PT92862A - METHOD FOR THE PREPARATION OF PURINE NUCLEOSIDES AS WELL AS PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS - Google Patents

Description

German, industrial and commercial BOEHRINGER MANNHEIM GmbH, established at 6800 Mannheim 31, Federal Republic of Germany, (inventors: Dr. Alfred Mertens, Dr. Harald Zilch, Dr. rer. Bernhard König and Dr. Edith Koch, residents of Western Germany), for "PROCESS FOR THE PREPARATION OF PURINE NUCLEOIDS AS WELL AS PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS".

The invention relates to substituted 2 ', 31-dideoxy-21,33-didehydropurine nucleosides, to processes for their preparation, as well as to medicaments containing these compounds.

The aim of the present invention are nucleosides and nucleotides of general formula I N.

in which stands for a hydrogen atom or an amino group, R2 signifies a halogen atom; a C1-6 alkyl group; a C2 -C6 alkenyl group; a C1-6 alkoxy group; a C1 -C6 cycloalkyl-C1 -C6 -alkoxy group; a C --C ciclo cycloalkoxy group; a C6 -C6 cycloalkylthio group; a C1-6 alkylthio group or signifies an amino group R4 R6 N-, wherein one of the groups R3 or R6 may be a hydrogen atom, or else R4 and R8 may be the same or different and independently a C1 -C6 alkyl group, a C2 -C8 alkenyl group, a C1 -C6 alkoxy group, a C1 -C6 hydroxyalkyl group, a C6 -C6 cycloalkyl group, a cycloalkyl group, C1 -C6 -alkyl-C1 -C6 -alkyl, a cycloalkenyl-C1 -C6 -alkyl-C1 -C6 -alkyl group, a C1 -C6 -alkoxy-C1 -C6 -alkyl group, a dialkoxoxy- C1 -C6 -alkoxy, a C1-6 -alkoxy-carbonyl-C1-6 -alkyl group, an aryl group, an aryl C1-6 -alkyl group, or a heteroaryl- C -C-C;-alkyl; or is an aryl, Ar-C1-6 alkyl, aryloxy, Ar-C1-6 alkoxy, arylthio, Ar-C1-6-alkylthio, or heteroarylthio; and the " aryl " and " heteroaryl " in all the above-mentioned cases of the aryl- or heteroaryl- containing groups, these may be mono- or polysubstituted by hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, amino or halogen groups; or is a saturated, unsaturated or aromatic heterocyclic ring with one oxygen atom and / or one sulfur atom and / or one or two nitrogen atoms and 3-7 carbon atoms, these rings being substituted by one or more groups hydroxy, C 1 -C 8 -alkyl, halogen or C 1 -C 6 -cycloalkylthio; 2 ì

means hydrogen or the amino group, and R 2 represents hydrogen or a C 1 -C 6 -alkylcarbonyl group or a mono-, di- or tri-phosphate group, as well as the respective optically active forms, tautomers or physiologically assimilable salts of inorganic and organic acids and bases, as well as processes for their preparation and pharmaceutical compositions containing these compounds.

Since the compounds of formula I contain asymmetric carbon atoms, the optically active forms and the racemic mixtures of these compounds are also the object of the invention.

The compounds of the present invention have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections caused by DNA viruses such as Herpes-Simplex virus, Cytomegalie virus, Papilloma virus, Varicella-Zoster virus or Epstein-Barr virus, or by RNA virus such as the Toga virus, or in particular by retroviruses such as the HTLV-I and II onco-viruses, as well as the Visna lentiviruses and HIV-1 and 2 human immunodeficiency viruses.

The compounds of formula I are shown to be particularly suitable for the treatment of clinical manifestations of human retroviral HIV infections, such as generalized persistent lymphadenopathy (PGL), advanced AIDS-related complex (ARC), and spectrum of AIDS.

It has now surprisingly been found that the compounds of formula I inhibit DNA or RNA virus multiplication in the transcription phase of virus-specific DNA or RNA. The substances may act on the multiplication of the retroviruses in particular by inhibiting the enzyme reverse transcriptase (see Proc Natl Acad Sci USA, 3, 1911, 1986 or Nature, 325, 773, 1987).

Of special therapeutic interest is the inhibitory effect on the HIV virus, the causative agent of immune deficiency disease, AIDS. For the treatment of AIDS, patients are currently administered only S. azido-S deoxythymidine (German patent regulations DE-A-3,608,606). However, the secondary effects

3'-azido-3'-deoxythymidine on bone marrow in approximately 50% of patients treated, necessitate the use of blood transfusions. The compounds of formula I do not have these disadvantages, they have an antiviral effect without being cytotoxic at pharmacologically relevant doses.

The compounds of the present invention and their pharmaceutical compositions may also be applied in combination with other medicaments for the treatment and prophylaxis of the above-mentioned infections. Examples of these other medicinal products include medicinal products applicable for the prophylaxis and treatment of HIV infections or accompanying diseases, such as 3'-azL-3'-deoxythymidine; 2 ', 3'-dideoxynucleosides such as for example 2', 3'-dideoxycytidine; 2 ', 3'-dideoxyadenosine and 2', 31-dideoxyinosine; acyclic nucleosides (for example acyclovir); interferons such as interferon A; renal secretion inhibitors such as probemicide; nucleotide transport inhibitors such as dipyridamole; and. yet immunomodulators such as interleukin II or stimulation factors such as granulocyte colony-macrophage colony factor. The compounds of the present invention and the further medicament may be administered singly, simultaneously in a single or two separate formulations, or at regular intervals, so as to obtain a synergistic effect.

Some compounds of general formula I, which are not encompassed by the present invention, are already known as medicaments. Thus, from EP-A-0,286,425 9-f-D-2 ', 3'-dideoxyribofuranosides of purine, which are used for the treatment of HIV infections. Mitsuya et al. (Proc Natl.

Acad. Know. USA, 2, 7096, 1985) and DeClercq et al. (Biochem. Pharm 37, 1317, 1988) also disclose adenine, 9-β-D-2 ', 3'-dideoxy-2', 3'-dide sidroribofuranosides derived from adenine, 2,6-diaminopurine and 7-deazaadenine, with a positive effect against HIV virus in vitro. The 6-methylamino-21,31-dideoxy-21,31-didehydro-9-β-ribofuranosylpurine compound (Biochem., Pharm., 3, 3543, 1988) is also known in the literature with a similar effect. Further nucleosides are described in EP-A-0,286,028. deazapurine, nucleic acid sequencing and 1 as antiviral agents. 4

The following are examples of the compounds of formula I in which R 2 is hydrogen or the amino group, R 2 is halogen (eg chlorine); C 1 -C 6 -alkoxy (e.g., propyloxy or isopropyloxy) which may be substituted by C 1 -C 6 -cycloalkyl (eg cyclopropylmethoxy); C1-6 cycloalkyl (e.g. cyclobutyloxy or cyclopentyloxy); aryloxy (e.g., phenyloxy, arylalkyl (e.g. benzyl) or arylalkyloxy (eg benzyloxy), which aryl groups may be substituted by hydroxy, C 1 -C 6 -alkyl (e.g. methyl (e.g. phenylthio) or arylalkylthio (eg benzylthio), which aryl groups may be substituted by hydroxy, C 1 -C 4 -alkylthio, C 1 -C 6 -alkylthio, (E.g. methyl) or halogen, or R 2 denotes a saturated, unsaturated or aromatic heterocyclic ring having one oxygen atom and / or one sulfur atom and / or one or two nitrogen atoms and C 2 -C 4 atoms (e.g., piperidino, pyrrolidino or furyl), and which may be substituted on the ring by one or more hydroxyl, C 1 -C 6 alkyl (e.g. methyl), halogen, C 1 -C 6 cycloalkylthio or aryl (eg benzylthio) which may optionally be substituted on the aryl ring by hydroxyl, C 1 -C 6 -alkyl (eg methyl) or halogen, or R 2 denotes an imidazolylthio group in which the imidazole group of C2-C8-alkyl and / or nitro in the carbon, or R2 denotes an amino group, mono- or disubstituted by C1 -C6 alkyl (e.g. ex. methyl, ethyl or isobutyl), C --C alco-alkoxy (e.g. methoxy), hydroxy-C -C-C (-alkyl (eg hydroxyethyl) and / or C--C ciclo ciclo cycloalkyl (e.g. cyclopropyl or cyclopentyl, aryl (eg phenyl) or arylalkyl (eg benzyl), the aryl groups of which may be substituted by hydroxy, C 1 -C 6 -alkyl (eg methyl), or halogen, or allyl, which may be substituted by one or more C 1 -C 6 -alkyl groups (eg dimethylallyl) or C 1 -C 6 -alkoxy (eg methoxy allyl); a hydrogen atom The components " alkyl "

mentioned in the various definitions may be straight-chain or branched and contain from 1 to 6 carbon atoms, preferably 1 to 4, as for example the methyl, ethyl, n-propyl, isopropyl, isobutyl or tert-butyl groups. In this connection, the following groups are exemplified for R2: methyl, methoxy, ethoxy, methylthio, dimethylamino, allylamino, gamma, gamma-dimethylallylamino, hydroxyl, methylamino, hydroxypropylamino, tert-butylamino, isopropylamino, isobutylamino or ethoxycarbonylmethylamino .

The cycloalkyl components of the cycloalkyl, cycloalkoxy, cycloalkylthio or cycloalkenyl groups may contain from 3 to 8 carbon atoms, preferably 3 to 6, as for example the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. In this connection the following groups are exemplified: cyclopropylmethylamino or cyclopentylmethylamino.

In the definition of R 2 the amino group may be mono- or disubstituted, preferably however mono-substituted by C 2 -C 6 -alkyl, C 2 -C 6 -alkenyl, alkoxy, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, alkoxycarbonylalkyl, arylalkyl, or heteroarylalkyl, wherein the alkyl moieties of the mentioned groups may contain from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

For the group R 2 R 3 NR 2 NR 2 NR 2 R 2, R 3 and R 5 are preferably those groups in which R 2 and R 2 are the same as a C 1 -C 6 -alkyl group, or R 2. R 2 represents a hydrogen atom and R 2 is a C 2 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, alkoxyalkyl, dialkooxyalkyl, alkoxycarbonylalkyl, arylalkyl or heteroarylalkyl groups, such as p. ex. a furanylmethyl, thienylmethyl or pyridylmethyl group.

As aryl are meant aromatic groups having 6-14 carbon atoms, such as e.g. ex. phenyl or naphthyl.

By component " heteroaryl " in all the above-mentioned heteroaryl-containing groups are meant heteroaromatic groups having one or two nitrogen atoms and a ring of 5 to 7 atoms, such as for example pyridinyl, pyrimidinyl, furanyl or thienyl. 6 ϊι?

J

Heterocyclic rings saturated or unsaturated with one oxygen atom and / or one sulfur atom and / or one or two nitrogen atoms are for example the morpholine, piperidine or piperazine rings.

Where the previously defined aryl, heteroaryl or heterocyclic rings are substituted they may be once, twice or three times, preferably nevertheless once. As substituents for the aryl or heteroaryl moieties refer to hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or haloginyl groups.

As the haloginium is meant fluorine, chlorine or bromine, preferably chlorine.

In the case that the aforementioned groups have an alkyl group as a bridging bond, for example in the case of the cycloalkyl- " alkyl " groups, alkoxy- " alkoxycarbonyl- " alkyl " aryl- " alkyl "; or " alkyl " group, that " alkyl " and preferably a C 1 -C 3 -alkyl group, in particular the methylene group. In this context, for example, the phenylmethyl (benzyl), cyclopropylmethylamino, thienylmethyl or pyridylmethyl groups are mentioned.

Where the alkyl components contain additional substituents, for example in the case of the C 1 -C 6 -hydroxyalkyl, cycloalkyl-C 1 -C 6 -alkoxy, cycloalkyl-C 1 -C 6 -alkyl groups, etc., these substituents (in the foregoing examples the hydroxyl and cycloalkyl groups) may be present at any position of the alkyl component, i.e. in the 1, 2, 3, 4, 5 or 6 positions. However, they are often at the terminal position of the respective alkyl group .

In the case where R 2 represents a heterocyclic ring it may be attached to the purine system via a heteroatom or a carbon atom. The imidazole group may thus be, for example, attached through an atom of azide or a carbon atom, for example in the 1, 2 or 4 position, to the 6-position of the purine ring.

For the purposes of the present invention, for example, the following substituents are preferred as preferred: a hydrogen atom or the amino group, R2 is a C1 -C4 alkoxy group, C1 -C4 alkylthio, \

unsubstituted or substituted by a C1 -C4 -alkyl, C1 -C6 -alkenyl, C1 -C4 -hydroxyalkyl, C1 -C6 -cycloalkyl, C1 -C6 -cycloalkyl-C1 -C4 -alkyl, C 1 -C 4 -alkoxycarbonyl-C 1 -C 4 -alkyl, aryl, aryl-C 1 -C 4 -alkyl, or heteroaryl-C 1 -C 4 -alkyl; an amino group disubstituted by C 1 -C 4 -alkyl groups; or a five- or six-membered heterocyclic ring with one nitrogen and one oxygen atom; for example, the ethoxy, methylthio, methylamino, n-propylamino, isopropylamino, isobutylamino, tert-butylamino, C2-C6 alkylamino, 2-hydroxypropylamino, cyclopropyranamino, cyclopentylamino, cyclopropylmethylamino, cyclopentylmethylamino, ethoxycarbonylmethylamino, phenylamino, benzylamino, phenylethylamino, 1-phenyl-2-propylamino, wherein the phenyl components may be substituted by methyl, methoxy or chlorine, or the thienylmethylamino, pyridylmethylamino, furylmethylamino or morpholino group, a hydrogen atom, a mono-, di- or tri-phosphate group or an acetyl group.

Possible salts of the compounds of general formula I are mainly concerned the alkali, alkaline earth and ammonium salts of the phosphate groups. As the alkali metal salts, lithium, sodium and potassium are preferred. The alkaline earth metal salts are magnesium and calcium salts. The ammonium salts are those salts according to the invention which contain the ammonium ion substituted by up to four alkyl groups having 1-4 carbon atoms and / or arylalkyl. The substituents of the ammonium ion may be the same or different.

The compounds of formula I may contain basic groups, especially amino groups, which with suitable acids can be converted into acid addition salts. Suitable acids for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.

The compounds of formula I are novel compounds. They may be prepared by analogy to known related compounds (Robins, Hansske THL 25, 367, 1984 and literature cited therein). It has proved to be particularly convenient for 8 Λ

the preparation of the compounds of formula I is a process in which a compound of formula II

(II),

in which

R 1, R 2 and R 3 have the abovementioned meanings, with a compound of formula

(III) / in which

X stands for halogen, such as fluorine, bromine or iodine, to give a mixture of the isomers IVa, b and Va,

(IV a, b) (V a, b)

a = H

in which R 2, R 2, R 2, R 2, R 2 and X have the above meanings, and thereafter the mixture of the isomers IVa, b and V a, b is reduced with a reducing agent, for example the zinc / copper pair or with similar derivatives, obtaining the compound of formula I from the crude product obtained after removal of the protecting groups of compounds IV and Vb with ammonia.

In addition to this process other processes for dideoxygenization and simultaneous introduction of double bond are described in the literature (see Jain et al., JOC 39, 30, 1974, Robins et al., JACS 98, 8204 and 8213, 1976, Adachi et al. 4, 2404, 1979, Mengel et al., THL 4203, 1977, Classon et al., Acta Chem Scand SC 3, 251, 1982, Chu et al., JOC 54, 2217, 1989). Compounds of formula I may also be prepared from the corresponding 21-deoxyriboses according to known processes of monodeoxygenation with simultaneous introduction of the double bond (see Horwitz et al., JACS 86, 1986) 1964;

McCarthy et al. JACS 88, 1549, 1966; Samukov et al, Biorg. Khim. 9, 52, 1982). Another process for the preparation of compounds of Formula I is the reaction of a 2 ', 3'-dideoxy-21,13-didehydroribose with a suitable substituted purine derivative as known in the literature by the skilled person (see p EP 0,286,028). Another method for the preparation of analogous substances is described in US-A-3,817,982.

The compounds of formula II are either known in the literature or may be prepared according to known processes. A usual method is, for example, the reaction of 6-chloropurine derivatives (Nude Acid Chemistry, Editors: L.B. Townsend, R.S. Tipson, part II, page 611, John Wiley & Sons, 1978) with nucleophiles, e.g. ex. primary or secondary amines, alcohols or thiols.

For the preparation of pharmaceutical compositions

The substances of general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavors, flavors and colorants, for example into tablets or dragees, or suspended or dissolved, Suitable carriers are those in water or oil, e.g. ex. olive oil The novel substances of general formula I according to the invention and their salts may be applied in liquid or solid form enterally or parenterally. As the medium for injection, water containing the usual additives for injectable solutions, such as stabilizers, solubilizers or buffers, is preferably used. Such additives are e.g. ex. tarato and citrate tar buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carriers are e.g. ex. amide, lactose, mannitol, methylcellulose, talc, high dispersing silica, high molecular weight fatty acids (such as stearic acid), gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable oils and high solids polymers molecular weight (such as polyethylene glycols). For oral application suitable compositions may contain if flavors and sweeteners are desired.

The compounds according to the invention are normally applied in amounts of 0.1-100 mg, preferably 0.2-80 mg per day and per kg of body weight. It is preferred to divide the daily dose by 2-5 applications, with 1-2 tablets having an active ingredient content of 0.5-1000 mg being administered per application. The tablets may also be delayed by reducing the number of applications per day to 1-3. The active ingredient content of the delayed tablets may be 20-2000 mg. The active ingredient may also be administered by injection one to eight times a day or by prolonged infusion, with doses of 5-4000 mg per day normally being sufficient.

In addition to the compounds mentioned in the examples, the following substances are further preferred in particular: 6-piperidino-2 ', 3'-dideoxy-2', 3'-didehydro-9- [D-ribofuran] silpurine 11

2. 6-chloro-21,31-dideoxy-2 ', 3'-didehydro-9-D-ribofuranosylpurine 3,6-ethylamino-21,3' -dideoxy-21,3'-didehydro-9- { 3-D-ribofuranylpurine 4. 6-ethylmethylamino-21,31-dideoxy-21,3-didehydro-9-D-ribofuranylpurine 5.6-iodo-21,3'-dideoxy- , 3'-didehydro-9- [D-ribofuranosylpurine] 6-cyclopropylmethylamino-2 ', 3'-dideoxy-21,3'-didehydro-9- [D-ribofuranosylpurine] 7,6-isopropylamino-21 2-Amino-6-n-propoxy-2 ', 3'-dideoxy-21,31-didehydro-9- 9-β-D-ribofuranosylpurine 9. 6-ethylthio-2 1,3'-dideoxy-2 ', 3'-didehydro-9- β-D-ribofuran-silpurine 10. 2-Amino-6-benzylthio-21 , 3'-dideoxy-2 ', 3'-didehydro-9-D-ribofuranosylpurine 11. 6-Ethoxy-2', 3'-dideoxy-2 ', 3'-didehydro-9- [3- 12. 6-hydroxyethylamino-2 ', 3'-dideoxy-21,31-didehydro-9-D-rifurfuranosylpurine 13. 6-cyclopentylamino-2', 3'-dideoxy-2 ', Dihydro-9-β-D-ribofuranosylpurine 14. 2-Amino-6-methoxy-2,3-dideoxy-2 ', 3'-didehyd D-ribofuranosylpurine 15. 6-n-propoxy-21,31-dideoxy-2,31-didehydro-9-D-ribofuran-silpurine 16. 6-n-butoxy- Dideoxy-21,31-didehydro-9-β-D-ribofuranosylpurine 17. 6-cyclopropylmethoxy-2 ', 3'-dideoxy-2', 3'-didehydro-9-D-ribofuranosylpurine 18 6-cyclopentyloxy-2 ', 3'-dideoxy-2', 3'-didehydro-9-D-ribofuranosylpurine 19. 6-cyclohexyloxy-2 ', 3'-dideoxy-2', 3'- dideoxy-21,3-dideoxy-D-ribofuranosylpurine 12. 6-Diethylamino-2 ', 3'-didehydro-9- dideoxy-2 ', 3'-dideoxy-2', 3'-didehydro-9-O-D-ribofuranosylpurine 23. 2-Amino-6-morpholino-2 ', 3'-dideoxy-2', 3'-didehydro-9-O-D-ribofuranosylpurine 246-gamma, gamma-dimethylallylamino-2 ', 3'- 2 ', 3'-dideoxy-2', 3'-didehydro-9-β-D-ribofuranosylpurine 26 (2-furylamino) -2 ', 3'-dideoxy- 6-benzylmercapto-2 ', 3'-dideoxy-2', 3'-didehydro-9- [D-ribofuranosylpurine 27.6 2-Amino-6-ethoxy-2 ', 3'-dideoxy-2', 3'-dideoxy-2 ', 3'-didehydro-9- 3'-didehydro-9-β-D-furanylpurine 29. 2,6,8-triamino-2 ', 3'-dideoxy-2', 3'-didehydro-9- [D-ribofuranosylpurine 30. 2-amino-6-benzylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9-D-ribofuranosylpurine 31. 2-Amino-6-cyclopropylamino-2 ', 3'- 2 ', 3'-didehydro-9'-D-ribofuranosylpurine 32. 2-Amino-6-methylamino-2', 3'-dideoxy-2 ', 3'-didehydro-9-D-ribofuranosylpurine 33 2-Amino-6-n-propoxy-2 ', 3'-dideoxy-2', 3'-didehydro-9-D-ribofuranosylpurine 34. 6-benzylamino-2 ', 3'-dideoxy- , 3'-dideoxy-2 ', 3'-didehydro-9-and-D-ribofuranosylpurine 36. 6-Isopropoxy-2', 3'-dideoxy- 2 ', 3'-dideoxy-2', 3'-dideoxy-2 ', 3'-didehydro-9-D-ribc furanylpurpurine 37. 6- (2-methyl) , 3'-didehydro-9-β-D-ribofuranosylpurine 38. 6-methyl-2 ', 3'-dideoxy-2', 3'-didehydro-9- β-D-ribofuranosyl purine 39. 6-cyclopentylmethylamine no-2 ', 3'-dideoxy-2', 3'-didehydro-9-A-D-ribofuranosylpurine 1340.

(Cyclopenten-1-yl) methylamino-2 ', 3'-dideoxy-2', 3'-dideoxy-9- (3-D-ribofuranosylpurine 41. 6-hexylamino-2 ', 3'- 2 ', 3'-didehydro-9- (3-D-ribofuranosylpurine) 42. 6-neopentylamino-2', 3'-dideoxy-2 ', 3'-didehydro-9- [D-ribofuranosylpurine 6- (2-hydroxy-1-propyl) amino-2 ', 3'-dideoxy-2', 3'-didehydro-9-D-ribofuranosylpurine 44 6- (2,2-dimethoxy-1 didehydro-9-D-ribofuranosylpurine 45. 6-ethoxycarbonylmethylamino-2 ', 3'-dideoxy-21,3'-didehydro-9-dideoxy-2', 3 ' D-ribofuranosylpurine 46. 6- (4-chlorobenzyl) amino-21,3'-dideoxy-2 ', 3'-didehydro-9-D-ribofuranosylpurine 47. 6- (4-methoxybenzyl) amino -21,3'-dideoxy-2 ', 3'-didehydro-9-β-D-ribofuranosylpurine 48. 6- (3-methylbenzyl) amino-2', 3'-dideoxy-2 ', 3'-didehydro D-ribofuranosylpurine 49. 6- (4-methylbenzyl) amino-2 ', 3'-dideoxy-2', 3'-didehydro-9- [3-D-ribofuranosylpurine 50. 6- ( 2-furylmethyl) amino-2 ', 3'-dideoxy-2', 3'-didehydro-9- S -D-ribofuranosylpurine 51. 6- (2-thienylmethyl) amino-2 ', 3'-dide 2 ', 3'-didehydro-9-D-ribofuranosylpurine 52. 6- (2-pyridylmethyl) amino-2', 3'-dideoxy-2 ', 3'-didehydro-9- -D-ribofuranosylpurine 53. 6- (3-pyridylmethyl) amino-2 ', 3'-dideoxy-2', 3'-didehydro-9-D-ribofuranosylpurine 54. 6- (4-pyridylmethyl) amino -2 ', 3'-dideoxy-2', 3'-didehydro-9-β-D-ribofuranosylpurine. EXAMPLE 1 6-Propylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9- [D-ribofuranosyl purine] a) 100 ml of chloroform, 2.1 ml of distilled dimethylformamide and , 5 ml (76 mmol) of thionyl chloride under

a nitrogen atmosphere and the mixture was stirred for 15 minutes at room temperature. 10 g (25 mmol) of 2 ', 3', 5'-triacetylinosine were introduced and the clear solution was stirred for 5 hours under reflux. The reaction mixture was poured into a solution of 250 ml of water and 6.25 g of sodium hydrogen carbonate, extracted several times with dichloromethane, the organic phase was again neutralized with 250 ml of the sodium hydrogen carbonate solution sodium hydroxide solution, dried over sodium sulfate and finally evaporated to dryness. 10.6 g of 6-chloro-9- (β-D-ribofuranosylpurine in the form of an oil are obtained. B) 4.1 g of the compound obtained in a) is stirred with 30 ml of isopropanol and 2 , 3 g (39 mmol) of n-propylamine for 3 days at reflux. The reaction mixture was brought to the mixture, the residue was dissolved in isopropanol and stirred with 10 ml of a 1M solution of sodium methoxide for 1 hour at reflux. The reaction mixture was partitioned between dryness and purified on a silica gel column (eluent: dichloromethane / methanol 98: 2). There are 2.0 g (68%) of 6-propylamino-9- β-D-ribofuranosylpurine, m.p. 165-167 ° C. (c) 2.0 g (6.47 mmol) of the compound obtained in b) were dissolved in 110 ml of absolute acetonitrile, 4 ml (26 mmol) of -acetoxyisobutyryl bromide were added and the mixture was stirred for 2 hours at room temperature. The reaction mixture was neutralized with saturated sodium hydrogencarbonate solution, extracted with ethyl acetate, dried over sodium sulfate and evaporated to dryness. 3.2 g of product are obtained which are used for the next reaction without purification. d) 2 g of the crude product obtained in c) were dissolved in 32 ml of absolute dimethylformamide, reacted with an excess of the zinc / copper pair and stirred for one hour under nitrogen. The solid wastes were filtered and the solids were distilled under high vacuum. The residue of distillation was taken up in 140 ml of ammoniated methanol and stirred for 2 hours at room temperature. The reaction mixture was evaporated to dryness and purified on a silica gel column (eluent: dichloromethane / methanol 98: 2) and the desired fractions were stirred with ether after evaporation. 0.3 g (68%) of the compound are obtained; 15, melting point 146-15 ° C. EXAMPLE 2

In an analogous manner to that of Example 1, the following compounds were obtained: a) 6- (2-methylphenylmethylamino) -21,3'-dideoxy-2 ', 3'-didehydro-9-β-D-ribofuranosylpurine with yield (yield) 58% and melting point (mp) 141-142 ° C. b) 6-Dimethylamino-2 ', 3'-dideoxy-2', 3'-dideoxy-2 ', 3'-didehydro-9-D-ribofuranosylpurine. Rend. 78%; mp 134-137 ° C. c) 6-Allylamino-21,3'-dideoxy-2 ', 3'-didehydro-9-D-ribofuran-silypurine. Rend. 51%; 138-140 ° C. d) 6-Isobutylamino-21,3'-dideoxy-2 ', 3'-didehydro-9- [D-ribofuranosylpurine]. Rend. 49% (obtained as a foam). e) 6-morpholino-21β-dideoxy-2 ', 3'-didehydro-9- β-D-ribofuran-silypurine. Rend. 71%; 75-83 ° C (with decomposition). f) (L) -6- (1-phenyl-2-propylamino) -2 ', 3'-dideoxy-21,3'-didehydro-9-D-ribofuranosylpurine. Rend. 54%; m.p. 68-750 (decomposition). g) 6-cyclopropylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9- [S-D-ribofuranosylpurine; Rend. 47%; mp 112-1140 ° C. h) 6- (2-phenylethylamino) -21,3'-dideoxy-2 ', 3'-didehydro-9- [D-ribofuranosylpurine. Rend. 58%; m.p. 116-117 ° C. i) 6-methylmercapto-2 ', 3'-dideoxy-2', 3'-didehydro-9- [D-ribofuranosylpurine]. Rend. 57%; mp 133-160 ° C. j) 6-Phenylamino-21,31-dideoxy-2 ', 3'-didehydro-9- β-D-ribofuran silpurine. Rend. 47%; mp 123-125 ° C. k) 6-methylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9- β-D-ribofuran silpurine. Rend. 64%: mp 87-920 ° C. l) 6-Ethoxy-2 ', 3'-dideoxy-2', 3'-didehydro-9- [D-ribofuranosylpurine. Rend. 45%: mp 128-130 ° C. m) 6-gamma-dimethylallylamino-2 ', 3'-dideoxy-21,31-didehydro-9? -D-ribofuranosylpurine. Rend. 48%; mp 105-109 ° C. 16

6-Propylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9-D-ribofuranosyl purine-51-triphosphate x 3 mol NEt

55.1 g (0.2 mmol) of 6-propylamino-21,31-dideoxy-2 ', 3'-didehydro-9-D-ribofuranosyl purine (Example 1) was suspended in absolute toluene and the mixture was allowed to cure under high vacuum at a slightly above room temperature (2 x 1 ml). The residue was dissolved in 2 mL of phosphoric acid trimethyl ester at 25 ° C, cooled on ice, 85 mg (0.4 mmol) of " Proton Sponge " (1,8-bis-dimethylamino naphthalene), 0.027 ml (0.15 mmol) of phosphorus oxychloride was added dropwise and after 15 minutes 0.04 ml of absolute DMF (dimethylformamide) was added. The reaction mixture was stirred for an additional fifteen minutes in an ice bath and then added dropwise to a solution of 0.5 mmol of bis-tributylammonio pyrophosphate, 2 ml of DMF, 2 ml of pyridine and 0.2 ml of tributylamine under ice-cooling. After 5 minutes, 2 ml of a 0.2 M aqueous solution of triethyl ammonium hydrogen carbonate was added to the reaction after 30 minutes, the reaction mixture was diluted with water, applied to a Sephadex DEAE column and was eluted with a linear gradient, 0.1-0.5 molar, of triethylammonium hydrogen carbonate. The desired fractions were pooled, and after two lyophilizations 68 mg (41.7%) of the title compound were obtained as the triethylammonium salt. 31 P-NMR (D 2 O / H 2 O + ethylenediaminetetraacetic acid): = 7.70 (d, P- and P), -20.16 (t, P-). EXAMPLE 4

In a manner analogous to Example 3, the following final compounds are obtained: a) 6- (2-methylphenylmethylamino) -21,3'-dideoxy-2 ', 3'-didehydro-9-D-ribofuranosylpurine- 51-triphosphate x 3 mol of NEt 31 P-NMR: Î'= -8.51 (d, P-OC and Pt), -21.04 (t, CH2). b) 6-dimethylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9- (S-D-ribofurane) - x>

milsylpurine 5'-triphosphate x 3 moles of NEt3 32 P-NMR: Î'= -7.60 (d, P- o C), -7.79 (d, P- *). -20.14 (t, P- (3) c) 6-allylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9- [D-ribofuran] -spurpurine 5'-triphosphate 3 mol of Net 3 31 P-NMR: s = -8.50 (d, P-OC), -8.74 (d, P-fr), -21.03 (t, P-O). d) 6-Isobutylamino-21,3'-dideoxy-2 ', 31-didehydro-9- [D-ribofuranosylpurine-51-triphosphate x 3 mol of NEt 31 P-NMR: Î'= -8.51 (d, P- <), -8.58 (d, P-fr), -21.08 (t, P-β). e) 6-morpholino-2,3'-dideoxy-21,3'-didehydro-9-SD-ribofuran-silpurine 5'-triphosphate x 3 mol of NEt 3 31 P-NMR: Î'= -8.62 ( d, P-1), -8.73 (d, P-fc) / -21.08 (t, P- (3) propylamino) -2 ', 3'-dideoxy-2,3'-didehydro-9-D-ribofuranosylpurine-51-triphosphate x 3 mol NEt 31 P-NMR: δ = -8.25 (d, , -8.53 (d, P-fr), -20.98 (t, CH2). g) 6- (2-phenylethylamino) -2 ', 3'-dideoxy-21,3'-didehydro-9-D-ribofuranosylpurine-51-triphosphate x 3 mol of NEt3 31 P NMR: S = -8 , 53 (d, P-CC and P-C), -20.97 (t, Ρ-β). h) 6-methylmercapto-2 ', 3'-deoxy-2', 3'-didehydro-9- [Î ± -D-ribofuranosylpurine 5'-triphosphate x 3 mol NEt3 31 P-NMR: = -8.53 (d, P-o C), -8.58 (d, P-fr), -21.14 (t, β-β). i) 6-methylamino-21,3'-dideoxy-2 ', 3'-didehydro-9- β-D-ribofuranylpurpurine 5'-triphosphate x 3 mol NEt3 31 P-NMR: Î'= -7.61 ( d, P-o C), -7.80 (d, P-fr), -20.11 (t, β-β). EXAMPLE 5 2-Amino-6-methylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9- [D-ribofuranosylpurine] a) 3.5 g (11.8 mmol) of 2-amino-6-methylamino-9-β-D-ribofuranosylpurine in 70 ml of absolute DMF was added 1.93 g (28.3 mmol) of imidazole. After stirring, t-butyldimethylsilyl chloride (2.14 g, 14.2 mmol) was added dropwise and stirring was continued for a further 20 hours. The solvent was distilled under high vacuum and the residue was purified by silica gel column chromatography

gel (eluent: dichloromethane / methanol, 98: 2). 3.18 g of 2-amino-6-methylamino-5'-O- (tert-butyldimethylsilyl) -9-β-D-ribofuranosylpurine are obtained as an amorphous solid. b) 0.44 g (1.07 mmol) of the compound obtained in a) were dissolved in 3 ml of DMSO, 0.27 g (3.58 mmol) of CS 2 and 0.46 ml of a solution 5 M NaOH, after 20 minutes 0.34 g (2.36 mmol) of methyl iodide was added dropwise and stirring continued for 2 hours at 25 ° C. The solvent was distilled off under high vacuum and the residue was chromatographed on silica gel (eluent: ethyl acetate). Fractions containing the major product were evaporated and recrystallized from ether / isohexane. 0.3 g of 2-amino-6-methylamino-5'-O- (tert-butyldimethylsilyl) -2 ', 3'-bis-O- (methylthio) thiocarbonyl-9- ribofuranosylpurine. c) 0.3 g (0.5 mmol) of the compound obtained in b) were heated to reflux temperature in 24 ml of toluene and a solution of 0.58 g (2.0 mmol) of tri-n-butyltin hydride and 27 mg (0.16 mmol) of azoisobutyric acid dinitrile in 25 ml of toluene. After 1 hour the residue evaporated on silica gel (eluent: ethyl acetate / methanol, 99: 1), 0.1 g of 2-amino-6-methylamino-2 ', 3'-dideoxy-21 , 3'-didehydro-5'-O- (tert-butyldimethylsilyl) -9-β-D-ribofuranosylpurine, melting point 97-99 ° C. d) 0.1 g (0.26 mmol) of the compound obtained in c) are dissolved in 5 ml of absolute THF (tetrahydrofuran) with 0.8 ml of a molar solution of tetrabutylammonium fluoride in THF. After 5 hours at 25 ° C the reaction mixture is evaporated to dryness, taken at 0 ° C, washed with water and dried. After chromatography on silica gel (eluent: ethyl acetate) there is obtained 60 mg of the title compound, m.p. 108-110 ° C. EXAMPLE 6

In an analogous manner to Example 5a-d the following final compounds are obtained:

2-hydroxy-6-methylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9-p-D-ribofuranosylpurine; Federal Police. ? 19

b) 2-amino-6-ethoxy-2 ', 3'-dideoxy-2', 3'-didehydro-α-D-riboxy. ranosylpurine; Federal Police. ?

c) 6- (2-thienylmethylamino) -2 ', 3'-dideoxy-21,31-didehydro-9- [D-ribofuranosylpurine] m.p. 150-152Â ° C. d) 6- (2-pyridylmethylamino) -21,3'-dideoxy-2 ', 3'-didehydro-9-

-D-ribofuranosylpurine; mp 154-156 ° C

e) 6- (4-methylphenylmethylamino) -2 ', 3'-dideoxy-2', 3'-didehydro-9- [D-ribofuranosylpurine; m.p. 133-135Â ° C. f) 6-Isopropylamino-21,31-dideoxy-2 ', 3'-didehydro-9- [3-D-ribofu

ranosylpurine; m.p. 132-133Â ° C

g) 6-cyclopentylmethylamino-2 ', 3'-dideoxy-21,31-didehydro-9-

-D-ribofuranosylpurine; m.p. 131-133C

h) 6-phenylmethylamino-2 ', 3'-dideoxy-21,31-didehydro-9- [D-ribofuranosylpurine; m.p. 127-128Â ° C

i) 6- (4-methoxyphenylmethylamino) -2 ', 3'-dideoxy-2', 3'-didehydro-9- [D-ribofuranosylpurine; m.p. 127-129 ° C. (j) 6-tert-Butylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9-β-D-ribofu

ranosylpurine; mp 184-185 ° C

k) 6-ethoxycarbonylmethylamino-21,31-dideoxy-2 ', 3'-didehydro-9- [D-ribofuranosylpurine; mp 118-120 ° C

l) 6- (2-hydroxypropylamino) -2 ', 3'-dideoxy-2', 3'-didehydro-9-D-ribofuranosylpurine; foam

m) 6- (4-chlorophenylmethylamino) -2 ', 3'-dideoxy-2', 3'-didehydro-9- [D-ribofuranosylpurine; mp 155-157 ° C

n) 6- (3-methylphenylmethylamino) -2 ', 3'-dideoxy-2', 3'-didehydro-9-β-D-ribofuranosylpurine; mp. 102-105 ° C.) 6- (2-furyl-methylamino) -2 ', 3'-dideoxy-2', 3'-didehydro-9- [D-ribofuranosylpurine; mp 158-152 ° C. EXAMPLE 7 5'-Acetyl-6- (2-methylphenylmethylamino) -2 ', 3'-dideoxy-2', 3'-dideoxy-9 - [(D-ribofuranosylpurine ___

250 mg (0.75 mmol) of the compound obtained in Example 2a in 15 ml of dichloromethane was reacted with 5 mg of dimethylaminopyridine and 113 mg (1.11 mmol) of acetic anhydride. 20

and the mixture was stirred for 4 hours at 25 ° C. The solvent was then distilled off and the residue was chromatographed on silica gel 60 (eluent: CH2 Cl2 / CH3 OH, 99: 1). 200 mg of the title compound are obtained, melting at 125 ° C. 21

Claims (1)

i t A process for the preparation of nucleosides and purine nucleotides of formula I, (I) in which stands for a hydrogen atom or an amino group, R2 means a halogen atom; a C1-6 alkyl group; an alkenyl group; a C1-6 alkoxy group; a C 2 -C 6 cycloalkyl-C 1 -C 6 -alkoxy group; a Cg-Cg cycloalkoxy group; a C6 -C6 cycloalkylthio group; a C1-6 alkylthio group; or is an amino group R RNRNN-, wherein one of the groups R ou or R pode may denote a hydrogen atom, or else R - and R podem may be the same or different and are independently of one another a C alquilo-C grupo alkyl group A C2 -C8 alkenyl group, a C1 -C6 alkoxy group, a C1 -C6 hydroxyalkyl group, a C3 -C6 cycloalkyl group, a C3 -C8 cycloalkyl group, C1 -C6 -alkyl-C1 -C6 -alkyl-C1 -C6 -alkyl group, a C1 -C6 -alkoxy-C1 -C6 -alkyl-C1 -C6 -alkyl group, A C1 -C6 alkoxy-C1 -C6 -alkylcarbonyl group, an aryl group, an aryl-C1 -C6 -alkyl group, or a heteroaryl-C1 -C6 -alkyl group or means an aryl, Ar-C 1 -C 6 -alkyl, aryloxy, Ar-C 1 -C 4 -alkoxy, arylthio, Ar-C 1 -C 6 -alkylthio or heteroarylthio; and the &quot; aryl &quot; and &quot; heteroaryl &quot; in all cases 22 aryl- or heteroaryl- containing groups may be mono- or polysubstituted by hydroxyl, C1-6 alkyl, C1-6 alkoxy, amino or halogen groups; or is a saturated, unsaturated or aromatic heterocyclic ring with one oxygen atom and / or one sulfur atom and / or one or two nitrogen atoms and 3-7 carbon atoms, these rings being substituted by one or more groups hydroxy, C1-6 alkyl, halogen or C1-6 cycloalkylthio; R4 is hydrogen or the amino group, and . . R 2 represents hydrogen or a C 1 -C 6 -alkylcarbonyl group or a mono-, di- or tri-phosphate group, as well as of the respective optically active, physiologically equivalent or physiologically assimilable salts of inorganic or organic acids and bases, with with the exception of 6-methylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9-ribofuranosylpurine, characterized by reacting a compound of formula II in which (II), R1, R2 and R3 have the abovementioned meanings, with a compound of formula III, (III) in which X is halogen, such as fluoro, chloro, bromo or iodo, to give a mixture of the isomers IV a, b and V a, b a means b means R? And X are as defined above, and the mixture of the isomers IVaebeVaeb is then reduced, with a reducing agent such as the zinc / copper mixture or the like, and isolating the compound of formula following the removal of the protecting groups by reaction of the compounds IV and Vb with ammonia and the compounds prepared in the respective physiologically assimilable salts are converted if desired by usual procedures. 2. A method according to claim 1, Claim 1, characterized in that nucleosides and nucleotides of purine of formula I in which R4 is hydrogen or the amino group R2 signifies halogen; C 1 -C 6 -alkoxy which may be substituted by C 1 -C 6 -cycloalkyl; C ciclo-C ciclo cycloalkyloxy; aryloxy, arylalkyl or arylalkoxy, which aryl groups may be substituted by hydroxy, C1-6 alkyl or halogen; C 1 -C 6 -alkylthio; arylthio or arylalkylthio, the aryl groups of which may be substituted by hydroxy, C 1 -C 6 -alkyl or halogen, or R 2 denotes a saturated, unsaturated or aromatic heterocyclic ring with oxygen atom and / or a sulfur atom and / or one or two nitrogen atoms and C -C-C átomos carbon atoms, and which may contain in the ring as substituents one or more hydroxyl, C -C-C alquilo alkyl, halogen, C--C ciclo cycloalkylthio or aryl-alkylthio groups, which may have if desired, on the aryl substituent, hydroxy, C1 -C6 -alkyl or halogen, or R2 denotes an imidazolylthio group in which the imidazole group may be substituted by C1 -C4 -alkyl and / or C-substituted by a nitro group or R 2 is an amino group which is mono- or disubstituted by C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkyl and / or C 3 -C 6 -cycloalkyl; an aryl or arylalkyl group, which aryl groups may be substituted by hydroxyl, C1-6 alkyl or halogen; or an allyl group which may be substituted by one or more C -C-C alquilo alkyl or C alco-C alco alkoxy groups. 3. A process according to claim 1 or 2, wherein nucleosides and purine nucleosides are prepared. formula I, in which R 2 represents a hydrogen atom. - 4S-25 ¢ 5- I * 4. A process according to any one of claims 1 to 3, characterized in that the nucleosides and purine nucleotides of formula I are prepared in which 1 * 2 denotes a C1 -C4 -alkoxy group; a C1-4 alkylthio group; an amino group monosubstituted by a C 1 -C 4 -alkyl, C 2 -C 8 -alkenyl, C 1 -C 4 -hydroxyalkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -cycloalkyl- C alco-C alco-alkoxy-C--C--aralkyl-C -C-C alquilo-alkyl, aryl, aryl-C -C-C ou-alkyl or heteroaryl-C alquilo-C alquilo-alkyl; an amino group disubstituted by C1-4 alkyl; or a five- or six-membered heterocyclic ring with one nitrogen atom and one oxygen atom. 5. A process according to any preceding claim wherein one of the following compounds of formula I is prepared: 6-cyclopropylamino-21,31-dideoxy-21,3'-didehydro-9-D-ribofu arosylpurine; 6- (2-methylphenylmethylamino) -2 ', 3'-dideoxy-2', 3'-didehydro-9- [3-D-ribofuranosylpurine; 6-allylamino-2,3'-dideoxy-21,3'-didehydro-9- [3-D-ribofuranosyl-purine ' 6-isobutylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9- β-D-ribofuran silpurine. A process for the preparation of a pharmaceutical composition having anti-viral activity, characterized in that a nucleoside or nucleoside of 26 * purine of Formula I is prepared as active ingredient as prepared according to any of the preceding claims, with suitable conventional and physiologically assimilable carriers and / or standard pharmaceutical additives. The applicant claims the priority of the German application lodged on 14 January 1989, P 3900 964.5. Lisbon, January 12, 1990. © A BSSB ®, 58, 321K, 311, 311, 27