FR2491761A1 - ADENOSINE DERIVATIVES WITH ANTI-INFLAMMATORY AND ANALGESIC ACTIVITY AND THERAPEUTIC COMPOSITIONS CONTAINING THE SAME AS ACTIVE INGREDIENTS - Google Patents

Abstract

THERAPEUTIC COMPOSITION WITH ANTI-INFLAMMATORY, ANALGESIC AND ANTIPYRETIC ACTIVITY, INCLUDING AS AN ACTIVE PRINCIPLE AT LEAST ONE COMPOUND OF GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH R IS AN ALCOYL RADICAL WITH LINEAR OR A BRANCHED CHAIN OF 18E CONTAINING 1 C OR A PHENYLALCOYLENE IN WHICH THE ALCOHYLEN CHAIN CONTAINS 1 TO 6 ATOMS OF C; R IS H, AN ALIPHATIC ACYL RADICAL WITH 1-6 ATOMS OF C OR AN AROMATIC ACYL RADICAL, R IS H; AN ALIPHATIC ACYL RADICAL WITH 1-6 ATOMS OF C OR AN AROMATIC ACYL RADICAL; POSSIBLY, THE RADICALS R FORM TOGETHER AN ISOPROPYLIDENE CHAIN, N IS EQUAL TO 0 OR 1.

Description

The present invention relates to active adenosine derivatives

  anti-inflammatory, analgesic and antipyretic, as well as. therapeutic compositions containing them

as an active ingredient.

  The compounds with therapeutic activity according to the present invention correspond to the general formula NE-R 1 (O) n

The H2-S-R

  Wherein R is a linear or branched alkyl radical containing 1 to 18 C atoms or phenylalkylene wherein the alkylene chain contains 1 to 6 C atoms; R 1 is H, an aliphatic acyl radical of 1-6 carbon atoms or an aromatic acyl radical; R2 is H, an aliphatic acyl radical having 1-6 carbon atoms or an aromatic acyl radical; optionally, the radicals R 2 together form an isopropylidene chain;

n is 0 or 1.

  In addition, when R is a hydrogen atom, the invention

  also relates to the acid addition salts of the compounds

of formula (I).

  The preferred radicals represented by R are as follows: ## STR1 ## ethyl, propyl, isopropyl, butyl, isobutyl and butyl

  sec., pentyl, hexyl, heptyl, octyl, decyl, dodecyl, hexamino

decyl, octadecyl or benzyl.

  Rla preferably have the following meanings:

  gene, acetyl, propionyl, butyryl, benzoyl or tosyl.

  R2 preferably has the following meanings:

  gene, acetyl, propionyl, butyryl, benzoyl or tosyl.

  The preferred acid addition salts of the compounds of formula

  mule (I) are chlorides, sulphates, phosphates, formates, acetates, citrates, tartrates,

  methanesulfonates or p-toluenesulfonates.

  The compounds of formula (I) are in part new.

  The compounds of formula (I) are prepared by different

  methods according to the meaning of the various radicals.

  To separate the group of compounds of formula f (Ia)

H2-S-R

  In which R has the meanings given above, the method of Legraverand (Legraverand M., Ibanez S. and their collaborators (1977), J. Med Chem 12, 105-108) was followed,

  that adenosine is converted to 5'-chloro-5'-

  deoxyadenosine by reaction with thionyl chloride in

Hexamethylphosphoramide.

  Then the 5'-chloro-5'-deoxyadenosine is converted into the desired thioether by reaction with the corresponding mercaptan.

  in 2N sodium hydroxide solution at 802 °.

  The thio-ethers obtained are purified by recrystallization.

  tion-from water or from aliphatic alcohols

  laughing. The compounds (Ia) can then be salified with the

  stochiometric amount of the required acid.

Compounds of general formula

: NH-R

He b)

CH2-S-R

OR2 OR2

 22 2

  in which R, R and R2 have the meanings given below.

  above, with the proviso that R1 and R2 must be other than H or an isopropylidene chain, have been prepared by the method of Satom and Makino (Satom K, Makino K (1951) Nature

  167, 258) by reacting the compounds of formula (Ia)

  corresponding with the desired acyl chloride in anhydrous pyridine. Preferably, the products are recrystallized at

  from a 1: 1 mixture of chloroform / petroleum ether.

  the compounds of formula H - I I (Ic) 2-. in which R and R 1 have the meanings given above, are further prepared by the method of Satom and Makino (previously mentioned) by reacting the corresponding compounds of formula (I), in which R2 is hydrogen, with acetone in the presence of ZnCl2. The

  products obtained are preferably purified by crystallization

  from a 1: 1 mixture of chloroform / petroleum ether.

LO Compounds of formula (Id)

CH2 - R

  in which R, R 1 and R 2 are as defined above, are prepared by oxidation of the corresponding thioethers, obtained by the abovementioned methods, using 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 recrystallization from water.

  Of all the products prepared, the one which has proved to be of particular interest for the purposes of the present invention is 5'-deoxy-5'-methylthioadenosine (MITA) of the formula: r -2 (IM)

/> 2 - CH3, - '

2 3 H H

  which is a physiological compound already present in organisms

living organisms.

  For the preparation of this product, a process has been found which is particularly simple and economical from an industrial point of view. The new process consists essentially of hydrolysis of the above-mentioned Sadenosylmethionine: SAME

  under conditions of decisive importance, strictly controlled

  This results in almost complete hydrolysis and complete crystallization of the IPA:

+ 2 20

OE - C -CH C-COOH->

  a2 -C 1 2 2 (a) OH OH- NH_ | 2 to t2- 3 H 2

+ HC- -CHE -.- CH-COOH + H

  The controlled hydrolysis process can be applied to a SAME prepared in any manner. However, the process of preparing the EMS solution is also an important factor in leading the new process so

economically adequate.

  The following process steps are the most economical embodiment of the process: a) Ordinary bread yeast is enriched in SAIE by methionine treatment according to Schlenk's method (Schlenk F. (1965) Enzymology 29, 283); b) The yeast cells, suspended in water, are lysed by treatment with ethyl acetate or methyl at room temperature (German patent application P 23 36401.4). By adjusting the pH to a value between 4 and 6 and filtering, an aqueous solution is obtained which contains substantially all of the SAME present in the starting yeast; c) The solution is concentrated under vacuum at 35-40 ° C to about 1/10 of its initial volume; d) The compound is kept boiling under reflux for about 30 minutes and the pH is adjusted to 7 with sodium carbonate;

  e) The solution is allowed to stand at 0-5C20 and the MTA precipitates

  is collected almost entirely and with good

purity.

  Phases c, d and e, which are considered rigorous

  necessary to obtain a selective hydrolysis

  ve complete the SAME in MTA without product training

secondary, are new.

  The preparation of some products used according to

  The present invention is described below.

Example 1

  Preparation of 5'-deoxy-5'-methylthioadenosine (MTA) 11 liters of ethyl acetate and 11 liters of water at room temperature are added to 90 kg of bread yeast which has been enriched with SAME by adding methionine up to

  that the SAME content is 6.88 g / kg.

  After stirring vigorously for 30 minutes, the pH is adjusted to 4.5 with dilute H 2 SO 4, the mixture is filtered and the residue is washed with water to give 140 liters of a solution having a SAME content of 4.40 g. / l, which corresponds to

  99.5% of the SAIE present in the starting material.

  The lysate thus obtained is concentrated under vacuum (30 mm Hg, -40 °) to a volume of about 14 liters. The concentrated solution is boiled under reflux at normal pressure for 30 minutes. It is cooled to CO, the pH is adjusted to 7 with 40% sodium carbonate and the solution is left overnight in a tank.

refrigeration (+ 32C).

  A white precipitate forms which is filtered, dissolved in 10 liters of boiling distilled water and crystallized by

  cooling of the solution thus obtained.

  410 g of high purity crystalline MTA are obtained, corresponding to a yield of 90% on the basis of the SAME subjected to hydrolysis. The characteristics of the product obtained coincide with those of pure M4TA prepared by other means.

Example 2

  Preparation of 5'-deoxy-5'-ethylthioadenosine

  1 kg of adenosine is dissolved, under a nitrogen atmosphere, in 10 liters of hexamethylphosphoramide and added under

  cooling 7.5 liters of thionyl chloride.

  The mixture is allowed to react at room temperature for 20 hours. 10 liters of water are added and the mixture is

neutralized with 2N NaOH.

  It is allowed to crystallize overnight at 32 ° C the 5'-deoxygenate.

  -chloradenosine which is formed under these conditions. We have it

  filtered off and 0.950 kg of 5'-deoxy-5'-is obtained.

  chloradenosine (89% yield). 0.950 kg of 5'-deoxy-5'-

  chloradenosine are dissolved in 10 liters of 2N NaOH and 200 ml of ethanethibol are added thereto. The mixture is heated to 80 and allowed to react for 1 hour. We neutralize it with

  glacial acetic acid. Let's rush peln-

  overnight at 5'-deoxy-5'-ethylthioadenosine which forms under these conditions. It is separated by filtration and

recrystallized from water.

  We obtain 0.830 kg of product (80% yield based on

from the previous stage).

Example 3

  Preparation of other compounds of category Ia is carried out according to the process described in Example 2, but

  using propane-thiol, butane-thiol, isobutane-

  thiol, pentane-thiol, hexane-thiol and benzyl-thiol

  respectively, instead of ethane-thiol.

-9 2491761

Example 4

  Preparation of N6, 2 ', 3'-triacetyl-5'-deoxy-5'-thioadenosine

  1 kg of MTA is suspended in 10 liters of pyridine

  anhydrous dine and add 3 liters of acetic anhydride. The mixture is allowed to react for 4 hours. 20 liters of water are added thereto and the mixture is concentrated in vacuo to give an oily mass free of pyridine. This is dissolved in a hot 1: 1 mixture of petroleum ether / chloroform (10 liters) and allowed to crystallize. The product is recrystallized from a 1: 1 mixture of petroleum ether / chloroform. We

  gets 1,140 kg of product (80% yield).

Example 5

  Preparation of other compounds of category Ib.

  The procedure is as described in Example 4, but

  using, in place of MTA, other thio-ethers or anhy-

  propionic acid, butyric anhydride, benzoyl chloride,

yl or tosyl chloride.

Example 6

  Preparation of 5'-deoxy-2 ', 3'-isopropylidene-5'-methylthio-

adenosine.

  1 kg of IPA is suspended in 25 liters of anhydrous acetone and 2.5 kg of molten ZnCl 2 are added thereto. The reaction is carried out under reflux for 5 hours. The mixture is then concentrated under vacuum to 1/3 of its original volume and 7.5 kg of barium hydroxide octahydrate in aqueous suspension are added thereto. Carbon dioxide is then bubbled to neutrality. The mixture is filtered and the residue is washed with acetone. The filtrate is concentrated in vacuo to give a syrupy residue. It is taken up in a 1: 1 hot mixture of chloroform / petroleum ether (10 liters), filtered and left

  crystallize. The product is recrystallized from chlorinated

  form / petroleum ether 1: 1, to give 0.795 kg of product

(70% yield).

Example 7

  3j Preparation of other compounds of category Ic.

  The procedure is as described in Example 6, but starting from the corresponding derivatives of adenosine, at

place of I.A.

Example 8

  Preparation of the sulfoxide of IMTA. 1 kg of ITA is suspended in 10 liters of water and bromine is added under cooling. The aqueous solution containing bromine becomes discolored immediately, because of the

  transformation of MTA into sulfoxide by oxidation. We can

  following the addition of bromine until the solution does not fade anymore. We decolorize the solution by adding more

small amounts of MTA.

  The aqueous solution is treated with Amberlite resin

  IRA 93 (registered trademark of Rohm und Haas for a resin exchange

  weakly basic ion generator with polystyrene matrix)

  until the reaction of the bromine ions disappears.

  The mixture is filtered and the residue is washed with water. The aqueous solution is concentrated to 10 liters, treated with

  activated charcoal (100 g) and lyophilized.

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

Example 9

  Preparation of other compounds of category Id.

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

of the MTA.

  As was stated at the beginning, it was found that the

  compounds of formula I had a strong anti-

  inflammatory, with analgesic and antipyretic action.

  The anti-inflammatory activity was initially demonstrated.

  for certain terms of the class of products, by testing the experimental edema produced in the rat by carrageenin, by determining the percentage of protection by

  Winter's method (J. Pharm, exper Therap 141, 369, 1963).

  The values obtained are presented in Table 1.

he

Table i

  Dose administered orally (mg / kg) Compound of formula (I) n = 0, R = = OH 2, R 1 = R 2 = H n = 0, R = -CH 3, R 1 = R 2 = H n = 0, R = -CH2-C6H5, R1 R2 = H n = 0 R

-, R1 = R2 = H

  n = o, R '= - (cH2) lT-c.H3, R1 = n = o, R = - (OH2) 14 -H3, R1 = R2 = HC n = 0, R = -C2-CH-H3 , R1 = R2 = H CH3 n = 0, R = - (CH2) -C R1 = R2 = n = 0, R = C- (-C H3 R1 2 = H CH3 n = 0, R = - (C 2 ) -C H3, R1 2 = R2H n = 0, R = -CH2COH3, R1 = R2 = H n = 1, R = - H3, 1 R = n = 0, R = - (CH2) 2-C, R1 = Rs = H n = 1, R = -CH3, R = R2 = H-CH3 n = 0, R = -CH C, R1 = R2 = H n = 0, R = CH-CH3, R1 = R2 = ## STR5 ## wherein R 1 = R n = 0, R = -CH 3, R 1 = R 2 = tosyl n = 0, R = -OH, R = R = isopropyl n = 0, R -CH 3 R 1 R 2 = CO C 6 n = O, R = -CH, R = R = isopropyl 23 (a) 8.6 Percent

of protection

  tion, calculated from the development of edema (a) nd omethacin 9 50

  (a) means that the product has been administered intra-

muscular.

  As can be seen from this table, the ED 50 of IMTA is 37 mg / kg and is therefore the lowest dose, by oral administration, of the compounds tested. Under the same experimental conditions, the ED50 of indomethacin is 9 mg / kg. With these doses, serious gastric lesions appear, whereas at the ED50, the I4A does not give rise to any side effect on the gastrointestinal system. It should also be noted that the ED of indomethacin in rats is 12 mg / kg (Martelli A, Aspetti di farmacologia dell'infiamnmazione, page 73, edited by Tamburini, Milan 1973), while the ICA LD50 in the rat is greater than

mg / kg / oral route.

  The following therapeutic indices are therefore obtained: Indomethacin, IT = 1.3

I1TA, IT => 54.05.

  The compounds of the invention have also been subjected to a series of pharmacological tests to confirm their

  anti-inflammatory activity and to highlight their activity

  analgesic and antipyretic activity.

  The results obtained in some of these tests with MTA are given below: the MTA is a product which, in all cases, has proved to be the most active per os and which is certainly the most harmless, because it is a compound that is physiologically present in the body, as previously seen. From the point of view of industrial production, the process for the preparation of MTA from SAME according to the invention is, let us repeat it, by far the simplest and most economical

  and it allows the product to be marketed at a special price.

low.

  As can be seen from the results of Table 1, the sulfoxide of methylthioadenosine is particularly active when administered intramuscularly. Most

  high activity of this compound in intra-muscular administration

  has been confirmed in all the tests carried out. We give-

  There are still some significant results regarding S-ulfo-

  However, it should be noted that all compounds tested were found to be active in all cases, albeit at different levels. A - Anti-inflammatory activity The products were tested by pleuritis caused in the rat by carrageenin, according to the method of Velo (Velo G. P., Dunn C. J. et al., (1973) J. Path.

149).

  MTA at 75 mg / kg po provided 42.4% protection based on exudate volume, and

  48.8% calculated on the basis of the total number of cells pre-

in the exudate.

  Comparable protection was obtained with 10 mg / kg of indomethacin, ie with a dose much closer to the LD50. Under the same experimental conditions, the MITA sulfoxide provides a protection of 75.8% calculated on the basis of the volume of exudate, and 76.4% calculated on the basis of the total number of cells present in the exudate, when it is administered intramuscularly at the dose

of 80 mg / kg.

  B - Anti-inflammatory activity In the rat granuloma test with cotton pellets (Winter C.A., Riseley E.A. et al., (1963) J. Pharm, Exper Ther 141, 369) which is significant in

  chronic inflammation, MITA provided protection against

  30% at the oral dose of 9 mg / kg, with an IT of 222.

  C - The analgesic activity of the products was tested by

  two tests considered very significant.

  In the hot plate test in the mouse, following the Roberts method (Roberts E., Simronsen DG (1966) Biochem Pharmac., 1575), MTA provides 50% protection at oral dose of 37%. mg / kg. Approximately equivalent protection of 58% is obtained with 100 mg / kg of amidopyrine

administered orally.

  Under the same experimental conditions, the IMTA sulfoxide gives 50% protection at the dose of 20 mg / kg intramuscularly and at a dose of 100 mg / kg orally. - In the test of extension caused by phenylquinone

  (Siegmund E., Cadmus R., Go-Lu (1957) Proc.Soc.Expl.

  Med. 95, 729), the MTA provides 51% protection to the

oral dose of 37 mg / kg.

  Under the same experimental conditions, the MTA sulfoxide has an ED 50 of 10 mg / kg when administered intramuscularly. D Antipyretic activity

  It has been measured for new products in

  for fever in the rat by brewer's yeast (Winder C.V.

  and his collaborators (1961) J. Pharmacol. Ext. Ther. 133, 117).

  The antipyretic effect, evaluated one hour after administration

  MITA oral treatment at a dose of 300 mg / kg gave a fall in temperature of 4.59% compared with controls treated only with yeast. This percentage corresponds to a

  temperature drop from 38.8 C to 37.40 C.

  By way of comparison, amidopyrine administered orally

  at a dose of 200 mg / kg produced a reduction in

  4.69% and the intramuscular administration of

  the dose of 80 mg / kg gave a temperature drop of 2.35%.

  3 - Anti-Agglomeration Activity of Platelets The compounds of the invention were also evaluated with regard to their possible platelet anti-agglomerating power. As is known, platelet agglomeration is a complex phenomenon that can be divided into a primary stage due to the direct action of a stimulus (eg, adenosine diphosphate, i.e. ADP, or epinephrine) and a secondary stage due to agglomeration caused by platelet-released ADP. In this respect, when platelets enter

  contact with subendothelial collagen, the latter triggered

  a complete series of reactions that lead to the

  ADP release by platelets. It is this ADP that provokes

  than the second wave of agglomeration of platelets. -

  The following tests were performed to evaluate the anti-caking effect of the new compounds:

  1) In vitro tests on the agglomeration of platelets

  by ADP and collagen, in the presence of new products;

  2) In vitro tests on the agglomeration of platelets

  arachidonic acid (AA);

  3) In vivo tests on agglomeration of platelets

  by ADP t-collagen in subjects treated with

new products.

  In this case, the most significant results were still obtained with the XTA and, for this reason, the results

  obtained using this product are given as

  the behavior of the entire class of products.

  1) "In Vitro" Tests Blood was taken without stagnation and an anticoagulant (3.8% sodium citrate) was added to obtain a blood / citrate ratio of 9: 1. Platelet-rich plasma

  platelet-poor plasma were obtained by centrifugation

  fugation at room temperature. The agglomeration of

  25.uettes was evaluated by the method of Born and Cross (G.V.R.

  Born and M.J. Cross, J. Physiol., Lond. 168, 178, 1963) on the platelet rich plasma fraction. The agglomerating agents were used in the following concentrations: ADP (Signa) i pi; collagen (Horn) 5 μg / ml; 4 × 10 -4 arachidonic acid. Adenosine was used at a concentration of 1 × 10 -5

  as a reference substance for anti-agglomerating activity.

  The results obtained with the ADP are presented graphically

  ent on fig. 1, on which the abscissa

  in minutes and on the ordinate the percentage of agglomeration.

  Curve 1 refers to the witnesses, curve 2 to the samples

  ions treated with 1 x 10 5 M adenosine and curve 3

  samples treated with 5 x 10-4 M MTA.

  From the plot of the curves, it appears that the IMTA decreases sharply

  primary aggregation of platelets due to ADP and, therefore, inhibits the second wave of agglomeration. The same tests conducted with collagen gave negative results, ie the MTA showed no inhibitory capacity worthy of being reported with respect to

  platelet agglomeration caused by collagen.

  10) FIG. 2 shows the effects of different concentrations of MTA on AA-induced platelet aggregation at a concentration of 4 x 10-4 M. Curve 1 refers to controls, curve 2 to 1, TA at a concentration of 2.5 x 10-4, MITA curve 3 at a concentration of 5 x 10-4 I, and MTA curve 4 at a concentration of 10-3 Mi. As can be seen, the inhibitory effect of M TA on the agglomeration of

  platelets is proportional to its concentration. We also

  The ability of I: A to enhance the inhibitory effect of prostacyclin (PGI2) in the agglomeration produced by AA was investigated. In fig. 3, curve 1 refers to controls, curve 2 to MTA at a concentration of 5 x 10-4 M, curve 3 to PGI2 at a concentration of 5 x O1-9 M and curve 4 to a mixture. composed of 5 x 10-4 M MTA and 5 x 10-9 M PGI2. It is visible in fig. 3 that in case of use in

  mixture, there is a strong increase in

  clumping at concentrations that are ineffective on their own. 3) "In Vivo" Trials Three healthy, seemingly healthy volunteers aged 35, 42 and 48 years, who had not taken any drugs for at least 15 days, were tested for after consuming the new products at the dose of 100 mg every 8 hours for 3 days, then these tests were analyzed. The blood sample for determination of platelet aggregation was taken 2 hours before the last dose of

product being tested.

  Fig. 4 presents the results obtained with the tCA.

* Specifically, solid lines refer to values obtained with blood samples taken from untreated patients, while dashed lines refer to values obtained with the same patients treated with MTTA. It is apparent that MTA strongly inhibits platelet agglomeration caused by ADP

(1 -) in vivo ".

  The same tests, repeated with addition of 5 Eg / ml of collagen to the blood, showed that the MTA is not able

  to inhibit platelet agglomeration caused by colitis

  lagene, but that it only prolongs the latency of the

phenomenon.

  The fact that ITA (and, to a more or less comparable extent, other products of the same class) strongly inhibits platelet aggregation caused by ADP, while it has virtually no effect on agglomeration due to collagen, indicates that the MTA inhibits the first wave of agglomeration, while it has a negligible direct effect

  on the second wave of agglomeration. His employment in association

  with other known anti-caking drugs, which

  are generally active with respect to the second wave, tan-

  say that they are hardly effective in the first

  wave, so is particularly interesting.

  The activity highlighted suggests the use of MTA (and other compounds in the series, even though they are less effective), not only as a platelet anti-agglomerative drug, but also as an antithrombotic drug. and anti-atherosclerotic, since besides being the basis of thrombogenesis mechanisms, the altered relationship between

  platelets and vascular walls also play a key role in

  mordial in atherosclerotic disease.

F - Sleeping activity

  The iMorris test (Morris R.W. (1966) Arch.

  int. Pharmacodyn. 161, n-2, 380). During this test, the IRA

  increased by 87% the sleep duration caused by pento-

  barbital in mice at an intramuscular dose of 20 mg / kg. G Acute toxicity

  Administered orally, the compounds of this invention

  are practically free of acute toxicity, they are practically free from toxicity at therapeutic doses,

  10 regardless of the route of administration.

  The following values were obtained for AD and ITA sulfoxide: IA-LD50 in mice: per os> 2000 mg / kg i.v. 360 mg / kg I1TA-LD50 sulfoxide in mice: per os> 2000 mg / kg

i.v. 400 mg / kg.

  The adenosine derivatives of formula (I) can be administered, in a diluted state with acceptable excipients

  pharmacologically, in any therapeutically useful form, orally, parenterally, ven-

  the. They can also be used in products to

  external use for topical application.

  Some examples of typical pharmaceutical compositions

  quss, containing the MITA, are given below as an example.

  - Carsules 100 mg IIA 100.2 mg IMIannitol 195.0 mg Magnesium Stearate 5.0 mg 300.2 mg - Capsules 50 mg ITA Mannitol Magnesium Stearate, 1 mg, 0 mg 3.0 mg 153.1 mg v - 100 mg Compounds I7TA Starch Magnesium Stearate Lactose - 50 mg Tablets E3DA Starch Magnesium Stearate Lactose - Suppositories 100 mg MTA Suppository Paste SupDositories 50 mg MTA Suppository Paste - 50 mg MTA Injectable Ampoule. HOC1 (equivalent to 56.15 mg base) Lidocarne HCOi

Sau q.s.

  - Injectable ampule of 25 m IMTA. HCl (equivalent to 28.07 mg base) Lidocaine HOl Water qs - Oral dose of 100 mg ITA. HC1 (equivalent to 112.3 mg base) Lemon fragrance Sugar Anti-fermentation agent Water, 2 mg, 0 mg, 0 mg, 0 mg 300.2 mg, 1 mg, 0 mg, 0 mg, 0 mg 300, 1mg, 2mg 1700.0mg 1800.2mg, 1mg 1450.0mg 1500mg mg 3mg mg 2mg mg 0.025mg mg p. 5 ml p. Dl p. q. s - Oral dose of 50 mg ISA. HC1 (equivalent to 56.15 mg base) Lemon fragrance Sugar Anti-fermentation agent Water qs - 0nguent at 100 g IMTA

Base for hydro-ointment

  soluble, q.s Antioxidant mg 0.015 mg 0.5 g mg p. 5 ml, g, p. 100 g 0.1 g

REVE DICATIONS

  1. Therapeutic composition with anti-inflammatory activity,

  analgesic and antipyretic, characterized in that

  takes as active ingredient at least one compound of the general form NE-R LI> C EIR 2 2 in which

  R is a linear or branched chain alkyl radical containing

  from 1 to 18 C atoms or phenylalkylene whose alkylene chain contains 1 to 6 C atoms; R1 is H, one. an aliphatic acyl radical having 1-6 carbon atoms or an aromatic acyl radical; R2 is H, an aliphatic acyl radical having 1-6 carbon atoms or an aromatic acyl radical; optionally, the radicals R 2 together form an isopropylidene chain; n is equal to O or l1

  2. Therapeutic composition according to claim 1, characterized

  characterized in that it comprises, as active principle, a compound of formula (I) in which R 1 - R 2 = H, R = CH 3, n = O. 2- Therapeutic composition according to claim 1,

22491761

  characterized in that it comprises, as active ingredient, a compound of formula (I) wherein R1 = R2 = He,

R = CH3, n = 1.

  4. Therapeutic composition according to claim 1, characterized in that it comprises, as active ingredient, a compound of formula (I) in which R = R2 = HP R = linear or branched chain alkyl containing 1 to 12

C atoms, n = 0.

  5. Therapeutic composition according to claim 1, characterized in that it comprises, as active ingredient, a compound of formula (I) in which R1 = R2 = H,

R = benzyl, n = 0.

  Therapeutic composition according to claim 1, characterized in that it comprises, as active principle, a compound of formula (I) in which R1 = R2 =

benzoyl, R = methyl, n = 0.

  7- The therapeutic composition according to claim 1, characterized in that it comprises, as active ingredient, a compound of formula (I) in which R1 = R2 =

tosyl, R = methyl, n = 0.

  8. ' Therapeutic composition according to claim 1, characterized in that it comprises, as an active ingredient, a compound of formula (I) in which R2 - 2 =

isopropylene, R = methyl, n = 0.

  9. Process for the preparation of 5'-deoxy-5'-methylthio-

  adenosine, characterized in that an S-adenosyl-methionine, in concentrated aqueous solution, is hydrolysed by heating under reflux and in that the 5'-deoxy-5'-methylthioadenosine formed

  is separated by cooling after neutralization of the

reaction.

  10. Process according to claim 9, characterized in that the aqueous solution of S-adenosyl-methionine is concentrated

  by heating under vacuum at 35-402 C.

  11. Process according to claim 9, characterized in that the 5'-deoxy-5'-methylthioadenosine formed is precipitated by

cooling M 0-5 C.

  12. Use of a compound of the general formula, (O) oR OR in which

  R is an alkyl radical with a linear or branched chain containing

  from 1 to 18 C atoms or a phenylalkylene whose alkylene chain contains 1 to 6 C atoms; R 1 is H, an aliphatic acyl radical having 1-6 carbon atoms or an aromatic acyl radical; R2 is H, an aliphatic acyl radical having 1-6 carbon atoms or an aromatic acyl radical; optionally, the radicals R 2 together form an isopropylidene chain, n is 0 or 1; for the preparation of active pharmaceutical products

  anti-inflammatory, analgesic and antipyretic.

  13. Use of the compound of formula (I) wherein R1 = R2 = H, R = CH3, n = O for the preparation of pharmaceuticals with anti-inflammatory, analgesic and antipyretic activity. 14. Use of the compound of formula (I) wherein R 1 = R 2 = H, R = CH 3, n = 1 for the preparation of pharmaceuticals with anti-inflammatory, analgesic and antipyretic activity.