NL8101984A - Anti-inflammatory and analgesic anti-inflammatory drugs and therapeutic compositions containing these derivatives as an active ingredient. - Google Patents

Description

* VO 1867

Anti-inflammatory and analgesic adenosine derivatives and therapeutic compositions containing these derivatives as active ingredients.

The invention relates to adenosine derivatives with anti-inflammatory, analgesic and antipyretic activity and to therapeutic preparations containing these derivatives as active ingredient.

The compounds with therapeutic activity according to the invention have the general formula 1 of the formula sheet, in which R is a straight or branched alkyl radical with 1-18 C atoms, or phenylalkylene in which the alkylene chain has 1-6 C atoms, H is an aliphatic acyl radical with 1 to 6 C atoms or an aromatic acyl radical, R 2 is H, an aliphatic acyl radical with 1 to 6 C atoms or an aromatic acyl radical, or the radicals R 1 together form an iso-15 propylidene chain, and n is 0 or 1.

Furthermore, when R 1 is H, the invention also relates to the acid addition salts of the compounds of formula 1.

Preferably R represents: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, hexadecyl, octadecyl or benzyl.

Preferably R 1 is hydrogen, acetyl, propionyl, butyryl, benzoyl or tosyl.

Preferably hydrogen, acetyl, propionyl, butyryl, benzoyl or tosyl.

The preferred acid addition salts of the compounds of the formula I are chloride, sulfate, phosphate, formate, acetate, citrate, tartrate, methanesulfonate or p-toluenesulfonate.

-------- 8101984 * * - 2 -

The compounds of the formula I are partly new.

The compounds of the formula I are prepared according to different methods depending on the meaning of the different radicals.

For preparing the group of compounds of the formula.

1a, in which R has the above meanings, the Legraverand ^ * method (Legraverand M. Ibanez S., et al (1977] Eur. j. Pled. Chem. 12, 105 - 108) has been followed, whereby adenosine is converted into S 1-chloro-ro-5'-deoxyadenosine by reaction with thionyl chloride in hexamethyl-10-phosphoramide.

The 5'-chlaro-5'-deoxyadenosine is then converted to the required thioether by reaction with the corresponding mercaptan in a 2N sodium hydroxide solution at 8G ° C.

The thioethers obtained are purified by recrystallization from water or from fegere aliphatic alcohols.

The compounds 1a can then be converted into salts with the stoichiometric amount of the required acid.

Compounds of the general formula 1b, wherein R, R 2 and R 2 are as described above, provided that R 2 and R 2 are other than H, or an isopropylidene chain, have been prepared by the method of Satom and

Makino (Satom K, Makino K (1951] Nature 167, 238) by reacting the corresponding compounds of the formula la with the required acyl chloride in anhydrous pyridine. The products are preferably recrystallized from a 1/1 chloroform / pe 25 troleum ether mixture.

The compounds of the formula Ic, wherein R and are as defined above, are prepared by reacting the corresponding compound of the formula 1 wherein R 1 is H, with acetone in the presence of ZnC 2, again according to the (previously mentioned) method. -30 method of Satom and Makino. The products obtained are preferably purified by recrystallization from a 1/1 chloroform / petroleum ether mixture.

The compounds of the formula Id, wherein R, R 4 and R 4 are as defined above, are prepared by oxidation of the corresponding thioethers obtained by the above methods 8101984 using bromine or hydrogen peroxide in aqueous solution (Green Stein JP, Winitz M. [1961) - Chemistry of the amino acids - John Wiley & Sons Inc. 2146). The products obtained are purified by recrystallization from water.

Of all the products prepared, the 5'-deaxy-5'-methylthioadenosine (MTA) of formula 2, which is a physiological compound already found in living organisms, is of particular interest for the purposes of the present invention.

A method has been found to prepare this product which is very simple and economical from an industrial point of view. This new process mainly consists of hydrolysing the S-adenosylmethionine (SAME) under strictly controlled critical conditions, which leads to almost complete hydrolysis and ...... complete crystallization of the MTA (see reaction scheme on the formula sheet) .

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

However, the preparation method of the SAME solution is also an influential factor in carrying out the new method 20 in an economically suitable manner.

The following process steps provide the most economical embodiment * of the method: a) normal baker's yeast is enriched in SAME by treatment with methionine according to the method of Schlenk (Schlenk F.

25 (1965) Enzymology 29, 283); b) the yeast cells suspended in water are lysed by treatment with ethyl acetate or methyl acetate at ambient temperature (DT-OS P 23 36401.4).

By adjusting the pH between 4 and 6 and filtration, an aqueous solution is obtained which contains almost all of the SAME present in the initial yeast; c) the solution is concentrated under vacuum at 35-40 ° C to about 1/10 of its initial volume; d) the concentrate is refluxed for about 30 minutes and the pH adjusted to 7 with soda; The solution is left to itself at 0-5 ° C and the precipitated MTA is almost completely collected and in good purity.

Steps c, d and e which, as noted, are Critically Necessary for obtaining fully selective hydrolysis of SAME to MTA without the formation of by-products are new.

The preparation of some compounds of the invention is described below.

Example I

The preparation of 5'-deoxy-5'-methylthioadenosine. (MTA].

3 3 11 dm ethyl acetate and 11 dm water at ambient temperature are added to 90 kg of baker's yeast enriched in SAME by adding methionine until the SAME content is 6.38 g / kg.

After vigorous stirring for 30 minutes, the pH is adjusted to 4.5 with dilute 1-LSQ. then the mixture is filtered and the residue is washed with water to give 140 dm 3 of solution with a SAME content of 4.40 g / dm equal to 99.5% of the SAME contained in the starting material.

The lysate thus obtained is concentrated under vacuum (30 mm Hg, 35-40 ° C] to a volume of about 14 dm3. The concentrated solution is boiled under reflux and normal temperature for 30 minutes. It is cooled to 20 ° C. , the pH adjusted to 7 with 40% soda and left in a refrigerator (+ 3 ° C] overnight.

White precipitate is formed, which is filtered, dissolved in 10 dm boiling distilled water and crystallized by cooling this solution.

410 g of high purity crystalline MTA are obtained being 90% yield based on the hydrolysis of SAME.

The properties of the product obtained are the same as those of pure MTA obtained by other means.

Example II

The preparation of S-deoxy-S-ethylthioadenosine.

1 kg of adenosine are dissolved under nitrogen atmosphere in 10 8101 984, - - - - - - 5 - 3 3 dm · hexamsthylphosphoramide and 7.5 dm thionyl chloride are

Cooling added.

The mixture is allowed to react at room temperature for 3 to 20 hours. 10 dm water are added and the mixture is mixed.

; 5 'neutralized with 2 N NaOH. The 5'-deoxy-5'-chloro-adenosine thus formed is allowed to crystallize at 3 ° C overnight. It is filtered off. 0.950 Kg of 5'-deoxy-5'-chloroadenosine are obtained [yield 89%]. 0.950 Kg of 5'-deoxy-5'-chloroadenosine 3 '3 were dissolved in 10 dm 2 N NaOH and 200 to add ethanethiol. The mixture is heated to 80 ° C and menilate to react for 1 hour. It is neutralized with glacial acetic acid. The 5'-deoxy-5'-ethylthioadenosine thus formed is allowed to precipitate overnight at 3 ° C. It is filtered and recrystallized from water. 0.830 Kg of product are obtained (yield 80% involved-15 Ken at the previous step).

Example III

The preparation of other Class 1a compounds.

The method as described in Example II is carried out using propanethiol, butanethiol, isobutanethiol, penanethiol, hexanethiol and benzylthiol in place of the ethanethiol.

Example IV

g

The preparation of N, 2'3'-triacetyl-5'-deoxy-5'-thioadenosine.

3 1 Kg MTA is suspended in 10 dm anhydrous pyridine 3 and 3 dm acetic anhydride are added. One leaves. react the mixture for 4 hours. 20 dm of water are added and the mixture is concentrated in vacuo to obtain an oily mass free of pyridine. This is dissolved in a hot 1/1 mixture of petroleum ether / chloroform (10 dm) and allowed to crystallize. The product is recrystallized from a 1/1 petroleum ether / chloroform mixture. 1,140 Kg of product are obtained (yield 80%].

Example V

The preparation of other compounds of the Class lb.

The method described in example IV is carried out using only other thioethers or propionic anhydride, butyran hydride, benzoyl chloride or tosyl chloride instead of MTA.

Example VI

The preparation of 5'-deoxy-2'.3'-isopropylidene-5'-methylthioadenosine.

3 5; 1 Kg MTA is suspended in 25 dm anhydrous acetone and 2.5 Kg molten ZnCl 2 are added. The 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 is added. Carbon dioxide is then allowed to bubble through to neutral. The mixture is filtered and the residue is washed with acetone. The filtrate is concentrated in vacuo to yield a syrupy residue. This is taken up in a hot 1/1 chloroform / petroleum ether mixture (10 dm], filtered and allowed to crystallize. The product is recrystallized from 1/1 chloroform / petroleum ether to obtain 0.795 Kg of product (yield 70 %).

Example VII

The preparation of other Class lc compounds.

The method described in Example VI is carried out but starting from the corresponding adenosine derivatives instead of MTA.

Example VIII

The preparation of MTA sulfoxide.

3 25 1 Kg of MTA is suspended in 10 dm water and bromine is added under cooling.

The aqueous bromine-containing solution is immediately decolorized by oxidation of the MTA to sulfoxide.

Addition of bromine is continued until the solution no longer decolorizes.

The solution is decolorized by further addition of small amounts of MTA.

The aqueous solution is treated with Amberlite IRA 93 resin (Rohm & Haas trade mark for a weakly basic ion exchange resin with a polystyrene matrix) until the reaction of 6th bromide ions disappears.

8101984 I · “'—— 1' '" ”“:,: - 7 -

The mixture is filtered and the residue washed with water. The aqueous solution is concentrated to 10 dm, treated with activated carbon (100 g) and lyophilized.

0.950 kg of product is obtained (yield 90%).

Example IX

The preparation of other compounds of Class ld.

The method described in Example VIII is followed but assuming the corresponding adenosine derivatives instead of ΙΊΤΑ.

As stated at the outset, it was found that the compounds of the formula I have a strong anti-inflammatory action, also an analgesic and anti-fever activity.

Anti-inflammatory activity was demonstrated for some Class compounds, by the experimental edema test of the rat paw with carrageenan by determining the percentage protection according to the Winter method (J. Pharm. Exper, Therap. 141, 369 (1963)). . The values obtained are shown in Table A.

Table A

Compound of formula 1 Administered% Protection dose orally calculated on mg / Kg edema development- _________ Keling n 3 0 R = -CH2, R 3 R2 3 H 37 50 n 3 0 R 3 -CH, Rn 3 R 3 H 23 (a) 50 n = 0 R = -CH -C H_, R_ 3 R_ 3 H 47 10

. ά b b 1 <L

25 / CH3 n 3 0 R 3 -CH2-CH, R 3 R2 3 H 85 62 N CH3 n 3 0 R 3 - (CH_) -CH_, R 3 R „3 H 95 20 ά OOXLn 3 0 R 3 - (CH2) -CHg, R 3 R2 = H 112 10 30 n 3 0 R = - (CH2) 4-CH3, R 3 R2 3 H 90 25 n 3 0 R = -CH2-CH3, R1 3 R2 = H 80 44 n 3 0 R 3 - (CH 2) 2 -CH 3, R 3 R2 3 H 80 53 CH 3/3 n 3 0 R 3 -CH, R 3 R 3 H 80 45 \. 1 2 35 CH3 8101984 - 8 -

Table A (continued) η = 0 R = - (CH) -CH, R = R2 = H 85 39 n = 0 R = CH-CH2-CH3, R = R2 = H 85 35 5 n = 0 R = - ( CH ^ -CH, R - R2 - H 100 47 n = OR = -CCH2) g-CH3, R = R2 = H 106 33 n = 1 R - -CH, R = R2 = H 156 ... 50 n - 1 R - -CH3 ,. Rx = R2 = H 8.6 (a) 50 n = 0 R = -CH3, R = R2 «-CO-CHg Ί14 47 10 π = 0 R -CHg, Rx = R2 = ^ osy * * 204 15 n = OR * -CH „, R, = R„ = -CO-CeHc 164 10 d 1 2 bo π = OR = -CHg, R ^ = H, R2_Ri = isopropyl 91 20 indomethacin 9 50 (a) means that the product was intramuscular administered.

As can be seen from this table, the ED ^ q of the bedraagt 27 mg / kg is therefore the lowest of the tested compounds when administered orally.

In the same experiment, the ED5Q of indomethacin is 9 mg / kg. At these doses, severe gastric lesions occur, while j in the EDj.g stages does not produce any side effects on the gastrointestinal system.

It should also be noted that the LD of indomethacin in the rat is 12 mg / kg (Martelli A. in Aspetti di pharmacologia dell'infiammaziohe, p. 73, published by Tamburini-Milan 1973), while the LD3Q of MTA in the rat is greater than 200 mg / kg / 25, among others.

The following therapeutic indices are therefore obtained: indomethacin TI = 1.3 ΓΤΓΑ TI => 54.05

The compounds of the invention have also been subjected to a series of pharmacological tests to confirm their anti-inflammatory activity and demonstrate their analgesic and antipyretic activity.

The results obtained in some of these tests with zijn are set out below, being a product which was most active under all circumstances when administered orally and which ....... 810 1 9 8 4 ..... ...................

- 9 - «is certainly the safest since it is a compound that is already physiologically present in the organism.

From an industrial point of view, the process for preparing MTA from SAME as found is by far the simplest and most economical allowing the product to be marketed at a low price.

As seen from the data in Table A, methylthioadenosine sulfoxide is particularly active when administered intramuscularly. The greater activity of this compound in intramuscular administration was confirmed in all experiments performed. Some significant numbers regarding MTA sulfoxide are also given, it should be noted that all tested compounds showed activity in all cases, albeit in different sizes.

15 A - Anti-inflammatory effect.

The products were tested by pleurisy induced in the rat by carrageenan by the Velo method (Velo GiP., DUNN C.J. et al. (1973), J. Path. Ill, 149).

MTA at a dose of 75 mg / kg when administered orally gave a protection of 42.4% based on the volume of the e: xudate, and 48.8% based on the total number contained in the e xudate cells.

A similar protection was obtained with 10 mg / kg indomethacin, ie with a dose much closer to the LD5Q. In the same test, the MTA sulfoxide gives a protection of 75.8 # based on the volume of the e-udate and 78, 4% calculated on the total number of cells present in the e. xudate when administered intramuscularly at a dose of 80 mg / kg.

B - Anti-inflammatory effect.

In the rat granuloma test by cotton pellets (Winter CA, Riseley EA et al (1936) J. Pharm. Exper. Ther. -141, 369) which is significant in chronic inflammation gpf MTA protection of 30% with oral dose of 9 mg / kg at a TI of 222.

35 C - According to two 81 019 8 4 τ * · .... the analgesic effect of the products was

Γ7Γ ~ ~ 7 ~ .........

I tested tests considered very important.

- According to the mouse warming plate test according to Roberts (Roberts E. Simonsen DG (1966] Biochem. Pharmac. 15, 1875]), it gave MTA protection of 50% at an oral dose of 37 mg / kg. An approximately equivalent protection of 58 % was obtained with 100 mg / kg orally administered amidopyrine.

In the same test, MTA sulfoxide provides 50% protection at a dose of 20 mg / kg by intramuscular administration and at a dose of 100 mg / kg by oral administration.

[10] Stretch test by phenylquinone (Siegmund E., Cadmus R., GQ-LU (1957] Proc. Soc. Exp. Biol. Med. 95, 729] gives the MTA a 51% protection at an oral dose of 37 mg / kg.

In the same experiment, MTA sulfoxide has an EDgQ of 10 mg / kg when administered intramuscularly.

15 0 - Antipyretic effect.

This was determined for the new products using fever with rat brewer's yeast (Winder C.V. et al (1961) J. Pharmacol. Exp. Ther. 133, 117).

The antipyretic effect was evaluated. 1 hour after oral administration of MTA at a dose of 300 mg / kg gave a temperature decrease of 4.59% with respect to the blanks treated with yeast only. This percentage corresponded to a temperature drop from 38.8 ° C to 37.4 ° C.

For comparison, orally administered at a dose of 200mg / kg, amidopyrine gave a temperature reduction of 4.69%, and intramuscular administration of MTA at a dose of 80mg / kg gave a temperature reduction of 2.35%.

E - Platelet Anti-Aggregation Activity.

The compounds of the invention have also been tested for their above-mentioned action.

As is known, platelet aggregation is a complex phenomenon that can be divided into a first stage due to the direct action of a stimulant (eg adenosine diphosphate, ie ADP, or epinephrine) and a second stage due to the aggregation induced by the platelet 81 01 - 11 - jss released ADP. In this respect, when the platelets come into contact with the subendothelial collagen, the collagen initiates a whole series of reactions leading to the release of ADP by the platelets. It is this ADP that causes the second 5 wave of platelet aggregation. The following tests were carried out to determine the anti-aggregation effect of the. to evaluate new compounds: 1] "in vitro" platelet aggregation tests generated by ADP and collagen in the presence of the new compounds; 23 "in vitro" platelet aggregation tests generated by arachonic acid CAAI;

33 "in vivo" platelet aggregation experiments elicited by ADP

and collagen in subjects treated with the new products. In this case, the most significant results were again obtained with MTA, based on which the results obtained using this product are regarded as indicative of the behavior of the whole class.

13 "in vitro" tests:

Blood was drawn without stasis and an anticoagulant (3.8% sodium citrate3 was added to give a blood citrate ratio of 9: 1. Plasma rich in platelets and plasma platelets were obtained by centrifugation at ambient temperature. Platelet aggregation was estimated using the method of Bom & Cross (GVRBorn and MJCross, 25 J. Physiol., Land ». 168, 178, 19633 of the platelet fraction rich in platelets. The aggregating agents were used in the following 3 concentrations: ADP ( Sigma3 1 yf'l; collagen (Horn3 5 yg / cm; ara-chidonic acid 4 x 10 ^ M.

• -5

Adenosine at a concentration of 1 x 10 M was used as the anti-aggregating activity reference substance.

The results obtained with ADP are shown in the graphs of Figure 1, the abscissa showing the time in minutes and the ordinate representing the percent aggregation.

Curve 1 refers to controls, curve 2 to 35 samples treated with 1 x 10 ^ adenosine and curve 3 to sample 8101984; - 12 - -4 stars treated with 5 x 10 M MTA.

It is clear from the Curves that MTA greatly decreases the primary platelet aggregation due to ADB and consequently inhibits the second aggregation wave.

The same tests conducted with collagen gave negative results, i.e. MTA showed no notable retarding capacity versus platelet aggregation induced by collagen.

2) Fig.2 shows the effects of different MTA concentrations} on platelet aggregation elicited by AA at a concentration of -4 IQ 4 x IQ M. Curve 1 refers to controls, curve 2-4 on MTA at a concentration of 2 .5 x 10 M, curve 3 on MTA at -4 a concentration of 5 x -10 M and curve 4 on MTA at a concentration of 10 M. As can be seen, the platelet aggregation inhibiting effect of the MTA is proportional to its concentration. The power of MTA to increase the retarding effect of prostacycline (PGI2) in aggregation induced by AA was also investigated. In

Figure 3 refers to curve 1 to the controls, curve 2 to MTA

-4 at a concentration of 5 x 10 M, curve 3 on PGI- at a concentration of 5 x 10 M and curve 4 on a mixture consisting of 20 x 10 ~ 4 M MTA and 5 x ίο " 9 M PGI2 <It can be seen from Fig. 3 that when used in a mixture there is a strong increase in apti aggregation activity at concentrations which are ineffective in themselves.

3) "in vivo" trials: 25 Three apparently healthy volunteers aged 35, 42 and 45 respectively. 48 years who had not used drugs for at least 15 days were subjected to aggregation tests before and after using the new products at a dose of 100 mg every 8 hours for 3 days, after which the tests were evaluated. The platelet aggregation blood sample was taken 2 hours before consuming the last dose of test product.

Fig. 4 shows the results obtained with MTA.

More precisely, the fully drawn curves refer to the value obtained with blood samples from untreated patients, while the dotted line curves refer to the values obtained in the same patients treated with MTA.

It appears that MTA strongly slows platelet aggregation induced by ADP Cl yM] "in vivo".

. The same samples were repeated upon addition of 5 µg per om collagen to the blood and showed that PITA is not effective in slowing platelet aggregation induced by collagen but only prolongs the latent time of the phenomenon.

IQ The fact that MTA fen strongly inhibits platelet aggregation induced by ADP in a more or less comparable manner to the other products of the same class, while having almost no effect on aggregation induced by collagen, indicates that MTA slows down the first aggregation wave while on the other hand one.

15 has negligible direct effect on the second aggregation wave.

Its use in combination with other known anti-aggregating agents that are generally active towards the second wave while only slightly effective against the first is therefore of particular interest.

The demonstrated activity suggests the use of MTA (and "of the other compounds of the range even if less effective] not only as a platelet anti-aggregation drug, but also as an antithrombotic and anti-atherosclerotic agent, therefore in addition to being the basis of thrombogenesis mechanisms, the altered platelet-vasal wall relationship also plays a primary role in atherosclerotic disease.

F - Sleep-inducing activity.

• The Morris test was used (Morris R.W. (1966) Arch. Int.

Pharmacodyn 161, No.2, 380],

In this trial, MTA increased by 87% the duration of sleep induced by mouse pentobarbital at an intramuscular dose of 20 mg / kg.

G - Acute toxicity.

The compounds of the present invention are practically 81 0 1 9 84 '-14-.

. »Free from acute toxicity when administered orally. They are practically free of toxicity at therapeutic doses for any method of administration.

The following values are obtained for MTA and MTA sulfoxide: PITA - DLgg in mouse oral> 2000 mg / kg intravenous 360 mg / kg MTA sulfoxide - DL ^ g in mouse oral> 2000 mg / kg intravenous 400 mg / kg 10 The adenosine derivatives of formula 1 can be administered diluted with suitable pharmacologically acceptable excipients in any therapeutically suitable form, orally, parenterally or through the veins or rectally. They can also be used in products for external use by topical application.

Some examples of typical pharmaceutical preparations with MTA are exemplified below.

- 100 mg capsules MTA 100.2 mg mannitol 195.0 mg 20 magnesium stearate 5.0 mg 300.2 mg - 50 mg capsules MTA 50.1 mg mannitol 100.0 mg 25 magnesium stearate 3.0 mg 153.0 mg - 100 mg tablets MTA 100.2 mg starch 100.0 mg 30 magnesium stearate 15.0 mg lactose 85.0 mg 300.2 mg - 8101984; - 15 - - 50 mg tablets MTA 50j1 mg starch 120.0 mg magnesium stearate 15.0 mg 5 lactase 115.0 mg 300.1 mg - 100 mg suppositorla MTA 100.2 mg suppository mass 1,700.0 mg 10 1,800.2 mg - 50 mg suppositories MTA 50.1 mg suppository mass 1,450.0 mg 1,500.1 mg 15 - 50 mg injectable ampoule MTA.HC1 [56.15 mg basic equivalent) 50 mg lidocaine HC1 25 mg 3 water to make up to 3 cm 20 - 25 mg injectable ampoule MTA.HC1 [28.07 mg basic equivalent) 25 mg lidocaine HC1 20 mg 3 water to supplement up to 2 cm 25 - 100 mg oral dose of MTA.HC1 (112.3 mg basic equivalent) 100 mg citrus flavoring 0.025 mg sugar 1 g 30 anti-fermentation agent 50 mg 3 water to supplement up to 5 cm - 50 mg oral dose of MTA.HC1 (56.15 mg basic equivalent) 50 mg 35 citrus flavoring 0.015 mg 8101984 1 ......- - - - , Π · - -τ-, - - -; - IB - • sugar 0.5 g anti-fermentation agent 30 mg 3 water to supplement up to 5 cm - 100 g ointment 5 MTA 5 g base for water-soluble ointment, to supplement up to 100 g antioxidant 0.1 g \ 81 01 9 84

Claims (14)

1. Therapeutic preparation with anti-inflammatory, analgesic and antipyretic activity, characterized in that it is as. active ingredient contains at least one compound of the general formula 1 of the formula sheet, wherein 5. is a linear or branched alkyl radical with 1-18 C atoms, or phenylalkylene wherein the alkylene chain has 1 - B C atoms, R ^ is H, an aliphatic aoyl radical with 1 - B C atoms or an aromatic acyl radical, R2 is H, an aliphatic acyl radical with 1 - B C atoms or an ara-IQ. matically acyl radical, or the radicals together also form an isopropylidene chain, and n is 0 or 1, Therapeutic preparation according to claim 1, characterized in that the active ingredient contains a compound of formula 1, wherein = H, R = CH 2, and n s 0. Therapeutic preparation according to claim 1, characterized in that the active ingredient contains a compound of the formula 1, wherein R 1 = R 2 = H, R * CH 3 and n = 1. Therapeutic preparation according to claim 1, characterized in that it contains as active ingredient a compound of the formula 1, wherein R 1 = R 2 = H, R = a linear or branched alkyl chain with 1 - 12 C atoms and n = 0. - Therapeutic preparation according to claim 1, characterized in that the active ingredient contains a compound of the formula 1, wherein R 1 = H, R = benzyl and n = 0. Therapeutic preparation according to claim 1, characterized in that it contains as active ingredient a compound of the formula 1, wherein R 1 = R 2 = benzoyl, R methyl and n * 0. Therapeutic preparation according to claim 1, characterized in that it contains as active ingredient a compound of the formula 1, wherein R 1 = R 2 = tosyl, R = methyl and n = 0. s ..... ..... 8101984 - ia - The therapeutic preparation according to claim 1, characterized in that it contains as active ingredient a compound of the formula 1, wherein R 1 - R 2 = isopropylene, R = methyl and n = 0. Process for preparing 5'-deoxy-5'-methylthiadenosine, characterized in that S-adenosyl-methionine is hydrolyzed in concentrated aqueous solution by heating under reflux and the 5'-deoxy-5 'formed methylthioadenosine is separated by cooling and neutralizing the reaction mixture. 10. Process according to claim 9, characterized in that the aqueous solution of S-adenosylmethionine is concentrated by heating under vacuum to 35-40 ° C, Process according to claim 9, characterized in that the 5'-deoxy-5'-methylthioadenosine formed is precipitated by cooling to 0-5 ° C. 12. Use of a compound of the general formula 1, where in R is a linear or branched alkyl radical having 1 to 18 carbon atoms, or phenylalkylene, wherein the alkylene chain has 1-6 carbon atoms, R 1 = H, an aliphatic acyl radical with 1-6 C atoms or an aromatic acyl radical, R ^ = H, an aliphatic acyl radical with 1-6 C atoms or an aromatic acyl radical, or also the radicals R ^ together form an isopropylidene chain, to prepare pharmaceutical products with inflammatory, pain-relieving and anti-inflammatory springs. 13. Use of the compound of formula 1, wherein = R2 = R = CHg and n = 0 for the preparation of pharmaceutical products with anti-inflammatory, analgesic and antipyretic action. 14. Use of the compound of formula 1, wherein R ^ = R ^ = H, R = CH3 and π s L for the preparation of pharmaceutical products with anti-inflammatory, analgesic and antipyretic action. 81 01 984 M'H1 1 ra2 Ια Λ \ (o) a Λ \ Vn / 0H2J-S 03 -3 ORg CRg OH OH lc w, lb ra "R1 s ^ y \ iVv LI>> VAS / Srd / ra, - sa f 2- ^ d W d », ra-ai 1d nh2 2 fï \ o ΑΝ ^ kAn / cHala ^ ιΛι / ™ ld d 3r2 ORg OH OH Bioresearcii Sr1. 8101984 Pa REACTION CHART α>. r. ,, 2) 22 OH ΟΗ ΝΗ ίΤ> 1 / \ ι \ | / + H3M3H2-CH-CE-COOH + Η OH ΟΗ Bioresearch Sr1. 810 19 8 4