BE737949A - Purinyl hydroxy alkanoic acid derivs - useful as hypocholesterolaemic agents - Google Patents

Abstract

9 Purinyl hydroxy alkanoic acid derivs useful as hypocholesterolaemic agents. M3A. And their salts are new cmpds. of formula (I) (where A = N or N right arrow O; R1 = H, Hal, OH, SH, OAlkyl, SAlkyl, OAralkyl, NH2, NHAlkyl, N(Alkyl)2, NHAralkyl, NHAcyl, or NHOH; R2 and R3 = H, Hal, OH, SH, NH2, Alkyl, Aryl, OAlkyl, OAralkyl or SAlkyl; R4 = alkylene (pref. 2-6C) substd. by one or more OH groups (but no OH on the C atom attached to the N atom) opt. protected by acyl, alkyl, aralkyl or, where OH groups exist on adjacent C atoms, alkylidene or aralkylidene groups, R5 = OH, OAlkyl, NH2, NHAlkyl, N(Alkyl)2). Preferred cmpds. (I) are 4-purine-9-yl-4-desoxy-D-erythronic acids, amides and esters esp. where A=N, R2=R3=H,R1=NH2 and R5 = OH1 OMe, OEt or NH2 or R1 = EtNH, PhCONH, or OH and R5 = OH or R1=OH, R2=NH2, R3=H, and R5=OH, or R1=NH2, R2=H, R3=Me and R5=OH and the cmpd. (I1 R1 = NH2R2=R3=H, A=N O, R4 = CH-CHOH-CHOH- and R5 =OH).

Description

  

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  New derivatives of purine.

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     The present invention relates to novel purine derivatives, their preparation and their applications.



   In this description, the term "lower" which refers to derivatives of alkanes, such as alkyl or alkylene, is used to denote, unless otherwise indicated, derivatives having from 1 to 8 carbon atoms.



   The purine derivatives in accordance with the present invention correspond to the following formula:
 EMI2.1
 f1 7 'l3 (1) 1-5 5 B4-CO-R5 in which A is a nitrogen atom or an N - 0 group, R 1 is a hydrogen or halogen atom (for example chlorine, bromine, iodine or fluorine), a hydroxyl, mercapto, lower alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy a-) ralcoxy (lower) radical such as phenyl (lower) alkoxy (eg benzyloxy, phenethyloxy (lower) alkyl thio (eg methylthio, ethylthio, propylthio), amino, lower alkyl amino (eg methylamino, ethylamino, propylaino dialkyl (lower) amino, (eg dimethylamino, diethylamino, methylethyl-;

   amino, aralkyl (lower) amino, such as phenyl (lower) alkylamino (eg, benzylamino, phenethylamino), acylamino such as (lower) alkanoyl amino (eg, acetylamino, propionylamino, octanoylamino), or benzoylamino or hydroxyamino;

       R-, and R- each represent a hydrogen, halogen atom (for example chlorine, bromine, iodine or fluorine), a hydroxyl, mer capto, amino, lower alkyl radical (for example methyl, ethyl, propyl, isopropyl), aryl such as phenyl, lower alkoxy (eg methoxy ethoxy, propoxy, isopropoxy), aralkoxy (lower) such as phenyl lower alkoxy (eg benzyloxy, phenethyloxy), - or alkyl (lower) thio (eg methylthio, ethylthio, propylthio);

   R4 represents a lower alkylene radical preferably comprising from 2 to 6 carbon atoms (for example ethylene, trimerylene propylene), bearing as substituents one or more hydroxyl radicals (but without the presence of a hydroxyl group on 3 'atom of carbon attached to the atom

  <Desc / Clms Page number 3>

 nitrogen ring), which may be protected by an acyl radical such as lower alkanoyl (eg acetyl, propionyl) or benzoyl, lower alkyl (eg methyl, ethyl, propyl, i
 EMI3.1
 sopropyl), aralkyl (lower) such as phny3aL = .Yl (lower), .5 (for example benzyl, phenethyl) or else, when there is a pair of hydroxyls on the alkylene group, with a lower alkyli dene radical ( for example ethylidene, propylidene,

     isopropyli-
 EMI3.2
 d6neX or by an aralkyl (lower) -idene radical such as phenyl (lower) alkylidene (for example benzylidene) and R5 is a hydroxyl, lower or higher alkoxy radical (for example methoxy, ethoxy, nropoxy , isopropoxy, actyloxy decyloxy, heptadecyloxy), amino, (lower) alkyl amio (e.g. methylamino, ethylamino, propylamino) or di-lower alkyl amino (e.g.
 EMI3.3
 ple dimethylamino, diethylamino, Bethylethylamino).

   Also included in this group are their salts such as metal salts (e.g. sodium salt, potassium salt, calcium salt), ammonium salt, amine salts (e.g.
 EMI3.4
 dimethylamine salt, trimethylamine salt), and addition salts with an acid, i.e. addition salts with an organic or inorganic a-) acid (for example the hydrochloride, hydrobromide, sulfate, nitrate, phosphate, tartrate, citrate).



   As specific examples of compounds (I) of the puri-
 EMI3.5
 ne, the following can be mentioned: 4- (purine19-yi) -4-deo-1 xy-D-erythronic acid, 4 - {- aminopurine- y1) -4 - deox; yD¯ erythronic acid , 4- (8-aminopurine-9-yl) -4-dsoxy-D-erythronic acid, steel - (6-aminopurine - yl) -4 - deoxs-D-erythronic, 4- Lower alkyl (α-aminopurin-9-yl) -4-deoxy-D-erythronate (eg methyl 4- (6-aminopurin-9-yl) -4-deoxy-D-erythronate, methyl 4- E- (6-aminopurine-9-yl) -4-deoxy-D-erythronate
 EMI3.6
 thyl, propyl 4- (6-aminopurin-9-yl) -4-deoxy-D - 6rythronate, butylp 4- (6-aminopurine-9-yl) -4-deoxy-D-erythronate , t - C6-ami.nopurîne-g 1) -t - deoxy-D-erythronamic3e, 3-lower H-alkyl ---- (6-aai.nopurine-9 yl)

  -4-deoxy-D-erythronamidel (e.g. N-ethyl-4- (6-aminopurine-9-yl) -4-deoxy-D-erythronamidel ii3I3- (lower) alkyl -4- (ô-aminopurine- -yl) -4-deoxy-D-erythronamide, (e.g. Iv, 2d-dietiyl-4- (6-aminopurine-9-yl) -4-deoxy-D-erythronamid, 4 - {6 acid -aminopurin-9 yl- 4-deoxy-2,3-0-alkyl (lower) idene-D-erythronic (e.g. S - (ô-aminopurin-9-yl) -4-cesox -, - ., jD-.ëthylidene-D-

  <Desc / Clms Page number 4>

 
 EMI4.1
 erythronic acid, 4- (6-acinopurin-9-yl) -4-deoxy-2,3-0-isopropyiiàene-Û-> àrytboeoniqu4, 4- (6-a = inopurin-9-yl) acid -4-deox-, 3-t? -Ral.?: Yï (lower) id: ne-L-er3throniue (e.g. 4- {û-tinopurine- -S3 acid) -4-3.:asox- , 3-G-benzylidene-ï-er3¯ 5 thronicu, a 4- (α-aoeinopurine-S-yl) -4-deoxy- <, µ-0-alk-3.lidene;

   lower alkyl inner-D-6r.tron, (eg 4- (6aino purinc-a-51) - cesoR% -c "., - it-i.saprop5lidene-p-ethyl rrßthronate, - (6-sinop arin-9-I) - deox¯, y -, - Ethyl u-isopropylideneD-erythronate, la -alkyl I: lower-4 -; .- a: ixopurine-9- 0 yl) -4-deoxJ-t3-0-alkylidene (icf & rieu-D-erythroQSEide (for example 16 ii-eth - == 1-Lr- (6-aninopurin ± --9-à.l) -4-deso: ç, - ?, 3-il-isopropyliàene-D4r7thronamide), 4- (E - ainopuri.e - $.) --3esoxy-2, j¯ 0-di-slc3soyl (lower) -D-erythronic, (e.g. = - (; - ainug :: riuo-9-?) -d4aoA -, .- t3-d.iacéi-J-er thrcnic acid, 5 - (Ja ::. ino # , zrine-9-3'1) - dée --'.- U - ;? iprcp.ion; 1 - er-.rthronlqut :), a 4- (to-az inopurine-9 - ;. 1) - / - de-so: w -, ...: .-. Q-.ài-eiéa; oyi (lower) -D-erythronste lower alkyl (paz-. rap3e the 4- (6iniropurin-9-yl ) -4-désoJqy.a, bQ-diecetyl-D-er3.thioz:.:

  methyl e, the - (=, - a.:inopurïne-9-d I) --- deoacy-s, 3-t3-d .: cetri-3¯;: rd throna-) te eï 'é t' r, 1, 4- (6-aBino-8-3lkyl (iBferieur) purine) -4-deox3.-D-4r3-th-onic acid, (for example 4- (α-amino <-met% l5Jnine- 1 - d: sot .; - err-ti.roaiçue, 4- (6-3sino-S-ethylpuriBe-9yl) -4 # .îesoxy-D-erythroDiquc acid 4- (6-anino-8-alkyl (lower) pulin-9-j + i) # - d = -soxy-1, µ-Ô-aiky, iaaiéxieur lidene - ;. rytàroni.ue '' (for example kid 4- (6-a <ino-S - = - ethxylpcrî = -e-9-yl) -4-deoxy-é, 3U-isopro3 .-- J = IidènE = -āéythroniçue, acid 4- (6-scir.o- è-etbylpurin- 9-yl) -B-eso; a.- <, 3-O-isopropylidene-D-er3-throrigufll 1.cide 4- (6aino - nerca # to: urine-Q-3) --- ûéso -.- rv, hroaitae, çcide 4- (- aino - nercaptopuri.ne-¯I3¯: .. ¯d4so -, - U-a3.k, b.3d.è:

   inférie-u - D4rv-tl = or-icue (e.g. 4- (6-anino-S-üercaptopurine-9-; ri) - eso: -, - isoprop.dene-d - é .rt: rcni.:; u, 4- (6, E-3iansnopurine-9 -; - 1)> é-d-lsoxy-D-ény'throniq <ae, 4- (6acino-8-hydroxypure-9-Jl) -4-deoxy-D-er; tt onic acid, 4- (2alkyl acid = .ar-thic - ainepur.ne- -3) - deoxrY = -.

   toniue (eg 4- (Q-Nethylthio-Ea = Î-xcpurine-9-jvl) -4-deoxyD-erythronic acid, "(é-é = hylthio-6-e = -inopurine-Pyl ) # - deoxy-D-erjhroniqu, 4- (1-elkyl lower-6-a - = - in'opu-ine-9i) - deoxy-i5-errthrcniue acid, (by execple 4- acid (-methyl-6ainopurine-ß 3.) - ia-deox¯33-erythronic acid, 4 - (, 6-diamiDopurine-9-J) -dsoxy-D-erythronic acid, 4 - (- bydroxy- acid Ó-aci-

  <Desc / Clms Page number 5>

 
 EMI5.1
 nopurine - 91) - 4 - de9oxy-3-erythronic ', 4- (6-alkyl (lower) aminopurine-5-yl) -4-deoxy-D-erythronic acid, (for example 4-Ethylarinopurine-9-y2) -4-desvxy-D-erythronic acid, 4-ethylaminopulin-9-yl) -4-deoxy-D-ery.thnonic acid, 4- (6- 5-butylaninopurine- 9 - yl) '--dëso, y-1-eryt:

  .oniquc, 4- (6-ailkyl (lower) aminopurire-9 yl) -deoxy 33-0-lower avlidene-D-erythronic acid, (eg 4- (6-ethylaminopurine-9 3 '.) ¯ - deox-23-O-.sopropylidene - 3 - electron), a% = 6-di-alkyl (lower) aminopure-9 1 ---- deox-, D -erythrnac9 3 (e.g. 4- (5-dimé-hylaeinoptzrins- acid:

   3) --- dea- ¯ erythronic acid, 4- (6-diethylaminopurin-9-yl) -4-deoxy-D- erythronic acid, 4- (6-hydroxyaminopurine-9-y) -4-deoxy acid -D- erythron.que, 4- (6-PhenYl alkyl (Inlérievw) ininopulin-9yl) -4-deoxy-D-erythronic acid, (e.g. 4- (6-ben3ylanina acid, sar.? Eq i) -:

  -? esoxy-D-er, ythronig, ue3 4- (6-phellethylaminopurin-9-yl) -4-deoxy-D-erJ "thronic acid) 4- (6-benzoyla- .nopuria- acid) 3 i) ... c '.- deso <yD-erythrol, 4- (6-hydroxypsriBc-3 '-' yl) -4-deoxy-D-erythrolic acid, 1f- (6-hydroxypurin-9-yl) - 4- lower alkyl deoxy-D-erythronate, (e.g. 4- (6-) nydroxypurin-9-yl) -4-deoxy-D-4rythronate due to methyl, 4- (6- 'hydroxypuriDe-3-yl) -4-Dêsoxy-D-é.EytIiroDate (ethyl), -la l {6-bydro.pure-9.) - deoxy-D¯erythron.cie, a 4 - (6-] ydroxypuriEe # 9- yl) -4-deox7-2,3-0-di-lower alkanoyl-D-erythroDate of lower eagle, (e.g. 4- <6-inydxourine-9-yl> -4-esoxy-Z, methyl sj 0-diacetyl-D-erythroBa-ce, 4- (64hydroxzwuoeine-9-yi) r .-- deexy-'L ', j -f7-diacé vyī'-é; thranate d $ ét ', =: yie ,, acid 4- (6,3d.ydrox, y-çuri: 3e - yl, éss-.I-er, yr .'cniqeze, 4- (;

  2 .. 6-di.hydroa4gpure-- i) ...- deo -: - ery? Oni.que, 4- (2-s! Si] 3C- -dro-pazriae-3 - yL) acid -F ---. Ése: TJ-eryt-.r.ron? that, an acid 4- (6-haloPU "h = -9-Yl) -4-deoxy-D-erytb.rDnîqa, (for example 1 '; cide 4- (6 # .errpugine: - 5 -) - '? é ac¯yD-' ron ix acid.-6-àrepurine-9 â'i) -.- d, so-D-ery Lro.uîque),. cide 4- (6- hn1 <= yunaTe-% Tl) - 'GlF'SOXy-2,3-o-eikyiidene lower # D-erytirssic acid, (eg = -.; -.: .. 3.orop.urine' i) - déscxy?, 3--:

  ivcprony- aene-D-en + h1tOnîre, i.acid # - (e-bnomoz. ine-9-yij - # - de> ozy-a, 3- -ïcproyüdène-7ü-éaytron.que, acid 4- {6-ercaptopuriDe-9-. Yl) -4 - desoxy-D-erythroDiqHe, an acid - {6-a'y .. {irrieux Iu-- PUrine "v-yl) Àmesox? -D-énythroniç9e, ( for example acid 4 * - (6- éyit.iopure - 9-3i.) - .-- désoy-pa - er, hr, niqu, i'acid 4- (6-é-. thy.lth ± Tpuoei = e-9-yl) -4-deoxy-D - erythnonic) an acid 4- (6-a34 0- -

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 EMI6.1
 xy (lower) purin-9-yl, (eg -. 6-raethaxypurine-9-yl) -4-deoxy-D-erythronic acid), 4- (6-alkanoyl (lower) aminopurine- acid 9-yl) -4 - deoxy-D-erytbronic.

   (eg 4- (6-acetylarinopurine-9-y3 -) - 4-deoxxv-.D-er acid; thronic acid, 4- (6butyrylGainopurine-9-'I) -4-âsoxy-D- -Erythro.niQuc 3- (b-aminopunîne-9-yl) -2-hydroxy-3-hyàrozymethyl-propioniqpe, 6-amino-9- (3 - carboxy-2,3-dihydrox-ypropyl? puriûe - 1-oxide, 6-aminoG- (3-carboxy-2,3-isopropylidèxeoxypropy3) purzne -.- oxide, 4- {6-anopurine-9 yl) -lt -. deOxy-Is -thréouique, etc.



   According to the present invention, the compounds of purine 1 can be obtained by various methods, most of which fall into the following classification: (1) Construction of the fundamental structure (purine nucleus + 9 side chain) (1 -1) Closure of the cycle (1-1-1) from the pyrimidine nucleus
 EMI6.2
 (1-1-2) from the 3 'core? mzdazo's.e (1-2) Nitrogen substitution (2) Transformation on the fundamental structure (2-1) Hydrolysis (2-2) Reduction (2-3) Amination (2-4) Esterification
 EMI6.3
 (2-5) .A.m.dation (2-6) Acylation
 EMI6.4
 (2-7) Acetalation (2-8) Other transformations We describe in detail some techniques below.
 EMI6.5
 characteristics of each category.



  .. ¯¯ ¯ {3-1¯l Closure @ µcycle starting from the nucleus of the pyi: 3die. - One of the techniques that fall into this category can be represented by the following formulas:
 EMI6.6
 

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 in which R 1 is a hydrogen, halogen atom (for example chlorine, bromine, iodine or fluorine), a hydroxyl, mercapto, lower alkoxy radical (for example methoxy ethoxy, propoxy, isopropcxy ), lower aralkoxy such as phenyl-alk'oxy (lower
 EMI7.1
 5 laughing), (eg benzyloxy, phenethylorJ), (lower) alkyl thio, (eg methylthio, ethylthio, propylthio), amino, 3cyl (lower) amino, (eg Bethylasino, ethylamino, propylamino), di- allyl (lower) amino,

   (eg dimethylamino, diethylamino, nethylethyleminµ, aralkyl (lower) amino, such as pheJ nylall <y1 (inside) anino, (for example benzyisniino, phenethylamino), acylamino such as (lower) alk'anoyl amino, (for example acetylamino, propionylamino, octylamino), or benzoylaillino or hydroxyemino; 1-it represents an atom d ,, ydrogen, halogen (for example chlorine, bromine, iodine or fluorine), a hydroxyl radical, 3 zercapto, amino, lower alkyl, (by example methyl, ethyl, propyl, isopropyl), aryl such as phenyl, lower alkoxy (eg methoxy, ethoxy, propoxy, isopropox, lower aralkoxy
 EMI7.2
 such as phenylalkoxy (lower), for example benzoyloxy phenethylox4,%), or (lower) alkyl thio, (for example a0tbyltbio, zthy.lthio, propylthio);

   Ra3 represents a hydrogen atom or a mercapto, amino, lower alkyl (for example methyl, ethyl, propyl or isopropyl) radical, or else aryl such as phenyl; R4 is lower alkylene preferably comprising from 2 to 6 carbon atoms (for example ethylene, trimethylene, propylene), bearing as substituents one or more hydroxyls (but without the presence of hydroxyl groups on the carbon atom attached to the nitrogen atom of the nucleus), which can be protected by an a- radical
 EMI7.3
 cyl such as lower aloanoyl (eg acetyl, propionyl), or benzoyl, lower alkyl (eg ethyl, ethyl, isopropyl), lower aralkyl, such as pbenylalkyl (lower), (eg benzyl, phenethyl),

   or when there is a pair of hydroxyls on the alkylene group, with a lower alkylidene
 EMI7.4
 laughing (eg propylidene, isopropylidene), or a lower aralkylidene such as lower phenylalkylidene (eg benzylidene); R5 is a hydroxyl, lower or higher alkoxy radical, (for example methoxy, ethoxy, propoxy, isopropoxy, octylaxy decyloxy, heptadecyloxy), amiro, (lower) alkyl amino (for
 EMI7.5
 example meth, y3ayirc, ethylamino, propylamina), or di-alkyl (lower) amino, (for example diuethylamino, diethylamino, methyl-
 EMI7.6
 th, ylaino);

   X represents an amino, nitro, nitroso, aryl- radical

  <Desc / Clms Page number 8>

 
 EMI8.1
 diazo such as Dhényldiezoi acylamino such as fornylaaino, alkanoyl (inf 'rieu.r.1 sGino, (for example acetylscino, propionylaaino, butyrylamino), tio-for1JYlaëlino, thio-alc: anoyl (infsrieur -amino 2, thio .Jt ;; 1sl! 1ÎDo, tUopnopylamino, thiocutyrylaisino), or 1 eràloyls; îro (eg benzoylemino, naphthoylanino, t0111oy1a- ::. 3na), or alcozy (infcirieur) nethymymeneaino, ethylene methoxethyl - neamîno); and fi, Ii., Ruz and R, are each as defined above. e compound I3C: of 1a7'Vrl1itin is subjected to a treatment
 EMI8.2
 
 EMI8.3
 ) chemical suitably chosen according to the nature of the symbol X in
 EMI8.4
 
 EMI8.5
 the latter, resulting in the compound tia) purine.



  For example, the compound II of pyrixidine in which the symbol represents a r3dical amino is reacted with fornic acid or with one of its functional derivatives such as kor. aLide, lower alkyl formate, a:, 2 - i-garlic (lower) foraide, with a lower alkyl orthofornate, with a lower alkyl formate, sodium dithioforate or the fora3.3ine, if necessary, then heat or treat with a base. Where does tza: ¯ïtue3leeat the main reaction
 EMI8.6
 cipale at a temperature between room temperature and
 EMI8.7
 the tenprst'jre boiling of the reaction medium, if necessary in a solvent such as water, methanol or ethanol.

   We
 EMI8.8
 can, if desired, use a condensing agent such as hydrochloric acid., acetic anhydride, an alcoholate of
 EMI8.9
 sodius or phosphorus oxychloride, depending on the nature of the agent. the subsequent trgitenent with a base such as an oxide of r: .ft, é31 clealin (eg sodium hydroxide, gotase hydroxide), alkaline earth metal hydroxide (eg & t3? le hydroxydo de c3lciu:;:, hydroxide de: a, 2ésiur), an alkaline ml-tai alcoholate (eg sodium methylate, thy12t dt2 potassius, sodium ethoxide) , or a tertiary amine (eg, trimethylamine, triethylanine, N-Qethylpiperssise, pyridine), is usually made in a
 EMI8.10
 solvent such as water or aqueous alcohol.
 EMI8.11
 



  In addition, for example, the compound is reacted <1IJ of prria.c3irs, in which the symbol Á represents an amino radical, with a thiocarbon1que derivative such as thiophosgene, la. thiomeric sodium xthonate, potassium xanthogenate except carbon disulphide, dimethyl thiocarbonate, diethyl thiocarbonate, or 1, 1'-diiid3zo1e of thio- acid.

  <Desc / Clms Page number 9>

 carbonic.

   The reaction is normally carried out in a solvent such as water, methanol, ethanol or propanol, at a temperature between the ambient temperature and the boiling temperature of the reaction medium, if this is necessary in the present. - 5 cc of a condensing agent such as an alkali metal alcoholate (eg sodium methoxide, sodium ethoxide, potassium ethylate), or a tertiary amine (eg triethylamine pyridine).



   In addition, for example, the pyrimidine compound (II) (in which the symbol is a nitro, nitroso or aryldiazo radical) is reduced, for example, in the presence of formic acid, if necessary by then heating or treating with a based. For reduction, the combination of a metal (eg iron, tin, zinc) and an acid (eg hydrochloric acid, acetic acid) can be adopted, the combination of a metal (eg sodium, sodium amalgam, aluminum amalgam, zinc, iron) and water or an alkanol (eg methanol, eth- nol), a sulphide (eg ammonium sulphide, ammonium sulphide, sodium sulphide, sodium polysulphide, sodium sulphide, hydrogen sulphide), sodium dithionite or sodium bisulphite ,

   phenylhydrazine or hydrazine, the combination of titanium trichloride and hydrochloric acid, the combination of hydriodic acid and hy pophosphorous acid, electrolytic reduction, etc. Electrolytic reduction is particularly preferred using a catalyst such as platinum, platinum oxide, palladium, palladium oxide, palladium on carbon, palladium on barium sulfate, palladium on carbon. barium carbonate, palladium on silica gel, rhodium, iridiun, ruthenium, nickel oxide, Raney nickel, Raney cobalt, reducing iron, Raney iron, reducing copper, Raney copper, Ullmann copper or zinc,

   The reduction is usually carried out in a suitably chosen solvent, depending on the nature of the reducing agent and of the catalyst. As the base for the subsequent processing, an alkali metal hydroxide (eg sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxide (eg calcium hydroxide, sodium hydroxide) can be used. magnesium).) an alkali metal alcoholate (e.g. sodium ethylate, sodium ethoxide, potassium ethylate), a tertiary amine (e.g.

  <Desc / Clms Page number 10>

 
 EMI10.1
 t: .dnét1lylac.ine, tr3ethylaaine, N-nethylpiperazine, pyridine), etc <In this case, the processing is carried out noecalenently.
 EMI10.2
 smells in a solvent such as water or aqueous alcohol.
 EMI10.3
 



  Further, for example, the compound rI:} of pyrinidine 5 in which the synbol 2 represents an acylaaino or a2CV- radical. x =; (1n ± & ricur) ethylene-amino is heated or treated with a base. ' Heating is usually carried out in a solvent (eg in fornstlide, orriaride, disiethylsulfoy, preferably in close proximity to a dehydrating agent (eg, acetic anhydride).

   Coe base one can for example cite an alkali metal hydroxide (for example sodium hydroxide, potassium hydroxide), an alkaline earth metal hydroxide, (for example calcium hydroxide, hydro-- <3fde won-
 EMI10.4
 sium), an alkali metal alcoholate (for example
 EMI10.5
 5 sodium, sodium ethoxide, potassium ethylate), tertiary amines (such as trimethylamine, triethylamine, K '# aethyl-piperasine, pyridine), ar-7iLonia, etc. The treatment with the base is normally carried out in a suitable solvent.
 EMI10.6
 water, alcohol or aqueous alcohol.



  ) During these various treatments, one or more of the
 EMI10.7
 substituents represented by the symbols R'l, Re 21 R 'and Rf5 can be influenced. some of these influences are
 EMI10.8
 the following: transformation of halogen latoe shown
 EMI10.9
 by R 1 or by R'2 in a hydroxyl radical, lower alkoxy or mercepto, transformation of the hydroxyl group acylated or etherified in H 'into a free hydroxyl, transformation of the lower alkoxy group or 4no, represented by R', in a free hydroxyl, etc.



  The starting pyrinidine compound (I] can be obtained from
 EMI10.10
 held by various processes. For example, 4- (5-a-
 EMI10.11
 rino-6-chl oro-4-pyrz: ridinylanzno) --- deoxy -, 5-0-isopropyl.ideneD-erythronic by reacting -a: ino -, 6-d.ichloropyrimidine with cia acid 4-ani.no-4-de socy-, iG-isopropylzdene-.D- erythronic, or by reacting 4,6-dichloro-5-nitro-pyrimidine with, --aLino-4 acid -de.oxy - '> - 0-isopropy3.idene-D-erythronic and reducing 4- (6-chlono-5-nitno- -.- pyriidïnylaino) -4-deoxy-c'-ù-isopropylidèrce -D-Lrthraniqus resulting.

   4- (5,6-diamino-4-pyriillidinylaaino) - 4- acid is prepared <, 3-O-isopiopylîàene-fi-eiythronic by reacting 6araino-5-nitra -.-- chloro-pyrinidine with 4-amino acid = 4-deoxy-2,3-b-isopiopylidene-D -erythronic and reducing acid 4-

  <Desc / Clms Page number 11>

 
 EMI11.1
 -aino - nitro - ¯p3idin ;; L = i3oj-t! --- daox -,> - i.opropy l.dèreu-crj'.L'.rOi.i, lc'3 resulting * Acid '-.-- w-âz's is prepared .J ^ - '.'> 2'rCip'ricidinû 3aizo -: - dsa -r ,, - v-isepropr lzdéno -.-- rtLroy3rua es faire3nt ràegir de la = -c3oro-j itra - arcpyriidine s? # -c of 4-aiiû- ": - '' ts: soxyrG -u-isopropjldIG.e - i? rythrQnlEigc. --i-au.3na-5 nitro - 1- riLidinIa ..ino .--- dso-3-t, diben2fl3 - thr: ethyl unct by making r-3Sir 4-ctla + O- -Ditro-6- * aninopyriidiEe with 4-aoeîro-deoxy- Ethyl <, µ-V-dibenzoylL-threonate.

   4L- (µL = oimicidoÀPauina-4- .0 pyr1àliàin 1-aniro) HWdeoxj-D-é = y% hionic acid is prepared by reacting 6-aciiBo-5-Qitro-4-chloro-pyriQidiso with + -aeino-4-asoxy -., 3-0-isopropylidè.ae'-D-erythroBic acid and reducing 4-5-azno - n3.txo-4 priiâin acid; la.ino-s .-dsu -, - O-isopropylidene-D-enythronic resulting in the presence of fornic acid. In a sinilar fashion, prepare other starting compounds.



  (1-1-2) Cyclization from the isidazole nucleus The u.nG of techniques falling into this category may
 EMI11.2
 be represented by the following formulas
 EMI11.3
 fl Zß 1 / t \\ JL 11 ;; : D 1 <2 --1: J // iII - 1 "jl) 8-: ¯; 35 in which iî2 is an amine or hydroxyl radical, R represents a hydrogen atom, ci'h4lōene (for example chlorine, bromine, iodine or fluorine), a cnino radical, lower alkyl (for example reth3l, et: y3e, propyl), aryl such as phenyl or aral-, kyl (lower) such as phnyl (lower) (eg benzyl, phenétbgyùe); the symbol Y represents a cyano, carbaroyl, aoidino or -C (= Ni) (o- * 1ny.le lower) radical; and E) 1 ± 4 'R5' B'4 and R '5 are each as defined above.



  The compound of i =: idazol.e III is reacted with a derivative of inidic acid corresponding to the formula: R6-C-Rr: Il 1 im! Aj '
 EMI11.4
 in which R6 is a hydrogen atom, an lower alkyl radical (for example ethyl ethyl, propyl), aryl such as phenyl or aralkyl (lower) such as phGnJ131kyle (lower) (by

  <Desc / Clms Page number 12>

 
 EMI12.1
 example benzyl, phenctl; yl) ct 117 is an anino or lower alkoxy radical (p # 1 example m.0thoxy ,, :: thoX3 ', propoxy) or with an ester d.c1do ort'-oc - roxylîlue oysrt for formula :
 EMI12.2
 
 EMI12.3
 in 3a, i2e is a lower 81cBnoyl radical (for example: '\ - ".:') 1 4.c. t ;; 3.c, pnopio-; yl, butwl <;), or inferior clty19 (prt? i.e3 ethyl, pro: ß le,. and 1 r1,; pr.: st - ':! tcjt each a lower alkyl radical' r1. 'c :. : plE;

   : é.swt: T, ', E', ethyl proP: 11e) and 8¯ is such that 1 that it ,,) ft: r, vf ..: plus t} 1-111 ;, and "e; : - = :; 1> c, which gives the cO ',. J:; f.;> S': 41st. 1; l'llrh.f.3 8. 0'n carried out Il 13 reaction in us zol w "::: 1t, such it water, the zv'ïit3.i. Otw th3nol, in the c: u; of reagent {b -; , de pr.jr ":; rû1ce en prse: c--:; un ecide CO.9 :::! e the killer chlo: '1.: ri. :: ue, sulfuric acid, l' 3L ,: .. acetic liiie, 1 p-toluene sulfOEiM balance, etc. When the starting count is 3: co, :: pos'; of ir, iJzole {! II: Y ". c3rb = Yle), 0: .. obtains con, Ee produces the co: zposi of the purine (11): (- hydroXYl) In other caz, the product is the co = 'pos <S of Il purine Irlb: R = ssiro.



  In the course of this tréitent, one or more of the substituents represented by the symbols nose st R * can be influenced. 0 can cite by = 1 some influences the following: tr3B5for-; tic of the group: .drox: 3 acylated or ait.ri'i, represents by t4 'in free hydroxyl, \' l '; 1!: S! or :: ation of the hydroxyl or sisoxy group 1; 1, laughing, represented by h. is an amino group, etc.



  .,. cospose of isid'3sole (III) from dpsrt can be obtained by various procedures. Ox çràpene for example = ple Ilmeide 4 - (- cJano-j-: i: .a - 1-â ::. Id% zah "vl.-.- ;; so - ¯, r, ri ;. en fsissst react ic.i C'y IiLT t i-f't '"' ..." 7. 'lCt; .t $: ethyl 2'Tr3C of acid a <ino-4dsoXJ-r: -0ryt'broDigue. 0 can, from a = =: riere analogous to prepare cG == cutters starting.



  (1-) SubstitutioE at 3.'eot.



  The technique represented by the following forces in-
 EMI12.4
 be in this category:

  <Desc / Clms Page number 13>

 
 EMI13.1
 
 EMI13.2
 t (Icl in which --ti represents a hydrogen atom, a lower alkoxy radical (for example nethoxy, ctrox-, propoxy), amino; 3 alyl (in, fer.eur) 4ino (for example nethylamino, ethylamino, propylamino ), di-alkyl (lower) asiino (eg dimethylamino, diethy3.arino) aralkyl (lower) amino, such as phenylalkyl (±n ± to ± riEUr) 4ino, (eg benzylanino, phenethylamino), or acylamino conne ^ 2tanoyl (lower) -aino (eg acetylanino, piopionylanino, butyrylarino, octanoylaminc), or benzoylamino;

   R3 represents a j1.Ydrogen atom or an avino, lower alkyl (per eX6sple nethyl, ethyl, propyl) or aryl radical such as phnylo; qb represents a hydrogen atom or a lower amino alkyl radical (for example methyl, ethyl, propyl or aryl such as phenyl;

   - represents a hydrogen atom, a ra-
 EMI13.3
 dical amino7 lower allcyl (eg methyl, ethyl, propyl) or aryl such as phenyl, R4 is a lower alkylene radical.
 EMI13.4
 preferably comprising 6 carbon atoms (par.

   xetaple stethylene, triaethylene, propylene), bearing as substituents one or more hydroxyl radicals (but without the presence of a hydroxyl group on the carbon atom adjacent to the nitrogen atom of the nucleus), which are protected by lower alkyl radicals (e.g. methyl, ethyl, propyl, isopropyl),
 EMI13.5
 aralkyl (inicri2ur) such as phenyla1} le (lower), (by vexezple benzyl, paenéthyl) or when there is a pair of hydroxyl radicals on the group aikqyiéne, by lower alkylidene radicals (for example ezhylidè--, propylidene, isopropylidè), or alternatively lower aral-kylidene, such as phen7lalkylidene (lower) (; replicated benz3dene); and 3 is as it was finished above.



   The compound IV of the purine is reacted with a lactone having the formula :.
 EMI13.6
 
 EMI13.7
 in laçnc33e R4 is as defined above, which

  <Desc / Clms Page number 14>

 gives the compound of purine (the ?.



   The reaction is usually carried out in a solvent.
 EMI14.1
 (eg in dimethylformarid, dibasic sulfoxide-, xylene), in the presence of a condensing agent such as an alkali metal (eg lithium, sodium, potassium), a hydride of alkali netal (e.g. lithium hydride, hy
 EMI14.2
 sodium dride, hydride of potpssiua), an alkaline earth metal hydride (e.g. calcium hydride, barium hydride), an alkali metal carbonate (e.g. carbonate 0 of sodiun, potassium carbonate), an alkaline earth metal carbonate (e.g. calcium carbonate, carbonate
 EMI14.3
 from agnesiu),

   alkali metal bicarbonate (eg sodium bicarbonate, potassium bicarbonate), alkaline earth alal bicarbonate (r-: r eg calcium bicarbonate, bicarbonate of I: l :? n6siu! r :), mJtsl alkali-n hydroxide (eg sodium hydroxide, potassium hydroxide, α-netal hydroxide (eg sodium hydroxide) of calcium, hydroxide of D3En8siuD of alkali metal fluoride (for example cestuci fluoride, potassium fluoride, lithium fluoride), an alkali metal alcoholate (e.g. sodium ethoxide, potassium tert-butoxide, at a temperature cooperating between the ambient temperature and the abullitium temperature of the reaction medium.



  The starting purine compound Y ext is known or can be prepared by various methods.



  (2-1) -È:, '=' Ydro3, sef -
The technique represented by the following formulas falls into this category:
 EMI14.4
 
 EMI14.5
 In these formulas Rz represents an atom of hydrogen, dehclosene (by example of chlorine, brone, iodine, fluorine), or a hydroxcyl, mercapto, amino, lower alkyl radical (for example ethyl methyl2, propyl, isopropyl) , aryl such as phnyl., lower alkoxy (eg nethoxy, 1 fthOxy., propoxy, isqpropoxy), ara3.koxy (lower) cosise pheoyl alkoxy (lower), (eg.

  <Desc / Clms Page number 15>

 
 EMI15.1
 ple benzyloxy, ph3nthyloXj-), or 2lkyl (lower) thio (by vexezple aéthyltàio, éthylthio, propylthio); and A, Â, il, R. R4 Ru, Ri, R, R 'and Il are each as defined above.



  Compost it from l. purine, depsrt, * V in which are present one or more groups h, drolyzable such as hydroxyl rcttyl4, hydroxyl etbrifié, n7iino ecylé, est6rifi crboxyl or carbar: oIe, is treated with an acidic substance oū bc-
 EMI15.2
 sic an aqueous medium, so as to obtain the coripose of the pu-
 EMI15.3
 rine (Ie. desired, and in which any one of the hydro-) lysable groups present in the derivative is hydrolyzed to form a free group such as free hydroxyl, free 3cino or
 EMI15.4
 free carboxyl.
 EMI15.5
 



  For this substance, hydrochloric acid, sulfuric acid, fluoric acid, scientific acid, benzoic acid, etc. can be used. 000tc examples of basic substances one p-Jut indicate the hydroxide àe -odiu:., L'l *, dno> ysde of potsssiua, sodium enrbonate, crbon: te of potassium, the ..: sodium thrlate, sodium ethoxide, potassium ether, etc. 0n can be operated with a basic or acidic ion exchange reside. A reaction is usually carried out at a temperature understood between the cubic temperature and the boiling temperature of the reaction medium.



  The hydrolysis continues in gen-4rn! L of sese 4 niére,
 EMI15.6
 whether an ecid or basic substance is used. it is essential
 EMI15.7
 to operate with an acidic substance to transrort the group 1a3droxyl é.t: rzfzé in R4, in a free hydroxyl <.
 EMI15.8
 



  As indicated above, the present process relates to the hydrolysis of one or more of the hydro- substituents.
 EMI15.9
 lysables present on the nucleus of the purinc or ei.s the chain la-
 EMI15.10
 teral. However, during treatment, any other
 EMI15.11
 substituent can be found influence. ;, L-.¯ :: ¯a examples of these influences include the following: trsnsforastion of a? Torus of hsiogen or of a ucrcapto or nlkylthio group, represented by Eïl R2 or to, into a hydroxyl radical or lower alkoxy, etc.



  (2-2) Reduction.
 EMI15.12
 



  The transformation which can be represented by the following formulas falls into this category:

  <Desc / Clms Page number 16>

 
 EMI16.1
 
 EMI16.2
 In these formulas, A, R1, R-C-1 F13-14, R51, R1, R2 'RJ, R4 and R5 are each as defined above.



  Thus the compound of purine in which a or t). several reducible groups (including transformable groups
 EMI16.3
 in an atarze d, n, 7drogeme) are present, is subjected to a reduction, which gives the compound of the purine Ie in which one of the reducible groups present in the starting compound is reduced.



   In order to carry out the reduction, reduction with reducing agent, catalytic reduction, electrolytic reduction, etc. can be adopted. Examples of reducing agents include the combination of a dotal (eg iron, eta zinc) and an acid (eg hydrochloric acid, acetic acid.), The combination of a metal (for example sodiun, 1
 EMI16.4
 alg30e of sodiua, aluminiuri aralsane, zinc, iron) and esu or of an alcrnol (for example: tàano2, ethanol), a sulfide (for example aCLoniu2 sulphide, hydrosulfide;

   a4 n3.u :, sodium sulfide, sodius polysulfide, sulihy. sodium drate, hydrogen sulphide), sodium dithionite sodium bisulphite, phenylbydrezine or 1'h3.drezine, the cc bin # ison of titanium trichloride and hydrazine, the combina: bran of the hydriodic scl and hypcphosphorous acid, etc. Goc eutnlyseur for the catalytic reduction, we can for example cite platinum, platinum oxide, pal2adiun, palladium oxide, palladium on carbon, palladium on bar sul- 3te, u :, le palladiuD on barium carbonate, pelJ diua on silica salt, rhodium $ iridium, ruthenium, nickel oxide, Raney nickel, Raney cobalt, reducing agent, Raney iron reducing copper, Re copper
 EMI16.5
 ney, copper OQ 10 sine da IJIL nm1.

   Usually 1; reaction in a suitable solvent chosen according to the nature of the reducing agent or of the catalyst and as examples of these solvents one can indicate water, acetic acid, methanol
 EMI16.6
 1 f eth: mol, etc.

  <Desc / Clms Page number 17>

 
 EMI17.1
 (-3) AciinatioD. 1-one of the techniques falling into this category can be represented by the following formulas:

   
 EMI17.2
 in which R11 and R12 each represent a hydrogen atom, a lower alkyl radical (for example methyl, ethyl,
 EMI17.3
 propyl, isopropyl), analkyl (inl-rieun) such as phenylalkyl (lower), (eg benzyl, phzneth, yl), acyl such as lower alkane (eg acetyl, propionyl, butyr;

  yl), p.hényla3eanoyl (inférieun), (for example phenacstyle), or benzoyl or hydroxyl, Z represents a halogen atom (for example chlorine or bromine), or an oercapto, alkyl (infériear) thio radical (for exot.ple Dethylthio, ethylthio, propylthio), arylthio such as phenylthio, aralkyl (lower) thio, (eg benzylthio, phenylthio), alkenyl (lower) thio (eg allylthio), alkyl (lower) sulfonyl , (eg methanesulfonyl, ethanesulfonyl), arylsulfonyl such as benzenesulfonyl or toluene sulfonyl
 EMI17.4
 aralk, yl (infariur) sulfonyl, such as phenyl (lower) alkyl sulfonyl (eg phenylaethanesulfonyl, phenyletlanesulfonyl), or al-enyl (lower) sulfonylet (eg allylsulfonyl);

   and R, R3 R4, R5 R4 and R5 are each as defined above.



   The reaction is carried out by treating the compound of purine VII with an amine having the formula:
 EMI17.5
 wherein R11 and R12 are each as defined above, usually in a solvent (e.g. in water, methanol, ethanol), while heating - it is preferred to use the amine D in excess over compound VII of purine.



  When the hydroxyl group (s) of the hydroxylated alkylene group represented by the R4 syribole is (or are) acylated, the acylated hydroxyl group may be transformed into a hydroxyl at the same time.

  <Desc / Clms Page number 18>

 that the amination takes place under vigorous reaction conditions.



   When the symbol R5 represents a lower alkoxy radical, it may be replaced by the group having the formula:
 EMI18.1
 during the reaction (2-4) Esterification 0 A typical technique in this category can be practically represented by the following formulas:
 EMI18.2
 in which R13 is a lower or higher radical (for example methyl, ethyl, propyl, isopropyl, octyl, decyl, hep-) tadecyl); and R1 R2 R, R4 and R4 are each as defined above.



   The reaction is carried out by treating the compound VIII of purine, or its functional derivative at the carbonyl group, with a reagent represented by the formula
R13 = X CE.3 in which X is a halogen atom (eg chlorine, bromine), hydroxyl, hydroxysulfonloxy or (lower) alkoxy sulfonyloxy (eg methoxysulfonloxy ethoxysulfonyloxy), and R13 is as defined above, with a reagent having the formula:

  
R13 = N2 F where R13 is a lower alkylene radical (eg methylene, ethylene), in a solvent (eg in methanol, ethanol, benzene, toluene, dimethylformami, acetone, ether, tetrahydrofuran), at a temperature between room temperature and the boiling point of the reaction medium. as functional derivative of compound VIII of purine, there may be mentioned, for example, an acid halide, an acid azide, an acid anhydride, an amide, etc.

  <Desc / Clms Page number 19>

 



   Depending on the nature of the reagent E or F, an acidic or basic catalyst can be used, or else a condensing agent, of which the following examples can be cited hydrochloric acid, sulfuric acid, boron trifluoride, l 'acid
 EMI19.1
 5 benzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, ferric chloride, aluminum chloride, zinc chloride, lo, 2c'-dicyelohe: y3carbodi?: Ïde ,, Iv i: -. Cyc? oh: xyl -? '- orpho-. lino-étbylc3rboÓ.iir.dde,;: Li-cyclohex-sl-H "'- (4-diéthy13w.nocyclohe- 1) -caràodiï.ide, z, I'-dzéthy? caràodüide, the; -:' -dizsopr4- .0 pylcsrbodiinide. 3-thy3 .- = r - (.- d.thyla: ropropyl) -carbodüride, 1 Iv - Lth, y; '- {3-dëthylaaâ.ropropyl) -caroodü:

  de, û, i'¯ carbonyldiinidazole, i, '- carbonyl-ci- (2-ethyli.idazole), i, i'-carbanyl-dipyrazole, pentaethylenccetene -; - cyclQheÀ71; r; ne, diphenylkete -H-cyclohexyline, pscoxyacetylene, 1- 5 aleoig-1-cbloroethylen, tetraalkyl phosphire, 2-ethyl-5- (N-sulfophéDyl) -isoxszoliua, a salt of ± --4ethyl- 2-hydroxybenzisoxazolium, ethyl polyphosphate, isopropyl polyphosphata, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, a resin
 EMI19.2
 ) strongly acidic ion exchanger, molacular t3is, alkali metal hydroxide, alkaline earth netal hydroxide, alkali netal carbonate, alkaline earth metal carbonate, etc.



   During the above treatment, the etherified hy) droxyl group (s) of the symbol R4 may be converted into a hydroxyl radical.



     1 on-5) Amidatin
This category includes the technique represented by the following formulas:
 EMI19.3
 
 EMI19.4
 wherein R4 is a lower slkylacino radical (eg methyla4ino, ethylaaino) or (eg diaethylaDino, di & thylaLlino, rethyîeth, yl4.ino); and iZ, 'y E - R, R4' Ri, R2 'R3 and tt are each as defined

  <Desc / Clms Page number 20>

 upper.



     The reaction is carried out by treating the purine compound IX or its functional derivative at the carboxyl group with a
 EMI20.1
 ssincdoforaule: Ri4 - rj H14 - H where R14 is as defined above, usually in a solvent (e.g. in water, methanol, ethanol, benzene, acetone , dioxane, acetoni-
 EMI20.2
 trile, chloroform, ethylene chloride, tetrahydrofuran, ethyl acetate, fornic acid, pyridine), at a temperature between room temperature and room temperature.
 EMI20.3
 boiling pjreture of the reactiocnel mixture.



  CJ. e ùxccplcs of functional derivatives of the compound of the purine I, one can quote: ha3ogrurs of acid, d-s anhydri-? dov azid acids, esters, etc. we prefer in particular
 EMI20.4
 bind the ci ,, 1 * runo = - of acid, the acid azides, a wixte anhydride of the cid. phosphoric acid, an anhydride ;;; iXte dt the bBnzylphosphorique, 'an ant-3, anide L.> ixte of acid that hslegése, un = n5. aridc cixte of al.Iccrboniçue acid, a (t-methyl,' an ethyl ester, a cynnolophenyl ester, a f: ±: ": ...: r p-nitronhr, sli çuc :, a pentscnlorophenyl ester, a propargyl ester, a tbioastcr ctrbox3.iethylie, a ster pyran.9liāu: , a 6thcXYQtrlic ester, a thiocster phar.; liue, etc.



   The amine can be used in free form or in the form of a salt such as the hydrochloride or the sulfate. In the latter case, it is claimed that there is a presence of a base in the reacting system. We can, when desired, use an agent
 EMI20.5
 condensation such as N, '- dicJcloh0J: ylcarbodiide, N-. cyclohexyl-N '- ::: orp ::. olino6thylc: 1Xbodlkide, ii-c'yclohexyl-n' - (4dithyl3inocycloa. <jxyl) -c8rbodiinide,; i, li'-d2thylcabodiimide 1-, '- d.isouropylcarbo3üid :, N-ethyl -'- (J-di = ethylain0pr p; 1) -cenbodil - uifc, S, 5'-Crùonyldiidzole, -isr'-carbon, y3- 4 $ 'G:, s # t.ll¯srd4LOI' ..,.), Pentgethylene-cftene-i-cJclohexyl1rxLne, 13 dipvlcet4ne-zc; cloba: 2iriz3e, an alkoxyacetylene, the isopropyl ester of polyphosphoric acid, oxal chloride, 3a triphenylphosphinc, etc.



  In the course of the reaction, the halogen atom, the aercspto or GI 1 group (infrîeur) thio, r e; xsented by the sysboles .ra, RI ots li! can hearth ral-plactS p3r part R14 of the 3ine used ?. In addition, the acylated hydroxyl group of the sya-

  <Desc / Clms Page number 21>

 bole R4 can be converted into a hydroxyl.



   2-6 Acylation. The following formula technique falls into this category:
 EMI21.1
 
 EMI21.2
 In these formulas, RI 'R.9 R3, 1.14' R5, RI RI R.3 'R> au
R5 are each as defined above.



   In the above procedure, one or more substituents to be acylated are aclyated, i.e. the amino group (s) represented by the symbols R1R2 and R3 can be transformed.
 EMI21.3
 into acylamino groups and also the hydroxyl group (s) of the symbol R4 can be converted into acyloxy groups.



   The reaction is carried out by treating the compound x of the purine with an acylating agent such as an aliphatic carboxylic acid (eg, acetic acid, propionic acid, a-.
 EMI21.4
 butenoic acid, pentanoic acid, isppentanoic acid, pyvalic acid, 2-ethyl butcnoic acid), an aromatic carboxylic acid (for example benzoic acid, p-bromo acid)
 EMI21.5
 benzoic acid, p-nitrobenzoic acid, phenylacetic acid, cinnamic acid) or a heterocyclic carboxylic acid (eg nicotinic acid, isonicotinic acid) and their carboxyl functional derivatives, such as their acid halides (e.g. acid chloride), a- anhydride
 EMI21.6
 filthy,

   aside, azide and ester, (e.g., netyl ester, ethyl ester, cyanoethyl ester, p-nitrophecyl ester, pantachlorophenyl ester, ... , ester, 4,5-trich1orophFnyl1qua, propargyl ester, carboxyïaetayl thioester, PY7: ic ester, ethoxyethyl ester, phenyl thioester, la -hyc; ro-szacci.ïâ..ïdej, usual in a solvent (eg ether, Ilac4tone, dioxane, acetonitrile, chloroform, 1-tbylene chloride, tetrehhydrofurenne, ethyl acetate, pyridine), while cooling to the ambient temperature or by heating.

   We can, yes. it is necessary
 EMI21.7
 If necessary, use a condensing agent such as. ',; 3'-dicyc3a-

  <Desc / Clms Page number 22>

 
 EMI22.1
 hexylcerboà [mide, 1V'-cycloheL-tt-orpho.inoét'r, yl - caxhodü.mide,? I-cyclohexyl-Y '- (4-diethylaminocyclohexyl) -canbodiimide, N, N'-diethyl- carbodilide, N, N'-diisopropyl-carbodiiwide, N- ethyi-N '- (3-dirét' ,, ylarinopropyl) -carboIÜride, l, N '- carbonyl-5 diimidazole, N, Is'- carbonylpyrazole, N, li'-ccrbonyldi- (2-methylicidazole), pentara.etilene-ketene 1V-cyclohēxylirine, diphenyLketene-it-c, ßeloherylitt.ne, alkoxyacetylene, 1-alkoxyhy-1-chlcrétylene .ene, a salt of 2-ethyl - hydroxybenzzsoxazo3.ia.cl, 2-ethyl-5- (m-sulfophenyl) -isoxezoliuu hydroxide, etc.

   A base such as an alkali metal carbonate, a trialkylamine or pyridine can also be added.
 EMI22.2
 By choosing the appropriate reaction conditions, it is possible to carry out either one or both acylations of the hydroxyl group and of the healthy group.
 EMI22.3
 5 (2-7) 'therxficat3on.



   In this category between the technique that can be represented by the following formulas:
 EMI22.4
 Wherein R4 is lower alkylene preferably comprising from 2 to 6 carbon atoms (eg ethylene, trimethylene propylene), have as substituents one or more hy-
 EMI22.5
 droxyls (but without the presence of a hydroxyl group on the carbon atom adjacent to the nitrogen atone of the ring);

   R4 is lower alkylene preferably comprising from 2 to 6 atoms of
 EMI22.6
 carbon (for example éthàvlèzd, trinétb3 = lènc, propylene), carrying as substituents one or more hydroxyls (but without the presence of a hydroxyl group on the adjacent carbon atom: \ the nitrogen atom of the ring), at least one of which is protected by a lower alkyl or lower aralkyl radical or, when there is a pair of hydroxyls on the alkylene group, with
 EMI22.7
 lower alkylidene or lower 3ralkylidene groups, and Ru, R2, R3 and R4 are each as defined above.



     The reaction is carried out by reacting compound XI of purine with a reagent of formula

  <Desc / Clms Page number 23>

 
 EMI23.1
 in which R15 is a hydrogen atom or an alkyl radical
 EMI23.2
 5 lower (eg methyl, ethyl, propyl, iso, ropyle 'R 16 represents a hydrogen atom, a lower alkyl radical (for
 EMI23.3
 example methyl, uthyl, propyl, isopropyl), ara2k¯ the (lower) such as phcnylalky3e (ini.rieur), (for example benzyl, pnénêthyle3)
 EMI23.4
 or aryl such as phcnyl, and Y and Y each represent lower alkoxy (eg methoxyethoxy, propoxy, isopropoxy), or both represent an oxo group, or again with a reagent of formula:

   
 EMI23.5
 9j o- - 1 (J) in which R17 is a lower alkyl radical (for example me
 EMI23.6
 5 tr, yl, .3thylG, propyl, isopropyl), or arai'v3e {ini.ieur such as: ph6nyl alryi: {i.rfrietr ,, (for example benzyl, phCn '; thyl.?), And re is a hydroxyl rs'iical or a; Jt0 ::: '' :: halogen (p = uxesiple to chlor3 or bro! 2), in a solvent, usually at a t,? p ature between the tt5lltpGreture 8J: " <ois: ote and te:.: 1p.reture of boiling of the reaction medium without the case where one uses the reagent n it is preferred to add to the reaction medium a Lewis acid, except for hydrochloric acid, hydrobromic acid, perchloric acid, zinc chloride, a-
 EMI23.7
 toluene sulfcnic acid, di-n phosphate;

   trophLazy., 3e o- 3 phosphorus xychloride, ion exchange resins of the type When operating with the rectif (Jj, it is 4 r'crr tt4 to incorporate a condensing agent such as 1 ' sulfuric acid acid
 EMI23.8
 toluene sulfonic acid, sodium acid sulfite or silver oxide. (2-8) Other Transformation In addition to the techniques discussed above, a wide variety of other common techniques can be adopted for the transformation of any substituent present on the purine nucleus. For example the chlorine atom (s) present in position 2 6 and / or 8 are converted into hydroxyl radicals by heating.
 EMI23.9
 fage with formic acid to aQuous silica.

   The chlorine atom (s) present in position 27 and / or 8 are transformed into mercapto groups by reaction with thiourea in a solvent, then
 EMI23.10
 when dealing with a substance: lea.I2rae. The chlorine atom (s) in position 2, 6 and / or 8 can be transformed into Itydroxysmino groups by reaction with hydroxy2am1nc.

   The ato-

  <Desc / Clms Page number 24>

 chlorine in positions 2, 6 and / or 8 are converted to lower alkoxy radicals by reaction with an alkali metal alcoholate (e.g. with sodium methoxide, ethylate
 EMI24.1
 sodium, potassius ethoxide) - The mercadto group (s) in the 5 positions 2, 6 and / or 8 can be transformed into (lower) alkyl thio groups by reaction with a lower alkyl hslogenide (eg. methyl, mdtbyl iodide, chlorine :: ether + 1 <), in -Pr usunce of a base. The amino group (s) in positions 2, 6 and / or 6 can be converted into hydroxyl groups by reaction with av, -, c da 1. f nitrous acid.



  1-The compounds ("J of purine obtained as indicated above can be transformed into their salts, such as metal salts, ammonium salts and their addition salts with acids, by conventional techniques .



  The compounds (I) of purine and their salts manifest
 EMI24.2
 in general a marked bypocholesterolemic activity. The results of the tests carried out on the normal compound, that is to say the acid 4- (E> -ai.sopurina-Q yl) -4-dsox-.T'3-erstnronic: are set out below. - under.



   1.Test method.



   Groups of rats of the wistar strain (average weight: 74 g), 5 weeks old, each group consisting of 10 animals, were raised for three days, using a fatty diet consisting of 2% cholesterol, 1% d. cholic acid, hardened oil (12% fish extract (12% and some other products, simultaneously administering the test compound once a day; then fasted overnight and the sacrifices in the morning follow.

   The concentration of serum or cholesterol is measured according to the Zak-Henly method. The
 EMI24.3
 test compound is edmim-ist> 4 in aqueous solution acidified with hydrochloric acid, or else in aqueous suspension with lt. carbcxysethyl cellulose. Co = positive, thyroxine is administered orally at a dose of 0.5 mg per animal.



   2. Test results.



   Route: Dose: Serum cholesterol,% inhibition
 EMI24.4
 rat): cg / dl t â ..:
 EMI24.5
 Intraperitoneum 0.5 337 + 4S, 8 37.4 Intraperitoneal: 0.2 338 24.9 37.2 Pcroral 0.5 49 ¯ + 26.6 53.7
 EMI24.6
 
 <tb>
 <tb> Peroral <SEP> 0.2 <SEP> 271 <SEP> 28.0 <SEP> 49.6
 <tb>
 

  <Desc / Clms Page number 25>

 
2. Test results (continued).



  Route Dose: Serum cholesterol% inhibition
 EMI25.1
 administration: {mg / g rat): rgd3 - S.E.



  Thyroxine 0.05 2Elt- ¯- 28.4. - 47.2 5 Controls 538 + 48.1 Other compounds, for example methyl 4- (6-asirt0purin-9-yl) -4-dµsozy-D-enythronate, - (ēainopurine-9 1 Ethyl-deoxy-D-erythronate, 4- (6-am0'purin-9-yl) -4-deoxy-0 D-erythronamia, 4- (6-benzoylaninopurin-S-yl) -4 acid -desoxy-D- erythronic acid, 4- (6-anino-8-methylpurin-9-yl) -4-deoxy-D- erythronic acid, 4 - (î-aaino-6-hydroxypurine-9 -yl) -A-deoxy-D- erythronic acid - (6-et3laminopurine-9-1) -: - desox -, yD.-rthronic, 4- (6-hydroxypuriDe-9-yl) acid -4-d'jsoxy-D-erythronic, 6 - a..no - (3-carbox-2,3-dihdropropyl) -purinV-3-oyde and their salts exhibited similar activity.



   Further, the toxicity of purine 1 compounds and their salts is extremely low. For example, the toxicity of
 EMI25.2
 4- (6-Aminopurine-3-yl) -4-deoxy-D-erythronic acid (4- (6-aminopurine-3-yl) -4-deoxy-D-erythronic acid poar) in rats and mice is as follows:
Animal Route of administration LD50 (in mg / Kg)
Mouse Subcutaneous 2700
 EMI25.3
 Rat: Intrapcritoneal 1000 # 2000 Rat Peroral 4000
Thus, the purine compounds 1 and their non-toxic salts are of great interest as therapeutic agents in the treatment of atherosclerosis.



   The purine compounds 1 and their non-toxic salts are stable to chlorine and to light and can be administered by conventional methods, in the usual dosage unit forms or with the usual pharmaceutical excipients, to determine in patients. humans have hypocholesterolemic activity. Thus, they can be used in the form of pharmaceutical preparations which contain them in admixture with an organic or inorganic pharmaceutical excipient, suitable for enteral or parenteral applications.

   Oral administration in the form of tablets, capsulas or in liquid form such as that of suspensions, solutions or emulsions, or applications by injection are particularly advantageous.

  <Desc / Clms Page number 26>

 



   When in tablet form, use may be made of the binding and disintegrating agents commonly used in unit therapeutic doses. As illustrative examples of binding agents, mention may be made of glucose, lactose, - the kidney. acacia, gelatin, mannitol, starch paste, mange sium trisilist and talc. As illustrative examples of disintegrating agents, starch, keratin, colloidal silica and potato starch can be mentioned. When administered in liquid form, conventional liquid excipients can be used.



   The dose or therapeutically effective amount of the compounds (CI) of purine and their salts, for humans, can vary within wide limits such as 10 to 1000 mil ligrams per day for an adult. The upper limit is set only by the degree of effect desired and by economic considerations. For oral administration, approximately 5 to 30 milligrams of the therapeutic agent should be used per unit dose. For injection applications the active ingredient can be used in an amount of 1 to 10 mg per unit dose. The dose of the therapeutic agent considered can of course vary considerably depending on the age of the naiad and the degree of therapeutic effect sought.

   By the term of pharmaceutical excipient is meant non-therapeutic substances which are commonly used with unit doses, namely in particular fillers, diluents, binders, lubricants, disintegrating agents and solvents. It is of course possible to administer the new therapeutic agents of the invention, that is to say the compounds in the pure state, without using a pharmaceutical excipient.



   The practical and currently preferred embodiments of the invention are set out by way of illustration in the following examples:
Example 1.



     (A) 400 ng of triethylamine and 250 mg of formamindin acetate are added to a suspension of 500 mg of 4- (5,6-di-amino-4-pyrimidinylamino) -4-deoxy-2,3 -0-Isopropylidene-D- (Rhythmic to 10 ml of methyl Cellosolve. The mixture is heated under reflux for 20 minutes. The solvent is removed from the reaction mixture under reduced pressure. The residue is dissolved in water and the mixture is stirred. adjusts the pH of the aqueous solution to 3 with acid

  <Desc / Clms Page number 27>

 dilute hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to give 250 mg of acid.
 EMI27.1
 = - (6-aincpusin- yl) -4-deoxy-, 3.-0-isopropylidene - erythronic.

   Melting point: 214 C (after recrystallization from water). 5 (B) A solution is heated under reflux for one hour.
 EMI27.2
 of 120 d'scido .- (5, ô-diaaino - =, - ryridicr-ls, ¯àno) -4-dsō 2, jO-.soprap; lâè.éze -. 'J-eryton: that in 3 al of fornic acid at 90 s = .¯ After cooling, the fornic acid is removed from the reaction mixture by evaporating it under reduced pressure. Water is added to the residue and the solvent is again evaporated off under reduced pressure.

   A small amount of water is added to the residue and the precipitated crystals are collected by filtration, washed with
 EMI27.3
 water, then with cethanol and recrystallized in water to give 75 sg of 4- (6-anino-5-fornea # ido- -: d3.s, y3c acid columns. = o). = a - desOx-p-er throniauL .. Melting point: 190 C (with d8cofuposition). A solution of 0.50 g of 4- (6-aaino-5-foraido-4--., :: - d: ',, 3.aïoâ ..-: is heated for 10 minutes in a boiling water bath: --d.soxy-D-: rthroLïque d, ns 5 nl of standard sodium hydrox7d-, e solution. After cooling, 5 ml) of normal hydrochloric acid are added to the reaction mixture and it is collected by filtration the precipitated crystals.

   These crystals are washed with water, then with methanol, which gives 0.34 g of acid.
 EMI27.4
 4- (6-aminopuri-tne-g-yl) -4-d, soxy-D-erythroniquG. Melting point: (with decomposition). r 5 = + 30 (C = O, a3, in di-) .vti, ylsulfoxde). 5.26% ultraviolet spectrum (G = 14-.? 00). enters the ultra-violet bzz61 The substance prepared above is identified by the following cnière, namely the acid 4- (6-inopurine-9-, 1) -4-d: soxy-D-erythroni0, with the newly isolated substance of I "3ntinus edodes:
We triturate 10 kg of Lentinus edodes and add 20
 EMI27.5
 liters of 80% aqueous Ctethsnol. The mixture is subjected to reflux extraction of the effective substance for 3 hours. This operation is repeated twice.

   The extracts thus obtained are mixed, concentrated to 6 liters under reduced pressure and ether is added thereto. After sufficiently shaking the ethereal solution, the aqueous layer is separated. The aqueous layer is diluted with 20 liters of water and then passed over an e- resin.
 EMI27.6
 strongly acidic ion changer C ".A ± lber1ite IR-10" Type R). The resin is washed with water, then it is eluted with ammonia.

  <Desc / Clms Page number 28>

 
 EMI28.1
 to 2. The eluate was created under reduced pressure and lyophilized to obtain 50 g of brown powder. This powder is therefore dissolved 400 1 4 * esu and the solution is passed through an echo resin; u: s, 5 ùîors fort.:nt scido ("Dowcx 50 X 2", 7 type H).

   We wash 5 1 # ré1-i-nc? Vac ri,) the = ::: 1u the eluted it graduated with solutions of Pc.l. hydrochloric acid from 1: i to 4N. We mix together the fractions which give a nsxiemn of 260 r-n dr.ns the ultra- spectrum
 EMI28.2
 purple and freeze-dried to give a white powder. We
 EMI28.3
 dissolve ci - tt4j lay dr * ss duke 1, L-lu and we again pass C) lx solution on a, r. ;; 1n ..: echng ..:; us ;: strongly scide ions ( "De TIOX 55 X 2", s â3. Or 1 =%. E In resin with water and it is removed by,: rs i> :: r "vec d. 1" -; cid-- , hydrochloric from 1 K to 4 N. The Lerzctieno "lui 'éi ië2.n one of 260: 3t in the spic tr.) u1tr'Jv' 11t, -: t in lyophilized, cc which gives a powder? bl ': Hche <.

   We .-: it:; :: -: mt "'-.:t,t0 poucre, ÔÎ2DS of the esu and we do notl. N>.;.; <i;:. "'; -' ra sol2t.lo ;:;: 1J un. * ion curing resin iortuLaez" 'âr., s> (t1E.ëi:' ': µS 11 2 ", e54 O '' 'd Os eluted 3- 3-w? 1¯iF = with xnro. nia4uc Éà: C j: t Ci: Ijï) r; hilisf: 1 t elected 3t, ce: e:: s'7n2iG 'a powder â; 6.é' t4I J; '1; H; r,:; J. <m dissolves this powder 6.4f..J <j ¯ rascal of acetate D d: pyridin .. 'O, 1 01 passes 1 solution sm -, ina resin chc i = iâre-. , e> Fi'.Oï, strongly :: Cs.eN .. 'y tW. .. ': preliminary study with a tsepor:' ccitt- z pyridisa 0.1 it. We then read the resin ^ c du 'Ga: ^ 3 of eaJt t3 1 # p3.ri, ii-xe bzz 4.

   Cn divide the & luat into 1r-Bctior of 25 1 ch above. vs;; zll = 1xjc the fractions which give a maximus 1 to 60 jjt i-nas le ± t ..., ztr ,; d '- :: ultr: 1-violct absorption and lyophilized, resulting in crude crystals which are recrystallized from 3.!. lS dl ::! f (:' it1, to obtain 5G -1. approximately of pure crystals Coat d.5 fusion: 79 (?? cc decomposition).



  (C) Ci; heats u reflux rc-ndcnt 30 3.nutcs a solutic (iç 20-G ::, 1 ', icit-e 4- (j, -îamino-43z # i.i.33; il, 3,': pniµsoxy-2, j <isopro²71ièn - f: rJthroi doens un u .. ::. = of 1 cl decides fci r.i, yx == at 95% t ds 1 -e.1 dge ioa-r.; ii = *. Oj3 adds ethanol to:;: {ar; nsl .: r ': rtionn'1 and we .r :: cu311o you filter the crystals ^ rc3.p; r = :. Bone: dissolves cs crist-mx in water and we treat 1: solution a :: a. v: from 1'3. r <3Mdr <t 'of charcoal, then filtered. But C: â ^ .5-y le and we added: ûsa-301 to the residue. We recoil ': the by filtration 1 precipitated crystals and washed with ce <ni gives 40. as to '= 4- (6-ce- = inopurà-tae-9-yl) -4deox3.-b-olrytbionic cide. Fusicn point: 273 "C (3V & C decoaposi #
 EMI28.4
 tion).

  <Desc / Clms Page number 29>

 
 EMI29.1
 



  3.80 g of 4- (6-aainopurin-9-yl) -4deoxy-D-6rytbxonio-iiil acid prepared above are dissolved in 17 ml of normal sodium hydroxide solution, heated to 40 ° C. and we filter. Dropwise added to the filter *; 30 ml of ethanol. The precipitated crystals are collected by filtration and washed with ethanol.
 EMI29.2
 thanol, which gives 3.40 g of sodium 4- (6-aciinopurin-9-yl) -4-deoxy-D- "erythronate. Melting point: 272 C (with decomposition) Ultraviolet spectrum  0 261 mil, (c. = 141700).



  (D) Has a suspension of 610 ag of scidc 4 - (5¯anzno - chloJ ra - 4-piriidinylanino) -4 - desov -., 3-0-iso, prog: lidene-D-erythronic 0.36 ml of concentrated hydrochloric acid is added dropwise in 25 ml of triethyl orthoforsipte. The mixture is stirred for 3 hours at room temperature. The reaction mixture is condensed under reduced pressure and the residue is dissolved.
 EMI29.3
 ? in dichlorosethane.

   An insoluble substance is filtered off, the filtrate is evaporated under reduced pressure and the residue is dissolved in isopropyl ether. By rubbing the inside of the reaction vessel, precipitated crystals were collected by filtration to give 640 mg of 4- (6-chloropuri- acid.
 EMI29.4
 nē¯yl) ¯, zso-c: 3-0-isoproplidene-p-Gr3rtLrorzqut..iende2nt 76 îQ. Melting point: 150 C (with decosposition) after recrystallization from isopropyl ether. r - 25 5Ia, 6 (C = 0.835 in nethanol).



   (E) 0n heat at 100 C for 2 hours a solution of
 EMI29.5
 700 mg of 4- (µ-xzino-to-chlono-4-pyrinsdinylsnino)> ndeoxy-2,3-o-isopropyH.dene-D-erythronic acid in 15% of 90% fornic acid. The reaction mixture is evaporated off under reduced pressure. We
 EMI29.6
 Dissolve the residue in a mixture of 3El of 10% sodium b, 7-hydroxide solution and 5 ml of water. The reaction mixture is heated in a water bath for 15 minutes and, after cooling, it is neutralized with hydrochloric acid.

   We pass the med
 EMI29.7
 The resulting mixture on a column contains z0 cil of strongly acidic ion-exchange resin (".tiID.berlite TIR 120 B", Type H, the solonne 2--: '; is washed with water until the eluate becomes neutral, then it is eluted with 3'svvaJUe at d; ... The eluate is evaporated under reduced pressure and the residue is recrystallized from aqueous ethanol, which gives slightly brown coverslips. (280 mg) a-
 EMI29.8
 4- (E-1hydroxypuninc-9-yl) -4-desooegr-D-é% t-nonic acid. This substa :. c ssgglocerates at around 85 G, it swells between bzz0 and i05 C then it melts around 185CC.

   The nendenent is 48.

  <Desc / Clms Page number 30>

 F Has a suspension of 6.76 g of 4- (5-amino-6-
 EMI30.1
 Chloro-4-pyriridirylamino) -4-deoxy-D-erythranic acid in 20U ml of triethyl onthoionate, 3 ml of concentrated hydrochloric acid is added and the mixture is stirred at room temperature for 24 hours. The reaction mixture is condensed under reduced pressure from which an insoluble substance has separated. Ethyl acetate is added to the residue and the crystals are collected by filtration.
 EMI30.2
 insoluble levels to give 4- (6-Chlonopurinc-9-yl) -4deoxy-D-6rythronic acid. The filtrate was condensed under reduced pressure and ethyl acetate was added to the residue.

   An insoluble substance is collected by filtration, which gives the same substance as that sought. The total yield is 6.71 g. This substance is recrystallized from isopropanol to give the adduct with isopropanol Melting point: 110 ° C. (with de-
 EMI30.3
 > composition). (ce) 5: + 34 (C = 0.541 in diaethylsulfide oxide).



  Spectrum in 1 "alt = + a-iiolcl c 1 ;. hGi 0.1: rI <265 I: 1f1 (4. ¯¯ 9,000); > .R 266 mi-i = 8.G0); ;). Ji IfaOH 0 N 26-5 (CO '' nr) Max ze6 z; a ç = s, soo>; Max 1 'z65: = 1 # (. = 9.).



  (G) A solution of 2.0 g of 4- (2-aethylthio-5-forES3Liido-6-3Ciino-4-pyrinidinyla2tino) - 4-dioxy-D-erythronic acid in 20 ml of solution is heated for 20 minutes. normal sodium hydroxide. After cooling, hydrochloric acid is added to the reaction mixture to adjust the pH to between 2 and 3. The precipitated crystals are collected by filtration and washed.
 EMI30.4
 with a mixture of water and eth2ll01, which gives 1, to # g of 4- (c'-retlts: .ia-ô-ai: oopurina-9-3rI) -4-deso- -b -ért, ronique Melting point: 249 C (with decomposition) after recrystallization from aluetbylsuiioxyde. i) 2 5 = + 49 (G 0 p2 in diactllsulfoyde).

   Ultraviolet spectrum À ìli 0.1 N 220 m ¯. 7. 900); Hal 011 117 270 np (E = 15,000): α- H2O 234 bare Max rax 21.SOO); h, ± j ± e? 6.5 (\: ..)! 3 OH 0 1 N 7: .11 5 21,500); 276.5 rag (. = 13,800); 1234.5 rig (S = 23,100); 9'Ej 0 tel 1 '. 77 mil (... = 15 "ooo)" CE) We heat for an hour and a half in a water bath
 EMI30.5
 boiling a solution of 1.5 g of 4- (5-ac2tawido-6-anino-4pïriin; :: "io) -4-deso-2, -t-isopropylidene-D-erythronzic acid in 15 ml of normal solution of sodium hydroxide.

   The reaction mixture is left to stand to cool, neutralized with normal hydrochloric acid, then condensed under reduced pressure to a third of its volume. The precipitated crystals are collected by filtration and washed with some water,

  <Desc / Clms Page number 31>

 then with methanol, which gives 0.7 g of 4- (6-amino-8
 EMI31.1
 ¯; tiylpurin:, - 9-51-4-deox-2,3-0-isopropy3idènv-D-erythronic.



  .Melting point:: b5 C (with deconposition).



  (1) To a solution of 560 g of 4- (5,6-dia! Nino-4- 5 piri;: .. idi: Jyhmino) -4-deso: h.-y-2, 3- 0-isoprop; lidènc-D-erythronic. in a solution of 180 Qg of sodium in 0 nl of ethyl alcohol, 1 ml of carbon disulfide is added. The mixture is heated under reflux for 4 hours. Ethanol is removed from the reaction mixture under reduced pressure. A little water is added to the residue and the aqueous solution is adjusted to pH 3 with dilute hydrochloric acid. The precipitated crystals are collected by filtration and washed.
 EMI31.2
 with methanol to give 650 ng of 4- (-anilio-1-nercapto-9H - pure i na-9- 1) --d, soy-2 'j-0-is oprop acid. 1 idên c -IJ-c: r thron i çue.



   Melting point: 203 C (with deconposition) -.



  (J) A solution is heated under reflux for 3 hours
 EMI31.3
 1.1 g of acid - (2-ch3oro-5, G-diawino.-ETirit.3n.l..i.no) --- deoxy-2,3-O-isoprcpylidèna-D-crythronic in 5 l of fornic acid. Fornic acid is removed by distilling it under reduced pressure. 14 ml of normal sodium hydroxide solution are added to the residue.
 EMI31.4
 and heated under reflux for 7 hours. After cooling, the reaction mixture is adjusted to mp 2.5 with hydrochloric acid. The precipitated crystals were collected by filtration, decolorized with charcoal powder and recrystallized in water to give 670 zig of 4- (c-hydroxy-, yf-airo, pugine- acid. 9-yl) -4-deoxy-D-e.nythronic. The melting point is above 300 C (with decomposition). Spectrum in 11 µltr-violet: H-0 245.5 [, ljJ.

   (Z = 6,200), 289.5 I: ljJ. (z = 10¯900); 7- .. hCx: l 0.1 N 234.5 n C = 5.5duo), 2s3 mu (¯ i3.4.o0; h NaOH 0.1 N "48 Ep (t. = 6.200), 286 my ( '- == 10.600).



  (K) Add 4- (2 -: -. Drox -, y-5-foraeido-b-sïno-4-psrii.dix., - lG :: airo) --- de so - c, 3-O-is ogroplidèno-D- ry thronique prepared from 1.1 g dlzcîdc - (2-cr7.oro-5, b-d3.air¯o ---- pynimidinyl == aino) - 4-dàsoxy - &, 3-c-isoprop3 "lidèr-eD-ewthronîgue and 5 ml of fornic acid, to 14 ml of normal sodium hydroxide solution and the mixture is heated under reflux for 7 hours.
 EMI31.5
 After cooling, the reaction rate is adjusted to mp 2.5 with hydrochloric acid. The precipitated crystals are collected by filtration, decolorized with charcoal powder.
 EMI31.6
 and they are recrystallized in 3cu which gives 670 vg of acid = + - {2-drox3 - b-ainopurina- I-4 - deox-ü-.t: rhythmronic.

   Point da

  <Desc / Clms Page number 32>

 
 EMI32.1
 fusion greater than 30Ole (with decooposition).



  (L) A mixture of 0.5 g of acid --- (5,6-diïno-4 pyri: idiriylsina) - dwsox is heated for vs úÍ! Jut6S in an oil bath, between 170 and 180 C --f, 3-ü-isopropylidene -. û-rhythmronic and 0.41 g of urea and a small amount of 93% ethanol is washed. Excess urea is removed and the substance is dissolved. insoluble
 EMI32.2
 dens a small amount. of water. The aqueous solution is adjusted to pi
 EMI32.3
 3 with 10 50 hydrochloric acid, to ensure crystallization. The crystals were collected by filtration and washed) with 3 'water to give 150 µg of 4- (6-a :: acid. ino-3-hydroxypu, ri.; e-9 yî) - dsa, yBt: r,; tthron3qE. Melting point: 215 to 217 C (av-: c dcposition). & p.ctre in ultraviolet fi 0 210 r = p, 270 mp.



  In a similar fashion, the following coiposents are obtained nethyl 4- (6-3sinopuri3e-9-yl) -4-desoxy-D-crythronate (Melting point: 231 C, with dLco-laying); i - (6-s.inapurine - yî) -4-dsc-D .-. rytî3rancta of ethnicity (Melting point: 159 to 1: i C3 with decomposition); - (6-aciaaopu # ine-9-yl) - 4-dàsoxy-D-éij'thronanide (Melting point: 264 to 268 * Cl with decomposition); 4- (6-> ci.a ---. t?, plpur.ne-9-yl) - âso: -D-.r3tbroniaue acid (Melting point: 211 C, svec dcposition); --- {6-3.ino --- rercaptopurine-9-yi) - = - d.sor-7-rytironic acid (Melting point: 65 to 2b8 C nvoc decoiposition); 4- (6 - t: âinopurine-S-? 1) --- dsaxy-, 3-G-isopra pylzdn-I3 -: methyl rhythmronate (Melting point: 180 to 181 C) acid 4- (6 -sinopurin-9-yl) -4-d6soxy-2,3-0-bcnzylidene-D-erythrûniqua (Melting point: 198 to 19 ° C, with decomposition);

   4- (è-r = ina-6-rdrcxypurinc - y1) - deox, -t-Erythronic acid (Melting point: 223 ° C, with decomposition); 4- (6 hydrourin-9 yl) - + dàsoxy-Dorythronanide (Melting point: 247 C, with deconposition); 4- (ô-et% <larinopulin-9-yl) -4-esoxy.-D-erythro = 1c (Melting point 242-24-Cl with decomposition); 4- (6-di6thyleninopurine-9-yl) -4 * -desoxy-D-erythronic acid (Point of
 EMI32.4
 hydrochloride fraction: 187 C, with decomposition); 4- (6-hy- acid
 EMI32.5
 draxy: .inopurinc -'- yl) -4-d; saxy-D-: rrthroniçue (Melting point: 206.5 C, with decomposition); 4- (E-benzylzninopurme-9-yl] 4-dsoxy-D- & rJthronic acid (Melting point: 206-2U6.5 C, with d composition); cido w- (6-benzoylacinapuri.ne-9-yZ) - + - tosoxy-D-cx9 thronic (Melting point: 232-235 C, with decomposition);

   acido + -. (G-aainapurine - 9-f1) - dsoxy-2'j-ü-diectyl-D-rhythmroni c (Melting point: 25b C, with decomposition); 4- (6-Ji, inopu-

  <Desc / Clms Page number 33>

 
 EMI33.1
 rine-9 Sl) -.- desa-2,3-.0-diacetyl-B-erytbronate methyl (Melting point: 228 C, with decomposition); ccids 4- (6-hydroxypurine- -yl) 4-dcsoxy., 3-U-d.z.acetyl-D-erythronic (Melting point: 10e, 5-189 C, with decomposition); 4- (6-eninopurin-9-yl) -4-deoxy-L-threonic acid (Melting point: 291 to G33 C with decomposition); 4- (6-hydroxypurin-9-yl) -4-desaxy-D-erythronate of e-
 EMI33.2
 tbyle (Melting point: 212 C, with decomposition), acid 4- (6-
 EMI33.3
 Qercaptopurin-9-yl) -4-deoxy-D-erythronic (Melting point: 24c C, with decomposition):

   4- (6-Methylthiopurin-9-yl) -4-) deoxy-D-erythronic acid (melts at 85 ° C, solidifies at 9 ° C and decomposes at 260 C); 4- (purin-9-yl) -4-deoxy-D-erythronic acid (Melting point: 230 C, with decomposition); N-etl] yl-4- (6-adinopurine-9 yI) -4-deoxy-c, 3-0-isopropylidèno-D-erythronaraide (Melting point: 1? 8 to 1? 9 C, with decomposition) ;

   I-eth, yl --- (6-air3opurine-9-y1) -4-deoxy-D-erythronaIilide (Melting point: 166-1680, with decomposition); i3, RT-diê ty3-4- (6-aainopurine-9-yl-4-deoD-erythronamide (Melting point: 192 to 193 C, with decomposition); acid 4- (6-ethyleninopurine-9-yl) - 4-deoxy-2,3-isopnopylidene-D-erythronic acid; 4- (6-nGthoxypurin-9-yl) -4-dfsoxy-D-erythronic acid (the sodium salt forms vesicles between 168 and 170 C and
 EMI33.4
 stains between 220 and 230 C with formation of vesicles); 4- acid
 EMI33.5
 (2,6-dihydroxypurine- <;; - yl) -4-deoxy-D-erythronic (melting point: 204-206 C, with d, 5composition); 4- (2-Cethyl-6-aninopurin-9-yl) -4-deoxy-D-erythnonic acid; 4- (6-Butyrylaminopurine-9 yl) -4-deox.y-D-erythronic acid; 4- (6.8-3ihydnoxypunin-9-yl) -4-deoxy-D-erythronic acid;

   4- (2,6-Diewinopunin-9-yl) - 4-deoxy-D-erythronic acid 4- (6,8-diaminopurine-5-yl) -4-deoxy-D-erythronic acid; 4- (2 -eminopurin-9-yl) -4-esoxy-D-erythronic acid; 4- (8-eninopunin-9-yl) -4-deoxy-D-erythronic acid, etc.



  E: -: .e! :: pl z 2. - (A) To a solution of 3.13 g of 4- (6-aLxino-5-nitro-4 pyrimidinylamino) -4-deoxy-2 acid, 3-0-isopropylidene-D-erythronic in 45 µl of 90% fornic acid, 0.4 g of 10% palladium carbon is added and the mixture is subjected to ca- hydrogenation.
 EMI33.6
 talytic. Once the reaction is complete, the catalyst is removed by filtration and the formic acid is evaporated off under reduced pressure. The residue is dissolved in water and the solvent is evaporated off under reduced pressure. A small amount of water is added to the residue and the precipitated crystals are collected by filtration. These crystals are washed with methanol, which gives small columns

  <Desc / Clms Page number 34>

 
 EMI34.1
 deoxy-D-erythronic. Melting point .279cl (with decomposition).



  Amsoniuc salt: melting point 265 to 26? C (with decomposition).
 EMI34.2
 



  Sodium salt: melting point 272 C (with decomposition).



  The following compounds are obtained in a similar manner:
 EMI34.3
 Methyl 4- (6-aninopurine-9-yl) -4-desox, y-D-xthronae, (melting point: 231 Ci 4 with decomposition); Ethyl 4-C6-aminopurin-9-yl) -4deoxy-D-eryth-onr-to (fusal point: 359-160 C, with deconposition); 4- (6-aninopurine-9-yl) -4-deozy-D-erythnonsmide
 EMI34.4
 (melting point: 264 to 268 C with decomposition); acid 4- (2-
 EMI34.5
 0 methylthio-6-eminopurin-9-yl) -4-dscxy-D-erythronic (melting point: 249 C, decomposition); - (-. e.inopurzne-9 y3) -4-deoxy-2,5-0-isopropylidene-D-orythronic acid (melting point: 214 C, with decomposition); Methyl 4- (6-emi, iDpurin-9-yl) -4-deoxy-2,3-0isopropylidena-D-erythronate (melting point: 180-383 C, with decomposition);

   4- (6-3Binopurin-9-yl) -4-deoxy-2,3-0-benzylid, -ne-D-erjthroniqui.- acid (melting point: 198-19C, with decomposition); - (6-ainopurine - yl) - 4 - d: soy-, 3-4diacetyl-D- "7rythro - ic acid (melting point: 2.5t C, with splitting); 4- (da ? nopurzna-9-Yl) --- deoxs-- 93-0-dicêt, 3-y-erythro-) nste, methyl (melting point: 228 C, with dcoaposition); acid 4- (6-aninopurine-9 -yl) -4-deoxy-L-thrjonic (melting point: 291 to 293 C, with decomposition); N-ethyl-4- (6-atiDopurin-9-yl) -4 - dsso-2,3- 0-isoprops3idene-D-4ryt: .. ronaid (melting point 178-1? SC, with decomposition); N-dthyl-4- (6-aniLurine-9-yl) -4-deoxy-D-5rythronewide (point fusion: 3joz at 168'0, with decomposition);

   IIIF-diet: .3 .---- (6-ainopuri.ne-9-ï) - desoy-D-erytbronaQide (melting point: 192 to 193 C, with decomposition); 4- (6-bydroxypurin-9-yl) -Y-deoxy-D-ezy + hronic acid (sinter at about 85 C, swells between 100 and 105 C, then melts around 185 C); 4- (2-ami-no-6-h.7d: roxZ-purin-0-yl) -4-dbsoDy-D-emythronic acid (melting point: E1'3 C, with deconposition); Ethyl 4- (6-hydroxypurin-9-yl) -4-deoxy-2,3-0-discetyl-D-erythronate (melting point: 1c38.5-189 C, with decomposition); Ethyl 4- (6-hydroxypurine '-3) .- 4-desax ,, -D-.erythronate (melting point: 32 C' with decomposition); 4- (6-bydroxypurin-9-yl) -4-deoxy-D - erythrorsaide (melting point: 247 C, with decomposition); 4- (6-year> o-8-5Tdkoxypurine-9-yi)> Bdessxy-Deryllronic acid (fusic point: 215-217 C, with decomposition);

   4- (6-Ethlaznogurino-9 r3) - # - desoCF-2,3-O-isoFrapslidnc-D. ertironic acid; 4- (-mety3-6-aaincp.rrin-9 3) - desoxy.-I3-.êrr truncated acid; acid -

  <Desc / Clms Page number 35>

 
 EMI35.1
 (2.37 g) 4 --- (6-anino-5-forarido-4pdrid.ir3.ac-dcsoy-D-erythronic acid. Melting point: 190 C (with decomposition). Heat for 10 minutes. in a boiling water bath a solution of 0.50 g of this acid in 5 nl of normal hydroxide solution
 EMI35.2
 5 sodium. After cooling, 5 ml of normal hydrochloric acid are added to the reaction mixture. The precipitated crystals are collected by filtration and washed with water and then with mete.
 EMI35.3
 th3nol'Y which gives 3.5- g decides - {.- O.inopurine-j yl) -4-cesoxy-D-erythronic. Melting point: 2 fl5.

   C (with decomposition 0 (ci 25 = + 30 (C = 0.93 in the. -. '= "Thylsulfoxide). Spectrum in the ultraviolet: 7 g2x 261 mu (1 = I4. -F OG. 3oniuQ salt: melting point 265-267 c (with decomposition) Sodium salt: melting point 272 C (with decomposition).
 EMI35.4
 



  (B) z a solution of 1.0 g of 4- (5-aQino-5-nitro-5 4-pyriridiny laLino) -4-deoxy -., 3r-isop, ropylidene-D-erythronic2 acid in 10 ml 98% fornic acid is added dropwise a solution of 1.5 g of sodium dithionite in 5 ml of water. Once
 EMI35.5
 When the addition is complete, the 13ng is heated under reflux for one hour. Fornic acid is removed from the reaction mixture by distilling it under reduced pressure. The residue is dissolved in water and the solvent is evaporated off under reduced pressure. 10 ml of normal sodium hydroxide solution are added to the residue to make it alkaline, and the solution is then heated for 10 minutes in a boiling water bath. The reaction mixture is condensed to half its volume and allowed to cool.

   The precipitated crystals were collected by filtration to give 0.12 g of 4-
 EMI35.6
 Sodiun (6-aninopurine-9-yl) -4-deoxy-D-erythronate. This substance is dissolved in water. The aqueous solution is adjusted to pH 3 and the precipitated crystals are collected by filtration, which
 EMI35.7
 gives the 3cidc 4- (6-e: ix <opurine-9-j; 1) -4-esoxj, -D-erythronic. (Melting point: 279 C, with deconposition).
 EMI35.8
 



  (C) A solution of 6.1 g of 4- (2-aL.ino-5-nitro-6-h ;, droxy -; - pyrinidinylanino) -4 - deox, y-2, 3-0-isopropylidene-D-arrytonic acid in 120 ril 98% fornic acid, 0.5 g of palladium black is added and the mixture is subjected to catalytic hydrogenation at room temperature and atmospheric pressure . After absorption of the hydrogen gas has ceased, the catalyst is filtered off and the filtrate is refluxed for one hour. Fornic acid is removed from the reaction mixture by distillation under reduced pressure. We dissolve the

  <Desc / Clms Page number 36>

 residue in a little water and the solvent was removed by distillation under reduced pressure.

   The residue is dissolved in 90 ml of solution
0.5 N sodium hydroxide the solution is heated to reflux for one hour and condensed under reduced pressure to about 5 third of its volume. The concentrate is acidified with dilute hydrochloric acid and let it rest. The precipitated crystals are collected by filtration, washed with water and then
 EMI36.1
 they are crystallized in water to give 1.45 g of + -t2-aino --- hydroxuria-; jl) -D-zrthroniue acid. (Melting point 0.223 C, with decomposition. Ultrz-violet spectrum: /. 2233!: 1J.l {f = 32.t-Ut3) 3r '' "270 mil (.. = 9.100) ; / - izaoh 0.5 Ii & 70 DJl (¯ 10.600). À. Hel 0 5 t 25: rj (1? .tOU); ¯ ax '5 280 z ( <c = 7,900).



  5 (D) A solution of 2.5 g of --- (nitro-6-a ii-. Ne --'- t-pri? Idßn3.no) --- dsov -, -, 3-0 is subjected -dibenzol-; ¯thrt> ethyl onate in 40 ml of fornic acid at 90 mlcataly hydrogenation
 EMI36.2
 tick in the presence of pallcdi6 carbon, at cmbianteg temperature after which it is filtered to separate the pallaid carbon. Condensed.



  ) the filtrate under reduced pressure and 45 ml of solution are added to it
 EMI36.3
 normal dl !! Zrdrox¯; 7de of sodium and -5 ml of ethsnol. The lite mixture is heated under reflux for 30 minutes and then condensed under reduced pressure. the residue is dissolved in water and the aqueous solution is adjusted to pH 3 with 10% hydrochloric acid. The precipitated crystals are collected by filtration and washed with
 EMI36.4
 with c0u, then with: c: t4t. ethyl, which gives 0.54 g of lT- (6-aznosurz =: L-9-1) - cso: y-1-t3 oniue acid. -Melting point: 291 to 293 C (with decosposition) after recrystallization teeth acetic acid at 10. [aJ5 = g j 9 0 (C = 0.505, dÍilltrlsuif oxide).

   Ultraviolet spectrum: / - 2262 QJ.l (1 = 14.6oxo); / Hel 0.5 1: i 2 ..... - ', (::: - 14, zoo>; /, NAOH 0.5 2 "" 2 5 ...... (F Max 260' - Jl 14.200 Max '4- 14.500).
 EMI36.5
 



  (E) We submit to a <a c # t hydrogenation, alytiqle a solution of 2.4 g of lt --- (5-.nitro-6 - :: tho-3 ---- pyri.iâinyl: ino) -4-- deoxy acid -D-erythronic in 60 ml of 9G% fornic acid in the presence of 500 mg of palladium black, after which it is filtered to separate the palladium. The filtrate is refluxed for 2 hours and the fornic acid is removed by distillation under reduced pressure. 25 ml of normal solution of hydrogen are added to the residue.
 EMI36.6
 sodium droxide and the mixture is heated 3u reflux for 30

  <Desc / Clms Page number 37>

 
 EMI37.1
 1nutcs. After cooling, the reaction mixture is absorbed on 400 μl of resin Jchamgouse d'ioss ..: brliL IRA 400 ", type OH) and the resin is washed with emu until the liquid at-e 1 = age ksi.:L Dcutr-3S.

   The obtained elust was combined with 0.5% fornic acid, to give 1. 1 g of solid product; it was recrizt311iBc dOLS from isopropanol to give lucid 4- (6 - idroypurin-9-yl) - ': sca:; xy-ï3 - kythron. This sintered substance about 85 ° C., 11 swelled: rx: 1Da and 105 C, then it melted around 185C.



  0 It gets una> .e.â.r; si = .il3ira the conposts E1ivan1 ;-( 6 - n.insuri <:: - .-- = g. , ¯, g., - wr¯, 'srrx: te dl .: = ï.s (Melting point: ï 231 "C, ai =; <= fq.G '$ 5cß.tâ' $ ± -. ß = .I3.é: ^, --tc: r j, "" - e b, v dthyl. (Point -'1 melting: 159 to 160oC with:; ßi;: 3.sm;> 'N - =. I: -: .m> yl = - fr.ç w - D- rthrcide 5 (Point ., t ... iIvâ i> 'jiJ. a 1 ± j, C,' y '.;: c ,, c:. "" 33 ^ ""' ,. '. rl'i's's%' '! ci .de 4- (6- 5'¯: ".:. tr 'a-: a: T': ,,, -; x ..... kg ^ a. ± 'ß.'â i:, , -: f, .. a :; "'& M.xis .. -." g'kiqr' .C "9.Ti. ô '", merge r: 81 Or ";., 7 ic {:' I; O: 3ition); c1tl l; .. (6 - ,,: .i ,, p? Ri-9 "-yl) -4-dsox: j 2-Xv '.. opr; e' ..: "t ': ^ ¯ :. Z"' P''on: E3.'àiC "e.s'.2.ic3 '.;:"': sio! 1: z14CC, .xv, .c;: - ..cs .t.:, j; 3.¯, .. âcp.'ix> .-.: a ..: 3: -:, .. ¯¯.

     .-. û> isopropyli-) dèLe-D- / Erythron # 1: o du;,.: thylQ (the fusion anoint: 1 ± 0 at 181 C, f, .V " <decomposition); t.lci1v g .-- i.> s -.- = rl - purîn; --- yL, -. soxy- 3-c - isopropjli.3n: -: ..- r .: vtYErrrk.e : T (Melting point: 25 "C, av; 1.: co :: position); 3cidc 4 - (; - wiâ, e: .- 9-yl) - dsoxy., 3; -benz lidéne-D -ér3Khrc 1:> ù (Foixt, le iu- = 1? n 195 to 199 <:;, 8with decor.



  > position); acid ¯t; > -: F; .ri r-5- â; is - ,; L sox - :. rythroni? uc = '3.s.rt 1: -rt ":.; n" "..- :: 15cC- <', .gs. 3, ¯'. .r% 'e-.4¯-z.n' $ ¯ ¯¯ to. '. . ¯¯¯¯¯¯¯ ¯ hydroxypuri: -; -.,, -...: ¯ ",:., =, .. u:, 01.r.:" 'C fusion 23 C, s? cc d ± CC: lposition, 4 - (E-Ej-iiroxxyp; rin-9-yl)> wd3soxy-Dai "'.'. iGT ::. dC- (Poist ..k .t'1151on: 247 ( ;, yvcc c, 'r.erCG.' ^ O. '.' '.. C' ". a se1i ¯. .-. m; 4l: ^. i ::; m1. ^ c-'i1; - .-dsos.D-ryth.oniu9 (oist of fi sion: é4Z at 43 C, c '? ec' rwt3ï: hydrochloride of the acid <, a - (.;,; i: - ,; r ... i.ntxri.> '- yl) -4-as, ..; .- â:' r r'-sic (Zion point: 167 "c, VçC dcs: ro.3n; scide 4- {6-hyçlroxyciDCpurin 6" s' - +? :: 7c: 'fi.a "" - i'a'ï' é = s.It {Point de fusion:

   G "6I'L. ' g 6r: #ii of composition); zcido .s¯ (6-beryl, i "pure - r .--; ... = s-drythrosique (Melting point 206 to 06, .5" C., with decc =: positiOB); rcidc 4 -.-- 'nr, r-icincpuri. s- = l) -; so-D-ery'onique (Fusion po: 232 to 235 C9 nvec cia; si. acidg. + - (6 - = - ninopurine-9-) -} sox, -t-diàt 3¯tz'c.cuc (Melting point: 50 C, 3Vec ao :: ts.'GS¯:; 4- ( e - inopurin -> yi) -m.

  <Desc / Clms Page number 38>

 
 EMI38.1
 w ms s methyl 2, -o-diacety1-D-erythronaG (Melting point: 228 * 0 with decomposition); Ethyl 4- (6-hydroxypurin-9-yl) -4-deoxy-2,3-0-diacety3-D-ciythronate (Melting point: 188.5 to 189 * Gl with decomposition); 4- (6-Aciinopurin-9-yl) -4-dssoxy-L-threonic acid (Melting point: 291 to 2930, with d: coposition); Ethyl 4- (6hydroxypurin-9-yl) -4-dsoxy-D-arythronato (Melting point: 212'0, with decomposition);

   4- (b-Eierc3ptopurin-9-yl) - 4-d: soxy-D4rythxenic acid (Melting point: -. 240 ° g with decomposition); 4- (6-methylthiopaxrin-9-yl) acid> Pàesoxy-D-enythroniqe 0 (Melting point: 210 C, with decoaposition); 4- (purin-9-yl) -4-deoxy-D-erythronic acid (Melting point: 230 ° C, with deconposition); i3-etn = p1-4- (6-arixaopurine-9-yi) -4-3aoxy-2,3-Q - isopropy = lidene-D-erytbronmzide (Melting point: 178 to 179 C, with decomposition);

   I-é.hy3 --.- (6-aznopur.ne- yi) -4 deoxy-D-êrSth..Tonsa; of 5 (Melting point: 166 to 168 C, with d, com-posîtio9, â3I- -disthyl --'- (6-ainopurine-9 - yl) -4-dssoxy -D - rytronas id.e (Melting point: 192 to I93 C with decomposition); acid :-( 6 - et33a! inopurine-9y3) -t - de so: y-2 3-0¯? sopropy lidene-D.-ë-, thron3 ue; acid 4- (6-amino-8-hydroÁurin-9-yl) -4- d0soxy-D-erythronic (Melting point) 215 to Ô17 G, with decodosition); acid "- (z- = ethyl-6-aminopunine- YZ) -4-deox-D - t'sryth.ron? āuc; cide -. ('- diY..yâxox, ypurine-R 5 '1) - + - desaxy - D-4rythroriquc; 4- (6,8-diesinopurine-9-yl) -4-deso-xy-D-erythroniql1e acid; 4- (2-aQinopurin-9-yl) acid -4-deoxy - D-erythro-
 EMI38.2
 picnic acid; acid
 EMI38.3
 i that '(Melting point: 204 to 206 C, with decoctposition); acid B (6-butynylenino- - = .., - :: - -:.: ..;

   '...: ..: ---- .. :: -: "¯ -': '= ---- ::"' 3--8 -.:.....- - -: ' o "" -. ",, -: ...... ¯ ..-: ;;:; .-" ': a1 ... ,, i 3i-éso-y -: - sxâ-rronque etc. Example 3 '(4) A solution of 500 mg of 4- (5-ac! ino-4-cy3no "l-isidszolyl) -4-deoxy-D-erythronic acid, dnms is heated under reflux for 3 hours. 5 ml of aliethoxyuetbyl acetate After cooling, the solvate is removed by distilling it off under reduced pressure The residue is dissolved in methanolic ammonium hydroxide.



  The 50: 11.1. :: "" "; - 1 was left to stand for 24 hours. The ethesaol was removed under reduced pressure and the residue dissolved in water. The aqueous solution was adjusted to pH 3 with water. hydrochloric acid at 5%. The
 EMI38.4
 precipitated crystals and washed with water, then with
 EMI38.5
 .êtro7 which gives 130 ng of acid t -, .. (6-.ainogu, re- î) - ¯ ¯

  <Desc / Clms Page number 39>

 
 EMI39.1
 (6, $ - 3il, ydrōurïnc - ïj-4-diso-D-trythroacue; 4 # acid (2,6dis: inopur.ne -? - ï) -: - deox; rD-cr3 = throniue; ecide 4 - (- aminopurine-9-: yl) -4-déscx¯, yD-erythroniqua; acid 4- (8-3Eiinopurinc-9-yI) -4dsoxy-D-Órythroniquo3 etc.



  5 Example 4.



  (r) to a solution of 1.35 g 18dic QSLS 25 ml of diGethylsulfoxyë0 is added 094- g of sodium hydride. Mix for an hour at tempônturo Tcbicnte, then at 5 :? :; during 30 minutes. Solange 1.58 g of ,, 3-0-isopropl¯ 0 idene-D-èr - thronc 1 actant is added and the reaction mixture is stirred at 120 (for 20 hours. The eimetbylsulfoxide of the reaction mixture is allowed to be stirred. by distillation under reduced pressure and the residue dissolved in Ilecu. The aqueous solution is washed with Thor and the aqueous layer is adjusted to pH 3 with hydrochloric acid.
 EMI39.2
 5 that, then In let stand. Precipitated crystals were collected by filtration and removed from 11eu to give - (6¯mi.sopuriü - yl) --- â.so -, - isopropylidene-D-r; ¯ acid.

   On the one hand, 10 filtrate is condensed under reduced pressure and the residue is trr-ito = with esu, which gives the same substance as that which was obtained above. J., E: nd61 ::: C: Qt: 3} :.



  Melting point: 211t- G (with dicom-Dosition) after recrystallization from 50% ethanol (B) 0.96 g of sodium hydride is added to a solution.
 EMI39.3
 2.7 g dsns -5 r-1 adeniria of dia6thylforffiami. The reaction mixture is stirred at room temperature for one hour, then at 50 ° C. for 30 minutes. 3.15 g of
 EMI39.4
 2,3-0-isopropylidene-D-erythronclsctone. There is thus obtained a mixture which is heated under reflux for 8 hours. We evaporate the di-
 EMI39.5
 methylfor'npiEide under reduced pressure and the residue dissolved in water: The aqueous solution is washed with ether and neutralized with hydrochloric acid. The solution is condensed under reduced pressure.

   The residue is treated with water, the precipitated crystals are collected by filtration and dried.
 EMI39.6
 gives 3.4 g of - (S-2miepurine-9-3) --'- dcsox-, f-0-isopTopwlidene-D-erythuonic acid. : Melting point 214 C (with decomposition) -. On the other hand, the filtrate is condensed under reduced pressure and the residue is treated with water, which gives U.44 g of the same substance as the glue obtained above. Yield: 65.5% (C) A solution is heated under reflux for 6 hours.
 EMI39.7
 of 1.3 g of adenine, of 1.5 g of c ::::, 3-0-isopropylidne-D-rhythmro: '! o-.

  <Desc / Clms Page number 40>

 
 EMI40.1
 



  Isctone and, 7 g of potzssiua carbonate in <S al of d3.thylfor3iQ. un treats the reactional alznge, brow co8Ze '.' $ X2T: ple '!;' (. 6) which denotes 0.6 & g of acid + - (@ ninop.urine-5-yl) -4dis-, 3 --C-is: propylidr: -. Ic: rytn, roniçuL. Melting point: 5214 C (with decoaposition). Yield: = 3U CD), A suspension of 151 g of dna, -1-ode, from to, is heated under reflux for b hours, with stirring. <1 g of. ::, 3-isorop lidènc -.-. Rr LL.roelûctrie and this L, 38 g of ca rbcnate of potassina in 5C al do dz, ahlfor3; ido. The diID:; tb; y1.foraü- 3 is eliminated using Solange r ..; actiol1! L {; l by distinction under reduced pressure.



  The residue is dissolved in a small quantity of water and a solublo sucs4vzce is removed by filtration. The filtrate is adjusted to p .3 ::: vc d l * 3cid chlorh3, at b, ¯0 We collect by filtration the crystals #i <: CiJ? vs'-. ïsy C3 which rJT ::: 0, O g of ..- c. ¯'ïI30-J-3-C3T- 5 box-e, -isor roplzErec..p¯ep1) .uriß; l-ox "-de. Melting point at 7 '= c (with dco = .positio3 after rcrist31listioD in of 'Géthanon.



  (E) Heated [or refluxed for 1 hour, in the egit2n't, a suspension of 1, bl g of; inzne-1-ox ;; - of, of, 1 g of, 3-iso-) .f, roP: 'ïliè.t.rl - :: - I: -, n'Ythro ::::: o13ctonG and 1.06 g of sodium carbonate d "ns 50 ni di:.;", -t;: YUorr: .. '1! 1Íde. 01J tr :: i te le mJl, .1n; c r + <? ctional co:;: c ;;: t1 of 1DS 1? atî: LC. 4 (D), which gives 1.10 g of J-c <inc-9 - ("- car- -ox; --c, 3-ïß o ro.î .dn;: ak rop 1) - porïn: -.- o de. oznt of fusion. é fl (' 7.; C .j, 'co. ;;. R.osi:, i0n);' pr's rbcrist llisption in methst col.



  (r),.; heat at lJW'C for b hours, stirring it, iina ::,; sr, .msio: 1 of 1 ,,;: .. 1 b '9:' r¯ <! f, Tl = ¯'- CXG ', from <- :, <1 g of, 3-isop, "! J'pylit'nû-D - '': ythr (1;: l ') l - :. cto :: ï. (Qt (1c 1, C6 g of c ;;. rbon: Jte of sodium d:> ::: 1s 5 <J ni 1 d ..: 1iLl: tl1; 11s'ÜtoXJ-'d0o We trsite the t: 1 '; lntrc ractioDnel, co. ; '-,.,; <1, nx- 1 'e ;;;:' ': 4plc <4 (D) t C2 which è ..:;. Nre 1,) 0 g of 6 - *; ino-b- (àc: z tcxy =, -is.r.roryli: Fnooxyropyl) -vurine-'1 oxide. Melting point 4 {O "C (-3VM: d8CO.:;position) 3pres recrystcliis * ion in ntb.noi.



  (G) Q = heat at 160 C for 1 hour, while stirring, uno si.spens1on d: J 1.51 g of adeninc-1-oY = .de, 2.21 g of 2.3- isopropylidènc-D-crythronol'ictone ec 1.06 g of sodium carbonate dsos 5l \ Ctl Je d: t, y? : catceada. The reaction mixture is worked up co ::::, ') d \ :. s 3': x,:. O 4 (D), which gives 0.00 g of 6-D.Qino-9-C5c '; rbo}: J'- ", j-iG01", r'ol'ylidéncoxypropyl) -purine-1-oxy? -e. Melting point i0.,; (with decomposition): near recrystallization from

  <Desc / Clms Page number 41>

 methanol.



   H A mixture is heated under reflux for 24 hours.
 EMI41.1
 of 1.63 g of 2,3-O-isopropylidene-D-erythronolactone and 1.06 g of sodium carbonate in 32 ml of diet formamide. The diwetbylforceLide is distilled off and more is added. water in the residue. An insoluble substance is filtered off and the filtrate is neutralized with 7.3 ml of 10% hydrochloric acid and then
 EMI41.2
 concentrate to give 4- (6-ethylaginopurin-9-yl) -1F-deoxy-2,3-0-isopropylidene-D-erythronic acid. This substance is then subjected to transformation into 4 - (- ethylaminopurine-S-yl) -soxz-.7-r; threnic acid. Add 50 µl of 10% acetic acid to the substance, reflux for 30 minutes and concentrate.

   The concentrate is adsorbed on an exchange resin
 EMI41.3
 of ions ("IRA 400", type 03), the resin is washed with acic acid, 0µl, and eluted with acic acid 0.5l. The elust is concentrated to give 0.56 g of acid - (6-ethylaminapurine-S-: 1) -4 - dcsox.1-D-4r; vhrcniquß. Melting fo3nt 242 to 2430 (with decomposition) after recrystallization from ethanol. Sp0Ctre in ultj - violet / À ... n20 269! Il1 (= = 1? .4do). (I) Heated under reflux for 19 hours, with stirring,
 EMI41.4
 a mixture of 1.35 g of 4denine, 2.69 gd: bnzylidene-er thronolçctor8 ct 110C g of sodium carbonate in 50 ml of dineth; y) fC'1 .. '1 ¯, .Mid . . 0'-: 7 -tcWrf 10 di. ^ ¯tiiforL :: .. ide by distilling it svu: pressure r :: - i-e. The residue is dissolved in 20 μl of water then 5 gold:; Í l t; L'0.

   Now: jz .--; te the 3-fold filtrate with 2U ml of hydrochloride acid. Il '' - 'ilor¯'C'L The precipitated crystals are collected by filtration:' 1tioD, they are treated with charcoal powder and recreated
 EMI41.5
 Telilised twice in hot 8 & thanol, to give 4- (6-2zazsapurine-9-y 1 d-4-de soxy- '', 3-0-benzylidene-D-erythroraic acid.



  Melting point 198 to lb9 C (with deconposition). Spectrum in ultr-3-violet: 7% O 261 mil. (J) Heat at reflux for 19 hours while stirring.
 EMI41.6
 so much, a mixture of 1.51 g of adenine-N-oxide, 2.89 g of benzylidene4Ithronolactone and 1.06 g of sodium carbonate in 50% of dim6ethylformamide. The dinethylforoeamide is removed by distillation under reduced pressure and the residue is dissolved in 20 ml of water. The solution is filtered and the filtrate is neutralized with 20 ml of normal hydrochloric acid. The precipitated crystals are collected by filtration and recrystallized in the hot state from
 EMI41.7
 r. ethanol to give 4- (6-a8inopurinc-9-yl) -4-deoxy- acid

  <Desc / Clms Page number 42>

 
 EMI42.1
 1, 3-O-benzylidene-D-erythronic. Melting point 198 to 199 ° G (with decomposition).

   Spectrum in ultra-violet: TE2 261 mil.



  (Ii) A mixture of 1.35 g of adenine, 27 ml of di-methylformanide and 01.84 g of potassium hydroxide is heated at 120 ° C. for 30 minutes, then at 14 ° C. for 10 minutes. . To this mixture are added 1.90 g of 2.5-O-iso-propyliden --- D-erythronolactu in 5 ml of diaethylformamide and the mixture is heated under reflux for 18 hours. The hydrochloride is removed by distillation, water is added to the residue and a substance is separated off.
 EMI42.2
 0 soluble. We adjust the diaper <3gueu "p: d 3 with 10% hydrochloric acid and then concentrated. A small amount of water is added to the residue and the crystals are collected by filtration.
 EMI42.3
 precipitated to give 0.73 g of - (6-aminopurin-9-yl) -4dcsoxy-2,3-0-isopropylidene-D-erythronic acid. Melting point: 214 C (with decomposition).



  (L) A mixture of 1.35 g of adenine, 20 ml of dimethylforoarlide, 1.58 g of 2,3-G-isopropslidene - D-erythronolactoye of 0.75 is refluxed for 2 hours. g of cesium fluoride. The dicthylfora 3 is evaporated off under reduced pressure, the residue is dissolved in water and the insoluble material is separated.



   The aqueous solution is adjusted to pH 3 with 10% hydrochloric acid. The solution is condensed under reduced pressure. The residue is treated with water and collected by filtration.
 EMI42.4
 precipitated crystals, giving 11.4 g resolves 4- (6-aRinopurin-9-yl) - 4-deoxy-2,3-O-isopropylidene-D-erythronic. Melting point: 214 ° C (with decomposition).



   M A mixture of 1.35 g of adenine, 2.20 g of 2,3-O-isopropylidene-D-erythronolactone, and 1.68 g of potassium tert-butoxide is heated under reflux for 24 hours. and 27 ml of
 EMI42.5
 dir.éth3foraaraide. The 5Bctionncl mixture was treated as in Example 4 (L) to give 1.41 g of acid - (6-a.inopurire-9-y3) -4-deoxy-2,3-0-isopropylidene- D-erythronic. Fusion point ; 214 C (with deconposition).



   N A mixture of
 EMI42.6
 1.35 g of adenine, 27 r1 of disethylsulfoxide, 1.68 g of potassium tert-butylote and 0 g of 2'3-0 - isopropylidè.ne-D-erythronolactonc. The reaction mixture is treated as in
 EMI42.7
 Example 4 (L), which gives 1.41 g of 4- (6-ominopurine-9yl) -4-deoxy-2,3-0-isopropylidene-D-er5-thronic acid. Melting point: 214 C (with decomposition).

  <Desc / Clms Page number 43>

 (0) A solution is heated under reflux for 18 hours.
 EMI43.1
 1.35 g of adenine, 2.4G g of é, 3-o-isopr, opyliàène-D-erythronolectone and 1.26 G of sodius bicarbonate in 27 ml of di- -5 & thyliormaniàe.

   Or treat the reaction mixture as in Example 4 (L), to give 0.88 g of 4- {±> -ac.iopurine- 'li Ir-dcso-'3-0 acid -isa; repyli3Èna ¯D-Lr, throniq: ed Melting point: 214 C (with decomposition).
 EMI43.2
 



  (P) A mixture of 1.50 g of 6-0thoxypurine, of .90 of 2,3-C-isopiopylidene-D- .0 erythronolactone, of 0.64 g of carbonate is heated at 140 G for 5 hours. sodium and 30 ml of di ;;: JtbylforIJ.2 ± .ide. The di :: ethylforaI: lide is filtered off by distillation, after which the residue is dissolved in water and gold. add to the aqueous solution 4.5 ml of 10 μe hydrochloric acid. 0 # concentrate the r1ectioDéel 15nge, 50% acetic acid gel 5 is added to the concentrate and the mixture is heated to reflux for
30 minutes. After concentration, the residue is dissolved in a small amount of water. the aqueous solution is adsorbed on a resin
 EMI43.3
 ch3ng "ion use, (" wbar.3te IRA 400 ", type OH) and washed with water.

   The eluct obtained is concentrated with 0.55 foric acid and then treated with ethanol to give a
 EMI43.4
 mixture of acid - (6-: t.: oxt, purine =; - 9-yI, =: dsox-D-rhythmronic and acid = a - (6 = .droxypuriz, e-9 yl) -: -d sox-yD-rhythmic Each component is separated thin.



  (,) 0n reflux for 6 hours 1.3 g of 6-oc-
 EMI43.5
 tanoy1aBinoadenine, 0.55 g of potassium carbonate3 1.18 g of 2'3-O-isopropylidèr¯v-D-rhythmronolctone and 26 i1 of dimethylforcaide. The diLiethylforsscidc is removed by distillation and evu is added. An insoluble product is filtered off, and the filtrate is adjusted to pH 3 with 10% hydrochloric acid.
The seprated oil was extracted with ethyl acetate and the aqueous layer concentrated. A small amount of water is added to the residue and the precipitated crystals are collected by filtration.
 EMI43.6
 which gives 0.36 g of 4- (6-inopurine-yl) -d6soxy-2,3-Gisopropylidene-D-enythronic acid. -Melting point 214 C (with d8cos- position).



   The following compounds are obtained in a similar manner:
 EMI43.7
 - (6-aaincpurine- - 1) --'- deoxy, 3-U-isopropy2idane-I7-.rythronic acid (melting point: with decomposition); R-ethy1- 4- (6-aainopurino-9-yI) --- d sōcy-2 3 -G-is oprop: liden e-D-. rythrona-

  <Desc / Clms Page number 44>

 
 EMI44.1
 , etc.
 EMI44.2
 Example 5.
 EMI44.3
 



  (A) Stirred at 16 '= pwbinnte temperature, for 3 hours, a suspension of 100 4g of - (- actirapurine-9-yI) -4-deoxy-, 3-0¯ 5 di cGtyl-p c: xyt'sonr t. ndthyl in 201 normal sodium hyd1-oxide solution. the mixture is adjusted to pH 3 to 4 with 1 = hydrochloric cid. The precipitated crystals are collected by filtration, washed with water and dried, which gives 44 ng of acid --5-a:.: >> puri ^ e-9-z) - dso-D-; rt, throDnic. Melting point 279 C (with o.coczpasïtion).



  (B) A solution of 8U .z ci ': Gid4 4 - (- baf: zsaidopurine-9- * 1) + -dso-D-rhythmic in 5 zi due to cethasol renf creating 5? sig of metallic sodium.



  Du n61-nge r, ^ cti.on .-: 1, on 61iin6 1; m ± thenol by wûportation under reduced pressure and the residue dissolved in water. The aqueous solution is adjusted to rH 3 to 4 with hydrochloric acid to 'f :. The aqueous layer was then removed from the aqueous layer before, Ct "1Cl" and allowed to stand. The precipitated crystals were collected by filtration, 1v0 with IIQCU, then read to dry, which: illP 36 = 6 d'-) cid. 4- (6-citjourin-9-yl) - desoxy-D-rythroniqj. Painted with fusian 79 C (: ': "" (: 0 Cc.CG.' .: OSi, t.GTI) (C) Cn dissolves, increasing sufficient, 100!: LE of j + - (- 3r.nE.Â: urïneS-y1) -1t-dsoX) '- D-.Jr7tl: ronu ::::. ide in 5 µl of solution to. 10 5 ... of:; "c.rc # ce of sodium. Os chrufft. the solution under reflux is hung and daied, adjusted to p ± 3 = vv of dilute hydrochloric acid and allowed to stand.

   Now r # collected by filtration the precipitated crystals and washed them with water, which gives 8 us decided - {- a: inopurïn ..- 9 3 '-) - ds ± .3' --4: r,; truncated. Melting point G79 C (= with decomposition).



  (D) It chuff "u bain: r10, pendit 30 ainutes, a solution of 13-0: JE d ': cide - (t> -w: .inopur inr-'.) - 4-â.sa-G ,,, - fr "'¯ .-; -' '' ^ '' 'c. dzns 5 = 1 of fornic acid at 10. n CC ?:, .. :: i: S 1 = r: loergr: r "r; ± <(1 ..: c :. under,:. SSIs'S1 ".c reduced and we him.



  # add do the eu. Or: rocucilla by filtration the crystals precipitated..d, one 12S lvc 2VCC of J'cau and they are dried, c which gives 130 ng of: 1cid (.; - (- ¯ '.:. "Ùpi: iiC: -. '., 1 -'- Gt'BGa.-TißraIk: .cu> Melting point 2? 9 C (vc deco.pcsitâon,).



  (E) Dissolve (; c! 2lf'î :: 'nt 40v ng of 4- (6-affiino-8L thyIpurin-9-yl) - 4-w so: -, - Q-iscpropylidene-- r; thronique 3 ars 10 mi of acetic 3Cid at 20. Or chiuir 1 solution with ro-

  <Desc / Clms Page number 45>

 
 EMI45.1
 flow for 30 minutes, it is treated with charcoal powder and then filtered. The filtrate is allowed to cool and collected.
 EMI45.2
 by filtration the precipitated crystals and washed with 1% cau, which gives 232 rg of acid crystals 4- (6-eEtiBC-8-EethylpuriDe- 5 9-yi) # - ààso ,, - D4-jthroniqp -. Melting point: 2810G (with daconposition) after recryst311isation in water). Spectrum in ultra-violet 9l ± ± 263 np (t = 14.300).



  (F) We suspend 300 ng of 6-amino-9- (3-earboxy-2,3-0-isoproprlidene-ddropropy2j arine 1-oxidized in 10% of acetic acid to 10%. the solution at reflux for
 EMI45.3
 30 minutes. Add a small amount of charcoal powder to the
 EMI45.4
 reaction mixture, then filtered. Concentrate the filtrate
 EMI45.5
 under reduced pressure - The crystals are collected by filtration
 EMI45.6
 precipitated and recrystallized in Oe: U, which gave 165:;! g of -aï.ro - 9- (3 - c. = r'oY-, 3-dïbdroprozI puri.se-- 1-o, gde.



  Melting point 75 C (with decocposition).



  (G) Qn heated under reflux for 2 hours a suspension of 300 ag of acid u - {n - a,; ro -.;: Rcvptcpurïue-- ïj., .- deox-: c3, - 0- isopropIidèro = r-rroiçzze in 20 al of acetic acid at 10 6.



  The reaction BgG is treated with charcoal powder and
 EMI45.7
 it is filtered at chsud. The filtrate is concentrated under reduced pressure.
 EMI45.8
 te and we add? ':. 2: to the residue. The precipitated crystals were collected by filtration and washed with ffietb3no12 to give 220 wg of scido 4- (G-ni "': # - C -: -, orc" 1Ytopurin-9-yl) -4- d.éscxy- 1 D -. te2 "- ythro -, ic. Melting point 265 to 268 (av \:. ,,, - aùw <., oe ... <= zL == 3- Spectrum in a.z..tr4-ziolet:) \ H20 240 p <-i = 19,000) / 'L O 288 daily (t = 25,500); / \. : 306 I: l / -l (t = 23G4 (H) 0n reflux heater for one hour a mixture = se of f 1, oo g of acid: - {5-¯riopurï: s-9 èsex, g -2.3-t - 7cal 3rd- i D-eryth: ronic t of 30: nI of acetic acid at 10 We treat the ré5ctioB; .sl 7 with charcoal powder, then we wire it-- be.

   The filtrate is pore under reduced pressure and the residue washed with: 2ei; hanol to give 265 bzz of crude crystals of -6-alcp.zrir - y) & soxy --.-- rytoniq, e. Melting pot 279 0 (37GC ééc, 1: weighing) after hot r0crystallization in e;:; u, with efcnbon powder trrxwset.

   Spectrum doens ultrz-vio? E "i = 9% / ± fl 263 E!. * Oa obtains from a series of sisilsirë the following cOpOSé5: i clCir.3. ^ T Î- '.: t t.âJûllY' lC J a8 '.J- "4:, - d.sG'" -D -! ". kr'iqe '(melting point- 249 C, with deco51position); - 4- (6-; amino- acid S-.:

  <Desc / Clms Page number 46>

 
 EMI46.1
 nercaptapurino-9-, 1? -4-dLsoxy D-erthronic (melting point 265-2680, following composition); minion 4- (2-hydroxy-6-a2.inopuriQe-9yD-4-deoxy-D-erythroniquG (melting point above 30uoO, with decomposition); ceide 4- (6-hydroxypurin-9-yl) -4- erythronic dcsoxy-D- 5 (sintered at around E5 C, swells between 1t7i1 and lQ5 C, then melts around 185 C); acid 4- (2-: :: ino -; - rdrox5purine-9-1) -4 -deoxy-D-erythro.niciie e (melting point 223 C, with djcociposition);

   4- (6-chloropurine-9 yI) - t - oy-L-erythonic acid (melts at 85 C, solidifies at 90'0, then decomposes at 260 C; uvc addition product isopropano2 : melting point 110 G, with decomposition); 4 - (6-th "zlanznopurznc-9 91) -. 4-dzsoxy-D-er acid; thronic (mp 24 to 243 G, with decomposition); 4- (6-diétnyl3cinopurine- acid hydrochloride) 9-yl) - 4-dJsoxy-D-3rythronic (melting point 187 C, with âeco L, position); 4- (6-hydro-xyaninopurine-9-yl) -4-deoxy-D-erythronic acid (melting point 206.5 C, on decomposition); 4- (6-benzylarinopurin-9-yl) - 4-dsoxy-D-ethroDic acid (melting point 206 at & 06, µ C, ± vcc deconposition); acid - (benzoyl2einopurine --- 1) -ri - âsoß-D-.sryt'nronic (mp 232-235 C, with decomposition);

   scide -) (6-Q.2inopurino-9-yl) -4-deoxy-L-thrcon (mp 291-2 C :, with decomposition); 4- (6-'aorcaptopurin-9'-yl) -4-deoxy-D-erythronic acid (mp 240 C, deconstructed); 4- (6-ethylthiopurine-9-yl) -lP-deoxy-D-erythronic acid (sintered at 114 * cl, stained at approximately 220 C, then gradually decozposed); @ (purin-9-yl) -4-deoxy-D-erythronic acid (mp 230 * cul, deconposed); N-ethyl-4- (6-aninopunin-9-yl) - 4-desoxy-D-erythroncmide (mp 166-168 C); - (6-emino-8-bydioxypurin-9-yl) -4-deoxy-D-Ôiythro = acid (mp 215-217% with decomposition).



  Example 6.



  (A) To a solution of 300 mg of 1 - (2-étgithia-6-? Ui opnrinc-9-yi) -deoxy-D-erjthnonique dJns 5 lil of an aqueous solution of 90 rg of sodium bicarbonate, 5 nl of Rr-ney nickel are added and the celunge is heated in a wet bath in 1agit3nt, for 4 hours. The reaction mixture is filtered hot and washed with water VOC. Mix the filtrate and the liquids
 EMI46.2
 lifting and condensed under reduced pressure. We adjust the
 EMI46.3
 mixture at about pH 3 with hydrochloric acid. The precipitated crystals were collected by filtration and then dried to give 9U s: g of 4 - {ô-rTincβurine - 9 -.) --- dâsoxy - i-er-, yrthronirue.

  <Desc / Clms Page number 47>

 
 EMI47.1
 



  Fusion point; 79 C (with decomposition).



  (B) .1 a solution of 90 mg resolves 4- (6-alin-8-oeicaptopurin-9-yl) -4-deoxy-D-erythronic G in 5 l of an aqucuse rGner21 solution; 30 reg do biccrboDte of sodium 0.3 s2 5 of nickel from Bcnpy are added. The m: lrr = a is heated at reflux for one hour. 0 filter for sc.p: 'rur le c ^. : 13-sor of r: <c: l :: 1go r3cctionionnel, then we 12v this ct2lyscur with ecu. The leavening liquids are 2Jlcnge a:.;, C the intricurcent filtrate obtained. The: .1 = ng is condensed under pressure rl'cluite and the residue d2.cs 0 is dissolved in a small battery. The aqueous solution is adjusted to pH 3 with dilute hydrochloric acid. We collect by filtration the crystals hlcncs p.:r5cipit,)s and they are with 3.'water then: with thcno3, which gives 56 ag of cide 4- (6-aiînopuiî = -c-9yl) -4-d3soxy-D- $ rhythmic. Fusion point : <79 C (with decompression
 EMI47.2
 5th position).
 EMI47.3
 



  (0) 10 ng of acid - (6-chloropulin-9-yl) -4-deoxy-to-silythnoniquoe was dissolved in: an 18th of 0.4 L of concentrated ion and 15 μl of G 2 u. To this was added so: ution 50, cc of carbon at 5; de}?: - 11r diu ;. and the 5 is shaken under hydrogen. D0 once the hydrogen absorption ceases, the c, tlysa =: pr filtration is liir.c and it is washed with eu.



  The leavening liquids and the filtrate are stirred and concentrated.
 EMI47.4
 be under reduced pressure. On: just the concentrate at pH 2 with
 EMI47.5
 concentrated hydrochloric acid and further concentrated under reduced pressure. The c.4is residue is recrystsilized from squous Ecthosol to give 480 µg of recidc 4- (purine # 9-yl) -4-d6soxy-L-Jr3-thnonic. Melting point 230 C, with decoperation. Spectrum in ultrn-violet. 7 \. O. ::: 65 l: 1j.l (E = 7ëù0); / \. CI 0.1 N 264 nyCt .: 5.600);} \. 1 \ C..d. '"& 65 zR (6 = 7.4i .." \ O).



  (D) To a solution of 850 Dg of 4- (6-benzyla.ainopurine-9-1) --- dsoriβ-J-r; throuiqu; dns) 0 ml of forced acid at 50, 830 LE is added. black from p - 11-dîun. The .alîrg ;: pesdrnt 11 hours; ntn1-6G and 75 ° C. are heated under: 1t..ospherc of hydrogen from 2 to 3 atmospheres. Once the ctclyseur is eliminated, the ri-mixture r6ac-vio =, el is condensed under reduced pressure, which gives b5t7 àzg of crystals of acid beers 4-; b-: ir.purioe- 1-i - d: so - D-erythronic. Melting point: 79 C (#with d5cor - position) after recryst ^ 3.I3stior¯ d s from 3 'eu. ¯ (E) Gn dissolves 500 mg of 4- (6-hydroxy3Einopurin-9-yl) '- 4-deoxy-D-erythronic acid in 10 BI of 10% fornic acid.

  <Desc / Clms Page number 48>

 
 EMI48.1
 



  To this solution is added 500 ng of platinum dioxide and the mixture is subjected to a glycemic hydrogenation for 6 hours: After the reaction has finished, it is filtered to collect the catalyst and washed with water. ún, p.:. el3-nge the liquids of the 5 '? 3 age and the ìlti; t and they are condensed to dryness. The residue was washed with water, then with ethanol and reinstalled in 1% carbonate to give 29G ng 4 # acid (6 # 3E! Nopuri. so # 3 # yl) -4 # dL; soxy # D-rhythmic. Melting point 279 C (with d: CO '= L? OSlt2S'.rT).



  0 (F) 20G Eg of i -, .. (- hdr0 zL3 :: Opur7T '-Q; 1 - = - dso-P - ;. r-trojique dazs 1 1 d :. nominal solution of Sodium bydro xide The solution is heated for 2 hours under reflux with Rasey nickel. After cooling, the catalyst is filtered off and washed with water. The liquids are mixed. of livege and the filtrate and concentrated. 0 adjust the concentration to about 3 with fornic acid. The precipitated crystals are filtered off and recrystallized in 1G Celtic acid, which gives 40 mg of acid 4 - (- 9., irorurin -yl) - d: sō - zr ;; tror.iquc. Melting point: 273) (avüc à 6corpoi-îtio #).



  (G) 250 μg of 6- .zuo -? - C-c = 'rbo-, 3-dibydroxy, rol) -gurīL-1-ode are dissolved in 10 ml of 0.1 N sodium hydroxide solution. We add; in the solution a small amount of Ranoy nickel is carried out by catalytic hydrogenation under túosph5ric pressure. Once the absorption of hydrogen gas has ceased, we release: d.! 1 {. the catalyst for filtration.



  On nz.-utr3lis. the filtrate av ,,: c hydrochloric acid 0.1 leaked and
 EMI48.2
 it is concentrated under reduced pressure until the coity of its vo
 EMI48.3
 1u = <;. The precipitated crystals are collected by filtration and dissolved in the case of 1 v-a; v; c civ l'ec? U ,. which gives 11.7 g of 4- (ô-aTi.uopurinc-9-yl) -4- acid <Isoxy-D-rythroniquc. Point of. fusion 79 C (with
 EMI48.4
 decomposition).
 EMI48.5
 



  One obtains from a first soil the compounds according to the .- (ci-a: i: .oçuriLC-Jfï) -4-cièsoy-i.-4r3thronatL of nethyl (melting point 231 C, zv,> c d6co = position ); - (arrino.-8- = thyipurine -'- yl) -Esox-2'-0-; sopropylidene --- r; thronic acid (mp 65 C, with decomposition), etc.



  Example 7.



  (.t4) 500 µg of scids 4- (6-chloropurin-9-yl) - 4--3soxy-Il-ryt'oronique are dissolved in 30 l of ethanol s: 3tu: r, 8oniac, at

  <Desc / Clms Page number 49>

 
0 C. The solution is heated at 120 ° C. for 21 hours in a hermetically sealed container. After cooling, the ethanol is evaporated off from the reaction mixture. The residue is dissolved in a small amount of water. the aqueous solution is adjusted to pH 3 with hydrochloric acid. The precipitated crystals are collected by filtration, lifted with water and dried.
 EMI49.1
 dries them, 00 which gives 300 cc of 4- (6-ainopurine-9-y1) -ü-deoxy # D-erythronic acid.

   Melting point = -à? 9 G (with decomposition) - (B) 500 sg of scida 4- (6-chloropurine-) 9-yl) -4-deoxy-2,3-0- are dissolved at 0 C isopropylene-D-erythronic in 30 Si of almonia-sctured ethanol solution. The solution is heated at 120 ° C. for 21 hours in a hercièiquenent closed container.



  After cooling, the methanol from the reaction mixture is distilled off. The residue is dissolved in a small amount of water and the aqueous solution is adjusted to pH 2-3 with hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to give 320 mg of acid.
 EMI49.2
 4 - (6-aninopurine-G-yl) - dsoxû-2, J-0-isopropylidene-D-erythronic. Melting point: 214 C (with decomposition) after recrystallibation from 95 ethanol. [a) 5 = + 60 (C = 0.503, dinethylsulfoxyda>. Ultra violet spectrum λ- .i: I. "P 261.5 ill..l (= 14,200); 7L n..x 0, 1 N 258.5 fi (t = 13.soo>; À.NaO: a: 0.1 hui 261.0 m 8 15.300).



   (C) A solution of 1.36 g of 4- (6-chloropurin-9-yl) -4-deoxy-D-erythronic acid is refluxed for 8 hours.
 EMI49.3
 and 1.61 g of this benzylemire in 30 L of ethanol. The ethanol is removed by evaporating it under reduced pressure and the residue is dissolved in 10 ml of water. To the aqueous solution, ethyl acetate is added to extract excess benzylamine. The aqueous layer is separated and its pH is adjusted to between 2: and 3 with hydrochloric acid, then it is cooled overnight with ice-cold water. The precipitated crystals are washed with water to give
 EMI49.4
 1.10 g of 4- (6-BenzylJninopurin-9-yl) -4-esoxy-D-erythronic acid. Melting point: 206 to 206.5 C (with decor-position) after recrystallization from water.

   Spectrum in the ultraviolet
 EMI49.5
 H-0 271 nec 20.400) BCI 0 1 Ii 268 19. ± ¯00); \. MX 2'11 m, (± = 20,400); i \. 0.1 '268 n, (E = 19,500); N3 OH Oe 1 N 271 au (E = 20,400). max (D) A solution is heated under reflux for 2 hours
 EMI49.6
 750 mg of 4- (6-chloropurin-5-yl) -4-esoxy-D-erythnonic acid

  <Desc / Clms Page number 50>

 
 EMI50.1
 in r3 ml of 70% aqueous ethyla2ine ;. The solvent was removed from the reaction mixture by distillation. The residue is dissolved in a small amount of water and the aqueous solution is made up to p 2 with hydrochloric acid at l) 1. The crystals are collected by filtration :, the precipitated crystals and washed 3with water, which astonishes 4-00 s of acid; - (r ,, - thy ïz.¯inopurßn;: -: - yI j -4-dsoxy-'D¯éry tronique.

   Melting point 24 at (with decomposition) after recrystallization Q ^ = S un J: l1: mg0 â'e;: u and d1éthaDol. QP <:: ctr8 d3.11s., 1'u.LÜrv-v3.fllGl,. ' 1 CG 267 2.l (8 = t? .I11.; L1, -, Vi Ol If260 Dax rr # x. / J (E. = 17,000).



  (E) A solution of 1.0 g of 4- (b-chlonopurine-b-yi) -4-deoxy-D-erythboeonic acid in 10 µl of aqueous diethylmmine at 50% is refluxed for 2 hours. The solvent is removed from the n:;,; l $ nge rctior.ncl by distillation, the pu is adjusted to 3 with? 10% hydrochloric acid, then condensed under reduced pressure. They dissolved the oily residue in ethanol. We add to it a mixture of hydrochloric acid and ethnol. The precipitated crystals were collected by f4-ltration and recrystellized from L-018TICG of ethanol and ether to give 1.0 g of crystals of 4- (6-diethylscinopurine acid hydrochloride. --yl) - dJsoxy - S- erythronic Melting point le7 G (V0C decosiposition).



  The following cosposes are obtained of a similar nature: ethyl 4 - (- cinop urino - yl) -4-dLso-L-rytaron.te (melting point 31, evc d - 'coi-ipositi-on) ; 4- (α-Gino-d-Qfthylpurineyl) -4-dsoxy-D-arythroniçus acid (melting point with decocposition); Acid λ - (i-hydroxy-6-3ninopunin-5-yl) -% - α = soxy-D-1 = rhythmronic (over-point greater than with decomposition); 4- (6-arinourinc-yl) - 4-f -, = - u-isopropylidene-α-methyl erythrocyte (melting point 10 to with deccoiliposition); 4- (6- 2rino-8-rathLylpurine -. 1) - T-.cSOxy-L, -U-ZSOprop 3idene-D-erythronic acid (melting point 6;

   G, evfc # ecocposition); z (6eninopurinc - yl) - 4-d.:soxy-,--0-bcnzylidënc-D-4rythron.quc acid (melting point 158-159'cul, with df: coDposition); acid 4 - (- ainopuri-
 EMI50.2
 (Fusion point
 EMI50.3
 i 0 C, with splitting); Ncthyl 4 - {- oinopurine-r-5 -) - desoxy-, ¯ 0-diacetyl-D-erythronate (melting point; & 1 c, with 3conposition); acid <- (6-aninopunin- 9-yl) -4-d: soxy-L-thr & onic (melting point <1 to ¯: 0, with d8couposition), etc.



  Bx: eoJ21e C.



  (A) On = and in suspension> v ag of 4- (6-ar.; Inopurine-

  <Desc / Clms Page number 51>

 
 EMI51.1
 tIl) -'- dtr - '. SOs, sr- J-d3..tj-SCt ".Tr'-ia: .i''Lri? n.vtt? dcns 4 si de t- ± t-zhydrofur- = 'nne and c. addition of this suspension, while 6itnt! wl -.' a solution e <1 L2 (Ï: iQC2thçne d-ss ether. Un = # itù 1 = .iZ¯ wC. '' = L two more hours. In concentrate the = 1- 5 13n r2zctio1 under reduced pressure. A SCLl? ia 1- residue in a chro2tor: i on a neutral rz.ZT..ßllv column and it is rblue with UE 1n0 (iszi) chloroform i: t dc .: 'ft'.LO which does.aE :: 1 of crîst; :.

   Q. "".:; "¯ (t: ¯r <:. 5'n "opurin ..; - ::; - yl) -4 - d"; so: xy-c., / - dt; -0 - ::: c3thyle ctylL-2rytbronte. = fusion joint -1 C (8VC dGco> position) - (B) shot and in suspension lù0 ug of .scide 4- (6-ôBinopuxin .-> I) - 4-d4sc:;, - D-.rytr, ronzçue in 16 cil d t.arah, vârofurn.ne and to this we add. : it of an ether-c solution contains 2 n :: t 5 of diazonethane. Or -¯ ^ .1t? the nelacgj at 1s t:. '. r ûIlT'? ¯iî2i.B. C'n 5 concentrates the 13th reaction under reduced pressure to give 8f mg of needles at 4- (o-wJinopurin-5-yl)> 9 at escXy-v-erythronates of tthy12. = fusion anoint 1 C 'C decomposition) pres recrïstîlîzst; or Q2nS a rlan # of ciethsnol and water.



  (C) Dot is suspended 1.00 g of 4- (6-a2ÍTIOpurin-3 9-yl) -dsoJ-D-rhythmic acid in 5G nl d0 8thnol. To this solution and aGitnt, ni of a complex of ether and of boron trifluoride is added dropwise. The Solange is stirred for 5 hours and the 1th8nol evaporated under reduced pressure, 0.11 the residue in the ecu is dissolved and neutralized with sadiun bicarbonate. We collect .; per filtration the crystals preqipit <s, we washed them ::: V ..: C of 1'0 "11 0t then evo = c of> et3iznol, then we re-crystallize them in a 10bC of wth5nol. and in water, which gives 0 , 16 g of --e.znopurin; -; 1) -4-d.isox; -L-rhythmrontc of 2.] tb; rle. Òint d fusion <) 1 X (#with decomposition) (D) or nei n suspension 50u Di :; of acid T- => - y .ui.i iiÜ4lJ.nc- 1) - I - 3,: sox-y -D-Lryty.roniue in vl to et31 "ncl. To this solution is added 0 , 4 g of ^ cid :: sulfuric conc¯tr4.

   The 13n ± c was refluxed for c hours and poured into c / nl of a solution which contains, g of sodium c-rboncte. The subst.nc pr: cipite is separated by filtration. The filtrate is concentrated under reduced pressure, at Ir tepcrturc aabinte. The concentrate is dissolved in ethunol and the insoluble product is filtered off. Concentrate the filtrate under reduced pressure, dissolve the concoltret in solute, and add ketone to the ethyl solution. It is precipitated by

  <Desc / Clms Page number 52>

 
 EMI52.1
 i.Is3Gïon and then add '1': keton worse than the filtrate.

   Gn collects> = r filtration ls .ri: zta. pr.'c: ipït.s, .t on 1 <z rccristnilise <à.'L5 a: .. ::: 1, ¯''u ù'ct.-noj. and Ct. -'Cß,. 'f2? ..:, Ct qui Gj.aX:ï7c: 25u L1G d # 4- ("' -: lr ;;, ino.JUrin-S-; l) -4-dC : SO) Ç -'-. IJ - ,: 'r.Ythron:.' Tu z-anoint de fusion: 1, à ï..3:.



  CE) We dissolve 1 j e1-cidc t uh, G'ro3'tlric.e-iw3'3'r, - .. ciso -: rß: .roXZit :: "'.us Lu si ca: 3: na3 ; .n% .dre. We Add to c "t soiutioza .1 *, Zj s dt c.Üorurt: d ;;; ttÍony1 \) and we heat lc z3Ll ".ne: tu reflux 1-t-eurcs and from; = 1 ;. after r.::i'roidi sser: 1ent, po we add" u;: 1ù - ;, x ¯i = <= rl <.- = tion-u - 1 a r. sin ..: ccnz; etzsc: d'ions '> L.vCi'.3c.ë ..' t: L -tls, typo 0).

   On - ^. Ī '? Ij le: .î¯, .11y' on Deutrsl5s <ce, ni.-réz cveir n-lpmr-l In X '%: S' <: f: tC: 1:,. X3, t.tlSï: ions, we ror it, ^: Grc = Under pr.-csio-1 r., Cluitt ,,;, which gives',) 70 g of crystals d.,. ¯s¯ "" .. û, wf? ". I", v :: 2r1 ..-..-, ß ,, ^ -: r.CJ?. '.',% - âi-t: iß '.isr OiTi' '' rE: d c.tL1; 14 ..COlIl f, fi- fusion: 51 - "- to (Ticc # '.. C'J' <, 3t): a.a.CIl a9, 'tri.: I 2'Cr.S21.3.i5 ^ ft: 1 giving a .¯ ,; "Ta c: c ': t ::' '1:" l ... t ..': 't ,: e.C7L3t., Ai r'-cup-rs 4 <:. 0 r- acid 4C '.-: yl.irCiiFfF.éiil'i .-' t..j "s..m: 9..âO: CT-ss .. '¯'. # BdRrC32 ? lt <'. ti en 1 = vint l: -, rsin0 eh'.nus- .:' .04, ct ..: ll .. CO "':: 1. above to> ssus.



  On 1> ± ti = z> 1: 'r .: n'nièru sir: .il: .1îr0 3.w .. = c.oss =% 1tivJnts: J 4- (Q -. ::, ir.cpt : ril1c -'- yl) -: "-: 1 '! 3oX".; - .., - <¯.r.ythron; tt? d :: '.! "r" #z .. 012Yt CR3 .fu5ion .1.J il 1, i'C,. "t ,, ... decomposition); 1," - (C: .- ,; ; ::;. inopuriIJe-9-yl) -4- 1 ':;:) - ..; , -, - U-is (! Propylidén. :: - Dr .: t hronr, tf .: de c :: r''t (point de-'fusion 1BO to ivL-e d.; Co p .., if t 10 :: :); 4- (é-t.ydroxypurin.c-i7) - - "J: soXJ -.:;"....- o-'a, c, ¯; t'l <.. r :: t1: ron:) to d '':; thyle (melting point 1 & .., 5 5 at lo? cC, ovec d: crr, pcsztze; 4- (b-ldroxypurinc -? - y1 ) -4-dsoxyw-ry :: rotc d'i th; ïe (fusion ocist 1 &, ovec decposition),
 EMI52.2
 etc.
 EMI52.3
 



  : e: -ple 9.



  (A) We have t * n suspension 5Lu g of 4- (Ê-a = -inopurmt - 9j yl) - # dsox? -D-Jrythroi.'it & c <n ,, tl #, 1 = dJns t:. 7. d f? I :::.: on ::: 1quc to 0 On ch-uffu Ct: 'tz.'. :: 5'Lu:; p ..: r.sioLl; {VÙ C, "t ': iît: ût c- hours in a hr¯ti container; ïuc: - ::. :: nt f: rm. Os conc, - :: trè; ' lu nàlanqe r.:""working! under Pri: reduced scion. 0 ls'v with zic the ecu the crystals ic <cipits cz if the e: CTlÂ'-tS ,; d%. '. "F. of' E == ü, which gives & à0 ng! of 'Y --- Cs.a..3.iC.â; iiI: G - v 7 -.4SOi d- -t.rilr0'.3's: V.lds âml'.t "de feusion: v 4. '' 'at :::.' t..QC (3YEiC d <5cc ':; positios).



  (2) #, chr-ç <1 <at LÇC: give hours a suspension of 1.0 g of - (- hdro 7Purin-S-jl) -4-soxy-D-erytron3te of ethyl in s .t i of otmcol scturt? d 'tr-cn i ic: After r :: f.roï.disseeot, we chrsse the so'iv # by distillation, to collect by filtration

  <Desc / Clms Page number 53>

 
 EMI53.1
 the insoluble crystals and one r; cristailise in 1 r eth!: i: n J ::, at S5 fi. "which gives 5jU ng of ¯ (c¯ ,,, o-3'puz.ine- 1 ) -4-dsox! R '' '' D-er3thran4ida. Poijst du fusion; - "G (with decosposition. Spe8-JÎÔ / 1 tre d: 'Jns ultrc-violet: À. Ii20 0, au.- . '1 CC) A mixture of 4- (6-eiinopurine = ", 5-yl)> 9d ± soxy-D-lrythronite is chosen at 50 ° C. for one hour and for a long time in a closed container. and 5 cl of 4.3 ethyl ethanol solution The reaction mixture is concentrated under reduced pressure.

   Cn washes the crystals pre-) C7.L'.lti: 8 with ethanol, which gives 4c.O ng of li-thyl-4-6-szinopurine-S-yJ) -4dsox - rytor.ûirle. Ai melting point li at 15'5C (with dscupo #
 EMI53.2
 sition).
 EMI53.3
 cl) Ori heated to 10 ° C for 2 hours a 50% mixture of ethyl 4 - (-.- 2ninopurizie - yl) -4-deoxy-D-erythronate. from 1 to s of ethylasin and oc il of eth-nol. The solvent is removed from the distillation to give an oily substance. Dissolve a substance in th5nol with hydrochloric acid and add th0r to solution, which gives lvng of 1., N-di- t I --.- (-crz, op .zrin - -5I) - dssox -, - rthren -ide. Foint de fuJion 166 to 12-r C (with 3 corçositzon).



  (E) As in Example 9 (c), we end up with a sJisnge of j00 ng of (Ó-r-Dinopurinc-S-yl) -4-1jsoXY-L7-ú-isopropylidène-Dsrythronste d- Gstbylc and 3 cl d solution .tûanol3ue 4% dc th3aïney which gives <-50 hl;:; of tI4tbyl-4 - (& - sùinopurine-5i) ---- dso ..x-, y-èyj-G-isafrrogIi.dèna-3-r-, trona: ide. melting point 179 to 160 C (Qvec decomposition) after racrisallis2tion d8Ds of
 EMI53.4
 Ethyl acetate.
 EMI53.5
 



  * Example 10.



  (A) The 4- (6-asinopurine-1} ':, .sor; - D -, :: thronigaL acid is suspended in 1 µl of pyridine. It is added to this 0, j suspension. Neither anhydrous-scstic acid and gold: let the 51qnge stand for 4 hours. The reaction salt is poured in with ice-cold eia and concentrated: E! ".:" 3 reduced pressure. ; #cuei? 5.e by ilt.T¯'c-'r103. r.Cl3t-cs crist3ux and we r2Cr-t:; 11ise in a - ': an;, :: of nàthanol and c "water which gives 3 t of needles of acid = 9 -: -. urine-r l) - dsox -, - di - û - .: cLty'i - thronique. i'o: i: rrt; of fusion: 2C C (with deconpositàon).



  (B) On = and in suspension 5 K to ng of 4- (β-arinopunin-9yl)> 9oesoxy-D-erythronate of; thI4 in 6% of pyridine-.
 EMI53.6
 add to this suspension 3 μl of anhydrous acetic acid and

  <Desc / Clms Page number 54>

 
 EMI54.1
 stirred with enbi * nte-teér8ture for 6 hours. The mixture is poured into ice-cold water and extracted with chloroform. Os washed the extract with water and dried over anhydrous D.gn '; siu; :: 1 sulfate. The chloroform is evaporated off under
 EMI54.2
 Reduced zion; we thus obtain raw crystals, we wash them
 EMI54.3
 in iah: -ro3. and recrystallized from r: hanoz, yielding 90 ng of methyl 4 - (6-aninopurine-5-yl) -4-t-esoxy, 3-dî-0-acetyl-D-erythron3te . Melting point 2soG (nvoc decomposition).



  (C) 5 µl of anhydrous acetic acid is added to a 500 µg solution of 4- (6-hydroxypurin-9-yl) -4-sooxy-eXY.throDate in 10 µl of pyridine. The n.3ane is stirred at room temperature for <3 hours, poured into ice-cold ecu, then strained with chlorofilm. The croraforïçue9 layer is washed with enu, dried and concentrated. an adding
 EMI54.4
 5% ether to the residue and the sides of the
 EMI54.5
 reaction, which determines a crystallis2.tion.

   The crystals were collected by filtration, washed with ether and recrystallized from khcnol to give 550 µg of 4- (α-b-7dnoxypa.riue- -rl) - = -. -.sov- ,: -G-ac: t2-D - r: ethyl thronrt. o..nt I of fusion 1 & S, 5¯a 2 ± 5 C (evcc decoaposition). spectrum in the ultraviolet: 8 ± µfl 250 ng- (bzz) One adds, oU g of benzoyl chloride to a suspension of leu5 g of -6-3Ginopurinc - yl) -4 # deoxy-D-erythronc: te of methyl in 60 l of pyridine, while cooling with. ice cream. The m,> 1 - ngu is stirred for 15 hours, poured into ice-cold water and extracted with chlorohydrin. The extract is dried over anhydrous magnesium sulfate and then evaporated.
 EMI54.6
 chloroform under reduced pressure. The residue is subjected to a chro-
 EMI54.7
 Column Biatography using O g neutral z1UBe.

   A substance a = ause obtained from the fraction eluted with benzene and chloroform is dissolved in 0 μl of pyridine and 3 u 3 of 2N solution of sodium hydroxide are added to this solution. The nélznzù is stirred at 1 teGperatur cncisnte for 3.! In the summer of one hour and passed through a column packed with 30 rays of a 2ch ::: ionic resin ("Do.?ex 50" -, type at). The ion changeusQ resin is washed with 1 ml of pyridine at 50: ...
 EMI54.8
 effluents and washing liquids; then we concentrate them. We
 EMI54.9
 dissolve the residue in tth8nol, treat 1 ± with charcoal powder and let stand, yielding 50 tl6 of acid crystals (--ben: olâinepurinL-: 1) -'- dso-r- -é, thrsa-

  <Desc / Clms Page number 55>

 
 EMI55.1
 fuck. 1-anointed do fusion 232 to 235 C.



  The following compounds are obtained from a similar example: 4- (G-butyrylatlinopurine-yl) -4-d :: sox, y-Dr, J.throniue acid; acid -; G-cct4noy., inopurinc -, - J1) - + - d = soxs-D-erythroniçue,
 EMI55.2
 .5 etc.
 EMI55.3
 example ¯11.



  (±) One net in suspension 1.00 g of 4- (G-aninopurin-yl) -4-deoxy - rytnrontc of Z: .ti, y3c in & 0 ni 3'ccétona. G. Add to this suspension c, 0 g of phosphorus oxychloride. The mixture was left for 0 6 hours and poured into 50 µl of an aqueous solution of sodium bicarbonate. The reaction mixture was left for 50 minutes and evaporated: the acetone under reduced pressure - a residue extract with chloroform and the extract was dried over anhydrous L-eFnt sulphate, after which 10 was stripped off. chloroform by distillation, giving crude crystals.

   Recryst311is these crystals from 1actone, cc which gives 0.82 g of scales of - (c¯a.¯..inopurine - vl) -4¯ dQSoxy- & 3-0-isopro? YlideDe-I.- 6rytùro.Datc de néthj, lc. anoint of madness 160 to 13 G .. .¯¯¯¯) (3) 50 ml of acetic acid at 30, ¯ are added to 3cid0 .¯ (; ¯étïla: iao.purinc- ^ 1; - '--- dsox -, -, - G-isopropßlidENE-D-er -,' ¯ throniquc, prepared by heating a r :: ...: lcnge of 163 g of 7-ethhlGdenine, of <, dü 5- de, rt-G¯3sopropylidene-O-: ry tronolactone and 1.06 ge of sodius carbonate in j2 nil of ditibylforaide; and heating at reflux for c; 4 hours, removing the dz.; etblfrnv. #. sde by distillation, adding water to the residue, filtering off an insoluble substance and neutralizing the filtrate zvec?, > if hydrochloric acid at 10 w. The reaction mixture is heated to reflux for 40 seconds and concentrated.

   The concentrate is adsorbed on a resin ech = mj; -tusc of ions ("L + 400" type OR). The resin is washed with a 0.05 N solution of scid: acetic and eluted with acid acetic O ,; NOT.



  The elust is concentrated to give 0.5 g of 4- (6- <= thylasinopurine - yl) -4-dsoxy-D-erythronic-. anointed with fusion <-42 to 24 / oC, (Jvec décos-osition) after recryst11js3tion dpns of ethono7 3queux. : Dctre in the ultra-violet 7 \ .. ± l.0 9 r.; 'Lj.i (# = 17.400) ..



  The following compounds are obtained in a similar manner: -vnino - (3-c¯rba -., 3-isopropy.idcneolpropyl) ïua'in-1-ayde (melting point <70 C, with decomposition); 4- (6-aDinopure- 1) -4 - d, so -,> - i, -isopropy.idèn-D..Lr, ytbroniquc acid (dot to

  <Desc / Clms Page number 56>

 
 EMI56.1
 214 C fusion, elV8C decomposition); 4- (6-arJino-8-ethylpurine- 9-, 1-1? -d; soh -, - fl-isogropwlidn p - :: rhythmro.nie acid (melting point: = è6µ C, with decomposition) ; acid # - (@ anino-5-nerc # ptop * = rirae f yl} -r-dse: -L, - G-3seproplidene -: - a-thn3çue (melting point:

   I9 to 03 C, 2.with decomposition); == id6W (E - a = Îa-opurineY-à - ') - 4-à ± so% n-n, # = - benzylidéno-D - àrythronîquc (melting point 15Ù to 19: i C, with decomposition); 4-1'6-eblonopunin -> - yl) - --d2sax - ',> - O ^ isopropylldne - erthron.que acid (melting point 15Q C, with decomposition); 'R-ethyl - 4 - (6-a = iropurine-S-yl) - 4-o-aése- 3 xy- <,> - G-isopnoDylider-D-erythronamide (melting point 17 & at 3% C, with decomposition); 4- (6-thyl # -inopunin-b-yl) dàsoxy- acid <, to-5-iso = -ropj.lidene-DJrà% lwoniquc, etc. k.Y.:BDPle 12.



  (A) 1.1S g of 4- (6-chloropurine-9-y) 1 -4-dcsoxy-D-brythroBic acid are reacted with% 0 g of thiou.r8e, in 70 µl of ethasol, for j hours at reflux. 15 Si of sodium hydroxide solution and 10 liters of water are added to the reaction mixture and mixed for one hour. The rethenol is removed by distillation and the residue is just distilled to pH 1 with hydrochloric acid driquo. The precipitated crystals are collected by filtration and recreated. <zlli = e in water to give b60 # 6 of z (6- = erceptopurire-j-yl) -4-d & sow-1-Erytl-ronic acid. Fusion point <4o c (vc decomposition). bpoctrc doe; s ultraviolet: A. èc ,, 5 nu (É = 9.400);? '... HO d25 np (t == 10.100), 3c ::: 4 su (É = é2. <JQ), Ajµfl * i; <, 5 (el i; .Joo>, jip, 5 z <.4ov>. rsx OI N ';). ::, 5 D.J (± = 14.300),) 10.5!: 1; .. 1 (E. == 2.400).



  EC) 1.5b g of '+ - (6-neicaptopurin-5-yl) -' 4-deoxy-D-erythroniçu acid are dissolved <dsns 10 ni GO 0.1 N sodium hydroxide solution c; t we add .:. 13 solution, 4 al of clethyl iodide.



  The reaction mixture is stirred at t: p: rturc, abinnte for 4 hours and conccntri. Adjust the concentrate to p & 1 with hydrochloric acid, then concentrate to dryness. The residue is extracted with very hot neth-nol; raw crystals are thus obtained; they are recrystsilized dD ± from rahuol, which gives 3.3 g of 4- (1-nàthylthiopurme-B-yl) -4-deoxy-exythronic acid. Melting point: 1G C (with dco.osition). Spectrum in iuitra-viiet / \ ..: 221 (t = Il ..:> (0), 2b7 Q.1 (# = 17.; CU), 233 Q..L <1 1'i.4-00); / \. 0.2 N 222.5 w; .. L (f = io, 5oo>, ': 75.7li1.1 15.?vu);),Ô? <é> n; a (la.6VD), 25? 1? .100 to '- = 15.'700; /"',:J.X f 1 N c ::: r: ta; ..! (: = 10.600), 287 I: lJ.1 (t. = 17.100., ..--

  <Desc / Clms Page number 57>

 293 m 8 17,000).
 EMI57.1
 



  (C) 2.4 g of 4 - (- chloropur2ne-yl) - 4-deoxy-D-erythronic acid is dissolved in 20 l of ethanol. To this is added 45 si of an ethanolic solution of hydroxylemine prepared with 1.63 g of hydroxylamine hydrochloride and 1.50 g of potassium hydroxide. The mixture is heated under reflux for 6 hours on.
 EMI57.2
 a Marie bath. The solvent is removed by distillation and the residue is dissolved in a small amount of water. The aqueous solution is adjusted to pu 2 with fornic acid and allowed to mix overnight. The precipitated crystals are collected by filtration and recrystallized from 70% ethanol to obtain a solution.
 EMI57.3
 gives 20 µl of 4- (6-sninopurin-9-yl) -4-deoxy-D-erythronic acid. Melting point ZGG, 5'C (with decomposition).

   Specter in 1 ', altro-rape <-t: .7. .cL21.J 2..67 G1. (E 16.10u); 7 \ .. LiCl 0.1 Ii 267 5 mg 5 (e = 13. & OR). D.ax ¯ ¯¯¯¯ ¯¯ ¯. .-, .. r .. ..¯.



  (D) 1. U of 4- (6-chloropurine-yl) -4dsoxy-D-erythronic acid was dissolved in 10 µl of 50 formic acid, and the solution was heated under reflux for one hour. The solvent is removed by distillation and the residue is recrystallized from iso-) propsnol followed by ethanol to give 760 mg of acid 4-.
 EMI57.4
 (6-3, ydroxypu: .ine - yl) -! - d.:soxy-D-Érthroniqua. - * ±, G15 C fusion anoint (with decomposition). Ultraviolet spectrum Max 250r5: - .. ', (: = I0. &00); G'250.5-ï (= IC.ODO); 'a0. , '255: .q.t C = Il.700). (E) 0.5 g of 5- (6-chîorEpurîne-9-yi) -4-> dsoy-7-: r,; throriauo acid is added to a solution of GJ Gê, ketallic soditzû in 10 1 d absolute ethanol. The reaction mixture is heated under reflux for 2 hours and the precipitated sodium chloride is removed by filtration.

   The nothonol is removed by distillation and the residue dissolved in ethanol. The solution is left to stand.



    The precipitated crystals were collected by filtration and recrystallized from 99 ethanol to give needles.
 EMI57.5
 of Sodium E- (C-u-thoxypurin-9-yl) - # - deoxy-D- & 13'thronate. This substance forms vesicles between 168 and 170 ° C. and it stains between 220 and 230 ° C. with formation of vesicles. Spectrum in the ultra-violet H2O 250 m
 EMI57.6
 (F) 1.0 g of 4- (α-aninopurin-9-yl) -Lî-deoxy-D-erythronic acid is dissolved in 15 r.:7 .. of forniqua acid and 4.1 nl of water. .



  To this solution is added dropwise, over one hour and while cooling with ice, 40 g of sodium nitrite in 15 ml of water. The mixture is stirred while cooling it with ice,

  <Desc / Clms Page number 58>

 then at room temperature for 24 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved.
 EMI58.1
 in water and adsorbed on ion cheneus8 resin (fI 400 ", OH type). The resin was washed with i: t3: u, eluted with acid. fornic at 2, then 1 + 2luat is concentrated under reduced pressure ;, which gives crystals.

   These crystals are recrystallized from ethoenol to give 4- (6-hydroxypurinQ - yl) -4-dsoX, yDr, yt4rQnique- This substance sintered at about 85 C, swells between IC3 and 10 U , then melts around I8 G.



  0 (G) A eLβi: fe: u reflux, - ';'. 3 :: 1 hour a mixture of 300 μg of t.; .- (t: -cl '"oropurine-S-yl) acid Rhythmronic acid and 6% hydrochloric acid to 5, then the solvent is removed by distillation The residue is dissolved in water and the aqueous solution evaporated. The remaining oil was dissolved in a small amount of methanol and acetone was added thereto, the mixture was allowed to stand, the precipitated crystals were collected by filtration.
 EMI58.2
 They are then dried to give 10J of 4- (G-hydroxypur so:> -. y-1) 4rvth-roniqi acid, .e.

   This substance sintered at around 85 C, swells between 100 and 105 C, then it melts around 185 C
H 1.00 g of sodium nitrite are added to a solution
 EMI58.3
 of 1.00 g of 4- (± -crano-à-leyé-noxàqpurin-h-yl) -4 Aesoxy-D-àrythronic acid in 60 nl of solution containing -G: t of acetic acid. The mixture is stirred at the terpr tur: bint0 for 24 hours and one; concentrates it under reduced pressure. The residue is dissolved in a small amount of water and adsorbed on an ion exchange resin line ("Il1A 400", type?). Wash the resin with 500 ml of water and elute with 10% fornic acid. Separate the first eluate (100 µl) and condense the next eluate (500 µl).



  A small amount of water is added to the residue and the aqueous solution is allowed to stand. the precipitated crystals were collected by filtration and then washed to give 0.75 g of 4 - (, 6-di- acid.
 EMI58.4
 droypurine - s 1) -4--3.Lso -, - D-eryt? roniczue. : .- Anoint 'the melt 204 at 206 C (with decomposition) after recrystallization from water.



  Spectrum in the ultra-violet:: Î ".... fi'iP c: j5 mit <= 7,900) t46 mg (= 9aoo); - 0, ¯5 D 23 mg (Î = 6,700), 262 au (c = 9,400); "" .L.t ::. O. , 7 24d an (8 = Co 000) 27S a, (C b.> Oo).



   Example A.



   A suitable tablet formulation consists of:

  <Desc / Clms Page number 59>

 
 EMI59.1
 (1) Acid - '' 3 -. WslOpurla'2v-5 jl) - 1 - GcSOXD-rthran? .Çu 3 gracies (2) Lactose 6..5 gn # naés (3) .rl5¯idon 7 gr = s 5 (4) ùterate of G? Si # 2 large r ':, 1-¯ ^ ¯T3; C tiD0nt 1 3Êr: di c. active, lactose and 3 2.1.i0û then os ¯ ul .- .. t'OUr 1 oisc en co ':: priss, oc vj 3t st6'? r.ts ¯c: 2:; ':;.:. l.:siü ': ", where lu = 1: L'JG JC les tr: .rm10s and we tr2 :: 1 ±: -: fcr ..:; le; = 11-mjz;: t c' :; ri: ": 0 !: C una pics = <t; .i "': \ ;: 81 C .friilu 5 - ::.:.; i 100 c #:'" T'ri: .és: r. ::! 1f '.:; r: .- , ;; t c1- "3ili :: 3 <l l 'i = - ;; r:; d.ic ::: rt: ctif.



  D: .. ::: p ..! .. c 13.



  UT: j Dutrú formulation co = zn¯: blE .le cor-pri "- = c :::; 1; corstitu.:..z Q <;:: (1) mcidr - {6-v: .iâcy.rinG- 1) - = soy- 5 D-erythronic 2 grn.¯as (2) litL'it0 86 gr î.¯ïi: S ( 3) Starch 10 granas (4) Stearate, from 2gnsiUD 2 grs'Les On :::: 1 :: 1250 i, .mt3¯cīLt the active ingredient, ¯. =. Nitol and) starch, then we gr [; Di11 &. For ior # / r ls cosprÍ'-6s, we add 1 Dgnsi #. Stearate, we r :: l¯3rg cvc the granules and we trinsforae 1; celange in co-taken: s on a rotary press. We make 100 con? Riu! '' S rnf0r2nt c'hccun 20 sg of 2 'in grdï: Lt active.



  ¯4.ule C. i A r-ppropricated dredger for .laion consists of: (1) Acid 1? - (6 - r.ainoß urine, ¯, -9-51) - = - '= sox ¯ D-6rythronic 18.üOO grsues (2) A0rosil 4.300 gr: ā4s (3) k8iao de ncis 4-.SOO gr; XJcs (4) Stecricuo acid 700 grades (5) Ethanol 6.0 liters (6) Gelatin 1 .BOO g, rI :: es (7) àùiu purée 20 liters (8) Tcic 600 gr ':. :: L s (9) St6arate binds D2gnsiun 375 gracies From the above products, we fsbrrique à la sisnière usual 600,000 dragees of which chscunc contains 30 8g of the ingredient
 EMI59.2
 active member

 

Claims (1)

EMI60.1 CLAIMS. EMI60.2 1. Compounds of purine, c: 3rctris: s by the formula: EMI60.3 EMI60.4 ) in lcgucllc represents' uri tO0 of nitrogen or N -7 C, Ê is a to: ... t of hydrogen or hclosènc, a hydroxyl radical, L :: erc3pto, "Icoxy ini'ri, - ur, ::. 1:,:> lco: i irfericur, Iyl (infvrïeur) -thio, 2.ina, ciw.i (; = iér; <ur) * ii.io, dialy3 (ir.fricur) ino , aralkyl (lower): J: .iliD, "'cyl? ¯DW or bydroxyl8,:. ino, the symbols IL, and R, repneseL-; tl.nt each 11;: ..- :: to, cd lh; yo: 1rogènt. :, halogen, a hydroxyl rsdical, r crct: nta, ':: inc, l1: ylc infritur, nr3-le, alkoxy infôricur, Dr? lc-ox5 (i.ari,: urj, or ¯. = l (irftric.ur) thia; R4, ¯ is a lower olkylene carrying cono substituents one or more 1r-y, ± # a.wl; s (but without there being prs.nc0 with hydroxyl group on 3 '- ,. nw of carbon 3ttcnLt & 1 'Tt, o = -' :: zote of the nucleus), which can be protected by a root # = 1 rcy3.a, úl1çlc iaféricur or bicn arclkyle (inferior) or biun, when it is; a psirc of hydroxyls on the group <: 11kylene, pr a lower rlkylidesis or a r31kylidene infri = :, acg <t R, is a radical "'l hydroxyl, lower or higher alkoxy, anino, Dlkyl (in: r0riur) o or ülr3 (ïaic: riL = ur-: ino, as well as the salts of these compounds. 2. Cōpos sclos le r4vendicstion 1 characterized in that i is constituted by the acid 4- (6-GEincpvTine-9-yl) -4-deoxy-D4tytr oiqua, a 4- (5-e # i < -noy1-arinc-9-yi) -4-dôsaxy-D-aiythnonnte d'slkylc lower t 11ot ::: r: .-: eLt the i- (G-nninopunin-9-y1) - 9 ± / 20xy -D- erythrOn3ti d; Lth-2e, psr là + - (Er'3, inorurine - ylj - dGsox-g: - àwthroD2td d'4b, .lc, the 4- (6-aìnoputiDù-91)> ntàsoXy-D - oµ ± ythron =; = ide, un ccido% --- (± - ^ 3w 1 (ir: friourja zit: opurino - 31) - dzsaxD -, ::::: -. throni ..., t; 1 ' -lU \? l'ccid # -. (- cahZW: .¯inopwrin: - yI) -4dsoxy-D-rytnroEiqu, l'scide - (- .: cg3an inapurina- $ 1) -üso- - rythronïcuL, p # r 1 r scidc - (6-r.nzorîa.Hopurine-9 - ,; 1) = Tdscxy-D-1rytb.rciguc acid 4- (64hyéroxypuri = e-9-yl) -4-dàsoxy - --drytron; uc, l'scidc # - -aiino-6-% 1c-roxypurirc-9-yl) -4-déscoeyL4rythroziqu #, un = cià <- (6-sio-8-a '! 3 (infcriouxjpuro-9 3- # 4-dsoxy-D-rhythmroaic such as m- (6-a = ino-8-aéthàvlpunina- <Desc / Clms Page number 61> EMI61.1 g-yl) -4-d, ésox-D.-é: rhythronàgue, or by 6.-a3.no-9-i3-carbox -,;, ¯ düdroxypropl) purine-1-ox "vdē Cholesterolemic composition characterized in that it comprises as an active ingredient a purine compound according to claim 1, in an inert excipient. 3. Process for manufacturing a cholesterol composition. EMI61.2 legal, crystallized by mixing a compound of the purinc according to claim 1 or a salt thereof as an active ingredient, with an inert excipient. ) 4. Application of purine compounds or their EMI61.3 salts according to claim 1; jams cholustcroleic agents. 5. Z + process for the manufacture of a purine compound corresponding to the formula - EMI61.4 in which R1 represents an atom of hydrogen, halogen, a EMI61.5 hydroxyl radical, Dercapto, clcoxy (lower), arlcox3 (lower), alkyl <lower> thio, 8Gino, LI11 (lower) āino, dial3syl (lower) a.:lillO, aralk ,? 1 (infèrisur, ino, acylasino or hydroxylanino, represents a hydrogen atom, dlialogen, a -radicrl hydroyl, nercapto Daino, alkyl (lower), aryl, alboxy (lower), 8ralGOxy (iniàrie.ar>, or alkyl (lower ) thio, 1Í.3 represents a hydrogen atom or a hydroxyl radical and sercapto, anino, anky- 'the lower or -ryl; , is a lower 31kylene carrying cocine substituents one or more hydroxyls but without the presence of hydroxyl group on the carbon atom adjacent to the nitrogen atom of the ring), which can be protected by an acyl radi cal , lower alkyl or aralkyl ;; lower) or, when there is a pair of hydroxyls on the alkylene group, with EMI61.6 a lower or 3ralk - .. id: ae alk7lidem, and .t is a hydroxyl, lower or higher alkoxy radical, Brino, # Tà3 $ le! - (lower) amno, or d¯ia3i: (lower) ssino ,. this process ' . .. / being characterized pr.r the: fn3t on.'on scurei a coaosé of the .. oey- -: t iiflonù. - - l .ç u1 ... r2s.ú2.nc re? o! lQ.vn, a .q ..... or :: Q:.: ',. - <Desc / Clms Page number 62> EMI62.1 EMI62.2 in lçuel3o represented a 3tooe- of hydrogen- or h810gene, a radical hydroxyl, ncrcapto, lower alkoxy, lower erelçoxy, - ': 3Jkyl (: LctfcriGur) thic, aciinc, aï3 (inf triaur a: airc dialkil (ir- f4rieur) a.L2i-no, Iz: er [71k ccylsnino or hydro- 3 xyeino, R2 is a 3toe of hydrogen or halogen, or a hydroxyl, cercpto, suino, lower alkyl, aryl, ilcoxy iBfe # laughing radical , lower orzleo3cy or alkyl (infricur) thio, .R4 has a -lower alkyleno carrying comio substituents one or more radicals vdroxy10, (but without the presence of a hydroxyl group on 11 - toao of carbon ^ ttnant to the '3tO !.': of nitrogen of the nucleus (u), which can be grown by a radical scyl,; 3lkyle lower or lower srnlkyle or, when there is a pairw of b7droxyls on 1. alkylene group, by a lower alkylidene or an aralkylidè- nejnIri0ur, H5 represents a re.dics <1 hydroxyl, lower or higher gelcoxy, 1-n-iino, alkyl (lower) Lino or dialkyl (inside) awino, nitro, nitroso, aryldiszo,? -cyl8Qino or aloxy ( i.afvriournvt'nylèni: a.3.no, to a chinic treitément. 6. Process according to rvcB & icetioD 5, characterized in that the treatment consists in fcire r ';. <; Gir 1 ..: collipos-1 of pyriûidine with .fornic acid or with one of its functional derivatives, if it is 0C0SSGirc, then to heat and process EMI62.3 with 'a base'. 7. The method of claim 5 characterized in that EMI62.4 that the chemical tsai'ceent, 2 consists in reacting the pyrimidine compound with a thiac4rbonwāuo acid derivative. . Process according to 18 roven 3ic = tior 5, characterized in that the chemical trcitGQeDt consists in reducing the cozipose of the EMI62.5 pyricidin in the presence of fornic acid, if necessary, then EMI62.6 to heat or treat with a bcse. EMI62.7 9. Method according to claim 5, characterized in that EMI62.8 that the trcitrmont chiniq7je is to heat or treat the compound-5 of pyriuidine with a base. 10. process for .pr: p: ri: r a purine compound having EMI62.9 for formula: <Desc / Clms Page number 63> EMI63.1 EMI63.2 in laguelloe a is an erdno or b radical; 7dro, - <ylel is a zone of hydrogen, halogen or a cniao, lower alkyl, a-0 xyl or or.3y3o lower radical, 3 is a 3toe to 1bydr05ene, d 'h? logbne., a hydroxyl radical, -> 8rc. :: pto, ari-nc, s?., - 3 lower, r: ryl -.:, 31coxy lower, aralkoxy infi1 # or elkyl (infliieGi) thio, 9 is a lower alkylene bearing eo: ¯ c substituents one or more hydroxyls, (but without the presence of the lQ'dro- 5 xyla sun 1 "ito # e group of c3rbonu adjoining 3. $ 3't" .CJ.ß; d'ssotc du nucleus), which can be prot6SBs by a cyle, nlkyle înfàrîeun or r .-: 3h-yi radical: .ri'.¯.riour or bi0n, when there is a p1ir of hydroxyls on the 3'¯.-yïënc group, by iar: Ük-; rli .È ::. Ic irf5ri.:ur, or a 3r ::: lower lkylidene, and Rc ast 'us radical Yy3rox, l, lower elcoxy) or higher, t.nL-1c, il3.:riurj.¯râ:.o or dïiy. (ïnfvrüur) :: r4ino, C8I2. Cc: rât: per 1, - f, -it that 1 \ it r "; ':, cir a coL-pose' d- .; iaidazole aY3TIt for farrz3e:: EMI63.3 EMI63.4 where 114 <.: s1; us :: lkyle :: lower 1e bearing COJ; 1C substituents one or more iwd = oJ3Qles (terminated without there being a hydroxyl group present on the carbon atom adjoining the bottom of the ring), which pcuT? e :: st 2tr = prot8 {s p.3r des --cyle, lower alkyl or lower alkyl, you well, when there is a psiru of hydroxyls on the group z-1ky, lènù, pr r des al- kylidècGeiEf # laughing or lower 3r2kJlien0s., R5 is hydroxyl r3diccl, lower or higher 21coxy, 71minc, :: #! ç.-1 (in: ftr1eur) m: ino or di3H! yl (iBféri & ur2iBo, T represents cy, -Ino ,, crboyle, aldino or -C1 = fiX) (O-lower alkylq) and Bx is as defined above, with a derivative of formula icidinic acid; <Desc / Clms Page number 64> EMI64.1 EMI64.2 ds I ::.: -. 14 ïi- mcplésea-te a eta2e hydrogen, a CIkyle zrylc or ara3Ie îri; ricnr, and Hy is a lower rsdica.1 z or 3co, or else pnr a --srur orthoc : 3rboxyliqae de foraule: EMI64.3 EMI64.4 djss in which Es r, prsaiv an rL, iiCa lower denoyie or lower cl-kyl, R9 and O each represent a lower alkyl radical and Ho is as defined above, and 1'3 ::. tJ: ':?. G. 11. iTocdJ of imbrication of a cocposi due to the purine yJnt for .for: ul.3 d EMI64.5 EMI64.6 dr-rs lwhich the symbol A represents a: tOI.ll: c: 'waot :: or ri #) 0, the symbol Ri is a hydrogen atom or UI- réic31 31coxy icffrieur, <.; r.:;1no , x1% i (irr: = iiur) i..ino, dilkyl (L'1f, riur) 8c.ino, 3ralkyl (iniàn ':. Jr) c # 1 = o or ecylanino; Ez rC: ZL3K ::? 'T? an i'0: 2 of hydrogen or a rrdic: 1 r :: 1 ;; o, 3l'lowerkyle or Jryle, R is a r.to, d b; c: raFne, or u. rudicnl (ino alkyl infuriéun or ar7lé and RZ is a lower alkylene carrying cosne substituting one or more hydroxylus (but without it nit of hydroxyl group present on 1 '; to # <of cbonc 4zout at the nitrogen station of the ring ), which are protected by lower alkyl or lower alkyl or bi radicals,: n, when there is a \ :: pair of hydroxyls on the 11lene group, pr a lower 31kylidene or a lower ralk9lidene, co proceed to remove characterizing p : r the fact that we ± 2it rgir an er, -àposite the liquid manure represented by the formula: <Desc / Clms Page number 65> EMI65.1 EMI65.2 wherein Ra, B2 and R "are each as defined above, with a (; lacton having the formula: EMI65.3 in which R4 is as defined above. EMI65.4 12. Procl: ed6 dc manufacture of a CODpOScl of purine corresponding to the formula: EMI65.5 in which the symbol A represents a nitrogen atom; or else N 0, R is a hydrogen or halogen atom or a hy- radical EMI65.6 droxyle nercepùo, elcoxà. inf Engineer, lower aralkoxy, eHyl (in # f6rieur) thio, inc, nlL-yl (4nfterieur) 3mino, dia3'yl (infrider) sino, aralb3 {.af :: ri;: ur) :: ino, ecy13ùino or hydroxyzanîno, R- and R3 each represent a hydrogen atom, halogen or a hydroxyl, mercapto, lower alkyl, aryl, lower alkoxy, lower aralkoxy or alkyl (lower) thio, R4 represents lower alkyl both have us substituents or several hydroxyls (but without the presence of a hydroxyl group on the a. EMI65.7 tome of carbon cttcnsnt to the nitrogen atom of the #oy>), which may be protected by a lower acyl, lower alkyl or lower aralkyl radical, or, when there is a pair of hydroxyls on the group alkylene, by an alkylidene or an aralkylidene and R- is a lower or higher alkoxy hydroxyl radical, a EMI65.8 sino, alkyl (lower) ar-, ino or el% y1 (engineer) * nino, this process being characterized by the fact that a purine compound having the formula <Desc / Clms Page number 66> EMI66.1 EMI66.2 dsns which ni is a hydrogen, halogen or hydroxyl radical, i.-crcaptc, lower cicoxy,: r # lcoc, .v lower, alkyl t3 (lower) th: io, Rino, a'¯. ryl {i-fc. ":?: ') m :: 1ino, dil3 (infriaur aas.līO, rll..71 (i:; ::; f' ri.t: ur) erÜ.IlO, 'cCylc', ¯ ' ¯¯'-J or i ', yfro'> 'Yûlti0y B.2 and N.3 each represent a ¯toL2 of hydrogen, halo6ene or a hydroxyl, Grcapto, 2Gio, lower alkyl, aryl, lower alkoxy, lower er31coxy or alk71 (lower) thio, 114 is a lower slylene bearing con7-e substituents one or more bj-droxyls, (ie sense present, of a bydroxylof group; ur 1 carbon atom cttenznt to the nitrogen atom of the nucleus), which can be protested by radicals -cyl, lower alkyl or lower ara1ky12 or, -. when there is: a pair of hydroxyls) on the clkylene group, by lower or lower clkylidens, ot R5 is a hydrcxyl, y;: lower or higher lcory, 61; ino, alkyl (inf ± ricur) Dcino or diaL1cyl (infJriBt23 ') 2-in0 3V - C an acidic, or basic substance or aqueous 1-L1G-'u, from three to one of the hydrolyza- .- 'substituents present:; 8 the latter composes, one substitutes '-nt h; ydrolys, 3 - cûrrcspondaitt. 13. P.rGc6d of manufacturing a cc :: pos; of 11 manure; # yant for foraul: EMI66.3 EMI66.4 in which the symbol RI represents a hydrogen atom :, d 'h:; logene or a hydroxy10, nercapto, sicoxy inf4ricun, lower analcoxy, li {w'rrxeurtio' inc, 43.; I {Lîûr3.v radical '' l: .rcs: .l ros dislkyl (lower) 5i.:ino, er31kyl (lower) c.ï:., ino, <:: cyl ::::: lino or ürox, yc.ne5 the symbols R and R3.rùprcisecDt each an atom of hydrogen, halogen or a hydroxyl radical, zsercapto, =: ino9 <Desc / Clms Page number 67> EMI67.1 lower alkyl, aryl ,. lower cicoxy, ersiccxy 22: .T¯'3a: ïir eu '-: Tw'Î'ricTe.TtlO R is a 3lklèn îi'frlt: -t3i' carrying co # - <svbstitu3nts one or more hydroxyls (2is meaning c7. '1 is presence of: hydroxyl group on the carbon atom and retaining the nitrogen atom of the ring), which can be derived from acyl, lower alkyl or srsisylj i.-¯.îri ; ur or, - when there is 12; 3 (; ir, - f¯ h, ro; ls on the alkylene group, by an alh71ideLe Ífriur'ou us srclkylidènc lower, and 2c is a radiczl hydroxyl, elcoxy 1i. '.Î ..T 3 S "eZ' or superior; ur., Sr¯i7.ry-a, alkyl (i-Ef # j iieur) * # ino or iplk.rl (Í! L.f ':; riGur): ¯i :: 1o, characterized gs-i le f; it cufon makes 1 = 2 ± ît a syssi copos for f undulates: EMI67.2 EMI67.3 in which the syz-, bole A represents a nitrogen stone or li --7 0, Ri is a u'h7fdroS-ene or halogen atone or a hydroxyl radical, 1 D8rcapto, 7coxß lower,:> r "1lcoxy lower,:! 11 {infcricar) thio, û8ino, 3l ± yl (lower) ino, Q1.UÏ = 'Ï {lßkforic'ar2.¯n0, zi # 1kyl (Í3èricur) 3io, ac; l ¯ino or h3- drovanir: o, .nG and j ic each contain an eto :: e of hydrogen, û'Î3.ÏOÈ, 1C: o-1 us r3dÏCâÏ hydroxyl, erc2pta, c'aino, cl> 1. infrlour, aryl,: Ücox ; y inf.r: ic: u, ar = Wcox- infl: ri ::. r or Lyl {infri: urjtbzo9 R 'is ur el1: lower ylene carrying cO :: f1e substituted: nts one or more hydroxyl & s (usis without that there is piese cn on the: û0 E¯ 'of carbon adjoining 1' = to = -e of nitrogen), which can be protected = s p ': r of rudiC2UX ccyle, lsy? lower 01: : - #: Lower JlkylG or, when there is a 1 .rc of hydroxyls on the alkylene group, ppr ur lower oL3idènc or a 3r :: Lkylidene lower, and R5 is an r - :::: dical 1- ..ydroxylc, sicoxy inil-riiui or higher, from the Thong to Irsnsforue at the corners a reducible substituents, present therein, with the corresponding reduced substituent. 14. J? Roc:; é. (; Of û0ricútion of a compound of the purine cynt for formula: <Desc / Clms Page number 68> EMI68.1 EMI68.2 in lacquer, and. rcpr sf-ntunt each one atom of hydrogen, ::; dfh) 10èn.c or a rrà? c; 1 hyuroxyl, iercipto, t = i = ino, s3-kyl i + ± <riuur, 3rylL, lcoxy infricur, -'nicoxy lower or elky.1 (in = rérieur) thio, R. is u :. slkylènc icf-riur carrying co-: .e substituents one or more lt.aioxywles without the presence of the group hJ'0x1- on 1 1 n-.o- e zii cìbone Qtt.:;DËut to the 3toe I'nzot- du UCD, u), rui can 3tr <w protâ6és p2r r-3dic-mx cy- 1 '., "' Iky! In:" ¯ :: ':! T; 11!' c = u -.i: l = ;; the inner, or bics, when., xist; a.; j <>, i ,,, ctir the "31kylene group, by a" 1kylidèr.o or a ".rlylideo 5-JiJr1 ,, - =, is a hydroxyl rodicil., iccxj; inîlri iaç or greater, ==. inc, rll (infériur) 1J; .in, J or éi # liKy1 (iri.iiiur) ar: ino and Rl and R, reps ::. n't each a #ta <' hJro5é, us refiic? 1 alk3.le inferit ':. tr, r31kyle infriur, cu hydrcxylc- c .; proc ... è. ": etnrt characterized by the fiit that 1-it rsci, ir a couposà of 1 cycnt purine pc-uz òr-:, U103: EMI68.3 EMI68.4 S 3:; uI3 ,,. E; is -a #i:.:, 1 :. inferior portsst co = - = - e substi- 1; u ':. cts un or 1> lvziou- = Òo> = ylcs =' 3.5 sns that there is groupi 'roxl i' ": Sr: 1 :; on the: '1:;>'): .. <<: Ge cirboné :: tert the atone tzo1 :; of no7-, u), which can be because, prote6às pcr of the a-. cul radicals; , eHsyl # 1 # Tlricw or = .aLtg.l; lower or, when UDv p: .ir 'tyJrCÀ71s exists on lu rup = 1kylene, .pr a1kylidene inf: riêr or u. rlkylidn lower, 5 is a radic-1 hyaroxyl1 lower or higher clcoxy, z = ino, a1kyl (in ± laughing): i.c or r'¯i-31 (irLritura.iro., is an atone deh .-- Iogene <Desc / Clms Page number 69> EMI69.1 or a zuorecpto, s3-kyl (lower) thio, sry it'hio, aralkyl (lower) thio, Ble6nyl (lower) thio, al3ltïnftrieur) sulfonl, srylsulfonyl, 8r21kyle (lower) sulfonyl or sl'c6Eyl (lower) radical sulfonyl and R2 and R, are each as defined above, with an amine of the formula: EMI69.2 o where R11 and R12 are each as defined above. 15. A process for manufacturing a purine composition with the following formula: EMI69.3 EMI69.4 1 in which R1 is a stone of hydrogen, h9loúèn6 or'unr3dical hydroxyl, Qrcapto, lower alkoxy, lower aralkoxy, alkyl (inf, .rieur) thio, DDino, lkyl (lower) 3Dino, di-al3 (infrisurj enino , 3ralkyl (lDfrig'ur) ainiao, acylanino or hydroxyamino, R2 and 13 each represent a stocie .hàroene, halojene, a hydroxyl, nercapto, amino, lower alkyl, aryl, lower alkoxy, arelcoxy (lower) or alkoxy ( lower) thio, R4 is a lower alkylene bearing as substituents one or more hydroxyls (but without the presence of hydroxyl group on the carbon atom adjacent to the nitrogen atom of the ring), who can EMI69.5 may be protected by acyl, lower alkyl or lower alkyl or, when there is a pair of hydroxyls EMI69.6 on the alk-ylene group, by a lower alkyliàsme or a lower aralkyllidene, and R3 is a lower or higher alkyl radical, c proed.3 e.itent characterized by the fact that one reacts a C2pOS & lE pure ine having for cwule: <Desc / Clms Page number 70> EMI70.1 wherein R4 is lower alkylene bearing as a substituent one or more hydroxyls (but without the presence of a hydroxyl group on the carbon atone adjoining the ao atone of the noayu which may be protected by acyl, lower alkyl or lower aralkyl radicals or, when there is EMI70.2 a pair of hydroxylos on the ilkylene group, through a lower alkylidena or a lower aralkylidene, and R, R and R3 are each as defined above, or a functional derivative thereof to the group carboxyl, with a reagent having the formula R13 X in which is a halogen atoce or a hydroxyl radical, EMI70.3 hdrox; , Jsulfon3lox or alcoXY (infàrieur) sulfonYloxy and R1 is as) as defined above, or with a reagent having the formula R13 = N2 where R15 is lower alkylene * EMI70.4 l6..Procéda for manufacturing a COCPOS0 of, purine having for formula EMI70.5 in which R1 is a hydrogen or halogen atom, a hydroxyl, mercapto lower alkoxy, lower aralkoxy radical, EMI70.6 alkyl (inner) thio, anino, al.-1 (infériwuracino, dial-alkyl (infcrieur) aaino, r: 1'l (lower) awino, acy12ino or hydroxyaoino, R. andR3 each represent a hydrogen or halogen atom or a hydroxyl, mercapto anino, lower alkyl or aryl radical, EMI70.7 lower alkoxy, lower eralcoxy or llinfriur) thi °, R is a lower alkylene having as substituents one or more hydroxyls (but without the presence of a hy- <Desc / Clms Page number 71> EMI71.1 droxylù on 1 "carbon atone adjoining the nitrogen atone of the nucleus), which pave 2tr <protect s pan from acyl, slkyl & lower or lower 3r3lkylù or, when there is a psirc of hydroxyls on a group 4llene, p3r an iniàrisur alkylidene or us 5 ar31kyliènc f; .rieu.z, and R4 is a r9diczl elkyl (ir-f5 = 1, Ju =) c:> 1no or di-Qlkyl (ifricur) & 2io, Cc proceeds lt = Restricted by the fact that we 1 #: it rôc = & i a compound of 1 manure ,: aY2t for formula: EMI71.2 EMI71.3 ) in which RI is a 4to: a of hydrogen, halogen or a hydroxyl, erc3pto, lower alkoxy, aralkoxy, lower, xikyl (infri8ur) thio, anino, elh7l (lower) 3wino, di-lky1 (lower) anino, arlkyl (infrieur) aino, ccylaDino or hydrcxyaùino, and R3 each representing a hydrogen atom, halogen or a hydroxyl, nerccpto, 8wino, clkylo-inferior, aryl, lower alkoxy, lower arsicoxy or lkyl (inf ± laughing) thio, and it is a lower sILkylene carrying as substituents one or more hydroxyls (but sense that there is presence of a bydrokyle group on the carbon atone adjacent to the nitrogen atom of the nucleus), which can ± tne pnott-sés psr of acyl, lower alkyl or lower aralkyl or else, when there is a hydroxyl pair on the alkylene group, by a lower a3kylideno or by EMI71.4 a lower aralkylidene, with an amine of the formula: EMI71.5 "14 - H in lac011e 1 is as it has ± tC defined above. 17. Method 4c manufacture in a cocpose of 1 purine having for iornule: EMI71.6 EMI71.7 where fi is a G'h3-enogenous, hilogenous or un- rdi # <Desc / Clms Page number 72> EMI72.1 cal hydroxylc, nercôpto, nicoxy -iafrie-m *, sralcoxy inférie '8 (3.r; .ī.?' '.? îo, .w, -ßsit3s 8. (2L.r 2.0 3-3v ri2ur) a #iiio, rzJGl (iÎri0ur) in, ec; 1;> ino or hydroxy = - '1.:;. and h3 r <2prsci:' cci3t tr iiW GL.Ts a 2..0 ^ x: 'byogë! 1é , halogenated ¯5 un rscîic32 j ---.- = ror 3, nercepto, a-7-ino, alkyl 3SJnàeur, aç alkoxy r.rln.'v3 ', aralkoxy 1: .f6riur, or 2. (: rlc: lii ''. '' 'is "11k; yl: r: .i :: in.f,; ricur portsBt com> substitutes # nts uri or sieurs bydroxyles (C3is without there being presonc. 3 xyl group on the 3'.v's'1¯: 'to 1' = tone , igZ 3'rc of the J which could be protected by acyl radicals, lky13 in or lower prsikylc, or else, when it existed a pair. 1L-S on the roup ...: 'L1.çrlène.,? Rr a. iriérieur alkylidesis o ral'kylidesis i - fzērî-cur, and it, is a rJ.ài = al hy2roxyl., lco riur or higher, cio, îI (iuf; .r3r z: io or i-clky 5 t : r 'w'.lr1 = tO, cv proced6 t''t ^ L' 'crctri5 pir le rnit que' re., "ir A cOCiposL of azrant purine for 2'OX'ii: l. ± ' EMI72.2 EMI72.3 din = - lrquùlli R-! st un .tcr: ù of.lrogenx or halogen or alicr: 1 h3 ± roxyli, ncrcapto, alkoxy înfàri; ur, -raiccxy infj olkyl (infcricur) thio, s-inc, i1k3 "1 (ini, ± laughing ) ncino, di-alk f <I laughing) eatno, 7 ::: r ::: ükyl (ir..f6ricur).: .. lino7: .àcyln = -ino cu hydro; Ei and R3 rjpru & Btct each a stotzz of hs., Droien #, of a hydroxyl rd1c1, uerc, 31) tC, 3E.i.:o, lizr1e intricur, ç lower alkoxy, aralkoxy isf.ri <3ur or alkyl ( infrivur) th ... 5t a lower alkylene carrying co. ::.! .. subztituAnts one or sieurs hydroxylcs (is sense that there 31t pr = lsdncç d group xyl <t on the octoe of carbona adjoining 1 ' = tto ± c of isolated from which p * uvent ûtro protàeàJ by r1ca teyle, alkylc- or c.rslk71 isf-riaur or, when there was a pciry xyles on the group elkylèno, t> vu-c an alkylid & B izf ± nrolkylidèna inf-rîeur and RI --at a hydroxylù radical, from r ": r1 (: UT or sup '; xl ... ur, anino ,, cD! yl (ii: f sorter)? siso or (it : fàriJur) i = ino, or bit.-n sv <.- <: a delecylation gen, do transform <jr au = oins a d-s groups [vtlroXjl present in <Desc / Clms Page number 73> EMI73.1 symbol Ri and 3s groups :: l5..no not represented by the symbols RI. , m and% in by <-3cylated hydroxyls or e1; 1 ar: in.o 2cylated .. 1 &. Dd process (tbricetion of us consists of eyont purine for fo: r :::. 1Ùe -: EMI73.2 EMI73.3 d; ...! 1S which fi r4uré: s2''t. an atoni Ci 'hyè.rogèn.3 of halogè = - or a radical hy-droxylo, crc2pto, alkoxy frirur, lower rlcoxy, alyl (infricur) th.io, <nino, 2? (infcrie4r) sino, di-a] 31 (inferieur) c - .. o, erl1Ç: 1 (inî0rit :: ur) a2ino, ac: y18;:. ino or bydr (Xj'5 ..... ixo, R- ct R3 each reirects an atom of hydrogen, eralcow or a hydroxyl, rercepto, r¯: i: o, lower alkyl arylù, lower alkoxy, lower eralcow or (lower) alkyl thio, .1: 1 "4.- is a lower î.3rlènv carrying conne substitusnts or several h ,, # ârclcs (anise without the presence of hydroxyl grom on 11c; tÓr :: e carbon att0nnt to the nitrogen atom of Doysu), at least one of which is protected by an alkyl radical inf-5ridur or sr¯ ^ .I'.yle lower or when it exists -., - .. ¯cp # Oe d'hy: roxylcs on lc group l2èae, by a :: infJied lidene or us eralkylidene lower, and h is a hydroxyl, a lower coxy or supJril..lur waro, clkyl (lower) sairt0 or di a1l :; ï (ï.nf.:. ri: ur) e - .. ro,, this proceeds'; as characterized by the. fact that i ": Üt r:.:.; i :, a compound 2 ..: 1c purine having the formula: EMI73.4 EMI73.5 d as which R "4 is a lower alien carrying conae substitutes one or more hydroxyls (In view of the presence of a rqdroxylc group on the carbon atom adjacent to the nitrogen atom of the nucleus), and, ú2 'R 3 and .5 are each such q have -13 defined plus hsut, with an x0cct1f having the formula <Desc / Clms Page number 74> EMI74.1 EMI74.2 in which 15 rcprusen a #tome dThyJrogèn or ur rdic: lkIe.'ïfrï: r, 25 repreDic ur wiore athyétogene or a rndiCe! slkyle r = ctzr, rsL.,; - lower 3a or a: ryle, 4t If and Y "represent Cfi2C ¯s'rçdic8UX elcoxy im ± ers or else rcpr # sent = nt all 3; u a group-: oxo or well reactive having ponr 3 iorrule: 17 - Y- 0.51: 5 lç.e3lv n is a lower eliririe radical or lower r, ^ ¯3 1e, and Y "'is a hydroxyl r-dicsi cn bies a halo [: tO-0 EMI74.3 uncomfortable. EMI74.4 5 19. -Process of f2JiCi'C.O of a compound d, 1 1t¯T'3rt'c ::. Yz.nt for formula EMI74.5 EMI74.6 d '.' ms Iscuellc li'j and RE represent ctncuE a hydroxyl radical, Qrcpto, lower alkoxy, 01; 1 (greater) thio or hydx-ùxy- 'ni n 0 R4 is a lower alkyl having coe substituents one or several hydroxyls (: ¯: is without the presence of a hydroxyl group on the carbon atone adjacent to the nitrogen atom of the nucleus), which can ttr0 protected by due r = 3ic.u.¯ = acylu, Lower alkyl or lower aralk-jlc or bin9 when there is a pair of hydroxyls on their allvlènc- group, by a lower # lkylidene or by an infricur, rul'ylidne, and B5 is a hydrcxyl, lower or higher sicoxy rdzc ^ 1 , 3cino, 3l1çrl (inf5rieur) aQino, or di-aihy (ànf, rzour) c3.oy C .: proceeds being characterized by the fact that one sounct a cazpos-z ': of purine having for f orau- EMI74.7 the : <Desc / Clms Page number 75> EMI75.1 EMI75.2 dns 1 = oue? lc -à-,, R -yc R- rcpr3scntintclLzc = lun-oextar = w of chlorine or -un r.Lic> 7 iércatc or l, and R- are ch2cun that they have t Li; ia h = uÉ, to a tr3nsforzi! tîon ci.âquc c..r a; t-: chi - ;? Uc known in ùllc-aene.