PT89482B - PROCESS FOR THE PREPARATION OF DISESOXYDESIDRO-CARBOXYLIC NUCLEOSIDE DERIVATIVES - Google Patents

Abstract

Compounds of the formula <IMAGE> in which X = H, NRR<1>, SR, OR or halogen; Z = H, OR<1> or NRR<1>; R, R<1> and R<2> are H, C1-4-alkyl or aryl and pharmaceutically acceptable derivatives thereof are described. The use of the compounds as antiviral and antitumour agents is likewise described as well as pharmaceutical formulations and methods for the preparation of the compounds and their intermediates.

Description

Description

The present invention relates to dideoxy-carbocyclic nucleoside analogs. More specifically it refers to the purine nucleoside analogs 2 ', 3'-didesoxy-2', 3 '-did sidro-cyclic cycles and their use in therapy, in particular as anti-viral agents.

Given the similarity between the functions of the virus and the host cell, it is difficult to selectively attack one if the host cell is to be kept intact »Thus, viruses effective against anti-viral tests, ie for bird 1, are relatively few agents per se and it is difficult to find agents that have an acceptable therapeutic index, that have a significant anti-viral effect at the dosage level at which the agent has a profile of toxicity or side effects »

U: n group of viruses that assumed color. z eme n t o; ’, .Ί'ΐ essenci & l importance is constituted by the res- | thinkable by the syndrome of Itr.un od e f i ciên ci · - <Acquired Human (AIDS) (òIDâ). Previously these viruses have been designated by different terminologies but recently they are designated as human immunodeficiency virus (HIV * s); two of these

rus, HIV-I and HIV-II, have been isolated, by uni repeat process— active, in pa cien t e s that suffered from AIDS and d and e s t a d o s associates - such as the complex associated with AIDS (, .RC) and lymphadenopathy patif! generalized persistent. Although if you adrr.ita who d i v e r s o s nucleosides

are useful for the treatment of conditions associated with HIV infections, only zidovudine (aZT, Retrovirus) received the

I regulatory approval for the treatment of such states. However, it is known that zidovudine has serious side effects, causing bone marrow suppression resulting in a decrease in white globes with the consequent pronounced anemia, being necessary for effective entities to be less cytotoxic.

A new class of nucleoside analogs that have anti-viral activity has now been discovered. Consequently, in a first aspect, a compound of formula (l) is provided

X

^H ° _C ^H \ _ / o “o (I) eni that X represents hydrogen,

represents hydrogen, OR or NRR;

R, R and n can be the same or different and are selected from hydrogen, 1 (C 0 0) tryl and aryl;

and their pharmaceutically acceptable derivatives.

It is noted to those skilled in the art that the compounds of formula (i) are cis compounds and, in addition, that the cyclopentene ring of the compounds of formula (l): sing two chiral centers (indicated in formula (i) by * ) and therefore can exist in the form of two optical isomers (ie, enantiomers) and their mixtures, including racemic mixtures. These isomers and their mixtures including racemic minerals are considered to fall within the scope of the present invention.

Thus, in the compounds of the formula or the chiral center at which the base is connected to the R configuration and its

CIÍpOH is linked if it is designated as the D isomer), or if and

center chiral to Wed 1st radical in conf i i.uraçao O t the 1. a if lead to- center how u1 to i j u: -i 1 to b a s e e s

The bond is in the S configuration and the chiral center to which: the CH ₂ 0H radical is bonded is in the R configuration (hereinafter referred to as the L-isomer) _o Conveniently, the compounds will be in the form of a racemic mixture or essentially as pure D isomer. D-isomers can be represented by the formula (Ia)

(Ia)

I

where X and 4 have the defined meanings (Ι) »The following references to the compounds of the formula (l) include the compounds of fórniul · ·

It is also important to observe that specialists in the formula (1) may have tauto-american forms considering all of these some of the tautonier compounds included in the scope of the pressing invention

As used now, the halogen content refers to fluorine, chlorine, bromine and iodine; Since X is halogen, chlorine is predominantly represented.

As used now, (C ₁ -C 4) alkyl refers to a straight or branched chain alkyl group, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl and t -butyl. Conveniently (C - 0,) alkyl has methyl.

As used herein, aryl means a rionic- or polycyclic aromatic radical and encompasses substituted and substituted (such as phenyl, tolyl, unsubstituted aryl and anisyl) and unsubstituted and substituted aralkyl including (C ₁ -C) aralkyl such as phenalauyl (C ^-C ^), for example benzyl or methylene.

In the compounds of formula (i), 2 preferably represents amino »

In a preferred class of compounds of form la (1), X represents OR, in particular Oh.

In another preferred class of compounds of formula (l), X represents NRR3, in particular N1, or hydrogen or i

Compounds for rt i cul a rmer. t and favorites of formula (I) are auels in which /. represents AH ,, and .v represents | ii, XE., or especially OH. Such particular compounds have therapeutic desires especially desirable as an agent to act on.

With the derived term farir.aceuticaniento;

acceptable is intended to mean any salt, ester or salt of such a pharmaceutically acceptable ester of a compound of formula (I), or any other compound which is administered to the? a patient is likely to provide (directly or indirectly) a compound of formula (i) or a merabolite or an anti-viral active residue.

Preferred esters of the compounds of formula (I) include esters of carboxylic acids in which the non-hydrogen, carbonyl ester of the ester group is selected from alkyl that is straight or branched (for example methyl, ethyl, n-propyl, t-butyl, n-butyl), 1-coxy-a Igui (eg methoxy-methyl), aralkyl (eg benzyl) aryl-oxy-alkyl (eg phenoxy-methyl), aryl (eg example-ί j I phenyl optionally substituted by halogen, alkyl-j (C (-C-)) or ί 1 coxy (C-C ^)); sulfonate esters such as alkyl or aralkyl sulfonyl (for example methanesulfonyl); amine esters (eg <Je L-valyl or L-isoleucyl)! and mono-, di- or tri-phosphate esters. '

I I

With respect to the esters previously described, unless otherwise specified, any alkyl radical present contains between 1 and 18 carbon atoms, particularly between 1 and 'carbon atoms.

any aryl radical present in such esters advantageously contains a phenyl group.

The pharmaceutically acceptable salts of the compounds of formula (i) include those derived from bases and

ve i s,

f organic and inorganic acids pharmaceutically Examples of suitable acids include nitric, perchloric, fumaric, maleic lactic, s.olicyl, succinic, toluenoacetic, citric, metar.o-sulfonic, naphthalene-2-sulfonic and benzene hydrochloric acids, phosphoric, glycolic sulfuric,

-p-sulfonic, tartaric, benzoic, malonic,

Other acids such as oxalic acid, although not pharmaceutically acceptable, may be the preparation of salts useful as intermediates for pfarmic,

- S tyl f ics and they are useful for obtaining pharmaceutically acid compounds

Salts derived from appropriate alkaline bases (eg sodium), of monon and encompass alkaline earth metal salts (eg ΝΓ <^ + magnesium (where R represents C-C, alkyl)) .

in relation to: a compound according to banned so many compounds of formula that are ceutically and c iably the following in invention encompasses the present (I) as its derivatives encompass:

The specific compounds of formula (l) (la, 4cc) - 4- (6-hydroxy-9H-purin-9-yl) -2-cyclo-oentene 1-carbinol (ia? ^ Or) -4 - (6 -amin o-9H-purin-9-yl) -2-cyclo-pentenyl-carbinol);

(lq ;, 4 <f) - 4- (6-layered - OH-pur in-9-yl) -2-cyclo-pentenyl-carbinol (ioc, W -4 - (2-a min o-6 - heat ro-9H-pur in-9-i 1) -2-cyclo-pentenyl-carj (1 q-, 4 <j) -4 - (2-amino-6-hydroxy-9H-pur in-9- il) -2-cyclo-pentenyl-rbinol;

(lqf, 4 <ç) - 4- (2,6-diamino-9H-purin-9-yl) -2 in the form of a racemic mixture or a simple enantiomer »cyclopentenyl-carbinol;

The compounds of the present invention themselves have anti-viral activity and / or are netabolizable in such compounds. In particular, these compounds are effective in inhibiting the replication of retroviruses, including human retroviruses such as human immunodeficiency viruses (HIV's), the causative agents of AIDS.

Some compounds of the present invention have anti-cancer activity, in particular those in which Z represents hydrogen.

Thus, as a further aspect of the invention, a compound of formula (i) or a pharmaceutically acceptable derivative thereof is provided for use as an active therapeutic agent, in particular as an anti-viral agent, for example for the treatment of retroviral infections, or as an anti-cancer agent.

is linked

In an additional aspect or a method for the treatment of an alternative viral infection, in particular an infection caused by a virus such as HIV, in a mammal including man, the administration of an effective amount of which consists of admitting anti-viral compound of formula (i) or a pharmaceutically acceptable derivative thereof 1.

Also provided in a further or alternative aspect is the use of a compound of formula (i) or a pharmaceutically acceptable derivative thereof for the preparation of a medicament for the treatment of a viral infection or for use as an anticancer agent.

The compounds of the present invention that have anti-viral activity are also useful for the treatment of AIDS-related conditions such as the AIDS-related complex (ARC), generalized lymphadenopathy progres7

siva (FGL), neurological states related to:> dl;.; (such as dementia or tropical paraparesis), anti-HIV positive body and HIV states, Kaposi's sarcoma and thrombocytosis and ρ or p ur a.

The anti-viral compounds in the present invention are also useful in preventing the progression of clinical diseases in individuals who have anti-HIV antibodies or HIV positive antigens and in prophylaxis after exposure to HIV _O

The anti-viral compounds of formula (i) or their pharmaceutically acceptable derivatives can also be used to prevent viral contamination of physiological fluids such as blood or semen in vitro.

some of the compounds of formula (i) are also useful as intermediates for the preparation of other compounds of: the present invention.

It is noted to those skilled in the art that the references contained herein about treatment are extended to prophylaxis as well as to the treatment of known symptoms or infections.

Also if the compound of the present invention treatment will vary not only with the amount of one required for use in the particular compound selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and finally it will depend on the opinion of the attending doctor or veterinarian. However, an adequate dose is generally considered

what varies between 1 and 750 mg / kg, for example between 10 and 750 mg / kg body weight per day, such conio 3 a 120 mg per kilo- β r a m a body weight d 0 patient a day, preferably find tre 6 and 90 mg / kg / day, more preferably between 15 θ 60

mg / kg / day «

\. ·

Λ y

I r-entemente is converted in a single dose or in divided doses ι dm ini stradajò ¹ is sub-doses per day.

The convenient compound is administered in a unit dosage form, for example containing between 10 J and 100 mg, conveniently between 20 and 1000 mg, often between OJ 7θ0 mg of active ingredient in dosage form.

more convenient— per unit

Ideally, the active ingredient will be administered to achieve peak plasma concentrations of the active compound in the range of approximately 1 to 75 æM approximately, preferably between 2 and 5 θ / μM, more preferably between and 30 approximately, for example, at 5 μm. ingredient by administering a large pill containing between 1 and ί The desirable levels in san- |

This can be achieved by intravenous injection of a solution from 0.1 active agent, optionally saline, oral traction n, ·

100 mg / kg of active ingredient. which can be maintained by continuous infusion to provide between 0.01 and 5> θ mg / kg / hour approximately, or by intermittent infusions containing between 0.4 and 15 mg / kg of ingredient a

Although for use in therapy it is possible to administer a compound of the present invention in raw chemical form and it is preferable to present the active ingredient as a pharmaceutical formulation.

Accordingly, the invention also provides a pharmaceutical formulation consisting of a compound of formula (i) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable vehicles.

acceptable and optionally with other therapeutic and / or prophylactic ingredients. Vehicles must be 'acceptable' in the 'sense that this term means compatibility with other' ingredients of the formulation and is not harmful to the patient. T ¹ .The pharmaceutical formulations include those for oral, rectal, nasal, topical (including mouthpiece and sub-tongue1), vaginal or parenteral (including intramuscular and intravenous) or forms suitable for administration by inhalation or insufflation. (where appropriate, it is possible to conveniently present the formulations in discrete dosage units and can be prepared by any of the methods known in the pharmaceutical art. All methods include the step of combining the active compound with liquid vehicles or with finely solid vehicles. divided or with both and then, if necessary, give a configuration to the product in the desired formulation.

Pharmaceutical formulations suitable for oral administration can conveniently be presented as discrete units such as capsules, pills or tablets each containing the active ingredient in a predetermined amount; in the form of powder or granules; as a solution: suspension or emulsion »The active ingredient can also be presented in the form of a large pill, electuary or paste. I lozenges and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrating agents or humectants. the tablets can be coated accordingly. methods well known in the art. Liquid oral preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, ₍ ! Or they may be presented 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-oil vehicles (which may comprise edible oils), or components.

It is also possible to formulate the compounds according to the present invention for paronteral administration (for example by injection, in the form of a dough for injection or continuous infusion) and it is possible to present them in unit dosage form in vials, syringes, pr filled, or in multiple dose containers with the addition of a preservative. The compositions can take forms such as suspensions, solutions, or emulsions in oil or in aqueous vehicles, and can contain formulation agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by acetic isolation of the sterile solid or by lyophilization from the solution, to be constituted with a suitable vehicle, for example sterile pyrogen-free water, before use.

For topical administration to the epidermis, it is possible to formulate the compounds according to the invention in the form of ointments, creams or lotions, or in the form of a transdermal patch. For example, it is possible to formulate ointments and an aqueous or oily base with suitable thickening and / or gelling agents.

creams with a genotype can and will be formulated with an aqueous or oily base, one or more emulsifying agents, pain agents, dispersing agents, suspending agents, generates agents and special agents,

Formulations suitable for topical administration in the mouth include tablets consisting of the active ingredient in a flavored base, usually sucrose and acacia or alcantira gum; tablets consisting of the active ingredients on an inert basis such as gelatin and

glycerin or sucrose and acacia; and mouthwash products consisting of the active ingredient in a suitable liquid vehicle.

Pharmaceutical formulations for rectal administration in which the carrier is suitable only for unit dose suppositories are preferably also used as

Suitable vehicles include cashew butter and other materials normally used in the art, suppositories can be made and mixed by mixing the active station with the soft or molten vehicles, followed by cooling and formatting in the molds

Formulations suitable for the administration of p or s, buffers, creams, gels, pastes, foams or sprays in addition to the active ingredient are suitable carriers known in the art.

vaginal intercourse can be presented

For intranasal administration, it is possible to use the compounds of the invention in the form of a liquid sponge or a large number of droplets.> The droplets can be formulated in water containing also one or more non-agent bases and dispersants, from pressurized packages

For administration by inhalation, the compounds according to the present invention are conveniently supplied from an insufflator, nebulizer or pressurized package or in another convenient means to provide an aerosol spray. Pressurized packages may contain a suitable propellant such as dichloro -difluoro-methane, trichloro-fluoro-methane, dichloro-tetrafluoro-ethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be detached by adapting a valve to supply a calibrated quantity.

Alternatively, for administration by inhalation or inhalation, the compounds according to the invention may take the form of a dry powder composition, eg a mixture of

POWDER of the compound and a suitable powder base such as lactose or starch. The powder composition can be packaged individually, for example in capsules or cartridges or for example in gelatin packs or ampoules from which the powder is administered with the aid of an inhaler or an insufflator.

When desired, it is possible to use the previously described formulations adapted to provide a sustained release of the active ingredient.

The pharmaceutical compositions according to the present invention can also contain other active ingredients such as anti-microbial agents, or preservatives.

It is also possible to use the compounds of the invention in combination with other therapeutic agents, for example other anti-infection agents.

In particular, it is possible to use the compounds of the invention in conjunction with known anti-viral agents. In this way, the invention provides in a further aspect a combination consisting of a compound of formula (i) or a physiologically acceptable derivative thereof together with another agent therapeutically active, in particular an anti-viral agent.

The aforementioned combinations can be presented conveniently for use in the form of a pharmaceutical formulation whereby pharmaceutical formulations consisting of a combination as previously defined in conjunction with conventional vehicles: ce u t i uni ca j.

are a further aspect of the present invention

Therapeutic agents suitable for use in such combinations include acyclic nucleosides such as acyclovir, interferons such as / -in inhibitors of renal nucleoside excretion such as probenicide, such as dipyridamole, deoxy-nucleoside inhibitors such as

- d i d e s o x i - c i t i d in a

-dide soxi-a dina sina, 2 ', 3 ¹ -didesoxy-inosine,, 3'-didesoxy3' - didesoxy-2 ', 3'-dideshydro-thiiiiidine θ -modulators such as interleukin II (IL2) and side of colony of granulocyte macrophages (O

- tinionine and 2 ', i-CSF), itinun and stiniu— erythropoietin and ampligen

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

When one or a pharmaceutically derived derivative thereof is used in the formula, it is used in combination with -

Ç éi The virus, with a second therapeutic agent active against the dose of each compound, may differ from that used when only the compound is applied are easily determined by specialists

o) it is possible to prepare the compounds of formula (l) and their pharmaceutically acceptable derivatives by any method known in the art for the preparation of compounds of similar structure.

end '.! o η o r .ί r

·.

The methods follow; os - rupos Á e - fo specified from another river d o

Ll t of arid ary that have functional groups or can be conveniently applied to them, for which protection may be necessary as an intermediate adhesion step ^; ι

or end to provide the desired compound. The protection and protection of functional groups can be carried out using means, for example, it is possible to protect groups; selected from aralkyl (e.g., 'i-dinitro-phenyl);

conventional, lssir.1, pos amii) o with a pio benzyl group), acyl or aryl (for example when desired, subsequent removal of the protecting group by hydrolysis or by hydrogenolysis as appropriate, using standard conditions Hydroxyl groups can be protected using any conventional hydroxyl protecting group, for example as described in 'Protec-L □ McOmie (Plenum I had Groups in Organic Chemistry *, Gd. J

Press, 1973) or 'Protective Groups in Organic oynthesis' by

Greene (John Wiley and Gons, 1Ç81)

Tlieodo ra

Examples of the t-butyl or d if enyl-nyl groups as tetra-hide suitable hydroxyl protecting groups include those selected from alkyl (for example methyl, methoxy-methyl), aralkyl (for example benzyl, or triphenyl-methyl), heterocyclic groups such as dropyranyl, acyl (for example ecetyl or benzoyl) and j silyl groups such as trialkyl-silyl (for example t-butyl-dimethyl) it is possible to remove the hydroxyl protecting groups eg, heterocyclic ί

-silyl) conventional techniques. Thus, because it is possible to remove the sciluses by staining, or the tongue.

alkyl, silyl groups, for example by hydrolysis

Similarly, groups a can be removed under acidic conditions such as hydrolysis such as triphenylmethyl by solvolysis, for example already under acidic conditions. Aral-uyl groups such |

Aralkyl groups such as benzyl can be cleaved by hydrogenolysis in the presence of a noble metal catalyst such as palladium on carlyl using a source of flue ions such as tetra-n-butyl ammonium fluoride

In a first process (.-.) It is possible to prepare the coretoids of formula (i) and their derivatives which are acceptable by reacting a compound of formula (II)

Ε

(II) (in which they are substituents having the meanings j in formula (i) or represent their protected forms; hydroxyl in the cyclopentenyl-carbinol group may be in protected form) or an acceptable derivative thereof with one. reagent selected from the indicated ones and the chemical form group: en t and formic acid and its reactive derivatives, followed by said reagent

I tion of unwanted groups introduced by and / or following the removal of any remaining protective groups

Examples of suitable formic acid derivatives that can be used in the above process (.- \) include banning ortoforms (by di-methyloxymethyl tact), dithiophonic acid, example of triethyl orthoformate), ace (for example, diethoxy-metiformamide acetate, formamidine acetate or s-triazine

The unwanted groups introduced into formic acid or by its reactive derivative can be removed by gentle hydrolysis, for example

conve - | using an inorganic acid such as anhydrous hydrochloric acid.

When using such a form as the orthoformate, the convenient solvent for which it can be used encompasses -forniamide or dimethyl-tannate) using a trialitriethyl orthoformate will constitute such a reaction. The other solvents are ammonia (for example dimethyl, chlorinated hydrocarbons (for example chloro-methane), esters (for example tetrahydrofuran furan) or nitriles (for example acetonitrile).

In some cases, (for example when using a trialkyl orthoformate such as orthoformate o) the reaction is preferably carried out using a strong acid such as strong acid (ca acid from a concentrated nitric or hydrochloric acid). you uni? temperature between -25 ° C, between 0 ° C and 100 ° C, and convenient at ρ o d e e + 150 ° C, sulfuric, j

I e i e ct ua r-sa for example t ura enviroment o

In another process (B) the compounds of formula (1) and their pharmaceutically acceptable derivatives or their protected forms are subjected to a cytin-conver reaction; therefore, the substituent X initially present is replaced by a different substituent X and / or the group r present is initially replaced by an ijuando necessary to remove gifts.

different Z group followed by any protective groups

In one aspect of the process (b) it is possible to prepare the compounds of formula (i) in nu -v represents a group RR ^ (where R and R ^ have the previous meanings) by auination of a corresponding compound of formula (i) e: u that X represents a halogen atom (for example chlorine)

* it is possible to carry out the amination by reaction with, · -.1 ·. ~ r-t-u ·. (in çi-ie r. and R have the inner / venient meanings in a solvent such as an alcohol (for example methanol ^

It can be done

Use of reflux j u v and cu u u. ·

Ll do n a sealed tube if using a liquid ammonia.

temperature between fluid. -. 3 a from q u to d a s ρ; Conversion of halogens and secondary mines has also been described by 'Ϊ.Τ. Harrison et al., Compendiam or Organic áynthetic Xethods, 'iley-Inerscience, New York (1971) on pages 250-252 miseive1 with water such as an alcohol (by ether (eg dioxane a ketone (eg acetone), tyl -formamide) or a sulfoxide (by or ethanol),

Ull;

conveniently in an example i t e t r a ~ b.hydr o. uniy starch (for example d i nie tyl-sul acid or a

In another aspect of process (B) it is possible to prepare the compounds of formula (i) in which x represents an OR group (in which R has the above meanings) by displacing the halogen atom (for example chlorine) with an appropriate RO anion. When R represents a hydrogen atom, the displacement reaction can be carried out by hydrolysis, which can take place in water or in a mixture of water and simultaneously (pyrolysis). base. Suitable acids include organic acids such as p-toluene sulphenic acid and inorganic acids such as hydrochloric, nitric or sulfuric acid. .The bases; they include inorganic bases such as alkali metal hydroxides or carbonates (for example sodium or potassium hydroxide or carboxyl). An aqueous acid oli-base may also be used as the reaction solvent. Hydrolysis can conveniently be carried out at a temperature between -10 ° C and + 150 ° C, for example at reflux. When R represents a (C1 -C4) alkyl or aryl group the RO anion is conveniently formed from a corresponding R1 alcohol ί using an inorganic base such as an alkali metal (eg

example metallic sodium) or alkali metal hydride (eg sodium hydride). The reaction with the anion formed ir. if you can do it conveniently at room temperature. '

In a further aspect of the process (B) it is possible to prepare the compounds of formula (l) in _Vj ue _ <represents a SH group by reacting the halogenated compound of formula (l) with thiourea in a suitable solvent such as an alcohol ( for example n-propanol) at an elevated temperature (for example at reflux) followed by alkaline hydrolysis ₀ .-, 3 suitable bases that can be used include hydroxy-! alkali metal (eg sodium hydroxide). The reaction can conveniently be carried out according to the method of GG Urquart et al., Org. Syn. Goll. Vol. 3, 363 (1953), for example by refluxing the intermediate product | sodium aqueous NaOH for a period of time; between 0.25 and 5 hours approximately. i

In another aspect of process (b) it is possible to prepare the compounds of formula (1) in which X represents a hydrogen atom by reducing the halogenated compound of formula (1) 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 degeneration reaction include metallic zinc / water using the method described by J. R. Marshall et al., Jo Cheir .. Soc., 1004 (1951) «I

Alternatively, it is possible to carry out the reaction by photolysis in a suitable solvent such as tetrahydrofuran containing 10% triethylanine and conveniently in a Rayonet (2537-- ') photochemical reactor according to the V _o Nair | the others, J. Org. Cliern. , 52, 13 ² + (198?)

In yet another aspect of process (b) it is possible to prepare the compounds of formula (1) in which X represents a halogen atom from a halogenated compound other than formula (i) by conventional peroxide / halide / halide methods. Alternatively, when -protecting chlorine, this subset can be replaced by -other halogen atoms using various p- (halo) -) benzene-diazonium chlorides according to well-known procedures.

possible

(I) where .í represents an SP group. in <. _; that R represents alkyl (qC) or aryl from the corresponding thiols using standard alkylation or arylation methods, for example as described in United States Patent N-. 4 383 1) 14 it is possible to prepare convenience with the

tts of formula (1) of a compound in which X represents a hydroxyl group to a corresponding pa_r of formula (±) in. which represents NIÚ, by reaction with nitrous acid, for example using the procedure used by J. Davoll in J. ámer. Chem. Soe ',

22, '30 -74 (1951) ”«

Many of the reactions described above have been intensively reported in the context of the synthesis of the purine nucleosides, for example in Nucleoside Analogs, Eiology and Medical Àpplications, RT wa 1ker et al., Eds, Plenum Pless, New York (1979) on pages 193- 233, whose indication is now indicated as a reference.

Possible acceptable values of the compounds are to prepare the pharmaceutically salts of the invention as described in United States No. 3. 4 383 114 whose indication is left here for reference. Thus, for example, when it is desired to prepare an acid addition salt of a compound of formula (i), it is possible to convert the product of ... u-.i It.uer from the previous procedures into a salt by treatment of the free base resultant with a suitable acid using conventional methods. It is possible to prepare acidic addition salts (to make the mixture acceptable by reacting the free base with an appropriate acid, optionally in the presence of a suitable solvent to prepare sodium salts) such as an alcohol

ta 1 or isopropanol) possible inorganic inhalation such as an alkoxide (for example optionally in the presence of (for example methanol). Also a possible solvent for salts, including other pharmaceutically salts) compounds of formula (i) using conventional methods (i) in a phosphate or it is possible to convert a compound into another pharmaceutically stereochemically viable reaction with a phosphorylation agent, such as a;

or crhal halide, as appropriate it is possible to convert an ester or salt of a compound of formula (i) into the original body, for example by hydrolysis

The salt compounds represent new compounds of the present invention.

The compounds contain hydrogen or hydroxide from compound 2a

NH • · of formula (li) and theirs and are an aspect of this formula (li) in which they can be prepared directly by reaction with an excess of a pyrimidine of formula (III)

(III)

(en; that Y represents a halogen atom, for example chlorine and L represents hydrogen or hydroxyl) in the presence of an amine base such as triethylamine and in an alcoholic solvent (for example n-butanol), conveniently at reflux .

possible to prepare compounds of formula (li) in which z represents NH _? using the compound of formula 2a by reaction with an excess of pyrimidine of formula (IV)

(IV) / \ A

H ₂ xny (where Y has the meanings defined in the form ΪΪ1 ula (III) above) under conditions identical to those immediately described above for the preparation of the compounds of formula (li) in which Z represents hydrogen or hydroxyl to provide a compound of formula (v)

(V) v, uai can be diazotad (where Ar represents a (Τ ’

-phenyl, such as an anion, for example a solvent such as water, a ni co such as a chloride) in an acetic acid or a mixture thereof, acid halide near ambient temperature, to provide a compound of formula, (VI)

(SAW)

HO-CH

X

(where Ar has the meanings immediately defined above) which can be converted into the desired compound of formula (li) by reduction using, for example, a reducing metal such as zinc in the presence of an acid, for example acetic acid. It should be noted that the choice of reducing agent will depend on the nature of group X,

pent-2-ene (la) by hydrolysis in the presence of a mild base, such as an alkaline earth metal hydroxide.

The following is a particularly convenient process for synthesizing the compounds of formula (i) using 6-chlorine compounds of formula (li)

It i! i i il

1 'i:

NHAc

HO— / \\ / // \ /

HO--

* 25

compound 2a and the compounds of formulas (V) and (VI) are new intermediates and constitute additional aspects of the present invention.

compound la is a known compound described in United States Patent No. 2. 4 138 562.

When a compound of formula (l) is desired in the form of a simple isomer, it is possible to obtain it either by resolving the final product or by stereospecific synthesis from isomerically pure starting material or from any convenient intermediary.

Resolution of the final product or a corresponding intermediate or starting material can be carried out by any suitable method known in the art: see for example * Stereochemistry of Carbon Compounds 'by Eo Lo Eliel (McGraw Hill, 1962) and' Tables of Resolving Agents' by S _o H. Xilen »

A convenient method for obtaining pure chiral center compounds of formula (i) is the enzymatic conversion of a racemic mixture of the compound or a precursor thereof. Through such a method it is possible to obtain both (+) and (-) compounds of formula (i) in an optically pure form. Suitable enzymes include deaminases such as adenosine deaminase.

The invention will be further described with reference to the following detailed examples where elementary analyzes were carried out in Laboratories MHW, Phoenix, AZ _{o The} melting points were determined in a Mel-Temp equipment and corrected. Nuclear magnetic resonance spectra were obtained on Jeol FX 9OQFT or Nicollet NT300 spectrometers and were recorded in DMSO — Dg

Chemical shifts are expressed in ppm

downstream from Me ^ Si. The spectra of KBr granules with a spectrometer and the UV spectra were determined

IV were determined

Nicollet 5OXC FT-IR in a coBeckmann DU-8 _O spectrophotometer Mass spectra were obtained with an AEI Scientific Apparatus Limited MS-30 mass spectrometer. Was performed to thin layer chromatography (TLC) on 0.25 mm layers of Merck silica gel (230-400 mesh) All _the chemicals and solvents are of a quality for pro Pria reagents unless otherwise specified.

The term active ingredient as used in the examples means a compound of formula (i) or a pharmaceutically acceptable derivative thereof.

Example 1 (+) - (10 (, 4 ^) -4- / V 5-amino-6 '-chloro-4-pyridiminyl) -in 7-2-cyciopentenyl-carbinol (3a)

A mixture of ΙΑ-acetyl-amino-3-acetoxy-methyl cyclopent-2-ene (la) (3.0 g, 15 mmol) and aqueous barium hydroxide (θ, 5; I 300 ml). After cooling, it was 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 provide 1.6 g (14 mmol) of 2a as a colorless syrup _and

To this syrup was added 5-amino — 4.6

-dichloro-pyrimidine (4.59 g?

mmol) and n-butanol (5θ ml) mmol), triethylamine (4.2 g;

and the mixture was refluxed for 24 hours.

The volatile elements were removed, the residue was absorbed on silica gel (7 g), an intermittent chromatography column (4.0 cm x 12 cm) was added and eluted with CHCl ^ / MeOH (20: 1) for (74%) of compound 3a ♦ mp 13θ-132 ° 0 _ο analytical by recrystallization from ethyl acetate (EtOAc), m.p. 134-135 ° C, EM (30 ev, 200 ° C); m / e 240 and 242 provide 2.69 g

A sample i was obtained

(Μ ⁺ β Μ ⁺ 42), 209 (Μ ⁺ 31), 144 (B ⁺ ); IV: 3600-2600 (0Η), 1620, 1580 (C = C, C = N); Anal »(C _{1 ()} H CIN ^ O) C, Η, N»

Example 2 (+) - (lq, 4 <\) -4- / 72-amino-6-chloro-4-pyrimidinyl) -amino7-2-cyclopentenyl — carbinol (4a)

(3.7 g; 22.8 mmol) refluxing, 2-amino-4,6-dichloro-pyrimidine triethylamine (15 ml) and n-butanol (75 ml) θ of the mixture were added over 48 hours hours. The volatile solvents were removed, the residue was treated with methanol to separate the undissolved by-product (the double nucleoside of pyrimidine)

The methanol solution was absorbed into silica gel (8 g) packed in a column (4.0 x 14 cm) and eluted (40: 1) to provide 1.52 g (42%) of composition.

The product recrystallized from portion 4a; mp 132—134 ° C, MS 242 (M ⁺ and M ⁺ +2), 209 ethyl acetate for pro (30 ev, 200 ° C); m / e 240 e (M ⁺ ~ 31), 144 (B ⁺ ); IV: 3600 - 300 (NH _O , OH), 1620, 158 _O (C = C, C = N);

Anal '(C _1O H ₁₃ C1N ₄ ) C, H, N.

Example 3 (+) - (1 ^, 4 ^) - 4 - (/ 7 2-amino-6-chloro-5- (4-chloro-phenyl) -azo7-4-pyrimidinyl — amino) -2-cyclopentenyl -carbinol (5a)

A cold solution of diazonium salt was prepared from p-chloroaniline (1.47 g - 11.5 mmol) in HC13N (25 ml) and sodium nitrite (. 87O mg; 12.5 mmol) in water (10 ml). This solution was added to a mixture of 4a (2.40 g, 10 mmol), acetic acid (5θ ml), water (5 ° ml) and sodium acetate trihydrate (20 g). The reaction mixture was stirred overnight at room temperature. Fil- 28

the yellow precipitate was taken and washed with cold water until neutral, then air dried in the hood to provide 3.60 g (9%) of 5a, mp 229 ° C (decomposition). The analytical sample was obtained from acetone / methanol (1: 2), m.p. 21 + 1-243 ° C (decomposition), MS (30ev, 26O ° C): m / e 378 and 380

M ⁺ +2), 282 (B ⁺ ); IV: 3600-3000 (NH, OH), 1620, 158O (C = C, C = N);

Anal. (Α6 ^Η 16 ^Ο1 2 ^Ν 6 ^{Ο) C} » ^H » ^N '

Example h (+) - (let, U> () -U- / T2, õ-diamlno-ó-chlor o-1 + -pyrimidyl) -amino7-2-cyciopentenyl-carbinol (6a)

For 3 hours, a mixture of 5θ (379 ^m g 1 mmol), zinc powder (0.65 g, 10 mmol), acetic acid (0.32 ml) water (15) was refluxed under nitrogen. ml) and ethanol (15 ml), the solvents evaporated.

(2 g),

The zinc was removed and the residue was left on silica gel (2 g), a column (2.0 x cm) was packed and eluted with CHCl3 / MeOH (15 ^: 1). Additional purification provided 170 mg (66% of 6a in the

168-17 ° C, MS (M ⁺ 31), 159 (B ⁺ ); C = N);

from form

Federal Police.

+ (30 ev, 220 ° C) iv ·. 3600-3000 m / e (NH _O ,

Anal. (C10H _1Zí C1N ₅ )

C, N, N.

A methanol / ether-colored syrup was obtained

255 OH) e 257 (M ⁺ +2) crystals, 224 1620, 1580 (C = C, pink,

Example 5 +) -10 (

-1 | - (6-chloro - urin-9-yl) -2-ci clopen tenil-ca rbino1

A mixture of 3a (1.3θ gi 5A mmol), triethyl orthoformate (30 ml) and hydrochloric acid (12N; 0.50 ml) was stirred overnight at room temperature »

The solvent was evaporated at 35 ° C in vacuo, Aqueous hydrochloric acid (0.5N; 30 ml) was added to the residue and the mixture was mixed 7-8 with silica (8 g), packed with CHCl / White MeOH for 1 hour, the IN sodium oxide mixture was neutralized and absorbed on a column gel (4.0 x 8 cm) and eluted (2: 1) to provide 1.12 g (82%) of crystals

The crude product was crystallized from mp 108-110 ° C _? MS (30

219 (M ⁺ “31), 154 (B ⁺ );

li i d r e ev acetate, 200 ° C);

GO; 36007a and tyl to provide 7 ^a , πι / e 2p0 and 252 (M ⁺ and M ⁺ + 2), -2800 (OH), 1600 (C = C, C = N) barely, (C ₁₁ H ₁₁ C1N ^ O ) C, H,

N.

Example 6 (+) (1 ^, 4 ^) - 4- (6-hydroxy-9H — purine-9 ~ i1) -2-cyclopentenyl-carbinol (8a)

For 3 hours a mixture of 7 ^a (251 mg, 1 mmol) and aqueous sodium hydroxide (0.2N; 10 ml) was refluxed. After cooling, the reaction mixture was adjusted to pH 5-6 with acetic acid. The reaction mixture was absorbed on silica gel (2 g) packed in a column (2, θ) x 11 cm) and eluted

105 mg (45% of 8a, with

CHCl ^ / MeOH (10: 1) to provide white crude product recrystallized from water / methanol (3 ^J 1) to provide 8a, mp, 248-250 ° C (decomposition), MS (3θ and v, 300 ° c) ; m / e 232 (M), 214 (M ⁺ “18), 136 (B ⁺ ); IV; 3600-2600 (OH), 1680, 1600 (C = 0,

C = C, C = N);

Anal, (0 _1χ Η ₁₂ Ν ₄ 0 ₂ ) C, Η, N.

Example 7 (+) - (ltf., 4 qQ -4- (6-amino-9H-purin-9-yl) - 2-cyclopentenyl-carbinol

12 * 1

Liquid ammonia was passed to a pump containing a solution of 7a (250 mg; 1 mmol) in methanol (5 ml) at -80 ° C sealed or — if the pump was heated at 60 ° C for 24 hours Ammonia and methanol were evaporated and the residue was recrystallized from water to provide 187 mg (81%) of 9a off-white crystals, mp 198-200 ° C »EM (10 ev, 210 ° C): m / e 231 (M ⁺ ), 213 (M ⁺ 18), 135 (B ⁺ ); IV: 3600-2600 (NH, OH), 1700, 1600 (C = C, C = N);

Anal »( ^C h ^H ₁ 3 ^N 5 °) ^c » ^h ? ⁿ °

Example 8 (+) - (10 (, 4 <<) —4- (6 — mer capto —9H — purin — 9- * il) —2 —cyclopentenyl —carbinol 10a

A mixture of 7a (125 mg, 0.5 mmol), thio-urea (40 mg, 0.64 mmol) and n-propanol (5 ml) was refluxed for 2 hours o After cooling, if the precipitate by filtration was seen in sodium hydroxide to pH 5 with acetic acid, crude 10a (90 mg; 73%), mp 'washed with n-propanol and dissol (1N; 5 ml) if the solution

Product 260—262 ° C (decomposition) was isolated again and recrystallized from N, N — dimethylformamide to provide 10a, p »f» 263-265 ° C (decomposition) EM (30 ev, 290 ° C): m / e 248 (M ⁺ ), 23O (M ⁺ “18), 152 (B ⁺ ); TV: 3600-3200 (OH), 3100, 2400 (SH), 1600 (C = C, C = N);

Anal »(O ^ H ^ N ^ O s) C, H, N <>

Example 9 (+) - (1 ^, 4 QQ-4- (2-Amino - 6 ~ chloro-9H-purin-9 ~ yl) -2-cyclopentenyl-carbinol (13a)

A mixture of

6a (1.41 g, 5.5 mmol), triethyl orthoformate (30 ml) and hydrochloric acid (12N; 1.40 ml) o The suspension was dried in vacuo.

hydrochloric acid (0.5 ^; 40 ml) and the mixture was reacted at room temperature for 1 hour. _The mixture was neutralized to pH 8 with 1N sodium hydroxide and absorbed on silica gel (7 » 5 g) packed in a column (4.0 x 10 cm) and g (80%) of crystals were eluted from -147 ° Co MS (30 ev, 30), 169 (B ⁺ ); IV:

with CHCl ^ / MeOH 520: 1) 13¾ dirty white »to provide

1.18 crude product containing ethanol to provide 13a, mp 145220 ° C): m / e 265 and 267 (M ⁺ and M ⁺ +2), 235 (M ⁺

3600-2600 (NH ₂ , OH), 1620-1580 (C = C, C = N);

Anal. (C _1X H ₁₂ N 0C1.3 / 4 HgO) C, Η, N.

Example 10 (+) - (1 ^, 4 ^) - 4- (2-a mino — 6-hydroxy-9H ~ purin-9-yl) —2-cyclopentenyl-carbinol (14a)

For a period of 5 hours, a mixture of 13θ (266 mg; 1 mmol) and aqueous sodium hydroxide (O, 33N) was refluxed, absorbed on silica gel (2 g) packaged in a column ( 2.0 x 7.5 cm) and eluted with CHCl3 / MeOH (5: 1). The crude product was recrystallized from methanol / water (1: 4) to provide 152 mg (61%) of 14a white crystals, mp 254-256 ° C (decomposition), MS (30 ev, 200 ° c) : m / e 247 (M ⁺ ), 217 (M ⁺ 30), 151 (B ⁺ ); IV: 3600-2600 (NH ₂ , OH), 1700, 1600 (C = C, C = C, C = N);

Anal. (C ₁ i ^H i3N5 ⁰ 2.3 / 4 H., 0) C, H, N _o

Example 11 (+) - (1 ^, 4 ^) -4- (2,6 — diamino — 9H-purin-9-yl) -2-cyclopentenyl-carbinol (15¾)

Liquid ammonia was passed to a solution of 13¾ (265 mg; 1 mmol) in methanol (10 ml) at -80 ° C in a pump _{0 The} pump was sealed and heated to 75 ° C for 48 frogs. ammonia and methanol were evaporated. The residue was absorbed

in silica gel (2 g) packed in a column (2.0 x 10 cm) and eluted with CHCl3 / MeOH (15 »1) <> The crude product was recrystallized from ethanol to provide 196 mg (80 ^) G) 15a, mp

152-155 ° Co MS (30 ev, 200 ° c): m / e 246 (M ⁺ ), (M ⁺ “30), 150 (B ⁺ ); IV: 3600-3000 (NH _{2 -} OH), (C = 0, C = C, C = N); 229 (M ⁺ 17), 216 1700, 1650, 1600 Anal. ( ^C h ^H i4 ^N 6 °) ^C » ^H » ^No

Example 12 (1S, 4R) -4- (2,6-diamino-9H-purin-9-yl-Z-cyclopentenyl-carbinol / ΓlS _t 4R) -4- (2,6-diamino-9H-purin — 9 -yl) -2-cyclopentene methane17 (a) Intermediate li For 2.5 hours it was stirred at room temperature (IR, 2S, 3R, 5R) - amino-9H-purin-9-yl / ~ 5-7 (( 1,1-di- | methyl-ethyl) -dimethyl-silyl-oxy) methyl 1 - 7-1,2-cyclopentanediol (-) Aristeromycin ¹ (12,5θ5 g) * tert-butyl-dimethylsilyl chloride ( ?, 8 g) and imidazole (12.96 g) in dry dimethylformamide (85 ml) o The resulting solution was diluted with ethyl acetate (5® ml), then washed with water (3 X 100 ml) ) and with a saline solution (50 ml) before a white solid crystallized. This solid was collected by filtration, washed with ethyl acetate and then dried in vacuo to provide the title product (3.92 g); ¹ Hn.m _o r <> (DMSO-d ₆ ) 8 »15 (1H), 8„ O9 (lH), 7.19 (2H), 5.00 (1H) _P 4.72 (ih), 4o69 (ih), 4.36 ( 1H), 3 »85 (1H), 3.67 (2H), 2.23 (IH), 2.09 (1H), 1.79 (IH), 0 _or 89 (9H), 0.07 (6H) _O

1.

Journal of the American Chemical Society 1983, vol, 105,

4049-4055 „(b) Intermediate 2: (4R, 3« · 8, 6R, 60R) —4 — yS — amino —9H — purin-9— - i 2 ^ 7-6- yT (1, l-dimet ylethyl) - dimethyl - silyloxy) met i 1 ^ 7-3 a, 5,6,6a - - tetra — hydro-4H-cyclopenta — 1,3 — d ioxo1 —2 —t iona

A suspension of Intermediate 1 (3.45 g) in dry dimethyl-formamide (56 ml) was treated with 1,1 '-thio-carbonyl-di-imidazole (3.3 g) providing

After 15.5 hours yellow.

at room temperature an ambient solution was combined with terior (and

The resulting solution was diluted with a scale of 6 /) the residual oil originated in the ane experiment removed - the solvent was washed with water (2 n: 1), dried (HgSO ^) of the yellow »Dual washed with ethyl acetate x 20 ml) and with a solution and evaporated to give this solid with diethyl ether (25 ml), it is with ^ max (IH)

3.78 and a solid (E ^ ^ 59) ctn (2H), 5.81 2.28 (2H), cream color ^Χ Η r

Γϊί «13 o (IH),

0.90

5-37 (9H), air the product (3.61 g);

dg) 8.27

5-28 (1H), (c) Intermediate 3 methyl silyl-oxy) me (1 * R, 4’s) -9-Z5 - (((1

1-dimethyl-ethyl) di9 til) -2-οϊο1ορβηΐθη-1-ΐ] / 7-9Η-ρατ in-6-amine

A solution of Intermediate 2 (3> 57 g) in dry tetrahydrofuran (25 ml) was treated

1,3 ~ dimethyl-2-phenyl-1,3,2- <iiazaf the spholidine with a solution of (4.94 g) in dry tetra — hydrofuran (10 ml) and then stirred at room temperature for 8 ^ / 4 hours, the solvent was removed by evaporation »The residual oil was combined with the product from the previous experiment (40% scale), then subjected to silica column chromatography (200 g, Merck 7734 ), eluted with chloroform and then with mixtures of chloroform / eta a white solid. This solid was washed (ml) and then collected by filtration 'and then dried in the title product (1.47 g);

, '44-3); 1H nmr (DMSO-d ^) (1H), 7 »20 (2H), 6 _O 12 (1H), 5» 95 (1H), 5 ° 6O 2.96 (1H), 2.69 (1H), 1.65 ( 1H), 0 o 74 (9H), provide diethyl (25 still the solid with ether (10 ml) va cuo to provide λ (ethanol) 261 _o 4nm (E, max

8 „14 (1H), 80OO (1H), 3.66 (2H)

0.02 (6H) nol with ether

Wash u

(d) Intermediate 4: (1'R, 4'S) -9- / (- (((1,1-dimethyl-ethyl) dimethylsilyloxy) methyl) -2 — cyclopenten -l-i17-9H-purin-6-amine

A solution of Intermediate 3 (1> 37 g) in chloroform (3θ ml) was treated with 80-90 ^ m (chlorine-peroxy-benzoic acid) (1.29 g) and then stirred at room temperature for 3 hours. The solvent was removed by evaporation and residual gum dissolved in ethyl acetate (10 ml). Obtain a white crystallized solid. This evaporation was recovered and the filtrate was dissolved, then sodium products (3 x 10 ml) were washed with aqueous products, they were seen to be solid and in chloroform with an aqueous solution and with a washing solution. not the material per (100 ml) saturated saline bicarbonate (2 x 10 ml). The extracts were again extracted with chloroform (50 ml), dried (MgSO4) from the combined organic solutions, and then poured to provide a solid. This solid diethyl ether (25 ml) was washed and then collected by filtration. The white solid was further washed with ether (10 ml) and then dried in vacuo to provide the title product (1.16 g);

(ethanol) 235.4nm 1324), 263 »2nm (248), ^ Hr.m.n. (

5.87 (1H), 5.72 (IH), 0.89 (9H) ^ max, 0 /

3OO, 2nm (E ^ '1 cm

7.16 (IH)

75);

(2H), 6.21 (1H),

2.82 (1H), 1.74 if evacuation

1324), 263 »2nm (lcm lcm (CDC1 _q ) 8.72 (1H), 8.02 (1H), (1H), 3.68 (2H), 3.0¼

0.06 (6h) o (l 'R, 4’S) -7-25 - (((l, l (e)

-dimethyl-ethyl) dimethyl-silyl-oxy) methyl) -2- cyclopenxen-1-yl_7-2-imino-1,2-dihydro2 (lf 2, k ^ oxadíazoloTZÍ, 2-_17 ~ 9H-purina

Intermediate 5: hydrobromide

An agitated and ice-cold 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 allowed to warm to room temperature providing a solution. After 9θ minutes, the solvent was removed by evaporation. The residue was washed with diethyl ether (25 ml) and then collected by filtration. Washed yet

the sodium is gone with ether (25 ml) and then dried in vacuo to pro-! portion the title product (1.37 g); n (ethanol) | no / _η c / ^ max '

228 _o 22nm (E ^X '° 530), 285.2nm (445) 5 H rm _o n, (CDC1J

J. cm 1 cm3

10 _o 20 (1H), 10.02 (1H), 8.37 (1H), 6.25 (1H), 6.01 (1H),} (1H), 3.69 (2H), 3.05 (1H), 2.86 (1H), 1.73 (1H) ), 0 _o 86 (9 «), 0.03 (6h) o (f) Intermediate 6: (1 * R, 4 ♦ S) -9- / Í- ((((1,1-d ime t il-e t il) dimethyl-silyl-oxy) methyl) -2-cyclopenten-1-11 ^ 7-6-cyanoimino-1,6-di-ihydro-1-methoxy-9H-purine!

I

A mixture of Intermediate 5 (1.36 g) in dimethylformamide was stirred at room temperature and then treated with triethylamine (1.2 ml). After minutes, iodine-methane (0.54 ml) was added, providing a 3

After 3/4 hours the solvent was removed. The residue was partitioned between ethyl acetate (20 ml). The solution was further washed and with brine (20 ml), (MgSO4) and evaporated to provide a solid, this solid with diethyl ether (25 ml) and then collected by filtration This white solid was further washed with ether (10 ml) and then dried in vacuo to provide the title (0.865 g) i 7 (ethanol) 227 »2nm (E,

------- Tc / Amax 'lcm 287 <> Onm (E, ¹⁰ 544); 1H rmn cm

5.85 (1H), 5.65 (1H), (1H), 1.68 (1H), O088 yellow solution by evaporation. (100 ml) and water (2 x 20 ml) (MgSO.) Water (10 ml) organic with dried

Product 449) was washed,

6.24 (1H), (ethanol) 227 »2nm (E

8.23 (1H), 7.96 (1H),

4.21 (3H), 3.66 (2H), 3.04 (1H), 2.77 (9H), 0.05 (6H).

(g) Intermediate 7 ^! (1 · R, 4 · S) -9 -. ^ - ((((1, l ~ d ime tj 1 —et il) -di- me t il-si lil-oxy) me t il) -2-cyclopenten -l-ijJ7-6-methoxy-amino-9H-purin-2 — amine

A solution of Intermediate 6 (802 mg) and 1,8-diazabicyclo / 5.4.07 undec-7-ene (0.45 ml) in ethanol (80 ml) was stirred and refluxed. The cement was stopped after 9 hours and the solution was left at room temperature.

environment at night. The solvent was removed by evaporation. The residual oil was combined with the product from the previous experiment (4% scale, then chromatographed on a silica column (40 g, Merck 9385), eluted with chloroform and then with mixtures of chloroform / ethanol to provide a foam. This foam was triturated with diethyl ether (10 ml) and the resulting solid was collected by filtration. The solid was further washed with ether (5 ml) and then dried.

cou- I do not know go cuo (594 rng); λ max -dg) 9 to 76 (IH), 5th 26 (IH), 3.72 (1H) 0.83 (9H)

to provide the title product (ethanol) 282.2nm (£ ⁷ ° 409); ^ Hr.mn (DMSO— lcm

7.32 (1H), 6.53 (2H), 6.08 (1H), 5.88 (1H), (3H), 3.61 (2H), 2.90 (1H), 2.50 (1H), 1.52 0.02 (6H).

(h) Intermediate 8: (1S, 4R) -4- ^ 2-amino-6-methoxy-amino-9H-purin-9-i_17 ~ 2-cyclopentene-meolol

A solution of intermediate 7 (356 mg) in tetrahydrofuran (35 ml) was stirred at room temperature and then treated with tetrabutyl ammonium fluoride (solution 1, OM in tetrahydrofuran; 1.4 ml). After 90 minutes, the reaction was quenched with water (1 ml) and then the solvents were removed by evaporation. The residual oil was subjected to silica column chromatography (20 g, Merck 7734), eluted with chloroform and then with chloroform / ethanol mixtures to provide the title product in the solid state (243 mg); λ (H 6 at pH6) 280.2 nm (E ^ 534); ¹ H rmn (DMSO-dg 9 ° 75 (1H), 7.39 (1H), 6.52 (2H), 6.10 (1H), 5.84 (1H), 5.27 (IH), 4.73 (1H), 3-40 (2H) , 2.83 (IH /, 2.55 (1 '), 152 (1H).

(1S, 4R) -4- / 2,6-diamino —9H ~ Purin-9-yl7-2-cyclopentene-carbinol

A stirred, ice-cold solution of Intermediate 8 (210 mg) in water (10 ml) and tetrahydrofuran (50 ml) was treated with an amalgamation of aluminum / from aluminum (237 mg) and a aqueous mercury chloride solution 37 -

0.5 ^ 7 curio which was added in small portions for 15 minutes »After 15 minutes the stirred mixture was allowed to warm to room temperature» After 15 hours the resulting mixture was filtered through diatomaceous earth to remove the insoluble components. These were washed with water / tetrahydrofuran (1; 5; 60 ml).

The residue was subjected to a column of silica (10 g, Msrck 9385), and eluiucloroform / ethanol to provide a foam pro forma (159 mg>'- ⁸¹ ° max ( ^breadth at pH6) 255.0 nm (E 302) , 2

UlGl A 1 CCU

H r.m.n »(DMSO-d ^) 7» 61 (1H), 6.66 (2H),

3.45 evaporation of the combined filtrates, chromatography in -se with mixtures in the title in the one in (cl.04, methanol);

280.8 nm (E ⁷ ^ 381), lcm '

6.10 (1H), 5, 87 (1H), 5.76 (2H), 5.38 (1H), 4.76 (1H), (2H), 2.87 (1H), 2.60 (1H), 1.60 (ih).

Example 13 (IS, 4R) -4-amino-6-hydroxy '.9H-purin-9-yl) -2-cyclopentenyl-carbinol (1 * R, 4 * s) -2-amino-1,9-di -hydro-9 ~ 2 ^ ~ hydroxy-methyl-2-cyclopenten

- 1-iJL / - 6H — pur in-6-one

A cloudy solution of the compound of the epigraph of Example 12 (144 mg) was treated in pH 6 Ο, 1M buffer (10 ml) (from 28.4 g of di-sodium orthophosphate in 2 liters of water, adjusted with orthosphoric acid) with a solution of adenosine deaminase (0.5 ml - 778 units), in 5% glycerol / 0.01M potassium phosphate, pH 6.0, and then stirred and heated to 37 ° C ° C. After 18.5 hours, the suspension was cooled

Example 14

Preparation of (1X, 4x) -4- (2-amino-6-hydroxy-9H-pur) -2-cyclopentenylcarbino1 enantiomers (a) IS, 4R) -4- (2-amino-6- hydroxy-9H-purin-9-i1) -2-cyclopentenyl-carbinol

The diamino analog compound (100 mg) (Example 11) was dissolved in 3 ml of 0.05M K ^ PO ^ buffer (pH 7.4) with heating (5θ ° θ) <> The solution was cooled to at room temperature and 40 units of adenosine deaminase (sigma, Type VI, calf intestinal mucosa) were added. After 3 days of incubation at room temperature, a precipitate formed and was removed by filtration providing 18.2 mg. The filtrate was concentrated to 1.5 ml and cooled for 2 days. The solid is 26.8 mg. Water started

mp 209-272 ° C, additional obtained by filtration provides recrystallization of the two fractions to provide

Z <£ 7 _d solid title product

62.1 (£ 0.3 MeOH) o (b) (IR, 4 S) - 4- (2-amino-6-hydroxy-9H-Pur in-9-yl) -2-cyclopent nil-carbino1

The filtrates were combined from the preparation of the IS, 4R isomer (Example 14a) and evaporated to dryness. The unaltered diamino starting material was separated on an intermittent column of methanol / chloroform silica gel. The buffer compound was dissolved PH ^ ΡΟ ^ 0.05M „PH7.4 (15 ml) and adenosine deaminase was added. It was done at 27 ° C. TLC indicated 96 hours to react. Heated using 10; t

800 units tion during 3 hours of incubation of the solution while some of the solution in water product in boiling was left to remove the

Another 800 units of adenosine were added in minutes and filtered out of

- 39 water. The title product is white and in the solid state collected by filtration from water. mp 265-270 ° C _o

61.1 (ç0o3 MeOH).

+

it was pray ^ ⁴

Example 15 (+) (1 ^, 4th () -4- (2-amino-6-hydroxy-9H-purin-9-yl) - 2-cyclopentenyl-a ketoxy-carbinol (130 mg, 0, mmol) one (0.09 ml);

0.6 mmol).

hours.

To a suspension of the product of Example 10 (50 mmOl) and 4-dimethyl-amino-pyridine (5 mg; 0.04 mixture of acetonitrile (6 ml) and 0 _- 66 mmol triethylamine) was added acetic anhydride ( 0.06 ml; The mixture was stirred at room temperature for

Methanol (1 ml) was added for tempering, the solution was concentrated and reacted in (1.5 g) packed in a column (2.0 x 12 cm) and the silica gel fractions eluted. if with

CHCl3 / MeOH (20: 1). Collected, yielded to

The solid product was washed with MeOH / AcOEt: 123 mg production (85%) o Further purification from methanol provided the title product as needle-like crystals, mp, 237-239 ° C «product and proconcentration to provide a white solid.

Example 16 (1 S, 4R) -4- / 2-amino «» 9H-Purin-9-yl7-2-cyclopentenyl-carbinol

Treat a stirred solution of ice · arrefeci- of (1S, 4R) -4-2i2 ' to ⁿ i ⁱⁿ "tne methoxy-6-amino-9H-purin-9-il7-2-cyclopentene-methanol ( intermediate 8, Example 12) (1,202 g in tetrahydrofuran (25θ ml) and water (5θ ml) with aluminum amalgam (from aluminum (1,761 g) and a 0% aqueous solution of mercury chloride), 5%) added in small portions over 1 hour and 47 minutes After 35 minutes, the stirred mixture was allowed to warm to room temperature.

After 16 hours and $ C minutes, more aluminum amalgam (from 235 mg aluminum) was added over 14 minutes. »After a further 4 hours and 10 minutes, the resulting mixture was filtered through diatomaceous earth to remove the components. insoluble »These were washed with tetrahydrofuran / water (5: 1, 300 ml) _{o The} combined filtrates were evaporated to obtain a yellow foam. The foam was subjected to silica column chromatography (33.8 g, Merck 7734) prepared in chloroform and eluted with chloroform / ethanol mixtures to provide several fractions (578 mg, 420 mg and 40 mg). Λ starting from isopropanol, the crystallization was carried out separately from the two largest fractions »The filtrates were combined with the lowest fraction on the column and subjected to preliminary thin layer chromatography (Merck 5717) processed three times in chloroform / ine tan ol 10: l _{o The} plates were eluted with ethyl acetate / ethanol (1: 1) to provide The solid was subjected to Merck 7734 chromatography) prepared in chloroform chloroform / methanol / ethyl triethylamine and with acetate of a brown solid (45 mg, 'on a silica column (2.7 g, and eluted with mixtures to provide a gum (17 mg). After crystallization not achieved from isopropanol and treatment with charcoal in methanol, an aqueous solution of the recovered material was freeze-dried to provide the title compound (15 mg).

‘‘ Hnmr (DMSO-d ₆ ) 1.62 (1H), 2.63 (1H), 2.89 (1H), 3.45 (2H), 4.73 (1H); 5.48 (III), 5.91 (1H), 6.14 (1H), 6.50 (2H),? «98 (1H), 8.57 (1H). Ma s s spec, 232.

Claims (2)

Process for the preparation of a compound of formula (i) in which X is hydrogen, NRR, SR, OR or halogen; 2 1 Z is hydrogen, OR or NRR; R, R and R can be equal or different and are separated from hydrogen, (C1 -C4) alkyl and aryl; and their pharmaceutically acceptable derivatives characterized by: (a) A compound of formula (li) (II) is reacted YCH where X and Z are as previously defined or are their protected forms and Y is OH or a protected form with a reagent formic acid selected from among reactives followed, if necessary, by removal streams present; or by removing and their derivatives from any group (b) interconverting themselves into another protected compound of formula (i) or a compound of formula (i) by substituting substituent Z for another substituent Z, followed, if necessary, by removing any protection groups present. - 2? Process according to claim 1, characterized in that in method (a) the reagent is selected from formic acid, an orthoformate, a dialcoxy-methyl acetate, di-thio-formic acid, formamide, s-triazine or formamidine acetate . - 3 ^ê - Process according to claim 1 or 2, characterized in that in method (A) the solvent is a trialkyl orthoformate, an amide, a chlorinated hydrocarbon, an ether or a nitrile » - M - Process according to any of claims 1 to 3, characterized in that in method (a) the reaction is carried out at a temperature between -25 ° C and + 150 ° C. - 5 «- Process according to claim 1, characterized in that in method (b) converting a compound of formula (i) in which X is halogen to a compound of formula (i) in which X is NRR, OR, SR or H _and - U3 Agreement process with any of the kings vindications from there 5, characterized by Z in the formula (II) be H, OH or NH 2' - 7- » Agreement process with any of the kings vindications her 6, characterized by Z in the formula (il) be nh ₂ » - 85 - Agreement process with any of the king vindications her 7, characterized by X in formula (II) be hydrogen, chlorine, NH ₂ , SH or OH » - 9 ⁵ - Agreement process with any of the kings vindications from there 7, characterized by X in formula (II) be OH. - 105 - Agreement process with any of the king vindications her 8, characterized by X in formula (II) be H or NH ₂ » - 115 _ Agreement process with any of the kings vindications from there 8, characterized by the compound of formula (l) be selected from: (13 (, 4 <f) -4- (6-chloro-9H-purin-9-yl) -2 - cyclo-penile tenil ca rbinol; (4 * ^) -4- (6-hydroxy-9H ~ purin-9-yl) -2-cyclo-pentenyl carbinol; (1 <y, 4 ^ -) - 4- (6-amino-9H-purin-9-yl) - 2-cyclo-pentenyl carbinol; (lcp 4 <γ) -4- (6-mer capto-9H-purin-9-yl) -2-cyclo-pentenyl carbinol; (4tf) -4 - (2,6-diamine — 9H — pur in-9-yl) -2 — cyclic tenil ca rbinol; (1 γ, 4e ^) - 4- (2-amino-6-chloro-9H-pur in-9-11) - 2-cyclo-pentenyl ca rbinol; and (1 ^, 4γ) -4- (2-amino-9H-purin-9-yl) -2-cyclo-pentenyl carbinol; Process according to any one of claims 1 to 5, characterized in that the compound of formula (i) is (IX, 4 *,) - 4- (2 — amino-6 — hydroxy — 9H-purin — 9-yl) -2 - clopent nil-ca rbinol o - 13 «- Process according to any of claims 1 to 12, characterized in that the compound of formula (II) is in the form of an essentially racemic mixture. - 14? - Process according to any of claims 1 to 12, characterized in that the compound of formula (li) consists essentially of an optical isomer. - 15 «- Process according to either king— T til d ί C e “0 S ^r '9 1 to 12, characterized by 0 formula compound (li) consist essentially in the isomer D. - 16- - Agreement process with any of the kings vindications of 1 to 14, characterized by if include 0 step to convert a racemic compound of formula (i) or formula (li) to a single optical isomer of a compound of formula (i) or formula (li) that is the same or different. The applicant declares that the first applications for this patent were filed under United States of America on 20 January 1988 and 5 December 1988, under serial numbers 146,252 United Kingdom on 7 September and 278,652 1988, under and respectively the number 8821011 »7»