JPH09512823A - Adenosine derivatives - Google Patents

Abstract

(57) [Summary] Formula (I): [Wherein R ₁ is one of many definitions including cycloalkyl and hydroxycycloalkyl, R ₂ is hydrogen, (C _1-4 ) alkyl, amino, (C _3-5 ) cycloalkyl or from atomic number 9 The compound represented by the halogen of 35 and R ₃ is (C _1-4 ) alkyl] is useful as an analgesic. The compounds of formula I in which R ₁ is hydroxyalkyl are new. The compounds of formula I may be prepared by alkylation of the 2'position in the presence of tetrabutylammonium hydrogen sulphate and a non-polar solvent.

Description

Detailed Description of the Invention                             Adenosine derivatives   The present invention relates to adenosine derivatives, and in particular A₁Of new use of receptor agonists Regarding provision.   In particular, the invention has the formula (I): (In the formula, R₁Is hydrogen, (C_1-4) Alkyl, allyl, methallyl, straight or branched (C_3-7A) Lucinyl, (C_3-8) Cycloalkyl, hydroxy (C_4-8) Cycloalkyl, phenyl (Wherein phenyl is a halogen of atomic number 9 to 35, (C_1-4) Alkyl, ( C_1-4) Alkoxy or CF_ThreeSelected from the group consisting of mono or independent Then di-substituted); or phenyl (C_1-4) Alkyl (where phenyl ring Is a halogen which is unsubstituted or has an atomic number of 9 to 35, (C_1-4) Alkyl, ( C_1-4) Alkoxy or CF_ThreeSelected from the group consisting of mono or independent At least one hydroxy group or at least two Having a phenyl ring of (C_1-4) Alkyl, endo- or exo-bicyclo [2, Bicycloalkyl such as 2,1] heptyl, naphthyl (C_1-4) Alkyl, asena Futylenyl (C_1-4) Alkyl or Formula A or Formula B (Where Z is hydrogen, hydroxy or (C_1-4) Alkoxy, Q is hydrogen or hydroxy, A is -CH₂-, -O-, -S- or a direct bond, Y is-(CH₂)_n-Or a direct bond, n is an integer from 1 to 3, And the dotted line in Formula A means any bond) A group represented by R₂Is hydrogen, (C_1-4) Alkyl, amino, (C_3-5) Cycloalkyl or atomic number 9 to 35 halogens and R_ThreeIs (C_1-4) Alkyl] Relates to a novel use of a compound represented by   Some of these compounds, for example R₁Is other than hydroxycycloalkyl Some are known, for example published British patent application No. 2226027A and European State patent applications EP-0378518 and EP-0269574 and US P. 4,843,066 and 4,985,049.   In the formulas described herein, the 2 ′, 3 ′, 4 ′ and 2 ′ of the tetrahydrofuran ring The 5'substitute has an adenosine-like configuration.   In one group of compounds of formula I, R₁Is hydroxycycloalkyl Other than In another group of compounds of formula I, R₁Is hydroxy (C_4-8) Cycloalkyl.   Preferably the compound of formula I is 6-cyclohexyl-2'-O-methyl -Adenosine, hereafter referred to as compound M.   Typically, the preferred compound A of formula I₁Adenosine activity is Will be decided:Affinity for adenosine receptors   Pig linear membranes were previously described in Molecular Pharmacology 29 (1986), 331-344, H. Prepare as described by Bruns et al.   ^ThreeH-NECA, a non-selective adenosine receptor agonist₁And A₂Receptor Used to label both. IC₅₀The value is a non-linear load that fits the Langmuir equation Derived from a permutation curve by a weighted non-linear least-square curve, p K_DCalculate the value.   Consistent with literature, CPA is A₁Effective and highly selective for binding to the receptor Proved to be a substituent, CV1808 is a relatively weak but selective A₂Receptor Is a ligand and CGS21680 is A₂High potency and selectivity for receptors .   Compound M in its 1.5 hydrate form is A₂A compared to the receptor₁To the receptor It shows good affinity and high selectivity.   The known compounds of formula I are known as antihypertensives and coronary vasodilators. is there.   Furthermore, the compounds of formula I inhibit both platelet aggregation and leukocyte activation. It is known to protect the vascular endothelium by doing so. Blood lipid levels are also reduced Reduce. In addition, compounds of formula I are suitable for the treatment of congestive heart failure, myocardial infarction or sudden Has a protective effect against diseases caused by hypertension such as cardiac death and renal failure ( See European patent applications EP-0378518 and EP-269574).   These compounds are used in neurodegenerative diseases, peripheral neuropathies such as diabetic neuropathy and Peripheral vascular disorder-related disorders and / or neuron degeneration-related disorders, high triglycerides Doemia / low HDL cholesterol levels, lipid dysfunction, elevated free fatty acids or Type I or Type II diabetes, including non-insulin-dependent diabetes mellitus, arrhythmia, especially on paroxysm Also for the treatment of ventricular tachycardia and atrial fibrillation tachycardia and for protection against myocardial infarction. It is known.   Applicants have found that compounds of formula I are particularly suitable for, for example, pain, eg acute or acute. It has also been found to be an interesting analgesic for the treatment of chronic pain.   The analgesic activity of the compounds of formula I is determined by standard animal studies such as inflammation and neuropathy. Harm models, such as stubborn inflammatory mechanical hyperalgesia [tests a) and b)] and In the reduction of stubborn neuropathic thermal hyperalgesia [study c)] showing chronic neuropathic pain , Indicated by its analgesic activity.Inflammatory hyperalgesia Study a) Freund's adjuvant-induced hyperalgesia   Complete Freund's complete adjuvant (100 mics) in one knee joint of a rat Injection). The load the rat withstands on its paws is reduced by 5 days and suppressed It has been done. This effect is mechanical hyperalgesia, NSAIDs and hemp React to sickness. Compounds of formula I can be administered by injection and preferably orally It is administered at a dose of 60 micrograms / kg of animal body weight. Increased withstand at injection site Weight is measured to determine recovery from hyperalgesia.   Compound M was administered at a p.o. dose of about 3 to about 60 micrograms / kg for about 1 hour of activity. It shows a particularly interesting activity during sex time. For 3, 30 and 60 micrograms / kg There is no apparent difference in the response between doses and maximum efficacy in the range of 3 to 30 micrograms / kg Suggests reaching the end. Study b) turpentine-induced mechanical hyperalgesia   Local intraplantar injection of turpentine oil / paraffin into rat paw (left rear) causes local inflammation It also reduces the escape threshold (separation threshold 340g) for response and mechanical stimulation (plantar pressure). Let me down. The compound of formula I is about 1 to 100 micrograms 3 days after injection. / Kg p.o. or s.c. dose, with further threshold readings taken 1 and 3 hours later And is active.   Compound M was active at 30 and 60 micrograms / kg po and The maximum effect is crogram / kg. Morphine contained 1.2 mg / kg s.c. ED₅₀Has a value.Neuropathic hyperalgesia Test c) Neuropathic thermal hyperalgesia (Z. Seltzer et al., Pain, 1990, 43, 205-2) (According to 18 principles)   One-sided partial ligation of the sciatic nerve removes fibers through the nerve distribution in the rat paw . Rats are sensitive to hyperalgesia and partial denervation in mechanical and thermal stimuli. Permanent pain develops without self-incision. Play thin glass in an organic glass box with animals Place the lamp-type thermal stimulus on the plantar surface. Measuring the latency of plantar escape . The compound of formula I is administered from about 1 to about 1 day after 12 to 15 days of nerve ligation. Active at doses of 00 microgram / kg injection (s.c. or preferably oral). Compound M is particularly active against heat hyperalgesia. Compounds M are 30 and 6 Significant activity at 0 microgram / kg, maximum effect at 30 microgram / kg It is. ED₅₀Is about 60 micrograms / kg p.o. Morphine is administered subcutaneously In case of, ED of about 3 mg / kg₅₀Having.Clinical trial   Clinical trials may be conducted as follows:   In patients suffering from pain, postoperative pain or postherpetic neuralgia, Compounds, especially Compound M, are administered i.v. at a dose of 0.02 to 5 mg. Pain relief Is recognized.   Thus, the compounds of the present invention may be useful as analgesics, for example in acute or chronic pain, such as Useful for chronic neuropathic pain.   Accordingly, in one aspect, the present invention provides a therapeutically effective amount of a compound of formula I as defined above. Methods of treating pain, including administering a compound to a patient in need thereof. Offer.   In another aspect, the present invention provides a compound of formula I as defined above for the treatment of pain Use as an analgesic in the manufacture of a medicament suitable for treatment.   In another aspect the invention provides a compound of formula I as defined above for use in the treatment of pain. The compound shown by is provided.   In another aspect, the present invention provides a compound of formula I as defined above as an analgesic. The present invention provides an analgesic composition containing an agent together with a pharmaceutically acceptable carrier or diluent.   Indications are pain, such as acute pain associated with tissue damage and inflammation (e.g., hand). Post-operative pain, burn pain, injury, etc.), chronic inflammatory pain (e.g. arthritis) and chronic god Translesional pain (e.g. diabetic neuropathy, postherpetic neuralgia, multiple sclerosis, burning Neuralgia, etc.)   The dose of the compound in the use of the invention suggested above will, of course, be the compound used, Depends on disease severity, patient, patient weight, dosage form and relative effects of the compound Change. However, in general, satisfactory results in animals have been found to be about A dose of 1 to about 100 micrograms / kg of animal body weight, eg 3 to 60, eg It is suggested that 10 to 60 microgram / kg can be obtained in 3 days. Large feeding In families, eg humans, a suggested daily dose is about 0.1 to about 10 mg, Stool is given in a unit dose of about 0.02 to about 5 mg, such a unit dose being 1 It may be administered more than once, for example 2, 3, 4, 5 or 6 times a day, but preferably once. Once or twice a day.   In test a) above, the NSAID ibuprofen was approximately 4 mg / kg p.o. Indomethacin has an ED of 13 mg / kg p.o.₅₀Having. Compound M is about 300 times as active It is sex. For Compound M, a preferred dose range is from about 0.1 mg / day to about 1 0 mg / day, eg 70 kg adult, severity and indication of indication (s) Depending on the frequency it is 3-30 micrograms / kg.   Compound M has severe adverse effects in humans after a single dose up to 5 mg p.o. Is shown to have no.   As used herein, the term "pharmaceutically acceptable" refers to human and Contains materials suitable for use in both livestock.   The compounds of the invention may be administered by any suitable route, the preferred route being Depending on the disease that requires treatment, preferably a human patient administers a unit dose himself It may be formulated in any possible unit dosage form or form. Advantageously, the composition is oral, rectal, topical Suitable for local, parenteral, intravenous or intramuscular administration.   The composition of the present invention may be used in tablets, capsules, sachets, vials, powders, granules, and mouths. In buccal tablets, suppositories, redissolvable powders, or oral or sterile parenteral solutions or suspensions It may be in the form of such a liquid formulation. Topical formulations also consider where suitable.   It is preferred that the compositions of the invention be in unit dose form for consistency of administration. New   Unit dose forms for oral administration include tablets containing 0.02-5 mg of a compound of the invention and It can be a capsule and binder such as syrup, acacia, gelatin, sorbitol Le, tragacanth or polyvinylpyrrolidone; fillers such as lactose, sugar , Corn starch, calcium phosphate, sorbitol or glycine; tablet moisturizing Lubricants, such as magnesium stearate; Disintegrants, such as starch, cross-linked polyvinyl Pyrrolidone, sodium starch glycolate or microcrystalline cellulose; or LA Known excipients such as pharmaceutically acceptable wetting agents such as sodium uryl sulfate Can be included.   Solid oral compositions may be manufactured by known methods of mixing, filling, molding and the like. Repeated mixture Combined operations can be used to disperse the active agent in these compositions using large amounts of filler. Let it.   Such manipulations are of course known in the art. Tablets are normal pharmaceutical practice It may be coated by known methods, especially with enteric coatings.   Oral liquid preparations are, for example, in the form of emulsions, syrups or elixirs. Available as a dry product that can be redissolved in water or other suitable solvent before use. Can be. Such liquid preparations include suspensions such as sorbitol, syrups, Chill cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose Lulose, aluminum stearate gel, hydroxylated edible oils: emulsifiers, eg resi Tin, sorbitan monooleate or acacia; non-aqueous solvents (may include edible oils Such as almond oil, fractionated coconut oil, esters of glycerin Oily ester, propylene glycol, or ethyl alcohol; preservatives, such as Eg methyl or propyl p-hydroxybenzoate, or sorbic acid; and If desired, known additives such as perfumes or dyes may be included.   Examples of solid oral compositions such as tablets and capsules are as follows:   Tablets are compressed from capsule granules of corresponding dose strength. Size number 3 yellow Capsules were used for encapsulation of Compound M, and those of 0.1 and 5 mg dose strength. The respective formulations are shown below.   The composition may also be administered in a sustained release form to provide an extended active period. obtain. Known drug delivery systems include sustained release, such as coated pellets. It can be used to provide an osmotic or push-pull osmotic system.   For parenteral administration, liquid unit dosage forms were prepared using the compound and a sterile vehicle. They can be made or suspended or dissolved in a medium, depending on the concentration used. For manufacturing solutions In water, dissolve the compound in polyethylene glycol or ethanol. Sterile, filter sterilize and seal before filling into a suitable vial or ampoule. . Advantageously, local anesthesia, preservatives and auxiliary agents as buffering agents can be dissolved in the medium. Wear. Parenteral suspensions may be prepared by suspending the compound instead of dissolving it and sterilizing by filtration. Manufactured in substantially the same manner except that it is not used. Before compound is suspended in a sterile container It can be sterilized by exposure to ethylene oxide. Advantageously surfactants or wetting agents Is included in the composition to facilitate uniform dispersion of the compound.   The composition, depending on the method of administration, is about 0.1% to about 99% by weight, preferably 10%. To 60% by weight of active substance.   Compound M of the present invention or a hydrate or an adduct with another solvent or a salt thereof may be It may be administered as a topical formulation in combination with known topical excipients.   Topical formulations include, for example, ointments, creams or lotions, poultices, gels, dizzers. It may be present as a stick, spray or aerosol, and may be a preservative or solvent. Such suitable known additives may be included in ointments and creams for drug penetration and Helps to soften the skin. The formulation is an ointment base cream and lotion It may include a suitable known carrier such as a norol or oleyl alcohol.   Compounds of formula I or hydrates or adducts with other solvents or salts thereof Suitable cream, lotion, gel, ointment, spray or aero that can be used Sol formulations include, for example, Harry's Cosmeticology, R, published by Leonard Hill Bokks. Like emington's Pharmaceutical Sciences and British and US Pharmacopoeia Formulations known in the art, such as those described in standard pharmaceutical and cosmetic textbooks.   In another aspect, the invention provides a compound of formula Ia (In the formula, R₁'Is substituted by a hydroxy group (C_4-8) Cycloalkyl, R₂Is as defined above or preferably hydrogen, (C_1-4) Alkyl or atomic number 9 to 35 halogens and R_ThreeIs defined above) And an adenosine derivative represented by   The compounds of formula Ia are referred to as enantiomers or diastereomeric mixtures And can exist.   In formula Ia, halogen of atomic number 9 to 35 is fluorine, chlorine or bromine; (C_1-4) Alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl , I-butyl, tert-butyl, especially methyl; and (C_4-8) Cycloalkyl is Clobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclo Cutyl, especially cyclohexyl or cyclopentyl.   The compound of formula Ia has the formula IIa (In the formula, R₂And R_ThreeIs the meaning defined above, and X is chlorine or bromine] A compound of formula IIIa                 R₁'-NH_Three                        IIIa [Wherein, R₁'Means as defined above) Can be produced by a process characterized by reacting a compound represented by   The above steps are simply performed by using the compound represented by the formula IIa and the compound represented by the formula IIIa. Both, in the presence of a solvent such as dioxane, about 80 to 120 ℃, preferably boiling By heating to a point.   In the compound of formula IIa used as a starting material in this step, X is It is chlorine. The compounds of formula IIa and their preparation are described in published European patent application No. No. 269574.   A further method for the preparation of compounds of formula Ia is described by formula IVa [Wherein, R₁', R₂And R_ThreeIs defined above) Treating the compound shown by with tetrabutylammonium fluoride trihydrate including.   The above reaction is carried out in an organic solvent such as tetrahydrofuran at room temperature with stirring. Can be. The compound of formula IVa is prepared by converting the compound of formula IIa into 1,3-dichloromethane. B-1,1,3,3-tetraisopropyldisiloxane and an alkaline solvent such as Formula Va obtained in this way after treatment in pyridine [In the formula, X, R₂And R_ThreeIs the meaning defined above) Obtainable by reacting a compound of formula IIIa with a compound of formula IIIa Can be.   In Examples 1-8 below, all temperatures are in degrees Celsius and are uncorrected.Example 1 6-[(trans) -4-hydroxycyclohexyl] -2'-O-methyl Luadenosine   6-[(trans) -4-hydroxycyclohexyl] -9-purinyl-2'-O -Methyl-3 ', 5'-O- (1,1,3,3-tetraisopropyldisiloxy-1,3 1 g of -diyl) -D-ribose, tetrabutyl in 20 ml of tetrahydrofuran Stir with 2 g of ammonium fluoride trihydrate for 15 minutes at room temperature. Then mix The residue is evaporated to dryness and the residue is extracted from silica gel with ethyl acetate / methanol 85:15. Elute with a mixture of. The purified product is crystallized from methanol / ethyl acetate. Mark The title compound crystallizes from 1 equivalent of methanol and has a melting point of 121-124 ° C. . [α]_D ²⁰= -50.2 ° (c = 1 in dimethylformamide)   The compound was also recrystallized from ethanol and left in high humidity air, then 1 equivalent of water. Can be crystallized. Melting point: 114-117 °. [α]_D ²⁰= -46.9 [deg.] (C = 1 dimethylformamide).   6-[(trans) -4-hydroxycyclohexyl used as starting material in the above step Hexyl] -9-purinyl-2'-O-methyl-3 ', 5'-O- (1,1,3,3-thel Traisopropyl-disiloxy-1,3-diyl) -D-ribose was prepared as follows. Can build:   6-chloro-9-purinyl-2'-O-methyl-3 ', 5'-O- (1,1,3,3- 2 g of tetraisopropyldisiloxy-1,3-diyl) -D-ribose was added to 1.32 g of trans-4-hydroxycyclohexylamine in 80 ml of Sun and And 1.4 ml of N-ethyl-diisopropylamine for 6 hours in an oil bath at 105 ° C. Stir at. Subsequently, the mixture is cooled to room temperature, filtered and the filtrate is concentrated to dryness. For purification, the mixture thus obtained is first mixed with hexane / ethyl acetate 7: Silica gel with a mixture of 3 and then 95: 5 ethyl acetate / methanol. Elute from the gel. The oily compound thus purified has an R of 0.3._fHaving value (vinegar Ethyl acid / methanol from 95: 5).Example 2: 6-[(cis) -4-hydroxycyclohexyl] -2'-O-methyla Denosine   The title compound was substituted with trans-4-hydroxycyclohexylamine to give When sp-4-hydroxycyclohexylamine was used, the same procedure as in Example 1 was performed. Obtained.   The title compound thus obtained was crystallized from semi-equivalent ethyl acetate to give 110- It has a melting point of 111 ° C. [α]_D ²⁰= -48.6 ° (c = in dimethylformamide 1).Example 3 6-[(1S, trans) -4-hydroxycyclopentyl] -2'-O- Methyl adenosine   Instead of trans-4-hydroxycyclohexylamine, the title compound is Example 1 using S, trans-2-hydroxycyclopentylamine It is obtained in the same manner as. The title compound thus obtained has the following properties: : Foam, R in ethyl acetate / ethanol 75:25_f= 0.44, [α]_D ²⁰= − 25.5 ° (c = 1 in dimethylformamide).Example 4: 6-[(1R, trans) -2-hydroxycyclopentyl] -2'-O- Methyl adenosine   Instead of trans-4-hydroxycyclohexylamine, the title compound is When R, trans-2-hydroxycyclopentylamine is used, Example 1 It is obtained in the same manner as. The title compound thus obtained has the following properties: : Melting point: 164-166 °, R in ethyl acetate / ethanol 75:25_f= 0.4 4, [α]_D ²⁰= -80.2 (c = 1 in dimethylformamide).Example 5: 6-[(1S, trans) -2-hydroxycyclohexyl] -2'-O- Methyl adenosine   Instead of trans-4-hydroxycyclohexylamine, the title compound is Example 1 using S, trans-2-hydroxycyclohexylamine It is obtained in the same manner as. The title compound thus obtained has the following properties: : Foam, R in ethyl acetate / ethanol 75:25_f= 0.42, [α]_D ²⁰= − 26.2 ° (c = 1 in dimethylformamide).Example 6: 6-[(trans) -4-hydroxycyclohexyl] -2'-O-ethyl Luadenosine   It is produced in the same manner as in Example 5. 0.4 hydrate, melting point 98 ° C. (liquefaction). [α]_D ²⁰= -58 ° (c = 1 in dimethylformamide).Example 7: 6- [1S, (trans) -2-hydroxycyclohexyl] -2'-O- Ethyl adenosine   Manufactured as described in Example 5.Example 8: 6-[(1R, trans) -2-hydroxycyclohexyl] -2'-O- Methyl adenosine   Instead of trans-4-hydroxycyclohexylamine, the title compound is Example 1 using R, trans-2-hydroxycyclohexylamine It is obtained in the same manner as. The title compound thus obtained has the following properties: : Foam, R in ethyl acetate / ethanol 75:25_f= 0.42, [α]_D ²⁰= − 69.5 ° (c = 1 in dimethylformamide).   The compounds of the invention have interesting pharmacological properties. Therefore, they Useful as a medicine. For this purpose, the compounds according to the invention are hydrates or organic solvents, It can be used, for example, as an adduct with methanol, ethanol or ethyl acetate. The most interesting compound of formula Ia is the compound described in Example 1 above, Hereinafter referred to as Compound 1.   The compounds of formula Ia are of interest as analgesics as described above. They are, Also interesting because of other activities. Among other activities, the compounds of the present invention are Has antihypertensive activity, as suggested by the results of the study:   Adenosine A in rat cortical or porcine brain cortical or striatal membranes₁And A₂Receiving MOLEC. PHARMACOL. 29, 331-346 (1986). BRUNS, G .H. LU and T.A. Measurements using the PUGSLEY method. Further testing of the activity of this compound Using isolated, perfused rat kidney for the following parameters: -Renin secretion -Kidney hemodynamics -HYPERTENSION 4, 251-256 (1982) P.M. VANHOUTTE, D. BROWNING, E. C OEN, T.J. VERBEUREN, L. ZONNE KEYEN and M.G. Kidney god according to the COLLIS method Inhibition of release of noradrenaline from nerve endings following trans-electrical stimulation -Am. J. Physiol. 247, R1003-R1008 (1984), J.F.M. SMITS and J.M.  As an i.v. administration or drip or pill of a compound of the invention according to the method of BRODY Implanting a catheter into the abdominal aorta and vena cava following administration of a compound of the invention Blood pressure in awake, NaCl-depleted and re-accumulated normotensive and essential hypertensive rats , Heart rate, urine production and renin activity in plasma.   The results of the study show that renin secretion and release of noradrenaline from nerve endings Both inhibitions and direct vasodilation contribute to the antihypertensive activity of the compounds of formula Ia It is speculated that Urine production and electrolyte secretion are altered in contrast to lower blood pressure. It remains absent. From this, the compounds of formula Ia can be used as antihypertensive agents. Not only can it be concluded that it is effective as a coronary vasodilator. Moreover, it inhibits vascular endothelium by inhibiting both platelet aggregation and leukocyte activity. Control. Blood lipid levels are also reduced.   For the above applications, the compounds of formula Ia, the compound of Example 1 are preferred. heart Protective and analgesic applications are preferred.   In addition, compounds of formula Ia can be prepared, for example, as described in test a) below. A₂Adenosine A, selective for its activity at the receptor₁Receptor jaw By nyst activity and as suggested in eg test b) below As suggested by the ability to prolong transmission through the atrial-ventricular (A-V) valve. It is also active in treating arrhythmias. Therefore, they are associated with upper ventricular tachycardia, especially Heart rate in tachycardiac atrial fibrillation that restores sinus rhythm in upper chamber tachycardia And restores β-adrenergic-induced sinus tachycardia to normal rhythm.   Compounds of formula Ia are shown to be short-term ischemic but tolerant to infarction from subsequent ischemia. Imitates the effect of "preconditioning", which is a method of giving Therefore, they are During myocardial infarction with or without additional thrombolytic therapy during unstable angina, Or (for example) coronary artery bypass graft surgery, angioplasty, heart transplant or non-heart surgery It is useful for the protection of the heart in ischemic diseases of patients undergoing surgery.   The compound represented by the formula Ia is apt to cause myocardial infarction as a result of diagnosis, Is particularly useful for administration to patients already suffering from myocardial infarction.   The compound of formula Ia can be administered in plasma without affecting glucose tolerance. It further reduces shrine. They promote insulin action and lead to glucose uptake. Increases leaning, reduces lipolysis of adipose tissue and reduces plasma free fatty acid levels (See test d below). Low plasma free fatty acids then lead to low triglycerides , Which leads to increased HDL cholesterol.   The insulin sparing effect and / or activity of low free fatty acids is shown in formula Ia To treat type I and type II diabetes, ie, non-insulin dependent diabetes Make it useful in treating diseases.   The compounds of formula Ia reduce plasma triglycerides and free fatty acids (See test e below), increases HDL cholesterol, that is, lipid dysfunction Conditions associated with harm and increased free fatty acids and glycerides and increased H It is useful for treatment when DL cholesterol is desired.   The compounds of formula Ia show good metabolic stability.   In another aspect, the invention provides the use of a compound of formula Ia for the treatment of pain. Alternatively, it provides a use in the manufacture of a medicament suitable for the treatment of pain.   In another embodiment is of formula Ia as defined above for use in the treatment of pain Provided by the present invention.   In a further aspect the present invention provides a compound of formula Ia as defined above An analgesic composition is provided which comprises a pharmaceutically acceptable carrier or diluent. This application One uses the compound of formula Ia in the indications defined above for formula I To expect.   The following pharmacological tests illustrate the above mentioned activities of the compounds of formula Ia. a)Affinity for adenosine receptors   Porcine filamentous membranes were transferred to H. Bruns et al., Molecular Pharmacology 29 (1986) 331-34. Prepare as described on page 4. Is a non-selective adenosine receptor agonist^ThreeH- NECA, A₁And A₂Used to label both receptors. IC₅₀value is, Weighted non-linear least-square that fits Langmuir equation ) Derived from the displacement curve by the curve, pK_DCalculate the value.   The compound of formula Ia has the formula A₁For the receptor, for example, 1 to 500 nM Shows affinity in the range. b)arrhythmia   Adenosine A₁Receptor activation can be, for example, paroxysmal supraventricular tachycardia, tachycardiac atrial fibrillation. And other arrhythmia symptoms detected by increased PR interval, atrial heart- Decreased by slowing conduction through the ventricle (A-V) valve. The test method is conscious Contains records of ECG changes in mature rhesus monkeys. The compound of formula Ia  Pharmaceutical Journal 244, 595-597 (1990), C.I. Described by Clarke et al. Test of about 0.1 mg / kg to about 1000 mg / kg p.o. or 0.03 to 3 It is administered in a dose range of 0 mg / kg i.v. For example, in this test, compound 1 is Between electrocardiogram (ECG) PR at doses of 0.1, 0.3 and 0.6 mg / kg p.o. Extends the distance, suggesting a delay in conduction through the AV valve. Like above, like this Activity results in termination of AV valve reentry tachycardia and reduced heart rate of tachycardiac atrial fibrillation You. c)Preconditioning protection against infarction   Preconditioning (5 minutes of ischemia, followed by 10 minutes of recovery) was performed on the heart for subsequent ischemia (30 minutes) and And highly resistant to infarction from reperfusion (3 hours). The test described is G.S.Li. u et al, 1991-Circulation (84), 1, 350-356 and J.D. Thornton et al, 1992. -Circulation (85), 659-665. Compound of formula Ia Is administered i.v. to rabbits at a dose of about 0.01 to 10 mg / kg. This test smell Rabbits receiving 100 μg / kg of Compound 1 were treated with coronary artery occlusion for 30 minutes. There was almost as much protection as endogenous conditional protection from infarcts evoked by the interstitial space. d)Glucose transport and lipolysis in rat adipose tissue   i) Adipocytes were collected from the normal test rat epididymal fat pad for collagenase Isolate by digestion. Cells (cell concentration 2% v / v) were transferred to adenosine deaminase (1 U / Ml) and test compounds such as Compound 1 and glucose transport Pre-incubate at 37 ° C with other additives as described.   Then, [3-^ThreeH] glucose (final concentration, 50 μM, 0.5 μCi / ml) was added to 3 Add after 0 minutes and continue incubation for another 60 minutes. [3-^ThreeH] Gluco Incorporation of radioactivity of glucose into cellular lipids (measurement of glucose transport) Extraction of 0.5 ml) with 5 ml of toluene-based scintillant, followed by liquid Evaluation by scintillation counting; water-soluble metabolites and residues remaining in the aqueous phase [3 −^ThreeH] glucose is not detected.   Lipolysis is measured by a known method. In one method, cells were Incubate with or without loterenol, then incubate Continue for 60 minutes. After centrifugation, the supernatant is separated from the cells by passing through dinonyl phthalate. And lipolysis is assessed by enzymatic measurement of glycerol released in the supernatant.   The compounds of formula Ia are active in the concentration range of 0.1 to 1000 nM.   Compound 1 shows lipolysis in rat adipocytes at a concentration of 0.1 to 100 nM. Suppress with.   In the presence of adenosine deaminase (1 U / ml), compound 1 was insulin-free In the presence of [3-^ThreeH] Clear to radioactivity uptake from glucose It has no effect, only the lowest effect in the presence of maximum insulin concentration (8 nM) However, in a concentration-dependent manner, radioactivity was collected at a concentration of 0.1 to 50 nM insulin. It clearly promotes the stimulus of involvement. These observations indicate that the compound responds to insulin To increase the sensitivity of glucose transport. Almost maximum effect concentration In the presence of Compound 1, [3-^ThreeH] Insulin stimulation of glucose uptake EC about₅₀Decreases between 2 and 3 times. Adenosine deaminase and In the presence of 1 μM isoproterenol, 10-50 nM of Compound 1 is insulin Increases both sensitivity and intensity of response to insulin; EC to insulin₅₀Is 5 times And the stimulation by the maximum insulin concentration is clearly increased. ii) Lipids and glucose in normal 18-hour fasted rats   Rats aged 2 to 3 months and weighing about 250 grams are subjected to an environmental temperature of 22 ° C. and 1 Place in a room controlled by a 2/12 hour light / dark cycle for 7 days.   Purina rat Food and water are available ad libitum. After fasting for 18 hours, Test compounds (5 / group) are given a gastric probe in 0.5% CMC. Animals are 1.0 ml / 100g body weight is administered. After 3 hours from the administration, CO₂Anesthetize and blood Collect by heart puncture. Serum was collected for glucose, free fatty acids and β-hydroxide. Used for Roxybutyric acid measurement. Acyl-COA peroxidase colorimetry of free fatty acids Glucose oxidase method (YSI model 27, Yell ow Spring, Oh) and β-hydroxybutyric acid with β-hydroxybutyric acid dehydrogen It is measured by the enzyme-linked enzyme assay (Sigma Kit 310-A-St. Louis, Mo.). formula The compounds represented by Ia are active at doses of about 1 to about 5000 μg / kg.   The dose of Compound 1 that reduces free fatty acids (the main consequence of its effect on adipocytes) is The dose after 2 hours is between 5 and 100 μg / kg. This is β-hydroxy It results in a dose-dependent decrease in butyric acid and blood glucose concentrations. iii) Effects in non-insulin dependent diabetic (NIDD) rats   In the NIDD screening test, rats (200-220 g) were fed a high fat diet. Eat freely. 40 mg of streptozotocin / kg of body weight at the dietary stage Inject through the tail vein. One week later, the rats were exposed to postprandial blood glucose after an overnight fast. Higher than 200 mg / dl, in the case of oral glucose tolerance test, blood glucose was measured 3 hours after the test. It has a lucose concentration of 40 to 80 mg / dl and is considered to be diabetic. After 4 days in blood Use animals for screening if glucose concentration is higher than 180 mg / dl . Blood glucose concentration is measured with a YSI Glucose Analyzer. Long-term screen The training test is performed as follows:   On day 1, deprive rats of food at 9:00 a.m .: first blood glucose reading Is administered via the tip of the tail and vehicle (subject) or compound (9 rats / treatment) is orally administered. Give. Blood glucose levels are measured 6 hours later; and immediately thereafter, in rats. Feed again.   The same rats are administered either vehicle or drug once daily for 11 consecutive days. blood Medium glucose is measured at 0, 4, 8 and 11 days and 6 hours after fasting I do. A compound of formula Ia, such as Compound 1 100 microgram / kg Results in a pronounced reduction in plasma free fatty acids, which significantly reduces blood glucose. e)Non-lipidemia characterized by increased serum triglycerides   Some studies have shown that serum triglyceride levels (and associated HDL cholesterol There is a clear relationship between decreased roll levels and the risk of ischemic heart disease (CHD). (Grundy, Cholesterol and Atherosclerosis: Diagnosis and Trea tment, Lippincott, Philadelphia (1990)). To reduce the risk of CHD The value of decreasing triglyceride concentration as a trial is Helsinki Heart Styd y revealed that treatment with Genfibrozil was followed by LDL-choles Both sterols and total serum triglycerides are increased and HDL cholesterol Of severe coronary events in patients with type IIB hyperlipidemia, where A big decrease occurs. Compounds of formula Ia have about 0.03 to 30 (eg, 0 0.1 to 30) mg / kg i.v. and 0.1 to 100 (eg 0.1 to 10) mg / kg It is active in rhesus monkeys in an amount of kg p.o. Compound 1 is 0.03-0.6 mg / kg i.v. and 0.1-1.2 mg / kg p.o. dose-dependent and long-term in rhesus monkeys It produces a subsequent decrease in plasma free fatty acids and triglycerides. Compound 1 0.6m g A typical result of / kg p.o. is up to about 60% release compared to the subject after 300 minutes. Shows up to 40% reduction of fatty acids and triglycerides.   The compounds of formula Ia are suitable for the administration of mean arterial blood pressure, bradycardia and peripheral It is also active in extended testing.   The experiment is a male Wistar rat, weight 300-350 g, and anesthesia with pentotar. (120 mg / kg i.p.), Salzmann et al. (J. Cardiovasc. Pharmacol. 12, 451-460, 1988). Catheter to the right jugular vein and right femoral vein, Left ventricle (inserted via right carotid artery), left femoral artery and aorta (via right femoral artery) Then insert). Measure or calculate the following variables: systole, diastole and And mean arterial blood pressure (mmHg; left femoral artery, Statham pressure transducer P23Gb) , Pulse pressure (mmHg), heart rate (beat / min; trigger from blood pressure curve), rate of increase in left ventricular pressure (dP / Dt_max, MmHg / s; Statham pressure transducer P23Gb), cardiac output (ml / Min / 100g body weight, thermodilution method, right jugular vein and aorta), total peripheral resistance (dynes-s.cm)^-Five / 100 g body weight), surface ECG. Aortic blood pressure, left ventricular pressure, dP / dt_max,Heart rate And electrocardiograms are recorded continuously on the Schwarzer polygraph. Parameter is trial Injection of test substance 30, 20, 10 and 2 minutes before administration of test substance and in the right femoral vein It is measured after 1, 5, 10 and 15 minutes. The compound of formula Ia has about 0 Inject in an amount of 0.001 to about 10 mg / kg animal body weight. Compound 1 has a cumulative amount of 0.00 3, 0.010 and 0.03 mg / kg, tested using 3 animals per dose . Compound 1 is blood pressure [ED₅₀= 49 micrograms / kg iv] and heart rate , Increased systemic vascular conductance.   The dose of the compound of formula Ia used in the above application depends on the severity of the disease, It varies in the usual way depending on the body weight and the relative effect of the compound. However As a general indicator, suitable unit doses are 0.1 to 10, 0.5 to 200, 0. 0.1 to 1000 mg, such as 0.5 to 100 or 0.5 to 10 mg, eg 0.1. Can be 1, 0.5, 1, 2, 3, 4 or 5 mg; and such unit dose Is a mammal including 70 kg of human, 0.007 to 3, 0.007 to 1.4, 0.0. About 0.001 such as 007 to 0.14 or 0.01 to 0.5 mg / kg / day La 20 mg / kg / day range, eg 0.01, 0.02, 0.04, 0.05, 0.0 6, 0.08, 0.1 or 0.2 mg / kg / day, about 0.1 to 1000 mg, eg Oral or 0.003 to 300 mg i.v. once a day or more, eg For example, it may be given 2, 3, 4, 5 or 6 times a day, but preferably once a day. Or two times administered; and such treatment may extend over weeks or months . For compound 1, the preferred dose range in all applications of the invention is 70 It is 0.1 mg / day to 10 mg / day for a kg adult. Preferred indications non-insulin Dose Applied in Humans for Dependent Diabetes and Hypertriglyceridemia 0.2 to 2 mg / day orally and 0.2 for the treatment of heart failure and other heart disorders 10 mg / day, especially 0.5 to 5 mg / day, oral or arrhythmia, eg atrial fibrillation 0.25 to 5 mg i.v. due to tachycardia.   The compounds of formula Ia are suitable for administration by a suitable route (preferred route to the disease in need of treatment). Dependent) and preferably in a unit dosage form or by the patient It may be formulated so that a single dose can be administered to the human body. Advantageously, the composition is for analgesic use. For oral, rectal, topical, parenteral, intravenous or intramuscular administration as described above. I do.   The unit dosage form for oral administration comprises 0.05-20 mg of the compound of formula Ia. It may be a tablet or capsule.   Suitably, the compound, hydrate or adduct with organic solvent of the invention comprises about 0% of the formulation. 0.5 to about 20% by weight, preferably about 1 to about 10%, for example 2 to 5% .   R '₁Is hydroxy (C_4-8) Cycloalkyl and R_ThreeIn formula Ia where is alkyl The compound shown is R₁Is (C_4-8) Cycloalkyl and R_ThreeA formula in which is alkyl When the compound represented by I is administered to warm-blooded animals such as rat, dog and human It is detected as a metabolite of.   Therefore, administration of Compound M is dependent on hydroxycyclohexyl-2'-O-methyl Guides the production of denosine.   In a further aspect, the invention provides N⁶-Cyclohexyl-2'-O-methyl adeno Administration of syn to warm-blooded animals,⁶-Hydroxycyclohexyl-2'-O-methyla A method of producing denosine is provided.   In another aspect, the invention provides N⁶-Hydroxycycloalkyl-2'-O-ar Killadenosine is provided in a pure form, eg, 95% or more pure. In this specification The exemplified compounds described meet this criterion.   In another aspect, the present invention provides cyclohexyl-2′-O-methyladenosine N not included⁶-Hydroxycyclohexyl-2'-O-alkyladenosine provided I do.   In another aspect, the invention provides adenosine in the presence of a phase transfer catalyst. Preparation of 2'-O-alkyladenosine comprising treatment with kylsulfate Provide the law.   Preferably 2'-O-alkyladenosine is a compound as defined above.   In a further aspect, the invention provides a compound of formula VI The compound represented by                               (R_Three)₂SO_Four A base solution of the compound shown by and tetrabutylammonium hydrogen sulfone The product is purified by recrystallization by reacting in the presence of a solvent and a non-polar solvent. There is provided a process for the preparation of a compound of formula I as defined above, comprising:   If desired, reactive groups may be temporarily protected.   Preferably the alkyl sulfate is di (C_1-4) It is an alkyl sulfate.   Preferably, the phase transfer catalyst is tetrabutylammonium hydrogensulfate. It is.   Preferably the reaction is carried out in a non-polar solvent, eg as described below.   R₁Is (C_3-8) Cycloalkyl, R₂Is hydrogen or (C_1-4) Alkyl and R_ThreeBut( C_1-4) A group of compounds of formula I, which is alkyl, is defined.   To date, the preparation of compounds of formula I has typically involved 6 steps, which Preparation of ', 3', 5'-triacetylinosine; 6-chloro-9-β-D-ribofla Chlorination and hydrolysis to nosyl-9H-purine; 3'-O- and 5'-O-positions Tetraisopropyridisiloxane (TIPDS-CL₂) Protection; 2'-O-a Purification and silica gel chromatography; 3'-O- and 5'- O-position deprotection; and R₁NH₂Reaction with and to obtain a compound of formula I It consists of recrystallization for   Applicants have observed that compounds of formula I are 3'-O- and 5'-O-disiloxa. Good, without the need for protection and deprotection or silica gel chromatography It was discovered that it can be produced with high yield and purity. Applicant is the prior art inosine- The 2 ', 3', 5'-triacetate starting material method is preferably applied to the lipophilic inosine-2 ', 3'. 5,5'-tripropionate can be converted to twice the efficiency and undesired pyridine dissolution. It has been discovered that it enables removal of the medium.   In the present invention, the compound represented by the formula I is reacted in the presence of a phase transfer catalyst as described below. Manufacturing according to the reaction scheme: [Wherein, R₁, R₂And R_ThreeIs the meaning defined above].   The compound of formula I is prepared by reacting a basic aqueous solution of the compound of formula (VI) with di- (C_1-4) Alkyl sulphate and tetrabutylammonium hydrogen sulphate It can be produced by reacting in the presence of a fate and an organic water-insoluble solvent. Basic aqueous The base used to prepare the solution is preferably sodium hydroxide or potassium hydroxide. It is an alkali metal hydroxide such as um. The compound of formula I is soluble in the solvent Water soluble or essentially insoluble solvents such as methylene dichloride or It is t-amyl alcohol. The reaction proceeds at about -20 ° C to about 50 ° C, especially at room temperature. Is also preferred. The reaction time is not critical, but preferably about 5 to 10 Over a period of time, especially about 7 to 8 hours. The crude compound of formula I is Isolation, followed by a 1: 1 mixture of water and an inert solvent, preferably toluene, Stir at room temperature for 5-7 hours, then filter and dry. Pure compound is fractionated Crystallization, preferably: 1) Dissolve the crude compound in a solvent at 80 ° C, heat at about 55 ° C for about 1 hour, and cool to room temperature And seeding the pure compound and filtering to give an inert solvent such as toluene. Recrystallization from En; 2) Repeated recrystallization of step 1), but heated at about 65 ° C before cooling to room temperature Do; and 3) Dissolve at reflux temperature, dilute with water, seed, then filter and dry Recrystallization from 100% ethyl alcohol Can be obtained by   Many of the compounds of formula VI are known and are described in USP 4,843,066 and And USP 4,985,409. In formula VI The compounds shown are suitable as described above according to the preferred reaction schemes below. Can be manufactured to: [Wherein, R₁And R₂Is the meaning defined above].   The compound represented by the formula VI is obtained by converting the inosine represented by the formula VII into propionic anhydride. Acylated, 2'-O-, 3'-O-, 5'-O-protected compounds of formula VIII A compound of formula VIII is halogenated with thionyl chloride to give a compound of formula IX To form the intermediate shown; and to simultaneously aminate and It can be produced by hydrolysis. The acylation of inosine is preferably 10 in a mixture of ene, tributylamine and 4-dimethylaminopyridine Perform at a temperature of 0 ° to 110 ° C. for 4 to 5 hours. Formula VIII The compound is isolated by precipitation with hexane. Halogenation of compounds of formula VIII Is preferably about 6 in a mixture of toluene and N, N-dimethylformamide. Of the compound of formula IX at a temperature of 0 ° to 70 ° C. for 3 to 4 hours. The solution can be used after washing with water and brine. Amination of the intermediate of formula IX And the simultaneous hydrolysis is preferably performed with the amine R₁H₂Is added from 100 ° to 11 It is carried out by reacting at a temperature of 0 ° C. for 15 to 20 hours. Shown by Formula VI The compound obtained is isolated by filtration at room temperature and purified by recrystallization.   The process of the present invention will be described by the following examples.Method Example 1: N ⁶ -Cyclohexyl-2′-O-methyladenosine Process A Inosine-2 ', 3', 5'-tripropionate   Inosine 271.2 g, tributylamine 966 ml, 4-dimethylaminopyri A mixture of 3.30 g of gin and 600 ml of toluene was added at an internal temperature of 104-105 ° C. Heat to 435 ml of propionic anhydride over 35 minutes at a temperature of 104-1. Add at a rate such that it is maintained at 05 ° C. The mixture is stirred at that temperature for a further 4 hours After that, the mixture is cooled to 5-10 ° C. in an ice bath; 1000 ml of heptane are added. The resulting suspension is stirred at room temperature (20-22 ° C) for 30 minutes, eg in a Buchner funnel. Filter. The solid is washed with a total of 450 ml heptane divided into 3 portions of 150 ml each, 4 After drying at 5-50 ° C (25 mmHg) overnight (14 hours), inosine-2 ', 3', 5'-tri 425.9 g of propionate are produced as a white solid (MP 171-172). ° C; yield 96.5%).Step B N ⁶ -Cyclohexyl adenosine   Inosine-2 ', 3', 5'-tripropionate 270.6 g, N, N-dimethyl A mixture of 240 ml formamide and 600 ml toluene is heated at 65 ° C .; 1 Over time, 67.84 ml of thionyl chloride were maintained at an internal temperature of 62-65 ° C. Add at a rate The mixture is stirred at that temperature for a further 2.5 hours, then 1 in an ice bath. Cool to 0 ° C. 600 ml of water that had been cooled to 10-15 ° C in an ice bath at a temperature of 20 After addition at a rate maintained below ℃, the organic phase was separated and divided into 4 portions of 200 ml each. Wash with a total of 800 ml of 10% aqueous sodium chloride. Crude 6-chloro-9- (2,3 , 5-tri-O-propionyl-β-ribofuranosyl) -9H-purine To the 620 ml of cyclohexylamine heated to 105 ° C while stirring the organic phase, 2 Add over time, at such a rate that the internal temperature is kept at 105 ° C. Add this mixture After stirring for 17 hours at room temperature, stir well at room temperature (25 ℃) for about 2 hours. While cooling, then the solution is filtered, for example in a Buchner funnel. N⁶-Cyclo 115 ml of solid containing hexyladenosine and cyclohexylamine hydrochloride Wash with a total of 460 ml of toluene divided into 4 parts and stir in a 51 flask equipped with a stirrer. Move to 2 liters of saturated aqueous sodium hydrogen carbonate solution and 2 ethyl acetate After adding 0.5 liters, the mixture was stirred until all solids were dissolved (about 10-15 minutes). Mix. The organic phase is separated; the aqueous phase is divided into 1 liter and 500 ml each for 2 minutes. Extract with 1.5 liters of split ethyl acetate.   Combine the organic phases and evaporate (40 ° C, 1 00-200 mbar). 500 ml of heptane are added to the residue; the resulting mixture The mixture is stirred for 30 minutes. The solid was separated on a Buchner funnel and divided into three 100 ml portions. Wash with a total of 300 ml heptane. The solid is then placed at 45-50 ° C (30-35 mba r) and dried for about 3 hours to obtain crude N⁶-148 g of cyclohexyl adenosine is white solid Produce as the body. Transfer this to a 1 liter round bottom flask equipped with a stirrer and Add 175 ml of% ethanol. The suspension is stirred for 15-20 minutes and 95% ethanol 175 ml are added. After stirring for 5 minutes, the suspension is cooled in an ice bath for another 15 minutes. Stir. The suspension was filtered through a Fuchner funnel and divided into 25 ml each, totaling 50 ml. Wash with tert-butyl methyl ether.   The filtered solid is dried at 45-50 ° C. (30-35 mbar) for 14 hours, N⁶-Cyclo 130 g of xyladenosine is obtained as a white solid (m.p. 185-187 ° C; yield). 60%).Step C N ⁶ -Cyclohexyl-2′-O-methyladenosine   N⁶-Cyclohexyl adenosine 94.33 g and 5% aqueous sodium hydroxide 720 g are stirred at room temperature (24-25 ° C.) until all solids are dissolved (about 5 minutes). Using an addition funnel, add 850 ml of dichloromethane and tributylammonium 5.5 g of idrogen sulfate was added, followed by 61.3 g of dimethyl sulfate. Add over 10 minutes while maintaining the internal temperature at 24-25 ° C. Additional funnel Is further washed with 50 ml of dichloromethane and it is added to the reaction vessel. Two-phase mixture After stirring at 24-25 ° C (internal temperature) for 7.5 hours, the organic layer was separated, and 40 ° C (2 Evaporate at 70-290 mbar) until the solvent is no longer distilled. The residue is toluene 2 Dissolve in 00 ml and at 45-50 ° C (30 mmHg) until the solvent is no longer distilled Evaporate.   A mixture of the above crude material and 2470 ml of toluene was stirred at room temperature for 10 minutes, then , 2470 ml of water are added over 22 minutes. The resulting suspension at room temperature for a further 6 hours Stir and collect the solid by filtration, eg, with a suction Buchner funnel. Solid toluene Wash with 114 ml and a total of 285 ml of water divided into 3 portions of 95 ml each to give a solid of 48-5. Dry overnight (14 hours) at 0 ° C. (25 mm Hg) to yield 53.0 g of a white solid. G A suspension of this solid in 397 ml of ruene was heated to 80 ° C. with stirring to give a clear solution. And cooled to 56 ° C. over 45 minutes and seeded with 10 mg of pure product. mixture The mixture is stirred at 55-56 ° C for 45 minutes and then cooled to room temperature over 1 hour. After stirring at room temperature for a further 1 h, the solid is collected, for example by filtration with a suction Fuchner funnel. I do. The solid was washed with a total of 75 ml of toluene divided into 3 portions of 25 ml each to give a white solid 6 It produces 0 g. A suspension of this solid in 159 ml of toluene is heated again to 80 ° C. Then, the seed crystal addition step is performed at 65 ° to 66 ° C.   After cooling at room temperature for 1 hour and stirring at the same temperature for another hour, the solid is filtered. And wash with a total of 42 ml of toluene divided into 3 portions of 14 ml each, 48-50 ° C (25 m Dry (mHg) overnight (14 h) yielding 57.7 g of a white solid. Solid and 10 122 ml of 0% ethanol was heated to reflux temperature with stirring to obtain a clear solution. 288 ml of water warmed to 55 ° C. are added over 25 minutes. Cool the mixture to 55 ° C And seeded with 20 mg of pure product. The mixture was cooled to room temperature for 1 hour and Stir overnight (16 hours) at the temperature. Solids are collected by filtration on a suction Buchner funnel Then, a total of 57 ml of 100% ethanol and water 1: 2.3 each divided into 19 ml. Wash with 6 mixtures (v / v). The solid was dried at room temperature (29 mmHg) and the product was 62.2 g. As a white solid in the form of a 1.5 hydrate (m.p. 88 ° -91 ° C; yield 42.5%). ).Method Example 2:   Follow the above method, but with equal amount of N⁶-Using cyclopentyl adenosine, N⁶− Cyclopentyl-2^'-O-methyladenosine is obtained.Method Example 3:   Follow the steps of Method Example 1, but replace the dichloromethane of step C) with tert-amylal. Following the first ethanol / water crystallization, switch the product to ethanol and Recrystallize from water. N⁶-Cyclohexyl-2'-O-methyladenosine 32. 1 g (yield about 30%) is obtained with a purity of 98% or higher.   The process of the invention is more time and economically practical than the methods known to date. It is a target. The method is N⁶-Selection of cyclohexyl adenosine under phase transfer conditions 2'-O-methylation and purification of 2'-O-methyl derivatives are provided. Expensive The use of various protecting groups and chromatography is avoided.

────────────────────────────────────────────────── ─── Continuation of front page    (31) Priority claim number 9416693.1 (32) Priority date August 18, 1994 (33) Priority claim country United Kingdom (GB) (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, M C, NL, PT, SE), OA (BF, BJ, CF, CG , CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, MW, SD, SZ, UG), AM, AT, AU, BB, BG, BR, BY, CA, C H, CN, CZ, DE, DK, EE, ES, FI, GB , GE, HU, IS, JP, KE, KG, KP, KR, KZ, LK, LR, LT, LU, LV, MD, MG, M N, MW, MX, NO, NZ, PL, PT, RO, RU , SD, SE, SG, SI, SK, TJ, TM, TT, UA, UG, US, UZ, VN (72) Inventor Prashad, Mahavir             United States 07843 New Jersey               Hopat Kong, West End A             Venue 228 (72) Inventor Kapa, Prasad Kay             07054 New Jersey               Parsippany, Favor Road 4             Turn

Claims (1)

[Claims] 1. Formula (I): [Wherein R ₁ is hydrogen, (C _1-4 ) alkyl, allyl, methallyl, straight chain or branched (C _3-7 ) alkynyl, (C _3-8 ) cycloalkyl, hydroxy (C _4-8). ) Cycloalkyl, phenyl (wherein phenyl is selected from the group consisting of halogens having atomic numbers 9 to 35, (C _1-4 ) alkyl, (C _1-4 ) alkoxy or CF ₃ and is mono or independent. Or phenyl (C _1-4 ) alkyl (wherein the phenyl ring is unsubstituted or halogen of atomic number 9 to 35, (C _1-4 ) alkyl, (C 4 _l-4 ) alkoxy or CF ₃ selected from the group consisting of mono- or independently di-substituted): (C _1-4 ) alkyl having at least one hydroxy group or at least two phenyl rings, Like endo- or exo-bicyclo [2,2,1] heptyl A bicycloalkyl, naphthyl (C _l-4) alkyl, acenaphthylenyl (C _1-4) alkyl or Formula A or Formula B (In the formula, Z is hydrogen, hydroxy or (C _1-4 ) alkoxy, Q is hydrogen or hydroxy, A is —CH ₂ —, —O—, —S— or a direct bond, and Y is — (CH ₂ ) _n. -Or a direct bond, n is an integer of 1 to 3, and the dotted line in formula A means any bond), R ₂ is hydrogen, (C _1-4 ) alkyl, amino, (C _{3 -5} ) Use of a cycloalkyl or a compound represented by halogen of atomic number 9 to 35 and R ₃ is (C _1-4 ) alkyl] as an analgesic in the manufacture of a medicament suitable for treating pain. 2. The use according to claim 1, wherein the compound of formula I is selected from 6'-hydroxy ( _C4-8 ) cycloalkyl-2'-O-methyladenosines. 3. Use according to claim 1, wherein R ₁ is other than hydroxycycloalkyl. 4. Use according to claim 3, wherein the compound of formula I is 6-cyclohexyl-2'-O-methyl-adenosine. 5. Use according to any of claims 1 to 4 for acute pain. 6. Use according to any of claims 1 to 5 for chronic neuropathic pain. 7. 7. Use of a compound according to any of claims 1 to 6 for the treatment of pain, or administration of a compound according to any of claims 1 to 6 to a patient in need thereof. An analgesic composition comprising the method for treating pain according to any one of 1 to 6 or the compound according to any one of claims 1 to 6 as an analgesic together with a pharmaceutical carrier or a diluent. 8. Formula Ia [Wherein R ′ ₁ is (C _4-8 ) cycloalkyl substituted by a hydroxy group, R ₂ is as defined in claim 1 and R ₃ is as defined in claim 1] . 9. The compound according to claim 8, wherein R ₂ is hydrogen, (C _1-4 ) alkyl or halogen of atomic number 9 to 35. 10.6-[(trans) -4-Hydroxycyclohexyl] -2'-O-methyladenosine 6-[(cis) -4-hydroxycyclohexyl] -2'-O-methyladenosine 6-[(1S, trans) 2-Hydroxycyclopentyl] -2'-O-methyladenosine 6-[(1R, trans) -2-hydroxycyclopentyl] -2'-O-methyladenosine 6-[(1S, trans) -2-hydroxycyclohexyl] -2'-O-methyladenosine 6-[(1R, trans) -2-hydroxycyclohexyl] -2'-O-methyladenosine 6-[(trans) -4-hydroxycyclohexyl] -2'-O-ethyladenosine , And 6- [1S, (trans) -2-hydroxycyclohexyl] -2′-O-ethyladenosine: a compound selected from the group consisting of: 11. A compound according to claim 8, 9 or 10 which is 11.95% pure. 12. The compound according to claim 8, 9 or 10, which is free of N ⁶ -cycloalkyl-2′-O-methyladenosine. 13. For the manufacture of a medicament suitable for the treatment of pain, for use against hypertension as a coronary vasodilator, for the inhibition of both platelet aggregation or leukocyte activity, for the reduction of blood lipid levels, for congestive heart failure, For myocardial infarction, sudden cardiac death, renal failure, for treatment of hypertriglyceridemia / low HDL cholesterol concentration, lipid dysfunction, elevated free fatty acid and / or type I and type II diabetes, arrhythmia or for myocardial infarction Use of a compound of formula Ia according to any of claims 8 to 12 for protection. 14． A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula Ia according to any of claims 8 to 12 together with a pharmaceutically acceptable carrier or diluent. 15. Pain, hypertension, coronary vasodilation, platelet aggregation, high blood lipid levels, congestive heart failure, sudden heart death, renal failure, hypertriglyceridemia / low HDL cholesterol levels, lipid dysfunction, elevated free fatty acids or type I or II Administering a compound according to any one of claims 8 to 12 or a compound of formula Ia for use in the treatment of type 2 diabetes, arrhythmia and protection against myocardial infarction to a patient in need thereof. Uses of such compounds, including. 16. A process for the preparation of 2'-O-alkyl adenosine which comprises treating adenosine with a suitable alkyl sulphate in the presence of a phase transfer catalyst. 17． A process according to claim 16 for preparing a compound of formula I as defined in claim 1. 18. 17. The method of claim 16, wherein the compound produced is N-cyclohexyl-2'-O-methyladenosine. 19. A compound produced by the method of any one of claims 16, 17 or 18. 20. N ⁶ - to produce hydroxycyclohexyl -2'-O-methyl adenosine, N ⁶ to a warm-blooded animal - method of administering cyclohexyl -2'-O-methyl adenosine.