CA1311201C - Desazapurine-nucleoside derivatives, processes for the preparation thereof, pharmaceutical compositions containing them and the use thereof fornucleic acid sequencing and as antiviral agents - Google Patents

Abstract

ABSTRACT
Desazapurine-nucleoside derivatives, processes for the preparation thereof, pharmaceutical compositions containing them and the use thereof for nucleic acid sequencing and as antiviral agents The present invention provides desazapurine-nucleoside derivatives of the general formula:-(I) wherein X is a nitrogen atom or a methine radical, W is a nitrogen atom or a

Description

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The present invention is concerned with new des-azapurine-nucleoside derivatives~ processes for the preparation thereof, as well as the use tllereof in the sequencing of nucleic acids, and also as anti-viral agen.s.
The new desazapurine-nucleoside derivatives accord-ing to the present invention are compounds of the general formula:-Rl R3 N
R2 l X ~
R7 R5¦
~' Y-O~O~
.' ~

wh~rein X is a nitrogen atom or a methine group, W is ~; a nitrogen atom or a ~ C-R4 radical, p~l, R2, R3 and R4, which can be the same or diferent, are hydrogen or halogen atoms, hydroxyl or mercapto groups, lower alkyl, lower alkylthio, lower alkoxy, aralkyl, aralkoxy or aryloxy radicals or amino groups optionally substituted once or twice, R5 is a hydrogen atom or a hydroxyl group and R6 and R7 are each hydrogen atoms or one of them is ~:~ a halogen atom or a cyano or azido group or an amino group optionally substituted once or ~wice, whereby one o~ R6 and R7 can also be a hydroxyl group when X is a methine radical and, in addition, R5 and R7 can together ' ' ' ' ~ 3 ~

represent a further valency bond between C-2' and C-3' and Y is a hydrogen atom or a mono-, cli- or triphosphate group1 as well as the tautomers and salts thereof and nucleic acids which contain compounds of general formula I as structural co~ponents.
The lower alkyl radicals in the definition of ~he substituents Rl, R2, R3 and R4 can be saturated or unsaturated, straight-chained or branched and contain up to 7 and preerably up to 4 carbon atoms. This definition of the alkyl radicals also applies to the alkyl moieties which occur in the definitions of the lower alkylthio and lower alkoxy radicals, The methyl and ethyl radicals are quite especially prefe~red.
By halogen in the defini~ion of the substituents Rl, R~, R39 R4, R6 and R7 are to be tmderstood fluorineg chlorine, bromine and iodine.
~ The aralkyl and aralkoxy radicals in the : definitions of the substituents R , R , R and R

contain an alkyl moiety with up to 5 and preferably with up to 3 carbon a-toms which are substituted one or more times with an aryl moiety suitably of 6 to 10 carbon atoms, for example, a phenyl or naphthyl radical. The aromatic radicals can, in turn, be substituted one or more times by an alkyl or alkoxy radical. The benzyl radical is especially preferred.

The aryl moiety of the aryloxy radical in the definition of Rl, R , R and R , suitably has 6 to 10 carbon atoms, the phenyloxy radical being especially preferred which canop-tionally be sub-stituted one or more times by further substituents, for example, nitro groups and alkyl and alkoxy radicals.
The amino group occurring in the definition of R , R , R , R , R and R , which can op-tionally be substituted onceor twice, contains, as possible sub-stituents, preferably alkyl radicals with up to 5 and preferably up to 3 carbon atoms which, in turn, can be substitu-ted by lower alkoxy radicals, halogen atoms or amino groups optionally substituted once or twice. I'hese substitutents can also represent an aralkyl radical with an alkyl moiety of up to 5, pre~
ferably up to 3 carbon atoms and an aryl moiety of 6 to 10 carbon atoms. The two nitrogen substituents can together also represent an alkylidene radical and preferably a methylidene radical which, in turn, can be substituted by lower alkoxy, substituted amino groups or halogen atoms. A quite especially preferred substituent of this kind is the dimethylamino-methylidene radical.

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The monophosphate group is ~he -PO(OH)2 group, the diphosphate group is the -P203(0H)3 group and ~he triphosphate group is the P305~0H)4 group.
As possible salts, there are especially preferred the alkali metal, alkaline earth metal and ammonium salts of the phosphate groups. The alkaline earth metal salts are especially the magnesium and calcium salts~
By ammonium salt~, according to the present invention there are to be understood salts which contain the ~ 10 ammonium ion which can be substituted up to four times : by alkyl radicals con~aining up to 4 carbon atoms and/or by aralkyl radicale, preterably the benzyl radical. Th~

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subs-tituents can hereby be the same or different. The salts of ~he phospha~es can be converted in known manner into the free acids.
The compounds of general formula I can contain S basic groups, especially amino groups, which can be converted into acid addition salts wi~h appropriate acids, As acids for this purpose, there can be used, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, tar~aric acid, citric acid, lactic acid, maleic acid and methanesulphonic acid.
The compounds of general formula I are new. They can be prepared analogously to known, related compounds.
For the preparation of the compounds of general formula I, a process has proved to be especially preferred in which a compound of the general formula:-~l R3 (II) R2 i X ~
Hin which X~ W, Rl~ R2 and R3 have the same meanings as above, is reacted with a compound of the general formula:-R R
n~-o~ (III) ` R

-.

- ~3~2~

in which R5 has the above-given meaning, R6 and R7 each represent hydrogen atoms or one of these two symbols represents an azido group or a hydroxyl group protec~ed by an oxygen protection group, R' is an oxygen protection group and Z is a reactive group~ to give a compound of the general formula:-Rl R3 R2 1 x ~ N (IV) ~'_o~

R6 l ~: in which X~ W, Rl, R2, R3, R5, R6 , R7 and R' have the above-given meanings 9 and oxygen protective groups ~;: 10 possibly present are split off and ~hereafter a compound thus obtained, in which R6 or R7 is a hydroxyl group, after selective protection of the 5'-hydroxyl group, is optionally converted with a halide, cyanide or azide in known manner into a compound of general formula I in which R6 or R7 is a halogen atom or a cyano or azido group or, in known manner, is deoxygenated to give a compound of general formula I, in which R6 or R7 is a hydrogen atom or a compound thus obtained of general formula I, in which R6 or R7 is an azido group, is reduced in known : 20 manner to a compound of general formula I in which R6 or R7 is an amino group and, if desired, a compound of ~ ' :

general forr.lula I, in which Y is a hyclrogen atom7 is converted in known manner into a mono~, di- or tri-phosphate and, if desired, a free base or acid obtained is converted into an appropriate salt or a salt obtained is converted into the corresponding free base or acid.
The compounds of general formula II are reacted with the compounds of general formula III especially advantageously under phase transfer conditions. Under the conditions of phase transfer catalysis, t~e bases of general formula II are converted into a corresponding anion, for example by means of a 50% aqueous solution of sodium hyd~oxide. The anion thus obtained is hydrophobed by a phase transfer catalyst, for example tris-[2-(2-methoxyethoxy)-ethyl]-amine, and transported into the organic phase in which it reacts with the reac~ive compound of general formula III.
As reactive groups Z in the compounds o~ general formula III, there are preferably used halogen atoms and alkoxy radicals. In the case of this reaction, the hydroxyl groups of the sugar residue are protected in the usual way by conventional oxygen protective groups, for example toluoyl, benzoyl or aeetyl radicals. Af~er completion of the reactionS the oxygen protective groups - can again be split off in known manner under alkaline conditions, a lM methanolic menthanolate solution prefer-ably being used.
During ~he reaction, it can also be preferable to .... .

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keep the radicals Rl, R2, R3 and R4 protected by appropriate protective groups.
Another advantageous method for the preparation of compounds of general formula IV is the solid-liquid phase transfer process with the use of solid, powd red potassium hydroxide, the above-mentioned kryptand, as well as compounds of general formulae II and III in an aprotic solvent~
Compounds of general formula I 9 in which R6 or R7 is a halogen atom or an azido group, are preferably prepared by starting from a compound of general formula I, in which R6 or R7 is a hydroxyl group. The hydroxyl group in the 5'-position is first to be selectlvely protected. For this purpose, too~ known processes are available. For example, in nucleotide chemistry, the 4,4'-dimethoxy-triphenylmethyl radical has proved to be useful. After the reaction has taken place, this can again be easily split of~ by mild acid hy~rolysis 9 whereas the also acid-labile glycosidic bond is not hydrolysed under these conditions. The reaction of the nucleoside to be protected with the oxygen protective group reagent for the S'-hydroxyl grsup is carried out in an appropriate organic solvent, preferably in dry pyridine, with a small excess of the oxygen protective group reagent 9 as well as possibly of an appropriate adjuvant base 9 for example N-ethyldiisopropylamine.
The so protected compound of general formula I is 9~33 ~2~

reacted with a halide, preferably with an alkali ~etal halide or an organic halide, or with an azide, prefer-ably with an alkali metal azide, in known mannerO The hydroxyl group on the C-3' atom is thereby nucleophilic-ally substituted by the halide or azide.
Compounds of general formula I, in which R6 or R7 i9 a hydroxyl group, can also, af~er previous protection of the 5'-hydroxyl group in the above-described manner, be desoxygenated by known me~hods ~o give compounds of general formula I, in which R6 and R7 are hydrogen atoms.
For this purpose~ the compound of general ormula I, in which R6 or R7 is a hydroxyl group and in which the 5l~
hydroxyl group has been protected in the above-described way and other functional radicals also carry protective groups, is first converted into a 3'-0-thiocarbonyl derivative which is subsequently reduced radically with tributyl tin hydride. Such me~hods for the desoxygen-ation of 2'-desoxynucleosides to giV8 2~ ,3'-didegoxy-nucleosides are known, the 3arton desoxygenation method having proved to be especially favourable (J. Chem. Soc., Perkin Trans. I (1975), 1574).
Compounds of general formula I, in which R6 or R7 is an amino group, are preferably prepared by reducing a compound of general formula I, in which the substit-uent R6 OI R7 is an azido group. This reduction of theazido group to the amino group can be carried out by various ge~erally known methods, the reduction wi~h .
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hydrogen in the presence of a palladium-charcoal catalyst having proved to be especially advantageous.
The phosphate groups are introduced in~o compounds of general formula I, ln which Y is a hydrogen atom; in known manner. The monophosphates are obtained, for example, by phosphorylating compounds of general formula I, in which Y is a hydrogen atom, with phosphorus oxy-chloride in trimethyl phosphate. The triethylammonium salts obtained in this way can be converted in known manner into other salts by transsalification. The di-and triphosphates are obtained according to known preferably from the monophosphates, by reaction with orthophosphates or pyrophosphates. Their various salts can also be prepared by known methods.
Compounds of general formula II are either known or can be prepared analogously to known compsunds. Such methods of prepara~ion are described, for example, in ~ Chemische Berichte, 110, 1462~1977; J. Chem. Soc., 1460, ; 131; and Tetrahedron Letters, 21, 3135/1980.
Some of the compounds of general formulaIII are also known. Compounds which have not hitherto been described can be prepared completely analogously to the known compounds. The preparation of such compounds îs described, for example, in Chem. Ber., 93~ 2777/1960 25 and in Synthesis, 1984, 961.
The new compounds according to the present invention possess valuable pharmacological properties.

In particular, by inhibition of the enzyme reversetranscriptase, the multiplication of retroviruses is prevented, i~e. the compounds according to the present invention possess especially cytostatic, as well as antiviral properties.
The structural units of nucleic acids contain, as glycosidic components, e-ther the ~-D-ribofuranosyl radical or the 2-desoxy derivative thereof. Besides these aglyconic radicals, modified D-ribofuranosyl derivatives are also found in nucleoside antibiotics.
Thus, for example cordycepin, which can be isolated from culture ~iltrates of ~ y~ militaris, contains the monosaccharide cordycepose. Besides this 2'- or 3'-desoxy derivatLve of the ribonucleosides, some consider-able time ago, 2',3'-didesoxynucleosides have been ~- prepared synthetically. They have an anti-viral action and can, in particular, via~the inhibi~ion of the enzyme re~erse transcriptase~ inhibit ~he multiplication of ~ retroviruses (cf. Proc. ~atl. Acad. Sci. USA, 83, 1911/
;~ 20 1986 and Nature, 325, 773/1987). The inhibitory action on the HIV virus 9 the cause of AIDS, is of especial therapeutic interest. However, they have the disadvantage ~ :
that they are also inhibitors of cellular DNA polymerase so that they act cytotoxically. Furthermore, they can be deactivated by cellular enzymesO The compounds o ~ general formula I do not display these disadvantages.
- ~ They have an antiviral action without being cytotoxic.

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The compounds of general formula I according to the present invention can also be ad~antageously used for DNA sequencing according to Sanger's method. The sequencing of d(G-C)-xich DNA fragments is, in particular~
made difficult by the formation of secondary struc~ures which lead to a band compression in the region of d(G-C) clusters. The reason for this is the Hoogs~een base pairing of guanosine molecules. By means o the replace-ment of 2'-desoxyguanosine triphosphate by the compounds according to the present invention, in which R6 is a hydroxyl group, the band compression is largely overcome.
The compounds of general formula I according to the present invention, in which R6 and R7 are hydrogen atoms, are used in DNA sequencing by Sanger's method as chain tenNnators instead of the known 2',3'-didesoxy ~ounds.
Nucleic acids which, as structural components, contain one or more compounds of general formula I, can be prepared according to known processes (for example as described in Nucleic Acids Research, 14(5), 2319 et seq./l986). However, they also resul~, for example, in the case of the DNA sequencing. If compounds of general formula I, in which R6 is a hydroxyl group, are used as s~ructural components, then a nucleic acid can contain several such structural componen~s; if, as s~ructural component, a compound of general formula I is used, in which R~ is a hydrogen atom, then such a st~uctural component can only be incorporated once, namely, on the end of the chain. The nucleic acids according to the present invention are made up of 2 to 1000 and prefer-ably of 8 to 50 nucleotide structural components, nucleic acids with 15 to 30 nucleotide struc~ural components being especially pref~rred.
These nucleic acids can also be used as antiviral agents. As so-called anti-sense nucleic acids~ these nucleic acids hybridise with the ssDNA/RNA of the virus and make difficult the transcription to the virus DNA.
Such nucleic acids can be used especially as agents against AIDS since they are not decomposed or only decomposed with difficulty by the cell's own restriction enzymes.
For the preparation of pharmaceutical compositions, the compounds of general formula I, the pharmacologically compatible salts thereof or nucleic acids containing them ~:`
~ are mixed in known manner with appropriate pharmaceutical -~ carrier substances, aroma, flavouring and colouring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, are suspended or dissolved in water or an oil, for example olive oil.

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, It will be understood that the salts of compounds (I), when used in pharmaceutical com-positions will suitably be both pharmacologically compatible and pharmaceutically acceptable, by which is intended salts which have the required characteristics to render them suitable for formu-la-tion in pharmaceu-tical compositions for administration to living bodies.
The compounds according -to the present invention can be administered enterally or parenterally in liquid or solid form. As injection medium i-t is preferred to use water which contains the additives usual in the case of injection solutions, such as stabilising agen-ts J
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solubilising agents and/or buffers.
Such additives include, for example, tartrate and citrate buffers, ethanol, complex oxmers (such as ethylenediamine-tetraacetic acid and the non-toxic salts thereof1 and nigh molecular weight polymers (such as liquid polyethylene oxide~ for viscosity regulation.
; Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dis-persed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnes-um stearate, animal and vegetable fats and solid high molecular weight polymers (such as poly-ethylene glycols). Compositions suitable for oral administration can, i~ desired, contain 1avouring and sweetening agents.
- The compounds according to the present invention are usually administered in an amount of from 1 to ~ ~ 100 mg. and prefexably of from 2 to 80 m~. per day and ; per kg. body weight. It is preferred to divide up the daily dose into 2 to 5 administrations, in which case each administration comprisas 1 or 2 tablets with a content o~ active ma~erial of from 5 to lOOOmg. The tablets can also be retarded, in which case the number ; of administrations per day can be reduced -to from 1 to :~ ~
3. The active material con~ent o ~he re~arded tablets ` can~be rom 20 to 2000 mg. The active material can also be administered by injection one to eight times per day , , .

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- 15a -or by continuous infusion, in which case amounts of from 500 to 4000 mg./day normally suffice.
The following Examples are given for the purpose of illustrating the present invention:-Example 1.
2-Amino-7-desaza-2',3'-didesoxy-9-~-D-ribofuranosyl-purin-6-one a) 2-~(4,4'-Dimethoxytriphenylmethyl)-amino]-7-desaza-2'-desoxy-5'-0-(4,4'-dime_hoxytriphenylmethyl)-9-~-D-ribofuranosylpurin-6-one.
1.0 g. (3.8 mMole) 7-desaza-2'-desoxyguanosine is evaporated twice with dry pyridine a~d then suspended in 20 ml. pyridine. 4.0 g. (11.8 mMole) 4,4'-dimethoxy-triphenylme~hyl chloride and 2.5 ml. ~14.6 mMole) Hunig ~; 15 base ~N-ethyldiisopropylamine) are added thereto and the reaction mixture is stirred for 3 hours at ambient temperature.
The reaction mixture is subsequently introduced into 150 ml. of a 5% aqueous solution o sodium bicarbonate and extracted twice with lS0 ml. amounts of dichloromethane. The combined organic ex~racts are dried ~over anhydrous sodium sulphate, filtered and chromato-;graphed on silica gel 60 H (column lO x 4 cm., dichloro-methane/acetone 9:1 v/v). After evaporation of the main zone, the residue is dissolved in a little dichlorornethane and~added dropwise to a mixture of n-hexane/diethyl ether 1 v/v)0 After filtration, there are obtained 2.04 g.
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~16-(61% of theory) of the desired colourless, amorphous compound. TLC (silica gel 3 dichloromethane/acetone (8:2 v/v): Rf = 0.7; UV (methanol: ~max ~ 272 9 283 nm (shoulder) ( = 18800, 16400).
lH-NMR ([~6]DMSO): ~ = 1.75 (m, 2'-Hb), 1.86 (m, 2'-Ha);
3.09 (m, 5'-H)9 3.79 (m, 4'-H), 4.10 (m, 3'-H)3 5.19 (d, 3'-OH, J = 4.3 Hz), 5.61 (pt, l'-H~ J ~ 6.5 Hz), 6.16 (d9 6-H, J = 3.5 Hz), 6.62 (d, 5-H, J = 3.5 Hz), 10.35 (s, NH).
Analysis for C53H50N408 calc.: C 73.07; H 5~79; N 6.43 found: 73.02; 5.98; 6.34 b) 2-~(4,4'-Dimethoxytriphenylmethyl)-amino]-7-desaza-2'-desoxy-3'-0-phenoxythiocarbonyl-5'-0~(4,4'-dimethoxy-triphenylmethyl)-9- ~ -one.
~` A suspension of 1.0 g. (1.1 mMole) of the compound `~- of la) in 15 ml. dry acetonitrile is mixed with 300 mg.
~ (2.5 mMole) ~-dimethylaminopyridine and 300 ~1 ~2.2 `;~ mMole) phenoxythiocarbonyl chloride and stirred Eor 16 hours at ambien~ temperature. The reaction mixture is evaporated and ~he residue chromatographed on a silica gel 60 H column (column 10 x 4 cm., dichloromethane/
acetone; 8:2 vlv). The residue obtained by evaporation ; ~ o~ the main zone is dissolved in a little dichloromethane and precipitated out by the dropwise addition of a ` ~ mixture o~ n-hexane/diethyl ether (1:1 vlv) to give . ~ _ 0.99 g. (39% of theory) of a colourless, amorphous ~' .

substance. TLC (silica gel, methylene dichloride/
acetone (8:2 v/v): Rf = 0.8; UV (methanol): ~ max =
269, 282 nm (shoulder) (~ = 19300, 16000).
lH-NMR ([D6]DMS0): ~ = 2.06 (ml 2l-Hb) 9 2.34 (m, 2'-Ha), S 3.26 (m, 5'-H), 4.25 (m, 4'-H), 5.61 (m, 3'~H and l'-H), 6.23 (d, 6-H, J = 3.5 Hz)~ 6.67 (d, 5-H, J = 3.5 Hz), 10.41 (s, NH).
Analysis for C60H54N4O9S (M~Wo 1007.2) calc. : C 71.77, H 5.40, N 5.56, S 3.18 found: 71.26, 5.43, 5.52, 3.11 c) 2-[(4,4'-Dimetho~ytriphenylmethyl)-aminol~7-desaza-2',3'-didesoxy-5'-0-(4,4'-dimethoxytriphenYlmethyl)-9-~-D-ribofuranos~lpurin-6-one.
;~ 500 mg. (0.5 mMole~ of the compound of lb) in 20 ml.
freshly distilled toluene are mixed with 30 mg. (0.2 mMole) 2,2'-azo-bis-(2-methylpropionic acid nitrile) and 300 ~1~ ( l o l mMole) tributyl tin hydride and stirred for 3 hours under an atmosphere of argon at 80C. (TLC
monitoring, chloroform/methanol 97:3 v/v). After completion of the reaction, the reaction mixture i9 evaporated and the residue chromatographed on silica gel .
60 H (column 30 x 4 cm.; dichloromethane/methanol 99:1 vfv). After evaporation of the main zone and ~aking up ;~ in a llttle dichloromethane, 320 mg. (75% of theory) of the desired amorphous, ~olourless compound is precipit-~- ated out by dropping into n-hexane/diethyl e~her. TLC
(silica gel, methylene chloride/methanol~ 95:5 v/v~:
Rf . 0.5.

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lH-NMR ~[D6]DMSO): ~ = 1.63, 1-80 (2 m, 2'-H and 3~-H), 3O07 (m, 5'-H), 4006 (m~ 4'-H), 5.43 (m, l'-H), 6.11 (d, 6-H, J = 3.5 Hz~, 6.65 (d, 5-H5 J = 3.5 Hz~9 10.34 (s, NH).
d~ 2-Amino-7-desaza-2',3'-didesoxy-9-~-D-ribofuranosyl-purine-6-one.
300 mg. (0.35 mMole) of the compound from lc) are dissolved in lO ml. 80% acetic acid and stirred for 15 minutes at ambient temperature. Subsequen~ly, the solvent is stripped off at oil pump va-cuum and ~he residue evaporated several times with wa~er. The crude product is chromatographed on silica gel 60H ~column 10 x 4 cm., dichloromethane/methanol 9:1 v/v). The foamy substance obtained by evaporation of the main fraction ls crys~allised from a little methanol to give 50 mg. (57% of theory) of colourless needles; m.p.
- 228C. (decomp.). TLC (silica gel, dichloromethane/
methanol 9:1 v.v): Rf = 0.3.
~ UV (methanol): ~max = 2613 281 nm (shoulder~ (~ = 133009 ;~ 20 7800).
H-NMR ([D6~DMSO): ~ = 1.96 ~m, 3'-H), 2.08, 2.27 (2 m, 2l-Ua and 2'-Hb), 3.48 (m, 5'-H)9 3.97 (m, 4'-H), 4086 (t, 5'-OH, J = 5.4 Hz)9 6.12 (pt~ l'-H, J = 5.5 Hz), 6.24 (m, NH2 and 6-H~, 6.92 (d9 5-H, J = 3.5 Hz), 10.34 (s, NH).
Analysis for CllHl~N4O3 (M.W. 250-3) calc. . C 52.79, H 5.64, N 22.39 found : 52.98, 5.80, 22.55 In an analogous manner, via the corresponding 2'-desoxynucleosides and subsequent deoxygenation as in c), there are obtained the following compound6:
A) 3?7-didesaza-2',3'-didesogy-9-~-D-ribofuranosyl-purine UV (0.1 N HCl): ~ max = 224, 274 nm Analysis for C12H14N202 (M.W. 218.2) calcO : C 66.0, H 6.4, N 12.8 found : 66.1, 6.4, 12.6 B) 3,7-didesaza-2',3'-didesoxy-9-~-D-ribofuranosyl-purin-6-one ) ~max = 264 nm ( = 11600), 282 nm ~ =
8000), 295 nm (~ = 5200) ~; Analysis for C12H14 2 3 calc. : C 61.5, H 6O0~ N 11.95 found : 61.3, 6.1, 11.8 C) 2-chloro-6-methoxy-3,7-didesaza-2',3'-didesoxy-9-~-D-ribofuranosylPurine .
UV (methanol): ~ max = 271, 280 nm ~alysis for C13Hl5N203Cl (M.W. 282.6) calcO C 55.2, H 5.3, N 9.9 found : 55.1, 5.3, 9.9 D) 6-amino-3,7-d_desaza-2',3'-d des~-9-R-D-ribo~
furanosylpurine Analysis for C12H15 3 2 calc. : C 63.65, X 6.16 N 17.13 found : 63~62, 6 11, 17.01 ' `' UV (methanol) ~max = 271 nm ( = 12800) E) 3,7-didesaza-2',3'-didesoxy-9-~-D-ribofuranosylpurine-.
2,6-dione An~lysis for C12H1gN2OA ~M.W. 250.2) calc. : C 57.55 H 5.6 N 11.2 found : 57.50 5~7 11.2 Example 2.
. _ 2-~{[(Dimethylamino)-methylene]~amino~-7-desaza-2e,3'-_ _ _ _ _ _ didesoxy-9-~-D-r _ofuranosyl~l-rin-6-one.
a) 2 [(Dimethylamino)-methylene]-a_ino-7 desaza-2'-desoxy-9-!3-D-ribofuranosylpurin-6-one.
270 mg. (1.01 mMole) 7-desaza-2'-desoxyguanosine in 5 ml. dry, amine-free dimethyl~ormamide are mixed with 2 ml. (11.7 mMole) N,N-dimethylormamide diethyl acetal and stirred for 1 hour at 50C. under an a~mosphere o ` argon. Subsequen~ly9 the reaction mixture is evapora~ed in a vacuum and the residue chromatographed on silica gel 60 H (column 10 x 4 cmO ~ dichloromethane/methanol 9:1 v/v). By evaporation of the solvent, from ~he main zone there are obtained 230 mg. (71% of theory) of a pale yellow, amorphous substance. TLC (sillca gel, dichloromethane/methanol 9:1 v/v): R~ = 0.3.
UV (methanol): ~max = 240, 311 nm (~ = 18300, 17400).
H~N~R ([D6lDMSO: ~ = 2.15 (m, 2'-Hb~, 2.41 (m, 2'~Ha), 3.02, 3.15 (s, 2 CH3), 3.52 (m, 5'-H)9 3O79 ~m9 4'~H), 4.32 (m, 3'-H), 4.91 (~, 5'-OH, J = 5.4 Hæ), 5.27 (d, 3'-O~d, J = 3.5 Hz~ 9 6.34 (d, 6-H, J = 3.5 Hz), ~ 3 ~

6.45 (pt, ll-H, J = 7.0 Hz)~ 7.Q7 (d; 5-H, J = 3.5 Hz), 8.56 (s, NH=C), 11.04 (s, NH).
Analysis for C14HlgN5O4 (M.W 321.3) calc. : C 52.33, H 5.96, N 21.79 found : 52.48, 6.14, 21.69 b) 2-{E(Dimethylamino)-methylenel-amino}-7-desaza 2'-desoxy-5'-0~(4,41-dimetho~ytriphenylmeth~l)-9-,B-D-ribofuranosylpurin-6-one.
100 mg. (0.31 mMole) of the compound from 2a) are ~ 10 dissolved in 2 ml. dry pyridine, mixed with 170 mg.
`~ (0.5 mMole) 4,4'-dime~hoxytriphenylmethyl chloride and 0.2 ml. (1.2 mMole) Hunig base and stirred for 3 hours at ambient temperature. Subsequently, the reaction mixture is evaporated and the residue chromatographed on silica gel 60 H (column 10 x 2.5 cm., elution agent ~:: chloroform/methanol 99:1 v/v). The residue obtained by .
evaporation oE the main fractio~ is dissolved in me~hylene chloride and, by dropping into a mixture of : n-hexane/dîethyl ether (1:1 v/v), 160 mg. (84% of theory) of a colourless, amorphous substance are precipi~ated out. TLC (silica gel, me~hylene chloride/
methanol 9:1 v/v): R~ ~ 0.6.
~ ~ .
UV (methanol): ~ max = 2363 311 nm (~ - 38200, 18100).
H-NMR ([D6]DMSO): ~= 2.23 (m, 2~-Hb)~ 2.42 (m, 2'-Ha), 3~03 (s, CH3), 3.14 (m, 5'-H and CH3), 3.90 ~m, 4'-H), :~;. 4.33 (m,~3'-H), 5.34 (d, 3'-OH, J = 4.3 Hz), 6.34 (d, ~ : 6-H, J = 3.5 Hz), 6~49 (pt, l'-H, J = 6.8 Hz), 6.90 (d, - : :

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~ . ~, . .

2~ ~
~22-5-H, J = 3.5 Hz), 8.58 (S9 NH=C)j 11.07 (s9 NH).
Analysis for C35H37N5O6 SM.W. 623~7) calc. : C 67.40, H 5.98, N 11~23 found : 67.319 6.00, 11.17 c) Z-{[(Dime-thylamino) methylene]-amino}-7-desaza-2'-desoxy-3'-0-phenoxythiocarbonyl-5' 0-(494'-dimethoxy-triphenylmethyl)-9-~-D-ribofuranosylpurin-6-oneO
900 mgO (1.4 mMole) of the compound from 2b), dissolved in 15 ml. dry dichloromethane, are mixed with 10 340 mg. (2.8 mMole) p-dimethylaminopyridine and 250 ~
(1.8 mMole) phenoxythiocarbonyl chloride and stirred for 16 hours at ambient temperature. The solution is evapor-ated in a vacuum and the residue chromatographed on silica gel 60 H (column 20 x 4 cm., chloroform/acetone 7:3 v/v). The residue obtained by evaporation of the main zone is ~aken up in a little dichloromethane and the desired colourless, amorphous compound precipitated ; out by dropping into n-hexane/diethyl sther (1:1 v/v).
TLC (silica gel, methylene chloride/me~hanol 95:5 v/v):
R = 0 5 ~ ma~ = 235, 277 (shoulder), 283, 312 nm-(~ = 41300, 11400, 12600, 17000).
H-NMR (~D6]DMS0): ~ = 2.73 ~m, 2'-Hb), 2.97 (m, 2'-Ha)9 3.01, 3.10 (s, 2 CH3), 3.37 (m, 5'-H), 4~33 (m, 4'-H), 25 5.90 (m, 3'-H), 6.40 (d, 6-H, J - 3.5 Hz), 6.55 (pt, H), 6.98 (d, 5-H, J = 3.5 Hz), 8.58 (s, CH=N), ~ 30 (s, NH).
,; , `

,:

L 2 ~ ~L

Analysis for C42H41N5O7S (M.W. 759.9) calc. : C 66.39, H 5.44, N 9.22, S 4.22 found : 66.49, 5.55, 9.25, 4.29 d) 2-~(Dimethylamino3-methylene]-amino}-7-desaza-2',3' didesoxy-5'-0-(4,4'-dimethoxytriphenylmethylj-. _ 9-~-D-ribofuranosylpurin-6-one.
500 mg. ~0.7 mMole) of the compound Erom 2c), dissolved in 20 ml. freshly distilled toluene, are mixed with 25 mg. (0.15 mMole) 2,2'-azo-bis-(2-methylpropionic acid nitrile) and 500 ~1. (1.9 mMole~ tributyl tin hydride and stirred for 16 hours at 80C. under an atmosphere of argo~. 5ubsequently, the reactlon mixture is evaporated under oil pump vacuum and the residue chromatographed on silica gel 60 H (column 20 x 4 cm., dichloromethane/acetone 9:1 v/v, chloroform/acetone 7:3 v/v, chloroform/acetone 6:4 v/v). The residue obtained by evaporation of the main fraction is dissolved in a little dichloromethane and precipi~ated out by dropping into n-hexane/diethyl ether to give 320 mg. (80% of theory) of the desired colourless~ amorphous compound.
TLC (silica gel~ methylene chloride/me~hanol 95:5 v/v):
R~ = 0.3.
~ max. = 236, 277 (shoulder3, 284 312 nm ( ~= 37200~ 12000, 13500, 1~000).
lH-NMR (~D6]DMSO): ~ = 2.02 (m, 3'-H), 2.20, 2.33 (m, 2'-Ha and 2'-Hb), 3.02~ 3.13 (s, 2 CH3), 3.08 (m, 5'-H), 4.17 (m, 4'-H), 6.31 (d, 6-H, J = 3.5 Hz), 6.38 (m, l'-H)p 2 ~ ~
-2~-6.92 (d, 5-H, J = 3.5 Hz) 7 8.61 (s, CH=N), 11.03 (s, NH).
Analysis for C35H37N~G7 (~-W- 607-7) calc. : C 69.18, H 6.143 N 11.52 found : 69.23, 6.24, 11.61 e) 2-{l(Dimethylam_no)-methylene] amino~-7-desaæa-2',3'-didesoxy-9-!3-D-ribofuranosylpurin-6-one.
130 mg. (0.21 mMole) of the compound from 2d) are dissolved in 80% acetic acid and stirred for 15 minutes at ambient temperature~ Subsequently, the acetic acid is evaporated off under oil pump vacuum and the residue is chromatographed on silica gel 60 H (column 20 x 2 cm., ,~ dichloromethane/methanol 95:5 v/v). The residue obtained by evaporation of the main fraction is foamed ~ up by repeated evaporation with acetone to give 43 mg.
; 15 (67% of ~heory) o~ the, desired colourless, amorphous compound. TLC ~silica gel, dichloromethane/methanol 9:1 v/v): R~ = 0.5. ' ) max. = 239, 282 (shoulder), 311 nm ~' ( = 17400, 10500, 16900).
lH-NMR ([D6]DMSO): S = 2.06, 2.3~ (m, 2'-H and 3'-H), 3.01, 3.14 (s, 2 CH30~, 3.51 (m, 5'-H), 4.00 (m, 4'-H), 4.87 (t, 5'-OH~, 6.33 (m, l'-H and 6-H, J = 3~3 Hz), 7.05 (d, 5-H, J = 3.3 Hz), 8.59 (s, CH=N), 11.02 (s, NH).
; Analysis for C14HlgN5O3 calc. : C 55.07 9H 6.27,N 22.94 found : 55.23,6.41, 22.75 ~:

, Example 3.
2-Amino-6-methoxy-7-desaza-2',3'-didesoxy-9-~-D-ribofuranosylpurineO
a) 2-Amino-6-methoxy-7-desaza-2' desoxy~
ribofuranosylpurine.
543 mg. (10 mMole) finely powdered potassium hydroxide and 68 mg. (0.2 mMole) tetrabutylammonium hydrogen sulphate in 30 ml. anhydrous dichloromethane are stirred for 15 minutes at ambient tempera~ure under an atmosphere of nitrogen. Subsequently, the reaction mixture is mixed with 330 mg. (2 mMole) 2-amino-6-methoxy-7-desazapurine (2-amino-4-me~hoxy-7H-pyrrolo[2,3-d]-pyrimidine) and stirred for a further 30 minutes. After the addition of 884 mg. (2.2 mMole) 2-desoxy-3,5-di-0-~-toluoyl-~-D-erythro-pentofuranosyl chloride, stirring is con~inued for a further 3 minutes. Insoluble compon- !
ents are filtered off with suc~ion, washed with a little dichloromethane and the filtrate concentrated to about`
10 ml. Ater mixing with 3 ml. lM sodium methoxide in methanol, stirring is continued for 3 hours at ambient temperature. After neutralisation with acetic acid, the solvent is stripped off, the residue is taken up in hot water, filtered and ~he filtra~e chromatographed on an exchanger column of Dowex*(l x 2 OH ~orm, 30 x 3 cm.) (water/methanol 9:1 v/v). After stripping off the ~ solvent and recrystallising from water, from the main ; zone there are obtained 260 mg. (63% of theory) of * Trade Mark .

, ,' : : ' - ~3~ ~2~

colourless crystals; m.p. 152 - 154C. TLC (silica gel, dichloromethane/methanol 9:1 v/v): Rf = 0.7.
UV (methanol): ~ max = 225, 259, 285 (~ = 24900, 36009 lH-NMR ([D6]): S = 6~27 (lH9 d, J = 3.7 Hz), 6.42 (lH, d~ Jl~,2~a ~-4 Hz~ Jl',2'b = 5 9 Hz), 7.10 (lH, d, J = 3.7 Hz) ppm.
13C-NMR (~D6]DMSO):~ = 52.49 (OCH3), 82.37 (C-l'), 98.85 (C-5), 119~45 ~C-63 ppm.
b) The compound 2-amino-6-methoxy-7-desaza-2'-desoxy-9-~-D-ribofuranosylpurine ob~ained according to a) is desoxygenated in the manner described in Example lc) to give 2-amino-6-methoxy-desaza-2',3'-didesoxy-9-~-D~
ribofuranosylpurine.
Example 4.
2-Amino-6-chloro-7-desaza-2',3'-didesoxy_9-~-D-ribouranosyl~urine.
a) The compound is prepared, after acetylation of 2-amino-7-desaza-2',3'-didesoxy-9-~-D-ribofuranosylpurin-6-one (prepared according to Example ld) by halogenation according to the method described in Liebigs Ann. Chem., 1987, 15 - 14~
bj The resulting crude mixture is~ for the removal of the ace~yl protective group, left to stand or 3 hours 2$ in methanolic ammonia solu~ion at ambient temperature, then evaporated to dryness and finally chromatographed on silica gel with the elution agent chloroform/methanol.

~ .
~ ~ ' . ' ' .

, After combining the main fractions and evaporating, the residue obtained is crys~allised from water.
UV (methanol): ~ max = 235, 258, 316 t = 27800, ~300, 5800).
Analysis for CllH13N402Cl (M.W. 268.7) calc. : C 49.1,H 4.8, N 20~8,Cl 13.0 ound : 49.3,4.85, 20.7, 13.1 Example 5.
2-Amino-7-desaza-2',3'-didesoxy-9-~-D-ribofuranosyl-purine.
268 mg. (1 mMole) 2-amino-6-chloro-7-desaza-2',3'-didesoxy 9-~-D-ribofuranosylpurine are dissolved i.n 25 ml. 70% aqueous methanol 7 added to a suspension o 30 mg. prehydrogenated Pd/C (10%) in 25 ml. 70% aqueous methanol and hydrogenated until the take up of hydrogen ` is complete. The solvent is stripped of and the residue is crystallised from methanol. Yield 180 m~O (77% of theory).
Analysis for CllHl4N4O2 calc. : C S6.4, H 6.0, W 23.9 found : 56.3, 6.0, 23.7 UV (methanol): ~ ~ax = 234, 2563 314 nm (~ - 30600 41009 5200).
Example 6.
2-Amino-6-mercapto-7-desaza-2',37-didesoxy-9-~-D
ribofuranosy~purine.
53~ mg. (2 mMole~ 2-amino-6-chloro-7-desaza-2',3'-;"
~, .

, 2 ~ ~

didesoxy-9-~-D-ribofuranosylpurine and 1.5 g. (20 mMole) thiourea are suspended in 30 ml~ ethanol and heated under reflux for about 15 hours. Thereafter, the solvent is distilled off, the residue is taken up in about 25 ml. methanol and then chromatographed on silica gel 60 H (column 20 x 3 cm., dichloromethane/methanol 9:1 v/v). By evapo-ration of the main fraction and crystallisation from methanol/water, there are obtained 2~0 mg. ~43% of theory) o~ the thio compound.
10 Analysis for CllH14N4O2S (M.W. 266.3) calc. : C 49.6, H 5.3~ N 21.0 found : 49.4, 5.4, 21.1 UV (methanol): ~ max = 235, 271, 345 nm ( = 1760009 11700, 18700).
15 lH-NMR ([D6~DMSO)- ~ = 1.9 (~, 3'-H), 2.1 (m, 2'-Hb)~
2.34 (m, 2'-Ha), 3.50 (m, 5'-H), 3.97 (m, 4'-H), 4.86 (t, S'- OH), 6.12 (m, l'-H), 6.24 (m, NH2 and 8-H), 6.92 (d, 7-H), 11.1 (s, NH).
~- ' ' ;
20 2,6-Diamino-7-desaza-2',3'-didesoxy 9-~-D-ribo-furanosylpurine.
26~ mg. (1 MMole) 2-amino-6-chloro-7-desaza-2',3'-; didesoxy-9-~-D-ribofuranosylpurine are mixed with 40 ml.
- aqueous concentrated ar.lmonia solu~ion and heated for 60 hours at 65C. on a waterbath in a tightly clased vessel.
After evaporation of the solvent, the residue is chromatographed on a silica gel column, first with . .

. ., . ~ , .

' ~ .

~ 3 ~

dichloromethane/methanol (9:1 v/v) (starting material) and then with chloroform/methanol (4:1 v/v). A~ter crystallisation from water, there are obtained 120 mg.
(48% oE theory) of the desired diamino compound.
Analysis for CllH15N5O2 (M.W. 249~3) calc. : C 53.0, H 6.0, N 28.1 found : 53.15, 5.9, 28.2 UV (methanol): ~ max = 264, 284 nm ( = 9800, 8000).
H-NMR ([D6]DMSO: ~ = 1.9 (mS 3'-H), 2.1, 2.4 (2 m, 2'-Ha b~ 3.4 (m, 5'-H), 3.8 (m, 4'-H)~ 4.8 (t, S'-OH), 5.6 (s, NH2), 6.2 (dd, l'-H), 6.3 (d, 7-H), 6.7 (s, NH2), 6.9 (d, 8-H~.
Example 8.
2-Methylthio-6-~e-th~-7-desaza-2',3'-didesoxy-9-~-D-ribofuranosy~ e.
a) 2-Methylthio-6-methoxy-7-desaza-2'-desoxy ~9-~-D-r~h~ IF~e L~-500 mg. (2.56 mMole) 4-Methoxy-2-methylthio-7H-pyrrolo~2,3-d]pyrimidine and 400 mg. (1.75 mMole) benzyltriethylammonium chloride are dissolved in 20 ml.
; dichloromethane with 20 ml. of a 5% aqueous solution of sodium hydroxide as counterphase and brie1y mixed up in a vibratory mixer. 1.2 g. (3.1 mMole) 2-desoxy-3,5-~; di 0-(~-toluoyl~-~-D-erythro-pentofuranosyl chloride in a little dichloromethane, is added there~o and the vibratory~mixing continued for 30 minutes. The organic phase is separated o~f and the aqueous phase shaken up .
' '`
"
~ .

, . . . . . . . . . .

~ ' ' ` , ' , :

2 ~ ~

with dichloromethane. The combined organic extracts are washed with water and dried with anhydrous sodium sulphate. After filtration, the filtrate is evaporated and the residue dissolved in 100 ml. lM sodium methanolate in methanol. The solution is stirred for about 12 hours at ambient temperature, then evaporated and the residue is -taken up in water and adsorbed on a Dowex l-X2 ion exchanger column (30 x 3 cm., OH form).
Elution with water-methanol (1:1 v/v) gives a main zone.
After evaporation of the solvent, the residue is re-crystallised from water; yield 321 mg. (40% of theory) of colourless needles; m.p. 118C. TLC (silica gel;
dichloromethane/acetone 8:2 v/v): R~ = 0.26.
UV (methanol): ~ ~ax ~ 283, 236 nm ( = 13000, 15500).
lH-NMR ([D~]DMSO): ~ = 2.20 (m, 2'-H), 2.40 (m, 2'-H), 2.56 (s, CH3S), 3.50 (m. 5'-H2), 3.81 (m, 4'-H), 4.01 (s, CH30), 4.35 (m, 3'-H), 4.90 (t, 5'-OH, J = 5 Hz)~
5.29 (d, 3'-OH, J = 4 Hz)~ 6.48 (d, 5-H, J = 4 Hz), 6.55 (t, l'-H, J = 5 Hz), 7.47 (d, 6-H, J = 4 Hz~.
Analysis for Cl3H17N3O4S (M.W. 311.4) calc. : C 50.15, H 5.50, N 13.50, S 10.30 found : 50.2~9 5.47, 13.56, 10.31 b) 2-Me~lthio-6-methoxy-7-desaza-2',3'-didesoxy-9-~3b~.
This is prepared by deoxygena~ion of the 2'-desoxy ` compound obtained according to a) in the manner des-cribed ln Example lc~.

-` ~3~ ~ 2~1 UV Smethanol): ~ max = 283, 236 (~ = 1300, 15500) Analysis for C13H17N3O3S (M.W. 295.4) calc. : C 52.8, H 5.75, N 14.2 found : 52.6, 5.70, 14.2 Example 9.
6-Methoxy-7-desaza-2',3'-d _esoxy-9~~-D-ribofuranosyl-a) 6-M~ xy-7-desaza-2'-desox~-9-~-D-ribofuranos~l-purine.
The synthesis of this co~pound takes place in the manner described in Liebigs Ann. Chem., 1985, 1360-1366.
b) The didesoxy derivative can be obtained by deoxygenation of the compound obtained in a) in the manner described in Example lc).
~, . .
An alternative way is the desulphurisation of 2-methylthio-6-methoxy-7-desaza-2',3l-didesoxy-9-~-D-ribofuranosylpurine from Example 8, also in the manner described in LLebigs Ann. Ghem. 9 1985, 1360 - 1366.
TLC (dichloromethane/methanol 9:1 v/v~ Rf = 0.8.
UV (methanol): ~ max = 261 nm (log ( ) = 3.86).
H-NMR (DMSO-d6): ~ = 2.04 (m, 3'-H), 2.24 (m, 2'-}lb), 2.40 (m, 2'-Haj, 3.55 (m, 5'-H), 4.04 (s, ~CH3), 4.07 (m~ 4'-H), 4.93 ( t, J = 5.5 Hz, 5'-OH), 6.47 (dd, J =
4.4 and 6.8 Hz, l'-H), 6.55 (d, J -- 3.7 Hz, 5-H), 7766 (d, J = 3.7 Hz, 6-H), 8.42 (s, 2-H).
, , Analysis for C12H15N33 (M-W- 249 calc. : C 57.89H 6.0, N 16.8 -~ fuund : 57.8, 6.05, 16.65 , ,(, . ......

~3~ ~2~1 Another possibility for the preparation of this compound is descxibed in Example 24i).
~.
7-Desaza-2',3'-didesoxy-9-~-D~ribofuranos~lpurin-6-one.
The preparation of this compound takes place via the 2'-desoxy compound as described in Liebigs Ann.
Chem., 1985, 312-320 and subsequent deoxygena~ion as described in Example lc).
UV ~methanol): ~ max = 2589 280 (shoulder) ~ = 9200, 6400?.
TLC (dichloromethane/methanol 9:1 v/v): Rf = 0.5.
;~ lH-N~R (DMS0-d6): ~ = 2.00 (m, 3'-H), 2.16 (m, 2'-Hb), 2.37 (m, 2'-Ha), 3.49 (dd7 J = 4.9 and 11.6 Hz, 5'~H), 3.58 (dd, J = 4.2 and 11.6 Hz, 5'-H), 4~05 (m, 4'-H), 6.33 (dd, J = 4.2 and 6.9 Hz, 1'-~), 6.50 (d, J = 3.5 Hz, 5-H), 7.36 (d, J = 3.5 Hz5 6-~), 7.90 (s, 2H).
AnalYSis for C11~13 3 3 calc. : C 56.1, H 5.5, N 1798 found : 56.0, 5.3, 18.0 ~; 20 A further possibility for the preparation of this compound is described in Example 24j~.
~ Example 11.
;~ 7-Desaza-2',3'-didesoxy-9-~-D-r bofuranosylpurine-2,6-dione.
The syn~hesis of this compound -~akes place via the 2'-desoxy compound as described in Liebigs Ann. Chem., 1985, 312-320 and subsequent deoxygenation as described in Example lc).

;
..

3~ ~2~1 UV (phosphate buffer; pH 7-0)o ~ max = 251~ 280 ~m ~ 500, 7400) Analysis for C11~13N3O4 (M.W. 251.4) calc. : C 52.5, H 5.2, N 16.7 found : 52.3,5.1, 1605 xample 12.
2,6-Dimethoxy-7-desaza-2',3'-didesoxy-9-~-D-ribouranosylpurine.
This derivative is synthesised by phase transer glycosylation and subsequent deoxygenation as described in Example lc).
UV (methanol): ~ ~ax ~ 257, 271 nm (~ = 7300, 7400) Analysis for C13H17 3 4 calc. : C 55.859 H 6.1, N 15.0 found . 55.7, 6.1 15.1 ; ` Example 13.
6-Amino-7-desaza-2',3'-didesoxy~-~~D-ribo ura~y ~' ` urin-2-one.
This compound is ob~ained according to J. Chem.
20 Soc., Perkin Trans. II, 1986, 525 - 530 by phase transfer glycosylation of 2-methoxy-6-amino-7-desazapurine, subsequent deme~hylation and finally deoxygenation ~- ~ analogously to Example lc).
UV (methanol): ~ max = 255, 305 nm ~ = 7600, 7200) 25 Analys iS 11 14 4 3 - calc. : C 52.7, H 5.6, N 22r4 ~ound : 52.75~ 5~5, 22.3 :

Example 14.
2-Amino-7-desaza-7-methyl-2',3'-didesoxY-9-~-D-ribofuranosylpurin-6-one.
This compound is synthesised via the 2'-desoxy-nucleoside described in Liebigs Ann. Chem., 1984, 708-721 with subsequent deoxygena~ion as described in Example lc).
) ~ max. = 224, 264, 285 nm (shoulder) (~ = 22500, 10500, 6500) Analysis for C12H16N403 (M.W. 264.3) calc. : C 54.5, H 6.05, N 21.2 found : 54.3, 6.1, 21.1 Example_15.
2-Amino-7-desaza-2',3'-didesoxY-3'-azido-9-~-D-ribofuranosylpurin-6-one.
.
This compound is prepared by glycosyla~ion of 2-amino-7-desazapurin-6-one with the azido sugar prepared according to Byatkina/Azhayev (Synthesis, 1984, 961-963).
UV (methanol): ~ max = 261, 281 nm (shoulder) ~ 20 (~ = 13300, 7800).
`~ Analysis for GllH13N73 (M.W. 291-3) calc. : C 45.3, H 4.45, N 33.65 ~ound : 45.4, 4-3~ 33-4 Example 16.
;~ furanosylpu_ine.
~ This compound is prepared by ribosidation of 3,7-':' 2 ~ ~

didesazapurine wi~h the azido sugar prepared according to Byatkina/Azhayev (Synthesis, 1984, 961-963).
UV (methanol): ~ma~ = 224; 274 nm.
Analysis for C12H13N502 calc~ : C 55.55, H 5.0 9 N 27.0 found : 55.4, 5.1, 26.8 Example 17.
6-Amino-8-aza-7-desaza-2',3'=didesoxy-9-~-D-ribo-furanosylpuri_e (4-amino-1-(2-desoxy-~-D-erythro~
; lO pentofuranosyl)-lH-pyrazolo[3,4-d]pyrimidine) a) 4-Benzoylamino~ 2'-desoxy-9-~-D-erY~hro-pento=
furanosyl-5'-0-(4,4'-dimethoxytriphenylmethyl)-lH-pyrazolo~3,4-d]~yrimidine.
`~ 6-Amino-8-aza-7-desaza-2'-desoxy-~-D-ribo-furanosylpurLne is prepared in the manner deseribed in Helv. Chim. Acta, 68, 563 - 570/1985. The benzoylation of the 4-amino group and the subsequent intxoduction of the dimethoxytrityl protec~ive group is carried ou~
analogously to known methods.
b) 4-Benzoylamino-1-(2'-desoxy-~-D-erythro-pento-furanosyl)-5'-0-(4,4'-dimethoxytriphenylmethyl)-3'-0-phenoxy~hiocarbo~yl-lH-pyrazolo~3,4-d]-pYrimidine.
200 mg. (0.3 mMole) of the product of Example 17a) :
are reac~ed in 4 ml. acetonitrile with 82 ~1. (0.6 mMole) phenyl chlorothiocarbonate at ambient ~emperature for 16 hours in the presence of 90 mg. (0.75 mMole) 4-'~
::
~,~.,."

~3~! ~2~

(dimethylamino)-pyridine. After chromatographic purification (silica gel, dichloromethane/ethyl acetate 95:5 v/v), there are isolated 150 mg. (63% of ~heory) of the de~ired product.
TLC (silica gel 9 dichloromethane/ethyl acetate, 95~5 v/v: R~ = 0.4.
H-NI~R ([D6]DMSO): ~ = 3.26 (mS 5'-H), 3.69 (s, 2 x OCH3), 4.45 (m, 4'-H), 5.98 (m, 3'-H), 8.45 (s, 3-H)3 8.78 (s, 6-H)7 11.72 (s~ NH).
10 c) 4-BenzQylamino-1-(2',3'-didesoxy-9-~-D-glycero-pentofuranosyl)-5'-0 _(4,4'-dimethoxytriphenYlmethYl)-lH-pyrazolo[3,4-d]pyrimidine.
200 mg. (0.25 mMole) of the product of Example 17b) are deoxygenated according to Barton's method in 7 ml.
15 toluene with 150 ~1. (0.55 mMole) tri-N-butyl stannane at 80C. under an a~mosphere of argon. After chromato-graphy (silica gel, dichlorome~hane/ethyl acetate 95:5 ,~ .
v/v), there are obtained 120 mg. (75% of theory) of the :
;~ desired colourless and amorphous product.
TLC (silica gel, dichloromethane/ethyl acetate 95:5 v/v):
Rf = 0.3 H-NMR ([D6]DMSO): ~ = 2.16 (m, 3'-H), 2.49 (m, 2'-H), 2.99 (m, 5'-H), 3.65, 3.68 (2s, 2 x OCH3)9 4.32 (m, 4'-H), 6.69 (m, l'-H), 8.41 (s, 3-H), 8.80 (s, 6-H), 11.66 (s, NH).
d) 6~Amino-8-aza-7-desaza-2',3'-didesoxY-9-~-D-ribo-fur_nosyleurine (4-amino-1-(2'~3'-didesoxy-~-D
glyceropentofuranosyl)-lH-pyrazolo~3,4-d]pyrimidine) ' ~''' , . ' ' :

:

a) 300 mg. (0.47 mMole) of th~ product of Example 17c) are treated in 40 ml. ammonia-saturated methanol at 60C. for 4 hours and then evaporated to dxyness. There are obtained 200 mg. (81% of theory) 4-amino-1-(2',3'-didesoxy-~-~-glyceropentofuranosyl)-5'~0-(4,4'-dimethoxy-triphenylmethyl) lH-pyrazolo~394-d]pyrimidine in the form of a colourless foam after chromatography on silica gel (dichloromethane/acetone 7~3 v/v).
TLC (silica gel, dichloromethane/acetone 8:2 v/v):
Rf = O. 25~
H-NMR ([D6~DMSO): ~= 2.16 (m, 3'-H), 2~45 (~ 2'-H~, 2.99 (m, 5'-H), 3.69, 3.70 (2s, 2 x OCH3)~ 4.25 (m, 4'-H), 6~52 (m, l'-H), 7.74 (s, NH2)~ 8.06 ts, 3-H), 8.24 `~ (s) 6~H).
b) 110 mg. (0.2 mMole) of the above product are stirred for 20 minutes at ambient temperature in 10 ml.
80% acetic acid. After chromatography (silica gel, ~; dichloromethane/methanol 9:1 v/v), there is obtained the ~ desired product in crystalline form. Subs~quent re-;~ 20 crystallisa~ion from isopropanol/cyclohexane gives 40 mg.
(85~/o of theory) of the desired product as a colourless ~ solid.
; UV (methanol): ~max ~ 260~ 275 nm ( ~ = 9000~ 10200)~
AnalySis for C10~13~52 calc. : C 51.06,H 5.57,N 29~77 found : 50.96,5.65, 29.80 ' ;
' :

3~2~L
-3~-3C-NMR ([D6]DMSO): ~ = 133 (C-8), 100.3 (C-5), 158.1 (C-6), 156.1 (C-2~, 153~6 (C-4), 84.4 (C-l'), 30.4 (C-2'), 27.4 (C-3'), 81.7 (C-4'), 64.3 (C-5').
TLC (silica gel, dichloromethane/methanol 9:1 v/v):
Rf = 0.4.
UV (methanol): ~max = 260, 275 nm (~-= 9000~ 10200 ).
lH-NMR ([D6]DMSO): ~ = 2.11 (m, 3'-H), 2~40 (m, 2'-H), 3.36 (m, l'-X), 4.0~ (m, 4'-~), 4.75 (m, 5'-OH), 6.45 (m, l'-H), 7.75 (s, NH2), 8.14 (s, 3-H), 8.18 ~s, 6-H).
Example 18.
a) 4,6-Dichloro-1-(2'-desoxy-3',5'-di 0-p-toluoyl-~-D-~rythro-pentofuranosyl)-lH-pyrrolo[3,2-c]pyridine.
A solution of 300 mg. (1.6 mMole) 4,6-dichloro-lH-pyrrolo~3,2-c]pyridine in 75 ml~ dry acetonitrile, which ~- 15 contains 450 mg. (8.0 mMole) potassium hydroxide and 30 mg. (0.1 mMole) tris-[2-(2-methoxyethoxy~-ethyl]-amine, is stirred at ambient temperature for 30 minutes under an atmosphere of nitrogen~ Whilé stirring, 625 mg.
- ~1.6 mMole) a-chloro-2-desoxy-3,5-di-0-~-toluoyl-D-erythro-pentofuranose ar~ added there~o and stirring continued for 15 minutes. Insoluble material is then filtered off and ~he filtra~e is evaporated in a vacuum.
The oily residue is chroma~ographed on silica gel (column 17 x 4 cm., elu~ion agent dichloromethane/e~hyl acetate 97:3 v/v). There are obtained 762 mg. (90% of ~heory) o$ ~he colourless, amorphous product.
H-NMR (Me2SO-d6j: ~ = 2.37 and 2.41 (2s, 2 CH3), 2.77 ' ~ . ' ''' ' (m, H-2's), 2.94 ~m, H-2'), 4.57 (m, H-41, H-5'), 5.68 (m9 H-3'), 6066 (pt, H-l'), 6.71 (d, J = 3.5 Hz, H-3), 8.00 (s, H-7).
C-N~R (Me2SO-d6): ~ = 36.8 (C-2')~ 64.2 ~C-5'), 74.9 (C-3'), 81.7 (C-1')9 85.6 (C-4'), 102.0 (C-3), 106.1 (C-7) 9 123.1 (C-3a), 129.7 (C-2), 140.0 (C-6), 140.6 (C-4), 142.4 (C-7a).
b) 4,6-Dichloro-1-(2'-desoxy-~-D-erYthro-~e~nto-furanosyl ? - lH-pyrrolo[3,2-c]pyridine.
500 mg. (0.93 mMole) of the compound of Example 18a) are dissolved in 30 ml. me~hanolic ammonia and stirred for 12 hours at 50C. The solu~ion is evaporated to dryness, the solid residue is adsorbed in silica gel 60 H (2 g.) and applied to a silica gel column (14 x 4 crn.9 elution agent chloroform/rnethanol 9:1 v/v). From the main fraction there is isolated the desired produet in the form of a colourless oil which crystallises roM
, aqueous ethanol in the forrn of colourless needles.
Yield 101 rng. (72% of theory); mOp. 180C.
lH-NMR (Me25O-d6): ~ = 2.28 (m, H-2's), 2.43 (rn, H-2'a), ; 3~56 Im, H-5'), 3.85 (m, H-4'), 4.38 (m9 H-3'), 5O02 (t, J = 5.2 Hz, 5'-oHj, 5.34 (d, J = 4.1 Hz9 3'-OH), 6.42 (pt, ~-1'), 6.67 (d, J = 3.4 Hz, H-3)9 7~89 (d, J = 3~4 Hz, H 2~, 7.96 (s, H-7)o 13C-NMR (Me2SO-d6): ~ = 40.6 (C-2'), 61.5 (C-51), 70.5 (C-3'), ~5~5 ~C-l'), 87.6 (C-4'), 101.3 (C~3) 9 106.1 (C-7)~ 123.1 (C-3a), 129.7 (C-2), 139.7 (C-6), 140.4 (C-4), 142.0 (C-7a)~

~'' . ~ .

, c) 4 Amino-6-chloro-1-(2'-desoxy~-D-erythro-pento-furan~y~ _l -p~_rolo[3 7 2-c]pYridine.
460 mg. (1.52 rnMole) of the compound of Example 18b) are dissolved in 6 ml. dry hydrazine and heated to 80C. for 60 minutes. The hydrazine is removed under a vacuum and the oily residue evaporated twice with, in each case, 10 ml. ethanol. The residue is dissolved in 40 ml. aqueous ethanol and ~hen 2 g. Raney nickel are added thereto and the mixture heated to the boil for 2 hours, while stirring. The catalyst is filtered off and thoroughly washed with hot aqueous ethanol. The filtrate is evaporated to dryness, the residue is dissolved in methanol, adsorbed on 2 g. silica gel and the solvent removed under a vacuum. This silica gel is suspended in chloroform/methanol (9:1 v/v) and applied to a silica gel column (6 x 3 cm.). Elution with chloroform/
methanol (9:1 v/v~ gives a colourless syrup from which, by crystallisation from methanol, the product can be obtained in the form of small, colourless crystals;
m.p. 232C. Yield: 207 g. (48% of theory).
TLC (chloroform/methanol 9:1 viv): Rf = 0.2.
UV (methanol)- ~ max = 277 nm ( = 14800 ), 285 nm ( = 13800).
H-NMR (Me2SO-d6): ~ = 2.20 (m, H-2'm), 2.40 (m, H-2'a), 3.51 (m, H-5'), 3.78 (m, H-4'~, 4.32 (m, H-3'), 4.89 (t, J = 5 Hz, S'-OH) 9 5.26 (d, J = 4 Hz, 3'-OH), 6.19 - (pt, H-l'), 6.S5 (s, NH2), 6.64 (d~ J = 3 Hz, H-3)9 6.83 (s, H-7), 7,36 (d, J = 3 Hz, H-2).
.

3C-NMR (Me2SO-d6): ~ = 40 (C-2 ), 61-8 (C~5 ), 70.
(C-3'), 84.7 (C-l') 9 87.2 (C-4'), 95.1 (C-7), 101.6 (C-3), 109.6 (C-3a~, 123.5 (C-2), 141.0 (C-6), 141.4 (C-7a), 152.9 (C-4).
Analysis for C12H14ClN303 calc. : C 50.80, H 4.97, N 14.81, Cl 12.50 found : 50.91, 5.05, 14.75, 12.53 d) 4-Amino-1-(2'-desoxy-~-D-erythro-pentofuranosyl)-yrrolo[3,2-c]~yridine.
A solution of 200 mg. (0.7 mMole) of the compound from Example 18c) in 30 ml. methanol, which contains 0.4 ml. o~ ammonia-saturated methanol, is hydrogenated in the presence of palladium/charcoal (50 mg., 10% Pd) at ambient temperature for 30 hours. The catalyst is fil~ered off and the solven~ removed in a vacuum.
Puri~ication by flash chromatography (column 4 x 4 cm.
elution agent chloroform/methanol/triethylamine 7:3:2 v/v/v) and crystallisation ~roM r~ethanol gives 70 mg.
(40% of ~heory) o~ the desired product in the form of colourless crystals; m.p. 205C.
TLC (elution agent chloroform/methanol/triethylamine 7:3:2 vlv/v): Rf = 0.4.
UV (methanol):~rnax. 27 H-NMR (Me2SO-d6): ~ = 2.20 (rn, H-2'b), 2.42 ~m, H-2'a), 3.51 (m, H-5'), 3.80 (m, H-4'), 4.32 (m, H-3'~, 4.91 (m, 5'-OH), 5.32 (m, 3'-OH), 6.08 (s, NH2), 6.23 (pt, H-1'), 6.65 (d, J = 3 Hz, H-3), 6.75 (d, J = 6 Hz, H-7~, ~` 42 ~3~
7.35 (d, J = 3 Hz, H-2), 7.55 (d, J = 6 Hz, H-6).
-N~ (Me2SO-d6): ~ = 39.8 (C-2'), 62.0 (C-5'), 70.8 (C-3'), ~4.5 (C-l'), 87.1 (C-4'), 96.9 (C-7), 101.5 (C-3), 11007 (C-3a), 122.5 (C-2), 13g.7 (C-6), 140.0 (G-7a), 153.7 (C-4).
AnalySis for cl2Hl5N3o3 calc. : C 57.82, H 6.07, N 16.86 found : 57.97,6.129 16.74 Example 19.
a) 6-Chloro-1-(2'-desoxy-~-D-erytnro-pentofuranosyl)-lH-pyrrolo[3,2-c]pyridin-4-one.
A solution of 400 rng. (1.32 mMole) of the compound of Example 18b) is heated to the boil ~or 30 hours in 2N
aqueous sodium hydroxide solution with a small amount of 1,4-dioxan. The reaction mixture is neutralised with 2N
hydrochloric acid, ~iltered and then applied to an Amberlite*XAD 4 column (17 x 2 cm.). Inorganic salts are removed by washing with water and then the produc~
is eluted with me~hanol. Crystallisation from wa~e~
;~ 20 gives 158 mg. (42% of theory) of colourless crystals;
m.p. 242 - 243C.
TLC (chlorofor~tmethanol 8:2 v/v): Rf = 0.5.
UV (methanol ? ~ max ~ 270 nm (~ = 11100), 292 nm ( - 9300).
lH-NMR (Me2SO-d6): ~ = 2.22 (m, H-2'b), 2.38 (m, H-2'a), 3.53 (m7 H-5'), 3.80 (m, H 4'), 4.33 (m, H-3'), 4.96 (m, 5'-OH), 5.29 (m9 3'-OH), 6.22 (pt9 H-l'), 6.54 (d, ~ Trade Mark J = 3.3 Hz, H-3), 6.96 (s, H-7), 7.38 (d, J = 3.3 Hz, H-2), 11.81 (br. NH)o 3C-NMR (Me2SO-d6): ~ = 40.5 (C-2'), 61.7 (C-5'), 70.6 (C-3'), ~5.0 (C-l'), 87.4 (C-4'), 94.g (C-7), 104.1 (C-3), 114.0 (C-3a), 123.2 (C-2)~ 129.1 (C-6), 139.2 (C-7a), 158.7 (C-4).
Analysis for C12H13ClN2O4 calc. : C 50.63, H 4.60, N 9.84, Cl 12.45 found : 50.79, 4.74, 9.80, 12.69 10 b) 1-(2'-Deso~y-~-D-erythro-pentofuranosyl)-lH-pyrrolo[3,2-c~pyridin-4-one.
A solution of 100 mg. (0.35 mMole) of the compound of Example 19a) in 15 ml. methanol is mixed with 0.5 ml.
2~% aqueous ammonia solution and hydrogenated in the presence of palladium/animal charcoal (10% Pd, 15 mg.) for 3 hours at ambient tempera~ure. The catalyst is filtered off and the filtrate evapora~ed to dryness.
The solid residue is crystallised frorn water. There are obtained 51 mg. (58% of theory) of the desired product, m.p. 147 - 148C.
~ TLC (elution agent chloroform/methanol 8:2 v/v):
; R = 0 3-f UV (met'nanol) ~ max = 264 nrn ( = 11700), 282 nm (sh, = 8000)~ 295 nm (sh, = 5100).
lH-NMR (Me2SO-d6): ~ = 2.22 (m; H-2's), 2.40 (m, H-2's), 3.52 (m, H-5'), 3.81 ~m, H-4')~ 4.32 (m~ H-3'), 4.93 (t, J - 5.4 Hz, 5'-OH), 5.32 (d~ H - 4.3 Hz, 3'-OH), 6.21 (pt, H-l'), 6.54 (d, J = 3 Hz, H-3), 6.62 (d, J = 7 Hz, H~7)~ 7.03 (d, J = 7 Hz9 H-6), 7.34 {d, J =
3 llz, H-2); 10.87 (br NH).
13C-NMR (Me2SO-d6): ~ = 40 (C-2'~ superimposed by solvent signals), 61.8 (C-5'), 70.7 (C-3'), 84.8 (C-l'), 87.4 (C-4'), 93.8 (C-7)~ 104.6 (C~3~, 115.9 (C-3a), 122.0 (C-2), 127.8 (C-6), 139.0 (C 7a), 15~.6 (C-4).
AnalySis for C13~14N24 calc. : C 59.08, ~ 6.10, N 10.60 found : 59.09, 6.07, 10.65 Example 20.
a) 1-(2' De~ y ~-D-grythro-pentofuranosyl)-4~6-dichloro-5'-0-(434'-dimethoxytrityl)-lH-pyrrolo-5~0 mg. (1.65 mMole) of the compound of Example 18b) are evaporated ~o dryness wi~h 10 ml. pyridine.
The material is dissolved in 10 ml. dry pyridine and 0.7 ml. (4.1 mMole) of Hunig's bases, as well as 690 mg. (2.0 mMole) 4,4'-dimethoxytrityl chloride, added thereto. The solution is stirred for 1 hour at ambient temperature. After the addi~ion of 75 ml. of 5% aqueous sodium bicarbnnate solution, it is extracted twice with, in each case, 75 ml. dichloromethane. The combined organic phases are dried over aTIhydrous sodium sulphate.
The sodium sulphate is filtered off and the filtrate evaporated. The residue is applied to a silica gel column (30 x 3 cm.; elution agent dichlorome~hane/
'.

11 $ ~

acetone 99:1 v/v). The product is obtained from ~he main fraction in the form of a yellowish amorphous mass. The product is dissolved in diethyl ether and precipitated out with n-hexane. Yield 740 mg. (74% of theory).
lH-NMR (Me2SO-d6): ~ = 2.39 (m, H-2'b~/ 2.64 (m, H-2'a)~
3.09 (m, H-5'), 3.72 (s, 2 OCH3), 3.96 (m, H-4'), 4.42 (m, H-3'), 5.41 (d, J = 4.8 Hz, 3'-OH), 6.47 (pt, H-l'), 6.65 (d, J = 3.5 Hz, H-3), 6.76 - 7.27 (aromat. H)~ 7.76 (ds J = 3.5 Hz, H-2), 7.89 (s, H-7).
l3C-NMR (Me2SO-d6): ~ = 40 ~C-2' superimposed by solvent signals), 55.1 (2 OCH3), 63.6 (C-5'), 70.05 (C-3'), 85.0 85.5. 85.5 (C-l', C-4', OCDMT)g 101.3 (C-3), 106.2 (C-7), 123.2 (C-3a), 129.1 (C-2), 139.8 (C~6), 140.5 (C-4) 7 142.3 (C-7a).
Analysis for C33H30C12N205 cale. : C 65.46, H 4.99, Cl 11.71,N 4.63 found : 6S.47, 5.09, 11.78, 4.56 b) ~
dichloro-5'-0-(4,4'-dimethoxytri~yl)-3'-0-phenoxy- 0 thiocarbonyl-lH-~yrrolo[3,2-c]pyridine.
300 mg. (0.5 ~Mole) of the compound of Example 20a) are dissolved in ll ml. dry acetonitrile and 350 mg.
(2.8 mMole~ 4-dimethylaminopyridine and 150 ~1. (1.1 mMole) phenyl chlorothiocarbonate added thereto and the solution is stirred for 16 hours at ambien~ temperature.
The reaction mixture is subsequently evaporated ~o dry-ness in a vacuum. The residue is chromatographed on J~

silica gel (elution agent dichloromethane). The colourless product is isolated from the main fraction.
Yield 310 mg. ( 84% of theory).
H-NMR (Me2SO-d6): ~ = 2.92 (m, H-2'a,b), 3.35 (m9 H-5'), 3.72 (s, 2 OCH3), 4.43 (m, H-4'3 9 5.89 (m9 H-3'), 6.61 (pt, H-l'), 6.71 (d, J = 3.5 Hz~ H-3), 6.81 - 7.52 (aromat. H), 7~76 (d, J = 3.5 Hz, H-2), 8.01 (s, H-7).
3C-NMR (Me2SO~d6): ~ = 37.0 (C-2'), 55.1 (2 OCH3), 63.8 (C-5'), 83.0, 84.2, 85.6~ 86.0 (C-l', C-3', C-4', OCDMT), 101.8 (C-3), 106.3 (C-7), 123.1 (C-3a), 128.9 (C-2), 140.1 (C-6)~ 140.6 (C-4), 142.4 (C~7a), 193.8 (C S).
Analysis for C40H3L~ 12 2 6 calc. : C 64.78, H 4.62, Cl 9.55, N 3.77, S 4.32 found : 64.66, 4.59, 9.65, 3.70, 4.40 c) 4,6-Dichloro-1-(2',3'-d desoxy~-D-glyceropen~o-furanosyl)-5'-0-(4,4'-dime~hoxytrityl)-lH-pyrrolo-[3,2-c]pyridine.
170 mg. (0.23 mMole) o the compound of Example 20 b) and 15 mg. (0.1 mMole) 2,2'-azo-bis-~2-methyl)-propionitrile are dissolved in, 10 ml. dry toluene under an atmosphere~of argon~ 140 ~1. (0.51 mMole) ~ri-n-butyl stannane are~added thereto, while s~lrring, and the reaction mixtùre is then further stirred for 3 hours at 80C. The solvent is removed under a vacuum and the residue chromatographed on silica gel (elutlon agent dichloromethane). From the main fraction are isola~ed 115 mg. (85% of theory) of the desired product.

. .

.
~ . .

--~7-lH-NMR (Me2S0-d6): ~ = 2.05 ~H-3'), 2.50 (H-2', super-imposed by signals of the solvent), 2.90 - 3.15 (m, H-5'), 4.25 (m, H-4')9 6.38 (m, H-l'), 6.63 (d, J =
3O4 Hz, H-3), 6~69 - 7.30 (aromat. H), 7.79 (d, J =
3.4 Hz, H-2), 7.89 (s, H-7).
d3 2,6-Dichloro-3,7-didesaza-2' 9 3'-didesoxy-9-~-D-rib_furanosylpu ine.
The dimethoxytri~yl protective group is removed from the compound of Example 20c) analogously to Example 24f).
; e) 6-Amino-3,7-didesaza-2',3'-didesoxy-9-~-D-ribofuranosylpurine.
The compound of Example 20d) is treated with hydrazine and subsequently reduced with Raney nickel in the manner described in Example 18c). There is thus obtained the compound described in Example llD).
f) 3,7-Didesaza-2',3'-didesoxy-9-~-D-~ibofuranosyl-purine.
The compound of Example 20d) is hydrogenated in the pxesence of palladium/animal charcoal/hydrogen analogously to Example 24g). There is obtained the compound already described in Example lA).
g) 3,7-Didesaza-2',3'-didesox~-9-~-D ribofuranosYl-:
purin-6-one.
The compound of Example 20d~ is ~reated with an aqueous solution of sodium hydroxide in the manner described in Example l9a) and subsequently hydrogenated ~ .

, ..

.

2 ~ ~

in the manner described in Example l9b). There is thus obtained the compound already described in Example lE).
Example 21.
2-Amino-(2',3'-didesoxy-~-D-~lYceropentofuranosYl)-lH-pyrazolo[3,4-d]pyrimidin-4-one.
This compound is prepared analogously to the method described in Example 17 via 2-amino-(2'-desoxy-9-~-D-ribofuranosyl)-lH-pyrazolo[3,4-d]pyrimidin-4-one and Barton deoxygenation of 2-amino-(2'-desoxy-3'-0-methoxy-thiocarbonyl-5'-tolUoylribofuranosyl)-lH-pyrazolo-~3,4-d]pyrimidin-4-one; m.p. 221C.
Analysis Eor CloH13~503 (M.W. 251.25) calc. : C 47.81, H 5.22, N 27.88 found : 48.01, 5.30, 27.83 13C-NMR (DMSO-d6): S = 135.1 (C-3), 99.7 (C-3a), 157.9 (C-4), 155.3 (C-6), 154.5 (C-7a), 83.8 (C-l'), 30.3 ~C-2'), 27.3 (C-3'), 81.6 (C-4'), 64.3 (C-5').
H-NL~R: ~ = 6.19 (dd, l'-H, J = 6.9, 3.5 Hz), 2.06 (m~ 3'-H).
Example 22.
3~7-Didesaza-2'-desoxy-9-~-D-ribofuranosylpurine (2'-desoxy-3,7-didesazanebularin) The compound of Example 18b) is hydrogenated in the presence of palladium/animal charcoal (10% Pd) in ammoniacal methanol. After fil~ering off ~he catalyst and evaporating the fil~rate in a vacuum, the product is purified fror,l inorganic salts by chromatography on .

Amberlite XAD (methanol/water)~ as well as by crystall-isation from water; m.p. 175 - 176C.
UV (0.lm aqueous hydrochloric acid): ~ max ~ 224, 274 nm 13C NMR ([D6]DMSO): ~ = 126.9 (C-2), 101.7 (C-3~, 125.5 (C-3a), 143.3 (C-4), 140.6 (C-6)~ 105.9 (C-7), 139.2 (C-7a), 84.6 (C-l'~, 70.8 (C-3'), 87.8 (C-4')~ 61.9 (C~S').
lH-NMR (DMSO-d6): ~ = 2.23 (m, 2'-Hb), 2.29 ~m, 2'-I-Ia), 3 55 (m, 5'-H2), 3.85 (m, 4'-H), 4.38 (m, 3'-H), 4.99 (5'-OH), 5.37 (3'-OH), 6.42 (pt, l'-H), 6.66 (d, J =
3 Uz, 3H), 7~62 ~d, J = 6 Hz, 7-H), 7.71 (d, J = 3 Hz, 2-H), 8.21 (d, J = 6 Hz, 6-H), 8.23 (s, 4-H).
Analysis for C12Hl4N2O3 calc. : C 61~53, H 6.02~ N 11.96 found : 61.55, 6.12, 12.02 Example 23.
a) 2-Chloro-6-methoxY-3,7-~ 3$b~
ribofuranosylpurine.
The compound of Example 18b) is heated for 40 hours in lN methanolic sodium methanolate solution.
The reaction product is purified on Amberlite XAD by hydrophobic chromatography (methanol/water).
UV (methanol): ~ max = 271, 280 nm.
Analysis for C13H15ClN2O4 calc. : C 52 27, H 5.U6, Cl 11.87, N 9.38 found : 52.24, 5.14, 12.05, 9.46 .

b) 2-Chloro-3,7-didesaza-2'-desoxy-9-~-D-ribo-furanosyl~urin 6-one.
Heating the compound of Example 18b) for 30 hours in 2N a~ueous sodium hydroxide solution/la4-dioxan gives the desired compound.
UV (methanol): ~ max = 262 nm Analy8iS for C13H16N24 calc. : C 59.08, H 6.10,N 10.60 fuund : 59.09, 6.07,10.65 lH-NMR ([D6]DMSO): ~ = 2.22 (m, 2'-Hb)3 2.38 (m, 2'-Ha), 3.53 (m, 5'-H2)~ 3.30 (m, 4'-H), 4.33 (m, 3'-~I), 4.96 (5'-OH) 9 5.29 (3'-OH), 6.22 (pt, l'-H), 6.54 (d, J =
3 Hz, 3-H)~ 6.96 (s, 7-H), 7.33 (d, J - 3 Hz, 2-H); 11.81 (NH).
Example 24.
a) 4-Chloro-7 (2l-desoxy-3,5-di-0-(p-toluoyl)-~-D-er~thro~entofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
1 g. (17.8 mMole) powdered potassium hydroxide is introduced at ambient temperature into 60 ml. dry acetonitrile. 100 ~1. (0.31 mMole) tris-[2-(2-methoxy-ethoxy)-ethyl~-amine.are added thereto, while stirringO
-~ A~ter 5 minutes) 1.23 g. (8.01 mMole) 4-chloro-7~-pyrrolo[2,3-d]pyrimidine are dissolved in the reaction mlxture which is stirred for a further 5 minutes.
~; ; 25 a-Chloro-2-desoxy-3,5-di-0-p-toluoyl-~-D-erythro-pento-furanose is th~n added thereto. After stirring ~or 15 minutes, insoluble material is removed by filtration.
-.

The filtrate is evaporated to dryness in a vacuum and the residue chromatographed on a silica gel column ~5 x 7 cm., chloroforr~l). After evaporation o~ the eluate in a vacuum there are obtained 3.26 g. (~1% of theory) of product which crystallises from ethano] in the form of colourless needles; m.p. 120C.
Further variants of the process of preparation:
(I) Solid-liquid glycosilation in the absence of a catalyst. The reaction is carried out as described above but without the use of a catalyst. After working up~ ~here are obtained 2.82 g. (70% of theory) of the product.
(II) By liquid-liquid phase trans~er glycosilation:
500 mg. (3.26 mMole) 4-chloro-7H-pyrrolQ[2,3-d]
pyrimidine are dissolved in 20 ml. dichloromethane.

9 ml. of 507O aqueous sodium hydroxide solution are ;~ added thereto. After the addition of 10 mg. (0.03 mMole) tetrabutylammonium hydrogen sulphate, the solution is stirred for 1 minute with a vibratory mixer.
Subsequently 9 1 ~ 4 g. (3.61 mMole) of the above-described halogenose is added thereto and mixing continued for a further 3 minutes, whereafter the phases are separa~ed.
The aqueous phase is extracted twice with, in each case, 25 ml, dichloromethane. The combined organic phases are dried over anhydrous sodium sulphate. The filtrate is evaporated to dryness and the residue is chromato-graphed on silica gel (column 5 x 5 cm., chloroform).

, .

Isolation of the product from the main fraction and crystallisation from ethanol gives 1.04 g. (63% of theory) of the desired product; m.p. 118C.
TLC (cyclohexane/ethyl acetate 3:2 v/v): Rf = 0.7.
U~ (methanol): ~ max = 240 nm (log ~ = 4.48).
lH-N~R (DMSO~d6): ~ = 2.37, 2.40 (s, 2 CH3), 2.77 (ml 2'-Hb), 3.18 (m, 2'-Ha), 4.60 (m, 4'~H and 5'-H), 5.77 (m; 3'-H), 6.75 (d, J = 3.7 Hz, 5-H), 6.78 (m, l'-H), 7.34, 7.91 (m, 8 aromat. H and 6-H), 8.65 (s, 2-H).
b) 4-Chloro~7-(2'-desoxy-~-D-erythro-pentofuranosyl)-- 7H-pyrrolo~2,3-d]pyrimidine.
2.4 g. (4.7 mMole) of the compound of Example 24a) are stirred ~or 24 hours at ambient ~emperature in 100 ml~ methanol saturated with ammonia. The solution is evaporated to dryness, ~he residue is adsorbed on 10 g. silica~gel 60 H and applied to a silica gel column (4 x 10 cm.~ chloroform/methanol 95:5 v/v). The product is isolated froDl the main fraction as a colourless, ~olid substance which crystallises from ethyl acetate as colourless needles. Yield 1.07 g. (84% of theory);
m.p. 162C.
TLC (chloroorm/methanol, 9:1 v/v): ~f = 0.6.
UV (methanol): ~ max = 273 mn (log ~ 3.69).
.
H-NMR (DMSO-d6): ~ = 2.28 (m, 2'-Hb), 2.53 (m, 2'-Ha), 3.57 (m, 5'-H), 3.87 (m, 4'-H), 4.40 (m, 3'-H), 5.00 ~; (t, J = 5.4 Hz, 5'-OH), 5.35 (d, J = 4.2 Hz, 3'-OH), 6.66 (m, l'-H), 6.72 (d, J = 3.8 Hz, 5-H), 7.99 (d, J =
3.8 Hz, 6-H), 8.66 (s, 2-H).

, , ., ~ 3 ~

c) 4 Chloro-7-(2'-desoxy-~-D-erythro-pentofuranosyl)-5'-0-(4,4'-dimethoxytrityl)-7H pyrrolo~2.3 d]-py~imidine.
1 g. (3.7 mMole) of the compound of Example 24b) is dried by evapora~ing with lO ml. dry pyridine. The material is dissolved in 20 ml. dry pyridine. 2 ~nl.
(11.7 mMole) Hunig's base and 2 g. (5.9 mMole) 434'-dirnethoxytrityl chloride are added thereto. The solution is stirred for 3 hours a~ ambient temperature. After the addition of ~0 ml. 5% aqueous sodium bicarbonatP solution, the solution is extrac~ed three times with 100 ml.
amounts of dichloromethane. The combined organic phases are dried over anhydrous sodium sulphate. After ; filtering off, ~he filtrate is evaporated in a vacuum.
The residue is purified by column chromatography (silica gel, elution agent dichloromethane and dichloromethane/
ethyl acetate 9:1 v/v). Isola~ion of the product from the main ~raction, dissolving in diethyl ethPr and pre-cipitation with petroleum ether gives 1.66 g. (78% of theory) of the desired product in the form of a yellowish amorphous substance.
Analysis ~or C32H30N305Cl (M.W. 572.1) calc. : C 67.19, H 5.29, Cl 6.20, N 7.35 , .
found : 67.03, 5.47, 6.19 7.29 TT,C (dichloromethane/acetone 9:1 v/v): R~ = 0.3.
UV (methanol): ~ max = 274 nm (log ~ = 3.~5).

, t~
-5~-lH-NMR (DMSO-d~): = 2.36 (m, 2l-Hb), 2.70 (m, 2'-Ha), 3.72 (s, OCH3) 9 3.18 (d, J = 4.5 I-lz, 5'-H), 3.99 (m, 4'-H), 4.45 (rn, 3'-H), 5.42 (d, J = 406 Hz, 3'-OH), G.65 (m, l'-}~), 6.69 (d, J = 3.7 Hz~ 5-H), 7.81 (d, 5 J = 3.7 Hz, 6-H), 8.64 (s, 2-H).
d) 4-Chloro-7-(2'-desoxy-~-D-erythro-pentofuranosyl)-5'-0-(4,4'-dimethoxytrityl)-3'-0-phenoxythiocarbony~
7H-pyrrolo~2,3-d]pyrimidine.
1 g. (1.7 mMole) of the compound of Example 24c) is dissolved in 30 ml. dry acetonitrile, 500 mg. (4.1 mMole) 4-dimethylaminopyridine and 400 ~l. (2.9 mMole) phenyl chlorothiocarbonate are added thereto and the solution is stirred for 16 hours at ambient temperature.
Subsequently, the reaction mixture is evaporated to dry-ness in a vacuum and the residue applied to a silica gel column (3 x 15 cm., dichloromethane). From the main fraction, there are isolated 950 mg. (76% of theory) of colourless, amorphous product.
Analysis for C3~H34ClN306S (M.W. 708.2) calc. : C 66.14, H 4.84, Cl 5.al~ N 5.93, S 4.53 found : 66.22, 4.94, 5.12, 5.93, 4~46 ~ TLC (dichloromethane/acetone 95:5 v/v): Rf - 0.8.
;~ UV ~methanol): ~ max = 274 nm (log = 3.87).
H-NMR (DMSO-d6): ~ = 2.84 (m, 2l-Hb)~ 3.21 (m, 2'-Ha)~
3.37 (m, 5'-H), 4.46 (m, 4'-H), 5.92 (m, 3~-H), 6~70 (m, l'-H), 6.76 (d, J = 3.8 Hz, 5-H~, 7.85 (d, J =
3.g H2, 6-H~, 8.61 (s, 2-H).

2 ~ ~

e) 4-Chloro-7-(2',3'-didesoxy-~-D-~lyceropento-furanosyl)-5'-0-(4,4'-dimethoxytrityl)-7H-pyrrolo-[2J3-d]p~rlmidine.
800 mg. (1.1 mMole) of the compound of Example 24d) and 40 mg. (0.2 mMole) 2,2'-azo-bis-(2-methyl)-propio-nitrile are dissolved in 40 ml. dry toluene under an atmosphere of a~gon. 600 ~1. (2.2 mMole) tri-n-butyl stannane are added thereto, while stirring, and the reaction is continued for 2 hours at 75C. The solvent is removed in a vacuum and the residue chromatographed on silica gel (column 15 x 3 cm., dichlorQmethane/ethyl acetate 95:5 v/v). From the main fraction, there are obtained 470 mg. (75% of theory) of the desired product.
Analysis for C32H30ClN304 (M.W. 556.1) calc. : C 69.12, H 5.44, Cl 6.38, N 7.56 ound : 69.07, 5.53, 6.33, 7~58 TLC (dichloromethane/acetone 95:5 v/v): Rf = 0.5.
UV (methanol): ~ max = 273 nm (log = 3.78).
H-NMR (DMSO-d6): ~ = 2.08 (m, 3'-H), 2.10 (m9 2'-Hb), 2.43 (m, 2'-Ha), 3.11 (d~ J = 4.4 Hz, 5'-H), 3.71 (S3 OCH3), 4.27 (m, 4'-H), 6.55 (dd, J = 3.6 and 6.9 Hz, H), 6.64 (d, J = 3.7 Hz, 5-H)~ 7.83 (d, J = 3.7 Hz, 6-H), 8067 (s, 2-H).
f) 4-Chloro-7-(2',3'-didesoxy-~-D-~lyceropento-furanosyl)-7H-pyrrolo[2,3-d]~yrimidine.
400 mg. (0.7 mMole) of the compound of Example 24 e)are diFsolved in 15 ml. 80% aqueous acetic acid and ~ . .

~, :
, stirred for 30 minutes at ambient temperature. Th~
solvent is removed in a vacuum and traces of acetic acid are removed by evaporation with water. The residue is purified by column chromatography (dichloromethane and dichloromethane/methanol 3 ~8 2 v/v)- From the main fraction there are obtained 120 mg. (67% of theory) of produc~ which, after crystallisation from ethyl acetate 9 is ob~ained in the form of colourless needles; m.p.
90C .
Analysis ~or CllH12ClN302 (M.W. 253.7) calc. : C 52.08, H 4.77, Cl 13.98, N 16.56 found : S2.20, 4.81, ~ 14.04, 16.54 TLC (dichloromethane/methanol 95:5 v/v): Rf = 0.5.
UY (methanol): ~ max = 274 nm (log = 3.65).
lH-NMR ~DMS0-d6): S = 2.04 (m, 3'-E), 2.28 (m, 2'-Hb), 2.46 (m, 2'-Ha), 3.57 (m, 5' H)~ 4.11 (m, 4'-H), 4.95 (t, J = 5.5 Hz, 5'~OH), 6.52 (dd, J = 3.8 and 6.~ Hz, ~ H), 6.69 (d, J = 3.8 Hz, 5-H)~ 8.01 (d, J = 3.8 ~z, ;~ 6-H), 8.64 (s, 2-H).
~-20 g) 7-(2',3'-Didesoxy-~-D-glyceropentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
A solution of 200 mg. (0.8 mMole) of the compound of Example 24f) in 20 mlO methanol, to which had been added 0.5 ml. (6.6 mMole) of concentrated aqueous ammonia solution, is stirred with palladium on animal charcoal (40 mg., 10% Pd) in an atmosphere of hydrogen at ambient -temperature or 3 hours. The catalyst is iltered of ~ :' :~, : '' ' ' ' ' ' 2 ~ ~

and the solvent removed in a vacuum. The residue îs dissolved in water and chromatographed on an Amberlite XAD-4 column (lst elution agent water, 2nd elution agent water/methanol 8:2 v/v). Isolation of the product from S the main zone gives 130 mg~ (75% of theory) of the colourless product in the form of needles; m.p. 131C.
Analysis for C~ 132 3 calc. : C 60.26, H 5.98, N 19.17 found : 60.19, 5.97, 19.18 TLC (dichloromethane/methanol 9:1 v/v): Rf = 0.6.
UV (methanol): ~ max = 270 nm (log ~ = 3~56)~
lH-NMR (DMSO-d6): ~ = 2.06 (m, 3'-H)~ 2.27 (m, 2'-Hb), 2.42 (m9 2'-Ha), 3.55 (m, 5'-H), 4.09 (m, 4~-H)~ 4.93 ~;~ (t, J = S.5 Hz, 5'-OH), 6.54 (dd, J = 4.3 and 6.9 Hz, l~-H)s 6.67 (d, J = 3.7 Hz, 5-H)~ 7.86 (d, J = 3.7 Hz, 6-H), 8.79 (s~ 4~H), 9.01 (s, 2-H).
hj 4-~ no-7-(2',3'-didesoxy~-D-~ly~eropento-furanosyl)-7H-pyrrolo[2,3-d]pyrimidine (2~,3'-dideoxy-tubercidin) ~: f~ 20 200 mg. (0.8 mMole) of the compound of Example 24f) are stirred in 60 ml. 257 aqueous ammonia solution for 15 hours at 100C. under pressure in a steel bomb.
Th solvent is subsequently removed in a vacuum and the residue dissolved in 200 ml. water. This solution is puriied on 3Owex 1 x 2 (OH form). Th~ column i5 washed with water and the product eluted with water/
methanol (9:1 v/v). From the main zone are obtained . . ~

120 mg. (6570 of theory) of produc~.
; Tl,C tdichloromethane/methanol 9:1 v/v): Rf = 0.3.
lH-NMR (DMSO-d6): ~ = 2.03 (m, 3'-H), 2.22 (m~ 2'-Ha)~
2.33 (m, 2'-Hb), 3.53 (m, 5'-H), 4.04 (m, 4'-H), 4.99 (m, 5'-OH3, 6.35 (m, l'-H), 6051 (d, J = 3.6 Hz, 5~H), 7.00 (s, NH2), 7.34 (d; J = 3.6 Hz, 6-H), 8.04 (g, 2-H).
i~ 7-(2',3'-Didesoxy-~-D~~lyceropentofuranosYl)-4-me~hoxy-7H-pyrrolol2,3-d]p~rimidine.
170 mg. (0.7 mMole) of the compound of Example 24f) are dissolved in 5 ml. ]M methanolic methanolate solution and stirred at ambient temperature for 4 hours. The solution is neutralised with 80% acetic acid, evaporated in a vacuum and the residue applied to a silica gel column (elution agent dichloromethane/methanol 98:2 v/v).
Isolation of the main zone gives a colourless oil which, upon storing, crystallises in the form of needles.
Yield 130 mg. (78% of theory).
jj 7-(2'~3'-D _esoxv-~-D-glyceropentofuranosyl)-4H-pyrrolo[2,3-d_~yrimidin-4-one.
200 mg. (0.8 mMole) o~ the compound of Example 24f) are suspended in l0 ml~ 2N aqueous sodium hydroxide solution and boiled under reflux fox 5 hours. The solution is neutralised with 80% acetic acid and the insoluble material is removed by filtration. The iltrate is applied to an Amberlite XAD-4 column. The ~-~ eolumn is washed with 500 ml. of water and the produc~
eluted with water/isopropanol (9:1 v/v). There are ~' :

;:

2 ~ ~

obtained 180 mg. (80% of theory) of product.
Example 25.
1-(2',3'-Didesoxy-~-D-glyceropentafuranosyl)-lM-pyrazolol3.4-d]pyrimidin-4-one.
The produc~ of Example 17d) is deaminated with adenosine deaminase from intestinal c:al-f mucosa cells.
The progress of the reaction is moni~ored UV spec~ro-scopically at 275 nm. The reaction gives the produc~
quantitatively in the form o~ colourless crystals;
m.p. 171C.
UV (methanol): ~max = 251 nm ( = 7700) ; TLC (silica gel, dichloromethane/methanol 9:1 v/v):
; R~ = 0.5.
3C-NMR ([D6]DMSO): ~ = 135.2 (C-8), 106.1 (C-5), 157.3 ~C-6), 14~.4 (C-2), 152.3 (C-4), 84~6 (C-l'), ~` 30.7 (C-2l), 27.3 (C-3'), ~2.2 (C 4'), 64.2 (C-5').
H-NMR ([D6]DMSO): ~ = 2.13 (m, 3'-H), 2.40 (m, 2'-H), 3~40 (m, 5'-H), 4.09 (m, 4t-H), 4.73 (m, 5'-OH), 6.43 (m, l'-H), 8.11 (s, 3-H), 8.13 (s, 6-H).
Example 26.
2-Amino-7-desaza-2',3'-didesoxy-9-~-D-ribofuranosyl-purin-6-one 5'-triphos~ate.
Analy8is ~or CllH14H4~2P3Na3 calc. : P 16.7 found : 16.4 UV (bufer9 pH 7 ): ~ max = 259 nm ( = 13400) :

~3~ ~2~
..

31P-NMR (D203~ 8.35 (d, P-Y), -10.0 (d, P~
-21.5 (t, P-~).
Example 27.
2-Amino-3,7-didesaza-2'-desoxy-9-~-D-ribofuranosyl-_ purin-6-one 5'-triphosphate.
AnalysiS fo~ C12H15N313P3 3 calc. : P 16.75 found : 16.5 UV (buffer, pH 7 0): A ma~ = 272 nm (~ ~ 12400).
Example 28.
3,7-Didesaza-2',3'-didesoxy-9-~-D-ribofuranosylpur:ine 5'-triphosphate.
AnalySis for C12H14N2llP3Na3 calc. P 17.7 : 15 found : 17.3 - UV (buffer, pH 7 0): ~max. 2 All of ~he triphosphates described in Examples 26 to 28 are prepared by phosphorylation of the corres-ponding nucleosides by the method described by Yoshikawa (Tetrahedron Letters, 50, 5065/1967) to give : .
he 5'-monophosphates and subsequen~ conversion into the 5'-~riphosphates by the method of Hoard and Ott . (J.A C.S., 87, 1785/1965).
`~ Exam~ 29.
:~; 25 Antiviral _ iVitY.
The stability of the N-glycosidic bond of 2',3'-didesoxynucleosides i9 bound up with the antivlral .

activityO
The hydrolysis of the bond was investigated at 25C. in three difEerent concentrations of hydrochloric acid. For this purpose~ the UV absorption (Et) was measured at 258 nm. Via ~he absorption/time cur~e, there were determined the velocity constants of the hydrolysis (k) and the half life times (T/2) on the basis of the following equation:
k = l/t x ln (Eo - Eoo)/(Et OO
EO b~ing ~he absorption at time t = 0 and Eoo being the absorption after complete termination of the reaction.
There were compared 2'93'-didesoxyadenosine (a) and 6-amino~8-aza-7-desaza-2',3'-didesoxy-4-~-D-ribofuranosylpurine (b) at 25C. The results obtained lS are set out in the following Table:
Table _ ~ lN HCl O.lN HCl O.OlW HCl ~ ~ _ _ (a) T/2 - l1.9 min. 31.5 min.
k _ 0.363 min l 0.022 min l (b) T/20.83 min. 20.4 min. 2~0 min.
_ k 0.85 min~l ~,033 ~ 0.0025 min 1 The above Table shows that the compound (b~ accord-ing to the presen~ invention is more than 10 times more stable and thus more antivirally effective than (a).

' :~
'

Claims (29)

1. Desazapurine-nucleoside derivatives of the general formula:-(I) wherein X is a nitrogen atom or a methine radical; W
is a nitrogen atom or a radical, R1, R2, R3 and R4, which can be the same or different, are hydrogen or halogen atoms, hydroxyl or mercapto groups, lower alkyl, lower alkylthio, lower alkoxy, aralkyl, aralkoxy, aryloxy, unsubstituted amino, or amino substituted once or twice by C1-C5 alkyl or C1-C5 alkyl substituted once or twice by C1-C5 alkoxy, halogen or amino; R5 is a hydrogen atom or a hydroxyl group; R6 and R7 are each hydrogen atoms or one of them is a halogen atom, cyano or azido, unsubstituted amino, or amino substituted once or twice by C1-C5 alkyl or C1-C5 alkyl substituted once or twice by C1-C5 alkoxy, halogen or amino; and one of R6 and R7 can also be a hydroxyl group when X is a methine radical and, in addition R5 and R7 can together also represent a further valency bond between C-2' and C-3'; and Y is a hydrogen atom or a mono-, di- or tri-phosphate group, as well as the tautomers and salts thereof and nucleic acids which contain one or more compounds of general formula (I) as structural components, provided that when X is nitrogen, W is CR4, and R1 is amino, at least one of Y, R2, R3, R4, R5, R6 and R7 is other than hydrogen;
and provided that when X and W are methine and R1 and R2 are both chlorine and R is hydroxy at least one of Y, R3, R5 and R7 is other than hydrogen;
and provided that when X is methine, W is nitrogen, R1 and R6 are hydroxyl and R2 is amino, at least one of Y, R3, R5 and R7 is other than hydrogen.

2. A nucleic acid containing one or more desazapurine nucleoside derivatives of formula (I), as defined in claim 1.

3. A nucleic acid according to claim 2, comprising 2 to 1000 nucleotide structural components.

4. A nucleic acid according to claim 2, comprising 8 to 50 nucleotide structural components.

5. A nucleic acid according to claim 2, comprising 15 to 30 nucleotide structural components.

6. A derivative of claim 1, wherein said aralkyl is benzyl.

7. A derivative of claim 1, wherein said aryloxy radical is phenyloxy.

8. A derivative of claim 1, wherein at least one of R1, R2, R3, R4, R6 and R7 is amino.

9. A derivative of claim 1, wherein at least one of R1, R2, R3, R4, R5, R6 and R7 is substituted at least once by an alkyl radical with from 1 to 5 carbon atoms.

10. A derivative of claim 1, wherein at least one of R1, R2, R3 and R4 is aralkyl.

11. A derivative of claim 1, wherein X is methine and at least one of R6 and R7 is hydroxy.

12. 2-Amino-7-desaza-2',3'-didesoxy-9-beta-D-ribo-furanosyl-purine-6-one.

13. 6-Amino 8-aza-7-desaza-2',3'-didesoxy-9-beta-D-ribofuranosylpurine.

14. 3,7-Didesaza-2',3'-didesoxy-9-beta-D-ribofurano-syl-purine-6-one.

15. 7-(2',3'-Didesoxy-beta-D-glyceropentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.

16. 4-Amino-7-(2',3'-didesoxy-beta-D-glyceropento-furanosyl)-7H-pyrrolo[2,3-d]pyrimidine.

17. A pharmaceutical composition comprising at least one compound of formula I

(I) wherein X is a nitrogen atom or a methine radical; W
is a nitrogen atom or a radical; R1, R2, R3, and R4, which can be the same or different, are hydrogen or halogen atoms, hydroxyl or mercapto groups, lower alkyl, lower alkylthio, lower alkoxy, aralkyl, aralkoxy, aryloxy, unsubstituted amino, or amino substituted once or twice by C1-C5 alkyl or C1-C5 alkyl substituted once or twice by C1-C5 alkoxy, halogen or amino; R5 is a hydrogen atom or a hydroxyl group; R6 and R7 are each hydrogen atoms or one of them is a halogen atom, cyano or azido, unsubstituted amino, or amino substituted once or twice by C1-C5 alkyl or C1-C5 alkyl substituted once or twice by C1-C5 alkoxy, halogen or amino, and one of R6 and R7 can also be a hydroxyl group when X is a methine radical and, in addition R5 and R7 can together also represent a further valency bond between C-2' and C-3'; and Y is a hydrogen atom or a mono-, di- or tri-phosphate group, or a tautomer thereof, or a pharmaceutically acceptable, pharmacologically compatible salt thereof, provided that when X is nitrogen, W is CR4, and R1 is amino, at least one of Y, R2, R3, R4, R5, R6 and R7 is other than hydrogen;
and provided that when X and W are methine and R1 and R2 are both chlorine and R6 is hydroxy at least one of Y, R3, R5 and R7 is other than hydrogen;

and provided that when X is methine, W is nitrogen, R1 and R6 are hydroxyl and R2 is amino, at least one of Y, R3, R5 and R7 is other than hydrogen in association with a pharmaceutically acceptable carrier.

18. An antiviral pharmaceutical composition comprising an acceptable, effective antiviral amount of a desazapurine-nucleoside derivative of formula (I) wherein X is a nitrogen atom or a methine radical; W
is a nitrogen atom or a radical; R1, R2, R3 and R4, which can be the same or different, are hydrogen or halogen atoms, hydroxyl or mercapto groups, lower alkyl, lower alkylthio, lower alkoxy, aralkyl, aralkoxy, aryloxy, unsubstituted amino, or amino substituted once or twice by C1-C5 alkyl or C1-C5 alkyl substituted once or twice by C1-C5 alkoxy, halogen or amino; R5 is a hydrogen atom or a hydroxyl group; R6 and R7 are each hydrogen atoms or one of them is a halogen atom, cyano or azido, unsubstituted amino, or amino substituted once or twice by C1-C5 alkyl or C1-C5 alkyl substituted once or twice by C1-C5 alkoxy, halogen or amino; and one of R6 and R7 can also be a hydroxyl group when X is a methine radical and, in addition R5 and R7 can together also represent a further valency bond between C-2' and C-3'; and Y is a hydrogen atom or a mono-, di- or tri-phosphate group, or a tautomer thereof, or a pharmaceutically acceptable, pharmacologically compatible salt thereof, provided that when X is nitrogen, W is CR4, and R1 is amino, at least one of Y, R2, R3, R4, R5, R6 and R7 is other than hydrogen;
and provided that when X and W are methine and R1 and R2 are both chlorine and R6 is hydroxy at least one of Y, R3, R5 and R7 is other than hydrogen;
and provided that when X is methine, W is nitrogen, R1 and R6 are hydroxyl and R2 is amino, at least one of Y, R3, R5 and R7 is other than hydrogen in association with a pharmaceutically acceptable carrier therefor.

19. A composition according to claim 18 containing an amount of said derivative (I), or salt thereof, effective to inhibit reverse transcriptase.

20. In a method of DNA sequencing according to Sanger's method, the improvement in which there is employed a derivative of formula (I) (I) wherein X is a methine radical, W is a nitrogen atom or a radical; R1, R2, R3 and R4, which can be the same or different, are hydrogen or halogen atoms, hydroxyl or mercapto groups, lower alkyl, lower alkylthio, lower alkoxy, aralkyl, aralkoxy, aryloxy, unsubstituted amino, or amino substituted once or twice by C1-C5 alkyl or C1-C5 alkyl substituted once or twice by C1-C5 alkoxy, halogen or amino; R5 is a hydrogen atom or a hydroxyl group;
R6 is hydroxyl;
R7 is a hydrogen atom, halogen atom, cyano, azido, unsubstituted amino, or amino substituted once or twice by C1-C5 alkyl or C1-C5 alkyl substituted once or twice by C1-C5 alkoxy, halogen or amino; or R5 and R7 together represent a further valency bond between C-2' and C-3'; and Y is a hydrogen atom or a mono-, di- or tri-phosphate group, or a tautomer thereof.

21. In a method of DNA sequencing employing a chain terminator in accordance with Sanger's method, the improvement in which the chain terminator is a derivative of formula (I) (I) wherein X is a nitrogen atom or a methine radical;
W is a nitrogen atom or a radical; R1, R2, R3 and R4, which can be the same or different, are hydrogen or halogen atoms, hydroxyl or mercapto groups, lower alkyl, lower alkylthio, lower alkoxy, aralkyl, aralkoxy, aryloxy, unsubstituted amino, or amino substituted once or twice by C1-C5 alkyl or C1-C5 alkyl substituted once or twice by C1-C5 alkoxy, halogen or amino; R5 is a hydrogen atom or a hydroxyl group;
R6 and R7 are both hydrogen atoms, and Y is a hydrogen atom or a mono-, di- or tri-phosphate group, or a tautomer thereof, in which R6 and R7 are hydrogen atoms.

22. A desazapurine-nucleoside derivative of formula (I), as defined in claim 1, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, or a tautomer thereof, or a pharmaceutically acceptable, pharmacologically compatible salt thereof, for use in the inhibition of the enzyme reverse transcriptase.

23. Use of a desazapurine-nucleoside derivative of formula (I), as defined in claim 1, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, or a tautomer thereof, or a pharmaceutically acceptable, pharmacologically compatible salt thereof, for the manufacture of a medicament for the treatment of virus infections.

24. Use of a desazapurine-nucleoside derivative of formula (I), as defined in claim 1, 6, 7 or 10, wherein R6 is a hydroxyl group and W is a methine radical, or a tautomer thereof, for DNA sequencing according to Sanger's method.

25. Use of a desazapurine-nucleoside derivative of formula (I), as defined in claim 1, 6, 7 or 10, in which R6 and R7 are hydrogen atoms, or a tautomer thereof, for DNA sequencing according to Sanger's method.

26. A pharmaceutical composition comprising an effectively acceptable amount of a derivative defined in claim 6, 7, 8, 9, 10 or 11, or a tautomer thereof, or a pharmaceutically acceptable, pharmacologically compatible salt thereof, in association with a pharmaceutically acceptable carrier.

27. A pharmaceutical composition comprising an effective, acceptable amount of a compound of claim 12, 13, 14, 15 or 16, in association with a pharmaceutically acceptable carrier.

28. An antiviral pharmaceutical composition comprising an acceptable, effective antiviral amount of a derivative as defined in claim 6, 7, 8, 9, 10 or 11, or a tautomer thereof, or a pharmaceutically acceptable, pharmacologically compatible salt thereof, in association with a pharmaceutically acceptable carrier.

29. An antiviral pharmaceutical composition comprising an acceptable, effective antiviral amount of a compound of claim 12, 13, 14, 15 or 16, in association with a pharmaceutically acceptable carrier.