MXPA96005046A - Derivatives of adenos - Google Patents

Abstract

The present invention relates to the compounds of the formula I: wherein R1 is one of several meanings, including cycloalkyl and hydroxycycloalkyl; R2 is hydrogen, alkyl with (C1-4), amino, cycloalkyl with (C3-5) or halogen with an atomic number from 9 to 35, and R3 is alkyl with (C1-4), which are useful as analgesic agents. The compounds of the formula I wherein R 1 is hydroxy alkyl are new. The compounds of the formula I can be produced by the alkylation at the tetrabutylammonium position and a non-pol solvent

Description

*, • * ADENOSINE DERIVATIVES FIELD OF THE INVENTION The present invention relates to adenosine derivatives, and in particular, provides a new use of the Al receptor agonists.

'' DESCRIPTION OF THE INVENTION In particular, the present invention relates to a new use of the compounds of the formula (I): where is hydrogen, alkyl with (C, 1-,), allyl; metalyl; REF: 23308 an alkynyl with branched or straight chain (C-,), cycloalkyl with (C-), hydroxy (C, g) -cycloalkyl, phenyl which is monosubstituted, or independently of each other, disubstituted by halogen with an atomic number from 9 to 35, alkyl with (£ 1-) »alkoxy with (C,,) or CF- ,; of enyl (C,,) alkyl wherein the phenyl ring is unsubstituted or is monosubstituted, or independently of each other, disubstituted by halogen having an atomic number of 9 to 35, alkyl with (C,,), alkoxy with (C,,) or CF_; alkyl with (C,,) having at least one hydroxy group or at least two phenyl groups, a bicycloalkyl such as endo- or exo-bicyclo [2, 2, 1] heptyl, a naphthyl group (C,) alkyl, an acenaphilenyl- (C.,) alkyl group or a group of the formula A or of the formula B is hydrogen, a hydroxy group or an alkoxy group with (Cj ^) Q is hydrogen or hydroxyl, A is -CH--, -0-, -S- or a direct bond, Y is - (CH-) - or a direct link, is an integer from 1 to 3 and the dotted line in formula A represents an optional link, R "is hydrogen, alkyl with (.C-,), amino, cycloalkyl with (C., -) or halogen with an atomic number of 9 to 35 and R_ is alkyl with (C,,).

Some of these compounds for example those in which R. is different from hydroxy cycloalkyl are known and described, for example, in published British Patent Application No. 2 226 027 A and European Patent Applications Nos. EP-0- 378 518 and EP-0-269 574, and USP 4,843,066 and 4,985,049. In the formulas described herein, the 2 ', 3', 4 'and 5' substituents of the tetrahydrofuran ring have the configuration as in adenosine. In a group of compounds under formula I, R. is different from hydroxycycloalkyl. In another group of compounds under formula I, R 1 is hydroxy (C, _) cycloalkyl. Preferably the compound of formula I is 6-cyclohexyl-2'-O-methyl-adenosine, hereinafter referred to as Compound M. Typically the activity of adenosine A. in the preferred compounds of formula I can be determined as follow:- Affinity towards adenosine receptors The striatal pig membranes are prepared as previously described by H. Bruns et al., In Molecular Pharmacology 29 (1986) pages 331-344. He 3 H-NECA, a non-selective adenosine receptor agonist, is used to label the receptors of both A. and A-. The ICe0 values are derived from the displacement curves by fitting the least squares, non-linear, weighted curve to the Langmuir equation and the calculated pK-j values.

Table: Affinity of the adenosine receptor ligands towards the receptors of A. and A ^ ll Selectivity of A,: A- n (D: nM) (KD; nM) CPA 0.74 + 0.08 930 + 110 1260 6 CV 1808 2460 + 757 269 + 70 0. 1 5 CGS 21680 4360 + 1080 18.6 + 4 0 .004 4 Compound M 23 + 2 24500 + 5160 1090 5 1.5 H-O CPA * Cyclopentyladenosine CV 1808 »2-Phenylaminoadenosine (Carbohydrates vol.181 1974) ref. 91898 K) CGS 21680-2- [p- (2-Carboxyethyl) phenethylamino] -5'-N-ethyl carboxamido-adenosine (FASEB J, 1989, 3 (4) Refs. 4770/3) According to the literature, the CPA has proved that it is a powerful and highly selective displacer of the binding or binding to the A receptor, the CV 1808 is a ligand of the relatively weak but selective A receptor and the CGS 21680 shows a selectivity and high power to receiver A ». The compound M in the form of its hydrate 1.5 shows good affinity and high selectivity towards the A ^ receptor against the A- receptor. / v 'The known compounds of the formula I are known to act as antihypertensive agents and coronary vasodilators. It is also known that the compounds of the formula 5 protect the vascular endothelium by inhibiting both the aggregation of the thrombocytes and the activation of the leukocytes. They also lower the lipid levels of the blood. In addition, the compounds of the formula I have a protective effect against the diseases caused by hypertension, such as congestive heart failure, myocardial infarction or sudden cardiac death and renal failure (see European Patent Applications Nos. EP-0-378 518 and EP-0-269 574). These compounds are also known for the treatment of disorders of neurodegeneration, peripheral neuropathies such as diabetic neuropathy and of disorders associated with peripheral vascular diseases and / or disorders associated with neuronal degeneration, hypertriglyceridemia / levels of low HDL cholesterol, lipid dysfunction, high free fatty acids or type I or type J1 diabetes, including non-insulin-dependent diabetes, arrhythmias in particular, paroxysmal supraventricular tachycardia and tachycardia atrial fibrillation 25 cardiac and for protection against myocardial infarction it gave . The present applicants have found that the compounds of formula I are particularly interesting analgesics, for example for the treatment of pain, for example acute or chronic pain. The analgesic activity of the compounds of the formula I makes them indicated by their analgesic activity in tests of standard animals, for example inflammatory and neuropathic models for example in the reduction of persistent inflammatory mechanical hyperanalgesia [(tests a) and b) ] and persistent neuropathic thermal hyperalgesia [test c)] indicative of chronic neuropathic pain.

Inflammatory hyperalgesia Test a) Hyperalgesia induced by Freund's adjuvant The rats are injected intra-articularly into a knee joint with Freund's complete adjuvant (1U0 microliters). The load that the rat will tolerate on this jy.erna decreases and remains depressed for up to 5 days. This effect is indicative of mechanical hyperalgesia, and is a response to NSAIDs and opiates. The compounds of the formula I are administered by injection and preferably in oral form at doses from about 3 to 60 micrograms / kg of body weight of the animal. The increased load tolerated on the injected side is measured to determine the inversion of hyperalgesia. Compound M shows a particularly interesting activity on p.o. from about 3 to about 60 micrograms / kg with a duration of action of about 1 hour. There is no significant difference in the response between doses of 3, 30 and 60 micrograms / kg suggesting that the maximum effect has been reached in the range of 3 to 30 micrograms / kg.

Test b) Mechanical hyperalgesia induced by Turpentine A local intraplantar injection of turpentine / para-raphine in the rat paw (posterior left) led to a local inflammatory response and a reduction in the extraction threshold (cut-off threshold of 340 g) for a mechanical stimulus (pressure of the paw). The compounds of the formula. I are active at doses from about 1 to 100 micrograms / kg p.o. or s.c. administered three days after injection, additional readings of threshold 1 and 3 hours are taken later.

Compound M shows significant activity at doses of 30 and 60 micrograms / kg orally, with the maximum effect at 30 micrograms / kg. Morphine has an ED5f value of 1.2 mg / kg s.c. in this test.

Neuropathic hyperalgesia Test c) Neuropathic thermal hyperalgesia (according to the principles of Z. Seltzer et al., Pain, 1990, 43, 0 205-218) The unilateral partial ligation of the sciatic nerve eliminates the fibers in all the innervation of a leg 0 claw of a rat. The rats developed hyperalgesia 15 to mechanical and thermal stimuli and allodynia of the leg to which the nerves were partially removed without the induction of autotomy. The animals are placed in a perspex box on a thin glass plate and a ramp-shaped heat stimulus is applied to the surface of the sole of a leg. The latent state to remove the leg is measured. The compounds of the formula 1 are active at doses from about 1 to about 100 micrograms / kg of injection (s.c. or preferably orally), administered 12 to 15 days after nerve ligation. The compound M is particu- larly active against thermal hyperalgesia. Compound M shows significant activity at doses of 30 and 60 micrograms / kg, with the maximum effect at 30 micrograms / kg. The ED, Q is almost 60 micrograms / kg p.o. Morphine has an ED5Q of almost 3 mg / kg in this test when it is administered subcutaneously.

Trials or clinical trials The tests or clinical trials can be carried out as follows: Subjects suffering from pain, postoperative pain or postherpetic neuralgesia are administered with the compounds of formula I, especially compound M, i.v. at a dose from 0.02 to 5 mg. Pain relief is noted. The compounds of the invention are therefore useful as analgesics, for example against acute or chronic pain, for example chronic neurospathic pain. In one aspect, therefore, the present invention provides a method for the treatment of pain which comprises administering a therapeutically effective amount of a compound of formula I as defined above, to a subject in need of such treatment.

In another aspect, this invention provides the use of a compound of formula I as defined above as an analgesic in the preparation of a medicament suitable for the treatment of pain. In another aspect, this invention provides a compound of the formula I as defined above for use in the treatment of pain. In a further aspect, this invention provides an analgesic composition comprising a compound of formula I as defined above as an analgesic in association with a pharmaceutically acceptable carrier or diluent. Indications include pain, for example, acute pain associated with tissue damage and inflammation (eg, postoperative pain, hard-burning pain, injuries, etc.) chronic inflammatory pain (eg, arthritis) and chronic neuropathic pain (for example, diabetic neuropathy, postherpetic neuralgia, multiple sclerosis, causalgia, etc.). The doses of the compound employed in the uses of the invention indicated above, will vary depending of course on the compound employed, the seriousness of the disorders, the host, the weight of the patient, the mode of administration and the relative efficacy of the compound. However, in general, satisfactory results are indicated in the animals which will be obtained with three daily doses from about 1 to about 100 micrograms / kg of body weight of the animal, for example 3 to 60, such as 10 to 60, micrograms / kg. In larger mammals, for example humans, an indicated daily dose is from about 0.1 to about 10 mg, conveniently administered in unit doses from about 0.02 to about 5 mg, and such unit doses may be administered more than once a day , for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times a day. In test a) above, the NSAID ibuprofen has an ED.-Q of about 4 mg / kg p.o. and indomethacin 13 mg / kg p.o. The compound M is approximately 300 times more active. For compound M the preferred dose range is from about 0.1 mg / day to about 10 mg / day, for example 3-30 micrograms / kg for a 70 kg adult, depending on the severity of the indication (s) and the frequency of administration. Compound M has been shown to have no serious adverse effects in man after single doses of up to 5 mg- ^ p.o. When used herein the term "pharmaceutically acceptable" encompasses materials suitable for both human and veterinary use.

The compounds of the invention can be formulated for administration by any suitable route, the preferred route depends on the disorder for which the treatment is required, and preferably in a unit dosage form or in a form that a human patient can be administered to. itself in a single or simple dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral administration, • x intravenous or intramuscular. The compositions of the invention may be in the form of tablets, capsules, sachets, ampoules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as sterile oral or parenteral solutions or suspensions. Topical formulations are also contemplated where appropriate. To obtain a consistency of administration it is preferred that a composition of the invention be in the form of a unit dose. Dosage forms for oral administration may be tablets and capsules containing 0.02-5 mg of a compound of the invention and may contain conventional excipients such as binding or agglutination agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine, foil lubricants eg, magnesium stearate, disintegrants, for example starch, cross-linked polyvinylpyrrolidone, starch glycolate and sodium or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate. The solid oral compositions can be prepared by conventional mixing, filling, tabletting or the like. Repeated mixing operations can be used to distribute the active agent in all these compositions using large amounts of fillers. Such operations are of course of conventional use in the art. The tablets can be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, edible hydrogenated fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if conventional coloring or flavoring agents are desired. Examples for solid oral compositions, for example tablets and capsules, are as follows: Tablets are compressed from the capsule granulation of the strength or concentration of the corresponding dose. The yellow capsules, of size # 3, are used for the encapsulation of the compound M, and the respective formation for the concentrations of the doses of 0.1 and 5 mg are shown below. 0. 1 mg Tab / Cap 5.0 mg Tab / Cap Compound M 0.1 5.0 Microcrystalline Cellulose 76.92 74.96 Lactose, hydrated 87.63 * 84.69 * Polyvinylpyrrolidine 7.4 7.4 Crospovidone »7.4 7.4 Magnesium Stearate 0.925 0.925 Retained Humidity 4.625 4.625 Capsule Size Three 50 50 0. 1 mg Tab / Cap 5.0 mg Tab / Cap Theoretical Capsule Filling Weight or Weight of the Tablet 185 185 Weight of the Theoretical Capsule 235 235"" "The amount of lactose is adjusted to compensate for themoisture content in the substance of the drug or drug. The compounds can also be administered in the form of a sustained release mode, to provide a prolonged duration of action. Conventional drug delivery systems can be used to provide sustained release, for example, coated pills or osmotic back-and-forth systems. For parenteral administration, fluid unit dosage forms are prepared using the compound and a sterile vehicle, and, depending on the concentration used, they can be either suspended or dissolved in the vehicle. In the preparation of the solutions the compound can be dissolved in polyethylene glycol or ethanol and diluted with water for injection and sterilized by filtration before filling in a suitable ampoule or vial and sealed. Advantageously, adjuvants such as a local anesthetic, a preservative and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared substantially in the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization can not be effected by filtration. The compound can be sterilized by exposure to ethylene oxide before suspension in the sterile vehicle. Advantageously, a surfactant or humectant is included in the composition to facilitate the uniform distribution of the compound. The compositions may contain from about 0.1% to about 99% by weight, preferably from 10 to 60% by weight of the active material, depending on the method of administration. The compounds M of the invention, or a hydrate or an addition product with other solvents or salts thereof, can also be administered as a topical formulation in combination with conventional topical excipients. Typical formulations may be presented as, for example, ointments, creams or lotions, impregnated bandages, gels, gel sticks, spray solutions and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to aid drug penetration and emollients in ointments and creams, the formulations may contain compatible conventional carriers, such as cream of ointment bases and ethanol or eleilic alcohol for lotions. The formulations of cream, locid, gel, ointment, Suitable spray or spray solution, which can be used for the compounds of the formula I or a hydrate or an addition product with other solvents or salts thereof, are conventional formulations well known in the art, for example, as In textbooks, he describes pharmaceutical and cosmetic substances, such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the British and US Pharmacopoeias. In another aspect, the present invention provides adenosine derivatives of the formula where V is cycloalkyl with (C, Q) substituted by a hydroxy group, it is as defined above or preferably hydrogen, alkyl with (C,,) or halogen with an atomic number of 9 to 35, and is as defined above.

The compounds of the formula can exist in the form of enantiomers or diastereomeric mixtures. In the formula, the haldgen with an atomic number of 9 to 35 is fluorine, chlorine or bromine; alkyl with (C,,) is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, especially methyl; and cycloalkyl with (C, _fi) is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, especially cyclohexyl or cyclopentyl. The compounds of the formula can be prepared by a process characterized in that the compounds of the formula where and R- possess the meanings given above it's chlorine or bromine, they are reacted with a compound of the formula Illa R -'- NH-Illa where V has the meaning given above The above process is conveniently carried out by heating a compound of the formula lal together with a compound of the Illa formula in the presence of a solvent such as dioxane at a temperature of between about 80 ° C to and including 120 ° C, preferably at the temperature of boiling. In the compounds of the formula lla, which are used as starting compounds in this process, X is especially chloro. The compounds of the formula Ia, as well as a process for producing them, are described in Published European Patent Application No. 269 574. An additional process for the preparation of the compounds of the formula comprises treating the compounds of the formula IVa where Ri '. R y ^ 3 P ° see the meanings given above with tetrabutylammonium fluoride trihydrate. The above reaction can be carried out in an organic solvent for example tetrahydrofuran at room temperature under stirring. The compounds of the formula IVa can be obtained by treating the compounds of the formula Ia with 1,3-dichloro-1,3,3-tetraisopropyl-disiloxane in an alkaline solvent, for example pyridine, and reacting the Compounds of the formula Va thus obtained where X, R- and have the meanings given above with the compounds of the Illa formula. In the following Examples 1 to 8, all temperatures are in degrees Celsius and are uncorrected.

Example 6 - [(trans) -4-Hydroxycyclohexyl] -2'-0-methyl adenosine 1 g of 6- [(trans) -4-hydroxycyclohexyl] -9-pu ^ inyl-2 • -0-methyl-3,, 5 '-0- (1, 1, 3, 3-etraisopropyldisilox-1, 3-diyl) -D-ribose is stirred for 15 minutes at room temperature with 2 g of the trihydrate of tetrabutyl ammonium fluoride in 20 ml of tetrahydrofuran. The mixture is subsequently evaporated to dryness and the residue is eluted on silica gel with a mixture of ethyl acetate / methanol 85:15. The purified product is crystallized from f ~ methanol / ethyl acetate. The title compound crystallizes with one equivalent of methanol and has a melting point of 121-124 ° C. 20 [C] -. - -50.2 ° (c * 1 in dimethylformamide). The compound can also be recrystallized from ethanol and crystallizes with one equivalent of water after remaining in moist air. Melting point: 114-117 °. 20 [OC] _ "-46.9 ° (c * 1 dimethylformamide) 0 The 6 - [(trans) -4-hydroxycyclohexyl] -9-purinyl-2'-0-methyl-3 *, 5 '-0- ( 1, 1, 3, 3-tetraisopropyl-disilox-l, 3-diyl-) - D-ribose used in the above process as the starting material, can be produced as follows: g of 6-chloro-9-purinyl-2'-0-methyl-3 ', 5'-0- (1,1,3,3-tetraisopropyldisilox-1,3-diyl) -D-ribose stir together with 1.32 g of the trans-4-hydroxycyclohexylamine and 1.4 ml of N-ethyl-diisopropylamine in 80 ml of dioxane for 6 hours in an oil bath of 105 ° C. The mixture 0 is subsequently cooled to room temperature, filtered and the filtrate is concentrated to dryness. For purification, the mixture thus obtained is eluted on silica gel, first with a hexane / ethyl acetate 7: 3 mixture and then with a mixture of ethyl acetate / me-5-tanol 95: 5. The oily compound thus purified has an Rf value of 0.3 (from ethyl acetate / methanol 95: 5).

Example 6 - [(cis) -4-Hydroxycyclohexyl] -2 '-0-methyl adenosine The compound named in the title is obtained analogously to example 1 when cis-4-hydroxycyclohexyl amine is used in place of trans-4-hydroxycyclohexyl-amine. The compound thus obtained named in the title crystallizes with one half of an equivalent of ethyl acetate and has a melting point of 110-111 ° C. [0] _ 20 « -48.6 ° (c • 1 in dimethylformamide).

Example 3: 6 - [(lS, trans) -2-Hydroxycyclopentyl] -2 '-0-methyl adenosine The compound named in the title is obtained analogously to example 1 when the IS, trans-2-hydroxycyclopentyl amine is used in place of the trans-4-hydroxy-cyclohexylamine. The compound thus obtained named in the title has the following characteristics: Foam, 20 in ethyl acetate / ethanol 75:25 - 0.44, [o] "- -25.5 (c = 1 in dimethylformamide).

Example 4: 6 - [(LR, trans) -2-Hydroxycyclopentyl] -2'-O-methyl adenosine The compound named in the title is obtained analogously to example 1 when the IR, trans-2-hydroxy-cyclopentylamine is used in place of the trans-4-hydroxycyclohexylamine. The compound thus obtained has the following characteristics: Melting point: 164-166 °, Rf in ethyl acetate / ethanol, 75:25 0.44, [e] 20 -80.2 ° (c "1 in dimethylformamide).

Example 5: 6 - [(lS, trans) -2-Hydroxycyclohexyl] -2 '-0-methyl adenosine The compound named in the title is obtained analogously to Example 1 when the IS, trans-2-hydroxy-cyclohexylamin is used in place of the trans-4-hydroxy-cyclohexylamine. The compound thus obtained named in the title, has the following characteristics: Foam, Rf in ethyl acetate / Ethanol 75:25 «0.42; [Ot] 20-26.2 ° (c • 1 in dimethylformamide).

"Example 6 _ 6- [(trans) -4-hydroxycyclohexyl] -2 * -0-ethyl adenosine Prepared analogously to Example 5. Obtained as the hydrate 0.4. P.f. 98 ° C (liquefaction). 20 [Oí -] -, * -58 ° (c * 1 in dimethyl formamide).

Example 7: 6- [lS, (trans) -2-hydroxycyclohexyl] -2 * -0-ethyl adenosine 0 Prepared analogously to that described in Example 5.

Example 8: 5- [(IR, trans) -2-Hydroxycyclohexyl] -2 '-0-methyl-5-adenosine The compound named in the title is obtained analogously to Example 1 when IR, trans-2-hydroxycyclohexylamine is used in place of trans-4-hydroxy-0-cyclohexylamine. The compound thus obtained named in the title, has the following characteristics: Foam; Rf in ethyl acetate / ethanol 75:25 * 0.42; [] = -69.5 ° (c-1 in dimethylformamide).

The compounds according to the invention have interesting pharmacological properties. They are therefore useful as medicines. For this, the compounds according to the invention can be used as such, such as hydrates or addition products with organic solvents, for example methanol, ethanol or ethyl acetate. The most interesting compound of the formula la is the compound of Example 1 above which is in the following compound named No. 1. The compounds of the formula are of interest as analgesics, as described above. They are also of interest for other activities. Among the other activities, the compounds according to the invention have antihypertensive activity, as indicated by the results of the following investigations. The measurement of the binding to Al and A2 receptors of adenosine in the membranes of the cortex or outer layer of the rat or of the bark or striatum of the pig brain, using the method of R.F. BRUNS, G.H. LU and T.A. PUGSLEY, which is described in MOLEC. PHARMACOL. 29, 331-346 (1986). An additional test of the activity of the compounds is carried out in the kidney of the perfumed rat, isolated, for the following parameters: - secretion of renin renal hemodynamic characteristics.

Inhibition of the release of noradrenaline from the nerve terminals following the electrical stimulation of the renal nerves according to the method of P. M. VANHOUTTE, D. BROWNING, E.COEN, T.J. VERBEUREN.L.ZONNEKEYEN and M.G. COLLIS described in HYPERTENSION 4, 251-256 (1982). 0 ~ The measurement of blood pressure, heart rate, urine production and renin activity in the plasma of spontaneously hypertensive or normotensive rats, full and out of NaCl, awake, with catheters implanted in the abdominal aorta 5 and in the vena cava, following iv administration or the administration of the compounds according to, - * with the invention as an infusion or bolus according to the method of J.F.M.SMITS and J.M.BRODY described in Am.J.Physiol. 247, R1003-R1008 (1984). It is deduced from the results of the examinations that both the inhibition of renin secretion and the release of noradrenaline from the nerve terminals, and direct vasodilation, take part in the antihypertensive activity of the compounds of the formula the. In contrast to the reduction of blood pressure _ / nea, the production of urine and the excretion of electrolytes remained unchanged. From this it follows that the compounds of the formula can not only be used as antihypertensive agents, but also have an effect on coronary vasodilation. In addition, they protect the vascular endothelium by inhibiting both the aggregation of the thrombocytes and the activation of the leukocytes. They also reduce the lipid levels of the blood. For the above indications, of the compounds of the formula la, the compound of Example 1 is preferred. The cardioprotective and analgesic indications are preferred. In addition, the compounds of the formula also are active in the treatment of arrhythmias as indicated by their adenosyl-A receptor agonist activity, which is selective against its activity against the A2 receptor, as established for example in the ) described here afterwards and for example its capacity20 to prolong conduction through the atrioventricular node A-V) of the heart as indicated in test b) described hereinafter. Consequently, they re-establish the sine rhythm in supraventricular tachycardias, particularly supraventricular tachycardia. paroxysmal, reduce cardiac velocity in fibrillation * atrial tachycardic and reverse the ventricular tachycardia induced by fi-adrenergic stimulation at normal rhythm. The compounds of the formula simulate or mimic the "preconditioning" effect, the procedure in which a brief period of ischemia makes the heart resistant to infarction from subsequent ischemia. The same, therefore, are useful to protect the heart / during unstable angina, against myocardial infarction with or without adjunctive thrombolytic therapy, or ischemic lesions in patients suffering (for example) coronary artery bypass graft surgery, angioplasty, cardiac transplantation or non-cardiac surgery. The compounds of the formula la are especially useful for administration to subjects prone to myocardial infarction, for example as a result of diagnosis ^ or those who have already suffered from a myocardial infarction. The compounds of the formula also reduce plasma insulin without influencing glucose tolerance. They enhance the effect of insulin to increase glucose uptake and decrease lipolysis in adipose tissue leading to lower, free plasma fatty acid concentrations (see test d) described hereinafter). Lower plasma free fatty acids, in turn, lead to lower triglycerides, which leads to turn to increased HDL cholesterol. The effect of insulin economy and / or the action of reducing free fatty acids makes the compounds of the formula useful for the treatment of Type I diabetes and type II diabetes ie non-diabetes dependent diabetes. insulin. The compounds of the formula reduce plasma triglycerides and free fatty acids (see test e) hereinafter) and raise HDL cholesterol and, therefore, are useful in the treatment of lipid dysfunction, and the conditions associated with free fatty acids and high triglycerides and where an increase in HDL cholesterol is desirable. The compounds of the formula show good metabolic stability. In another aspect, the invention provides the use of the compounds of the formula la for the treatment of, or in the preparation of, medicaments suitable for the treatment of pain. In another aspect, this invention provides a compound of the formula as defined above for use in the treatment of pain. In a further aspect, this invention provides an analgesic composition comprising a compound of the formula la as defined above in association with a pharmaceutically acceptable carrier or diluent. The present applicants contemplate the use of the compounds of the formula la in the indications described above for the compounds of the formula I. The following pharmacological tests illustrate the aforementioned activity of the compounds of the formula la. a) Affinity towards adenosine receptors Striatal membranes of the pig are prepared as previously described by H. Bruns et al. in Molecular Pharmacology 29 (1986) pages 331-344. 3H-NECA, a non-selective adenosine receptor agonist, is used to label both A. and A- receptors. The values of CI, -0 are derived from the displacement curves by the adjustment of the least squares curve, non-linear, weighted, to the Langmuir equation and the pKD values calculated. The compounds of the formula show affinity towards the A receptor, for example in a range from 1 to 500 nM. / "- b) Arrhythmias Activation of the adenosine A1 receptor reduces the incidence of, for example, supra-ventricular-paroxysmal tachycardia, atrial tachycardic fibrillation, and other arrhythmias by slow conduction through the atrio-ventricular (AV) node of the heart detected by the increments. in the PR interval. The test method involves the recording of ECG changes in Rhesus monkeys adults, conscious. The compounds of the formula la are administered at dosage intervals from about 0.1 mg / kg to about 1000 mg / kg p.o. or 0.03 to 30 mg / kg i.v. in the test referred to by C. Clarke et. to the. in The Pharmaceutical Journal 244, 595-597 (1990). By For example in this test compound No. 1 prolongs the P-R interval of the surface electrocardiogram (ECG), indicating the slow conduction through the AV node at doses of 0.1, 0.3 and 0.6 mg / kg p.o. As noted above, such action leads to the termination of the AV nodal tachycardia and to the reduction of the heart rate in atrial tachycardic fibrillation. c) Protection against infarction by preconditioning 25 Preconditioning (5 minutes of ischemia followed by 10 minutes of recovery) makes the heart very resistant to infarction from subsequent ischemia (30 minutes) and reperfusion (3 hours). This test method is described in the article by G. S. Liu et. to the. 1991 - Circulation (84), 1, 350-356 and J. D. Thsrnton et al., In 1992 - Circulation (85), 659-665. The compounds of the formula la are administered i.v. at a dose from about 0.01 to 10 mg / kg to rabbits. In this test, rabbits are given 100 Ug / kg of compound No. 1 and are protected to almost the same degree as the endogenous preconditioning of the infarction induced by a 30-minute period of coronary occlusion. d) Transport of Glucose and Lipolysis in Rat Adipocytes i) Adipocytes are isolated from the epididymal fat pads of rats fed normal food by digestion with collagenase. Cells (final concentration of 2% v / v) are preincubated with adenosine deaminase (1 U / ml) and with test compounds for example compound No. 1 and other additions as indicated for measuring glucose transport to 37 ° C.

The [3- H] glucose (final concentration, 50 μm, 0.5 ij.i.Ci / ml) is then added after 30 minutes, and the incubation is continued for an additional 60 minutes. The incorporation of radioactivity from the 3 [3- H] glucose in cell lipids (a measure of glucose transport) is evaluated by extracting the suspension from the cells (0.5 ml) with 5 ml of scintillating base toluene, followed by counting of flashes of liquid; metabolites soluble in water and the 3 [3- H] residual glucose remaining in the aqueous phase are not detected. Lipolysis is measured in a conventional manner. In one method the cells are incubated with and without isoprote-renol 1 U- and then the incubation continues for 60 min. The supernatant is separated from the cells after centrifugation through dinonyl phthalate and the lipolysis estimated by the enzymatic determination of the glycerol released in the supernatant. The compounds of the formula are active at concentrations from 0.1 to 1000 nM. Compound No. 1 suppressed lipolysis in rat adipocytes at concentrations from 0.1 to 100 nM. In the presence of adenosine deaminase (1 U / ml), compound No. 1 has no significant effect 3 on the incorporation of radioactivity of [3- H] -glucose into the lipids of cells in the absence of insulin and only a marginal effect in the presence of a maximum stimulation insulin concentration (8 nM), but significantly increases the stimulation of the incorporation of radioactivity in a concentration-dependent manner, at concentrations from 0.1-50 nM insulin. These observations indicate that the compound increases the sensitivity of glucose transport to insulin. In the presence of an almost maximum effective concentration of compound No. 1, the EC--. for insulin stimulation of incorporation 3 of the [3- H] glucose in the lipids is decreased between 2 and 3 times. In the presence of adenosine deaminase and 1 JJ-M of isoproterenol, 10-50 nM of compound No. 1 increase both the sensitivity and the magnitude of the insulin response; EC50 for insulin is reduced up to 5 times and stimulation by a maximum insulin concentration is significa increased. ii) Lipids and Glucose in Rats Subject to Fasting 18 hours, Normal Rats, 2 to 3 months old, weighing almost 250 grams are kept in a quarter to one controlled room temperature of 22 ° C and a cycle of 12/12 hours of light / dark for seven days. Purina rats food and water are available ad libitum. Following an 18-hour fast, the rats (5 / group) are given the test compounds by 0.5% CMC priming. The animals received 1.0 ml / 100 g of body weight. Three hours after the administration, the rats are anesthetized with C02 and the blood is collected by the cardiac puncture route. Sera collected and used for the determination of glucose, free fatty acid and ^ -hydroxybutyrate. Free fatty acids are measured by test or enzyme assay, calorimetric, of acyl-COA peroxidase, glucose is measured by the glucose oxidase method (YSI Model 27, Yellow Spring, Oh) and the fi-hydroxybutyrate is assayed or tested with an assay or test of enzymes linked or linked to the ^ -hydroxybutyrate dehydrogenase (Sigma Kit 310-A-St. Louis, Mo.). The compounds of the formula la are active at a dose of from about 1 to about 5000 lg / g.

Doses for reducing free fatty acids (the primary result of the effect on adipocytes) for compound No. 1 are between 5 and 100 μg / kg at 2 hours post-dose. This leads to a dose-dependent decrease in the levels of -hydroxybutyrate and blood glucose. iii) Effects in the Non-Dependent Diabetic Rats of Insulin (NIDD) In the NIDD selection test, the rats (200-220 g) are fed a diet high in fat ad libitum. In the fed state, 40 mg of streptozocin / kg body weight are injected into the tail vein. A week later, these rats are considered to be diabetic, which they have a blood glucose feed higher than 200 mg / dl and, after an overnight fast, when a tolerance test is applied to the oral glucose, had a blood glucose of 40 to 80 mg / dl three hours after the test. Four days later, the animals are used in the selection, if the glucose levels of The blood fed are greater than 180 mg / dL. Blood glucose is determined with a YSI Glucose Analyzer (YSI Glucose Analyzer). The chronic selection test is carried out as follows: On day 1, the food is removed from the rats at 9:00 a.m .; and after a glucose reading of the initial blood is taken through the tip of the tail, the vehicle (control) or the compound (9 rats / treatment) is administered orally. Six hours later the blood glucose level is measured; and immediately after this the rats are fed back. The same rats are provided with either the vehicle or the drug once a day for 11 consecutive days. The blood glucose is determined at 0 hours and after a dosage after fasting for 6 hours, on days 4, 8, and 11. 100 micrograms kg of a compound of the formula la for example compound No. 1 for 11 days it led to a significant reduction in plasma free fatty acids which results in a significant decrease in blood glucose.

Dyslipideaias characterized by elevated serum triglycerides Several studies have shown a positive correlation between serum triglyceride levels (and a decreased HDL cholesterol level)., associated) and the risk of coronary artery disease of the heart (CHD) (Grundy, in Cholesterol and Atherosclerosis: Diagnosis and Treatment, Lippincott, Philadelphia (1990)). The value of reducing elevated triglyceride levels as an approach to reduce the risk of CHD arose from the Helsinki Heart Study where, following treatment with gemfibrozil, the largest reduction in serious coronary events occurred in hyperlipidaemic patients of type IIB in whom both LDL cholesterol and total serum triglycerides are elevated, and HDL cholesterol levels are generally reduced. The compounds of the formula la are active in the Rhesus monkey at doses from about 0.03 to 30 (for example 0.1 to 30) mg / kg i.v. and 0.1 to 100 (for example 0.1 to 10) mg / kg p.o. Compound No. 1 produces prolonged and dose-related falls in fatty acids Free of plasma and triglycerides in the Rhesus monkey at doses from 0.03-0.6 mg / kg i.v. and 0.1-1.2 mg / kg p.o. Representative results for Compound No. 1 at 0.6 mg / kg p.o. 5 show a reduction of free fatty acids by almost 60% compared to a control after 300 minutes and triglycerides in 40%. The compounds of the formula are also active in the tests for average arterial blood pressure, bradycardia and peripheral vasodilatation in anesthetized rats. The experiments are carried out in male Wistar rats, of body weight of 300-350 g under anesthesia with Pentotal (120 mg / kg i.p.), according to the method of Salzmann et al. (J. Cardiovasc. Pharmacol. 1_2, 451-460, 1988). The catheters are placed in the right jugular veins and / * - right femoral, in the left ventricle (inserted through the right carotid artery), the left femoral artery, and the aorta (inserted through the right femoral artery). The following variables are measured or calculated: systolic, diastolic, and mean arterial blood pressure (mm Hg; femoral artery left, Statham P 23 pressure transducer Gb), pulse pressure (mm Hg), heart rate (beats / minute, activated blood pressure curve), rate of elevation of left ventricular pressure (dP / dt -, max mm Hg / s; Statham pressure P23 Gb), cardiac output (ml / min / 100 g of body weight, thermodilution method, right jugular vein and aorta), total peripheral resistance (dynes s.cm / 100 g of body weight), surface ECG. Arterial blood pressure, left ventricular pressure, dP / dt ma-x, heart rate, and electrocardiogram are continuously recorded with a Schwarzer polygraph. The parameters are measured at 30, 20, 10 and 2 minutes before the administration of the test substance and 1, 5, 10 and 15 minutes after injection of the drug into the right femoral vein. Compounds of the formula are injected at dosing intervals from about 0.001 to about 10 mg / kg of the animal's body weight. Compound No. 1 is produced in cumulative doses of 0.003, 0.010 and 0.03 mg / kg, three animals per dose are used. Compound No. 1 induced failures in blood pressure ~ 49 micrograms / kg iv] and at the speed of the heart and an increase in systematic vascular conductance.

The doses of the compound of the formula used in the above indications will vary in the usual way with the seriousness of the disorders, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, suitable unit doses can be 0.1 to 1000 mg, such as 0.1 to 10, 0.5 to 200, 0.5 to 100, or 0.5 to 10 mg, for example 0.1, 0.5, 1, 2, 3 , 4 or 5 mg; and such unit doses may be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times a day, so that the total daily dosage for a mammal of 70 kg including human beings, is in the range of approximately 0.1 to 1000 rag / kg pe oral and 0.003 to 300 mg iv, which is in the range of about 0.001 to 20 mg / kg / day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5 mg / kg / day, for example 0.01 , 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg / kg / day; and such therapy can be extended for a number of weeks or months. For compound No. 1 the preferred dosage range for all indications of the invention is from 0.1 mg / day to 10 mg / day for a 70 kg adult. For non-insulin dependent diabetes the preferred indication and for hypertriglyceridemia the dose indicated for humans is 0.2 to 2 mg per day per os and for the treatment of heart failure and other cardiac disorders of 0.2 to 10 mg per day in particular 0.5 to 5 mg / day per os or 0.25 to 5 mg iv for arrhythmias for example tachycardic atrial fibrillation. The compounds of the formula can be formulated for administration by any suitable route, the preferred route depends on the disorder for which the treatment is required, and preferably in the unit dosage form or in a form that a human patient can administer to himself in a unit dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration as described above with respect to analgesic use. The unit dose presentation forms for oral administration may be tablets and capsules containing 0.05-20 mg of a compound of the formula la. Suitably, the compounds according to this invention, or a hydrate or an addition product with organic solvents, will comprise from about 0.5 to about 20% by weight of the formulation, preferably from about 1 to about %, for example 2 to 5%. The compounds of the formula wherein R, 'is hydroxy (C, _g) cycloalkyl and R_ is alkyl, are detected as metabolites during the administration of the compounds of the formula I wherein R. is (C, _-) cycloalkyl and R "is alkyl to warm-blooded animals, for example rats, dogs and humans. Accordingly, the administration of compound M led to the production of hydroxycyclohexyl-2'-0-methyl adenosine. In a further aspect, the present invention provides a method for administering N-cyclohexyl-2'-O-methyladenosine to a warm-blooded animal to produce N-hydroxycyclohexyl-2 '-0-methyl adenosine. The present invention provides in another aspect N-hydroxycycloalkyl-2 '-0-alkyl adenosine in the pure form, for example with a purity greater than 95%. The exemplified compounds described herein satisfy this criterion. The present invention provides in a further aspect the free N-hydroxycyclohexyl-2 '-0-alkyl adenosine of cyclohexyl-2' -0-methyl adenosine. In another aspect, the present invention provides a process for the production of 2'-O-alkyladenosines which comprises treating adenosine with a sulfate of suitable alkyl sulfate in the presence of a phase transfer catalyst. Preferably the 2'-alkyl adenosine is any compound defined above. In a further aspect, the present invention provides a process or process for the production of the compounds of the formula I as defined above, which comprises reacting a compound of the formula VI H SAW with a basic solution of a compound of the formula (R3) 2S04 in the presence of tetrabutylammonium acid sulfate and a non-polar solvent and purifying the product by recrystallization. If necessary, the reactive groups can be temporarily protected. Preferably the alkyl sulfate is the di (C,,) alkyl sulfate. Preferably the phase transfer catalyst is the acid sulfate of tetrabutyl ammonium. Preferably the reaction is carried out in a non-polar solvent, for example as described hereinafter. A group of the compounds of formula I is already defined, wherein R. is cycloalkyl with (C-_R), R- is hydrogen or alkyl with (C,,), and R- is alkyl with < Cl-4 > Up to now, the repair of the compounds of formula I typically involved six steps, which include the preparation of 2 ', 3', 5'-triacetylininosine; C loration and hydrolysis to 6-C-9- / -D-ribof u-ranosi l-9H-purine; the protection of the 3 '-0- and 5' -0- positions with tetraisopropy ldisi loxane (TIPDS-CL2); the 2'-0-a lq ui lacidn and puri fi cation by chromatography in Silica gel; the deprotection of the 3 '-0- and 5 * -0- positions; and the reaction with Rj H- and recrystallization to obtain the compound of the formula I. The present applicants have found that the compounds of the formula I can be prepared in good yields and purity without the need for protection and deprotection of the compound. '-0- and 5' -0-disiloxane or for chromatography on silica gel. Applicants have found that the starting material of inosine-2 ', 3', 5'-triacetate from the prior art process can be advantageously replaced with lipophilic inosin-2 ', 3', 5 '-tripropionate , which allows to double the yield and the elimination of the undesirable pyridine solvent. In the present invention the compounds of the formula I are prepared under conditions of phase transfer catalysis according to the following reaction scheme.

Vile where R, R, and R are as defined above. The compounds of the formula I can be prepared by reacting a basic aqueous solution of a compound of the formula (VI) with a di- (C) sulfate.,) alkyl in the presence of an acid tetrabutylammonium sulfate and a water-immiscible, organic solvent. The base used to prepare the basic aqueous solution is preferably an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide. The solvent can be any solvent immiscible or essentially immiscible with water, in which the compound of formula I is soluble, such as methylene dichloride or t-amyl alcohol. It is also preferred that the reaction be run at temperatures between about -20 ° C to about 50 ° C, in particular, room temperature. The reaction time is not critical, but preferably it is carried out for a period from about 5 to 10 hours, especially in about 7 to 8 hours. The crude compound of formula I is isolated by evaporation followed by stirring with a 1: 1 mixture of water and an inert solvent, preferably toluene, at room temperature for 5 to 7 hours, then filtration and drying. The pure compound can be obtained by fractional crystallization, preferably by: l) recrystallization from an inert solvent, such as toluene, dissolving the crude compound in the solvent at 80 ° C, heating at about 55 ° C for about 1 hour, cooling to room temperature, sowing with the pure compound and filtering; 2) repeating the recrystallization procedure of step 1 but heating to about 65 ° C before cooling to room temperature; and 3) recrystallization from 100% ethyl alcohol by dissolving at reflux, diluting with water, seeding, then filtering and drying. Many of the compounds of the formula VI are already known and can be prepared by methods described in the literature such as the aforementioned USP 4,843,066 and USP 4,985,409. The compound of the formula VI can also be advantageously prepared, as indicated above, according to the following preferred reaction scheme: Vil VIII IX where R, and R- are as defined above.

The compounds of the formula VI can be prepared by acylating the inosine of the formula VII with the propionic anhydride to form the 2'-0-, 3'-0-, 5'-0-pro-tected compound of the formula VIII; halogenating the compound of the formula VIII with thionyl chloride to form the intermediate compound of the formula IX; and simultaneously aminating and hydrolyzing the compound of the formula IX. The acylation of inosine is preferably carried out in a mixture of toluene, tributylamine, and 4-dimethylaminopyridine at a temperature of from 100 ° to 110 ° C for a period of 4 to 5 hours. The compound of formula VIII is isolated by precipitation with heptane. Halogenation of the compound of formula VIII is preferably carried out in a mixture of toluene and N, N-dimethylformamide at a temperature of from about 60 ° to 70 ° C for a period of 3 to 4 hours, and the solution of the compound of Formula IX can be used after washing with water and brine. The amine and the hydrolysis of the intermediate compound of the formula IX simultaneously is preferably effected by adding the amine R.NH2 and reacting it at a temperature of from 100 ° to 110 ° C for a period of 15 to 20 hours. The compound of formula VI is isolated by filtration at room temperature and purified by recrystallization. The process or process of this invention is illustrated by the following examples Example of Process 1 N-cyclohexyl 1-2 '-O-methyladenosine Step A. Inosin-2 ', 3', 5 '-tripropionate A mixture of 271.2 g of inosine, 966 ml of tributylamine, 3.30 g of 4-dimethylaminopyridine and 600 ml of toluene is heated to an internal temperature of 104- 105 ° C; and for a period of 35 minutes, 453 ml of propionic anhydride are added at a rate which maintains the internal temperature between 104-105 ° C. After stirring the mixture at this temperature for an additional 4 hours, the mixture is cooled to 5-10 ° C with an ice bath; and 1000 ml of heptane are added. The resulting suspension is stirred at room temperature (20-22 ° C) for 30 minutes and then filtered, for example, on a Buchner funnel. The solids are washed with a total of 450 ml of heptane in three equal portions of 150 ml each and dried at 45-50 ° C (25 mm Hg) overnight (14 hours) to give 425.9 g of inosin-2 ', 3', 5 '-tripropionate as a white solid. (P.F. 171-172 ° C, 96.5% yield).

Step B. N-cyclohexyl adenosine A mixture of 270.6 g of inosin-2 ', 3', 5 '-tripropionate, 240 ml of N, N-dimethylformamide and 600 ml of toluene is heated to 65 ° C; and for a period of 1 hour, 67.84 ml of thionyl chloride are added at a rate which maintains the internal temperature between 62-65 ° C. The mixture is stirred at this temperature for an additional 2.5 hours and then cooled to 10 ° C with an ice bath. After the addition of 600 ml of pre-cooled water at 10-15 ° C in an ice bath at a rate which keeps the temperature below 20 ° C, the organic layer is separated and washed with a total of 800 ml of 10% aqueous sodium chloride in four equal portions of 200 ml each. The organic layer containing 6-chloro-9- (2, 3, 5-tri-0-propionyl-fi-ribofuranosyl) -9H-purine is added with stirring to 620 ml of cyclohexylamine heated at 105 ° C for a period of 2 hours at a rate which maintains the internal temperature at 105 ° C. After this mixture is stirred at this temperature for an additional 17 hours, it is cooled to room temperature (25 ° C) for about 2 hours with efficient agitation and then filtered for example in a Buchner funnel. with suction. The solid containing N-cyclohexyl adenosine and cyclohexylamine hydrochloride > - "is washed with a total of 460 ml of toluene in four equal portions of 115 ml each and is transferred wet to a 5 liter vessel equipped with a mechanical stirrer, after the addition of 2 liters of a bicarbonate solution. 5 saturated sodium bonate, aqueous, and 2.5 liters of ethyl acetate, the mixture is stirred until all the solid is dissolved (approximately 10-15 minutes), the organic layer is separated, and the aqueous layer is extracted with 1.5 liters. of r "ethyl acetate in two 1 liter and 500 ml portions, respectively. The organic layers are combined and evaporated until approximately 3 liters of ethyl acetate is removed or removed (at 40 ° C, 100-200 mbar). To the residue, 500 ml of heptane are added; and the resulting mixture shake for 30 minutes. The solids are separated on a Buchner funnel, and washed with a total of 300 ml r * of heptane in three equal portions of 100 ml each. The solids are then dried at 45-50 ° C (30-35 mbar) for about 3 hours to give 148 g of the crude N-cyclohexyl-20 adenosine as a white solid. These are transferred to a 1 liter round bottom vessel equipped with a mechanical stirrer, and 175 ml of 95% ethanol are added. The suspension is stirred for 15-20 minutes and 175 ml of tert-butyl ethyl ether are added. After stirring for 5 minutes, the suspension is cooled in an ice bath and stirred for an additional 15 minutes. This suspension is filtered on a Buchner funnel and washed with a total of 50 ml of tert-butyl methyl ether in two equal portions of 25 ml each. The filtered solids are dried at 45-50 ° C (30-35 mbar) for 14 hours to give 130 g of N-cyclohexyl adenosine as a white solid (mp 185-187 ° C, yield 60.0%).

Step C. N-cyclohexyl-2 '-0-raethyladenosine A suspension of 94.33 g of the N-cyclohexyl-nosine and 720 g of 5% aqueous sodium hydroxide is stirred at room temperature (24-25 ° C) until all the solids are dissolved (approximately 5 minutes). Using an addition funnel, 850 ml of dichloromethane and 5.5 g of tetrabutylammonium acid sulfate are added followed by 61.3 g of dimethyl sulfate for 5-10 minutes, while maintaining the internal temperature between 24-25 ° C. The addition funnel is washed with an additional 50 ml of dichloromethane which is added to the reaction vessel. After stirring the biphasic mixture at 24-25 ° C (internal temperature) for 7.5 hours the organic layer is separated and evaporated at 40 ° C (270-290 mbar) until no additional solvent is distilled. The residue is dissolved in 200 ml of toluene and evaporated at 45-50 ° C (30 mm Hg) until again no additional solvent is distilled. A mixture of the crude material mentioned above and 2470 ml of toluene is stirred at room temperature for 10 minutes and then 2470 ml of water are added over a period of 22 minutes. The resulting suspension is stirred at room temperature for an additional 6 hours and the solids are collected by filtration for example on a Buchner funnel with suction. After washing the solids with 114 ml of toluene and a total of 285 ml of water in three equal portions of 95 ml each, the solids are dried at 48-50 ° C (25 mm Hg) overnight (14 hours) to give 53.0 g of a white solid. A suspension of this solid in 397 ml of toluene is heated at 80 ° C with stirring to form a clear solution, which is cooled at 56 ° C for 45 minutes and seeded with 10 mg of pure product. The mixture is stirred at 55-56 ° C for 45 minutes and then cooled to room temperature for 1 hour. After stirring at this temperature for an additional 1 hour, the solids are collected by filtration, for example, on a Buchner funnel with suction. The solids are washed with a total of 75 ml of toluene in three equal portions of 25 ml each to give 60 g of a white solid. A suspension of this solid in 159 ml of toluene is again heated to 80 ° C, and the above sowing procedure is carried out in the range of 65 ° to 66 ° C.

After cooling to room temperature for 1 hour and stirring at the same temperature for an additional 1 hour, the solids are filtered and washed with 42 ml of toluene in three equal portions of 14 ml each and dried at 48-50 ° C ( 25 mm Hg) overnight (14 hours) to give 57.7 g of a white solid. The solid and 122 ml of 100% ethanol are heated to reflux with stirring to obtain a clear solution, and 288 ml of precalendated water at 55 ° C are added for 25 minutes. The mixture is cooled to 55 ° C and seeded with 20 mg of the pure product. The mixture is cooled to room temperature for 1 hour and stirred at this temperature overnight (16 hours). The solids are collected by filtration on a Buchner funnel with suction and washed with a total of 57 ml of a 1: 2.36 (v / v) mixture of 100% ethanol and water in three equal portions of 19 ml each. The solids are dried at room temperature (29 mm Hg) to give 62.2 g of the product as a white solid in the form of hydrate 1.5 (mp 88 ° -91 ° C, yield 42.5%).

Example of Process 2: Following the above procedure but using an equivalent amount of N-cyclopentyladenosine, the N-cyclopentyl-2'-0-methyl adenosine is obtained.

Process Example 3 The process steps of Example 1 are followed except that the dichloromethane in step C) is replaced by the ter-amyl alcohol, and subsequent to crystallization with initial ethanol / water, the product is recrystallized from ethanol and Water. 32.1 g (yield of about 30%) of N-cyclohexyl-2 '-0 - "*" methyladenosine with a purity in excess of 98% are obtained. The process or process of this invention is more economical in terms of time and cost than the processes known up to now. The process provides a convenient method for the selective 2'-0-methylation of N-cyclohexyl adenosine under transfer conditions. phase, and a purification method of the 2'-0-methyl derivative. Expensive protective groups and the use of chromatography are avoided.

It is noted that in relation to this date The best method known to the applicant for carrying out the said invention is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following

Claims (20)

R E I V I N D I C A C I O N S
1. The use of a compound of the formula I is hydrogen, alkyl with (C.), allyl; metalyl; an alkynyl with branched or straight chain (C-, 7), cycloalkyl with (C ~ g), hydroxy (C, ") cycloalkyl, phenyl which is monosubstituted, or independently of each other, disubstituted by halogen with a atomic number from 9 to 35, alkyl with (C,,), alkoxy with (C.,), or CF ,; or phenyl (C.) alkyl wherein the phenyl ring is unsubstituted or monosubstituted, or independently of each other, disubstituted by halogen with an atomic number from 9 to 35, alkyl with (Cj_ ^), alkoxy with (C,,), or CF-; alkyl with (C,,) having at least one hydroxy group or at least two phenyl groups, a bicycloalkyl such as endo- or exo-bicyclo- [2, 2, 1] heptyl, a naphthyl (C1_,) alkylaryl group, an acenaphthylene group (C, _,) alkyl or a group of the formula A or B where is hydrogen, a hydroxy group or a group (C.,) alkoxy Q is hydrogen or hydroxy, A is -CH2-, -0-, -S- or a direct bond, Y is - (CH, ¿,) m- or a direct link, is an integer from 1 to 3 and the line interrupted in (A) represents an optional link, , ** K, is hydrogen, alkyl with (C,,), amino, cycloalkyl with (C-1) or halogen with an atomic number of 9 to 35 and is alkyl with C,,) as an analgesic product in the production of a suitable medication for the treatment of pain.
2. 2. The use according to claim 1, wherein the compound of the formula I is selected from the 6'-hydroxy (C, fi) cycloalkyl-2'-O-methyladenosines.
3. The use in accordance with the claim 1, wherein R. is different from hydroxycycloalkyl.
4. 4. The use according to claim 3, wherein the compound of formula I is 6-cyclohexyl-2 '-0-methyl-adenosine.
5. 5. The use according to any preceding claim for acute pain.
6. 6. The use according to any preceding claim for chronic neuropathic pain. 5
7. 7. The use of a compound as defined in any preceding claim in the treatment of pain as defined in any preceding claim, or a method for the treatment of pain as defined in any preceding claim, characterized in that it comprises administering a compound such as in any preceding claim was defined a subject in need of such treatment, or an analgesic composition comprising a compound as defined in any preceding claim as an analgesic in association with a pharmaceutical carrier or diluent.
8. 8. A compound of the formula characterized because R., 'means cycloalkyl with (CA 4 _-? 8)' substituted by a hydroxy group and R- is as defined in claim 1 R .. is as defined in claim 1.
9. 9. A compound according to claim 10, characterized in that R 2 is hydrogen, alkyl with (C,) or halogen of an atomic number from 9 to 35.
10. 10. A compound, characterized in that it is selected from: 6- [(trans) -4-hydroxycyclohexyl] -2 '-0-methyl adenosine 6 - [(cis) -4-hydroxycyclohexyl] -2'-0-methyl adenosine 6- [ (lS, trans) -2-hydroxycyclopentyl] -2 '-0-methyl adenosine 6 - [(IR, trans) -2-hydroxycyclopentyl] -2' -0-methyl adenosine 6 - [(lS, trans) -2- hydroxycyclohexyl] -2 '-0-methyl adenosine 6- [(IR, trans) -2-hydroxycyclohexyl] -2' -0-methyl adenosine 6 - [(trans) -4-hydroxycyclohexyl] -2 '-0-ethyl adeno -sin, and 6 - [(lS, (trans) -2-hydroxycyclohexyl] -2'-0-ethyl adenosine.
11. 11. A compound according to claim 8, claim 9 or claim 10, characterized in that it has a purity of 95%.
12. 12. A compound according to claim 8, claim 9 or claim 10, characterized in that it is free of N-cycloalkyl-2 '-0-methyl-adenosine.
13. 13. The use of the compounds of the formula la as defined in any of claims 8 to 12 for the preparation of suitable medicaments for the treatment of pain, for use against high blood pressure, as coronary vasodilators, for the inhibition of both thrombocyte aggregation or activation of leukocytes, to lower blood lipid levels, against congestive heart failure, infarction to the myocardium, sudden cardiac death, renal failure, in addition to the treatment of hypertriglyceridemia / low HDL cholesterol levels, lipid dysfunction, elevated free fatty acids and / or type I diabetes and type II diabetes, arrhythmias or for protection against myocardial infarction.
14. 14. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of the compounds of the formula la as defined in any of claims 8 to 12 in association with a pharmaceutically acceptable carrier or diluent.
15. 15. A compound according to any of claims 8 to 12, for use in the treatment of pain, high blood pressure, coronary vasoconstriction, aggregation of thrombocytes, elevated blood lipid levels, congestive heart failure , sudden cardiac death, hypertriglyceridemia / low HDL cholesterol levels, lipid dysfunction, high fatty acids or type I or type II diabetes, arrhythmias and for protection against myocardial infarction, or a method to use such a compound which is characterized in that it comprises administering a compound of the formula la to a subject in need of such treatment.
16. 16. A process for the production of 2'-0-alkylanosines, characterized in that it comprises treating the adenosine with an appropriate alkyl sulfate in the presence of a phase transfer catalyst.
17. 17. A process according to claim 16, characterized in that it is used for the production of a compound of the formula I as defined in claim 1.
18. 18. A process according to claim 16 or claim 17, characterized in that the compound produced is N-cyclohexyl-2'-O-methyladenosine.
19. 19. A compound, characterized in that it is produced by the process of claim 16, claim 17, or claim 18.
20. 20. A method for administering N-cyclohexyl-2'-0-methyl adenosine to a warm-blooded animal to produce N-hydroxycyclohexyl-2-0 '-methyl adenosine.