RU2114846C1 - Dideoxydidehydrocarbocyclic nucleosides, pharmaceutical composition - Google Patents

Abstract

FIELD: organic chemistry, nucleosides. SUBSTANCE: invention proposes compounds of the formula:

where X means H, NR-R¹, SR, OR or halogen; Z means H, OR² or NR-R¹; R, R¹ and R² mean H, C₁-C₄-alkyl or aryl and their pharmaceutically acceptable salts. Invention proposes also the use of these compounds as antiviral and antitumor agents, pharmcomposition based on thereof and methods of synthesis of the parent and intermedium compounds.. EFFECT: improved method of synthesis. 16 cl, 2 tbl, 27 ex

Description

 The invention relates to analogues of dideoxycarbocyclic nucleosides. More specifically, the present invention relates to analogues of carbocyclic 2 ', 3'-dideoxy-2', 3'-didehydropurine nucleosides and their use in therapy, in particular as antiviral agents.

 In light of the similarities between viral and host-cell functions, it is difficult to selectively infect the virus and at the same time leave the host cell intact. Thus, there are only a few agents effective against viruses per se and it is very difficult to find antiviral agents that have an acceptable therapeutic index, that is, agents that have a significant antiviral effect at a dosage level at which the agent has acceptable toxicity or side effects, profile.

 One group of viruses that has recently gained major importance are the retroviruses responsible for human acquired immunodeficiency syndrome (AIDS). Such viruses previously had different terminology, but are now generally referred to as human immunodeficiency viruses (HIY'S); two such viruses, HIY-I and HIY-II, are reproductively isolated from patients with AIDS and related conditions, such as AIDS-related complex (ARC) and persistent common lymphadenopathy.

 Although a number of nucleosides are considered useful in treating conditions associated with HIY infections, only zidovudine (AZ1, Petrovir) has received ongoing approval for the treatment of such conditions. However, it is known that zidovudine has extremely undesirable side effects that cause bone marrow depression, which leads to a decrease in the number of leukocytes with subsequent severe anemia, and there is a need for effective agents that are less cytotoxic.

где
X обозначает водород, NRR¹, SR, OR или галоген, Z обозначает водород, OR² или NRR¹, R, R¹ и R² могут быть одинаковыми или различными, и их выбирают из водорода, C₁-C₄-алкила и арила, а также его фармацевтически приемлемых производных.Applicant has discovered a new class of nucleoside analogues having antiviral activity. Therefore, a first embodiment of a compound of formula (I) is provided:

Where
X is hydrogen, NRR ¹ , SR, OR or halogen, Z is hydrogen, OR ² or NRR ¹ , R, R ¹ and R ² may be the same or different, and are selected from hydrogen, C ₁ -C ₄ alkyl and aryl, as well as its pharmaceutically acceptable derivatives.

One skilled in the art will understand that the compounds of formula (I) are cis compounds, and the cyclipentene ring of the compounds of formula (I) contains two chiral centers (shown in formula (I) under ^* ) and mixtures thereof, including racemic mixtures. All such isomers and mixtures thereof, including racemic mixtures, are included in the scope of the present invention. So, in the compounds of formula (I), either the chiral center to which the base is attached is in the R-configuration, and the chiral center to which the CH ₂ OH part is attached is in the S-configuration (hereinafter the D-isomer), or the chiral center to which the base is attached is in the S-configuration, and the chiral center to which the CH ₂ OH portion is attached is in the R-configuration (hereinafter the L-isomer). The compounds may be in the form of either a racemic mixture, or mainly as a pure D-isomer.

где
X и Z имеют определенные выше значения. В дальнейшем ссылка на соединения формулы (I) включает соединения формулы (Ia).D-isomers can be represented by formula (Ia):

Where
X and Z are as defined above. Hereinafter, reference to compounds of formula (I) includes compounds of formula (Ia).

 It should also be understood that some compounds of formula (I) may exist as a series of tautomeric forms, and all such tautomers are included in the scope of the present invention.

 As used here, the term halogen refers to fluorine, chlorine, bromine, and iodine; when X is halogen, it is preferably chlorine.

C ₁ -C ₄ alkyl refers here to a straight or branched alkyl group, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. Preferably, C ₁ -C ₄ alkyl is methyl.

Aryl here refers to any mono- or polycyclic aromatic moiety and includes unsubstituted and substituted aryl (such as phenyl, tolyl, xylyl, anisyl) and unsubstituted and substituted aralkyl, including ap (C ₁ -C ₄ ) alkyl, such as phen ( C ₁ -C ₄ ) alkyl, for example benzyl or phenethyl.

 In the compounds of formula (I), Z is preferably amino.

 In one preferred class of compounds of formula (I), X is OR, in particular OH.

In another preferred class of compounds of formula (I), X is NRR ¹ , in particular NH ₂ , or hydrogen.

Particularly preferred are compounds of formula (I) in which Z is NH ₂ and X is H, NH ₂ or, especially, OH. Such compounds have particularly desirable therapeutic indices as antiviral agents.

 By "pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, ester or salt of such an ester of a compound of formula (I) or any other compound which, when administered to a recipient, is capable of producing (directly or indirectly) a compound of formula (I) or its antiviral active metabolite or residue.

Preferred esters of the compounds of formula (I) include carboxylic acid esters in which the non-carbonyl portion of the ester moiety is selected from hydrogen, straight or branched alkyl (e.g. methyl, ethyl, n-propyl, tert-butyl, n-butyl), alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl, optionally substituted with halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy); sulfonic acid esters such as alkyl or aralkylsulfonyl (e.g. methanesulfonyl), amino acid esters (e.g. L-valyl or L-isoleucyl) and mono-, di- or tri-phosphoric esters.

 As for the aforementioned esters, then unless otherwise indicated, any alkyl portion present preferably contains from 1 to 18 carbon atoms, in particular from 1 to 4 carbon atoms. Any aryl moiety present in such esters advantageously contains a phenyl group.

 Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-n-sulfonic acid, tartaric acid, tartaric acid, tartuene acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid. Other acids, such as oxalic acid, although not pharmaceutically acceptable per se, can be used in the preparation of salts useful as intermediates in the preparation of the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

Salts derived from suitable bases include alkali metal salts (e.g. sodium), alkaline earth metal salts (e.g. magnesium), ammonium salts and NR salts $\genfrac{}{}{0ex}{}{\text{+}}{\text{4}}$ (where R is C ₁ -C ₄ alkyl).

 Hereinafter, references to a compound in accordance with the invention include both compounds of formula (I) and pharmaceutically acceptable derivatives thereof.

Specific compounds of formula (I) include: / 1α, 4α / -4- / 6-chloro-9H-purin-9-yl / -2-cyclopentenyl-carbinol,
/ 1α, 4α / -4- / 6-hydroxy-9H-purin-9-yl- / 2-cyclopentenyl-carbinol,
/ 1α, 4α / -4- / 6-amino-9H-purin-9-yl- / 2-cyclopentenyl-carbinol,
/ 1α, 4α / -4- / 6-mercapto-9H-purin-9-yl- / 2-cyclopentenyl-carbinol,
/ 1α, 4α / -4- / 2-amino-6-chloro-9H-purin-9-yl- / 2-cyclopentenyl-carbinol,
/ 1α, 4α / -4- / 2-amino-6-hydroxy-9H-purin-9-yl- / 2-cyclopentenyl-carbinol,
/ 1α, 4α / -4- / 2,6-diamino-9H-purin-9-yl- / 2-cyclopentenyl-carbinol
in the form of a racemic mixture or a simple enantiomer.

 The compounds of the present invention either themselves have antiviral activity or are metabolized to such compounds. In particular, these compounds are effective in inhibiting the replication of retroviruses, including human retroviruses, such as human immunodeficiency viruses (HIY'S), AIDS pathogens.

 Some compounds of the present invention have anticancer activity, in particular compounds in which is hydrogen.

 Thus, another embodiment of the present invention is provided with respect to a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use as an antiviral agent, for example, in the treatment of retroviral infections, or as an anticancer agent.

 In another or alternative embodiment, the present invention provides a method of treating a viral infection, in particular a retroviral infection such as HIY, in mammals, including humans, in which an effective amount of an antiviral agent is administered as a compound of formula (I) or a pharmaceutically acceptable derivative thereof.

 It is also proposed, as an additional or alternative embodiment of the invention, the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of a viral infection or for use as an anti-cancer agent.

 Compounds of the present invention having antiviral activity are also useful in the treatment of AIDS-related conditions, such as AIDS-related complex (ARC), progressive widespread lamphadenopathy (PGL), AIDS-related neurological conditions (such as dementia or tropical paraparesis), anti HIY antibody-positive and HIY-positive conditions, idiopathic multiple hemorrhagic sarcoma (Kaposhi angiomatosis) and thrombocytopenic purpura.

 The antiviral compounds of the present invention are also useful in preventing the development of a clinical disease in patients who are anti-HIY antibody- or HIY-antigen-positive, and in prophylaxis following exposure to HIY.

 Antiviral compounds of formula (I) or pharmaceutically acceptable derivatives thereof may also be useful in preventing in vitro infection of physiological fluids, such as blood or seminal fluid.

 Some compounds of formula (I) are also suitable as intermediates in the preparation of other compounds of the present invention.

 It will become clear to the person skilled in the art that the reference here to treatment involves the prevention and treatment of established infections or symptoms.

 It is clear that the amount of the compound of the present invention necessary for use in treatment will vary not only depending on the type of compound selected, but also depending on the route of administration of the drug, the nature of the condition to be treated, the age and condition of the patient and will be completely competence of a doctor or veterinarian. In general, a suitable dose will be in the range of from about 1 to about 750 mg / kg, for example, from about 1 to 750 mg / kg of body weight per day, or from about 3 to 120 mg / kg of body weight of the recipient per day, preferably in the range of 6 up to 90 mg / kg, most preferably in the range of 15 to 60 mg / kg / day.

 The desired dose may be present as a single dose or as separate dosages administered at appropriate intervals, for example, as two, three, four or more sub-dosages per day.

 The compound is conveniently administered in the form of a unit dose, for example, containing from 10 to 1500 mg, more conveniently from 20 to 1000 mg, most conveniently from 50 to 700 mg of the active ingredient per dosage unit dosage.

 An ideally active ingredient should be administered in order to achieve a peak plasma concentration of the active compound of about 1 to 75 μM, preferably about 2-50 μM, most preferably about 3-30 μM. This can be achieved, for example, by intravenous administration of a 0.1-5% solution of the component, optionally in physiological saline, or by oral administration in the form of a bolus containing from about 1 to 100 mg / kg of the active component. Desired blood levels can be maintained by continuous infusion to obtain from about 0.01 to 5.0 mg / kg / h or by intermittent infusions containing from about 0.4 to 15 mg / kg of active ingredient.

 Although a compound of the present invention may be administered as a crude chemical for use in therapy, it is preferred that the active ingredient is present in the form of a pharmaceutical composition.

 The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and / or prophylactic components. The carrier (s) should be “acceptable” in the sense of being compatible with other components of the formulation and should not be harmful to the recipient.

 Pharmaceutical formulations include those suitable for oral, rectal, nasal, local (including buccal and sublingual), vaginal and parenteral (including intramuscular and intravenous) administration, or in a form suitable for administration by inhalation or insufflation. Formulations, where appropriate, may be present in the form of discrete dosage units and may be prepared by any methods well known in the pharmaceutical art. All methods include the step of binding the active compound to liquid carriers or finely divided solid carriers, or both, and, if necessary, the step of forming the product into the desired configuration.

 Pharmaceutical formulations suitable for oral administration may be present in the form of discrete units, such as capsules, starch wafers or tablets, each containing a predetermined amount of the active ingredient in the form of a powder or granules, in the form of a solution, suspension or emulsion. The active ingredient may also be present as a bolus, electuary (medicinal porridge) or paste. Tablets and capsules for oral administration may contain conventional excipients, such as binders, lubricants, wetting agents or disintegrants. Tablets may be coated according to methods well known in the art. Liquid preparations for oral administration may exist in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be present as a dry product for constitution with water or another suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents: emulsifiers, non-aqueous vehicles (which may include edible oils) or preservatives.

 The compounds of the present invention may also be formulated for parenteral administration (for example, by injection, for example, by administering a bead or by continuous infusion) and may be present in unit dosage form in ampoules, prefilled syringes or in a multi-dose drug package containing preservative substances. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain suspending agents, stabilizers and / or dispersants. Alternatively, the active component may be in powder form, obtained by aseptic isolation of a sterile solid or by lyophilization from a solution for constitution with a suitable vehicle, for example sterilized pyrogen-free water, before use.

 For topical application to the epidermis, the compounds of the present invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated together with an aqueous or oily base, and may also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or coloring agents.

 Formulations suitable for topical administration in the mouth include tablets containing the active ingredient in a flavoring base (usually sucrose and gum arabic) or tragacanth; lozenges containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and gum arabic; and mouthwashes containing the active ingredient in a suitable liquid carrier.

 Pharmaceutical formulations suitable for rectal administration, wherein the carrier is a solid, are most preferably presented as single-use suppositories. Suitable carriers include coconut oil and other substances commonly used in the art, and suppositories can be conveniently formulated by mixing the active compound with a softened or molten carrier (s), followed by cooling and molding in the molds.

 Formulations suitable for vaginal administration may be in the form of vaginal suppositories, tampons, creams, gels, pastes, foams or aerosols containing, in addition to the active component, such carriers as are known in the art.

 For intranasal administration, the compounds of the present invention can be used as a liquid spray composition or in the form of drops.

 Drops may be formulated together with an aqueous or non-aqueous base also containing one or more dispersing agents, solubilizers or suspending agents. Liquid spray formulations are conveniently enclosed in sealed bags.

 For administration by inhalation, the compounds of the present invention are conveniently delivered from an insufflator, nebulizer or sealed bag, or other suitable aerosol delivery vehicles. Sealed bags may contain a suitable dispersant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage can be determined by supplying a valve in order to deliver a measured amount of the compound.

 Alternatively, for administration by inhalation or insufflation, the compounds of the present invention may take the form of a dry powder composition, for example a powder mixture of the compound and a suitable powder base, such as lactose or starch. The powder composition may be presented in a dosage form, for example, in capsules or sleeves, or, for example, in gelatin or extractable transparent packages, from which the powder can be introduced using an inhaler or insufflator.

 If desired, the above compositions can be used to obtain a sustained release of the active component.

 The pharmaceutical compositions of the invention also contain other active ingredients, such as antimicrobials or preservatives.

 The compounds of the present invention can also be used in combination with other therapeutic agents, for example, other anti-infective substances. In particular, the compounds of the present invention can be used together with known antiviral agents.

 Thus, the present invention in a further embodiment provides a combination comprising a compound of formula (I) or a physiologically acceptable derivative thereof together with another therapeutically active substance, in particular an antiviral substance.

 The above combinations may be presented for use in the form of a pharmaceutical prescription, and such pharmaceutical compositions containing the combination defined above, together with a pharmaceutically acceptable carrier, constitute an additional embodiment of the present invention.

 Suitable therapeutic agents for use in such combinations include acyclic nucleosides, such as acyclovir, interferons, such as interferon, renal excretion inhibitors, such as probenicide, nucleoside transport inhibitors, such as dipyridamole, 2 ', 3'-dideoxynucleosides, such as 2' , 3'-dideoxycytidine, 2 ', 3'-dideoxyadenosine, 2', 3'-dideoxyinosine, 2 ', 3'-dideoxythymidine and 2', 3'-dideoxy-2 ', 3'-didehydrothymidine, as well as immunomodulators, such as interleukin II (1L2) and granulocyte-macrophage colony stimulating th factor (GM-CSF), erythropoietin and ampligen.

 The individual components of such combinations can be administered either sequentially or simultaneously in separate or joint pharmaceutical formulations.

 When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same virus, the dose of each compound may differ from that when the compound is used alone. Suitable doses will become apparent to one skilled in the art.

 The compounds of formula (I) and their pharmaceutically acceptable derivatives can be obtained by any method known in the art for preparing compounds of similar structure.

 Suitable methods for preparing the compounds of formula (I) and their pharmaceutically acceptable derivatives are described below; groups X and Z have the above meanings unless otherwise indicated. It should be understood that the following reactions may require use or may conveniently be adapted to starting materials having protected functional groups, and deprotection may therefore be required as an intermediate or final step to obtain the desired compound. Protection and exemption of functional groups from protection can be carried out using traditional methods. Thus, for example, amino groups can be protected by a group selected from aralkyl (eg, benzyl), acyl or aryl (eg, 2,4-dinitrophenyl); subsequent cleavage of the protective group is carried out, if necessary, by hydrolysis or hydrogenolysis using standard conditions. Hydroxyl groups can be protected using any conventional hydroxyl protecting group, for example, as described in "Protecting Groups in Organic Chemistry," Ed. T.F.W. Ms Omie (Plenum Press, 1973) or The Protecting Groups in Organic Synthesis (Theodora W. Greene / Tohu Wiley and Sons, 1981). Examples of suitable hydroxyl protecting groups include those selected from alkyl (e.g. methyl, tert-butyl or methoxymethyl), aralkyl (e.g. benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl (e.g. acetyl or benzoyl) and silyl groups such as trialkylsilyl (e.g. tert-butyldimethylsilyl). Hydroxyl protecting groups can be cleaved by conventional methods. Thus, for example, alkyl, silyl, acyl and heterocyclic groups can be cleaved by solvolysis, for example by hydrolysis, under acidic or basic conditions. Aralkyl groups, such as triphenylmethyl, can likewise be cleaved by solvolysis, for example by hydrolysis, under acidic conditions. Aralkyl groups, such as benzyl, can be cleaved by hydrogenolysis in the presence of a noble metal catalyst, such as palladium carbon. Silyl groups can also be cleaved using a source of fluoride ions such as tetra-n-butylammonium fluoride.

где
X и Z обозначают заместители, имеющие значение формулы (I), или обозначают их защитные формы, а гидроксильная группа в группировке циклопентенилкарбинола может быть в защитной форме или его фармацевтически приемлемого производного с реагентом, выбранным из муравьиной кислоты или ее реакционноспособных производных, с последующим, где необходимо, отщеплением нежелательных групп, вводимых таким реагентом, и/или отщеплением любых защитных групп.In the first process (A), compounds of formula (I) and their pharmaceutically acceptable derivatives can be prepared by reacting a compound of formula (II)

Where
X and Z denote substituents having the meaning of formula (I) or denote their protective forms, and the hydroxyl group in the cyclopentenylcarbinol moiety may be in a protective form or its pharmaceutically acceptable derivative with a reagent selected from formic acid or its reactive derivatives, followed by where necessary, by cleavage of undesirable groups introduced by such a reagent, and / or by cleavage of any protective groups.

 Examples of suitable formic acid derivatives that can be used in process (A) include orthoformates (e.g. triethyl orthoformate), dialkoxymethyl acetate (e.g. diethoxymethyl acetate), dithioformic acid, formamide, triazine or formamidine acetate.

 Undesired groups introduced by formic acid or a reactive derivative thereof can conveniently be cleaved by hydrolysis under mild conditions, for example, using an inorganic acid such as aqueous hydrochloric acid.

 When trialkyl orthoformate, such as triethyl orthoformate, is used, it is also a solvent for the reaction. Other solvents that may be used include amides (e.g. dimethylformamide or dimethylacetamide), chlorinated hydrocarbons (e.g. dichloromethane), ethers (e.g. tetrahydrofuran) or nitriles (e.g. acetonitrile).

In some cases (for example, when trialkyl orthoformate, such as triethyl orthoformate is used), the reaction is preferably carried out in the presence of a catalyst, such as a strong acid (for example, concentrated hydrochloric acid, nitric acid or sulfuric acid). The reaction can be carried out at a temperature of from -25 to 150 ^o C, for example, from 0 to 100 ^o C, and conveniently at ambient temperature.

 In another process (B), the compounds of formula (I) and their pharmaceutically acceptable derivatives or their protected form are subjected to an interconversion reaction wherein the substituent X present initially is replaced with another substituent X, and / or the Z group present initially is replaced with another Z group and, if necessary, then any protecting group present is cleaved off.

In one embodiment of process (B), compounds of formula (I) in which X is a group RR ¹ (where R and R ¹ are as defined above) can be obtained by amination of a corresponding compound of formula (I) in which X is a halogen atom (e.g. chlorine). Amination can be carried out by reacting with the reagent HNRR ¹ (where R and R ¹ are as defined above) in a solvent such as an alcohol (e.g. methanol). The reaction can be carried out at any suitable temperature and conveniently at elevated temperature, such as reflux temperature, or when liquid ammonia is used in a sealed tube at a temperature of about 50 - 80 ^° C. Suitable conditions for the conversion of halides into secondary and tertiary amines are also described by Harrison et . al., Compendium of Organic Sinthetic Methods, Wiley-Jntesscience, New York (1971) on p. 250 - 252.

In another embodiment of process (B), compounds of formula (I) in which X is an OR group (wherein R is as defined above) can be prepared by substituting a halogen atom (eg, chlorine) with the corresponding anion, RO ^- . When R represents a hydrogen atom, the substitution reaction can be carried out in water or in a mixture of water and a water-miscible solvent such as alcohol (e.g. methanol or ethanol), ether (e.g. dioxane or tetrahydrofuran), ketone (e.g. acetone), an amide (e.g. dimethylformamide) or sulfoxide (e.g. dimethyl sulfoxide), conveniently in the presence of an acid or base. Suitable acids include organic acids, such as p-toluenesulfonic acid, and inorganic acids, such as hydrochloric acid, nitric acid, or sulfuric acid. Suitable bases include inorganic bases such as alkali metal hydroxides or carbonates (e.g., sodium or potassium hydroxide or carbonate). Aqueous acid or base may also be used as the reaction solvent. Hydrolysis can be conveniently carried out at a temperature of from -10 to +150 ^o C, for example, at reflux temperature. When R is C ₁ -C ₄ alkyl or aryl, the RO ^- anion ^is formed from the corresponding alcohol ROH using an inorganic base such as an alkali metal (e.g. sodium) or an alkali metal hydride (e.g. sodium hydride). The in situ formation of the anion can conveniently be carried out at ambient temperature.

 In another embodiment of process (B), compounds of formula (I) in which X is an SH group can be prepared by reacting a halo compound of formula (I) with thiourea in a suitable solvent such as alcohol (e.g. n-propanol), at elevated temperature (for example, reflux temperature) followed by basic hydrolysis. Suitable bases that can be used in this case include alkali metal hydroxides (e.g. sodium hydroxide). The reaction can be carried out in accordance with the G.G. method. Urquart et al. Org. Syn. Coll., Vol. 3, p. 363, 1953, for example, by refluxing the intermediate product using an aqueous solution of NaOH for about 0.25-5 hours.

 In a further embodiment of process (B), compounds of formula (I) in which X is a hydrogen atom can be prepared by reducing a halo compound of formula (I) using a reducing system that does not affect the rest of the molecule. Suitable reducing agents that can be used to carry out the desired dehalogenation reaction are zinc / water. Recovery of this type is described by T. R. Marshall et al. J. Chem. Soc., 1004 (1951). Alternatively, the reaction can be carried out by photolysis in a suitable solvent, such as tetrahydrofuran containing 10% triethylamine, and conveniently in a Rayonet photochemical reactor (2537A) according to the method of V. Nair et al., J. Org. Chem., 52, 1344 (1987).

 In yet another embodiment of process (B), compounds of formula (I) in which X is a halogen atom can be prepared from another halo compound of formula (I) by conventional halide-halide exchange methods. Alternatively, when X is chlorine, this substituent may be substituted with other halogen atoms using various p- / halo / benzene-diazonium chlorides in accordance with well-known methods.

Compounds of formula (I) in which X is an SR group, where R is a C ₁ -C ₄ alkyl or aryl group, can be prepared from the corresponding thiols using standard alkylation or arylation techniques, for example, as described in US Pat. No. 4,38,114 .

Compounds of formula (I) in which Z is a hydroxyl group can conveniently be prepared from the corresponding compounds of formula (I) in which Z is NH ₂ by reaction with nitrous acid, for example, using the method described by J. Davoll in J . Amer. Chem. Soc. 73, 3174 (1951).

 Many of the reactions described above are broadly described in the context of purine nucleoside synthesis, for example, in Nucleoside Analogs-Chemistry, Biology and Medical Applications, R. T. Walker et al., Ed. Plenum Press, New York (1979) on p. 193 to 223, the description of which is incorporated herein by reference.

 Pharmaceutically acceptable salts of the compounds of the present invention can be prepared as described in US Pat. No. 4,383,114, the disclosure of which is incorporated herein by reference. So, for example, when it is necessary to obtain an acid addition salt of a compound of formula (I), the product of any of the above methods can be converted into a salt by treating the resulting free base with a suitable acid using conventional methods. Pharmaceutically acceptable acid addition salts can be prepared by reacting the free base with a suitable acid of choice, in the presence of a suitable solvent, such as an ester (e.g. ethyl acetate) or an alcohol (e.g. methanol, ethanol or isopropanol). Inorganic base salts can be prepared by reacting the free base with a suitable base, such as an alkoxide (e.g. sodium methoxide), optionally in the presence of a solvent, such as an alcohol (e.g. methanol). Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compounds of formula (I) using conventional methods.

The compound of formula (I) can be converted to a pharmaceutically acceptable phosphate or other ester by reaction with a phosphorylating agent, such as POCl ₃ , or a suitable esterifying agent, such as an acid halide or anhydride. An ester or salt of a compound of formula (I) can be converted into a related compound, for example by hydrolysis.

 The compounds of formula (II) and their salts are new compounds, and they constitute an additional distinguishing feature of the present invention.

 Compounds of formula (II) in which Z is hydrogen or hydroxyl can be prepared directly from compound 2a.

путем взаимодействия с избытком пиримидина формулы (III):

(где
Y обозначает атом галогена, например хлора, и Z обозначает водород или гидроксильную группу) в присутствии аминового основания, такого как триэтиламин, и в спиртовом растворителе (например, н-бутаноле), удобно при температуре флегмы.

by reacting with an excess of pyrimidine of formula (III):

(Where
Y represents a halogen atom, for example chlorine, and Z represents hydrogen or a hydroxyl group) in the presence of an amine base such as triethylamine and in an alcohol solvent (e.g. n-butanol), conveniently at reflux temperature.

(где
Y обозначает то же, что и в формуле (III) выше) при таких же самых условиях, которые только что описаны для получения соединений формулы (II), в которых Z обозначает водород или гидроксильную группу, с получением соединения формулы (V):

которое может быть диазотировано с использованием диазониевой соли ArN $\genfrac{}{}{0ex}{}{\text{+}}{\text{2}}$ E^- (где Ar обозначает ароматическую группу, например, п-хлорфенил, и E^- обозначает анион, например, галогенид, такой как хлорид) в растворителе, таком как вода, органическая кислота, такая как уксусная кислота, или их смесь, удобно при температуре окружающей среды, с получением соединения формулы (VI):

(где
Ar имеет вышеприведенное значение), которое можно превратить в желаемое соединение формулы (II) восстановлением с использованием, например, восстановительного металла, такого как цинк, в присутствии кислоты, например уксусной кислоты. Следует понять, что выбор восстановителя зависит от природы группы X.Compounds of formula (II) in which Z is NH ₂ can be prepared using a compound of formula 2a by reaction with an excess of pyrimidine of formula (IV):

(Where
Y denotes the same as in formula (III) above) under the same conditions as just described for the preparation of compounds of formula (II) in which Z represents hydrogen or a hydroxyl group to give a compound of formula (V):

which can be diazotized using the diazonium salt of ArN $\genfrac{}{}{0ex}{}{\text{+}}{\text{2}}$ E ^- (where Ar is an aromatic group, for example, p-chlorophenyl, and E ^- is an anion, for example, a halide, such as chloride) in a solvent, such as water, an organic acid, such as acetic acid, or a mixture thereof, conveniently ambient temperature to obtain a compound of formula (VI):

(Where
Ar has the above meaning), which can be converted into the desired compound of formula (II) by reduction using, for example, a reducing metal, such as zinc, in the presence of an acid, for example acetic acid. It should be understood that the choice of reducing agent depends on the nature of group X.

 Compound 2a can be prepared from the universal precursor, 1α-acetylamino-3α-acetoxy-methylcyclopent-2-ene (1a), by hydrolysis in the presence of a weak base such as an alkaline earth metal hydroxide.

 An extremely convenient synthesis of compounds of formula (I) by means of 6-chloro compounds of formula (II) is given below.

Соединение 2a и соединения формул (V) и (VI) являются новыми промежуточными соединениями и образуют дополнительные признаки настоящего изобретения.

Compound 2a and compounds of formulas (V) and (VI) are new intermediates and form additional features of the present invention.

 Compound 1a is a known compound described in US Pat. No. 4,138,562.

 When a compound of formula (I) is desired to be in the form of a simple isomer, it can be obtained either by peptization of the final product, or by stereospecific synthesis from an isomerically pure starting material or any suitable intermediate.

 The peptization of the final product or intermediate or starting product can be carried out by any suitable method known in the art: see, for example, “Stereochemistry of carbon compounds”, E.L. Eliel (McGraw Hill, 1962) and Tables of Peptizing Agents, written by S.H. Wilen.

 One convenient way to obtain chiral pure compounds of formula (I) is the enzymatic conversion of a racemic mixture of a compound or its precursor. Using this method, (+) and (-) compounds of formula (I) can be obtained in optically pure form. Suitable enzymes include deaminases, such as adenosine deaminase.

The present invention is further described with reference to the following detailed examples in which elemental analysis was carried out with the participation of MHW Laboratories, Phoenix, AZ. Melting points were determined on a Mel - Temp apparatus and corrected. Nuclear magnetic resonance spectra were obtained on Yed FX 90QFT or Nicollet NT300 spectrometers and were recorded in DMCO-d ₆ . Chemical shifts are expressed in ppm of Me ₄ Si. IR spectra were determined as KBr granules by a Nicollet 50XC FT IR spectrometer and UV spectra were determined on a Beckmann DU-8 spectrophotometer. Mass spectra were obtained with an AEI Scientific Apparatus Limited MS-30 mass spectrometer. Thin layer chromatography (TLC) was performed on 0.25 mm Merck silica gel layers (230-400 mesh). All chemicals and solvents are reagent pure unless otherwise indicated. The term "active ingredient" as used in the examples means a compound of formula (I) or a pharmaceutically acceptable derivative thereof.

Example 1. (±) - (1α, 4α) -4- / 5-amino-6-chloro-4-pyrimidinyl) amino-2-cyclopentenylcarbinol (3a)
A mixture of 1α-acetylamino-3α-acetoxymethylcyclopent-2-ene (1a) (3.0 g, 15 mmol) and an aqueous solution of barium hydroxide (0.5 N, 300 ml) was heated under reflux overnight. After cooling, the mixture is neutralized with dry ice. The precipitate was filtered off and the aqueous solution was concentrated to dryness. The residue was extracted with absolute ethanol and concentrated again to give compound 2a as a colorless syrup (1.6 g, 14 mmol).

5-amino-4,6-dichloropyrimidine (4.59 g, 28 mmol), triethylamine (4.2 g, 42 mmol) and n-butanol (50 ml) were added to this syrup and the mixture was heated under reflux for 24 h. Volatile solvents are removed, the residue is absorbed onto silica gel (7 g), packed in a flash column (4.0 x 12 cm) and eluted with CHCl ₃ -MeOH (20: 1) to obtain 2.69 g (74%) of the compound 3a; melting point 130-132 ^o C. An analytical sample is obtained by recrystallization from ethyl acetate (EtOAc), melting point 134-135 ^o C, mass spectrum (MC) (30 eV, 200 ^o C), m / e 240 and 242 (M ⁺ and M ⁺ +2), 209 (M ^{+ -} 31), 144 (B ⁺ ),
IR: 3600-2600 (OH), 1620, 1580 (C = C, C = N), Anal. (C ₁₀ H ₁₃ ClN ₄ O) C, H, N.

Example 2
(±) - (1α, 4α) -4 - (/ 2-amino-6-chloro-4-pyrimidinyl) / amino / -2-cyclopentenylcarbinol (4a)
To 14 mmol of crude compound 2a (Example 1), 2-amino-4,6-dichloropyrimidine (3.74 g, 22.8 mmol), triethylamine (15 ml) and n-butanol (75 ml) were added and the mixture was heated to reflux. refrigerator for 48 hours. Volatile solvents are removed, the residue is treated with methanol in order to separate an undissolved by-product (double pyrimidine nucleoside). The methanol solution was absorbed on silica gel (8 g), packed in a column (4.0 x 14 cm) and eluted with CHCl ₃ -MeOH (40: 1) to obtain 1.52 g (42%) of crude compound 4a. The product was recrystallized from ethyl acetate to give compound 4a; melting point 132-134 ^o C, MC (30 eV, 200 ^o C), m / e 240 and 242 (M ⁺ and M ⁺ +2), 209 (M ^{+ -} 31), 144 (B ⁺ ),
IR: 3600-3000 (NH ₂ , OH), 1620, 1580 (C = C, C = N). Anal (C ₁₀ H ₁₃ Cl-N ₄ ) C, H, N.

 Example 3

(±) - (1α, 4α) -4 - [/ 2-amino-6-chloro-5- / 4-chlorophenyl / azo-4-pyrimidinyl-amino] -2-cyclopentenylcarbinol (5a)
A cold solution of the diazopia salt is obtained from p-chloroaniline (1.47 g, 11.5 mmol) in 3N. a solution of HCI (25 ml) and sodium nitrile (870 mg, 12.5 mmol) in water (10 ml). This solution was added to a mixture of compound 4a (2.40 g, 10 mmol), acetic acid (50 ml), water (50 ml) and sodium acetate trihydrate (20 g). The reaction mixture was stirred overnight at room temperature. The yellow precipitate was filtered and washed with cold water until neutral, then dried in air to obtain 3.60 g (94%) of compound 5a; melting point 229 ^o C (decomposition). An analytical sample is obtained from a mixture of acetone-methanol (1: 2) melting point 241-243 ^o C (decomposition). MS (30 eV, 260 ^o C), m / e 378 and 380 (M ⁺ and M ⁺ +2), 282 (B ⁺ ),
IR: 3600-3000 (NH ₂ , OH), 1620, 1580 (C = C, C = N). Anal (C ₁₆ H ₁₆ Cl ₂ N ₆ O) C, H, N.

 Example 4

(±) - (1α, 4α) -4 - [/ 2,5-Diamino-6-chloro-4-pyrimidinyl / amino] -2-cyclopentenylcarbinol (6a)
A mixture of compound 5a (379 mg, 1 mmol), zinc powder (0.65 g, 10 mmol) of acetic acid (0.32 ml), water (15 ml) and ethanol (15 ml) was heated under reflux under nitrogen for 3 hours. Zinc was removed and the solvents were evaporated. The residue was absorbed on silica gel (2 g), packed in a column (2.0 x 18 cm) and CHCl ₃ -MeOH (15: 1) was eluted. A yellowish green syrup is obtained. Further purification from methanol-ether gives compound 6a in the form of yellowish-green crystals, 170 mg (66%), melting point 168-170 ^° C, MC (30 eV, 220 ^° C), m / e 225 and 257 (M ⁺ and M ⁺ +2), 224 (M ^{+ -} 31), 159 (B ⁺ ),
IR: 3600-3000 (NH ₂ OH) 1620, 1580 (C = C, C = N). Anal (C ₁₀ H ₁₄ ClN ₅ ) C, H, N.

Example 5
(±) - (1α, 4α) -4- / 6-Chloro-8H-purin-9-yl / -2-cyclopentatenylcarbinol (7a)
A mixture of compound 3a (1.30 g, 5.4 mmol), triethylorthoformate (30 ml) and hydrochloric acid (12 N, 0.50 ml) was stirred overnight at room temperature. The solvent is evaporated at a temperature of 35 ^o C in vacuum. 0.5 n was added to the residue. a solution of (aqueous) hydrochloric acid (30 ml) and the mixture is stirred for 1 h, then the mixture is neutralized to a pH of 7-8 1 N. sodium hydroxide solution and absorbed on silica gel (8 g), packed in a column (4.0 • 8 cm) and eluted with CHCl ₃ -MeOH (20: 1) to give white crystals of compound 7a, 1.12 g (82%) . The crude product was recrystallized from ethyl acetate to give compound 7a, melting point 108-110 ^° C., MC (30 eV, 200 ^° C.), m / e 250 and 252 (M ⁺ and M ⁺ +2), 219 (M ^{+ -} 31 ), 154 (B ⁺ ),
IR: 3600-2800 (OH), 1600 (C = C, C = N). Anal (C ₁₁ H ₁₁ ClN ₄ O) C, H, N.

 Example 6

(±) - (1α, 4α) -4- / 6-Hydroxy-9H-purin-9yl / -2-cyclopentenylcarbinol (8a)
A mixture of compound (7a) (251 mg, 1 mmol) and an aqueous solution of sodium hydroxide (0.2 N, 10 ml) was heated under reflux for 3 hours. After cooling, the reaction mixture was adjusted to pH 5-6 using acetic acid. The reaction mixture was absorbed on silica gel (2 g), packed in a column (2.0 x 11 cm) and eluted with CHCl ₃ -MeOH (10: 1) to give 105 mg (45%) of compound 8a. The crude white product was recrystallized from water-methanol (3: 1) to give compound 8a, melting point 248-250 ^° C. (decomposition), MC (30 eV, 300 ^° C.), m / e 232 (M ⁺ ), 214 (M ^{+ -} 18), 136 (B ⁺ ),
IR: 3600-2600 (OH), 1680, 1600 (C = O, C = C, C = N). Anal (C ₁₁ H ₁₂ N ₄ O ₂ ) C, H, N.

Example 7
(±) - / 1α, 4α - / -4 - / - 6-amino-8H-purin-9-yl / -2-cyclopentenylcarbinol (9a)
Liquid ammonia is passed into an autoclave containing a solution of compound 7a (250 mg, 1 mmol) in methanol (5 ml) at a temperature of -80 ^o C. The autoclave is sealed and heated at a temperature of 60 ^o C for 24 hours. Ammonia and methanol are evaporated and the residue recrystallized from water to obtain off-white crystals of compound 9a, 187 mg (81%), melting point 198-200 ^° C. MS (30 eV, 210 ^° C), m / e 231 (M ⁺ ), 213 (M ^{+ -} 18), 135 (B ⁺ ).

IR: 3600-2600 (NH ₂ , OH), 1700, 1600 (C = C, C = N). Anal (C ₁₁ H ₁₃ N ₅ O) C, H, N.

Example 8
(±) - (1α, 4α) -4- (6-Mercapto-9H-purin-9-yl) -2-cyclopentenylcarbinol (10a)
A mixture of compound 7a (125 mg, 0.5 mmol), thiourea (40 mg, 0.64 mmol) and n-propanol (5 ml) was heated under reflux for 2 hours. After cooling, the precipitate was isolated by filtration, washed with n-propanol and dissolved in sodium hydroxide (1 N. solution, 5 ml). The solution was adjusted to pH 5 using acetic acid for this purpose. Crude compound 10a (90 mg, 73%) was isolated again, melting point 260-262 ^° C. (decomposition), and recrystallized from N, N-dimethylformamide to give compound 10a, melting point 263-265 ^° C. (decomposition). MS (30 eV, 290 ^o C): m / e 248 (M ⁺ ), 230 (M ^{+ -} 18), 152 (B ⁺ ),
IR: 3600-3200 (OH), 3100, 2400 (SH), 1600 (C = C, C = N). Anal (C ₁₁ H ₁₂ N ₄ OS), C, H, N.

 Example 9

 (±) - (1α, 4α) -4- (2-amino-6-chloro-9H-purin-9-yl) -2-cyclopentenylcarbinol (13a).

A mixture of compound 6a (1.41 g, 5.5 mmol), triethylorthoformate (30 ml) and hydrochloric acid (12 N, 1.40 ml) was stirred overnight. The suspension is dried in vacuo. Diluted hydrochloric acid (0.5 N, 40 ml) was added and the mixture was reacted at room temperature for 1 hour. The mixture was neutralized to pH 8 using 1 N. sodium hydroxide solution and absorbed on silica gel (7.5 g), packed in a column (4.0 x 10 cm) and eluted with CHCl ₃ -MeOH (20: 1) to obtain off-white crystals of compound 13a, 1.18 g ( 80%). The crude product is recrystallized from ethanol to give compound 13a, melting point 145-147 ^° C. MC (30 eV, 220 ^° C): m / e 265 and 267 (M ⁺ and M ⁺ +2), 235 (M ^{+ -} 30 ), 169 (B ⁺ ),
IR: 3600-2600 (NH ₂ , OH), 1620, 1580 (C = C, C = N). Anal (C ₁₁ H ₁₂ -N ₅ OCl • 3/4 H ₂ O) C, H, N.

 Example 10

 (±) - (1α, 4α) -4- (2-amino-6-hydroxy-9H-purin-9-yl) -2-cyclopentenylcarbinol (14a).

A mixture of compound 13a (266 mg, 1 mmol) and an aqueous solution of sodium hydroxide (0.33 N) is heated under reflux for 5 hours, absorbed on silica gel (2 g), and packed in a column (2.0 • 7.5 cm) and elute with CHCl ₃ -MEOH (5: 1). The crude product was recrystallized from methanol-water (1: 4) to give white crystals of compound 14a, 152 mg (61%), melting point 254-256 ^° C. (decomposition). MS (30 eV, 200 ^° C): m / e 247 (M ⁺ ), 217 (M ^{+ -} 30), 151 (B ⁺ ),
IR: 3600-2600 (NH ₂ , OH), 1700, 1600 (C = O, C = C, C = N), Anal. (C ₁₁ H ₁₃ N ₅ O ₂ • 3/4 H ₂ O) C, H, N.

Example 11
(±) - (1α, 4α) -4- (2,6-Diamino-9H-purin-9-yl) -2-cyclopentylcarbinol (15a).

Liquid ammonia is passed into a solution of compound 13a (265 mg, 1 mmol) in methanol (10 ml) at a temperature of -80 ^o C in an autoclave. The autoclave is sealed and heated at a temperature of 75 ^o C for 48 hours. Ammonia and methanol are evaporated. The residue was absorbed on silica gel (2 g), packed in a column (2.0 x 10 cm) and CHCl ₃ -MeOH (15: 1) was eluted. The crude product was recrystallized from ethanol to give 196 mg (80%) of compound 15a, melting point 152-155 ^° C. MC (30 eV, 200 ^° C), m / e 246 (M ⁺ ), 229 (M ^{+ -} 17) , 216 (M ^{+ -} 30), 150 (B ⁺ ),
IR: 3600-3000 (NH ₂ , OH) 1700, 1650, 1600 (C = O, C = C, C = N). Anal (C ₁₁ H ₁₄ N ₆ O) C, H, N.

 Example 12

(1S, 4R) -4- (2,6-Diamino-9H-purin-9-yl / -2-cyclopentenylcarbinol [/ 1S, 4R / -4- / 2,6-Diamino-9H-purin-9-yl / -2-cyclopentenomethanol]
(a) Intermediate I: / 1R, 2S, 3R, 5R / -3- [6-amino-9H-purin-9-yl /] - 5 - [/ 1,1-dimethylethyl / - dimethylsilyloxy / methyl] - 1,2-cyclopentanediol
(-) Aristeromycin ¹ (12.505 g), tert-butyldimethylsilyl chloride (7.8 g) and imidazole (12.96 g) in dry dimethylformamide (85 ml) was stirred at ambient temperature for 2.5 hours. The resulting solution was diluted with ethyl acetate. (500 ml) is then washed with water (3 • 100 ml) and brine (50 ml), which leads to the crystallization of a white solid. This body was collected by filtration, washed with ethyl acetate, then dried in vacuo to give the title compound (3.92 g).

¹ H NMR (DMCO-d ₆ ) 8.15 (8.09 1H), 7.19 (2H), 5.0 (1H), 4.72 (1H), 4.69 (1H), 4.36 (1H), 3.85 (1H), 3.67 (2H), 2.23 (1H), 2.09 (1H), 1.79 (1H), 0.89 (9H), 0.07 ( 6H).

 1. J. Am. Chem. Society, 1983, Volume 105, p. 4049-4055.

 (b) Intermediate 2: (4R, 3a, 6R, 6aR) -4- [6-amino-9H-purin-9-yl] -6 - [/ 1,1-dimethylethyl / - dimethylsilyloxy / methyl] -3a 5,6,6a-tetrahydro-4H-cyclopenta-1,3-dioxol-2-thion.

 A mixed suspension of intermediate 1 (3.45 g) in dry dimethylformamide (56 ml) was treated with 1,1'-thiocarbonyldiimidazole (3.3 g) to give a yellow solution. After 15.5 hours at ambient temperature, the resulting solution was combined with the solution remaining from a previous experiment (6% scale), and the solvent was removed by evaporation. The residual oil is diluted with ethyl acetate (100 ml), then washed with water (2 • 20 ml) and brine (2 • 20 ml), dried with magnesium sulfate and evaporated to a yellow solid, which is washed with diethyl ether (25 ml), then collected by filtration, then washed with ether (25 ml) and dried in vacuo to give the title compound as a light cream solid (3.61 g).

λ _max (ethanol) 240.0 nm (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 459). ¹ H NMR (DMCO-d ₆ ) 8.27 (1H), 8.13 (1H), 7.33 (2H), 5.81 (1H), 5.37 (1H), 5.28 (1H) 3.78 (2H); 2.60 (1H); 2.28 (2H); 0.90 (9H); 0.09 (6H).

(c) Intermediate 3: / I'R, 4'6 / -9- [4 - /// 1,1-Dimethylsilyloxy / methyl / -2-cyclopenten-1-yl] -9H-purin-6-amine
A solution of intermediate 2 (3.57 g) in dry tetrahydrofuran (25 ml) is treated with a solution of 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (4.94 g) in dry tetrahydrofuran (10 ml), then stirred at ambient temperature for 8.25 hours. The solvent was removed by evaporation. The residual oil is combined with the oil obtained from the previous experiment (40% scale), then subjected to silica column chromatography (200 g, MEPK 7734), elute with chloroform, then with chloroform-ethanol, to obtain a white solid. This material was washed with diethyl ether (10 ml), dried in vacuo to give the title compound (1.47 g).

λ _max (ethanol) 261.4 nm E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ 443).

¹ H NMR (DMCO-d ₆ ), 8.14 (1H), 8.00 (1H), 7.20 (2H), 6.12 (1H), 5.95 (1H), 5.60 (1H ), 3.66 (2H), 2.96 (1H), 2.69 (1H), 1.65 (1H), 0.74 (9H), 0.02 (6H).

(d) Intermediate 4: / 1 ', R, 4' S / -9 [4 - /// 1, 1-Dimethylethyl / dimethylsilyloxy / methyl / -2-cyclopenten-1-yl] -9H-purine-6 amine, 1-oxide
A solution of intermediate 3 (1.37 g) in chloroform (30 ml) was treated with 80-90% m-chloroperoxybenzoic acid (1.29), then stirred at ambient temperature for 3 hours. The solvent was removed by evaporation and the residual gum. dissolved in ethyl acetate (10 ml). A white solid crystallizes, which (and with it the substance), restored by evaporation of the filtrate, is dissolved in chloroform (100 ml), then washed with saturated aqueous sodium bicarbonate (3 • 10 ml) and brine (2 • 10 ml) . Water washes were back extracted with chloroform (50 ml). The combined organic solutions were dried in the presence of magnesium sulfate, then evaporated to a solid, which was washed with diethyl ether (25 ml), and then collected by filtration. The white solid was further washed with ether (10 ml), dried in vacuo to give the title compound (1.16 g).

λ _max (ethanol) 235.4 nm E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ 1324), 263.2 nm E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ 248), 300.2 nm E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ 75).

¹ H-NMR (CDCl ₃ ) 8.72 (1H), 8.02 (1H), 7.16 (2H), 6.21 (1H), 5.87 (1H), 5.72 (1H), 3.68 (2H), 3.04 (1H), 2.82 (1H), 1.74 (1H) 0.89 (9H), 0.06 (6H).

(e) Intermediate 5: (I ', R, 4' S) -7- [4 -, /// 1,1-dimethylethyl / dimethylsilyloxy / methyl / -2-cyclopenten-1-yl] -2-imino -1,2-dihydro [1,2,4] oxadiazolo [3,2-i] -9H-purine bromohydrate
A stirred, ice-cooled suspension of intermediate 4 (1.08 g) in methanol (20 ml) was treated with a solution of cyanogen bromide (0.34 g) in methanol (20 ml) added over 5 minutes. After 15 minutes, the suspension was warmed to ambient temperature to give a solution. After 90 minutes, the solvent was removed by evaporation. The residue was washed with diethyl ether (25 ml) and collected by filtration. The solid was then washed with ether (25 ml) and dried in vacuo to give the title compound (1.37),
λ _max (ethanol) 228.2 nm (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ 530), 285.2 nm (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ 445)
¹ H-NMR (CDCl ₃ ) 10.20 (1H), 10.02 (1H), 8.37 (1H), 6.25 (1H), 6.01 (1H), 5.90 (1H), 3.69 (2H), 3.05 (1H), 2.86 (1H), 1.73 (1H), 0.86 (9H), 0.03 (6H).

(f) Intermediate 6: (I ', R, 4'S) -9- [4 - /// 1,1-dimethylethyl / dimethylsilyloxy / methyl / -2-cyclopenten-1-yl] -6-cyanoimino-1, 6-dihydro-1-methoxy-9H-purine
A solution of intermediate 5 (1.36 g) in dimethylformamide (10 ml) was stirred at ambient temperature, then triethylamino (1.2 ml) was treated. After 40 min, add to iodomethane (0.54 ml), which leads to the formation of a yellow solution. After 3 hours 45 minutes, the solvent was removed by evaporation. The residue was partitioned between ethyl acetate (100 ml) and water (20 ml). The organic solution was washed with water (2 • 20 ml) and brine (20 ml), dried in the presence of magnesium sulfate and evaporated to a solid. This solid is washed with diethyl ether (25 ml) and then collected by filtration. This white solid is then washed with ether (10 ml), dried in vacuo to give the title compound (0.865 g),
λ _max (ethanol) 227.2 nm (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ 449), 287.0 nm (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ 544)
¹ H-NMR 8.23 (1H), 7.96 (1H), 6.24 (1H), 5.85 (1H), 5.65 (1H), 4.21 (3H), 3.66 ( 2H), 3.04 (1H), 2.77 (1H), 1.68 (1H), 0.88 (9H), 0.05 (6H).

 (g) Intermediate 7: (1 ', R, 4'S) -9- [4 - /// 1, 1-dimethylethyl / dimethylsilyloxy / methyl / -2-cyclopenten-1-yl-6-methoxy-amino-9H purin-2-amine.

A solution of intermediate 6 (802 mg) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.45 ml) in ethanol (80 ml) was stirred and heated under reflux. Heating was stopped after 9 hours and the solution was left at ambient temperature overnight. The solvent was removed by evaporation. The residual oil is combined with that obtained from the previous experiment (4% scale), then subjected to column chromatography on silica (40 g, Merck 9385), eluting with chloroform, then with a mixture of chloroform-ethanol to obtain a foam. This foam was triturated with diethyl ether (10 ml) and the resulting solid was collected by filtration. The solid was then washed with ether (5 ml), dried in vacuo to give the title compound (594 mg),
λ _max (ethanol) 282.2 nm (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ 409)
¹ H-NMR (DMCO-d ₆ ) 9.76 (1H), 7.32, (1H), 6.53 (2H), 6.08 (1H), 5.26 (1H), 3.72 ( 3H), 3.61 (2H), 2.90 (1H), 2.50 (1H) 1.52 (1H), 0.83 (9H), 0.02 (6H).

(h) Intermediate 8: / 1S, 4 R / -4- [2-amino-6-methoxyamino-9H-purin-9-yl] -2-cyclopentene-methanol
A solution of intermediate 7 (356 mg) in tetrahydrofuran (35 ml) was stirred at ambient temperature, then treated with tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 1.4 ml). After 90 minutes, the reaction mixture was cooled with water (1 ml), then the solvents were removed by evaporation. The residual oil was subjected to silica column chromatography (20 g, Merck 7734), eluted with chloroform, then with chloroform-ethanol to give the title product as a solid (243 mg),
λ _max (pH 6 buffer) 250.2 nm (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 534),
¹ H-NMR (DMCO-d ₆ ) 9.75 (1H), 7.39 (1H), 6.52 (2H), 6.10 (1H), 5.84 (1H), 5.27 (1H) ), 4.73 (1H), 3.40 (2H), 2.83 (1H), 2.55 (1H), 1.52 (1H).

 (1S, 4P) -4- [2,6-Diamino-9H-purin-9-yl] -2-cyclopentenecarbinol.

A mixed, ice-cooled solution of intermediate 6 (210 mg) in water (10 ml) and tetrahydrofuran (50 ml) is treated with an amalgam (from aluminum (237 mg) and a 0.5% aqueous solution of mercuric chloride), added in small portions in 15 minutes After 40 minutes, the stirred mixture was warmed to ambient temperature. After 15 minutes, the resulting mixture was filtered through kieselguhr so as to remove insoluble matter. They are washed with a mixture of water: tetrahydrofuran (1: 5, 60 ml). The combined filtrates were evaporated. The residue was subjected to silica column chromatography (10 g, Merck 9385), eluted with chloroform-ethanol to give the title product as a foam (159 mg),
[α] _D -81 ^° (s, 1.04, methanol);
λ _max (pH 6 buffer) 255.0 nm (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 302), 280.8 nm (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 381)
¹ H-NMR (DMCO-d ₆ ) 7.61 (1H), 6.66 (2H), 6.10 (1H), 5.87 (1H), 5.76 (2H), 5.38 (1H ), 4.76 (1H), 3.45 (2H), 2.87 (1H), 2.60 (1H), 1.60 (1H).

Example 13
/ 1S, 4R / -4- / 2-amino-6-hydroxy-9H-purin-9-yl - / - 2-cyclopentenylcarbinol
/ 1 ', R, 4'S / -2-Amino-1,9-dihydro-9- [4-hydroxymethyl-2-cyclopenten-1-yl] - 6H-purin-6-one
A turbid solution of the title compound of Example 12 (144 mg) in 0.1 M, pH 6 buffer (10 ml) (from 28.4 g of disodium orthophosphate in 2 L of water brought with phosphoric acid) was treated with an adenosine deaminase solution (0.5 ml, 778 units) in a 50% mixture of glycerol - 0.01 M potassium phosphate, pH 6.0, then stirred and heated to a temperature of 37 ^o C. After 18.5 hours the resulting suspension was cooled. The collected solid was recrystallized from water to give the title product as a white solid (86 mg),
[α] _D -49 ^o (s, 0.5, dimethyl sulfoxide),
λ _max (pH 6 buffer) 252.6 nm E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 531),
¹ H-NMR (DMCO-d ₆ ) 10.60 (1H), 7.60 (1H), 6.47 (2H), 6.10 (1H), 5.86 (1H), 5.33 (1H ), 4.72 (1H), 3.45 (2H), 2.59 (1H), 1.58 (1H).

Example 14
Preparation of (1α, 4α) -4- (2-amino-6-hydroxy-9H-purin-9-yl / -2-cyclopentenecarbinol enantiomers
(a) / 1S, 4R / -4- / 2-amino-6-hydroxy-9H-purin-9-yl / -2-cyclopentenyl-carbinol
A diamine analog (100 g) (Example 11) was dissolved in 3 ml, 0.05 MK ₂ PO ₄ buffer (pH 7.4) with heating (50 ^° C.). The solution was cooled to room temperature and 40 units of adenosine deaminase (Sigma, Type VI, calf intestinal mucosa) were added to the solution, which was incubated for three days at room temperature, after which the precipitate was removed by filtration, to obtain 18.2 mg . The filtrate was concentrated to 1.5 ml and cooled for 2 days. Filtration gives an additional amount (26.8 mg) of solid. Two solid fractions were recrystallized from water to give the pure title product, melting point 269-272 ^° C., [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ -62.1 (s, 0.3 MeOH).

(b) / 1R, 4S / -4- / 2-amino-6-hydroxy-9H-purin-9-yl / -2-cyclopentenyl-carbinol
The filtrates resulting from the 1S, 4R isomer (Example 14a) are combined and evaporated to dryness. The constant diamino-starting material was separated on a flash column with silica gel using a 10% methanol / chloroform mixture. The diamine compound is dissolved in 0.05 M K ₂ PO ₄ buffer, pH 7.4 (15 ml), and 800 units of adenosine deaminase are added to the solution, which is incubated at 37 ^° C. for 96 hours. Thin layer chromatography indicates some the amount of unreacted product. The solution is heated in boiling water for 3 minutes and filtered to remove the denatured protein. Then add another 800 units. adenosine deaminases and the process is repeated. The deproteinated solution was evaporated to dryness and the product was crystallized from water. The title compound as a white solid was collected by filtration from water, melting point 265-270 ^° C.

[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ + 61.1 (s, 0.3 MeOH).

Example 15
/ ± / - / 1α, 4α / -4- / 2-amino-6-hydroxy-9H-purin-9-yl / -2-cyclopentenylacetoxycarbinol
Acetic anhydride is added to a suspension of the product of Example 10 (130 mg, 0.50 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in a mixture of acetonitrile (6 ml) and triethylamine (0.09 ml, 0.66 mmol). acid (0.06 ml, 0.6 mmol). The mixture was stirred at room temperature for 3 hours. Methanol (1 ml) was added so as to cool the reaction mixture. The solution was concentrated and absorbed on silica gel (1.5 mg), packed in a column (2.0 x 12 cm), and CHCl ₃ -MeOH (20: 1) was eluted. Product fractions were collected and concentrated to give a white solid. The solid was washed with MeOH-AcOEt: yield 123 ml (85%). Further purification from methanol affords the title compound as needle crystals, melting point 237 - 239 ^° C. Anal. (C ₁₃ H ₁₅ N ₅ O ₃ ) C, H, N.

Example 16
/ 1S, 4R / -4- [2-amino-9H-purin-9-yl] -2-cyclopentenylcarbinol
A stirred, ice-cooled solution of (1S, 4R / -4- [2-amino-6-methoxyamino-9H-purin-9-yl] -2-cyclopentene-methanol (intermediate 8, example 12) (1.202 g) in tetrahydrofuran (250 ml) and water (50 ml) are treated with aluminum amalgam (from aluminum (1.761 g) and a 0.5% aqueous solution of mercuric chloride), added in small portions over 1 hour 47 minutes, after 35 minutes the stirred mixture is heated to ambient temperature After another 16 hours and 50 minutes, an additional aluminum amalgam (from 235 mg of aluminum) was added over 14 minutes, after 4 hours and 10 minutes the resulting mixture was filtered through kieselguh in order to remove insoluble bodies which are washed with tetrahydrofuran: water (5: 1, 300 ml). The combined filtrates are evaporated to give a yellow foam. The foam is subjected to silica column chromatography (33.8 g, Merck 7734) in chloroform and elute chloroform-ethanol mixture to give several fractions (578 mg, 420 mg and 40 mg). The two largest fractions are crystallized separately from isopropanol. The filtrates are combined with the smallest column fraction and subjected to preparative thin layer chromatography (Merck 5717), showing three times in a mixture chloroform: methanol (10: 1). The plates were eluted with ethyl acetate-ethanol (1: 1) to give a brown solid (45 mg). The solid was subjected to silica column chromatography (2.7, Merck 7734) in chloroform and was eluted with chloroform-methanol-triethylamine mixtures to give gum (17 mg). Following the failed crystallization from isopropanol and treatment with charcoal in methanol, the aqueous solution of the reduced substance was freeze dried to give the title compound 15 mg.

¹ H-NMR (DMCO-d ₆ ) 1.62 (1H), 2.63 (1H), 2.89 (1H), 3.45 (2H): 4.73 (1H), 5.48 (1H) ), 5.91 (1H), 6.14 (1H), 6.50 (2H), 7.98 (1H), 8.57 (1H).

Mass spectrum: [MH] ⁺ 232.

Example 17
Tablet formulations
A. The following preparation was obtained by wet granulation of the ingredients and a solution of povidone in water, drying and sieving, followed by the addition of magnesium stearate and pressing (mg-tablet):
(a) Active ingredient - 250
(b) Lactose BP (British Pharmacopeia - British Pharmacopoeia) - 210
(c) Povidone BP - 15
(g) Sodium salt of carboxymethyl starch - 20
(e) Magnesium stearate - 5 - 500
B. The following preparation is obtained by direct compression, using the type of lactose for direct compression (mg / tablet):
(a) Active ingredient - 250
(b) Lactose - 145
(c) Avicel - 100
(e) Magnesium stearate - 5 - 500
C. (Controlled Release Drug). The preparation was obtained by wet granulation of the following ingredients with a solution of povidone in water, drying and sieving, followed by the addition of magnesium stearate and pressing (mg / tablet):
(a) Active ingredient - 500
(b) Hydroxypropyl methylcellulose (Methocel k4m Premium) - 112
(c) Lactose BP - 53
(d) Povidone BP - 28
(e) Magnesium stearate - 7 - 700
Example 18
Encapsulated drug
An encapsulated preparation is prepared by mixing the following ingredients and filling in two-part hard gelatin capsules (mg / tablet):
Active ingredient - 125
Lactose - 72.5
Avicel - 50
Magnesium Stearate - 2.5 - 500
Example 19
Injection
Active ingredient - 0,200 g
0.1 M Sodium hydroxide solution - up to pH about 11
Sterile water - up to 10 ml
The active ingredient is suspended in water, which can be warm, and adjusted to approximately 11 with sodium hydroxide. The portion is then adjusted to the required volume and filtered through a sterile membrane filter into a 10 ml sterile glass vial, hermetically sealed with a sterile stopper and over with a metal the lid.

Example 20
Candles (mg):
Active ingredient (63 microns) - 250
Solid Fat BP - 1770 - 2020
One fifth of the solid fat is melted in a bath equipped with a steam-heated jacket at a temperature not exceeding 45 ^o C. The active ingredient is sieved through a sieve (200 μm), added to the molten base and mixed until a soft dispersion is obtained using a highly efficient mixer. Leave the mixture at 45 ^° C, add the remainder of the solid fat to the suspension and mix until a homogeneous mixture is obtained. Continuing stirring, the entire suspension is passed through a stainless steel sieve (250 μm) and allowed to cool to 40 ^o C. At a temperature of the mixture from 38 to 40 ^o C suitable plastic forms with a volume of 2 ml fill 2.02 g of the mixture and allow to cool to room temperature.

Example 21
Antivirus activity
(A) Enti-HIY analysis
The compounds of formula (I) were screened for enti-HIY activity at the National Cancer Institute on cancer research equipment of Frederick, Frederick Maryland (FCPF). The following describes the current operational screening methods used in FCPF. The protocol consists of three sections:
(I) obtaining infected cells and distributing them on test plates;
(Ii) preparation of diluted drug plates and distribution on test plates; and
(Iii) XTT analysis procedure.

 See the work of D.A. Scudero et al. "A new simplified tetrosolium analysis for cell growth and drug susceptibility testing in culture." Cancer Res. 483827 (1988).

I. Infection and distribution of ATH8 cells on microtiter plates
Cells to be infected (normal lymphoblastoid line that expresses CD4) were placed in 50 ml conical centrifuge tubes and treated for 1-2 h with 1-2 μg / ml polybrene at 37 ^° C. Then the cells were centrifuged for 8 min at a rotation speed of 1200 rpm HIY virus diluted 1:10 with medium (RMRI-1640, 10% human serum or 15% calf fetal serum FCS), in the presence of 1α-2 and antibiotics) was added to the system to provide an MOI of about 0.001. Only virus was added to control cells not containing the virus. Assuming an infectious virus titer of 10 ^-4 , an MOI of 0.001 represents 8 infectious viral particles per 10,000 cells. Approximately 500,000 cells / tube was exposed to 400 μl of viral diluent. The resulting mixture was incubated for 1 h at 37 ^o C in the atmosphere: air - CO ₂ . Infected or uninfected cells were diluted to 1 • 10 ^-4 (human serum) or 2 • 10 ^-4 (calf fetal serum) cells. / 100 μl.

Infected or uninfected cells (100 μl) were dispensed into the corresponding recesses of a V-shaped microtiter plate containing 96 recesses. Each dilution of the compound was tested with infected cells, with duplicate experiments. Uninfected cells were tested for drug sensitivity in a single well for each dilution of the compound. The experiments with control cells, both infected and uninfected, were repeated three times. The B2-G2 recesses served as reagent controls; only medium was placed in them. The plates were incubated at 37 ^o C in the atmosphere: air - CO ₂ before drug pressure.

II. Dilution and addition of medicine
Dilution plates (flat bottom microtiter plates containing 96 recesses) were treated overnight with phosphate buffered saline (PBS) or medium containing at least 1% FCS or 1% human serum (depending on the medium used in the test), starting from the day preceding the analysis. The “blocking” technique was used to limit the adsorption of the drug on the microtiter plate during the dilution process. The recesses were completely filled with a blocking solution and stood at room temperature in a humidified chamber under the hood.

 The dilution process was started by first diluting the test compound to a ratio of 1:20. Blocked dilution plates were prepared by shaking the blocking solution and blotting dry with sterile gauze. Then, all the depressions in each plate were filled with 225 μl of the appropriate medium using a Cetus fluid handling system. Then, 25 μl of each of the compounds diluted in a ratio of 1:20 was manually added to row A of a blocked and filled dilution plate. Four compounds were added to the dilution plate, which is sufficient for two test plates. Then these four compounds were subjected to 10-fold serial dilution from series A to H using the Cetus system. At this point, the initial dilution of each compound in row A was 1: 200. Diluted plates were stored on ice until use.

Using a multichannel pipette with 6 micropipes, 100 μl of each diluent was transferred to a test plate that already contained 100 μl of medium and cells. Final dilution on the test plate began with a value of 1: 400 (recesses B4-G4). This dilution (up to 0.25% DMCO) prevents the negative effects of DMCO on cell growth. To drug-free infected and uninfected cells (B3-G3 depressions) and control reagents (B2-G2), only medium was added. The two remaining compounds were then transferred to the H7-H12 recesses on the second test plate using a similar technique. The plates were incubated at 37 ^o C in an atmosphere of air - CO ₂ for 7-14 days or until the lysis of the viral controls according to macroscopic definitions.

III. Quantification of viral cytopathogenicity and drug activity
A. Materials
1. A solution of 2,3-bis / 2-methoxy-4-nitro-5-sulfophenyl / -5 - / (phenylamino) carbonyl / -2H-tetrazolium hydroxy, (XTT) - a solution with a concentration of 1 mg / ml in medium, not containing FCS. The solution was stored at 4 ^° C. Prepared weekly.

2. A stock solution of phenazine methosulfonate (PMS). This solution can be prepared in advance and stored frozen until use at -20 ^° C. The concentration of Pb in such a solution can be 15.5 mg / ml.

B. Microculture Tetrazolium Assay (MHA)
1. Preparation: An XTT-PMS-XTT-PMS solution was prepared immediately before it was added to the recesses of the culture plate.

The PMS stock solution was diluted to a value of 1: 100 (0.153 mg / ml). Diluted PMS was added to each ml of XTT to a final PMS concentration of 0.02 mM. 50 μl of XTT-PMS mixture liquor was added to each of the respective recesses and the plate was incubated for 4 hours at 37 ^° C. Caps were removed from the plates and replaced with sticky plug plates (Dynatech cat 001-010-3501). The plates thus closed were shaken on a microculture mixer and the absorbance was determined at a wavelength of 450 nm.

IV. results
The data obtained are presented in the form of a graph of the percentage of test cells versus uninfected cells (%) for both infected and uninfected cells, depending on the increasing concentration of the test compound. Such graphs allow calculating the effective concentration (EC ₅₀ ) in relation to infected cells, the inhibitory concentration (IC ₅₀ ) in relation to normal cells and the therapeutic index (TI ₅₀ ).

 Inhibitory concentrations against HIY, determined in accordance with the above for the compounds of examples 7, 9, 10, 11 and 14b, are presented in table. 1 (in μg / ml) and in table. 2.

The therapeutic index was calculated as the quotient of dividing IC ₅₀ by EC ₅₀ .

 In this screening, the compounds of Examples 5 and 8 also exhibit antiviral activity.

An earlier analysis conducted with the compound of Example 10 at the Southern Research Institute yielded a TI ₅₀ of 200 for culturing MT-2 cells in the presence of H9 / HIIV-IIIB.

(B) Activity against the virus Felin's watering can
Antiviral screening for activity against FeIV-JAIDS was performed on 96-well plates (corning) using 81C indicator cells in Dulbecco's medium modified by Iskova, which was supplemented with 10% thermodeactivated calf fetal serum (FBS). Twenty hours before the analysis, the plates were seeded with 81C cells with a concentration of 5 • 10 ³ cells. / deepening. On the day of analysis, cells were pretreated for 30 min at 37 ^° C. with DEAE-dextran (25 μg / ml) in 0.1 ml of Hanks balanced saline. The solution was removed and then 0.1 ml of plant medium containing 32 TCID ₅₀ FIY-FAIDS, or 0.1 ml of plant medium only was added to each well. The virus was allowed to adsorb for one hour and then 0.1 ml of the test or positive control compound (2 ', 3'-dideoxycytidine; ddc) or plant medium was added. The plates were incubated at 37 ^o C. On day 4 after infection, the cells were fed with fresh vegetable medium containing the compound. The culture medium was completely exchanged and replaced with fresh medium containing the compound on the 7th day after infection. On the 10th day after infection, the cells were fixed with formalin, stained with 0.1% Kosmashi Brilliant Blue R-25o stain solution and observed under a microscope for CPE and drug cytotoxicity.

The compound of Example 14a had an ED ₅₀ value of the order of 1.9 μg / ml.

(C) Activity against AIDS Murin
Falcon records with 6 recesses for tissue culture were seeded 1.75 • 10 ⁵ cells. to deepen in a total volume of 2.5 ml of EMEM containing 5% thermally deactivated FBS. Twenty hours after plating, the medium was discarded and 2.5 ml of DEAE-dextran (25 μg / ml in phosphate buffer solution) was added to each well. The cultures were incubated for 1 h at 37 ^o C, after which the DEAE-dextran solution was drained and the cell layers were immediately rinsed with 2.5 ml of medium (without virus or drug). Control cultures per drug received 2.5 ml of medium containing drug without virus. Virus-infected control cultures received 0.5 ml of an appropriate dilution of CAS-BR-M uterine in order to produce counted plaques plus 2.0 ml of medium. 0.5 ml of the appropriate viral dilution and 2.0 ml of drug dilution medium were added to the test samples. Six concentrations of the test compound diluted with serial hemogarithmic dilutions were tested. Three concentrations of the positive control drug ddc were tested. Each assay included three depressions for each concentration of the test compound, as well as 6 viruses and 6 cell control cultures. On day 3, the post-viral inoculation toxicity of the drug with respect to C-1 cells was determined by microscopic examination of stained duplicated cell cultures and cultures with a control drug. The remaining test and control cultures were irradiated with light from a UV lamp for 20 s, and XC cells (5 x 10 ⁵ cells / well in 2.5 EMEM containing 10% thermo-defective FBS) were added to each culture. On day 3 after irradiation, the cultures were fixed with formalin and stained with crystal violet. Plaques were counted using an analytical microscope.

Antiviral activity for reducing the number of CAS-BR-M plaques was expressed by a decrease in the average number of plaques counted in drug-treated virus-infected cultures compared to the average number of plaques counted in untreated virus-infected cultures (percentage of control). The compound of Example 14a had an ED ₅₀ value of the order of 1.1 μg / ml.

(D) Activity Against SAIDS Retrovirus (SRY-2). Simian
Antiviral screening against SAIDS virus (D / Washington) was performed by analysis of inhibition of syncytium on Reggie cells. The drug was diluted in Iskov's complete medium, and then 100 μl of each dilution was added to the corresponding wells in a 96-well plate. Then, actively growing Reggie cells, 5 • 10 ³ cells, were added to each well. in 50 ml of complete medium Iskova. Then, 50 μl of clarified top layer from SRY-2 / Reggie cell culture was added. In this assay, DDS was used as a positive control drug. The plates were incubated at 37 ^° C. in a humidified atmosphere containing 5% CO ₂ . On day 7 after infection, syncytium was counted. Drug toxicity was determined by comparing the number of living cells in an uninfected, drug-treated sample with the viability of an uninfected, untreated control. The compound of Example 14a has an ED ₅₀ value of 2.8 μg / ml.

(E) Activity against Vishnu Maedi virus
Antiviral activity against a strain of Vishnu Maedi virus (VMV) WL C-1 was determined by measuring the decrease in the degree of virus-specific, immunohistochemical staining. Monolayers of sheep choroid cells were infected with VMV and loaded with serial dilutions of test compounds. After incubation for five days, the monolayers were additionally incubated in the presence of a virus-specific antiserum conjugated with primrose seaside peroxidase (HRP). Then, monolayers were incubated in the presence of a chromogenic substrate HRP, strain areas of viral replication. Such discrete foci were counted and the concentration of the test compound required to reduce the number to 50% of the corresponding number in the untreated control samples was calculated. The compound of example (+14) a had an ED ₅₀ value of 0.2 μg / ml.

Example 22. Cytotoxic activity
The compounds of examples 7a, 9a and 10a, defined in example 17, showed cytotoxic activity when tested against the cell culture of leukemia of P388 mice according to the analysis described by R.S. Aloquist and R. Vince in J. Med. Chem. 16, 1396 (1973). The resulting ED ₅₀ values (μg / ml) were:
Compound 5 - 12
Compound 7 - 40
Compound 8 - 3
Additional examples
Example 23
(22R) - 16α, 17α-butylidenedioxy-21-caprylyloxy-6α, 9α-difluoro-11 β-hydroxypregn-4-en-3,20-dione
To a solution of (22R) - 16α, 17α-butylidenedioxy-6α, 9α-difluoro-β, 21-dihydroxy-pregn-4-ene-3,20-dione (60 mg) in 4 ml of methylene chloride was added capryl chloride (35 mg) and 4- dimethylaminopyridine (30 mg). The reaction mixture was stirred at room temperature for 45 minutes. After evaporation, the residue was purified by Merk Keselgel 60 column chromatography using heptane: ethyl acetate 1: 1 as the mobile phase. The resulting product was purified by chromatography on a Sephadex LH-20 column (inner diameter 85 × 2.5 cm) using chloroform as the mobile phase. The 280-315 ml fraction was collected and evaporated, the residue was precipitated from methylene chloride: petroleum ether to obtain 28 mg (22R) - 16α, 17α-butylidenedioxy-21-caprylyloxy-6α, 9α-difluoro-11β-hydroxypregn-4-3,20 dione. Melting point 158-165 degrees Celsius.

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = +103.7 ^° C (c + 0.216; CH ₂ CL ₂ ); molecular weight 594 (calc. 594.7). Purity: 98.7% (HPLC analysis).

 Example 24. (22R) -16α, 17α-butylidenedioxy-21-capryloxy-6α, 9α-difluoro-11β-hydroxypregn-4-ene-3,20-dione.

A solution of capryl chloride (75 mg) in 2 ml of dioxane was added dropwise to a solution of (22R) - 16α, 17α-butylidenedioxy-6α, 9α-difluoro-11β, 21-dihydrooxypregn-4-gene-3,20-dione (60 mg) in 4 ml of pyridine. The reaction mixture was stirred at room temperature overnight and worked up as in Example 1. The crude product was purified by chromatography on a Sephadex LH-20 column (internal diameter 89 x 2.5 cm) using a mixture of heptane: chloroform: ethanol 20: 20: 1 in as a mobile phase. A 245-315 ml fraction was collected and evaporated, the residue was precipitated from methylene chloride: petroleum ether to give 58 mg (22R) - 16α, 17α-butylenedioxy-21-capryloxy-6α, 9α-difluoro-11β-hydroxypregn-4-en-3 , 20-dione. Melting point 168-171 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = +93.7 ^o (c + 0.302; CH ₂ Cl ₂ ); molecular weight 622 (calc. 622.8). Purity: 94.1% (HPLC analysis).

 Example 25

(22R) - 16α, 17α-butylidenedioxy-21-capryloxy-6α, 9α-difluoro-11β-hydroxypregn-4-en-3,20-dione
To a solution of (22R) - 16α, 17α-butylidenedioxy-6α, 9α-difluoro-11β, 21-dihydroxy-pregn-4-ene-3,20-diene (60 mg) in 4 ml of methylene chloride, caprylyl chloride (25 mg) and 4- dimethylaminopyridine (30 mg). The reaction mixture was stirred at room temperature for 30 minutes and worked up as in Example 28. After chromatography on a Merk Keselgel 60 column, the product was purified by chromatography on a Sephadex LH-20 column (internal diameter 85 x 2.5 cm) using chloroform phases. A 300-345 ml fraction was collected and evaporated, the residue was precipitated from methylene chloride: petroleum ether to obtain 20 mg (22R) - 16α, 17α-butylidenedioxy-21-capryloxy-6α, 9α-difluoro-11β-hydroxypregn-4-en-3 , 20-dione. Melting point 148-160 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = +107.3 ^o (c + 0.232; CH ₂ Cl ₂ ); molecular weight 566 (calc. 566.7). Purity: 99.3% (HPLC analysis).

 Example 26

(22R) - 16α, 17α-butylidenedioxy-21-butyryloxy-6α, 9α-difluoro-11β-hydroxypregn-4-en-3,20-dione
A solution of butyryl chloride (170 mg) in 5 ml of dioxane was added dropwise to a solution of (22R) - 16α, 17α-butylidenedioxy-6α, 9α-difluoro-11β, 21-dihydroxy-pregn-4-en-3,20-dione (150 mg) in 10 ml of pyridine. The reaction mixture was stirred at room temperature overnight and worked up as in Example 1. The crude product was purified by chromatography on a Sephadex LH-20 column (internal diameter 70 x 6.3 cm) using chloroform as the mobile phase. The 1440-1740 ml fraction was collected and evaporated, then purified on a Sephadex LH-20 column (inner diameter 70 • 6.3 cm) using a heptane: chloroform: ethanol 20: 20: 1 mixture as the mobile phase. The 2010-2230 ml fraction was collected and evaporated. The residue was precipitated from methylene chloride: petroleum ether to give 118 mg (22R) - 16α, 17α-butylidenedioxy-21-butyryloxy-6α, 9α-difluoro-11β-hydroxypregn-4-en-3,20-dione. Melting point 208-216 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = +114.4 ^° (c + 216; CH ₂ Cl ₂ ); molecular weight 538 (calc. 538.6). Purity: 99.4% (HPLC analysis).

 Example 27 (according to schemes I and II).

 The synthesis of (hydroxymethyl) cyclopentyl derivatives of formulas ba-11a and (hydroxymethyl) cyclopentyl derivatives of formulas 6b-11b on the cis- (4-acetamidocyclopent-2-enyl) methyl acetate precursor (1a) is carried out in accordance with Schemes I and II (see at the end of the text). Compound 1a is hydrolyzed with aqueous barium hydroxide to give amino alcohol 2a. Condensation of 2a with 2-amino-4,6-dichloropyrimidine gives the corresponding pyridinylamino derivative 3a. 5 - [(Para-chlorophenyl) azo] pyrimidine 4a is prepared using para-chlorobenzenediazonium chloride. Shealy and Clayton, J. Pharm. Sci., 62, 1482 (1973). Reduction of 4a with zinc and acetic acid gives pyrimidine 5a, which is then converted to 9-substituted 2-amino-6-chloropurine 6a by the formation of a cyclic compound with triethyl ortho-formate. 2-amino-6-chloropurine 6a is converted to a carbocyclic 2 ', 3'-didehydro-2', 3'-dideoxyguanosine analog 7a when refluxed in 0.8 N sodium hydroxide, while treating 6a with liquid ammonia results to obtain a 2,6-diaminopurine analogue 8a.

 The formation of a cyclic compound (cyclization reaction) 5a with sodium nitrite and acetic acid gives (+) - (cis) -4- (5-amino-7-chloro-3H-1,2,3-triazolo [4,5- d] pyrimidin-3-yl] -2-cyclopentylcarbinol (9a) in good yield. Basic hydrolysis of 9a with sodium hydroxide affords the 8-aza analog of 10a, carbocyclic 2 ', 3'-didehydro-2', 3'-dideoxyguanosine while treatment with liquid ammonia results in the corresponding 2,6-diaminopurine analogue 11a.

 2 ', 3'-saturated derivatives are obtained in accordance with scheme II. Catalytic reduction 1a leads to the production of a correspondingly substituted cyclopentane precursor 1b. The remaining stages of the synthesis of compounds of series b are similar to the stages of the synthesis of compounds of series a.

Claims (15)

1. Dideoxydehydrocarbocyclic nucleosides of the general formula I

where X is NRR ¹ , SR, OR ² , H or a halogen atom;
Z is a hydrogen atom or NH ₂ ;
R, R ¹ , R ² , identical or different, is a hydrogen atom, C ₁ is C ₄ alkyl,
or their pharmaceutically acceptable derivatives.  2. The compound of formula I according to claim 1 or its pharmaceutically acceptable salts. 3. The compound of formula I according to claim 1 or 2, characterized in that X is OH or NH ₂ . 4. The compound according to any one of claims 1 to 3, characterized in that Z is NH ₂ . 5. The compound according to any one of claims 1 to 4, characterized in that X is a chlorine atom, NH ₂ , SH or OH.  6. The compound according to any one of claims 1 to 5, characterized in that X is OH. 7. The compound according to any one of claims 1 to 5, characterized in that X is NH ₂ . 8. The compound according to any one of claims 1 to 7, selected from
(1a, 4a) -4- (6-chloro-9H-purin-9-yl) -2-cyclopentenylcarbinol;
(1a, 4a) -4- (6-hydroxy-9H-purin-9-yl) -2-cyclopentenylcarbinol;
(1a, 4a) -4- (6-amino-9H-purin-9-yl) -2-cyclopentenylcarbinol;
(1a, 4a) -4- (6-mercapto-9H-purin-9-yl) -2-cyclopentenylcarbinol;
(1a, 4a) -4- (2,6-diamino-9H-purin-9-yl) -2-cyclopentenylcarbinol;
(1a, 4a) -4- (2-amino-6-chloro-9H-purin-9-yl) -2-cyclopentenylcarbinol;
(1a, 4a) -4- (2-amino-9H-purin-9-yl) -2-cyclopentenylcarbinol;
9. (1a, 4a) -4- (2-amino-6-hydroxy-9H-purin-9-yl) -2-cyclopentenylcarbinol.  10. The compound according to any one of claims 1 to 9, mainly in the form of a racemic mixture.  11. The compound according to any one of claims 1 to 9, mainly in the form of an optically active isomer.  12. The compound according to any one of claims 1 to 9, mainly in the form of an isomer.  13. 1-Monophosphate ester of the compound according to any one of claims 1 to 12.  14. The compound of general formula I according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof having antiviral activity.  15. A pharmaceutical composition exhibiting antiviral activity, comprising an active substance and pharmaceutically acceptable additives, characterized in that as an active substance it contains a compound of general formula I according to any one of claims 1 to 14 or its pharmaceutically acceptable derivatives in an effective amount. 16. Dideoxide-dehydrocarbocyclic nucleosides of the general formula II

where X is NRR ¹ , SR, OR ² , a halogen atom; where R, R ¹ , R ² have the meanings indicated in claim 1;
Y is an OH group, possibly protected;
Z is NH ₂ ,
or their pharmaceutically acceptable derivatives. Priorities for items:
01/20/88 - according to paragraphs 3, 4, 8 and 9;
09/07/88 - according to claims 1 to 16;
12/05/88 - according to claims 1 to 16.

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