PROCESS FOR PREPARING 2 -0- ALKYL ADENOSINE DERIVATIVES

Abstract: Compounds of formula (I), wherein R1 is one of a number of significances, including cycloalkyl and hydroxycycloalkyl; R2 is hydrogen, (C1-4)alkyl, amino, (C3-5)cycloalkyl or halogen with an atomic number of 9 to 35, and R3 is (C1-4)alkyl, are useful as analgesic agents. Compounds of formula (I) wherein R1 is hydroxy alkyl are new. The compounds of formula (I) may be produced by alkylation in the 2' position in the presence of tetrabutylammonium hydrogen sulfate and a non-polar solvent.

Description: ADENOSINE DERIVATIVES This invention relates to adenosine derivatives, and in particular, provides a new use of A1 receptor agonists. In particular the present invention relates to a new use of compounds of formula (I): wherein R 1 is hydrogen, (C^alkyl, allyl; methallyl; a straight-chain or branched (C^alkinyl, (C^cycloalkyl, hydroxy(C 4 ^)cycloalkyl, phenyl being mono-, or independently of each other di-substituted by halogen with an atomic number of 9 to 35, (C^alkyl, (C^alkoxy or CF 3 ; or phenyl(C 1 _ 4 )alkyl wherein the phenyl ring is unsubstituted or mono- or independently of each other di- substituted by halogen with an atomic number of 9 to 35, (C^alkyl, (C^) alkoxy or CF 3 ; (C^alkyl 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 (C 1 alkyl-group, an acenapthylenyl (C^alkyl-group or a group of formula A or formula B wherein Z is hydrogen, a hydroxy group or a (C 1 _ 4 )alkoxy group Q is hydrogen or hydroxy, A is -CH 2 -, -0-, -S- or a direct bond, Y is -(CH 2 ) n - or a direct bond, n is a whole number from 1 to 3 and the broken line in formula A represents an optional bond, R 2 is hydrogen, (C 1w ,)alkyl, amino, (C^cycloalkyl or halogen with an atomic number of 9 to 35 and R 3 is (C^)alkyl. Some of these compounds e.g. those wherein R. is other than hydroxy cycloalkyl are known and disclosed, for example, in published British Patent Application 2226 027 A and European Patent Applications EP-0-378 518 and EP-0-269 574, and USP 4,843, 066 and 4,985,049. In the formulae described herein the 2', 3', 4 1 and 5' substituents of the tetrahydrofuran ring have the configuration as in adenosine. In one group of compounds under formula I, R 1 is other than hydroxycycloalkyl. In another group of compounds under formula I, R. is hydroxy(C 4-8 )cycloalkyl. Preferably the compound of formula I is of 6-cyclohexyl-2'-0-methyl-adenosine, 5 hereinafter referred to as Compound M. Typically the A, adenosine activity in the preferred compounds of formula I may be determined as follows:- 0 Affinity for adenosine receptors Pig striatal membranes are prepared as previously described by H. Bruns et al. in Molecular Pharmacology 29 (1986) pages 331-344. 3 H-NECA, a non-selective adenosine receptor agonist is used to label both A. and 5 A 2 receptors. IC 50 values are derived from the displacement curves by weighted non-linear least-square curve fitting to the Langmuir equation and pK D values calculated. Table: Affinity of adenosine receptor ligands for A. and A 2 receptors (K D ;nM) (K D ;nM) selectivity n CPA 0.74 ± 0.08 930 ± 110 1260 6 5 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 2 0 0 CPA = Cyclopentyladenosine CV 1808 = 2-Phenylaminoadenosine (Carbohydrates vol. 81 1974) ref. 91898 K) CGS 21680 = 2-[p-(2-Carboxyethyl)phenethylamino]-5'-N-ethyl carboxamido-adenosine (FASEB J, 1989, 3 (4) Refs. 4770/3) In agreement with the literature, CPA proves to be a potent and highly selective displacer of binding to the A. receptor, CV 1808 is a relatively weak but selective A 2 receptor ligand and CGS 21680 shows high potency and selectivity for the A 2 receptor. Compound M in the form of its 1.5 hydrate shows good affinity and high selectivity for the A 1 receptor vis a vis the A2 receptor. The known compounds of the formula I are known as antihypertensive agents and coronary vasodilators. Furthermore it is known that the compounds of formula I protect the vascular endothelium by inhibiting both thrombocyte aggregation and activation of leucocytes. They also lower the blood lipid levels. Further, compounds of formula I have a protective effect against diseases caused by hypertension such as congestive heart failure, myocardial infarction or sudden cardiac death and renal insufficiency (see Europ. Pat. Appl. EP-0-378 518 and EP-0-269 574). These compounds are also known for the treatment of neurodegeneration disorders, peripheral neuropathies such as diabetic neuropathy and of disorders associated with peripheral vascular diseases and/or disorders associated with neuronal degeneration, hypertriglyceridemia/low HDL cholesterol levels, lipid dysfunction, elevated free fatty acids or type I or type II diabetes including non-insulin dependent diabetes, arrhythmias in particular paroxysmal supraventricular tachycardia and tachycardiac atrial fibrillation and for protection against myocardial infarction. The present Applicants have found that the compounds of formula I are particularly interesting analgesics, for example for the treatment of pain, e.g. acute or chronic pain. The analgesic activity of the compounds of the formula I are indicated by their analgesic activity in standard animal tests, e.g. inflammatory and neuropathic models e.g. in reducing persistent inflammatory mechanical hyperanalgesia [(tests a) and b)] and persistent neuropathic thermal hyperalgesia [test c)] indicative of chronic neuropathic pain. Inflammatory hyperalgesia Test a) Freund's adjuvant-induced hyperalgesia Rats are injected intra-articularly in one knee joint with Freund's complete adjuvant (100 microlitres). The load that the rat will tolerate on that leg decreases and remains depressed for up to 5 days. This effect is indicative of mechanical hyperalgesia, and is responsive to NSAID's and opiates. The compounds of the formula I are administered by injection and preferably orally at doses of from about 3 to 60 microgram/kg animal body weight. The increased load tolerated on the injected side is measured to determine the reversal of hyperalgesia. Compound M shows particularly interesting activity on p.o. administration from about 3 to about 60 microgram/kg with a duration of action of about 1 hour. There is no significant difference in response between the doses of 3, 30 and 60 microgram/kg suggesting that the maximum effect had been reached in the range 3 to 30 microgram/kg. Test b) Turpentine-induced mechanical hyperalgesia A local intra-plantar injection of turpentine/paraffin in rat paw (left hind) results in a local inflammatory response and a reduction in the withdrawal threshold (cut-off threshold 340 g) for a mechanical stimulus (paw pressure). The compounds of formula I are active at doses from about 1 to 100 microgram/kg p.o. or s.c. administered three days after the injection, further threshold readings being taken 1 and 3 hours later. Compound M shows significant activity at doses of 30 and 60 microgram/kg orally, with the maximum effect at 30 microgram/kg. Morphine has an ED 50 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. 205-218) Unilateral partial ligation of the sciatic nerve eliminates fibres throughout the innervation of a paw of a rat. The rats develop hyperalgesia to mechanical and thermal stimuli and allodynia of the partially denervated paw 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 planter surface of a paw. Latency to paw withdrawal is measured. The compounds of the formula I are active at doses from about 1 to about 100 microgram/kg injection (s.c. or preferably orally), administered 12 to 15 days after nerve ligation. Compound M is particularly active against thermal hyperalgesia. Compound M shows significant activity at doses of 30 and 60 microgram/kg, with the maximum effect at 30 microgram/kg. The ED 50 is around 60 microgram /kg p.o. Morphine has an ED 50 of around 3 mg/kg in this test when administered subcutaneously. Clinical trials Clinical trials may be effected as follows:- Subjects suffering from pain, post-operative pain or post herpetic neuralgesia, are administered with compounds of the formula I, especially compound M, i.v. at a dose of from 0.02 to 5 mg. The alleviation of pain is noted. The compounds of the invention are therefore useful as analgesics, e.g. against acute or chronic pain, e.g. chronic neuropathic 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 medicament suitable for the treatment of pain. In another aspect, this invention provides a compound of 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 (e.g. post operative pain, burn pain, injuries, etc.) chronic inflammatory pain (e.g. arthritis) and chronic neuropathic pain (e.g. diabetic neuropathy, post- herpetic neuralgia, multiple sclerosis, causalgia, etc.). The doses of the compound used in the uses of the invention indicated above will, of course, vary depending with 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 in animals are indicated to be obtained at 3 daily doses from about 1 to about 100 microgram/kg animal body weight, e.g. 3 to 60 , such as 10 to 60, microgram/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 per day. In test a) above, the NSAID ibuprofen has an ED 50 of about 4 mg/kg p.o. and indomethacin 13 mg/kg p.o.. Compound M is about 300 times more active. For compound M the preferred dose range is from about 0.1 mg/day to about 10 mg/day, e.g. 3 - 30 microgram/kg for a 70 kg adult, depending on the severity of the indication(s) and frequency of administration. Compound M has been shown to have no serious adverse effects in man after single doses 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 may be formulated for administration by any suitable route, the preferred route depending upon the disorder for which treatment is required, and preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. The compositions of the invention may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions. Topical formulations are also envisaged where appropriate. In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose. Unit dose presentation 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 agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol, or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, cross-linked polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate. The solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. Oral 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, hydroxyethylcelluiose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible 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 esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents. Examples for solid oral compositions, e.g. tablets and capsules, are as follows: The tablets are compressed from the capsule granulation of the corresponding dose strength. Size #3, yellow capsules are used for the encapsulation of compound M, and the respective formulation for the 0.1 and 5 mg dose strengths are shown below. 0.1 mα Tab/Cap 5.0 mα Tab/Cap Compound M 0.1 5.0 Microcrystalline Cellulose 76.92 74.96 Lactose, hydrous 87.63 * 84.69 * Polyvinylpyrrolidine 7.4 7.4 Crospovidone 7.4 7.4 Magnesium Stearate 0.925 0.925 Moisture Retained 4.625 4.625 Size Three Capsule 50 50 Theoretical Capsule Fill Weight or Tablet Weight 185 185 Theoretical Capsule Weight 235 235 * The amount of lactose is adjusted to compensate for the amount of moisture in the drug substance. The compounds may also be administered in the form of a sustained release form, in order to provide a prolonged duration of action. Conventional drug delivery systems may be used to provide sustained release, for example, coated pellets or push-pull osmotic systems. For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in polyethyleneglycol or ethanol and diluted with water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate 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. Compounds M of the invention, or a hydrate or an addition product with other solvents or salts thereof, may also be administered as a topical formulation in combination with conventional topical excipients. Topical formulations may be presented as, for instance, ointments, creams or lotions, impregnated dressings, gels, gel sticks, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The formulations may contain compatible conventional carriers, such as cream of ointment bases and ethanol or oleyl alcohol for lotions. Suitable cream, lotion, gel, ointment, spray or aerosol formulations that may be used for compounds of 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 described in standard text books of pharmaceutics and cosmetics, 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 formula la wherein R.' is (C 4 ^)cycloalkyl substituted by a hydroxy group, R 2 is as defined above or preferably hydrogen, (C^alkyl or halogen with an atomic number of 9 to 35, and R, is as defined above. Compounds of formula la can exist in form of enantiomers or diastereomeric mixtures. In formula la, halogen with an atomic number of 9 to 35 is fluorine, chlorine or bromine; (C. alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert.-butyl, especially methyl; and (C 4 _ β )cycloalkyl is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cycloctyl, especially cyclohexyl or cyclopentyl. The compounds of formula la may be prepared by a process characterised in that compounds of formula Ha wherein R 2 and R 3 possess the significances given above and X is chlorine or bromine, are reacted with a compound of formula Ilia R/-NH 2 Ilia wherein R.' possesses the significances given above. The above process is conveniently effected by heating a compound of formula Ha together with a compound of formula Ilia in the presence of a solvent such as dioxane to a temperature of between about 80°C to and 120°C, preferably to boiling temperature. In the compounds of formula Ha, which are used as starting compounds in this process, X is especially chlorine. The compounds of formula Ha, as well as a process for the production thereof, are described in published European Patent Application 269 574. A further process for preparation of compounds of formula la comprises treating compounds of formula IVa wherein R , R 2 and R 3 possess the significances given above with tetrabutylammonium fluoride trihydrate. The above reaction may be performed in an organic solvent e.g. tetrahydrofuran at room temperature under stirring. Compounds of formula IVa can be obtained by treatment of compounds of formula Ha with 1 ,3-dichloro-1 ,1 ,3,3-tetraisopropyl- disiloxane in an alkaline solvent e.g. pyridine, and reacting the so obtained compounds of formula Va wherein X, R 2 and R 3 have the significances given above with compounds of formula Ilia. In the following Examples 1 to 8, all temperatures are in degrees Celsius and are uncorrected. Example 1 : 6-[(trans)-4-Hydroxycyclohexyl]-2'-0-methyl adenosine 1 g of 6-[(trans)-4-hydroxycyclohexyl]-9-purinyl-2'-0-methyl-3\5'-0-(1 ,1 ,3,3-tetraiso- propyldisilox-1 ,3-diyl)-D-ribose is stirred during 15 minutes at room temperature with 2 g of tetrabutyl ammonium fluoride trihydrate 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 crystallised from methanol/ethyl acetate. The title compound crystallises with one equivalent of methanol and has a melting point of 121-124°C. [α] D 20 = -50.2° (c = 1 in dimethylformamide) The compound may also be recrystallized from ethanol and crystallises with one equivalent of water after standing in moist air. Melting point: 114-117°. [α] D 20 = -46.9° (c = 1 dimethylformamide). The 6-[(trans)-4-hydroxycyclohexyl]-9-purinyl-2'-0-methyl-3',5'-0-(1 ,1 ,3,3-tetraiso- propyl- disilox-1 ,3-diyl-)-D- ribose used in the above process as starting material may be produced as follows: 2gof6-chloro-9-purinyl-2 , -0-methyl-3 , ,5'-0-(1 ,1 ,3,3-tetraisopropyldisilox-1 ,3-diyl)-D- ribose are stirred together with 1.32 g of trans-4-hydroxycyclohexylamine and 1 ,4 ml of N-ethyl-diisopropylamine in 80 ml of dioxane during 6 hours in an oil bath of 105°C. The mixture is subsequently cooled to room temperature, filtered and the filtrate concentrated to dryness. For purification the so obtained mixture is eluted on silica gel, first with a mixture of hexane/ethyl acetate 7:3 and then with a mixture of ethyl acetate/methanol 95:5. The so purified oily compound has a R, value of 0,3 (from ethyl acetate / methanol 95:5). Example 2: 6-[(cis)-4-Hydroxycyclohexyl]-2'-0-methyl adenosine The compound named in the title is obtained analogously to example 1 when cis-4- hydroxycyclohexylamine is used instead of trans-4-hydroxycyclohexylamine. The so obtained compound named in the title crystallises with a half of an equivalent of ethyl acetate and has a melting point of 110-111°C. [α] D 20 = -48,6° (c = 1 in dimethylformamide). Example 3: 6-[M S,trans)-2-Hydroxycyclopentyl]-2'-0-methyl adenosine The compound named in the title is obtained analogously to example 1 when 1S, trans-2-hydroxycyclopentylamine is used instead of trans-4- hydroxycyclohexylamine. The so obtained compound named in the title has the following characteristics: Foam, R { in ethylacetate/ethanol 75:25 = 0,44, [α] D 20 = - 25,5° (c = 1 in dimethylformamide) Example 4: 6-[(1 R,trans)-2-Hydroxycyclopentyl]-2'-0-methyl adenosine The compound named in the title is obtained analogously to example 1 when 1 R, trans-2-hydroxycyclopentylamine is used instead of trans-4- hydroxycyclohexylamine. The so obtained compound has the following characteristics: Melting point: 164-166°, R f in ethylacetate/ethanol, 75:25 = 0,44, [α] D 20 = -80,2° (c =1 in dimethylformamide). Example 5: 6-[(1 S,trans)-2-Hydroxycyclohexyl]-2'-0-methyl adenosine The compound named in the title is obtained analogously to example 1 when 1S, trans-2-hydroxycyclohexylamine is used instead of trans-4-hydroxycyclohexylamine. The so obtained compound named in the title has the following characteristics: Foam, R, in ethylacetate / Ethanol 75:25 = 0,42; [α] D 20 = -26.2° (c = 1 in dimethylformamide). Example 6: 6-[(trans)-4-hydroxycyclohexyl]-2'-0-ethyl adenosine Prepared analogously to Example 5. Obtained as 0.4 hydrate M.pt. 98°C (liquefies). [α] D 20 = - 58° (c = 1 in dimethyl formamide). Example 7: 6-[1S,(trans)-2-hydroxycyclohexyl]-2'-0-ethyl adenosine Prepared analogously to that described in Example 5. Example 8: 6-[(1 R,trans)-2-Hydroxycyclohexyl]-2'-0-methyl adenosine The compound named in the title is obtained analogously to example 1 when 1 R, trans-2-hydroxycyclohexylamine is used instead of trans-4-hydroxycyclohexylamine. The so obtained compound named in the title has the following characteristics: Foam; R, in ethylacetate/ethanol 75:25 = 0.42; [α] D 20 = -69.5° (c = 1 in dimethylformamide). The compounds according to the invention have interesting pharmacological properties. They are therefore useful as medicaments. For this, compounds according to the invention can be used as such, as hydrates or addition products with organic solvents e.g. methanol, ethanol or ethyl acetate. The most interesting compound of formula la is the compound of Example 1 above which is in the following named compound No. 1. The compounds of formula la are of interest as analgesic as described above. They are also of interest for other activities. Among other activities, the compounds according to the invention have anti-hypertensive activity, as indicated from the results of the following investigations: Measurement of the binding to adenosine A1 and A2 receptors in membranes from the rat's cortex or from the cortex or striatum of the pig's 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). Further testing of the activity of the compounds is effected in the isolated, perfused rat's kidney for the following parameters: - renin secretion - renal haemodynamics - Inhibition of the release of noradrenaline from the nerve endings following electro-stimulation of the renal nerves according to the method of P. M. VANHOUTTE,D.BROWNING,E.COEN,T.J.VERBEUREN,LZONNEKEYEN and M. G. COLLIS described in HYPERTENSION 4, 251-256 (1982). - Measurement of blood pressure, heart rate, urine production and renin activity in plasma of wake, NaCI-depleted and repleted, normotensive or spontaneously hypertensive rats with catheters implanted in the abdominal aorta and in the vena cava, following i.v. administration or administration of the compounds according to 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 of release of noradrenaline from nerve endings, and the direct vasodilation, take part in the anti-hypertensive activity of the compounds of formula la. In contrast to the lowering of the blood pressure, urine production and electrolyte excretion remain unchanged. It results from this that the compounds of formula la can not only be used as antihypertensive agents, but also effect coronary vasodilation. Furthermore, they protect the vascular endothelium by inhibiting both thrombocyte aggregation and activation of leucocytes. They also lower blood lipid levels. For the above indications, of the compounds of formula la, the compound of Example 1 is preferred. The cardioprotective and analgesic indications are preferred. Furthermore the compounds of formula la are also active in the treatment of arrhythmias as indicated by their adenosine A receptor agonist activity, which is selective via-a-vis their activity against the A2 receptor, as stated e.g. in test a) described hereinafter and for example their capability to prolong conduction through the atrio-ventricular (A-V)node of the heart as indicated in test b) described hereinafter. Thus, they restore sinus rhythm in supraventricular tachycardias, in particular paroxysmal supraventricular tachycardia, reduce cardiac rate in tachycardic atrial fibrilation and return ventricular tachycardias induced by β-adrenergic stimulation to normal rhythm. The compounds of formula la mimic the effect of "preconditioning", the procedure wherein a brief period of ischaemia renders the heart resistant to infarction from subsequent ischaemia. They are, therefore, useful to protect the heart during unstable angina, against myocardial infarction with or without adjunctive thrombolytic therapy, or ischaemic injury in patients undergoing (e.g.) coronary artery bypass graft surgery, angioplasty, cardiac transplantation or non-cardiac surgery. The compounds of formula la are especially useful for administering to subjects prone to myocardial infarctions, e.g. as result of diagnosis or those who have already suffered from a myocardial infarction. The compounds of formula la lower further plasma insulin without influencing glucose tolerance. They potentiate the insulin effect to increase glucose uptake and decrease lipolysis in adipose tissue leading to lower plasma free fatty acid concentrations (see test d) described hereinafter). Lower plasma free fatty acids in turn lead to lower triglycerides, which leads to increased HDL cholesterol. The insulin sparing effect and/or action to lower free fatty acids makes the compounds of formula la useful for the treatment of Type I diabetes and Type II diabetes i.e. non-insulin dependent diabetes. The compounds of formula la lower plasma triglycerides and free fatty acids (see test e) hereinafter) and raise HDL cholesterol and hence, are useful in treating lipid dysfunction, and conditions associated with elevated free fatty acids and triglycerides and where an increase in HDL cholesterol is desirable. The compounds of formula la show good metabolic stability. In another aspect, the invention provides the use of compounds of 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 formula la 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 la as defined above in association with a pharmaceutically acceptable carrier or diluent. The present applicants contemplate the use of compounds of formula la in the indications as described above for compounds of formula I. The following pharmacological tests illustrate the above mentioned activity of the compounds of formula la. a) Affinity for adenosine receptors Pig striatal membranes are prepared as previously described by H. Bruns et al. in Molecular Pharmacology 29 (1986) pages 331-344. 3 H-NECA, a non-selective adenosine receptor agonist is used to label both A. and A 2 receptors. IC 50 values are derived from the displacement curves by weighted non-linear least-square curve fitting to the Langmuir equation and pK D values calculated. The compounds of formula la show affinity for the A 1 receptor e.g. at a range of from 1 to 500 nM. b) Arrhythmias Adenosine A. receptor activation reduces the incidence of, e.g. paroxysmal supraventricular tachycardia, tachycardic atrial fibrillation and other arrhythmias by slowing conduction through the atrio-ventricular (AV) node of the heart detected by increases in the P-R interval. The test method involves recording of ECG changes in conscious adult Rhesus monkeys. The compounds of formula la are administered at dosage ranges 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. al. in The Pharmaceutical Journal 244, 595-597 (1990). For example in this test compound No. 1 prolongs P-R interval of the surface electrocardiogram (ECG), indicating slowing of conduction through the AV node at doses of 0.1 , 0.3 and 0.6 mg/kg p.o. As noted above such an action leads to termination of AV nodal reentrant tachycardia and reduction in heart rate in tachycardic atrial fibrillation. c) Protection against infarction by preconditioning Preconditioning (5 minutes of ischaemia followed by 10 minutes of recovery) renders the heart very resistant to infarction from subsequent ischaemia (30 min) and reperfusion (3h). The test method is disclosed in the article of G. S. Liu et. al. 1991 - Circulation (84), 1 , 350 - 356 and J. D. Thornton et al. in 1992 - Circulation (85), 659-665. The compounds of formula la are administered i.v. at a dose of from about 0.01 to 10 mg/kg to rabbits. In this test, rabbits given 100 μg/kg of compound No. 1 were protected to nearly the same extent as endogenous preconditioning from infarction induced by a 30 min. period of coronary occlusion. d) Glucose Transport and Lipolysis in Rat Adipocytes i) Adipocytes are isolated from the epididymal fat pads of normal chow-fed rats by digestion with collagenase. Cells (final concentration 2% v/v) are pre-incubated with adenosine deaminase (1 U/ml) and with test compounds e.g. compound No. 1 and other additions as indicated to measure glucose transport at 37°C. [3- 3 H]Glucose (final concentration, 50 μM, 0.5 μCi/ml) is then added after 30 minutes, and incubation is continued for a further 60 min. Incorporation of radioactivity from [3- 3 H]glucose into cell lipids (a measure of glucose transport) is evaluated by extraction of the cell suspension (0.5 ml) with 5 ml of toluene-based scintillant, followed by liquid scintillation counting; water-soluble metabolites and residual [3- 3 H] glucose remain in the aqueous phase and are not detected. Lipolysis is measured in a conventional manner. In one method cells are incubated with and without 1 μM isoproterenol and then the incubation continued for 60 min. The supernatant is separated from the cells after centrifugation through dinonylphthalate and lipolysis estimated by enzymatic determination of glycerol released into the supernatant. The compounds of formula la 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 on the incorporation of radioactivity from [3- 3 H]glucose into cell lipids in the absence of insulin and only a marginal effect in the presence of a maximally stimulating insulin concentration (8 nM), but significantly increases the stimulation of 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 a near-maximally effective concentration of compound No. 1 , the EC 50 for insulin stimulation of [3- 3 H]glucose incorporation into lipids is decreased between 2 and 3 fold. In the presence of adenosine deaminase and 1 μM isoproterenol, 10-50 nM of compound No. 1 increases both the sensitivity and the magnitude of the response to insulin; the EC 50 for insulin is reduced up to 5- fold and the stimulation by a maximal insulin concentration is significantly increased. ii) Lipid and Glucose in Normal 18 hr Fasted Rats The rats, 2 to 3 months of age, weighing ca. 250 grams are kept in a room at a controlled ambient temperature of 22° C and a 12/12 hour light/dark cycle for seven days. Purina rat chow and water are available ad libitum. Following an 18 hour fast, rats (5/group) are given test compounds by gavage in 0.5% CMC. The animals receive 1.0 ml/100 g body wt. Three hours after administration, the rats are anesthetized with C0 2 and blood collected via cardiac puncture-. Sera are collected and used for glucose, free fatty acid and β-hydroxybutyrate determination. Free fatty acids are measured by acyl- COA peroxidase calorimetric enzyme assay, glucose is measured by the glucose oxidase method (YSI Model 27, Yellow Spring, Oh) and β-hydroxybutyrate is assayed with a β-hydroxybutyrate dehydrogenase-linked enzyme assay (Sigma Kit 310-A - St. Louis, Mo.). The compounds of formula la are active at a dose of from about 1 to about 5000 μg/kg. The doses for lowering free fatty acids (the primary result of the effect on adipocytes) for the compound No. 1 are between 5 and 100 μg/kg at 2 hr post dose. This results in dose dependent decrease in β-hydroxybutyrate and blood glucose levels. iii) Effects in non-insulin Dependent Diabetic (NIDD) Rats In the NIDD screen test, the rats (200-220 g) are fed a high fat diet ad libitum. At fed state, 40 mg of streptozotocin/kg of body weight are injected via the tail vein. One week later, those rats are considered to be diabetic which have fed blood glucose of greater than 200 mg/dl and, following an overnight fast, when given an oral glucose tolerance test, have blood glucose of 40 to 80 mg/dl three hours after the test. Four days later, animals are used in the screen, if fed blood glucose levels are greater than 180 mg/dl. Blood glucose is determined with a YSI Glucose Analyzer. The chronic screen test is carried out as follows: On Day 1 , food is removed from rats at 9:00 a.m.; and after an initial blood glucose reading is taken via the tip of the tail, vehicle (control) or compound (9 rats/treatment) is administered orally. Six hours later blood glucose level is measured; and immediately thereafter the rats are refed. The same rats are given either vehicle or drug once a day for 11 consecutive days. Blood glucose is determined at 0 hour and after a 6-hour fast post dosing on days 4, 8, and 11. 100 microgram/kg of a compound of formula la e.g. compound No. 1 for 11 days results in a significant reduction in plasma free fatty acids that produces a significant decrease in blood glucose. Dyslipidemias characterised by elevated serum triglycerides Several studies have shown a positive correlation between serum triglyceride levels (and an associated decreased HDL cholesterol level) and the risk for coronary heart disease (CHD) (Grundy, in Cholesterol and Atherosclerosis: Diagnosis and Treatment, Lippincott, Philadelphia (1990)). The value of reducing elevated triglyceride levels as an approach to reducing the risk of CHD emerged from the Helsinki Heart Study where, following treatment with gemfibrozil, the greatest reduction in serious coronary events occured in Type IIB hyperlipidemic patients in whom both LDL-cholesterol and total serum triglycerides are elevated and HDL cholesterol levels are generally reduced. The compounds of formula la are active in the Rhesus monkey at doses from about 0.03 to 30 (e.g. 0.1 to 30) mg/kg i.v. and 0.1 to 100 (e.g. 0.1 to 10) mg/kg p.o. Compound No. 1 re¬ produces dose-related and long-lasting falls in plasma free fatty acids 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. show a lowering of free fatty acids by ca. 60 % compared to a control after 300 minutes and of triglycerides by 40%. The compounds of formula la are also active in tests for mean arterial blood pressure, bradycardia and peripheral vasodilation in anaesthetized rats. The experiments are carried out on male Wistar rats, body weight 300-350 g under Pentothal anaesthesia (120 mg/kg i.p.), according to the method of Salzmann et al. (J. Cardiovasc. Pharmacol. 12, 451-460, 1988). Catheters are placed in the right jugular and right femoral veins, in the left ventricle (inserted via the right carotid artery), left femoral artery, and aorta (inserted through the right femoral artery). The following variables are measured or calculated: systolic, diastolic, and mean arterial blood pressure (mm Hg; left femoral artery, Statham pressure transducer P 23 Gb), pulse pressure (mm Hg), heart rate (beats/min; triggered from the blood pressure curve), rate of rise of left ventricular pressure (dP/dt max , mm Hg/s; Statham pressure transducer P 23 Gb), cardiac output (ml/min/100 g body weight, thermodilution method, right jugular vein and aorta), total peripheral resistance (dynes s.cm "5 /100 g body weight), superficial ECG. Arterial blood pressure, left ventricular pressure, dP/dt maκ , heart rate, and electrocardiogram are continuously recorded with a Schwarzer polygraph. The parameters are measured 30, 20, 10 and 2 min before administration of the test substance and 1 , 5, 10 and 15 min after injection of the drug into the right femoral vein. The compounds of formula la are injected at dosage ranges from about 0.001 to about 10 mg/kg animal body weight. Compound No. 1 was tested in cumulative doses of 0.003, 0.010 and 0.03 mg/kg, three animals per dose being used. Compound No. 1 induced falls in blood pressure [ED 50 = 49 microgram kg iv] and heart rate and an increase in systemic vascular conductance. The doses of the compound of formula la used in the above indications will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and the relative efficacy of the compound. However, as a general guide suitable unit doses may 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 per day, so that the total daily dosage for a 70 kg mammal including humans is in the range of about 0.1 to 1000 mg e.g. per os or 0.003 to 300 mg i.v., that 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 may extend for a number of weeks or months. For compound No. 1 the preferred dose range for all the indications of the invention is from 0.1 mg/day to 10 mg/day for a 70 kg adult. For the preferred indication non-insulin dependent diabetes and for hypertriglyceridemia the indicated dose for humans is 0.2 to 2 mg per day per os and for treating heart failure and other cardiac disorders 0.2 to 10 mg per day in particular 0.5 to 5 mg/day per os or 0.25 to 5 mg i.v. for arrhythmias e.g. tachycardic atrial fibrillation. The compounds of formula la may be formulated for administration by any suitable route, the preferred route depending upon the disorder for which treatment is required, and preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration as described above with respect to the analgesic use. Unit dose presentation forms for oral administration may be tablets and capsules containing 0.05-20 mg of a compound of 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 10%, for example 2 to 5%. Compounds of formula la wherein R is hydroxy (C^cycloalkyl and R 3 is alkyl, are detected as metabolites on administration of compounds of formula I wherein R. is (C 4 . 8 )cycloalkyl and R 3 is alkyl to warm blooded animals, e.g. rats, dogs and humans. Thus administration of Compound M leads to the production of hydroxycyclohexyl- 2'-0-methyl adenosine. In a further aspect, the present invention provides a method of administering N 6 - cyclohexyl-2'-0-methyladenosine to a warm blooded animal in order to produce N 6 - hydroxycyclohexyl-2'-0-methyl adenosine. The present invention provides in another aspect N 6 -hydroxycycloalkyl-2'-0-alkyl adenosine in pure form, e.g. greater than 95% pure. The exemplified compounds described herein meet this criterion. The present invention provides in a further aspect N 6 -hydroxycyclohexyl-2'-0-alkyl adenosine free from cyclohexyl-2'-0-methyl adenosine. In another aspect, the present invention provides a process for the production of 2'-0-alkyladenosines which comprises treating adenosine with an appropriate alkyl sulphate in the presence of a phase transfer catalyst. Preferably the 2'0-alkyl adenosine is any compound defined above. In a further aspect, the present invention provides a process for the production of compounds of formula I as defined above, which comprises reacting a compound of formula VI VI with a basic solution of a compound of formula (R 3 ) 2 S0 4 in the presence of tetrabutylammonium hydrogen sulfate and a non-polar solvent and purifying the product by recrystallization. If necessary reactive groups may be temporarily protected. Preferably the alkyl sulphate is di(C 1 ^)alky! sulphate. Preferably the phase transfer catalyst is tetrabutyl ammonium hydrogen sulphate. Preferably the reaction is effected in a non-polar solvent, e.g. as described hereinafter. A group of compounds of the formula I is defined wherein R. is (C M )cycloalkyl, R 2 is hydrogen or (Chalky., and R 3 is (C,^ )alkyl. Hitherto, the preparation of compounds of formula I typically involved six steps, which include the preparation of 2',3',5'-triacetylinosine; chlorination and hydrolysis to 6-chloro-9-β-D-ribofuranosyl-9H-purine; protection of the 3'-0- and 5'-0-positions with tetraisopropyldisiloxane (TIPDS-CL 2 ); 2'-0-alkylation and purification by silica gel chromatography; deprotection of the 3'-0- and 5'-0-positions; and reaction with R^H j , and recrystallization to obtain the compound of formula I. The present applicants have found that the compounds of formula I can be prepared in good yields and purity without the need for 3'-0- and 5'-0-disiloxane protection and deprotection or for silica gel chromatography. The applicants have found that the inosine-2',3,'5'-triacetate starting material of the prior art process may be advantageously replaced with the lipophilic inosine-2',3',5'-tripropionate, which permits the doubling of throughput and the elimination of undesirable pyridine solvent. In the present invention the compounds of formula I are prepared under phase transfer catalysis conditions in accordance with the following reaction scheme: where R 1 ( R 2 and R 3 are as defined above. The compounds of formula I may be prepared by reacting a basic aqueous solution of a compound of formula (VI) with a di-(C 1 ,)alkyl sulfate in the presence of tetrabutylammonium hydrogen sulfate and an organic water-immiscible 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 water immiscible or essentially immiscible solvent 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 time of the reaction is not critical, but it is preferably carried out over a period of from about 5 to 10 hours, especially 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 inert solvent, preferably toluene, at room temperature for 5 to 7 hours, then filtering and drying. Pure compound may be obtained by fractional crystallization, preferably by: 1) recrystallization from an inert solvent, such as toluene, by dissolving the crude compound in the solvent at 80°C, heating at about 55°C for approximately 1 hour, cooling to room temperature, seeding with pure compound and filtering; 2) repeating the recrystallization procedure of step 1) but heating at about 65°C before cooling to room temperature; and 3) recrystallizing from 100% ethyl alcohol by dissolving at reflux, diluting with water, seeding, then filtering and drying. Many of the compounds of formula VI are known and may be prepared by methods described in the literature such as the aforementioned USP 4,843,066 and USP 4,985,409. The compound formula VI may also be prepared advantageously, as indicated above, in accordance with the following preferred reaction scheme: VII VIII IX where R. and R 2 are as defined above. The compounds of formula VI may be prepared by acylating inosine of formula VII with propionic anhydride to form the 2'-0-, 3'-0-, 5'-0-protected compound of formula VIII; halogenating the compound of formula VIII with thionyl chloride to form the intermediate of formula IX; and simultaneously aminating and hydrolyzing the compound of formula IX. 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 over 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 over a period of 3 to 4 hours, and the solution of the compound of formula IX may be used after washing with water and brine. Amination and simultaneous hydrolysis of the intermediate of formula IX is preferably effected by adding the amine R 1 NH 2 and reacting at a temperature of from 100° to 110°C over 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 of this invention is illustrated by the following examples. Process Example 1 : N 6 -cyclohexyl-2'-0-methyladenosine Step A. lnosine-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 over 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 e.g. 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 yield 425.9 g of inosine-2',3',5'-tripropionate as a white solid. (MP 171-172°C; yield 96.5%). Step B. N 6 -cyclohexyladenosine A mixture of 270.6 g of inosine-2',3',5'-tripropionate, 240 ml of N,N-dimethylformamide and 600 ml of toluene is heated to 65°C; and over 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 addition of 600 ml of water precooled to 10-15°C in an ice bath at a rate which maintains 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 crude 6-chloro-9-(2,3,5-tri-0- propionyl-β-ribofuranosyl)-9H-purine is added with stirring to 620 ml of cyclohexylamine heated to 105°C over 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) over approximately 2 hours with efficient stirring and then filtered e.g. in a Buchner funnel with suction. The solid containing N 6 -cyclohexyladenosine and cyclohexylamine hydrochloride is washed with a total of 460 ml of toluene in four equal portions of 115 ml. each and transferred damp to a 5-liter flask equipped with a mechanical stirrer. After addition of 2 liters of aqueous saturated sodium bicarbonate solution and 2.5 liters of ethyl acetate, the mixture is stirred until all the solid dissolve (approximately 10-15 min.). The organic layer is separated; and the aqueous layer is extracted with 1.5 liters of ethyl acetate in two portions of 1 liter and 500 ml., respectively. The organic layers are combined and evaporated until about 3 liters of ethyl acetate (at 40°C, 100-200 mbar) is removed. To the residue, 500 ml. of heptane is added; and the resulting mixture is stirred for 30 minutes. The solids are separated on a Buchner funnel, and washed with a total of 300 ml of heptane in three equal portions of 100 ml each. The solids are then dried at 45-50°C (30-35 mbar) for approximately 3 hours to yield 148 g of crude N 6 -cyclohexyladenosine as a white solid. This is transferred to a 1 liter round-bottomed flask equipped with a mechanical stirrer, and 175 ml. of 95% ethanol are added. The suspension is stirred for 15-20 min and 175 ml of tert-butyl ethyl ether are added. After stirring for 5 min, the suspension is cooled in an ice bath and stirred for an additional 15 minutes. This suspension is filtered in 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 solid is dried at 45-50°C (30-35 mbar) for 14 hours to yield 130 g of N 6 -cyclohexyladenosine as a white solid (m.p. 185-187°C; yield 60.0%). Step C. N 6 -cyclohexyl-2'-Q-methyladenosine A suspension of 94.33 g of N 6 -cyclohexyladenosine and 720 g of 5% aqueous sodium hydroxide is stirred at room temperature (24-25°C) until all of the solids are dissolved (approximately 5 min.). Using an addition funnel, 850 ml. of dichloromethane and 5.5 g of tetrabutylammonium hydrogen sulfate are added followed by 61.3 g of dimethyl sulfate over 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 further solvent distills. The residue is dissolved in 200 ml of toluene and evaporated at 45-50°C (30 mm Hg) until again no further solvent distills. A mixture of the above-mentioned crude material 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 min. The resulting suspension is stirred at room temperature for an additional 6 hours and solids are collected by filtration e.g. 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 yield 53.0 g of a white solid. A suspension of this solid in 397 ml. of toluene is heated to 80°C with stirring to form a clear solution, which is cooled to 56°C over 45 min 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 over 1 hour. After stirring at this temperature for an additional 1 hour the solid are collected by filtration e.g. 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 yield 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 seeding procedure is carried out at 65° to 66°C. After cooling to room temperature over 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 yield 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 water pre-warmed to 55°C are added over 25 minutes. The mixture is cooled to 55°C and seeded with 20 mg of pure product. This mixture is cooled to room temperature over 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 1 :2.36 mixture (v/v) of 100% ethanol and water in three equal portions of 19 ml each. The solids are dried at room temperature (29 mm Hg) to yield 62.2 g of product as a white solid in 1.5 hydrate form (m.p. 88°-91°C; yield 42.5%). Process Example 2: Following the above procedure but using an equivalent amount of N 6 -cyclopentyladenosine, there is obtained N 6 -cyclopentyl-2'-0- methyl adenosine. Process Example 3 The steps of process Example 1 are followed except that the dichloromethane in step C) is replaced by tert-amyl alcohol, and subsequent to the initial ethanol/water crystallisation, the product is recrystallised from ethanol and water. 32.1g (yield approx. 30%) N 6 -cyclohexyl-2'-0-methyladenosine are obtained in excess of 98% purity. The process of this invention is more economic in time and cost than hitherto known processes. The process provides a convenient method for selective 2'-0- methylation of N 6 -cyclohexyladenosine under phase-transfer conditions, and a method of purification of the 2'-0-methyl derivative. Expensive protecting groups and the use of chromatography are avoided.

Claims: CLAIMS 1. Use of a compound of formula wherein R, is hydrogen, (C^alkyl, allyl; methallyl; a straight-chain or branched (C g ^alkinyl, (C^cycloalkyl, hydroxy (C 4 ^)cycloalkyl, phenyl being mono-, or independently each other di-, substituted by halogen with an atomic number of 9 to 35, (C^alkyl, (C^alkoxy or CF 3 ; or pheny C^alkyl wherein the phenyl ring is unsubstituted or mono- or independently of each other di-, substituted by halogen with an atomic number of 9 to 35, (C^alkyl, (C^) alkoxy or CF 3 ; (C^alkyl 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 (C^alkyl- group, an acenapthylenyl (C^alkyl-group or a group of formula A or B wherein Z is hydrogen, a hydroxy group or a (C^alkoxy group Q is hydrogen or hydroxy, A is -CH 2 -, -0-, -S- or a direct bond, Y is -(CH 2 ) n - or a direct bond, n is a whole number from 1 to 3 and the broken line in (A) represents an optional bond, R 2 is hydrogen, (C 1-4 )alkyl, amino, (C^cycloalkyl or halogen with an atomic number of 9 to 35 and R 3 is (Chalky! as an analgesic in the production of a medicament suitable for the treatment of pain. 2. Use as claimed in claim 1 wherein the compound of formula I is selected from 6'-hydroxy(C 4 ^)cycloalkyl-2'-0-methyladenosines. 3. Use as claimed in claim 1 wherein R. is other than hydroxycycloalkyl . 4. Use as claimed in claim 3 wherein the compound of formula I is 6-cyclohexyl- 2'-0-methyl-adenosine. 5. Use as claimed in any preceding claim for acute pain. 6. Use as claimed in any preceding claim for chronic neuropathic pain. 7. Use of a compound as defined in any preceding claim in the treatment of pain as defined in any preceding claim, or a method of treating pain as defined in any preceding claim which comprises administering a compound as defined in any preceding claim to 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. A compound of formula la wherein R.' signifies (C 4 . 8 )cycloalkyl substituted by a hydroxy group and R 2 is as defined in claim 1 R 3 is as defined in claim 1. 9. A compound as claimed in claim 8 wherein R 2 is hydrogen, (C^alkyl or halogen of an atomic number from 9 to 35. 10. A compound selected from: 6-[(trans)-4-hydroxycyclohexyl]-2'-0-methyl adenosine 6-[(cis)-4-hydroxycyclohexyl]-2'-0-methyl adenosine 6-[(1 S,trans)-2-hydroxycyclopentyl]-2'-0-methyl adenosine 6-[(1 R,trans)-2-hydroxycyclopentyl]-2'-0-methyl adenosine 6-[(1 S,trans)-2-hydroxycyclohexyl]-2'-0-methyl adenosine 6-[(1 R,trans)-2-hydroxycyclohexyl]-2'-0-methyl adenosine 6-[(trans)-4-hydroxycyclohexyl]-2'-0-ethyl adenosine, and 6-[1 S,(trans)-2-hydroxycyclohexyI]-2'-0-ethyl adenosine. 11. A compound as claimed in claim 8, claim 9 or claim 10 which is 95% pure. 12. A compound as claimed in claim 8, claim 9 or claim 10 free from N 6 -cycloalkyl- 2'-0-methyl-adenosine. 13. Use of compounds of formula la as defined in any one of claims 8 to 12 for the preparation of medicaments suitable for the treatment of pain, for use against high blood pressure, as coronary vasodilators, for inhibition of both thrombocyte aggregation or activation of leucocytes, for lowering blood lipid levels, against congestive heart failure, myocardial infarction, sudden cardiac death, renal insufficiency further for the treatment of hypertriglyceridemia/low HDL cholesterol levels, lipid dysfunction, elevated free fatty acids and/or type I and type II diabetes, arrhythmias or for protection against myocardial infarction. 14. A pharmaceutical composition comprising a therapeutically effective amount of compounds of formula la as defined in any one of claims 8 to 12 in association with a pharmaceutically acceptable carrier or diluent. 15. A compound as claimed in any one of claims 8 to 12 for use in the treatment of pain, of high blood pressure, coronary vasoconstriction, thrombocyte aggregation, high blood lipid levels, congestive heart failure, sudden cardiac death, renal insufficiency, hypertriglyceridemia/low HDL cholesterol levels, lipid dysfunction, elevated fatty acids or type I or type II diabetes, arrhythmias and for protection against myocardial infarction, or a method for using such a compound which comprises administering a compound of formula la to a subject in need of such treatment. 16. A process for the production of 2'-0-alkyladenosines which comprises treating adenosine with an appropriate alkyl sulphate in the presence of a phase transfer catalyst. 17. A process as claimed in claim 16 for the production of a compound of formula I as defined in claim 1. 18. A process as claimed in claim 16 or claim 17 in which the compound produced is N-cyclohexyl-2'-0-methyladenosine. 19. A compound produced by the process of claim 16, claim 17 or claim 18. 20. A method of administering N 6 -cyclohexyl-2'-0-methyl adenosine to a warm¬ blooded animal in order to produce N 6 -hydroxycyclohexyl-2-0'-methyl adenosine.

Inventors: FOZARD JOHN R, GADIENT FULVIO, KAPA PRASAD K, MANGOLD BONNIE L K, PRASHAD MAHAVIR, FOZARD, JOHN, R., GADIENT, FULVIO, KAPA, PRASAD, K., MANGOLD, BONNIE, L., K., PRASHAD, MAHAVIR
Applicants: FOZARD JOHN R, GADIENT FULVIO, KAPA PRASAD K, MANGOLD BONNIE L K, PRASHAD MAHAVIR, SANDOZ AG, SANDOZ LTD, FOZARD, JOHN, R., GADIENT, FULVIO, KAPA, PRASAD, K., MANGOLD, BONNIE, L., K., PRASHAD, MAHAVIR, SANDOZ LTD., SANDOZ-ERFINDUNGEN VERWALTUNGSGESELLSCHAFT MBH, SANDOZ-PATENT-GMBH
Application year: 1995
Main classification: C07H19
IPC codes: A61K31, A61P25, C07H19