IL35658A - 2,6-diamino-9-(beta-d-arabinofuranosyl)-purine,its preparation and use in pharmacy - Google Patents

Description

its preparation and use in pharmacy THE WELLCOME LIMITED 33788 This invention relates to a purine sugar derivative is useful as suppressor of the response and as antiviral and to methods of preparation According to the present invention there is provided the oompound of the formula or a pharmaceutically acceptable salt This compound has a regarding the linkage between the purine and the Salts which are especially convenient for peutic use are salts of pharmaceutically acceptable carboxylic acids such as acetic or malic acid as well as salts of pharmaceutically acceptable mineral acids such as chloric or sulphuric The activity of any salt administered resides in the bas In addition to the toxic salts can also be made and converted into either the base or the pharmaceutically acceptable salts by standard a metathetical The compound of formula is particularly useful in treating viral resulting from DNA such as vaccinia and Additional uses of this compound 2 are in suppressing the immune response an animal or a human patient to the transplant of foreign ceils into the body and the treatment of autoimmune diseases in mammals such as Lupus Ulcerative colitis and British Patent Specification describes the preparation of a large number of purine and nucleoside via appropriate novel compound according to the present invention and its pharmacological aotivity are mentioned in that British There is described in French Patent Specification a purine sugar purine commonly referred to as and its is disclosed as having activity agalnst in DM In the treatment of viral the two most popular and suitable modee of administration of si drug are parenteral and oral and with regard to the latter it is viously of great importance that the fdrug in question es a sufficiently long with regard to the oral administration of the drugs own tendency to undergo deamination with concurrent loss in activity results in a reduced hal is a great disadvantage in view of the useful antiviral aotivity possessed by It has been found that the 2a a approximately the rate of of the compound is much more sta le and has a longer In another aspect of the present invention provided a pharmaceutical composition or comprising the compound of formula a pharmaceutically salt in association with a tically acceptable carrier therefor or in an effective unit dosage As used herein the term unit is denoted to mean a predetermined antiviral amount sufficient to be effective against the organism in Pharmaceutically acceptable carriers are materials recommended for the purpose of administering the and may be solid or gaseous which are otherwise or medically acceptable and are compatible with the active i These pharmaceutical compositions may be given as a applied as an optic applied topically as an on whether the preparation is used to treat internal or external virai infections or is used as an immune or autoimmune response Fox internal infections the compositions are used orally or parenterally at dose calculated on the of about 5 to preferably 20 to 100 of mammal aire preferably in man in a unit dosage administered a few times the amount of 10 to Tor use as immune the compositions are administered internally a times daily at dosages preferably of about to 10 of mammal oral fine powders or granules may contain dispersing surface active and may be presented in a draughty in Waiter or in a in capsules or sachets i the dry state or in a wherein suspending agents may in vhen binders and lubricants may be or in a suspension in water or Where desirable or necessary 1 thickening or agents can be Tablets and granules are and these may be For parenteral the compounds may be presented in aqueous infection solutions in a concentration of from to preferably vhich contain buffers For viral infections of the eye or other external tissues the compositions are preferably applied to the infected part of the body of the patient as a topical at a dosage of about one half of that used for internal up to 125 or 5 to 125 mg per unit The compound of formula possesses an erremely high antiviral for against the herpes Substantial and unexpectedly high activity against vaccinia virus has also been shown and it has been found to be unexpectedly useful in suppressing the immune response to transplanted The compound of formula can be conveniently prepared by reducing an appropriate compound of formula 02 wherein Z is a blocking group such as an alkyl preferably a an or or most preferably a benzyl must be such that when attached to the oxygen atom at the second position of the sugar moiety there is no interference with processes at of the sugars it is when under mild platinum Some these are weaker i catalysts and it may be necessary to apply pressure or a long hyd ogenation period to be fully The use of platinum oxide or platinum black has been found most convenient in this the compound of Formula can be reacted with a reducing especially with the type producing hydrogen atoms such as alkali preferably in liquid The compound formula can in turn be prepared by one of the following preferably chlorine or and Z is a blocking as hereinbefore preferably is reacted with an alkali metal preferably sodium The resulting ide derivative is catalytically hydrogenated to the of formula the additional formation of a small amount of the compound of formula Further reduction of compound of formula under the conditions described by catalytic hydrogenation or preferably by using an agent like sodium in liquid then produces the desired end Formula In practice it be advantageous to combine the two steps into one by using some of the more effective strong as platinum oxide or platinum black preferably under pressure or with a somewhat prolonged hydrogenation to produce the intermediate of the Formula and immediately reduce the same into of formula wherein and are each a Y being an group having 1 to 6 carbon atoms and being preferably a methyl and Z is a blocking as hereinbefore preferably is deacylated by hydrolysis under This may be for by dissolving product in a such as and adding an alkali metal such as sodium to the To produce the compound of formula preferably can be condensed with an arabinose sugar having one or more of its hydroxy1 groups blocked removable groups as hereinbefore according to the method described by Keller et al in Or The preferred for this purpose is arabinofuranosyl Acylation of preferably vith acetic followed by analogous sugar produces the compound of The of formula as hereinbefore are novel and are valuable in the production of the 7 The compound of formula can also be prepared the anomeric xyloside via the lyxoside according to the general procedures described by et Ibid and The final stage in the formation of the of formula by this method ia the of the corresponding lyxofuranosyl derivative by treatment with sodium acetate in an inert solvent such as aqueous The lyxofuranosyl is in turn obtained by epoxide formation of the appropriate with a suitable alcoholio such as methanolio sodium The starting xylofuranosyl compound can be formed by the following i The appropriately substituted at the 2 and 6 is reaoted with acetone containing ethane sulphonio acid to give the corresponding This is then reacted with methane sulphonyl ohloride to give the sulphonyl compound which for example in j aqueous to remove the protective isopropylidene The derivative is then further reaoted as hereinbefore The first mentioned xylofuranosyl purine may be obtained by condensation of with having its free amino protected by preferably Thus the present invention also provides the above methods of preparation of the compound of formula as hereinbefore or pharmaceutically acceptable salt θ In another aspect there is provided a method of preparing a compound of formula as hereinbefore which comprises the deacylation of a compound of formula as hereinbefore under basic In yet a further aspect the present invention provides a method for treating infections caused by D viruses in mammals by antiviral amount of the compound of formula as hereinbefore to an infected animal to an animal whic may be exposed to the In a particular aspeot there is the as hereinbefore for treating viral infections by administering the compound of formula as hereinbefore to the The following examples illustrate the EXAMPLE I 2 Λ solution of of J in 8 of 2 of acetone was heated with molecular of azide for 6 hours under reflux The ated sodium chloride was filtered and the yellow containing the showed absorption maxima at m in The filtrate directly for the reduction in the next EXAMPLE II The reaction product was reduced with a catalyst and hydrogen at 2 atmospheres of pressure at After the catalyst was removed and the filtrate was evaporated to dryness under reduced The residue was from ethanol to give of pale yellow which was on The analysis corresponded to EXAMPLE To 1 of added 200 of Small pieces of sodium were added until the blue color persisted for several A total of 5 of sodium was The blue color discharged with crystals of ammonium The ammonia was evaporated under a stream nitrogen and the residue was triturated with of The insoluble residue was taken up in a few of water and neutralized with acetic The product after melted at with The urine showed at 1 and X max at pH EXAMPLE IV 2 A well stirred suspension of 10 anhydrous in acetic anhydride heated at The solid isolated by filtration under and with The solid was a mixture of and The above material was added to 1 liter of absolute methanol containing 100 concentrated The flask was kept at room temperature for fifteen with occasional The insoluble solid removed b filtration under vacuum and dried at Yield The structure was confirmed by EXAMPLE V Λ suspension of and molecular sieves in dry methylene chloride containing arabinofuranosyl chloride stirred for two weeks at room The solution filtered through a Celite pad and the solvent removed in Extraction of the crude oil with cyclohexane gave of crude This then deacetylated by treating an ethanolic solution with 2 molecular equivalents of IN aqueous aOH or with a large excess of The solution was stirred at for The product was extracted from the solution with dried over sulfate and the chloroform removed in vacuo to give directly or upon When deacetylation had occurred precipitated from Eolution and was isolated by filtration under from methanol gave 12 EXAMPLE Injectable solution ingredient 10 Water for to to provide aqueous sterile weight 200 Active ingredient 10 Lactose pyrrolidone 5 Corn starch Magnesium Sterate 1 Capsule fill 200 Active ingredient 10 Lactose 0 Corn Starch 58 Magnesium Sterate 2 hard shell gelatin Tablet and capsule could be enteric coated to prevent disintegration the stomach and may also be sugar teaspoonful Active ingredient Liquid Sucrose Glycerine 1 Flavor Distilled water to Opthalmic Solution Active ingredient 1 Buffered to 5 to 7 Distilled qs to 10 Topical Ointment Active ingredient 10 Petrolatum In the the active ingredient is 14 insufficientOCRQuality

Claims (1)

1. CLAIMS The compound purine of the formula and pharmaceutically acceptable ealts A compound of formula in Claim 1 in the form of a salt with a pharmaceutically acceptable carboxyllc A compound according to Claim in which the acid is acetic or malic A pharmaceutical comprising or a pharmaceutically acceptable salt thereo an active in association with a pharmaoeutically acceptable carrier therefor in an effective unit dosage A pharmaceutical preparation for oral or parenteral use according to Claim comprising the compound in the amount of 10 to 250 mg per unit A pharmaceutical preparation accordin to Claim in the form of a preferably in a coated A pharmaceutical preparation according to Claim for parenteral comprising the compound in a concentration from to preferably from to in an aqueous 15 A pharmaceutical preparation according to Claim comprising the compound in a concentration about A pharmaceutical substantially as cribed in Example A method of preparing the compound of the formula in Claim which comprises reducing an appropriate compound of formula wherein 2 is a blocking A method according to Claim wherein the blocking group is a benzyl A method according to either of Claims 10 and wherein the reduction is carried out with hydrogen in the presence of a hydrogenation method acoording to either of Claims 10 and wherein the reduction is carried out with a reducing A method according to Claim wherein the reducing agent comprises an alkali metal in liquid A method according to Claim wherein the alkali metal is 1δ A method of preparing a compound of formula in Claim the of a compound of formula and are each a I being an group having 1 to 6 carbon and 2 is a blocking group 9 hydrolysis basic A method as in 1 which 1 is a methyl 1 A method in of 17 and in which a grou 0 20 o A method as claimed in any of Claims 17 to wherein the is carried out in an alcoholic preferably methanol0 with an alkali sodium hydroxide or Δ method for preparing the compound of formula X in Claim substantially described in method of preparing the compound of formula in Claim which comprises the reaction of t o purine derivative of formula 17 with a as sodium in inert solvents such as method according to Claim 2 in which the reaction is carried out at elevated 2 A for treating infections caused by viruses in which administering an effective antiviral amount of tho compound of formula in Claim 1 to an infected animal to an animal is exposed to the with such 25 o method according to Claim 24 wherein tho animal is infected or is exposed to with the herpes according Claim 24 wherein animal is infected or exposed to infection with vaccinia A according to any of Claims 24 wherein a pharmaceutical formulation according any of Claims 4 to is administered to tho 28 method according to any 24 27 wherein the compound is administered in a dooo level from about 5 10 250 preferably 20 100 18 o to Claim for the of about 125 Applicants insufficientOCRQuality