SK13192A3 - Using of 2'-o-alkyladenosine derivatives for preparing of medicine suitable for treating of neurodegenerative defects - Google Patents

Abstract

Use of 2'-O-alkylladenosine derivatives of the general of formula I wherein R 1, R 3 and R 3 are as defined above in claim 1, for the preparation of a medicament for the treatment of neurodegenerative disorders, some peripheral neuropathies, for example diabetic neuropathy, and related disorders with peripheral vascular disease and / or disorders associated with neuronal degeneration, hypertriglyceridaemia, increased levels of free fatty acids and / or type I and Π type diabetes and arrhythmias and for protection myocardial infarction. Some general compounds of Formula I can be used to lower the high level blood lipids.

Description

The invention relates to a novel use of 2-O-alkyladenosine derivatives which are the subject of British patent application 2226027 A and European patent applications 378518 and 269574, pharmaceutical compositions containing these compounds and their use in medicine. Furthermore, the invention relates to 6-cyclohexyl-2'-O-methyladenosine hydrate.

BACKGROUND OF THE INVENTION

It is known from the above British patent application that said compounds can be used as antihypertensive agents and coronary vasodilators. It is mentioned that both inhibition of renin secretion and inhibition of noradrenaline release from nerve endings and primary vasodilation contribute to antihypertensive activity. It is further disclosed that said compounds protect the vascular endothelium by inhibiting both thrombocyte aggregation and leukocyte activation. Said compounds also allegedly reduce blood lipid levels. It is further noted that some of the above 2-O-alkyladenosine derivatives also exhibit a protective effect against diseases caused by hypertension, such as congestive heart failure, myocardial infarction or sudden cardiac arrest and renal insufficiency (see European Patent Applications 3785 18 and 269574). .

SUMMARY OF THE INVENTION

It has now been found that compounds of British Patent Application 2226027 and European Patent Applications 378518 and 269574 have surprising potential applications in the treatment of peripheral vascular diseases such as intermittent claudication and Raynaud's disease.

The compounds are also effective in treating arrhythmias. As adenosine A 1 -receptor agonists, these compounds reastaurate the sinus rhythm in supraventricular tachycardia and return the ventricular tachycardia induced by beta-adrenergic stimulation back to normal rhythm.

In the function of adenosine A1 receptors, they precondition the heart by imitating a short period of ischemia and thereby making the heart resistant to infarction by subsequent ischemia. These compounds can therefore be used to protect the heart against heart attack.

Neuroprotective activity was also found for the compounds. These compounds are therefore useful for the treatment of neurodegenerative disorders and certain peripheral nauropathies, in particular diabetic neuropathy, and for the prophylaxis of peripheral vascular disorders associated with neuronal degeneration.

The compounds reduce the plasma level of insulin without affecting glucose tolerance. These compounds promote the effect of insulin on the growth of glucose in adipose tissue. The compounds also reduce the content of free fatty acids in the blood plasma. The effect of optimizing insulin management of the organism and / or reducing the content of free fatty acids in the blood plasma makes said compounds useful for the treatment of type I and type II diabetes.

Since these compounds lower the plasma levels of triglycerides and free fatty acids, these compounds are useful in cases where the plasma levels of triglycerides and free fatty acids have increased.

In conclusion, the compounds show good metabolic stability.

Accordingly, the invention provides a method of treating neurodegenerative disorders, certain peripheral neuropathies, for example diabetic neuropathy, as well as disorders associated with peripheral vascular disease and / or disorders associated with neuronal degeneration, hyperglyceridemia, elevated levels of free fatty acids and / or type I diabetes. and type II and the arrhythmia and method of protecting against myocardial infarction, which comprises administering an effective, non-toxic amount of a compound of formula I

in which

R ^- * is H, alkyl of 1 to 4 carbon atoms, allyl, methallvlovou group, a straight-chain or branched alkynyl group having 3 až'7 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, phenyl which is independently mono- or di-substituted with a halogen atom of 9 to 35, an alkyl of 1 to 4 carbon atoms, an alkoxy of 1 to 4 carbon atoms or a trifluoromethyl group, or a phenylalkyl group in which the alkyl radical contains 1 to 4 carbon atoms and wherein the phenyl ring is optionally independently non- or disubstituted with a halogen atom of 9 to 35, an alkyl of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms or a trifluoromethyl group, an alkyl group of 1 to 4 carbon atoms having at least one hydroxyl group or at least two phenyl groups, bicycloalkyl a naphthylalkyl group in which the alkyl radical contains 1 to 4 carbon atoms, an acenaphthylenylalkyl radical in which the alkyl radical contains 1 to 4 carbon atoms, or a group of formula II or formula III

(III) in which:

Z represents a hydrogen atom, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms,

Q represents a hydrogen atom or a hydroxyl group,

A is -CH4-, -O-, -S- or a direct bond, n is 1 to 3, and the dotted line in formula II is an optional bond, is hydrogen, C1-C4alkyl, amine a C 3 -C 5 cycloalkyl group or a halogen atom of 9 to 35 and

R 1 represents an alkyl group having 1 to 4 carbon atoms, to a person in need of such treatment.

The compounds of formula I may be used as such, as hydrates or as addition products with other solvents, for example ethanol, and some compounds of formula I may be used in the form of salts.

The invention further provides the use of a compound of formula I or a hydrate or addition product thereof with other solvents or salts thereof for the preparation of a medicament for the treatment of neurodegenerative disorders, certain peripheral neuropathies, e.g. diabetic neuropathy, and disorders associated with peripheral vascular disease and / or disorders associated with peripheral vascular disease. neuronal degeneration, hyperglyceridemia, elevated levels of fatty acids and / or diabetes of type I or type II, arrhythmias and for protection against myocardial infarction.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a hydrate thereof, or an addition product with other solvents or salts thereof, and a pharmaceutically acceptable carrier.

In particular, the invention relates to the use of a compound of the formula I in which R R represents a cycloalkyl group having 3 to 8 carbon atoms, in particular a cyclohexyl group,

R2 represents a hydrogen atom and R1 represents an alkyl group having 1 to 4 carbon atoms, in particular a methyl group, or a hydrate thereof for the preparation of a medicament for the treatment of neurodegenerative disorders, certain peripheral neuropathies, e.g. diabetic neuropathy, and disorders associated with peripheral vascular disease and / disorders associated with neuronal degeneration, hypertriglyceridemia, elevated levels of fatty acids and / or diabetes of type I and type II and arrhythmias, and for protection against myocardial infarction.

Compounds of formula Ia

in which

R a represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms optionally having at least one hydroxyl group or at least two phenyl groups, a bicycloalkyl group, a naphthylalkyl group in which the alkyl moiety contains 1-4 carbon atoms, an acenaphthylenylalkyl group in which the alkyl moiety it contains 1 to 4 carbon atoms or a group of formula II

Or of formula III

in which

Z, Q, A, Y and n are as defined above,

R 6a represents a hydrogen atom, an amino group, an alkyl group having 1 to 4 carbon atoms or a halogen atom having an atomic number of 9 to 35 and

R 6a represents an alkyl group having 1 to 4 carbon atoms, being very effective in reducing the plasma level of lipids.

Accordingly, the compounds of formula Ia are useful for treating disorders associated with high blood lipid levels, the method comprising administering to a person in need thereof an effective, non-toxic amount of a compound of formula Ia.

The compounds of formula Ia can thus be used for the preparation of medicaments for the treatment of high blood lipid content.

The following compounds 1 to 13 of formula I wherein R 1, R 2 and R 3 are as defined below are described in British patent application 2226027 A. The following compounds 14 to 41 of formula I wherein R 1, R 2 and R 2 are as defined below, are described in European Patent Application 378518 and the following compounds 42-54 of the general formula I, in which R 6 and R 6 and R 6 are as defined below, are described in European Patent Application 269574. preferred for use according to the invention.

table

Slouče- nina no. ^R 1 ^R 2 ^R 3 1 cyclopentyl H ch ₃ 2 p-methoxyphenyl pi ^CH 3 3 cyclopentyl H c ₂ h, 4 cyclopentyl ^CH 3 ch ₃ 5 cyclopentyl br ch ₃ 6 cyklopropy1 H CH ₃ 7 cyclohexyl H ^CH 3 8 cycloheptyl H CH ₃ 9 p-fluorophenyl H CH CH 3 10 p-chlorophenyl H ^CH 3 1 1 (R) phenyl-CH ₂ CH (CH ₃ ) - H ch ₃ 12 allyl H CH ₃ 13 prop-2-ynyl H CH ₃ 1 4 2,3-dihydroxypropyl H CH ₃ 15 benzyl H CH ₃ 16 2,2-diphenylethyl H CH ₃ 17 exo-dicyclopentadiene / 2.2.1 / heptyl H CH ₃ 18 endo-dicyclopentadiene / 2.2.1 / heptyl H CH ₃

Table (continued) Slouče- nina no. ^R 1 ^R 2 ^R 3 19 (1-naphthyl) methyl H ch ₃ 20 (1-acenaftyleny1) methyl H CH 3 21 (1,2-dihydro-1-acenaphthylenyl) of methyl H ^CH 3 22 (2,3-dihydro-1H-inden-1-yl) H CH ^e 3 23 (2,3-dihydro-1H-inden-2-yl) H CH 3 24 (2,3-dihydro-1H-inden-1-yl) methyl H CH 25 (3H-inden-1-yl) methyl H C ' ^{and C} 3 26 (5-methoxy-2,3-dihydro-1H-inden-1-y1) H ch ₃ 27 (1-tetrahydronaphthyl) H ch ₃ 28 (2-tetrahydronaphthyl) H ch ₃ 29 (3,4-dihydro-1-naphthyl) methyl H CH 3 30 (5-hydroxy-1-tetrahydronaphthyl) H CH 3 31 (1-hydroxy-1-tetrahydronaphthyl) methyl H ch ₃ 32 (5-methoxy-1-tetrahydronaphthyl) H ch ₃ 33 (6-methoxy-1-tetrahydronaphthyl) H CH ₃ 34 (7-methoxy-1-tetrahydronaphthyl) H CH 3 35 (4-chromanyl) H ch ₃ 36 (4-thiochromanyl) H CH 3 37 (9-fluoro enyl) H ch ₃ )

Table (continued)

Slouče- nina no. ^R 1 ^R 2 ^R 3 38 (9-fluorenyl) methyl H ch ₃ 39 (9-hydroxy-9-fluorenyl) methyl H C » ₃ 40 (9-xanthenyl) methyl H ch ₃ 41 cyclohexyl ^CH 3 ^CH 3 42 H H CH ₃ 43 H H c ₂ h 44 H H ^C 4 ^H 45 H ^CH 3 ch ₃ 46 H ^C 3 ^H 7 ^CH 3 47 H ch ₃ c ₄ h 48 ch ₃ H ^CH 3 49 ^C 4 ^H 9 H CH ₃ 50 CH ₃ ch ₃ CH ₃ 51 CH ₃ ch ₃ C ₂ H 52 ^C 4 ^H 9 ch ₃ CH ₃ 53 H Cl CH ₃ 54 H F CH ₃

The most important compound for use according to the invention is compound no. 7, which is preferably used in the form of a hydrate. This hydrate form of Compound # 7 is a novel compound and is also within the scope of the invention. This hydrate is formed by reacting the known monoetherate of Compound # 7 with an aqueous solvent.

A particularly preferred hydrate form is the 1,5-hydrate form.

Compound # 7, 5-Hydrate, i. 6-Cyclohexyl-2'-O-methyl adenosine-1,5-hydrate can be prepared as follows: 0.7 g of 6-chloro-9-purinyl-2'-O-methyl-D-ribose is rotten in 30 ml. cyclohexylamine at 80 ° C for 2 hours. The mixture was then evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel, eluting with methylene chloride / ethanol (95/5, v / v). The product thus purified is crystallized from a mixture of methylene chloride and diethyl ether. Since the product contains diethyl ether, which cannot be removed even under high vacuum, it is recrystallized from a mixture of ethanol and water.

The 6-cyclohexyl-2-O-methyladenosine-1,5-hydrate thus obtained has a melting point of 88-91 ° C and [α] D = -57.2 ° (c = 1 in dimethylformamide).

Elementary analysis:

Calculated: C: 52.3%

H: 7.2%

N: 17.9%

O: 22.5%

Found: C: 52.5%

H: 7.2%

N: 18.0%

O: 22.4%.

Infrared spectrum of this 1,5-hydrate, result

DSC-Thermal Analysis a. results of nuclear magnetic resonance spectroscopy are shown in the attached figures. The results of these measurements, together with the results of elemental analysis, show that 6-cyclohexyl-2'-O-methyladenosine-1,5-hydrate was prepared as described above.

The compounds of formula (I) are preferably in pharmaceutically acceptable form or in the form of a hydrate or as addition products with other solvents, for example ethanol or as salts. A pharmaceutically acceptable form is e.g. means the pharmaceutically acceptable purity of the compounds as well as pharmaceutical ingredients such as diluents and carriers, and does not include substances that are toxic at normal dosage concentrations.

The salts may be alkali metal salts, for example sodium and potassium salts, or addition salts, for example hydrochlorides.

The compounds of formula (I) may be formulated for administration in any suitable galenic form, with the preferred galenic form being dependent on the disease to be treated and preferably being a unit dosage form which can be administered to a human patient in a single dose. Preferably, the compounds of the formula are formulated in a galenic form suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration.

The compounds of formula (I) may also be formulated in galenic form, from which the active ingredient is released slowly and uniformly.

Compounds of the invention may be formulated into pharmaceutical compositions of the invention in the form of tablets, capsules, capsules, powder, granules, lozenges or liquid preparations such as sterile parenteral solutions or suspensions, or lace and reconstitutable powders. If desired, topical formulations are also contemplated.

3

In order to achieve consistency of administration, it is preferred that the pharmaceutical composition of the invention is in unit dosage form.

Unit dosage forms may be tablets and capsules, and these tablets and capsules may contain conventional excipients such as binders, for example syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone, fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol. or glycine, tabletting lubricants such as magnesium stearate, disintegrating agents such as starch, polyvinyl pyrrolidone, sodium starch glycolate or microcrystalline cellulose, or pharmaceutically acceptable wetting agents, such as sodium lauryl sulfate.

Solid oral compositions may be prepared by conventional mixing, filling, tabletting or other techniques. Repeated blending operations can be used to distribute the active ingredient in pharmaceutical compositions in which a large number of fillers are used.

Such operations and procedures are well known. The tablets may be coated by any of the well known methods, in particular by an enteric coating.

Oral liquid formulations may, for example, be in the form of emulsions, syrup or elixir, or may be in the form of dry powders, which are then reconstituted immediately prior to use with the liquid formulation using water or other suitable vehicle. Such liquid formulations may contain conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats, emulsifying agents such as lecithin, sorbitan monooleate or acacia, non-aqueous vehicles (which include non-aqueous vehicles) oils), for example almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol or ethyl alcohol, preservatives, for example sorbic acid methyl or propyl p-hydroxybenzoate, and optionally flavoring or coloring agents.

For parenteral administration, liquid unit dosage forms are prepared using the active compound and a sterile vehicle, the active ingredient being either suspended or dissolved in the liquid vehicle, depending on the concentration used. In preparing the solution, the active compound may be dissolved in polyethylene glycol or ethanol and diluted with water for injection and sterilized by filtration prior to filling into a suitable vial or ampoule and sealing or airtight sealing. Preferably, a suitable additive such as a local anesthetic or preservative or buffering agent may be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that the active compound is suspended in the vehicle rather than dissolved, and sterilization cannot be accomplished by filtration. The active compound may be sterilized by exposure to ethylene oxide prior to suspension in a sterile vehicle. Preferably, a surfactant wetting agent is included in the pharmaceutical composition to facilitate uniform distribution of the active compound.

These pharmaceutical compositions may contain from 0.1 to 99% by weight, preferably from 10 to 60% by weight of the active ingredient, depending on the mode of administration.

The compounds of formula I or a hydrate or addition product thereof with other solvents or salts may also be administered in the form of a topical formulation in which the active compound is in combination with conventional topical excipients.

Such topical formulations may take the form of, for example, ointments, creams or lotions, impregnated dressings, gels, sprays and aerosols, and may contain suitable conventional ingredients such as preservatives, penetration enhancers and emollients in ointments and creams.

5

These formulations may contain compatible conventional carriers such as ointment bases and ethanol or oleyl alcohol for liquid formulations, for example, for injectable solutions and emulsions.

Suitable pharmaceutical formulations in the form of cream, lotions, gel, impregnated patches, ointments, sprays or aerosols in which a compound of formula I or a hydrate thereof or an addition product with other solvents or salts may be used are well known conventional formulations which are for example, described in standard pharmaceutical and cosmetic literature such as Harry's Cosmeticology, published by Leonard Hill Books, Remington's Pharmaceuticals 1 Sciences, and the UK and US pharmacopoeias.

Suitably, the compound of formula (I) or a hydrate or addition product with other solvents or about 0.5 to 20% by weight of the formulation, preferably about 1 to for example 2 to 5%.

its salts 10%,

The dosage of the compound of formula (I) used in the above treatment will vary in a conventional manner depending upon the severity of the disease being treated, the weight of the patient, and relative. In general, however, a suitable unit dose may be 0.1 to 1000 mg, such as 0.5 to 200 mg, 0.5 to 100 mg or 0.5 to 10 mg, especially 0.5 mg , 1 mg, 2 mg, 3 mg, 4 mg or 5 mg, the unit dose may be administered more than once daily, for example 2x, 3x, 4x, 5x or 6x daily, but preferably once or twice. daily so that the total daily dose for an adult patient of 70 kg body weight is about 0.1 to 1000 mg, i. about 0.001 to 20 mg / kg / day, such as 0.007 to 3 mg / kg / day, 0.007 to 1.4 mg / kg / day, 0.007 to 0.14 mg / kg / day, or 0.01 to 0.5 mg / kg / day, especially 0.01 mg / kg / day, 0.02 mg / kg / day, 0.04 mg / kg / day, 0.05 mg / kg / day, 0.06 mg / kg / day day, 0.08 mg / kg / day, 0.1 mg / kg / day or 0.2 mg / kg / day. Such therapy may be carried out for several weeks or months.

6

The term pharmaceutically acceptable includes materials that are suitable for both human and veterinary use.

At the above-defined doses of the compounds of formula I, these doses of compounds of formula I were not found to have any toxic effect.

In order to determine the pharmacological activity of the compounds of the formula I, the following pharmacological tests were carried out.

(a) Affinity for adenosine receptors

The procedure described by H. Bruns et al. in Molecular Phar macology 29 (1985) p. 331 to 344, porcine stratial membranes are prepared. Non-selective adenosine H-NECA receptor agonists are used after ^{1 Ĺ} 3 to label both A. and ~ receptors.

The inhibitory concentration IC_ _n is derived from n 0 vvtesňovacích curves adapted to the non-linear curve drawn by the method of least square of the Langmuir equation and then calculate the value pl <.

,. . , 1, ^P

The results are shown in the ta'oulce, wherein in accordance with the CPA literarurou product has a potent and highly selective vytšsňovací activity of binding to the N -recepty rum, a product CV 1808 is a relatively weak but selective A2 receptor ligand and the ^_ product of CGS 21680 has high potency and selectivity for receptors. Compound # 7 in the form of the 1,5-hydrate shows good affinity and high selectivity for the A 1 receptor.

table

The affinity of adenosine receptor ligands for receptors

And, A ' A,: A ^ 1 2 1 2 (K _D ; nM) • (K _D ; nM) selectivity n CPA ^a 0.74 + 0.01 33 + 110 1260 6 CV 1808 ³ 2460 + 757 269 + 70 0.1 q CGS 21680 ³ 4360 + 1080 10 + 4 0,004 Compound No. 7 23 + 2 24500+ 5160 1090 5

CPA ^α = cyclopentyladenosine

CV 1 808 ^a = 2-phenylaminoadenosine (Carbohydrates vol.81 (1974) ref. 91898 K)

CGS 21680 ^a = 2- [beta] - (2-carboxyethyl) phenethylamino] -5-N-ethylcarboxamidoadenosine (FASEB J, 1989, 3 (4), refs. 4770 and 4773).

b) Arrhythmia

Activation of adenosine receptors reduces the incidence of suoraventricular tachycardia and other arthritis. The test method used was described by Clarke et al. in The Pharmaceutical Journal, Vol. 244, 595-597 (1990). In this test, the value no. 7 is used in the form of 1.5 hydrate.

c) Mean arterial blood pressure, bradycardia and peripheral vasociation in anesthetized rats

This test was performed using male rats

Wistar weighing 300-350 g (323 +3 g) anesthetized with inactin (150 mg / kg, intraperitoneally) according to the method described by Schroeder et al.

(Measurement of Cardiodynamics, Haemodynamics and the

ECG in anesthetized rat, effects of catecholamines (dopamine and isoproterencl) in Budden et al. The Rat Electrocardiogram in Pharmacology and Toxicology Oxford Pergamon Press

98 1, 15 55-9). Catheters are placed in the right jugular and right femoral veins, in the left ventricle (inserted through the carotid artery), the left femoral artery and the aorta (inserted through the right femoral artery). In the test the following variables were measured or calculated; systolic, diastolic and mean arterial blood pressure (mm Hg, left femoral artery, Statham pressure sensor P 23 Gb), pulse pressure (mm Hg), pulse (counts per minute; derived from blood pressure curve), left ventricular pressure rise rate (dP (dt, mm Hg / sec;

Stathamúv pressure transducer P 23 Gb), cardiac output (ml / min / 100 g body weight, thermal dilution method, right jugular vein and aorta), total peripheral resistance (dyn.s.cm ^5/100 g body weight), ECG III . Arterial blood pressure, dP / dt, max pulse and electrocardiogram are continuously recorded using a Sc'nwarzer polygraph. Said parameters are measured 30, 20, 10 and 2 minutes before administration of the test substance and 1, 10, 30 and 60 minutes after injection of the test substance into the right femoral vein. Compound 7 as the 1,5-hydrate was tested at doses of 0.003, 0.01, and 0.03 mg / kg, using five test animals for each dose of test compound.

d) Blood flow through the ischemic skeletal muscle of male rats of normal blood pressure (weighing about 300 g) is anesthetized with Evipan Ma (160 mg / kg, ip) and then the right femoral artery is ligated. Three weeks after this ligation, rats are anesthetized with penthotal (Thiopental-Na, 40 mg / kg, intraperitoneally) and placed in a special console for measuring resonances of phosphocreatine (PCr), inorganic phosphate (Pi), three phosphate ATP and phosphomonoesters and sugar phosphate (PM) using a Bruker Biospec 47/15 spectrometer equipped with a 4.7 T horizontal magnet (15 cm light aperture). The blood supply to the right hind leg was then temporarily stopped for about 30 to 40 minutes with a turnstile positioned around the upper portion of the leg until the PC value dropped to about 1/3 of its original state. The blood supply is then restored and the rate of restoration () of the PC is monitored. Thirty minutes later, the same procedure is repeated without and after intravenous administration of the test compound, i. Compound No. 7 in the form of 1,5-hydrate, again monitoring the rate of restoration of PC (ζ). The ratio of both Food chloro time (Ti / V ^ - ³ and considered as a criterion to evaluate the effect of test compound on the peripheral circulation. Any one of experimental animals was tested by sympathetic neurotoxin 6-hydroxydopamine-upon ligation of the femoral artery, were determined breaking or effects of Compound No. 7 in the form of 1,5-hydrate in the above-mentioned peripheral vascular insufficiency.

e) Glucose transport in rat adipocytes

Adipocytes are isolated from epididymal fat pads of normally fed rats by collagenase digestion. Cells (final concentration of 2% by weight) are preincubated with adenosine deaminase (1 U / ml), test compounds, for example compound 7 as 1,5-hydrate and other ingredients for 30 minutes at 37 ° C. . Then, [3- (H) -glucose (final concentration 50 µM, 0.5 µCi / ml) is added and incubation is continued for a further 60 minutes. Incorporation of [3 H] -glucose radioactivity into cell lipids (glucose transport rate) was evaluated by extracting the cell suspension (0.5 ml) with 5 ml toluene-based scintillant and then scintillation evaluation of said liquid scintillant. ; water-soluble metabolites and the remaining [3- H] -glucose remain in the aqueous phase and are not detected.

f) Dyslipidemia characterized by elevated blood serum triglyceride levels

Some research studies have shown a positive link between blood triglyceride levels and coronary heart disease (CHD) (Grundy in Cholesterol and Atherosclerosis: Diagnosis and Treatment, Lippincott, Pennsylvania) (1,990). heart disease by lowering elevated serum triglyceride levels results from the Helsinki Heart Study, where, after gemfibrozil treatment, the greatest reduction in serious coronary events was achieved in hyperlipidemic patients with type IIB, who had elevated levels of both LDL-cholesterol and total serum triglycerides Compound No. 7 in the form of 1,5-hydrate causes a significant and long-term decrease in free fatty acid and triglyceride levels in monkeys.

g) Protection against infarction by preconationalization

Preconditioning (5 minutes of ischemia followed by 10 minutes of regeneration) renders the heart very resistant to ischemia-induced infarction. The appropriate test method is described in G.S. Liu et al. published in Circulation 84, 1, 350 to

356 (1991). Compound No. 7 is used as the 1,5-hydrate in this assay.

Claims (12)

1. Use of the 2-O-alkyladenosine derivatives of formula (I) R. HN wherein R ¹ is H, alkyl of 1 to 4 carbon atoms, an allyl group, a methallyl group, a straight-chain or branched alkynyl having 3 to 7 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, a phenyl group which is independently mono- or di-substituted with a halogen atom of 9 to 35, an alkyl of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms or a trifluoromethyl group, or a phenylalkyl group in which the alkyl radical contains 1 to 4 carbon atoms and the phenyl ring of which is not independently mono or disubstituted with a halogen atom of 9 to 35, an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms or a tri fluoromethyl group, an alkyl group of 1 to 4 carbon atoms having at least one hydroxyl group or at least two phenyl groups y, a bicycloalkyl group, a naphcylalkyl group wherein the alkyl moiety contains 1 to 4 carbon atoms, an acenaphthylenylalkyl group wherein the alkyl moiety contains 1 to 4 carbon atoms, or a group of formula II or formula III in which Z represents a hydrogen atom, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms, Q represents a hydrogen atom or a hydroxyl group, A is -CH2-, -O-, -S- or a direct bond, n is 1 to 3 and the dotted line in formula II is an optional bond, 2 R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an amino group, a cycloalkyl group having 3 to 5 carbon atoms or a halogen atom having an atomic number of 9 to 35, and R 1 represents an alkyl group having 1 to 4 carbon atoms, or a hydrate thereof or an addition product thereof with other solvents or salts for the preparation of a medicament suitable for the treatment of neurodegerative disorders, certain peripheral neuropathies, e.g. diabetic neuropathy, and disorders associated with peripheral vascular disease; disorders associated with neuronal degeneration, hypertriglyceridemia, increased free fatty acids and / or type I and type II diabetes and arrhythmias, and for protection against myocardial infarction. Use according to claim 1 of a compound of the formula I in which R represents a cycloalkyl group having from 3 to 8 carbon atoms, R 'represents a hydrogen atom and R' represents an alkyl group of 1 to 4 carbon atoms. Use according to claim 2 of a compound of the formula I in which R ₁ represents a cyclohexyl group, R ₂ represents a hydrogen atom and R 1 represents a methyl group. 4. Use of the compounds of formula (Ia) R ₁ and (Ia) wherein R 6a represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms having optionally at least one hydroxyl group or at least two phenyl groups, a bicycloalkyl group, a naphthyl alkyl group in which the alkyl group contains 1 to 4 carbon atoms, an acenaphthylenylalkyl group wherein the alkyl radical contains 1 to 4 carbon atoms or a group of formula (II) or (II ') Q in which Z, Q, A, Y and n have the meanings defined in claim 1 a And R ₂ represents a hydrogen atom, aminoalkyl group having 1 to 4 carbon atoms or halogen of atomic number of 9 to 35 and R 6a represents an alkyl group having 1 to 4 carbon atoms, or a hydrate thereof or an addition product thereof with other solvents or salts for the preparation of a medicament suitable for reducing high blood lipid levels. 5th A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to claim 1 and a pharmaceutically acceptable carrier therefor, and suitable for the treatment of neurodegenerative disorders, certain peripheral neuropathies such as diabetic neuropathy, and disorders associated with peripheral vascular disease and / or disorders associated with neuronal degeneration, hyperglyceridemia, increased free fatty acids and / or diabetes type I and type II arrhythmias, and for protection against myocardial infarction. 6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (Ia) according to claim 4 and a pharmaceutically acceptable carrier therefor and suitable for reducing high blood lipid levels. 7. 6-Cyclohexyl-2'-O-methyladenosine hydrate. 8. 6-Cyclohexyl-2-O-methyladenosine hydrate according to claim 8 7, characterized in that it is a 1,5-hydrate. 9. A process according to claim 7, wherein the 5-cyclohexyl-2'-O-methyladenosine monoetherate is crystallized from an aqueous solvent. 10. A process for the preparation of 1.5-hydrate of 6-cyclohexyl-2 -0-methyladenosine of claim 8, wherein zese 6-phenyl-2 ^# -0 -methyladenosinmonoetherát crystallized from a mixture of ethanol and water. Use of 6-cyclohexyl-2'-O-methyladenosine hydrate for the preparation of a medicament suitable for treating high blood pressure, diseases requiring coronary vasodilators, for inhibiting platelet aggregation and leukocyte activation, for reducing blood lipid levels, against congestive heart failure, myocardial infarction, sudden cardiac arrest and renal insufficiency, further for the treatment of neurodegenerative disorders, some peripheral neuropathies, for example diabetic neuropathy, and disorders associated with peripheral vascular disease and / or disorders associated with neuronal degeneration, hypertriglyceridemia, elevated levels of free fatty acids and / or and type II and arrhythmias and for protection against myocardial infarction. 12. A pharmaceutical composition comprising a therapeutically effective amount of 6-cyclohexyl-2-O-methyladenosine hydrate and a pharmaceutically acceptable carrier therefor and suitable for treating high blood pressure, diseases requiring coronary vasodilators, for inhibiting platelet aggregation and leukocyte activation , for reducing blood lipid levels, against congestive heart failure, myocardial infarction, sudden cardiac arrest and renal insufficiency, for the treatment of neurodegenerative disorders, certain peripheral neuropathies, for example diabetic neuropathy, and disorders associated with peripheral vascular disease and / or neuronal disorders associated with neuron degeneration, hypertriglyceridemia, elevated levels of free fatty acids and / or diabetes type I and type II and arrhythmias, and for protection against myocardial infarction.