)p-,1 COR,I,la,, where p r is as defined under A: 7 D. Pyrimidine ring closure of a compound of the formula (CH 2 ) m -CH-(CH 2 ) n 0R 3a followed by removal of optional protecting groups, in which formula m, n, R 2 and R 3 are as defined under A, Z is NH 2 or alkoxy and R- j7a is NH 2 or guanidino; E. Imidazole ring closure of a compound of the formula (CH 2 ) m -CH-(CH 2 ) n 0R 3a followed by removal of optional protecting groups, in which formula m, n, R 2 and R~ are as defined under A and R,g is nitroso, nitro, amino or amino groups such as formyl amino or ortho ester amino; F. Substitution of a compound of the formula (CH,) 2 nOR3.a followed by removal of optional protecting groups, in which formula m, n, R 2 and R 3 are as defined under A, R, g is chloro, bromo, iodo, hydroxy or amino and R 2Q is fluoro, chloro, bromo, iodo or amino; where upon a compound obtained is optionally converted into a physiologically acceptable salt or optical isomer; for the preparation of a compound of the formula I wherein A is Ab: G. Condensation of a compound of the formula R 2b R 7b X b -CH 2 -C = C-CH 2 0R 3b to the N-9 position of a guanine derivative of the formula followed by removal of optional protecting groups, in which formulas: X. is a leaving group such as chloro, bromo, iodo or 0S0 2 R g , , where R g . is alkyl, fluorinated alkyl, arylalkyl or aryl; Y is hydrogen or a quaternary ammonium ion; R 3b is hydrogen or a protecting group such as acyl, alkoxycarbonyl, aryloxycarbonyl, silyl or S0 2 Rg b R 2b is Rύ or (CH 2 ) 0R gb and R b is RjJ or (CH 0R gb , where p is 1 to 4 and where R gb is a group R 3b as defined above or R gb and R 3b together form a di¬ valent group, that is a cyclic derivative such as a carbonate ester, thiocarbonate ester, orthoacid or acetal compound; R gb is hydroxy or a leaving group such as chloro, bromo, iodo, mercapto, alkylthio, S0 2 R g . or 0R, Qb , where R, 0b is alkyl, arylalkyl, substituted silyl, phosphoryl diester, phosphinothiolyl or S0 2 R gb ; R *b and R 5b are defined as group R 3b above,- H. Condensation of a compound of the formula to the N-9 position of a guanine derivative of the formula followed by removal of optional protecting groups, in which formulas R 2b' 4b' R 5b' R 6b and R 7b are as defined under G; J. Reduction of the derivatized or activated carboxylic acid groups in a compound of the formula R lib followed by removal of optional protecting groups, in which formula: and Rg b are as defined under G; R,, fa is a group R gb or group = CH0-; R, 2b is a group R 7b as defined under G or (CH 2 ) , C0R llb' and R 17b is a 9 rou P R 2b as defined under G or (CH 2 ) ,C0R-|, b , or R., b and R, 2b or R,, b and R, 7b together form a divalent group, that is a cyclic derivative such as lactone, cyclic ester, orthoacid, * aceta1 , ether or silyl type compound; K. Partial reduction of a compound of the formula followed by removal of optional protecting groups, in which formula R 3b' R 4b' R 5b ancl R 6b are as defined under G; L. Pyrimidine ring closure of a compound of the formula followed by removal of optional protecting groups, in which formula R 2b' R 3b and R 7b are as defined under G, Z is NH 2 , alkoxy and R 13b is NH 2 or guanidino; M. Imidazole ring closure of a compound of the formula followed by removal of optional protecting groups, in which formula κ' R 3h and R 7h are as de' * r' ' ne under G and R,« b is nitroso, nitro, amino or an amino derivative such as formylamino or ortho ester amino; N. Substitution of a compound of the formula followed by removal of optional protecting groups, in which formula. R 2b' R 3b and R 7b are as 'de'f:'iπed under G, R- |5b is chloro, bromo, iodo, hydroxy or amino and R,g b is fluoro, chloro, bromo, iodo or amino; where¬ upon a compound obtained is optionally converted into a physiologically acceptable salt or geometric isomer. 32. Compounds, processes, pharmaceutical preparations, and methods of treatment as claimed in any of the claims 1-31, and substantially as • described. 33. A compound of the formula I as defined in any of the claims 26-28 for use as a therapeutical agent. 34. A compound of the formula I as defined in any of the claims 26-28 for use as a prophylactical agent in the medical field.

Inventors: JOHANSSON KARL NILS-GUNNAR, LINDBORG BJOERN GUNNAR, NOREN JAN-OLOF, JOHANSSON, KARL, NILS-GUNNAR, LINDBORG, BJOERN, GUNNAR, NOREN, JAN-OLOF
Applicants: ASTRA LAEKEMEDEL AB, ASTRA LAEKEMEDEL AKTIEBOLAG
Application year: 1984
Main classification: C07D473
IPC codes: A61K31, C07C43, C07D473