GB2074446A - Adenosine derivatives of antiinflammatory and analgesic activity and therapeutic compositions containing them - Google Patents

Abstract

A therapeutic composition of antiinflammatory, analgesic and antipyretic activity comprises as its active principle, at least one component of the general formula: <IMAGE> in which R is a linear or branched alkyl radical containing 1-18 C atoms or a phenylalkylene in which the alkylene chain contains 1-6 C atoms; R1 is H, an aliphatic acyl radical containing 1-6 C atoms or an aromatic acyl radical; R2 is H, an aliphatic acyl radical containing 1-6 C atoms, or an aromatic acyl radical, or the radicals R2 together form an isopropylidene chain; and N is 0 or 1, or an acid additive salt of a compound of formula (I) in which R' is hydrogen. Various methods of preparing compounds of formula (I) are disclosed including a method of preparing 5'-deoxy-5'-methylthiodenosine by hydrolysing a concentrated aqueous solution of S-adenosyl-methionine by heating under reflux, neutralising the reaction mixture and cooling it to separate the 5'-deoxy-5'-methylthioadenosine formed.

Description

SPECIFICATION Adenosine derivatives of antlinflammatory and analgesic activity, and therapeutic compositions containing them This invention relates to adenosine derivatives having anti-inflammatory, analgesic and antipyretic activity, and to therapeutic compositions containing them as their active principle.

The compounds of therapeutic activity according to the present invention are of the general formula:

in which: R is a linear or branched alkyl radical containing 1-18 C atoms or a phenylalkylene radical in which the alkylene chain contains 1-6 C atoms; R, is H, an aliphatic acyl radical containing 1-6 C atoms or an aromatic acyl radical; R2 is H, an aliphatic acyl radical containing 1-6 C atoms or an aromatic acyl radical, or the radicals R2 together form an isopropylidene chain; and n isOorl.

Furthermore, when R1 is H, the invention also relates to the acid addition salts of the compounds of formula (I).

Preferred meanings for R are: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, hexadecyl, octadecyl or benzyl.

Preferred meanings for R, are: hydrogen, acetyl, propionyl, butyrryl, benzoyl ortosyl.

Preferred meanings for R2 are: hydrogen, acetyl, propionyl, butyrryl, benzoyl or tosyl.

The preferred acid addition salts of the compounds of formula (I) are: chloride, sulphate, phosphate, formate, acetate, citrate, tartrate, methanesulphonate or p-toluenesulphonate.

The compounds of formula (I) are partly new.

The compounds of formula (I) are prepared by various methods according to the nature of the various substituent radicals.

To prepare the group of compounds of the formula:

in which R has the aforesaid meanings, the Leg raverand method (Legraverand M. Ibanez S., et al.

1977) Eur. J. Med. Chem. 12, 105-108) may be followed, in which adenosine is converted into 5' chloro - 5' - deoxyadenosine by reaction with thionyl chloride in hexamethylphosphoramide.

The 5' - chloro - 5' - deoxyadenosine is then converted into the required thioether by reaction with the corresponding mercaptan in a 2N sodium hydroxide solution at 80"C.

The thioethers obtained are purified by recrystallisation from water or from lower al iphatic alcohols.

The compounds (la) can then be salified with the stoichiometric quantity of the required acid.

The compounds of the general formula:

in which R, R1, R2 are as hereinbefore defined, provided that R1 and R2 are other than H or an isopropylidene chain, may be prepared by the Satom and Makino method (Satom K, Makino K (1951) Nature 167, 238) by reacting the corresponding compounds of formula (la) with the required acyl chloride in an hydros pyridine. The products are preferably recrystallised from a 1:1 chloroform/petroleum ether mixture.

The compounds of the formula:

in which R and R, are as hereinbefore defined, may be prepared by reacting the corresponding compounds of formula (I), in which R2 is H, with acetone in the presence of ZnCI2, again by the Satom and Makino method (referred to above). The obtained products are purified, preferably by crystallisation from a 1:1 chloroform/petroleum ether mixture.

The compounds of the formula:

in which R, P1, R2 are as heretofore defined, may be prepared by oxidation of the corresponding thioethers, obtained by the methods hereinbefore described, by means of bromine or hydrogen peroxide in aqueous solution (Green Stein J.P., Winitz M. (1961 ) - Chemistry of the amino acids - John Wiley & Sons Inc. 2146). The products obtained are purified by recrystallisation from water.

Of all the products prepared, the one which has proved particularly interesting for the purposes of the present invention is 5' - deoxy - 5' - methyl thioadenosine (MTA) of the formula

in which a physiological compound already present in living organisms. A method has been found for preparing this product which is particularly simple and economical from an industrial viewpoint.

The new process consists essentially of carrying out hydrolysis of S-adenosylmethionine (SAME) under strictly controlled critical conditions, which lead to practically total hydrolysis and complete crystallisation ofthe MTA

The controlled hydrolysis process can be applied to SAME prepared in any manner.

However, the method of preparation of the SAME solution is also an influencing factor in carrying out the new process in an economically convenient manner.

The following operational stages provide the most economical embodimentofthe process: a) Normal bread yeast is enriched in SAME by treatment with methionine in accordance with the Schlenk method (Schlenk F. (1965) Enzymologie 29, 283) b) The yeast cells suspended in water are lysed by treatment with ethyl or methyl acetate at ambient temperature (DT-OS P23 36401.4).By adjusting the pH to between 4 and 6 and filter ing, an aqueous solution is obtained contain ing practically all the SAME present in the ini tial yeast c) The solution is concentrated under vacuum at 35-40"C to about 1110 of its initial volume d) The concentrate is boiled under reflux for about 30 minutes and the pH adjusted to 7 with soda e) The solution is left to stand at 0-5"C, and the precipitated MTA is collected practically com pletely and in good purity.

The steps c, d and e, which as stated are critically necessary for obtaining complete selective hyd rolysis of SAME to MTA without formation of by products, are new.

The preparation of some products used according to the present invention are described hereinafter.

Example I I Preparation of 5'- deoxy - 5' - metnylthioadenosioe (MTA) 11 litres of ethyl acetate and 11 litres of water at ambient temperature are added to 90 kg of bread yeast which has been enriched in SAME by adding methionine until the SAME content is 6.88 glkg.

After energetic stirring for 30 minutes, the pH is adjusted to 4.5 with dilute H2SO4, the mixture is filtered and the residue is washed with water to give 140 litres of solution with a SAME content of 4.40 g/l, equal to 99.5% of the SAME present in the initial material.

The lysate thus obtained is concentrated under vacuum (30 mm Hg; 3540 C) to a volume of about 14 litres. The concentrated solution is boiled under reflux at normal pressure for 30 minutes. It is cooled to 200C, the pH adjusted to 7 with 40% soda, and left overnight in a refrigeration cell (+3"C). Awhite precipitate is formed which is filtered, dissolved in 10 litres of boiling distilled water and crystallised by cooling this solution.

4.10 9 of crystalline MTA of high purity are obtained, equal to a yield of 90% with respect to the SAME subjected to hydrolysis.

The characteristics of the product obtained coincide with those of pure MTA obtained by other means.

Example 2 Preparation of5' - deoxy - 5' - ethylthioadenosine 1 kg of adenosine is dissolved under a nitrogen atmosphere in 10 1 of hexamethylphosphoramide, and 7.5 1 of thionyl chloride are added with cooling.

The mixture is leftto react at ambient temperature for 20 hours. 10 1 ofwater are added, and the mixture neutralised with 2N NaOH. The 5' - deoxy - 5' chloroadenosine which thus forms is allowed to crystalliseovernight at 3 C. It is filtered off. 0.950 kg of 5' - deoxy - 5' - chloroadenosine are obtained (yield 89%).

0.950 kg of 5' - deoxy - 5' - chloroadenosine are dissolved in 10 1 of 2N NaOH, and 200 ml of ethanethiol are added. The mixture is heated to 80 Cs and left to react for 1 hour. It is neutralised with glacial acetic acid. The 5' - deoxy - 5' - ethylthioadenosine which thus forms is allowed to precipitate overnight at 30C. It is filtered off and recrystallised from water. 0.830 kg of product are obtained (yield 80% with respect to the preceding stage).

Example 3 Preparation of other compounds of formula Ja The method as described in example 2 is carried out, but using propanethiol, butanethiol, isobutanethiol, pentanethiol, hexanethiol and benzylthiol, respectively, in place of the ethanethioi.

Example 4 Preparation ofN 6, 2, 3'- triacetyl - 5' - deoxy- 5'thioadenosine 1 kg of MTA is suspended in 10 1 ofanhydrous pyridine, and 3 1 of acetic anhydride are added. The mixture is left to react for 4 hours. 20 1 of water are added, and the mixture concentrated under vacuum to give an oily mass free from pyridine. This is dissolved in a hot 1:1 mixture of petroleum ether/chloroform (101) and left to crystallise. The product is recrystallised from 1:1 petroleum ether/chloroform mixture. 1.140 kg of product are obtained (yield 80%).

Example 5 Preparation of other compounds of formula Ib The method described in example 4 is carried out, but using otherthioethers or propionic an hydride, butyric an hydride, benzoyl chloride ortosyl chloride instead of MTA.

Example 6 Preparation of 5'- deoxy - 2',3' - isopropylidene - 5' methylthioadenosine.

1 kg of MTA are suspended in 25 1 of an hydro us acetone, and 2.5 kg of molten ZnCI2 are added. Reaction is carried out under reflux for 5 hours. The mixture is then concentrated under vacuum to 1/3 of its initial volume, and 7.5 kg of barium hydroxide octahydrate in aqueous suspension are added. Carbon dioxide is then bubbled through until neutral.

The mixture is filtered and the residue washed with acetone. The filtrate is concentrated under vacuum to give a syrupy residue. It is taken up in a hot 1:1 chloroform/petroleum ether mixture (101), filtered and left to crystallise.

The product is recrystallised from 1:1 chloroform/petroleum ether, to give 0.795 kg of product (yield 70%).

Example 7 Preparation of other compounds formula Ic.

The method as described in example 6 is carried out, but starting from the corresponding adenosine derivatives instead of MTA.

Example 8 Preparation ofMTA suiphoxida 1 kg of MTA are suspended in 10 1 of water, and bromine is added under cooling.

The aqueous solution containing bromine is immediately decoloured by the oxidation of the MTA to sulphoxide.

Addition of bromine is continued until solution does not decolourise further.

The solution is decolourised by further addition of small quantities of MTA.

The aqueous solution is treated with Amberlite IRA 93 resin (registered trademark of Rohm and Haas for a weakly basic ion exchange resin with a polystyrene matrix) until the reaction of the bromide ions disappears. The mixture is filtered and the residue washed with water.

The aqueous solution is concentrated to 10 l,tre- ated with activated carbon (100 g) and lyophilised.

0.950 kg of product are obtained (yield 90%). Example 9 Preparation of other compounds of formula Id.

The method described in example 8 is followed, but starting from the corresponding adenosine derivatives instead of MTA.

As stated above, it has been found that the compounds of formula I possess strong antiinflammatory activity, accompanied by analgesic and antipyretic action.

The antiinflammatory activity was demonstrated intially for some compounds by the test of experimental edema in the rat by carragen, by determining the percentage protection by the Winter method (J.

Pharm. exper. Therap. 141,369 1963). The values obtained are shown in Table 1.

TABLE 1

Compound offormula U) Dose administered Percent protection orally mglkg calculated on edema development n = 0 R = -CH,R, = R2 = H 37 50 n = 0 R = -CH3, R1 = R2 = H 23 fay 50 n = O R = -CH2-C6Hs, R1 = R2 = H 47 10 CH3 n = 0 R = -CH2-CH ,R, = R2 = H 85 62 CH3 n = 0 R = -(CH2)6-CH3,R1 = R2 = H 95 20 n = 0 R = -(CH2)11-CH3, R1 = R2 = H 112 10 n = 0 R = -(CH2)4cH3, R1 = R2 = H 90 25 n = 0 R = -CH2-CH3, R1 = R2 = H 80 44 n = 0 R = -(CH2)2-CH3, R1 = R2 = H 80 53 CH3 n = 0 R = -CH ,R, = R2 = H 80 45 CH3 n = 0 R - -(CH2)3CH3, R1 = R2 = H 85 39 n = 0 R = CH-CH2-CH3, R1 = R2 = H 85 35 I CH3 n = 0 R = -(CH2)CH3, R1 = R2 = H 100 47 n = 0 R = -(CH2)9-CH3, R1 = R2 = H 106 33 n = 1 R = -CH,,R1 = R2 = H 156 50 n = 1 R = -CH3,R1 = R2 = H 8.6 (a) 50 n = 0 R = -CH3, Rt = R2 = -CO-CH3 114 47 n = 0 R = -CH3,R1 = R2 = tosyl 204 15 n = 0 R = -CH3, R1 = R2 = -CO-C6Hs 164 10 n = 0 R = -CH3, R = H, R2-R1 = isopropyl 91 20 Indomethacine 9 50 (a) signifies that the product was administered intramuscularly. 1,, As can be seen from this table, the EDso of MTA is 37 mg/kg, and is thus the lowest of those of the compounds tested when administered orally.

In the same test, the EDso of indomethacine is 9 mg/kg. At these doses, there is the appearance of serious gastric lesions, whereas at the EDso doses the MTA gives rise to no secondary effect on the gastrointestinal system. It should also be noted that the LD of indomethacine in the rat is 12 mg/kg (Martelli A. in Aspetti di farmacologia dell'infiammazione, page 73, published by Tamburini - Milan 1973), whereas the LDso of MTA in the rat is 200 mg/kgloa.

The following therapeutical indices are therefore obtained: Indomethacine TI = 1.3 MTA TI = > 54.05 The compounds used according to the invention were also subjected to a series of pharmacological tests for the purpose of confirming their antiinflam matory activity and for demonstrating their analgesic and antipyretic activity. The results obtained in some of these tests with MTA are given hereinafter, this being a product which in all cases proved to be the most active when administered orally, and which is certainly the safest as it is a compound physiologically present in the organism, as already stated.

Again from the industrial production viewpoint, the method for producing MTAfrom SAME as discovered is by far the most simple and economical, and enables it to be marketed at a particularly low ' price.

As can be seen from the data of table 1, methyl thioadenosine sulphoxide is particularly active when administered intramuscularly.

The greater activity of said compound on intramuscular administration was confirmed in all tests carried out. Some significant data regarding MTA sulphoxide are also given, however it should be noted that all the compounds tested were in all cases shown to be active, although at different levels.

A - Antiinflammatory activity.

The products were tested by pleuritis induced in the rat by carragen in accordance with the Velo method (Velo G.P., DUNN C.J. et al. (1973) J. Path. 111,149).

MTA at a dose of 75 mg/kg by oral administra- tion gave a protection of 42.4% calculated on the volume of the exudate, and 48.8% calcu lated on the total number of cells present in the exudate.

A comparable protection was obtained with 10 mg/kg of indomethacine, i.e. with a dose much closertothe Also. In the same test, the MTA sulphoxide gives a protection of 75.8% calcu lated on the volume of the exudate, and 76.4% calculated on the total number of cells present in the exudate when administered intramuscu larly at a dose of 80 mg/kg.

B - Antiinflammatory activity.

In the granuloma test in the rat by cotton pel lets (Winter C.A., Riseley E.A. et al (1963) J.

Pharm. Exper. Ther. 141,369),- which is signif icant for chronic inflammation, the MTA gave a protection of 30% with an oral dose of 9 mg/kg, with a TI of 222.

C - The analgesic activity of the productswas tested by two tests considered very significant.

- In the hot plate test on the mouse according to Roberts (Roberts E. Simonsen D.G. (1966) Biochem. Pharmac. 15, 1875-) the MTA gives a protection of 50% with an oral dose of 37 mg/kg. An approximately equivalent protection of 58% is obtained with 100 mg/kg of amidopyrine administered orally.

In the same test MTA sulphoxide gives a protection of 50% at a dose of 20 mg/kg when administered intramuscularly, and at a dose of 100 mg/kg when administered orally.

- In the stretching test by phenylquinone (Siegmund E., Cadmus R., GOLU (1957) Proc. Soc. Exp. Biol. Med. 95,729), the MTA gives a protection of 51 % at an oral dose of 37 mg/kg.

In the same test, MTA sulphoxide has an EDso of 10 mg/kg when administered intramuscularly.

D - Antipyretic activity.

This was measured for the new products by means of fever induced in the rat by beer yeast (Winder C.V. etal (1961)J. Pharmacol. Exp.

Then 133,117).

The antipyretic effect evaluated one hour after oral administration of MTA at a dose of 300 mg/kg gave a temperature reduction of 4.59% with respect to the controls, which were tre ated only with yeast This percentage corres ponder to a temperature lowering from 38.8"C to 37.4"C.

By comparison, amidopyrine administered orally at a dose of 200 mg/kg produced a temp erature reduction of 4.69%, and intramuscular administration of MTA at a dose of 80 mg/kg gave atemperature reduction of 2.35% Platelet antiaggregation activity.

The compounds of the invention have also been evaluated with respect to their possible platelet antiaggregation capacity.

Platelet aggregation is known to be a complex phenomenon which can be divided into a primary stage due to the direct action of a stimulus (for example adenosine diphosphate, i.e. ADP, or epinephrin) and a secondary stage due to the aggregation induced by the ADP released by the platelets. In this respect, when the platelets come into contact with the subendothelial collagen, the collagen initiates an entire series of reactions which lead to the release of ADP by the platelets. It is this ADP which causes the second wave of platelet aggregation.

The following tests were carried out in order to evaluate the antiaggregation effect of the new compounds: 1) "in vitro" tests on platelet aggregation induced by ADP and collagen, in the pres ence of the new products; 2) "in vitro" tests on platelet aggregation induced by arachidonic acid (AA); 3) "in vivo" tests on platelet aggregation induced by ADP and collagen in persons treated with the new products.

In this case the most significant results were again obtained with MTA, because of which the results obtained using this product are given as indicative of the behaviour of the entire class.

1) "In vitro" tests.

Blood was withdrawn without stasis, and an anticoagulent (3.8% sodium citrate) was added to give a blood:citrate ratio of 9:1.

Plasma rich in platelets and plasma poor in platelets were obtained by centrifuging at ambient temperature.

The platelet aggregation was estimated using the Born & Cross method (G.V.R. Born and M.J. Cross, J. Physiol, Lond. 168,178, 1963) on the plasma fraction rich in platelets.

The aggregating agents were used in the following concentrations: ADP (Sigma) 1 ,aM; collagen (Horn) 5 yg/ml; arachidonic acid 4 x 10-4M.

Adenosine at a concentration of 1 x 1 0-5M was used as the antiaggregation activity reference substance.

The results obtained with ADP are shown on the graphs of Fig. 1, in which the abscissa indicates the time in minutes and the ordi nate the percentage aggregation.

Curve 1 relates to the controls, curve 2 to the samples treated with 1 x 1-5 Madenosine, and curve 3 to the samples treated with 5 x 10-4M MTA.

From the curve pattern it is apparent that MTA strongly reduces primary platelet aggregation due to ADP, and as a consequ ence inhibits the 2nd aggregation wave.

The same tests carried out with collagen gave negative results, i.e. MTA showed no inhibiting power towards platelet aggrega tion induced by collagen which was worthy of note.

2) Fig. 2 shows the effects ofvarious MTA con centrations on platelet aggregation induced by AA at a concentration of x 1 04M. Curve 1 relatesto the controls, curve 2 to MTA at a concentration of 2.5 x Cr4M, curve 3 to MTA at a concentration of 5 x 10-4M, and curve 4 to MTA at a concentration of 1 0-3MX 'As is apparent, the platelet aggregation inhibiting effect of the MTA is proportional: to its concentration. The capacity of MTAto increase the inhibiting effect of prostacylin (PGl2) in aggregation induced byAAwas also investigated.In Fig. 3, curve 1 relates to the controls, curve 2 to MTA at a concentra tion of 5 x 10-4M, curve 3 to PGl2 at a con- centration of 5 x 10-9M, and curve 4 to a - mixture consisting of 5 x 10-4M MTA and 5 x 100M PGI2. It is apparent from Fig.3 that when used in mixture there is a strong increase in the antiaggregation action at concentrations which are in themselves ineffective.

3) "In vivo" tests Three apparently healthy volunteer subjects aged 35,42 and 48 years respectively, and who had nottaken any drug for at least 15 days, were submitted to aggregation tests before and after consuming the new pro ducts at a dose of 100 mg every 8 hours for3 days, these tests then being evaluated. The blood sample forthe determination of the platelet aggregation was taken 2 hours before consuming the last dose of product undertest.

Fig. 4 shows the results obtained with MTA.

More precisely, the full-line curves relate to the values obtained with blood samples from untreated patients, whereas the dashed-line curves relate to the values obtained for the same patients treated with MTA.

It is apparentthat MTA strongly inhibits platelet aggregation induced byADP (1 ,mM) "in vivo".

The same tests repeated on adding 5 yg/ml of collagen to the blood demonstrated that MTA is not effective in inhibiting platelet aggregation induced by collagen, but only lengthensthe latency time ofthe phenome- - non.

The fact thatlMTA(and in a more orless comparablemann-erthe other products of the same class) strongly inhibits platelet aggregation i-rfduced byADP, whereas it has practically noteffecton aggregation induced by collagen, indicates that MTA inhibits the 1 sot aggregatioxr,waze, whereas it has a neg ligible direct effit on!the 2nd aggregation wave.

Its use in association with other known anti aggregation drugss which are generally active towards 2nd wave whereas are only poorly effecti"e towards the 1 st wave is therefore particularly interesting.

The demonstrated activity suggests the use of MTA (and of the other compounds of the series, even if less effective) not only as a platelet antiaggregation drug, but also as an antithrombotic and antiatherosclerotic drug, in that, besides being the basis of thrombogenesis mechanisms, the altered relationship between platelets and vasal walls also plays a primary role in atherosc lerotic illness.

F - Sleep inducing activity.

The Morris test was used (Morris R.W. (1966) Arch. int Pharmacodyn 161, No 2,380) In this test, the MTA increased by 87% the duration of the sleep induced by pentobarbital in the mouse, at an intramuscular dose of 20 mg/kg.

G - Acute toxicity.

The compounds of the present invention are practically free from acute toxicity when administered orally. They are practically free from toxicity at therapeutic-doses for any method of administration. The following val ues are obtained for MTA and MTA sulphox ide: MTA-DL in the mouse orally- > 2000 mg/kg intravenously 360 mg/kg MTAsulphoxide-DL00 in the mouse orally > 2000 mglkg intravenously 4000 mg/kg The adenosine derivatives of formula (I) can be administered, diluted with suitable pharmacologically acceptable excipients, in any therapeutically useful form, orally, parenterally or by venous or recital moans. They can also be used in products for external use by topical application.

Some examples of typical pharmaceutical com positions with MTA are given hereinafter by way of example: - 100 mg capsules MTA 100.2 mg Mannitol 195.0 mg Magnesium stearate 5.0 mg 300.2 mg - 50 mg capsules MTA 50.1 mg Mannitol 100.0 mg Magnesium stearate 3.0 mg 153.1 mg - 100 mg tablets MTA 100.2 mg Starch 100.0 mg Magnesium stearate 15.0 mg Lactose 85.0 mg 300.2 mg - 50 mg tablets MTA 50.1 mg Starch 120.0 mg Magnesium stearate 15.0 mg Lactose 115.0 mg 300.1 mg - 100 my suppositories MTA 100.2 mg Suppository mass 1,700.0 mg 1,800.2 mg - 50 mg suppositories MTA 50.1 mg Suppository mass 1,450.0 mg 1,500.1 mg - 50 mg injectable phial MTA. HCI (56.15 mg basically equivalent) 50 mg Lidocain HCI 25 mg Watertomakeupto 3 ml - 25 mg injectable phial MTA. HCl (28.07 mg basically equivalent) 25 mg Lidocain HCI 20 mg Watertomakeupto 2 ml - 100 mg oral dose MTA. HCI (112.3 mg basically equivalent) 100 mg Citrus flavouring 0.025 mg Sugar 1 g Antifermenting agent 50 mg Water to make up to 5 ml - 50 mg oral dose MTA. HCI (56.15 mg basically equivalent) 50 mg Citrus flavouring 0.015 mg Sugar 0.5 g Antifermenting agent 30 mg Watertomakeupto 5 ml - 100gointment MTA 5 g Base for water soluble ointment,tomakeupto 100 g Antioxidant 0.1 g

Claims (18)

1. A therapeutic composition of antiinflammatory, analgesic and antipyretic activity, comprising as its active principle at least one compound of the general formula:

in which R is a linear or branched alkyl radical containing 1-18 C atoms or a phenylalkylene in which the alkylene chain contains 1-6 C atoms; R1 is H, an aliphatic acyl radical containing 1-6 C atoms or an aromatic acyl radical; R2 is H, an aliphatic acyl radical containing 1-6 C atoms or an aromatic acyl radical or the radicals R2 together form an isopropylidene chain; and n isOor1, or an acid addition salt of a compound in which R1 is H.

2. Atherapeutic composition as claimed in claim 1, comprising as its active principle a compound of formula (I) in which R, = R2 = H, R = CH3, and n = 0.

3. Atherapeutic composition as claimed in claim 1, comprising as its active principle a compound of formula (I) in which R, = R2 = H, R = CH3, and n = 1.

4. A therapeutic composition as claimed in claim 1, comprising as its active principle a compound of formula (I) in which R, = R2 = H, R = a linear or branched alkyl containing 1-12 C atoms, and n = 0.

5. Atherapeutic composition as claimed in claim 1, comprising as its active principle a compound of formula (I) in which R, = R2 = H, R = benzyl, and n = 0.

6. A therapeutic composition as claimed in claim 1, comprising as its active principle a compound of formula (I) in which R, = R2 = benzoyl, R = methyl, and n = 0.

7. Atherapeutic composition as claimed in claim 1, comprising as its active principle a compound of formula (I) in which R1 = R2 = tosyl, R = methyl, and n= 0.

8. Atherapeutic composition as claimed in claim 1, comprising as its active principle a compound of formula (I) in which R2-R2 = isopropylene, R = methyl, and n = 0.

9. A process for preparing 5' - deoxy - 5' - methyl thioadenosine, wherein S-adenosyl-methionine, in concentrated aqueous solution, is hydrolysed by heating under reflux, and the 5' - deoxy - 5' - methylthioadenosine formed is separated by cooling after neutralising the reaction mixture.

10. A process as claimed in claim 9, wherein the aqueous solution of S-adenosyl-methionine is concentrated by heating under vacuum to 3540"C.

11. A process as claimed in claim 9 or claim 10, wherein the 5' - deoxy - 5' - methylthioadenosine formed is precipitated by cooling to 0-5"C.

12. Use of a compound of general formula:

in which: R is a linear or branched alkyl radical of 1-18 C atoms, or phenylalkylene in which the alkylene chain has 1-6 C atoms R, is H, an aliphatic acyl radical of 1-6 C atoms or an aromatic acyl radical R2 is H, an aliphatic acyl radical of 1-6 C atoms or an aromatic acyl radical, or alternatively the radicals Rtogetherform an isopropylidene chain.

for preparing pharmaceutical products of antiinflammatory, analgesic and antipyretic activity.

13. Use of the compound of formula (I) in which R, = R2 = H, R = CH3, n = 0, for preparing pharmaceutical products of antlinflammatory, analgesic and antipyretic activity.

14. Use of the compound offormula (I) in which R, = R2 = H, R = CH3, n = 1, for preparing pharmaceutical products of antiinflammato ry, analgesic and antipyretic activity.

15. Atherapeutic composition as claimed in claim 1 substantially as hereinbefore described.

16. A process as claimed in claim 9 substantially as hereinbefore described.

17. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 in association with a pharmaceutical carrier or diluant therefor.

18. A pharmaceutical composition as claimed in claim 17 substantially as hereinbefore decribed.