EP0112353A1 - Novel derivatives of guanine i - Google Patents

Novel derivatives of guanine i

Info

Publication number
EP0112353A1
EP0112353A1 EP83901965A EP83901965A EP0112353A1 EP 0112353 A1 EP0112353 A1 EP 0112353A1 EP 83901965 A EP83901965 A EP 83901965A EP 83901965 A EP83901965 A EP 83901965A EP 0112353 A1 EP0112353 A1 EP 0112353A1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
methoxy
fluoro
formula
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP83901965A
Other languages
German (de)
English (en)
French (fr)
Inventor
Karin Ingeborg Eklind
Kristina Birgitta Gotthammar
Curt-Erik Hagberg
Karl Nils-Gunnar Johansson
Zsuzsanna Maria Ilona Kovacs
Jan-Olof Noren
Göran Bertil Stening
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astra Lakemedel AB
Original Assignee
Astra Lakemedel AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astra Lakemedel AB filed Critical Astra Lakemedel AB
Publication of EP0112353A1 publication Critical patent/EP0112353A1/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/04—Saturated ethers
    • C07C43/13—Saturated ethers containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/16—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • 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.
  • 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.
  • herpes dermatitis including herpes labialis
  • herpes keratitis including herpes labialis
  • herpes genitalis including herpes labialis
  • herpes zoster including herpes encephalitis
  • infections mononucleosis and cytomegalovirus infections all of which are caused by viruses belonging to the herpes-virus 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.
  • 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.
  • R 1 is hydrogen, halogen, hydroxy, alkoxy, azide, thio, alkylthio, amino, alkylamino, or dialkylamino;
  • R 2 is hydrogen, halogen, alkylthio, acylamino, amino or azide
  • R 3 is hydrogen, straight or branch chain or cyclic alkyl, hydroxyalkyl, benzyloxyalkyl, or phenyl
  • R 4 is hydrogen, hydroxy or alkyl
  • R 5 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 sulphony!
  • R 6 is hydrogen or alkyl, provided that when X is oxygen and R 2 , R 3 , R 4 and R 6 are hydrogen, R 1 is not amino or methylamino when R 5 is hydrogen or hydroxy.
  • the present invention relates to the novel antiviral compound of the formula
  • R 1 is hydrogen, R 2 is hydrogen, fluoro, methoxy or methylthio and R 3 is hydrogen, hydroxy or mercapto; with the provisos that when R 3 is hydrogen then R 2 is methoxy or methylthio and that when R 3 is hydroxy then R 2 is fluoro, methoxy or methylthio; and with the further proviso that R 1 can also be methoxy or fluoro when R 2 is methoxy or fluoro; and physiologically acceptable salts or optical isomers thereof.
  • the invention thus provides a compound, and physiologically 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 sice 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 anitiviral 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.
  • the present invention relates broadly to a novel method for combating virus infections in animals and man, end compounds to be used at such treatment, it will be particularly useful in the treatment of herpesvirus infections.
  • herpesvirus infections include herpes simplex type 1 and 2, varicella (Herpes zoster), virus causing infectious mononucleosis (i.e. Epst ⁇ in-Sarr virus J and cytomegaloviru ⁇ .
  • Important diseases caused by herpesviruses are herpes dermatitis, (including herpes labielis), herpes genitelis, herpes keratitis, herpes encephalitis and herpes zoster.
  • 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 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 leucemias, lymphomas 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 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
  • 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 physiologically acceptable salt thereof in an amount sufficient for inhibiting said multiplication.
  • 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 therapeuti cal ly 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.
  • R 1 is hydrogen, R 2 is hydrogen, fluoro, methoxy or methylthio and R 3 is hydrogen, hydroxy or mercapto; with the provisos that when R 3 is hydrogen then R 2 is methoxy or methylthio and that when R 3 is hydroxy then R 2 is fluoro, methoxy or methylthio; and with the further proviso that R 1 can also be methoxy or fluoro when R 2 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:
  • R 3 is selected from hydrogen and hydroxy, R 1 is selected from hydrogen, fluoro and methoxy and R 2 is selected from fluoro, methoxy and methylthio, with the provisos that when R 1 is hydrogen and R 2 is fluoro then R 3 is hydroxy and that when R 1 is fluoro or methoxy then R 2 is also fluoro or methoxy; or (II) R 3 is hydrogen, R 1 is selected from hydrogen, fluoro and methoxy and R 2 is selected from hydrogen, fluoro, methoxy and methylthio, with the proviso that when R 1 is fluoro or methoxy then R 2 is also fluoro or methoxy; or
  • R 1 and R 2 are the same or different and are selected from hydrogen and fluoro, and R 3 is selected from hydrogen and hydroxy, with the proviso that when R 1 is hydrogen and R 2 is fluoro then R 3 is hydroxy; or
  • R 1 is selected from hydrogen and fluoro
  • R 2 is selected from hydrogen, fluoro, methoxy and methylthio
  • R 3 is selected from hydrogen and hydroxy, with the provisos that when R 1 is hydrogen and R 2 is fluoro then R 3 is hydroxy and with the further proviso that when R 1 is fluoro then R 2 is fluoro or methoxy; or
  • R 1 is selected from hydrogen, fluoro and methoxy
  • R 2 is selected from hydrogen, fluoro, methoxy and methylthio
  • R 3 is selected from hydrogen and hydroxy, with the provisos that when R 1 is hydrogen and R 2 is fluoro then R 3 is hydroxy and that when R 1 is fluoro or methoxy then R 2 is also fluoro or methoxy; or
  • R 1 is selected from hydrogen and fluoro
  • R 2 is selected from hydrogen, fluoro, methoxy and methylthio
  • R 3 is selected from hydrogen and mercapto, with the provisos that when R 1 and R 2 are both hydrogen then R 3 is mercapto; and that when R 1 is fluoro then R 2 is fluoro or methoxy; or
  • R 3 is selected from hydrogen and mercapto, R 1 is selected from hydrogen, fluoro and methoxy and R 2 is selected from hydrogen, fluoro, methoxy and methylthio, with the provisos that when R 1 is hydrogen and R 2 is hydrogen and fluoro then R 3 is mercapto and that when R 1 is fluoro or methoxy then R 2 is also fluoro or methoxy; or (VIII) R 1 and R 2 are the same or different and are selected from hydrogen and fluoro and R 3 is selected from hydrogen, hydroxy and mercapto with the provisos that when R 1 and R 2 are both hydrogen then R 3 is mercapto and that when R 1 is hydrogen and R 2 is fluoro then R 3 is selected from hydroxy or mercapto; or
  • R 1 and R 2 are the same or different and are selected from hydrogen, fluoro and methoxy and R 3 is selected from hydrogen, hydroxy and mercapto, with the proviso that when R 1 and R 2 are both hydrogen then R 3 is mercapto; or
  • R 1 is hydrogen
  • R 2 is selected from hydrogen, methoxy and methyl thio
  • R 3 is selected from hydrogen, hydroxy and mercapto, with the proviso that when R 1 and R 2 are both hydrogen, then R 3 is mercapto; or
  • R 1 is hydrogen
  • R 2 is selected from hydrogen, fluoro, methoxy and methylthio
  • R 3 is selected from hydrogen, hydroxy and mercapto, with the provisos that when R 2 is fluoro then R 3 is selected from hydroxy and mercapto and that when R 1 and R 2 are both hydrogen then R 3 is mercapto; or
  • R 1 is hydrogen, R 2 is selected from hydrogen and fluoro and R 3 is selected from hydrogen, hydroxy and mercapto, with the provisos that when R 2 is hydrogen then R 3 is mercapto and that when R 2 is fluoro then R3 is selected from hydroxy and mercapto; or
  • R 1 is hydrogen
  • R 2 is selected from hydrogen, fluoro, methoxy and methylthio
  • R 3 is selected from hydrogen, hydroxy and mercapto, with the provisos that when R 2 is hydrogen or hydroxy then R 3 is mercapto and that when R 2 is fluoro then R 3 is selected from hydroxy and mercapto.
  • the provisos in the definition for the groups R 1 , R 2 and R 3 above mean that the following specific compounds, including salts and optical isomers thereof, constitute part of the present invention:
  • 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.
  • the compounds of the invention may be obtained by one of the following methods A-D constituting a further aspect of the invention.
  • R 1 and R 2 has the meaning given above
  • X is a group such as chlorine, bromine, iodine or a group OSO 2 R 10 where R 10 is alkyl containing 1-8 carbon atoms, fluorinated alkyl containing 1-8 carbon atoms such as trifluoromethyl , al kyl aryl such as benzyl or aryl .
  • Y is hydrogen or a quarternary ammonium ion such as for example tetrabutyl ammonium.
  • R 5 is R 3 as defined above, or OR 6 or SR 6 where R 6 is hydrogen or a hydroxy! 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)” Vl/Ib, or in “Comprehensive Organic Chemistry” (D.H.R. Barton and W.D. Ollis eds., 1979) Vol. l, p. 623-629.
  • R 6 Just some examples of R 6 are acyl groups such as acetyl or benzoyl, alkoxy carbonyl or aryloxycarbony! groups, silyl groups such as for example tert butyl dimethyl silyl , alkylaryl such as benzyl and triarylmethyl , or SO 2 R 10 where R 10 is as defined above.
  • acyl groups such as acetyl or benzoyl, alkoxy carbonyl or aryloxycarbony! groups
  • silyl groups such as for example tert butyl dimethyl silyl
  • alkylaryl such as benzyl and triarylmethyl
  • SO 2 R 10 where R 10 is as defined above.
  • R 5 and OR 6 may together form an epoxide when R 3 is OH and R 5 and OR 6 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.
  • R 7 is hydroxyl, chlorine, bromine, iodine, thiol, thioeter, SO 2 R 10 where R 10 is as defined above; or an oxygen derivative OR 12 where R 12 is alkyl, alkylaryl such as benzyl, substituted silyl, phosphoryl diester, phosphinothioyl or SO 2 R 10 where R 10 is as defined above.
  • R 8 and R 9 are the same or different and are R 11 where R 11 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.
  • R 11 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.
  • organic solvent such as for example dimethylformamide, ethanol, acetonitrile or dichloromethane
  • 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 organic solvent such as for example ethanol or dimethyl formamide over a metal catalyst for 1-24 hours at a pressure of 0.1-5 MPa.
  • 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
  • hydrogenated with hydrogen gas in an organic solvent such as for example ethanol or dimethyl formamide over a metal catalyst for 1-24 hours at a pressure of 0.1-5 MPa.
  • R 6 , R 8 and R 9 are as defined above.
  • R 13 is R 1 , iodine or OSO 2 R 10 ,
  • R 14 is R 2 , iodine or OSO 2 R 10
  • R 15 is R 3 , iodine or OSO 2 R 10 where R 1 , R 2 , R 3 and R 10 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, methano!, methane thiol, water, ammonia or hydrogen sulfide or their respective ions or ion pairs.
  • R 6 , R 8 and R 9 are not hydrogen then in a following reaction step R 8 and R 9 are removed according to method A.
  • R 1 , R 2 , R 5 , R 7 , R 8 , R 9 and R 10 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.
  • R 1 , R 2 , R 5 and R 6 are as defined above, Z is NH 2 or alkoxy i.e. COZ is an amide or ester group and R 16 is NH 2 , 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.
  • a reagent such as for example guanidine.
  • R 1 , R 2 , R 5 and R 6 are as defined above and R 17 is nitroso, nitro, amino, or an amino derivative such as formic amide (-NH-CHO) or amino ortho ester
  • the ring closure may be peformed by known methods, the principles of which are given for example in "Comprehensive Organic
  • 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.
  • 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.
  • R 17 is nitroso or nitro, these groups first have to be reduced to amino groups by known methods.
  • R 6 is not H and R 5 is not R 3 , then the side chain protecting groups are removed in a following reaction step according to method A.
  • R 1 , R 2 , R 5 , R 6 and Hal have the meaning given above and R 18 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.
  • R 18 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 50°C for 1-24 hours, or enzymatically with adenosinedeaminase in water at a pH from 6 to 9 from 1 to 48 hours.
  • R 6 is not hydrogen and R 5 is not R 3 , 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.
  • 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 HCl, HBr, H 2 SO 4 , or an organic sulphonic acid.
  • compositions of the compounds of the invention constitute a further aspect of the invention.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, larminaria 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.
  • a solid, pulverulent carrier for example lactose, saccharose, sorbitol, mannitol, a starch such as potato starch, corn starch, amylopectin, larminaria 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.
  • 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.
  • 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 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.
  • 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.
  • sustained release tablets 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, saccha rine and/or carboxymethyl cellulose as a dispersing agent.
  • 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.
  • 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.
  • 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.
  • 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.
  • Butan 1,3-diol (1.0 g) was dissolved in pyridine (50 ml) and cooled to 0°C.
  • Orthq-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 ( ⁇ 100 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.
  • 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.
  • active substance denotes a compound according to the present invention or a salt thereof.
  • Each tablet contains:
  • Each suppository contains:
  • Polyethylene glycol 1500 50.0 g Polyethylene glycol 4000 15.0 g Propylene glycol ad 100.0 g
  • Each tablet contains:
  • This compound was synthesized in 39% yield from rac. 2-0-methyl-3, 4-0-isopropylidenerythritol as described for example 3a).

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP83901965A 1982-06-21 1983-06-20 Novel derivatives of guanine i Pending EP0112353A1 (en)

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SE8203855A SE8203855D0 (sv) 1982-06-21 1982-06-21 Novel derivatives of guanine i

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DD (1) DD210274A5 (es)
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NZ (1) NZ204640A (es)
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US5684153A (en) 1984-08-16 1997-11-04 Beecham Group Plc Process for the preparation of purine derivatives
IL73682A (en) * 1983-12-20 1991-08-16 Medivir Ab Antiviral pharmaceutical compositions containing 9-hydroxy aliphatic derivatives of guanine,some new such derivatives and process for their preparation
EP0152316B1 (en) * 1984-01-26 1989-07-26 Merck & Co. Inc. Substituted butyl guanines and their utilization in antiviral compositions
US4617304A (en) * 1984-04-10 1986-10-14 Merck & Co., Inc. Purine derivatives
ES2001094A6 (es) * 1985-08-16 1988-04-16 Glaxo Group Ltd Un procedimiento para la preparacion de un derivado de guanina
DE3627024A1 (de) 1985-09-24 1987-04-02 Hoechst Ag In 6- und 9-stellung substituierte 2-aminopurine, ihre verwendung, diese purine enthaltende arzneimittel und verfahren zur herstellung der purine
DE3604899A1 (de) * 1986-02-17 1987-08-20 Hoechst Ag Chirale umsetzungsprodukte aus mesogenen molekuelbausteinen und bifunktionell reaktionsfaehigen butantetraolderivaten und ihre verwendung als dotierstoff in fluessigkristall-phasen
US4916225A (en) * 1986-11-25 1990-04-10 Institut Organicheskogo Sinteza Akademii Nauk Latviiskoi Ssr 9-substituted guanines
US4973318A (en) * 1988-02-10 1990-11-27 D.C.P. Af 1988 A/S Disposable syringe
US5216141A (en) * 1988-06-06 1993-06-01 Benner Steven A Oligonucleotide analogs containing sulfur linkages
US4966895A (en) * 1989-02-02 1990-10-30 Merck & Co. Inc. Cyclic monophosphates of purine and pyrimidine acyclonucleosides as anti-retroviral agents
PT1144607E (pt) 1999-07-20 2009-04-22 Morphosys Ag Novos métodos para apresentar (poli)peptídeos/ proteínas em partículas bacteriofágicas através de ligações dissulfureto

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GB1523865A (en) * 1974-09-02 1978-09-06 Wellcome Found Purine compunds and salts thereof
US4230708A (en) * 1977-10-20 1980-10-28 Stichting Rega V.Z.W. Therapeutic application of (S) -or (RS)-9-(2, 3-dihydroxypropyl) adenine for use as antiviral agents
US4221910A (en) * 1978-09-15 1980-09-09 Newport Pharmaceuticals International, Inc. 9-(Hydroxy alkyl)purines
IL64501A (en) * 1980-12-22 1985-07-31 Astra Laekemedel Ab 9-substituted 4-hydroxybutyl guanine derivatives,their preparation and antiviral use

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See references of WO8400167A1 *

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AU1706083A (en) 1984-01-26
EP0103551A3 (en) 1984-06-13
PH19399A (en) 1986-04-10
GB2122198B (en) 1985-11-06
GR78621B (es) 1984-09-27
ATE18225T1 (de) 1986-03-15
GB2122198A (en) 1984-01-11
KR840005141A (ko) 1984-11-03
PT76902B (en) 1986-04-09
JPS59501112A (ja) 1984-06-28
NZ204640A (en) 1986-07-11
SE8203855D0 (sv) 1982-06-21
ES523425A0 (es) 1984-11-01
PT76902A (en) 1983-07-01
DE3362283D1 (en) 1986-04-03
ZA834532B (en) 1984-03-28
ES8500942A1 (es) 1984-11-01
WO1984000167A1 (en) 1984-01-19
GB8316743D0 (en) 1983-07-20
EP0103551B1 (en) 1986-02-26
DD210274A5 (de) 1984-06-06
IS2822A7 (is) 1986-02-28
EP0103551A2 (en) 1984-03-21

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