MXPA00004429A - Adenosine a1 receptor agonists - Google Patents

Abstract

A compound of formula (I) which is an agonist at the adenosine A1 receptor wherein R2 represents C1-3alkyl, halogen or hydrogen;R3 represents a fluorinated straight or branched alkyl group of 1-6 carbon atoms and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof. These compounds are agonists at the Adenosine A1 receptor.

Description

CHEMICAL COMPOUNDS FIELD OF THE INVENTION The present invention relates to new adenosine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. Accordingly, the invention provides compounds of formula (I) which are adenosine Al receptor agonists. wherein R "represents alkyl of 1 to 3 carbon atoms, halogen or hydrogen, R3 represents a straight or branched, fluorinated alkyl group of 1-6 carbon atoms, R1 represents a group selected from REF .: 120040 (1) - (alk) n-cycloalkyl- (C3-7) which include the cycloalkyl with bridges, the cycloalkyl group which is optionally substituted by one or more of the substituents selected from OH, halogen, - (1-3C) alkoxy, wherein (alk) represents alkylene of 1 to 3 carbon atoms and n represents 0 or 1. an aliphatic heterocyclic ring group of 4 to 6 elements containing at least one heteroatom selected from O, N, or S, optionally substituted by one or more substituents selected from the group consisting - (1-3C) alkyl, -C02- (C1-4) alkyl -CO- (C1-3) alkyl, -S (= 0) n- (C1-3 alkyl), -C0NRaRb (wherein Ra and Rb independently represent H or alkyl of 1 to 3 carbon atoms) or = 0; where there is a sulfur atom in the heterocyclic ring, and the sulfur is optionally substituted by (= 0) "/ where n is 1 or 2. (3) straight or branched alkyl of 1 to 12 carbon atoms, optionally including one or more 0, S (= 0) n (where n is 0, 1 or 2) or substituted N groups within the alkyl chain , the alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy or NRaRb wherein Ra and Rb both represent alkyl of 1 to 3 carbon atoms or hydrogen. (4) a fused bicyclic aromatic ring wherein B represents a 5- or 6-membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of the formula (I) by means of a ring atom , ring A and ring B is optionally substituted by -C02- (C 1-3 alkyl). (5) a phenyl group optionally substituted by one or more substituents selected from: -halogen, -S03H, - (alk) nOH, - (alk) n-cyano, - (O) n-alkyl (C? -6) ) (optionally substituted by one or more halogens), - (alq) n -nitro, - (0) m- (alq) n -C02Rc, - (alqn) - CONRcRd - (alq) n - CORc, - (alq) n -SORe, - (alq) n -S02Re, - (alq) n- S02NRcRd, - (alq) nORc, - (alq) n - (CO) m -NHS02Re, - (alq) n- NHCORc, - (alq) ) n-NRcRd where yn are 0 or 1 and alq represents an alkylene group of 1 to 6 carbon atoms or an alkenyl group of 2 to 6 carbon atoms. (6) a phenyl group substituted by a heterocyclic aromatic group of 5 or 6 elements, the heterocyclic aromatic group is optionally substituted by alkyl of 1 to 3 carbon atoms or NRcRd. Rc and Rd can each independently represent hydrogen, or alkyl of 1 to 3 carbon atoms when part of a group NRcRd, Rc and Rd together with the nitrogen atom can form a heterocyclic ring of 5 or 6 elements optionally containing other heteroatoms , the heterocyclic ring may be optionally further substituted by one or more alkyl groups of 1 to 3 carbon atoms.

Re represents alkyl of 1 to 3 carbon atoms and salts and solvates thereof, in particular, the salts and solvates thereof physiologically acceptable.

Conveniently, the adenosine Al agonists of the general formula (I) above exhibit greater activity to the adenosine Al receptor than the other subtypes of the adenosine receptor, particularly the A3. More particularly, the compounds exhibit little or no activity at the A3 receptor.

It will be appreciated that where R1 and / or R2 in the compounds of the formula (I) contain one or more asymmetric carbon atoms, the invention includes all diastereomers of the compounds of the formula (I) and mixtures thereof. Otherwise, the stereochemical configuration of the compounds of the invention is as shown in formula (I) above.

As used herein, the term "alkyl" means a straight or branched chain alkyl group. Examples of suitable alkyl groups within R1 and R2 include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl and 2,2-dimethylpropyl.

When used herein, the term "alkylene" means a straight or branched chain alkylene group containing 1-6 carbon atoms, for example methylene.

As used herein, the term "alkenyl of 2 to 6 carbon atoms" means a straight or branched chain alkenyl group containing 2 to 6 carbon atoms. Allyl represents an example of a suitable alkenyl group of 2 to 6 carbon atoms.

The term 'halogen' means fluorine, chlorine, bromine or iodine By "aliphatic heterocyclic group" is meant a cyclic group of 4-6 carbon atoms wherein one or more of the carbon atoms is / are replaced by heteroatoms independently selected from nitrogen, oxygen or sulfur. This group may be optionally substituted as defined herein above.

The term "heterocyclic aromatic group" refers to an aromatic mono or bicyclic ring system comprising from 5 to 10 carbon atoms wherein one or more of the carbon atoms is / are replaced by heteroatoms independently selected from nitrogen, oxygen and sulfur, such a ring system may be substituted as defined herein above.

The pharmaceutically acceptable salts of the compounds of the formula (I) include those derived from the pharmaceutically-acceptable organic and inorganic acids. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulfonic. A particularly suitable pharmaceutically acceptable salt of the compounds of the formula (I) is the hydrochloride salt. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. The solvates can be, for example, hydrates.

R preferably represents a fluoroalkyl group of 1 to 3 carbon atoms, especially a fluoromethyl or fluoroethyl group, more preferably F 2 C (Me) -, FCH 2 -.

R2 preferably represents hydrogen, methyl or halogen, more preferably hydrogen or chlorine.

Conveniently, R1 may represent (alk) C3-6 cycloalkyl wherein n is 0 or 1 and the cycloalkyl is either substituted by at least one substituent selected from halogen, particularly fluorine, and OH or is unsubstituted. Preferably n is zero. More preferably, the cycloalkyl group is ring-substituted with either OH or fluorine and more preferably the cycloalkyl ring has 5 carbon elements.

Alternatively, R1 may represent a substituted or unsubstituted aliphatic heterocyclic group, the substituent is selected from the group consisting of -C02- (C1-4) alkyl, -CO- (C1-3) alkyl, -S (= 0) n -alkyl (C1-3), CONRaRb (where Ra and Rb are defined hereinbefore), and when there is a heteroatom S in the ring, this heteroatom can be optionally substituted by (= 0) n where n is 1 or 2 More preferably, the heterocyclic ring is unsubstituted or the substituents are -C02- (C1-4) alkyl or when the heteroatom is S, the substituent (= 0) n is bonded to the heterocyclic sulfur atom.

Conveniently, the aliphatic heterocyclic group is unsubstituted or when the substituent is -C02-alkyl (C? -4), the heteroatom is N and the substituent is directly attached to the ring nitrogen atom.

Preferably, the heterocyclic ring is 6 elements and more preferably contains only one heteroatom 0, N or S.

Alternatively, R may represent a straight alkyl or. branched from 1-6 carbon atoms optionally with at least one S (= 0) n and / or N substituted on the chain, where there is an S (= 0) n in the chain, preferably n is 1 or 2. The group Conveniently alkyl may be substituted or unsubstituted by at least one OH group.

Alternatively R1 may represent a phenyl group which is substituted by one or more substituents selected from OH and halogen. Preferably, the phenyl is disubstituted in the 2,4-positions. Preferably both substituents are halogen, more particularly fluorine and chlorine. For example, a particularly preferred combination is 2-fluoro and 4-chloro.

It is to be understood that the present invention covers all combinations of the preferred and particular groups mentioned above.

Particular compounds according to the invention include: '-deoxy-5 '-fluoro-N- (tetrahydro-pyran-4-yl) -adenosine, 5'-deoxy-5'-fluoro-2-methyl-N- (tetrahydro-pyran-4-yl) - adenosine, 2-chloro-5'-deoxy-5 '-fluoro-N- (tatrahydro-pyran-4-yl) -adenosine, (2R, 3R, 4S, 5S) -2- [2-chloro-6- ( tetrahydro-pyran-4-ylamino) -purin-9-yl] -5-trifluoromethyl-tatrahydro-furan-3,4-diol, 2-chloro-5'-deoxy-5 '-fluoro-N- (2R-fluoro -clclopent- (R) -yl) -adanosine, 2-chloro-5'-deoxy-5 '-fluoro-N- (2S-fluoro-cyclopent- (S) -yl) -adanosine, N- (endo-bicyclo) [2.2.1] hept-2-yl) -2-chloro-5'-deoxy-5 '-fluoro-adenosine, ethyl ester of 4- [2-chloro-9- (5S-fluoromethyl-3R, S- dihydroxy-tetrahydro-furan-2R-yl) -9H-purin-6-ylamino) -piperidine-1-carboxylic acid, 1- (4- [2-chloro-9- (5S-fluoromethyl-3R, 4S-dihydroxy-tetrahydro -furan-2R-yl) -9H-purin-6-ylamino] -piperidin-1-yl) -ethanone, N- (endo-bicyclo [2.2.1 (hept-2-yl) -5'-deoxy-5 '-fluoro-adenosine, N- (exo-bicyclo [2.2.1] hept-2-yl) -5'-deoxy-5' -fluoro-adenosine, 5'-deoxy-5 '-fluoro-N- (2S -hydroxy-cyclopent- (S) -yl-adenosine, 4- [9- (5S-fluoromethyl-3R, 4S-dihydroxy-tetrahydro-furan-2R-yl) -9H-purin-6-ylamino] ethyl ester] -piperidine-1-carboxylic acid, 2-chloro-5'-deoxy-N- (1, 1-dioxo-hexahydro-1. delta.6-thiopyran-4-yl) -5 '-fluoro-adenosine, 2-chloro-5'-deoxy-N- (2,3-dihydroxy-propyl (5'-fluoro-adenosine, (2R, 3R, 4S, 5S) -2- [6- (cyclopropyl ethyl-amino) -purin-9-yl] - (1,1-difluoroethyl) -tetrahydro-furan-3, 4-diol, (2R, 3R, 4S, 5S ) -2- [6- (Bicyclo [2.2.1] hept-2-ylamino) -purin-9-yl] -5- (1,1-difluoro-ethyl) -tetrahydro-furan-3,4-diol, 2- [9- (5S-fluoromethyl-3R, 4R-dihydroxy-tetrahydro-furan-2R-yl) -9H-purin-6-ylamino] -etanosulonic acid methylamide, 5'-deoxy-5 '-fluoro- N- (2,2-dimethyl-propyl) -adenosine, N-tert-butyl-5'-deoxy-5'-fluoro-adenosine, 5'-deoxy-5'-fluoro-N- (tetrahydro-thiopyran-4) -yl) -adenosine, 2-chloro-5'-deoxy-5 '-fluoro-N-isobutyl-adenosine, 2-chloro-5'-deoxy-5' -fluoro-N- (1-methansul fonylpiperidin-4-) il) -adenosine, 2-chloro-5'-deoxy-N- (2, 2-dimethyl-propyl) -5'-fluoro-adenosine, N- (exo-bicyclo (2.2.1) hept-2-yl) -2-chloro-5'-deoxy-5'-fluoro-adenosine, 4- [2-chloro-9- (5S-fluoromethyl-3R, S-dihydr. Butyl) butyl ester oxy-tatrahydro-furan-2R-yl) - 9H-6-ylamino] -piperidine-1-carboxylic acid, 5'-deoxy-N- (1, 1-dioxo-hexahydro-1-delta.6-thiopyran) -4-yl) -5 '-fluoroadenosine-purin-6-ylamino] -piperidine-1-carboxylic acid, N- (4-chloro-2-fluoro-phenyl) -5'-deoxy-5'-fluoroadenosine, ethylamide 4- [2-chloro-9- (5S-fluoromethyl-3R, 4S-dihydroxy-tetrahydro-furan-2R-yl) -9H-purin-6-ylamino] piperidine-1-carboxylic acid.

The compounds according to the invention have applicability as inhibitors of lipolysis, , that is, they reduce the concentrations of free fatty acids in the plasma. The compounds can thus be used in the treatment of hyperlipidemias. Furthermore, as a consequence of their antilipolytic activity, the compounds have the ability to reduce high blood glucose, body levels of insulin and ketone and therefore may be of value in the therapy of diabetes.

Since the antilipolytic agents have hypolipidaemic and hypofibrinogenaemic activity, the compounds may also exhibit anti-atherosclerotic activity. The antilipolytic activity of the compounds of the invention has been demonstrated by their ability to reduce the concentration of non-esterified fatty acids (NEFA) in fasting rats dosed orally according to the method described by P. Strong et al. in Clinical Science (1993), 84, 663-669.

In addition to their antilipolytic effect, the compounds of the invention can independently affect cardiac function by reducing heart rate and conduction. The compounds can thus be used in the therapy of various cardiovascular disorders, for example cardiac arrhythmias, particularly followed by myocardial infarction, and angina.

The compounds of the invention are useful as cardioprotective agents, which have applicability in the treatment of ischemic heart disease. When used herein the term "ischemic heart disease" includes the damage associated with both myocardial ischemia and reperfusion, eg, associated with coronary artery bypass graft (CABG), percutaneous translumenal coronary angioplasty (PTCA). , cardioplégia, acute myocardial infarction, thrombolysis, stable and unstable angina and cardiac surgery including in particular cardiac transplantation. The compounds of the invention are additionally useful for treating ischemic damage to other organs. The compounds of the invention may also be valuable in the treatment of other disorders that arise as a result of widespread atheromatous disease, for example, peripheral vascular disease (PVD) and seizures.

The compounds can also inhibit the release of renin and are therefore of use in the therapy of hypertension and heart failure. The compounds may also be useful as CNS agents (for example as hypnotic, sedative, analgesic, and / or anticonvulsant agents which find particular use in the treatment of epilepsy).

In addition, the compounds of the invention can find use in the treatment of sleep apnea.

The compound of the formula (I) and the pharmaceutically acceptable acid addition salts thereof are useful as analgesics. They are therefore useful in the treatment or prevention of pain. They can be used to improve the condition of a host, typically of a human being, who suffers from pain. They can be used to relieve pain in a host. Accordingly, the compound of formula (I) and its pharmaceutically acceptable acid addition salts can be used as a preventive analgesic to treat acute pain such as musculoskeletal pain, postoperative pain and surgical pain, chronic pain such as such as chronic inflammatory pain (eg, rheumatoid arthritis and osteoarthritis), neuropathic pain (eg, postherpetic neuralgia, trigeminal neuralgia, neuropathies associated with diabetes and sympathetically maintained pain) and pain associated with cancer and fibromyalgia. The compound of the formula (I) can also be used in the treatment or prevention of pain associated with migraine, tension headache and severe headaches associated with the dilated carotid arteries, and the pain associated with them. Functional Bowel Disorders (for example IBS), non-cardiac chest pain and dyspepsia different from ulcer.

Accordingly, the invention provides a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy, and in particular in the treatment of human subjects or animals suffering from a condition in which there is a advantage in reducing the plasma free fatty acid concentration, or in reducing heart rate and conduction, or according to which therapy involves the treatment of ischemic heart disease, peripheral vascular disease or attacks , or the subject who is suffering from a CNS disorder, sleep apnea or pain.

In a further aspect, the invention provides a method of treating a human or animal that suffers from a condition in which there is an advantage in reducing the free fatty acid concentration of the plasma, or in reducing the speed of the plasma. heart and conduction, or in the treatment of the subject who is suffering from, or who is susceptible to, ischemic heart disease, peripheral vascular disease or attacks, or a subject who is suffering from a CNS disorder or who suffers from Sleep apnea or suffering from pain, such method comprises administering to the subject an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or a solvate thereof.

It is a further aspect, the invention provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt or a solvate thereof for the manufacture of a medicament for the treatment of a human being or an animal suffering from a condition wherein there is an advantage in reducing the concentration of the free fatty acid in the plasma, or in reducing the speed of the heart and conduction, or in the treatment of a subject who is suffering from or who is susceptible to a disease ischemic heart disease, a peripheral vascular disease or attacks, or a subject who is suffering from a CNS disorder or who suffers from sleep apnea or who suffers pain.

With respect to the aforementioned ischemic treatment, it has been found that according to a particular unexpected aspect of the present invention, not only the administration of a compound of the formula (I) prior to ischemia provides protection against myocardial infarction, but that the protection also occurs if the compound of the formula (I) is administered after the ischemic event and before the reperfusion. This means that the methods of the present invention are applicable not only where ischemia is planned or expected, for example in cardiac surgery, but also in cases of sudden or unexpected ischemia, for example in heart attack and in Unstable angina It will be appreciated that reference to treatment includes acute treatment or prophylaxis as well as relief of established symptoms.

In a still further aspect, the invention provides a pharmaceutical composition comprising at least one compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof in association with a pharmaceutical carrier and / or excipient.

In another aspect, the invention provides a pharmaceutical composition comprising, as an active ingredient, at least one compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof in association with a carrier and / or pharmaceutical excipient for use in therapy, and in particular is the treatment of humans or animals suffering from a condition in which there is an advantage in reducing the free fatty acid concentration of the plasma, or in reducing the speed of the heart and the driving, or treating a subject that is suffering from, or is susceptible to, an ischemic heart disease, a peripheral vascular disease or attacks, or from a subject who is suffering from a CNS disorder, sleep apnea or pain .

A process for preparing a pharmaceutical composition is further provided by the present invention, such a process comprising mixing at least one compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier and / or excipient.

The compositions according to the invention can be formulated for topical, oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred. The compositions can be adapted for sustained release.

For topical administration, the pharmaceutical composition can conveniently be given in the form of a transdermal patch.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example filled mucilage or polyvinylpyrrolidone, for example, lactose, microcrystalline cellulose or corn starch; lubricants, for example, magnesium stearate or stearic acid; disintegrants, for example, potato splint, sm croscamellose or starch glycolate and sm or wetting agents such as sm lauryl sulfate. The tablets can be coated according to methods well known in the art. The oral preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, I methylcellulose, or carboxymethylcellulose; emulsifying agents, for example, sorbitan monooleate, non-aqueous vehicles (which may include edible oils), for example propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid. The preparations may also contain buffer salts, flavoring agents, colorants and sweeteners (for example mannitol) where appropriate.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in the conventional manner.

The compounds of the formula (I) can be formulated for parenteral administration by bolus injection or continuous infusion and can be presented in a unit dosage form in ampoules, or in multiple dose containers with an added condom. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, pyrogen-free, sterile water, before use.

The compounds of the formula (I) can also be formulated as suppositories, which contain for example conventional suppository bases such as cocoa butter or other glycerides.

A proposed dose of the compounds of the invention for administration to the human being (of approximately 70 kg of body weight) is from 1 mg to 2 g, preferably 1 mg to 100 mg, of active ingredient per unit dose which could be administered, for example, from 1 to 4 times a day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient. The dosage will also depend on the route of administration.

In a still further aspect the invention also provides for the use of a compound the formula (I) or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of humans or animals suffering from a condition wherein there is an advantage in reducing the free fatty acid concentration of the plasma, or reducing the speed of the heart and conduction, or in the treatment of a subject who is suffering from, or who is susceptible to a disease ischemic heart disease, a peripheral vascular disease (PVD) or seizures, or a patient who is suffering from a CNS disorder, sleep apnea or pain.

The compounds of the formula (I) and the physiologically acceptable salts or solvates thereof can be prepared by the processes described hereinafter, said processes constitute a further aspect of the invention. In the following description, the groups R1, R2 and R3 as defined for the compounds of the formula (I) unless indicated otherwise.

According to the first general process (A), a compound of the formula (I) can be prepared by reacting a compound of the formula (II) wherein, L represents a separation group such as a halogen atom (for example a chlorine atom) and P1 and P2 represent hydrogen or a suitable protecting group (for example acetyl) with a compound of the formula R1NH2 or a salt of it, under basic conditions.

The compounds of the formula (II) can be used to produce the compounds of the formula (I) directly by the reaction with the group R1NH2 either in the presence or absence of a solvent such as an alcohol (for example a lower alkanol such as isopropanol, t-butanol or 3-pentanol), an ether (e.g. tetrahydrofuran or dioxane), a substituted amide (for example dimethylformamide), a halogenated hydrocarbon (for example chloroform) or acetonitrile, preferably at an elevated temperature (for example up to the reflux temperature of the solvent), in the presence of an acid scavenger suitable, for example, inorganic bases such as sodium or potassium carbonate, or organic bases such as triethylamine, diisopropylethylamine or pyridine.

This reaction can be preceded or followed where appropriate by the removal of the protective groups of P1 and P2. For example where P1 and P2 represent acetyl, this may be carried out with an amine such as ammonia or tert-butylamine in a solvent such as methanol at a convenient temperature.

The compounds of the formula (II) can be prepared by the reaction of a compound of the formula (III) wherein P represents a suitable protecting group for the example C 1-3 alkyl or acetyl, and P 1, P 2 and R 3 are as defined above, with a compound of the formula (IV) where L and R 'are as previously defined The reaction is conveniently carried out in a suitable solvent, such as acetonitrile in the presence of a silylating agent such as trimethylsilyl trifluoromethanesulfonate and a base such as diazabicyclo [5.4.0] (undec-7-ene (DBU). Alternatively the compound of the formula (IV) can be silylated first with a suitable silylating agent such as haxamethyldisilazane followed by the reaction of the silylated intermediate with a compound of the formula (III) and a suitable Lewis acid, for example trifluoromethanesulfonate of trimethylsilyl in a suitable solvent such as acetonitrile.

The compounds of the formula (IV) are either known in the art or can be prepared from the known compounds using methods analogous to those used to prepare the known compounds of the formula (IV).

The compounds of the formula (III) can be prepared from alternative protected compounds by replacement of the alternative protecting groups with P1 and P2; for example when P1 and P2 represent acetyl, the compounds of the formula (III) can be prepared from the compounds of the formula (V) wherein P4 and P5 represent C1-3 alkyl and P3 is as defined above by a acid-channel removal of the alkylidino protecting group, for example with hydrogen chloride in methanol, followed by acylation in itself for example with acetic anhydride in the presence of a base such as pyridine, in a solvent such as dichloromethane.

R3. -O .. ^ .OPJ (V) O / .4 / \ The compounds of the formula (V) are compounds known or prepared by methods analogous to those used in the art for preparing the known compounds of the formula V. It will be appreciated by a skilled person that the acetyl group in any of the above compounds could be replaced with any protective group, for example, other esters.

By the analogous methods, the compounds of the formula (I) or (II) can also be prepared from compounds wherein the alkylidene groups defined by P4 and P5 replace P1 and P2. This reaction represents an exchange of one protecting group by another and such reactions will be apparent to a person skilled in the art.

In accordance with Route B, the compounds of the formula (II) can be prepared from 6-chloropurine riboside (VI) which is commercially available or is prepared from inosine.

The first step of the process is to protect the 2 ', 3' -hydroxyl groups to produce the compounds of the formula (VII).

Cl P4 'P5 wherein p4 and P5 are defined herein above. When the 2 ', 3' -hydroxyl groups are protected with an isopropylidino group (P4 and P5 represent methyl) this can be effected by the use of acetone and PTSA (para-toluene sulphonic acid) or by other standard procedures using evident dimethoxypropane for a person with experience in the technique.

The compound of the formula (VII) is then fluorinated in a single step using TSF (para-toluenesulfonyl fluoride) and TBAF (tetra-n-butylammonium fluoride in THF (tetrahydrofuran).) This forms a compound of the formula (VIII) P X4 P5 It will be apparent to a person skilled in the art that the fluoroalkyl substituent in R3 can be modified in this step. Any R3 substituent can also be introduced at an appropriate stage.

Finally, the compound of the formula (VIII) is deprotected by standard conditions for example Dowex acidic resin and the chloro group is displaced by the group R1NH2 as described above to form a compound of the formula (I) According to an additional process (C), the compounds of the formula (I) can be prepared using a system of purine-pyrimidine transferase enzymes. This is demonstrated schematically right away: Dovrex resin r step 5 - desptOtecd? n Ganpuesto of the formula (I) This enzyme system in step 2 transfers the purine ring over the sugar ring of uridine. As shown in the reaction scheme, the R5NH- group has already been introduced around by standard methods but a person skilled in the art would appreciate that this could be added at any time during the reaction scheme.

Following step 2, the sugar ring is deprotected by groups P4 and P5 as described hereinabove, for example P4 and P5 represent methyl, followed by fluorination of the 5'-hydroxyl group. The compound is then deprotected to produce a compound of the formula (I).

This scheme of the reaction is the one proposed to demonstrate the use of the enzyme system. A skilled person could be able to adapt it to produce the compounds of the formula (I) with groups of R2 and R3 alternative. This could be by standard chemistry evident to a person skilled in the art.

An additional process (D) comprises converting a compound of the formula (I) to a different compound of the formula (I) by modifying the group R1, R2 or R3 therein.

Certain compounds of formulas (II), (III) and (V) are novel intermediate compounds and form a further aspect of the present invention.

The compounds of the formula R1NH2 are either known compounds or can be prepared from known compounds using conventional procedures with some exceptions indicated in the experimental section here below.

The specific optical isomers of a compound of the formula (I) can be obtained by conventional methods for example, by synthesis from an appropriate asymmetric starting material using any of the processes described herein, or where appropriate by separation from a mixture of isomers of a compound of the formula (I) by conventional methods for example by fractional crystallization or chromatography.

In the general process described above, the compound of the formula (I) obtained may be in the form of a salt, conveniently in the form of a pharmaceutically acceptable salt. Where desirable, such salts can be converted to the corresponding free kisses using conventional methods.

The pharmaceutically acceptable acid addition salts of the compounds of the formula (I) can be prepared by reacting a compound of the formula (I) with an appropriate acid in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl or an alcohol (for example methanol, ethanol or isopropanol). The pharmaceutically acceptable basic addition salts can be obtained in an analogous manner by treating a solution of a compound of the formula (I) with a suitable base. The pharmaceutically acceptable salts can also be prepared from other salts, including other pharmaceutically acceptable salts of the compounds of the formula (I), using conventional methods.

The invention is further illustrated by the following intermediate compounds and non-limiting examples.

The standard HPLC conditions are as follows: Automated Preparative HPLC Column Standard, conditions and eluent Preparative, automated high-resolution liquid chromatography (HPLC autoprep.) Was carried out using a Supelco® ABZ + column 5 μm 100 mm x 22 mm d.i. eluted with a mixture of solvents consisting of i) 0.1% formic acid in water and ii) 0.05% formic acid in acetonitrile, the eluent is expressed as the percentage of ii) in the solvent mixture, at a flow rate of .4 ml per minute. Unless stated otherwise, the eluent was used as a gradient of 0-95% ii) for 20 minutes.

LC / MS System Two systems of Alternative Liquid Chromatography Mass Spectroscopy (LC / MS) were used: If system A: This system used an ABZ + PLUS column, 3.3 cm x 4.6 mm d.i., eluting with solvents: A-0.1% v / v of formic acid + 0.077% w / v of ammonium acetate in water; and B-95: 5 acetonitrile: water + 0.05% v / v formic acid, at a flow rate of 1 ml per minute. The following gradient protocol was used: 100% A for 0.7 minutes; mixtures of A + B, gradient profile 0-100% B for 3.5 minutes; 100% B retention for 3.5 minutes; return to 100% of A for 0.3 minutes.

If system B: This system used an ABZ + PLUS column, 3.3 cm x 2.0 mm d.i., eluting with solvents: A-0.1% v / v of formic acid + 0.077% w / v of ammonium acetate in water; and B-95: 5 acetonitrile: water + 0.05% v / v formic acid, at a flow rate of 0.8 ml per minute. The following gradient protocol was used: mixtures of A + B, gradient profile 0-100% B for 3.5 minutes; 100% B retention for 1.5 minutes; return to 100% of A for 0.5 minutes.

Both systems used a micromass "platform" spectrometer, with an electrorode ionization mode, positive and negative ion switching, mass range of 80-1000 a.m.u.

HPLC system The analytical HPLC system used a 150 mM inertsil® ODS2 column x 4.6 mm d.i., eluting with solvents: A-0.1% v / v phosphoric acid and B-95: 5 acetonitrile: water + 0.1% v / v phosphoric acid. He used the following gradient protocol with a flow rate of 1.0 ml / minute: 100% A for 2 minutes; mixtures of A + B, gradient profile of 0-100% B for 40 minutes; 100% retention of B for 10 minutes.

The flash chromatography was carried out either on a Merck silica gel (Merck 9385), or on pre-packaged silica gel cartridges (Biotage).

Intermediary 1 Anomer ß: 4R-acetoxy-2s-fluoromethyl-5R-methoxy-tetrahydro-furan-3S-1-acetic acid ester Anomer a: 4R-acetoxy-2S-fluoromethyl-5S-methoxy-tetrahydro-furan-3S ester -acetic acid ethyl (3aS, 4S, 6R, 6Ar) -4-fluoromethyl-6-methoxy-2,2-dimethyl-tetrahydro-furo [3,4-d] [1,3] dioxol (Sharma, Moheshwar: Li, Yi X .; Ledvina, Miroslav; Bobek, Miroslav. Nucleosides Nucleotides (1995), 14 (9 & 10), 1831-52.) (4.0 g) is heated under reflux with concentrated hydrochloric acid (0.8 ml) in methanol (140 ml) for 1.5 h. The solvent evaporates, add more methanol (120 ml) and heat under continuous reflux overnight (16h). The solvent was evaporated again in vacuo, fresh methanol (120 ml) was added and it was heated under continuous reflux for 5 h. The solvent is evaporated in vacuo and the residue is converted to an azeotrope with methanol (15 ml) to give the intermediate compound of the crude diol as a colorless oil (3.04 g). The crude diol was dissolved in dry dichloromethane (80 ml) and treated with pyridine (6.3 ml) acetic anhydride (5.5 ml.; 5.85 mmoles) and 4-dimethylaminopyridine (100 ml). The mixture is stirred at room temperature under nitrogen for 16 hours, and the solvent is evaporated in vacuo to give a faint yellow oil (4.8 g). The oil is partitioned between dichloromethane and 8% aqueous sodium bicarbonate; the organic layers are washed with brine, dried (MgSO) and evaporated in vacuo to give the oil a faint yellow color (4.34 g). Purification by flash chromatography on silica gel (Biotage), eluting with ethyl acetate: cyclohexane 25:75 and 40:60, gives the title compound (anomers a and β). ß-Anomer: Colorless oil (2.2 g) TLC SiO2 (Ethyl acetate: cyclohexane 1: 2) Rf = 0.4 Anomer a: Colorless oil (0.945 g) TLC SiO2 (Ethyl acetate: cyclohexane 1: 2) Rf = 0.2 Intermediary 2 4S-acetoxy-2R- (6-chloro-purin-9-yl) -5S-fluoromethyl-tetrahydro-furan-3S-yl-acetic acid ester A suspension of 6-chloropurine (5.53 g) in hexamethyldisilazane (75 ml) ) and dry toluene (75 ml) is heated under reflux under nitrogen for 2 h. After cooling, the solvents were evaporated in vacuo and the residue was co-evaporated with toluene (50ml). The silylated purine thus obtained is dissolved in dry acetonitrile (75 ml) and the 4R-acetoxy-2S-fluoromethyl-5R-methoxy-tetrahydro-furan-3S-yl acetic acid ester (3.03 g) is added, followed by the trifluoromethanesulfonate. of trimethylsilyl (5.0 ml). The solution is heated at 90 ° C for 2 h, cooled, and poured into a 8% aqueous sodium bicarbonate solution (200 ml). The mixture is extracted with ethyl acetate and the extracts are dried (Na 2 SO 4) and evaporated in vacuo. An additional crude product was obtained from the 4R-acetoxy-2S-fluoromethyl-5S-methoxy-tetrahydro-furan-3S-yl ester of acetic acid (5.56 g) and 6-chloropurine (5.53 g) as described above. The crude products were combined and purified by flash chromatography on silica gel (Merck 9385), eluted with ether to give the title compound as a white solid (9.17 g). TLC Si02 (Ether) Rf = 0.2 Intermediate 3 Ester 4S-acetoxy-5S-fluoromethyl-2R- [6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -tetrahydro-furan-3R-yl-acetic acid A solution of the 4S-acetoxy ester -2R- (6-Chloro-purin-9-yl) -5S-fluoromethyl-tetrahydro-furan-3R-yl-acetic acid (3.03 g) in isopropanol (120 ml) is treated with opropylethylamine (8.4 ml) and hydrochloride 4-aminotetrahydropyran (Johnston, Thomas P., McCaler, George S., Opilger, Pamela S., Laster, Russell, Montgomery, John A. Kettering-Meyer Lab., J. Med. Chem. (1971), 14 ( 7), 600-14.) (3.26 g), and the mixture is heated under reflux under nitrogen for 8 h. The solution is cooled and the solvent evaporates in a vacuum. The residue is treated with 0% sodium bicarbonate (150 ml) and extracted with ethyl acetate. The extracts are dried (Na2SO4) and evaporated in vacuo to give the title compound as a foam (3.67 g). LC / MS (System A) Rt = 3.81 minutes.

Intermediary 4 PCT Int, Appl, WO9507921 Al 950323). 4S-acetoxy-2R- (2,6-dichloro-purin-9-yl) -5S-fluoromethyl-tetrahydro-furan-3R-yl ester of acetic acid 2,6-dichloropurine (6.1 g) is heated with hexamethyldisilazane ( 112 ml) at 130 ° C with stirring under nitrogen for 2 h. The mixture was evaporated in vacuo to give a white solid, which was azeotroped with dry toluene (80 ml). The residue is treated with a solution of the 4R-acetoxy-2S-fluoromethyl-5R-methoxy-tetrahydro-furan-3S-yl ester of acetic acid (Intermediate anomer l-β (2.5 g) in dry acetonitrile (100 ml) followed by Trimethylsilyl trifluoroethanesulfonate (6.63 ml) and the mixture is heated under reflux for 2 h.The mixture is partitioned between saturated aqueous sodium bicarbonate and dichloromethane and the organic layers are washed with brine, dried (MgSO4) and evaporated in vacuo. to give a brown gum (4.6 g) Purification by flash chromatography on silica gel (Merck 9385), eluting with ethyl acetate: cyclohexane 40: 60, gave the title compound as a white foam (2.67 g: 64%). TLC Si02 (Ethyl acetate: cyclohexane 2: 1) Rf = 0.55.

Intermediate 5 4S-acetoxy-2R- (6-chloro-2-methyl-purin-9-yl) -5S-fluoromethyl-tetrahydro-furan-3R-yl ester of acetic acid. 6-chloro-2-methylpurine (Bourguignon, Jean-Jacques, Desaubry, Laurent, Raboisson, Pierre, Ermuth, Camille-Georges: Lugnier, Claire, Bourguignon, Jean-Jacques, Desaubry, Laurent, Raboisson, Pierre, Wermuth, Camille -Georges; Lugnier, Claire, Laboratoire de Pharmacochimie Moleculaire, Center de Neurochimie, Strasbourg, 67084, J. Med. Chem. (1997), 40 (12), 1768-1770. (202 mg) is heated at 80 C with hexamethyldisilazane (2 ml) and dry toluene (3 ml) for 24 h. Dry toluene (5 ml) is added, the solvent is evaporated in vacuo, and the residue is converted to an azeotrope with additional dry toluene (5 ml). A solution of the 4R-acetoxy-2S-fluoromethyl-5R-methoxy-tetrahydro-furan-3S-yl acetic acid ester (98 mg) in dry acetonitrile (5 ml) is added the crude silylated purine, followed by trimethylsilyl trifluoromethanesulfonate ( 0.26 ml). The mixture is heated under reflux for 4 h, allowed to cool, and partitioned between saturated aqueous sodium bicarbonate (5 ml) and dichloromethane (40 ml). The organic layer is washed with water, dried (MgSO 4) and evaporated in vacuo to give the crude product. Purification by flash chromatography on silica gel (Merck 9385), eluting with cyclohexane: ethyl acetate (1: 1), gives the title compound as a white solid (109 mg).

Mass spectrum m / z 387 (MH +) Intermediate 6 Ester 4S-acetoxy-5S-fluoromethyl-2R- [2-methyl-6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -tetrahydro-furan-3R-yl-acetic acid ester. A solution of the 4S-acetoxy-2R- (6-chloro-2-methyl-purin-9-yl) -5S-tri fluoromethyl-tetra-idro-furan-3R-yl ester of acetic acid (108 mg), hydrochloride of 4 -aminotetrahydropyran (153 mg) and diisopropylethylamine (0.13 ml) in isopropanol (10 ml) is heated at 80 ° C for 72 hours. The solvent is evaporated in vacuo to give a semisolid brown residue. Purification by flash chromatography on silica gel (Merck 9385), eluting with ethyl acetate: cyclohexane 1: 1, ethyl acetate, and ethyl acetate: ethanol 10: 1, gave the title compound (61 mg). Mass spectrum m / z 452 (MH +).

Intermediate 7 4R, 5-diacetoxy-2-trifluoromethyl-tetrahydro-furan-3S-yl-acetic acid ester (3aR, 6S, 6As) -2, 2-dimethy1-6-trifluoromethyl-tetrahydro-furo [3, 4- d] [1, 3] dioxol-4-ol (Munier, Pascal; Picq, Dominique; Anker, Daniel. Munier, Pascal; Picq Dominique; Anker, Daniel. Lab. Chim. Org., Univ. Claude Bernard, -Villeurbanne, 69622, Fr. Tetrahedron Lett. (1993), 34 (51), 8241-4) (1.07 g) is dissolved in 9: 1 trifluoroacetic acid: H20 (15 ml) and the solution is stirred at 22 ° C for 4 hours. The solution is concentrated in vacuo, followed by repeated coevaporation with toluene to give a clear, colorless gum. The gum is dissolved in dry pyridine (30 ml), acetic anhydride (8.99 ml) is added, and the resulting solution is stirred at 22 ° C under N2 for 3 days. The excess pyridine and acetic anhydride were evaporated in vacuo, followed by repeated coevaporation with toluene to give a dark brown oil. Purification by flash column chromatography on silica gel (Merck 9385) eluting with cyclohexane: ethyl acetate 1: 1, gave the title compound as a faint yellow gum (1.37 g) TLC Si02 (Ethyl acetate) Rf = 0.9 Intermediate 8 Ester 4S-acetoxy-2R- (2,6-dichloro-purin-9-yl-5S-trifluoromethyl-tetrahydro-furan-3R-yl) acetic acid ester 4R, 5-diacetoxy-2-trifluoromethyl-tetrahydro -furan-3S-acetic acid (1.09g) is dissolved in anhydracetonitrile (5 ml) and 2,6-dichloropurine (0.788g) is added, followed by 1,8-diazabicyclo [5.4.0] undec 7-ene (DBU) (0.676 ml) and trifluoromethanesulfonate trimethylsilyl (0.94 ml) (TMSOTf) The resulting solution is stirred at 22 ° C under nitrogen for 16 h, and 2,6-dichloropurine (200 mg) is added. , followed by DBU (0.17 ml) and TMSOTf (0.24 ml) and the mixture is stirred at 22 ° C under nitrogen for 4 days, followed by heating under reflux for 4 hours.The mixture is cooled, and partitioned between ethyl acetate The water layer is extracted with ethyl acetate, and the combined organic extracts are dried (MgSO4), and concentrated in vacuo to give a brown gum. antigen on silica gel (Merck 9385), eluting with cyclohexane ethyl acetate, gave the title compound as a faint yellow foam (1.30g). TLC SiO- (Ethyl acetate) Rf = 0.6.

Intermediate 9 Ester 4S-acetoxy-2R- [2-chloro-6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -5S-trifluoromethyl-tetrahydro-furan-3R-yl of acetic acid. The 4S-acetoxy-2R- (2,6-dichloro-purin-9-yl) -5S-trifluoromethyl-tetrahydro-furan-3R-yl ester of acetic acid (177 mg) was heated at 60 ° C with hydrochloride from 4 ° C. -aminotetrahydropyran (110 mg) and diisopropylethylamine (0.17 ml) in isopropanol (5 ml) for 2 days. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (Merck 9385), eluting with ethyl acetate: cyclohexane 2: 1, to give the title compound as a white foam (0.146 g). of mass m / z 508 (MH +).

Intermediate 10 (3aS, 4S, 6R, 6aR) -4- (1, 1-difluoro-ethyl) -6-methoxy-2,2-dimethyl-tetrahydrofuro [3,4-d] [1,3] dioxolo. A solution of 1- (6R-methoxy-2,2-dimethyl-tetrahydro- (3aS, 6aR) -furo [3,4-d] [1,3] dioxol-4S-yl) -ethanone (Hampton, Alexander; Perini, Florian; Harper, .Peter J. Fox Chase Cent. Hampton, Alexander; Perini, Florian; Harper, Peter J. Fox Chase Cent. Cancer Med. Sci., Cancer Institute Res., Philadelphia, Pa., USA. Carbohydr. Res. (1974), 37 (2), 359-67.) (6.53g) in dichloromethane (200 ml) is treated with diethylaminosulfide trifluoride (10.4 ml) and the mixture is stirred at 22 ° C for 5 days. The solution is carefully added to 2M aqueous sodium carbonate (200 ml), and the mixture is stirred carefully, the organic phase is collected, and the aqueous phase is further extracted with dichloromethane. The combined organic layers are dried (Na 2 SO 4) and evaporated in vacuo. The residue is purified by flash chromatography on silica gel (Merck 9385) eluting with cyclohexane and cyclohexane: ether (19: 1-9: 1) to give the title compound as a faint yellow oil (4.72 g). 5.08 d (lH, brs, CH), 4.95 d (1H, brd, CH), 4.59 d (lH, d, CH), 4.21 d (lH, dd, CH, JF-C-CH6, 22Hz, 3.39 d ( 3H, s, OMe), 1.68 d (3H, t, JF-C-CH3), 1.5, 1.33 d (2x3 (2x3H, 2xs, 2xCH3).

Intermediate 11 (ß-anomer): 4R, 5S-diacetoxy-2S- (1,1-difluoro-ethyl) -tetrahydrofuran-3S-yl ester of re-acetic acid (Anomer a): 4R, 5R-diacerthoxy-2S- (1., 1-difluoro-ethyl) tetrahydrofuran-3S-1-yl ester of re-acetic acid (3aS, 4S, 6R, 6aR) -4 - (1, 1-di-fluoro-ethyl) -6-methoxy-2, 2-dimethyl-tetrahydrofuro [3,4-d] [1,3] dioxol (4.71 g) are dissolved in acetic acid: water (4: 1, 125 ml) and the mixture is heated under reflux under nitrogen for 18 hours. The solvents were removed in vacuo and the residue coevaporated twice with toluene, dissolved in dichloromethane. (70 ml), and treated with pyridine (8 ml), 4-dimethylaminopyridine (30 mg) and acetic anhydride (7 ml). The dark solution is left to stand for 41 hours. The solvents are removed in vacuo and the residue coevaporated twice with toluene. The residues are distributed between 8% aqueous sodium bicarbonate and dichloromethane. The organic extracts are dried (Na2SO4), and evaporated in vacuo and the residue is purified by flash chromatography on silica gel (Merck 9385), eluting with cyclohexane: ether (1: 1-2: 1-1: 4), to give the title compound (β-anomer): 2.51 g (41%); and the title compound (anomer a): 2.13 g (35%). (ß anomer): TLC Si02 (Ether) Rf = 0.10. (anomer a): TLC Si02 (Ether) Rf = 0.51.

Intermediate 12 Ester 4S-acetoxy-2R- (6-chloro-purin-9-yl) -5S- (1, 1-difluoro-ethyl) -tetrahydro-furan-3R-yl-acetic acid. The 6-chloropurine (1.52 g), hexamethyldisilazane (10 ml) and toluene (50 ml) were heated under reflux under nitrogen for 2 hours. The solvents were removed in vacuo, and the 4R, 5R-diacetoxy-2S- (1, 1-difluoro-ethyl) -tetrahydrofuran-3S-ethyl ester of rel-acetic acid (2.31 g) in dry acetonitrile was added ( 50ml), followed by 1,8-diazabicyclo [5.4.0] undec-7-ene (2.0 ml, 13.4 mmol) and trimethylsilyl tri fluoromethanesulfonate (4.8 ml). The mixture is stirred at 22 ° C for 17 h, then heated at 85 ° C for 90 minutes. The mixture is poured into 8% aqueous sodium bicarbonate and extracted with ethyl acetate. The organic extracts are dried (Na 2 SO 4) and evaporated in vacuo, and the residue is purified by flash chromatography on silica gel (Merck 9385) eluting with ether: cyclohexane 1: 1) and ether to give the title compound as a dim yellow rubber (2.49g). TLC Si02; (Ether) Rf = 0.30 Intermediate 13 2- (2S-hydroxy- (S) -cyclopentyl) -isoindole-1,3-dione The hydrochloride of (SS, 2S) -2-amimo-cyclopentanol (1.20 g) is dissolved in a solution of sodium methoxide (497 mg) in methanol (10 ml), filtered and evaporated in vacuo. The residue is dissolved in toluene (30 ml) and phthalic anhydride (1.55 g) is added, and the mixture is heated under reflux for 24 hours. After cooling, ethyl acetate is added and the mixture is filtered. The filtrate is evaporated in vacuo and the residue is purified by flash chromatography on silica (40 g) eluting with cyclohexane-ethyl acetate (2: 1) to give the title compound as a colorless solid (1.08 g). Mass spectrum m / z 232 (MH +).

Intermediate 14 2- (2S-fluoro- (S) -cyclopentyl) -isoindole-1,3-dione The 2- (2S-hydroxy- (S) -cyclopentyl) -isoindole-1,3-dione (3.42 g) is Dissolve in dry dichloromethane (55 ml) and add diethylaminosulfide trifluoride (3.43 ml), and the solution is stirred under reflux under nitrogen for 72 hours. The solution is carefully poured into 8% sodium bicarbonate solution (100 ml) and the organic phase is separated. The aqueous phase is further extracted with dichloromethane, the combined organic layers are dried (MgSO 4) and evaporated in vacuo. The residue is purified by flash chromatography on silica (100 g) eluting with cyclohexane-ethyl acetate (1: 1) to give the title compound as a cream-colored powder (1.29 g). Mass spectrum m / z 234 (MH +), 251 (MNH4 +).

Intermediate 15 (1S, 2S) -2-Fluorocyclopentyl-amine hydrochloride 2- (2S-fluoro- (S) -cyclopentyl) -isoindole-1,3-dione (6.75 g), hydrazine hydrate (1.55 ml) and ethanol (200 ml) are treated with water (1.55 ml) and heated under reflux for 4 hours. The mixture is cooled to 20 ° C, filtered and the filtrate treated with concentrated hydrochloric acid to pH 1. The solution is evaporated in vacuo and taken up in water, filtered, and the filtrate is evaporated in vacuo. The residue is recrystallized (with hot filtration) from ethyl acetate-methanol (3: 1) to give the title compound as a discolored white solid (2.59 g).

NMR d (DMSO) 8.3 (3H, brs, -NH3 +), 5.04, (1H, dm, CHF, J FCH, 52 Hz), 3.49 (1H, brdm, CH, J FCCH 20 Hz), and 2.2-1.4 ( 6 Hm, 3xCH2).

Example 1 5 '-deoxy-5' -fluoro-N-tetrahydro-pyran-4-yl) -adenosine. A solution of 4S-acetoxy-5S-fluoromethyl-2R- [6-tetrahydro-pyran-4-ylamino) -purin-9-yl] -tetrahydrofuran-3R-yl ester of acetic acid (3.67 g) in methanol (120 ml) is treated with a solution of potassium carbonate (3.50 g) in water (ca. 15 ml) and the mixture is stirred at 23 ° C for 17 h. The resulting solution is applied directly on silica gel (20 g) and purified by flash chromatography on silica gel (Merck 9385), eluting with dichloromethane: methanol (10: 1), to give the title compound as a colorless solid (2.16 g). Recrystallization from ethanol (75 ml) gave the title compound as a colorless solid (1.48 g). LC / MS (System A): Rt = 3.25 mim. Mass spectrum m / z 360 (MH +) Example 2 5'-Deoxy-5 '-fluoro-2-methyl-N- (tetrahydro-pyran-4-yl) -adenosine The 4S-acetoxy-5S-fluoromethyl-2R ester - [2-Methyl-6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -tetrahydro-furan-3R-yl-acetic acid (56 mg) is stirred with potassium carbonate (42 mg) in methanol (2 ml) and water (2 ml) at 22 ° C for 24 hours. The solvent is evaporated in vacuo, and the residue is purified by flash chromatography on silica gel (Merck 9185), eluting with dichloromethane: ethanol: 880 ammonia (100: 10: 1), to give the title compound as a white solid. (44 mg).

TLC Si02 (CH2C12: EtOH: 880 ammonia, 100: 10: 1) Rf = 0. 25. Mass spectrum m / z 368 (MH +) Example 3 2-chloro-5'-deoxy-5 '-fluoro-N- (tetra idro-pyran-4-yl) -adenosine The 4S-acetoxy-2R- ester (2,6-dichloro-purin-9-yl) -5S-fluoromethyl-tetrahydro-furan-3R-ethyl acetic acid (50 mg) is heated to 55-58 ° C with 4-aminotetrahydropyran hydrochloride (33 mg) and diisopropylethylamine (0.125 ml) in isopropanol (5 ml) for 21 h. During cooling to room temperature, methanolic ammonia is added (4 ml) and the mixture is allowed to stand at room temperature (22 ° C) overnight (16 h). The mixture is evaporated to dryness in vacuo to give the crude product which is purified by solid phase extraction (5g, Cartridge, Varian Mega Bondelut, aminopropyl bound phase, eluting with (i) CHCl3, (ii) acetone, to give the title compound (47 mg) TLC SiO2 (CH2C12: MeOH 9: 1) Rf = 0.5 Mass spectrum m / z 388 (MH +).

Example 4 (2R, 3R, 4S, 5S) -2- [2-chloro-6- (tetrahydro-purin-4-ylamino) -purin-9-yl] -5-trifluoromethyl-tetrahydro-furan-3, 4- diol The 4S-acetoxy-2R-2R-chloro-6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -5S-trifluoromethyl-tetrahydro-furan-3R-yl ester of acetic acid (141 mg) stir at room temperature with potassium carbonate (115 mg) in 2: 1 methanol: water (6 ml) for 17 hours. The solvent is evaporated in vacuo to give a yellow solid (0.274 g). Purification by flash chromatography on silica gel (Mere 9385), eluting with ethyl acetate and ethyl acetate: methanol 9: 1, gave the title compound as a white solid (96 mg). TLC Si02, (Ethyl acetate) Rf = 0.25. Mass spectrum m / z 424 (MH +).

Example 5 (2R, 3R, 4S, 5S) -2- [6-Bicyclo [2.2.1] hept-2-ylamino) -purin-9-yl] -5- (1,1-difluoro-ethyl) -tetrahydro -furan-3, 4-diol. The 4S-acetoxy-2R- (6-chloro-purin-9-yl) -5S- (1,1-difluoro-ethyl) -tetrahydro-furan-3R-yl ester of acetic acid (70 mg) is heated to 80 -85 ° C with (+) - eonono-norbonylamine hydrochloride and N, N-diisopropylethylamine (0.18 ml) in isopropanol (5 ml) for 24 hours. The solvent is evaporated to Ca 1 ml in volume, methanolic ammonia (3 ml) is added, and the mixture is allowed to stand for 17 hours. The solvent is evaporated and the residue is purified by extraction of the solid phase (Varian Bondelut cartridge, aminopropyl bound phase) eluting with chloroform (to elute the excess amine) followed by ethyl acetate: methanol 9: 1, to give the title compound (0.025 g). Mass spectrum m / z 396 (MH +). NMR (MeDO) 8.22 d (1H, s, heterocyclic CH), 8.17 d (1H, s, heterocyclic, CH), 6.08 d (lH, d, CH), 4.64 d (lH, t, CH), 4.49 d ( lH, dd, CH), 4.40 d (lH, vbrs, CH), 4.15 d (lH, ddd, CH) JF-C-CH, 7, 17H3), 2.57 d (1H, brt, CH), 2.3-2.08 d (2H, brt + m, 2xCH), 1.8-1.5 d (6H, t + 3xCH), 1.5-1.3 d (3H, m, 3xCH), 1.04 d (1H, ddd, CH). By analogous methods, the following examples were synthesized: Example 6 2-chloro-5-deoxy-5 '-fluoro-N- (2R-fluoro-cyclopent- (R) -yl) -adenosine Prepared from Intermediate 4 (as in Example 3) LC / MS (system A): R? = 4.01 minutes Mass spectrum m / z 390 (MH +).

Example 7 2-chloro-5-deoxy-5 '-fluoro-N- (2S-hydroxy-cyclopent- (S) -yl) -adenos prepared from Intermediary 4 (as in Example 3) LC / MS ( system A): R? = 3.55 minutes Mass spectrum m / z 388 (MH +).

Example 8 N- (endo-bicyclo [2.2.1] hept-2-yl) -2-chloro-5'-deoxy-5 '-fluoro-adenosine Prepared from Intermediate 4 (as in Example 3) LC / MS (system A): Rx = 4.32 minutes Mass spectrum m / z 398 (MH +).

Example 9 4- [2-Chloro-9- (5S-fluoromethyl-3R, 4S-dihydroxy-tetrahydro-furan-2R-yl) -9H-purin-6-ylamino] -piperidine-1-carboxylic acid ethyl ester Prepared from Intermediary 4 (as in the Example 3) LC / MS (system A): R = 3.90 minutes Mass spectrum m / z 459 (MH +).

Example 10 l-. { 4- [2-Chloro-9-) 5S-fluoromethyl-3R, 4S-dihydroxy-tetrahydro-furan-2R-yl) -9H-purine-6-ylamino] -piperidin-1-yl} -etanone Prepared from Intermediary 4 (as in Example 1) LC / MS (system A): R? = 3.67 minutes Mass spectrum m / z 429 (MH +).

Example 11 N- (endo-bicyclo [2.2.1] hept-2-yl) -5'-deoxy-5'-fluoroadenosine Prepared from Intermediate 2 (as in Example 1) LC / MS (system A) : R? = 4.05 minutes Mass spectrum m / z 364 (MH +).

Use 12 N- (Exo-Bicyclo [2.2.1] hept-2-yl) -5 '-deoxi-5' -fluoro-adenosine Prepared from Intermediate 2 (as in Example 1) Mass spectrum m / z 364 (MH +). HPLC Ri = 14.8 min Example 13 5'-deoxy-5 '-fluoro-N- (2S-hydroxy-cyclopent- (S) -yl-adenosine Prepared from Intermediate 2 (as in Example 1) Mass spectrum m / z 354 (MH +). HPLC Ri = 10.3 min.

Example 14 4- [9- (5S-Fluoromethyl-3R, 4S-dihydroxy-tetrahydro-furan-2R-yl) -9H-purin-6-ylamino] -piperidine-1-carboxylic acid ethyl ester Prepared from the Intermediate 2 (as in the Example 1) Mass spectrum m / z 325 (MH +). HPLC Ri = 14.0 min Example 15 2-Chloro-5'-deoxy-N- (1,1-dioxo-hexahydro-l.delta.6-hydropyran-4-yl) -5'-fluoro-adenosine Prepared from Intermediate 4 (as in Example 3) LC / MS (system A): R? = 3.66 minutes Mass spectrum m / z 436 (MH +).

Example 16 2-Chloro-5'-deoxy-N- (2,3-dihydroxy-prooyl) -5 '-fluoro-adenosine Prepared from Intermediate 4 (as in Example 3) LC / MS (system A): R? = 3.07 minutes Mass spectrum m / z 378 (MH +).

Example 17 (2S, 3R, 4S, 5S) -2- [6- (cyclopropylmethyl-amino) -purin-9-yl] - (1,1-difluoro-ethyl) -tetrahydro-furan-3,4-diol Prepared from Intermediary 12 (as in the Example 5) LC / MS (system A): R? = 3.73 minutes Mass spectrum m / z 356 (MH +).

Example 18 1- [9- (5S-Fluoromethyl-3R, 4R-dihydroxy-tetrahydro-furan-2R-yl) -9H-purin-6-ylamino] -etanesulonic acid methylamide Prepared from Intermediate 2 (as in he Example 1) Mass spectrum m / z 391 (MH +). HPLC R, = 10.1 min.

Example 19 5'-deoxy-5 '-fluoro-N- (2, 2-dimethyl-propyl) -adenosine Prepared from Intermediate 2 (as in Example 1) LC / MS (system A): R? = 4.26 minutes Mass spectrum m / z 340 (MH +).

Example 20 N-tert-butyl-5'-deoxy-5 '-fluoro-adenosine Prepared from Intermediate 2 (as in Example 1) LC / MS (system A): RX = 4.29 minutes Mass spectrum m / z 326 (MH +).

Example 21 5'-deoxy5 '-fluoro-N- (tetrahydro-thiopyran-4-yl) -adenosine Prepared from Intermediate 2 (as in Example 1) LC / MS (system A): R? = 4.09 minutes Mass spectrum m / z 370 (MH +).

Example 22 2-Chloro-5'-deoxy-fluoro-N-isobutyl-adenosine Prepared from Intermediate 4 (as in Example 3) LC / MS (system A): R? = 4.61 minutes Mass spectrum m / z 360 (MH +).

Use 23 2-chloro-5 'deomi-5' -fluoro-N- (1-methanesulfonyl-piperidin-4-yl) -adenosine Prepared from Intermediate 4 (as in Example 3) LC / MS (system A ): R? = 4.22 minutes Mass spectrum m / z 365 (MH +).

Example 24 2-Chloro-5'-deoxy-N- (2,2-dimethyl-propyl) -5 '-fluoro-adenosine Prepared from Intermediate 4 (as in Example 3) LC / MS (system A): R? = 4.77 minutes Mass spectrum m / z 374 (MH +).

Example 25 N- (Exo-bicyclo [2.2.1] hept-2-yl) -2-chloro-5f-deoxy-5 '-fluoro-adenosine Prepared from Intermediate 4 (as in Example 3) LC / MS (system A): R? = 4.92 minutes Mass spectrum m / z 398 (MH +).

Example 26 4- [2-Chloro-9- (5S-fluoromethyl-3R, 4S-dihydroxy-tetrahydro-furan-2R-yl) -9H-purin-6-ylamino] -piperidine-1-carboxylic acid ester Butyl ester Prepared from Intermediary 4 (as in Example 3) LC / MS (system A): R? = 4.84 minutes Mass spectrum m / z 478 (MH +).

Example 27 5'-deoxy-N- (1,1-dioxo-hexahydro-1, delta-6-thiopyran-4-yl) -5'-fluoro-adenosine Prepared from Intermediate 2 (as in Example 1) LC / MS (system A): R = 3.64 minutes Mass spectrum m / z 402 (MH +).

Example 28 N- (4-Chloro-2-fluoro-phenyl) -5'-deoxy-5'-fluoro-adenosine Prepared from Intermediate 2 (as in Example 1) LC / MS (system A): R = 4.03 minutes Mass spectrum m / z 398 (MH +).

Example 29 4- [2-Chloro-9- (5S-fluoromethyl-3R, 4S-dihydroxy-tetrahydro-furan-2R-yl) -9H-purin-6-ylamino] -piperidine-1-carboxylic acid ethylamide Prepared to from Intermediary 4 (as in Example 3) LC / MS (system A): R: = 4.04 minutes Mass spectrum m / z 458 (MH +).

Reporter Gene Experiments Agonist activity was measured in Chinese hamster ovary (CHO) cells containing the elements of the reporter gene of CRE / SPAP / HYG (CRE = cyclic AMP response element: HYG = hygromicine resistance; SPAP = alkaline phosphatase) secreted placental), which during the stimulation of cAMP levels produced SPAP. A cell line was used, which was stably transfected with either the human adenosine Al receptor or the A3 human adenosine receptor, in addition to the above elements. The cells were plated in 96-well plates in the culture medium and incubated at 37 ° C for 1 hour. For the measurement of potency, agonists were added to the appropriate cavities at a concentration range of approximately 10 ~ 10 - 10"5 M. 15 minutes later, the cAMP levels were stimulated by the addition of a maximum concentration of forskolin. All cells were then incubated for an additional 5 hours at 37 ° C, and cooled to room temperature, after which a substrate for phosphatase (para-nitrophenol phosphate, pNPP), which is converted by SPAP to a colored reagent) was then treated and the 96-well plates were read in a plate reader. For these readings, the dependence of the concentration of the inhibition by the agonist for SPAP production stimulated by forskolin can be calculated. One of the agonists tested on each 96-well plate was the standard non-selective agonist, N-ethylcarboxamidoadenosine (ECA), and the potency of all test agonists is expressed in relation to that of the ÑECA standard.

(ECR = equipotent concentration ratio relative to ÑECA = 1).

Table 1: Biological Data: ECR of the Reporter Gen Test, Receiver Al, A3 Example Al A3 1 1.9 > 226.00 2 11.8 > 226.00 3 2.41 > 139.00 4 190.10 - 5 7.14 > 257.00 6 0.91 > 156.00 7 0.45 > 91.00 8 0.21 > 91.00 9 3.00 > 129.00 10 66.80 > 162.00 11 0.47 > 152.00 12 0.54 Z152.00 13 1.47 > 152.00 14 1.68 > 435.00 15 9.16 > 435.00 16 7.29 > 240.00 17 22.30 > 353.00 18 0.71 > 353.00 19 3.51 > 353.00 20 8.17 > 353.00 21 1.64 > 353.00 22 3.30 > 145.00 23 11.20 48.90 24 7.83 > 233.00 25 0.78 > 151.00 26 4.50 > 233.00 27 6.20 > 162.00 28 2.05 > 170.00 29 51.60 > 236.00

Claims (25)

1. A compound of formula (I) which is an agonist of the adenosine Al receptor R 'NH HO OH saxate ptxque R2 represents alkyl of 1 to 3 carbon atoms, halogen or hydrogen; R3 represents a straight or branched, fluorinated alkyl group of 1-6 carbon atoms; R1 represents a group selected from (1) - (alk) n-cycloalkyl- (C3-7), which include the cycloalkyl with bridges, the cycloalkyl group which is optionally substituted by one or more of the substituents selected from OH, halogen, -alkoxy (C1) -3), wherein (alk) represents alkylene of 1 to 3 carbon atoms and n represents 0 or 1. (2) an aliphatic heterocyclic group of rings of 4 to 6 elements containing at least one heteroatom selected from O, N, or S, optionally substituted by one or more substituents selected from the group consisting - (1-3C) alkyl, -C02-alkyl (Cj._4), - CO-alkyl (d-3), -S ( = 0) n- (C alquilo_3 alkyl), -C0NRaRb (wherein Ra and Rb independently represent H or alkyl of 1 to 3 carbon atoms) or = 0; where there is a sulfur atom in the heterocyclic ring, and the sulfur is optionally substituted by (= 0) n, where n is 1 or 2. (3) straight or branched alkyl of 1 to 12 carbon atoms, optionally including one or more 0, S (= 0) n (where n is 0, 16 2) or substituted N groups within the alkyl chain , the alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy or NRaRb wherein Ra and Rb both represent alkyl of 1 to 3 carbon atoms or hydrogen. (4) a fused bicyclic aromatic ring wherein B represents a 5- or 6-membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of the formula (I) by means of a ring atom , ring A and ring B is optionally substituted by -C02- (C? _3 alkyl). (5) a phenyl group optionally substituted by one or more substituents selected from: -halogen, -S03H, - (alk) nOH, - (alk) n-cyano, '- (0) n-alkyl (Ci-e ) (optionally substituted by one or more halogens), - (alq) n -nitro, - (0) m- (alq) n -C02Rc, - (alq ") - CONRcRd - (alq) n - CORc, - (alq) ) n -SORe, - (alq) n -S02Re, - (alq) n- S02NRcRd, - (alq) n0Rc, - (alq) n ~ (C0) m -NHS02Re, - (alq) n- NHC0R, - ( alq) n-NRcRd where m and n are 0 or 1 and alq represents an alkylene group of 1 to 6 carbon atoms or an alkenyl group of 2 to 6 carbon atoms (6) a phenyl group substituted by a heterocyclic aromatic group of 5 or 6 elements, the heterocyclic aromatic group is optionally substituted by alkyl of 1 to 3 carbon atoms or NRcRd. R and Rd can each independently represent hydrogen, or alkyl of 1 to 3 carbon atoms when part of a group NRcRd, Rc and Rd together with the nitrogen atom can form a heterocyclic ring of 5 or 6 elements optionally containing other heteroatoms , the heterocyclic ring may be optionally further substituted by one or more alkyl groups of 1 to 3 carbon atoms. Re represents alkyl of 1 to 3 carbon atoms and salts and solvates thereof, in particular, the salts and solvates thereof physiologically acceptable.

2. A compound according to claim 1 characterized in that R3 represents a C1-3 fluoroalkyl group

3. A compound according to claim 2 characterized in that R3 represents F2C (Me) - or FCH2.

4. A compound according to any of claims 1-3 characterized in that R3 represents H, methyl or halogen.

5. A compound according to claim 4 characterized in that R3 represents H or chloro.

6. A compound according to any of claims 1-5 characterized in that R1 represents (alk) n-cycloalkyl-C3_6 wherein n is 0 and 1 and the cycloalkyl is substituted by at least one substituent selected from halogen, OH or is not substituted .

7. A compound according to claim 6 characterized in that n represents zero

8. A compound according to claims 6 or 7 characterized in that the cycloalkyl is 5 elements and is monosubstituted with OH or fluorine.

9. A compound according to claims 1 to 5 characterized in that R1 represents a substituted or unsubstituted heterocyclic group, the substituent is selected from the group consisting of -C02-alkyl (C? -4), -CO-alkyl (C? _3) ), -S (= 0) n- (C3_3 alkyl), -CONRaRb (wherein Ra and Rb are defined in claim 1, and wherein there is a sulfur atom in the ring of this heteroatom can optionally be substituted by (= 0) n, where n is 1 or 2.

10. a compound according to claim 9, characterized in that the heterocyclic ring is unsubstituted or substituted by -C02-alkyl (C? _), or when the heteroatom is S, the substituent (= 0) n is attached to the sulfur atom heterocyclic

11. A compound according to claim 9, characterized in that the heteroatom is N and the substituent is -C02-alkyl (C? -4) which is attached to the N atom.

12. A compound according to claims 9-11, characterized in that the heterocyclic ring is of 6 elements and contains only one heteroatom.

13. A compound according to any of claims 1-5, characterized in that R1 represents a straight or branched alkyl, substituted or unsubstituted, of 1-6 atoms of 1-6 carbon atoms, optionally with at least one S (= 0 ) n and / or N substituted in the chain, and n is 1 or 2.

14. A compound according to claim 13, characterized in that the alkyl group is substituted by at least one OH group.

15. A compound according to any of claims 1 to 5, characterized in that R1 represents a phenyl group substituted by one or more substituents selected from OH or halogen.

16. A compound according to claim 15, characterized in that the phenyl group is disubstituted in the 2,4-positions.

17. A compound according to claim 16, characterized in that both substituents are halogen.

18. A compound according to claim 17, characterized in that the substituent 2 is fluoro and the substituent 4 is chloro.

19. A compound according to claim 1, characterized in that it is: 5'-deoxy-5 '-fluoro-N- (tetrahydro-pyran-4-yl) -adenosine, 5'-deoxy-5'-fluoro-2-methyl-N- (tetrahydro-pyran-4-yl) - adenosine, 2-chloro-5'-deoxy-5 '-fluoro-N- (tatrahydro-prann-4-yl) -adenosine, (2R, 3R, 4S, 5S) -2- [2-chloro-6- ( tetrahydro-pyran-4-ylamino) -purin-9-yl] -5-trifluoromethyl-tatrahydro-furan-3,4-diol, 2-chloro-5'-deoxy-5'-fluoro-N- (2R-fluoro -clclopent- (R) -yl) -adanosine, 2-chloro-5'-deoxy-5 '-fluoro-N- (2S-fluoro-cyclopent- (S) -yl) -adanosine, N- (endo-bicyclo) [2.2.1] hept-2-yl) -2-chloro-5'-deoxy-5 '-fluoro-adenosine, 4- [2-chloro-9- (5S-fluoromethyl-3R, 4S-) ethyl ester dihydroxy-tetrahydro-furan-2R-yl) -9H-purin-6-ylamino) -piperidine-1-carboxylic acid, 1- (4- [2-chloro-9- (5S-fluoromethyl-3R, 4S-dihydroxy-tetrahydro -furan-2R-yl) -9H-purin-6-ylamino] -piperidin-1-yl) -ethanone, N- (endo-bicyclo [2.2.1 (hept-2-yl) -5'-deoxy-5 '-fluoro-adenosine, N- (exo-bicyclo [2.2.1] hept-2-yl) -5'-deoxy-5' -fluoro-adenosine, 5'-deoxy-5 '-fluoro-N- ( 2S-hydroxy-cyclopent- (S) -yl-adenosine, 4- [9- (5S-fluoromethyl-3R, 4S-dihydroxy-tetrahydro-furan-2R-yl) -9H-purin-6-ylamino acid ethyl ester ] -piperidine-1-carboxylic acid, 2-chloro-5'-deoxy-N- (1,1-dioxo-hexahydro-1. delta.6-thiopyran-4-yl) -5 '-fluoro-adenosine, 2-chloro-5'-deoxy-N- (2,3-dihydroxy-propyl (5'-fluoro-adenosine, (2R, 3R, 4S, 5S) -2- [6- (cyclopropyl ethyl-amino) -purin-9-yl] - (1,1-difluoroethyl) -tetrahydro-furan-3, 4-diol, (2R, 3R, 4S, 5S ) -2- [6- (bi-cyclo [2.2.1] hept-2-ylamino) -purin-9-yl] -5- (1,1-difluoro-ethyl) -tetrahydro-furan-3, 4-diol, 2- [9- (5S-fluoromethyl-3R, 4R-dihydroxy-tetrahydro-furan-2R-yl) -9H-purin-6-ylamino] -ethanesulfonic acid methylamide, 5'-deoxy-5 '-fluoro-N- (2, 2-dimethyl-propyl) -adenosine, N-tert-butyl-5'-deoxy-5' -fluoro-adenosine, 5'-deoxy-5 '-fluoro-N- (tetrahydro) -thiopyran-4-yl) -adenosine, 2-chloro-5'-deoxy-5'-fluoro-N-isobutyl-adenosine, 2-chloro-5'-deoxy-5'-fluoro-N- (1-methanesulfonylpiperidine) -4-yl) -adenosine, 2-chloro-5'-deoxy-N- (2, 2-dimethyl-propyl) -5'-fluoro-adenosine, N- (exo-bicyclo (2.2.1) ept-2 -yl) -2-chloro-5'-deoxy-5'-fluoro-adenosine, 4- [2-chloro-9- (5S-fluoromethyl-3R, 4S-dihydroxy-tatrahydro-furan-2R- butyl) butyl ester il) -9H-6-ylamino] -piperidine-1-carboxylic acid, 5'-deoxy-N- (1, 1- dioxohexahydro-1-delta-6-thiopyran-4-yl) -5 ' -fluoroadenosine-purin-6-ylamino] -piperidine-1-carboxylic acid, N- (4-chloro-2-flusro-phenyl) -5'-deoxy-5'-fluoroadenosine, 4- [2-chloro] -acetylamide 9- (5S-fluoromethyl-3R, 4S-dihydroxy-tetrahydro-furan-2R-yl) -9H-purin-6-ylamino] piperidine-1-carboxylic acid.

20. A compound according to claim 1, characterized in that it exhibits no activity or exhibits a small activity in the A3 adenosine receptor.

21. A compound according to any of claims 1-20, characterized in that its use is in therapy.

22. A compound according to any of claims 12-20, characterized in that together with the carrier and / or pharmaceutical excipient.

23. A compound according to any of claims 1-20, characterized in that it presents the manufacture of a medicament for the treatment of a patient suffering from a condition where there is an advantage in reducing the concentration of plasma free fatty acids , or in reducing the speed of the heart, or in a subject that is suffering from, or that is susceptible to ischemic heart disease, a peripheral vascular disease or attacks or in a subject suffering from pain, a disorder of the CNS or sleep apnea

24. A method of treating a patient suffering from a condition characterized in that there is an advantage in reducing the concentration of plasma free fatty acids, or in reducing the speed of the heart, or for the treatment of a subject who is suffering from, or that is susceptible to, ischemic heart disease, a peripheral vascular disease or attacks, or for the treatment of a subject suffering from pain, a CNS disorder or sleep apnea.

25. A process for the preparation of a compound according to claims 1-20, characterized in that it comprises reacting a compound of the formula (II). R 'NH HO OH Where L represents a separation group, R1, R2, and R3 are as defined in claim 1 and P1 and P2 represent a hydrogen or a protecting group, with a compound of the formula R ^ H2 or a salt thereof acid conditions. CHEMICAL COMPOUNDS SUMMARY OF THE INVENTION A compound of formula (I) which is an agonist at the adenosine Al receptor where R "represents C3 alkyl, halogen or hydrogen, R3 represents a straight or branched fluorinated alkyl group of 1-6 carbon atoms and salts and solvents thereof, in particular, solvates and physiologically acceptable salts thereof These compounds are agonists at the Adenosine Al receptor.