DE3116067A1 - THERAPEUTIC COMPOSITIONS WITH PAIN-RELEASING AND ANTI-INFLAMMATORY PROPERTIES THAT CONTAIN ADENOS IN DERIVATIVES AS ACTIVE INGREDIENTS - Google Patents

Description

description

The invention relates to adenosine derivatives with anti-inflammatory, analgesic and antipyretic activity, and it relates to therapeutic compositions containing these compounds as active ingredients.

The compounds with therapeutic activity, according to the present invention, have the following general formula:

NE-R

CH-S-H

(I)

OR CK
2 2

in which mean:

R is a straight-chain or branched alkyl radical with 1 to Carbon atoms, or a phenylalkylene radical in which the alkylene chain has 1 to 6 carbon atoms;

R- hydrogen, an aliphatic acyl radical having 1 to 6 carbon atoms or an aromatic acyl radical;

R _{2 is} hydrogen, an aliphatic acyl radical with 1 to 6 carbon atoms or an aromatic acyl radical, or the two radicals R- together form an isopropylidene chain; and

η 0 or the number 1.

If R _{1 is} hydrogen, the invention also includes the acid addition salts of the compounds of the general formula (I)

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

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Preferred meanings for the radical R ₁ are the following radicals: hydrogen, acetyl, propionyl, butyryl, benzoyl or tosyl.

Preferred meanings for the radical R ₂ are the following radicals: hydrogen, acetyl, propionyl, butyryl, benzoyl or tosyl. .

Preferred acid addition salts of the compounds of the general formula (I) are the chlorides, sulfates, phosphates, formates, Acetates, citrates, tartrates, methanesulfonates or p-toluenesulfonates.

Some of the compounds of the general formula (I) are new.

The compounds of the general formula (I) can as a function the meanings of the various radicals can be prepared by different processes.

For the preparation of the class of compounds of the general formula below

(Is)

OH OH

in which R has the meaning given above, the Legraverand method (Legraverand M. Ibanez S., et al. (1977) Eur. J. Med. Chem. 12, 105-108), in which adenosine is converted into the S'-chloro-S'-deoxyadenosine by reaction with thionyl chloride in hexamethylphosphosamide.

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- 7th

The 5'-chloro-5'-deoxydenosin is then converted by reaction with the appropriate mercaptan in 2N sodium hydroxide solution at 80 ⁰ C in the desired thioether.

The thioethers are then purified by recrystallization from water or from lower aliphatic alcohols.

The compounds of formula (Ia) can then with the stoichiometric Amount of the desired acid can be converted into the corresponding salt.

The compounds of the following general formula NH-R.

(Ib)

in which R, R. and R _{2 have} the above meaning, with the proviso that R ₁ and R _{2 are} not hydrogen or an isopropylidene chain, were prepared by the method of Satom and Makino (Satom K., Makino K .. ( 1951), Nature 167, 238), in which the corresponding compounds of the general formula (Ia) are reacted with the desired acyl chloride in anhydrous pyridine. The products are preferably recrystallized from a 1: 1 chloroform / petroleum ether mixture.

The compounds of the general formula

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NH-Ä

(Ic)

in which R and R- have the above meaning are prepared by reacting the corresponding compounds of the general formula (I), in which R _{2 is} hydrogen, with acetone in the presence of ZnCl ₂ , also by the method of Satom and Makino (which already mentioned above). The products obtained are preferably purified by recrystallization from a 1: 1 chloroform / petroleum ether mixture.

The compounds of the general formula

NH-S.

(Id)

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in which R, R ₁ and R "have the above meaning, are prepared by oxidation of the corresponding thioethers, which have been prepared by the process described above, with 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 produced, one compound has proven to be of particular interest for the purposes of the present invention, namely 5'-deoxy-5 ¹ -methylthxoadenosine (MTA) of the following formula:

CH-S-CH, 2 3

(II)

DH OH

which is a physiological one already present in the living organism Connection is.

A process has been found for the manufacture of this product which is particularly simple and from an industrial point of view is economical. The new process essentially consists in the hydrolysis of S-adenosylmethionine (SAME) Carries out under strict critical conditions, whereby one practically complete hydrolysis and a can achieve complete crystallization of the MTA:

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HH.

± I ²

CH-S-CH - (BI-CH-COOH 2 j 2 2

OH OH

CH-S-CH

NH.

+ HO-CH.-CH -CH-COOH + H 2 2

The controlled hydrolysis process can be applied to any SAME applied regardless of how it was made.

However, the way of making the SAME solution also represents is an influencing factor in the implementation of the new process in an "economically appropriate manner.

The procedural steps compiled below are provided represents the most economical execution of the process.

a) Normal bread yeast is made according to the Schlenk method (Schlenk F. (1965) Enzymologie 29, 283) enriched in SAME by treatment with methionine.

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b) The yeast cells are suspended in water by treatment with ethyl or methyl acetate at ambient temperature lysed (DT-OS 23 36 401.4).

By adjusting the pH to a value between 4 and 6 and filtering, an aqueous solution is obtained, which contains practically all of the SAME present in the original yeast.

c) The solution is concentrated its original volume under vacuum at temperatures of 35-40 ⁰ C to about one tenth.

d) The concentrate is refluxed for about 30 minutes and then the pH is raised with soda 7 set.

e) The solution is allowed to stand at 0-5 ⁰ C, and the precipitated MTA is practically completely collected in good purity.

The steps c, d and e, which - as already mentioned - for the complete selective hydrolysis of SAME to MTA without formation of by-products that are critically necessary are new.

The manufacture of some products used according to the invention is described below.

example 1

Production of 5'-Deoxy-5'-methylthioadenosine (MTA) 11 liters of ethyl acetate and 11 liters of water are added to 90 kg of bread yeast at ambient temperature, which is enriched in SAME by adding methionine until the SAME content is 6.88 g / kg. After 30 minutes of vigorous stirring, the pH is _{adjusted to 4.5 with dilute H 3} SO ₄ , the mixture is filtered and the residue is washed with water, so that a 140 liter solution with a SAME content of 4.40 g is obtained / Liter, which is equivalent to 99.5% of the original

P 1 181 - 12 -

the material present is SAME.

The lysate thus obtained is dried under vacuum (30 mm Hg; 35-40 ⁰ C) concentrated to a volume of about 14 liters. The concentrated solution is heated under reflux conditions at normal pressure for 30 minutes. It is then cooled to 2O ⁰ C, the pH is adjusted with 40% soda at 7, and then allowing the whole overnight in a cooling tank (+3 ⁰ C) are provided.

A white precipitate that has formed is filtered off, dissolved in 10 liters of boiling, distilled water and allowed to cool crystallized out of the solution.

410 g of crystalline MTA of high purity are obtained in one yield of 90% based on the SAME subjected to hydrolysis. The properties of the product agree with those from an MTA obtained by other means.

Example 2 Production of 5'-deoxy-5 ^ äthylthioadenosine

1 kg of adenosine is poured into 10 liters under a nitrogen atmosphere Hexamethylphosphoramide and dissolved with cooling 7.5 liters of thionyl chloride added.

The reaction mixture is allowed to react at ambient temperature for 20 hours. Then 10 liters of water are added and the mixture neutralized with 2N NaOH.

Which then forming 5'-deoxy-5'-chloroadenosine is allowed to crystallize out overnight at 3 ⁰ C. Then it is filtered off. 0.950 kg of 5'-deoxy-5'-chloradenosine are obtained (yield 89%). 0.950 kg of 5'-deoxy-5'-chloradenosine are dissolved in 10 liters of 2N NaOH, and 200 ml of ethanethiol are then added. The mixture is ^{heated to 80 °} C. and reacted for 1 hour. Then it is neutralized with glacial acetic acid. The 5'-deoxy 5'-ethylthioadenosine which then forms is allowed to precipitate at 3 ° C. overnight. It

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is filtered off and recrystallized from water. 0.830 kg of product are obtained (yield 80%, based on the preceding one Step).

Example 3

Preparation of other compounds of the general formula (Ia) The process of Example 2 is repeated, but using propanethiol, butanethiol, isobutanethiol, pentanethiol, hexanethiol and benzylthiol instead of ethanethiol.

Example 4

Preparation of N, 2 ', 3'-Triacetyl-S'-deoxy-S'-thioadenosine 1 kg of MTA is suspended in 10 1 of anhydrous pyridine, and 3 1 of acetic anhydride are then added. The mixture is allowed to react for 4 hours. 20 l of water are then added and the mixture is concentrated in vacuo, an oily mass free of pyridine being obtained. 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 petroleum ether / chloroform mixture. 1.140 kg of product are obtained (yield 80%).

Example 5

Preparation of other compounds of the general formula (Ib) The procedure described in Example 4 is repeated, except that other thioethers or propionic anhydride, butyric anhydride, benzoyl chloride or tosyl chloride are used instead of MTA.

Example 6 Production of 5'-deoxy-2 ', 3'-isopropylidene-5'-methyl-

thioadeno sin

1 kg of MTA are dissolved in 25 1 of anhydrous acetone, and it

2.5 kg of molten ZnCl are then added. The reaction is carried out under reflux conditions for 5 hours. The mixture is then reduced in vacuo to one third of its original volume and it is then 7.5 kg Barium hydroxide octahydrate added in aqueous suspension. Until the neutral reaction is then carbon dioxide through the Mixture bubbled through. The mixture is filtered off and the residue is washed with acetone. The filtrate is under Concentrated in vacuo and a syrupy residue is obtained. This is in a hot 1: 1 chloroform / petroleum ether mixture (10 1) taken up, filtered, and then allowed to crystallize out. The product is made from a 1: 1 chloroform / petroleum ether mixture recrystallized, and 0.795 kg of product are obtained (yield 70%).

Example 7

Preparation of other compounds of the general formula (Ic) The process of Example 6 is repeated, but starting from the corresponding adenosine derivatives instead of MTA.

Example 8 Manufacture of MTA sulfoxide

1 kg of MTA is suspended in 10 1 of water and bromine is added with cooling.

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

The addition of bromine is continued until the solution does not discolor again.

The solution is decolorized by adding a small amount of MTA. The aqueous solution is then coated with Amberlite IRA 93 resin (one

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registered trademark of Rohm & Haas for a weakly basic ion exchange resin with a polystyrene matrix) / until the reaction of the bromide ions disappears.

The mixture is filtered off and the residue is washed with water. The aqueous solution is concentrated to 10 1 with Treated and lyophilized activated charcoal (100 g). 0.950 kg of product are obtained (yield 90%).

Example 9

Preparation of other compounds of the general formula (Id) The process of Example 8 is repeated, but starting from the corresponding adenosine derivatives instead of MTA.

As mentioned above, it was found that the compounds of the general formula (I) have a strong anti-inflammatory activity, which is accompanied by a analgesic and antipyretic efficacy,

The anti-inflammatory activity was originally for some representatives of the compounds according to the invention by the Experimental edema test in rats caused by carrageenan demonstrated by looking at the percentage protection the method of Winter (J. Pharm. exper. Therap. 141, 369, 1963). The values obtained are in the following Table 1 compiled.

R = -CH ₃ , R ₁ »
R = -CH ₃ , R ₁ =
R = -CH - IVH-. ^S 2
^R 2
R. Table 1 oral ver
handed in
Dose in
mg / kg percentage
Protection, calc
net on the
Base of edema
development 37
23 (a) 50
50
10 Connection of the general
my formula (I) = H It Il Il
ο ο ο = H
. = R-

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CH.

η = O R = -CH-CH
^ CH ₃ • ^R i = R ₂ = Η 85 η = O R = - (CH ₂ ) ₆ -CH _3> R ₁ = I. ¹ Z ~ H .95 η = O R »- (0Η ₂ ) _η -0Η ₃ , ^R l ^{= R} 2 = H 112 η = O R * - (CH ₂ ) ^ - CH ₃ , R ₁ = ΐ ^{1 line =} H 90 η = O R = -CH ₂ -CH ₃ , R ₁ -B ₂ - = H 80 η = O R = - (CHg) ₂ -CH ₃ , R ₁ = I. I ₂ = H 80

η = 0 R = -CH

-CH.

= R ₂ = H

80

a = 0R = -

η = 0 R = CH-CH-CH. , R ₁ = R, = H

η = 0 R = η = 0 R = -

η = ί R = -CH _t R =

= H

η = 1 R = -CH-, R ₁ = R = H n = 0R = -CH ₃ , R ₁ = Rg = -C

η = 0 R = -CH, I. ^Η 1 - I. ^ι ζ ^s η = 0 R = -CH ₃ , ^R l = R ₂ - -CO- η = 0 R = -CH ₃ , H, ^ 2 "" ^R 1 Indomethacin

85 39 85 35 100 * 7 106 33 156 50 8.6 (a) 50 Z 15th 16 ^ 10 91 20th 9 50

(a) means that the product was administered intramuscularly.

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It can be seen from the table that the ED _5Q value of MTA is 37 mg / kg and is thus the lowest value for those compounds which were administered orally.

In the same test, the ED _5Q of indomethacin is 9 mg / kg. Serious gastric injury occurs at these doses, while the ED ₅ "doses of MTA have no gastrointestinal side effects. It is also noteworthy that the LD value of indomethacin in the rat is 12 mg / kg (Martelli A., in Aspetti di farmacologia dell: infiammazione, page 73, published by Tamburini-Milan 1973), while the LD _5Q value of MTA in the rat y 200 mg / kg, administered orally, is.

The following therapeutic indices are thus obtained:

Indomethacin TI = 1.3 MTA TI => 54.05

The compounds according to the invention were also subjected to a series of pharmacological tests with the aim of finding their anti-inflammatory properties Confirm effectiveness and demonstrate its analgesic and antipyretic effectiveness.

The results obtained in some of these tests with MTA are given below, this compound being in all In cases where oral administration was found to be the most effective product and certainly the safest Connection is because it is a physiological connection present in the organism, as mentioned above.

As already mentioned above, this is found within the scope of the invention Method of making MTA from SAME the simplest from an industrial point of view and the most economical method, and it allows the connection to be made and sold at a particularly low price bring to.

From the experimental results of Table 1, it can be seen that methylthioadenosine sulfoxide is particularly effective when it is administered intramuscularly. The greater effectiveness of this compound when administered intramuscularly was seen in all tests carried out. For MTA-SuIfoxid are also some significant values are given, but it should be pointed out that all compounds examined are in Proven effective in all cases, albeit at different levels.

A - anti-inflammatory effectiveness

The products were tested in rat pleurisy caused by carrageenan according to the method of Velo tested (Velo G.P., DÜNN CJ. Et al. (1973), J. Path. 111, 149).

At an orally administered dose of 75 mg / kg, MTA gave a protection of 42.4%, calculated on the basis of the Exudate volume, and 48.8%, calculated based on the number of all cells present in the exudate.

A comparable protection was given with 10 mg / kg indomethacin reached, i.e. with a dose that corresponds to the LDrn value is much closer. In the same test, the MTA sulfoxide gave a protection of 75.8%, calculated on the basis of the Basis of exudate volume, or 76.4%, calculated on the total number of cells present in the exudate, which administration was intramuscular and the dose was 80 mg / kg.

B - anti-inflammatory effectiveness

In the granuloma test, caused in the rat by Cotton pellets (Winter CA., Riseley E.A. et al. (1963) J.Pharm.Exper. Ther. 141, 369) used for chronic inflammation Significantly, the MTA gave 30% protection at an orally administered dose of 9 mg / kg, in one TI of 222.

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- The analgesic efficacy of the products was examined in two tests that were considered to be very important.

In the hot plate test on the mouse according to Roberts (Roberts E., Simonsen D.G. (1966), Biochem. Pharmac. 15, 1875) the MTA showed a protection of 50% at an orally administered dose of 37 mg / kg. A roughly equivalent 58% protection was achieved at an orally administered dose of 100 mg / kg of amidopyrine.

In the same test, MTA sulfoxide gave protection of 50% at an intramuscularly administered dose of 20 mg / kg and an orally administered dose of 100 mg / kg.

In the stretching test caused by phenylquinone (Siegmund E., Cadmus R., GO-LU (1957) Proc. Soc. Exp. Biol. Med. 95, 729) the MTA showed a protection of 51% at an orally administered dose of 37 mg / kg. In the same test, an ED _gQ value of 10 mg / kg was determined for the MTA sulfoxide, provided that it was administered intramuscularly.

- antipyretic activity

This effectiveness was measured for the new products on the basis of fever produced by brewer's yeast in rats (Winder CV. et al. (1961) J. Pharmacol. Exp. Ther. 133, 117).

The antipyretic effect achieved one hour after the oral administration of MTA at a dose of 300 mg / kg was demonstrated by a temperature decrease of 4.59% with respect to control animals which had only been treated with the yeast. This percentage corresponds to a decrease in temperature of 38.8 ⁰ C to 37.4 ° C.

In comparison, amidopyrine provided when administered orally Dose of 200 mg / kg for a temperature

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decrease of 4.69%, and when administered intramuscularly of MTA at a dose of 80 mg / kg, a temperature decrease of 2.35% was obtained.

- Efficacy against platelet aggregation The compounds according to the invention were also used with a view to examined for a possible effect on platelet aggregation.

Platelet aggregation is known as a complex phenomenon that can be divided into two stages can, in a first stage, which is due to the direct action of a stimulant (e.g. adenosine diphosphate, i.e. ADP, or epinephrine), and a second stage attributed to the aggregation itself caused by the APD released from the platelets. That is, if the platelet with subendothelem When collagen comes into contact, a whole series of reactions is started by the collagen lead to the release of ADP by the platelets. This APD then causes the second wave of platelet aggregation. In order to measure the effectiveness of the new compounds against this aggregation, the performed the following tests:

1) "in vitro" tests against platelet aggregation caused by ADP and collagen, in Presence of new products;

2) "in vitro" tests against platelet aggregation, caused by arachidonic acid (AA);

3) "in vivo" tests against platelet aggregation, caused by ADP and collagen in people treated with the new products.

In this case, the best results were obtained again with MTA, which is why those using this Results obtained product are given as representative of the properties of all compounds according to the invention will.

- / YES

1) "in vitro" tests

Without stasis, blood was drawn and an anticoagulant was used (3.8% sodium citrate solution) added to give a blood: citrate ratio of 9: 1. Platelet rich plasma and platelet poor plasma were obtained by centrifugation at ambient temperature. The platelet aggregation was determined by the method of Born & Cross (G.V.R. Born and M.J. Cross, J. Physiol., Lond. 168, 178, 1963) in the platelet-rich plasma fraction. The aggregating agents were used in the following concentrations: ADP (Sigma) 1 μΜ; Collagen (horn) 5 µg / ml;

—4
Arachidonic acid 4x10 M.

Adenosine at a concentration used by 1x10 M.

The results obtained with ADP are shown in Fig. 1, in which the abscissa represents the time in minutes and the ordinate indicates the percentage aggregation.

Curve 1 relates to the control samples, curve 2 the samples treated with 1x10 ~ M adenosine, and

-4
Curve 3 dxe samples treated with 5x10 M MTA. It can be seen from the course of the curve that the MTA causes a very strong reduction in the primary platelet aggregation, which can be attributed to the ADP, and thus inhibits the second wave of aggregation.

The same tests that were done on collagen gave negative results, that is, MTA showed no inhibitory properties against platelet aggregation caused by collagen became.

P 1 181 - ! Λ / - ZZ

2) Fig. 2 shows the effects at different MTA concentrations against platelet aggregation,

—4 caused by AA at a concentration of 4x10M. Curve 1 concerns the control samples, curve 2 relates to the samples with MTA at a

-4
Concentration of 2.5x10 M, curve 3 relates to the

-4 samples with MTA at a concentration of 5x10 M, and curve 4 finally relates to those samples which contained MTA at a concentration of 10 ~ M. It is evident that the inhibitory effect of the MTA on platelet aggregation is proportional to the concentration. The ability of the MTA to increase the inhibitory effect of prostacyclin (PGI ₂ ) on aggregation induced by AA was also investigated. In Fig. 3, curve 1 relates

/ ■ the control samples, the curve 2 samples with an MTA

-4
Concentration of 5x10 M, the curve 3 ones

_Q

Samples with a PGI., Concentration of 5x10 M, and curve 4 those samples which contained a mixture of 5x10 ~ ⁴ M MTA and 5x10 ~ ⁹ M PGI ₂ . It can be seen from Figure 3 that when used in admixture, there is a large increase in the effectiveness against aggregation at concentrations which are otherwise ineffective.

3) "in vivo" tests

Three apparently healthy volunteers aged 35, 42 and 48, respectively, who during at least 15 days had not taken any drugs before and after taking the new products at a dose of 100 mg every 8 hours for 3 days Subjected to aggregation tests, and these tests were then evaluated. The blood sample for the determination of the Platelet aggregation was taken 2 hours before taking the last dose of the product to be tested.

Figure 4 shows the results obtained with MTA.

Jϊϊ 311R067

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The solid curves relate to those values obtained with blood samples from untreated patients were, while the dashed curves concern those values with the same but with MTA treated patients.

It is evident that MTA strengthens the platelet aggregation induced by ADP (1 μΜ) "in vivo" inhibited.

The same test was repeated with the addition of 5 mg / ml collagen to the blood, and it was found that
MTA is not effective in inhibiting collagen-induced platelet aggregation, only the latent period of this phenomenon
extended.

The fact that MTA (and in a more or less comparable way also the other products of the same group) strongly inhibits platelet aggregation caused by ADP, while practically none
Has an influence on the aggregation induced by collagen shows that MTA inhibits the first wave of aggregation, while it has a negligible direct influence on the second wave of aggregation.

The use of the compounds according to the invention in conjunction with other known agents against aggregation, which are generally effective against the second wave, while they are only slightly
Having effectiveness against the first wave is therefore of particular interest.

By demonstrating effectiveness, MTA (and the other compounds in this series, itself when they are less effective) not only as anti-platelet aggregation agents, but also

P 1 181 - 2V ^ - JtY.

as a remedy for thrombosis and arteriosclerosis, there the changed relationship between platelets and vessel walls, besides the fact that these are the basis for the mechanism of thrombogenesis is also a primary role in arteriosclerosis disease plays.

F - sleep inducing efficacy

The Morris test was used for this purpose (Morris R.W. (1966), Arch. Int. Pharmacodyn 161, No. 2,380).

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

G - acute toxicity

The compounds of the invention have virtually no acute toxicity when administered orally. When used at therapeutic doses, regardless of the mode of administration, they exhibit virtually no toxicity on.

The following values were determined for MTA and MTA-SuIfoxid:

MTA - DL ₅₀ in the mouse, orally> 2000 mg / kg

intravenous 360 mg / kg

MTA-SuIfoxid - DL ₅₀ in the mouse

oral> 2000 mg / kg

intravenous 400 mg / kg

The adenosine derivatives of the general formula (I) can be diluted with any suitable pharmacologically acceptable Excipients, to be administered in any therapeutically useful form, either orally, parenterally, or intravenously rectal. For local treatment, they can also be used in products for external use.

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

- 100 mg capsules

MTA 100.2 mg

Mannitol 195/0 mg

Magnesium stearate 5.0 mg

300.2 mg - 50 mg capsules

50.1 _mg

Mannitol 100.0 mg

Magnesium stearate 3.0 mg

153.0 mg

100 mg tablets

MTA 100.2 mg

Strength 100.0 mg

Magnesium stearate 15.0 mg

Lactose 85.0 mg

300.2 mg

50 mg tablets

MTA 50.1 mg

Strength 120.0 mg

Magnesium stearate 15.0 mg

Lactose 115.0 mg

300.1 mg

100 mg of suppositories

MTA 100.2 mg

Suppository mass 1,700.0 mg

1,800.2 mg

ρ ι 181

- 50 mg of suppositories

MTA 50.1 mg

Suppository mass 1,450.0 mg

1,500.1 mg

- 50 mg vial for injection MTA · HCl (equivalent to

56.15 mg) 50 mg

Lidocaine HCl 25 mg

Water to 3 ml

- 25 mg vial for injection MTA · HCl (equivalent to

28.07 mg) 25 mg

Lidocaine HCl 20 mg

Water on. 2 ml

- 100 mg oral dose

MTA · HCl (equivalent to

112.3 mg) 100 mg citrus flavor 0.025 mg

Sugar 1 g

Antx fermentation agent 50 mg water to 5 ml

- 50 mg oral dose

MTA · HCl (equivalent to

56.15 mg) 50 mg citrus flavor 0.015 mg

Sugar 0.5 g

Antx fermentation agent 30 mg of water to 5 ml

- 100 g of ointment

MTA 5 g base for water-soluble ointment,

on 100 g

Antioxidant 0.1 g

End of description

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Claims (14)

DlPL-ING. GERHARD GUSTORF PATENTANWALT ΊΕΙΐ0 $ 2ΐ, / 25 719 8300 LANDSHUT April 20, 1981 P 1 181 BIORESEARCH S.r.l. Localitä Roggia Pirola Liscate (Milan), Italy Therapeutic compositions with analgesic and anti-inflammatory properties that contain adenosine derivatives as active ingredients 1. Therapeutic composition with anti-inflammatory, analgesic and antipyretic activity that contains at least one compound of the following general formula as active ingredient: NIWl. (D J I I DUO / P 1 181 - 2 - in which mean: R is a straight-chain or branched alkyl radical with 1 to 18 carbon atoms or a phenylalkylene radical, in which the alkylene chain has 1 to 6 carbon has atoms;
R _{1 is} hydrogen, an aliphatic acyl radical with 1 to Carbon atoms, or an aromatic acyl radical; R _{2 is} hydrogen, an aliphatic acyl radical with 1 to carbon atoms or an aromatic acyl radical, or the two radicals R ₂ together form an iso- propylidene chain; and
η 0 or the number 1. 2. Composition according to claim 1, characterized in that it contains as active ingredient a compound of the general formula (I) in which R. and R _{2 are} hydrogen, R is the methyl radical and η 0. 3. Composition according to claim 1, characterized in that it is a compound of the general as active ingredient Formula (I) contains, in which R. and R- hydrogen, R denotes the methyl radical and η denotes the number 1. 4. Composition according to claim 1, characterized in that it contains as active ingredient a compound of the general formula (I) in which R ₁ and R _{2 are} hydrogen, R is a straight-chain or branched alkyl radical having 1 to 12 carbon atoms and η 0. 5. Composition according to claim 1, characterized in that it contains a compound of the general formula (I) as active ingredient in which R ₁ and R _{2 are} hydrogen, R is the benzyl radical and η 0. 6. Composition according to claim 1, characterized in that it contains as active ingredient a compound of the general formula (I) in which R ₁ and R "denote the benzoyl radical, R the methyl radical and η 0. P 1 181 7. The composition according to claim 1, characterized in that it contains as active ingredient a compound of the general formula (I) in which R ₁ and R ₂ denote the tosyl radical, R the methyl radical and η 0. 8. Composition according to claim 1, characterized in that that it contains as active ingredient a compound of the general formula (I) in which R_ - R- denotes the isopropylene radical, R denotes the methyl radical and η 0. 9. Process for the preparation of 5'-deoxy-5'-methylthioadenosine, characterized in that one S-adenosylmethionine in concentrated, aqueous solution under Heating under reflux conditions hydrolyzed and the 5'-deoxy-5'-methylthioadenosine formed by cooling separated after the neutralization of the reaction mixture. 10. The method according to claim 9, characterized in that the aqueous solution of S-adenosylmethionine is concentrated to 35 to 40 ⁰ C by heating under vacuum. 11. The method according to claim 9, characterized in that the formed 5'-deoxy-5'-methylthxoadenosxn by Cooling to 0 to 5 ° C fails. 12. Use of a compound of the general formula CH ₂ -SR (I) P 1 181 - 4 - in which mean: R is a straight-chain or branched alkyl radical with 1 to 18 carbon atoms, or a phenylalkylene radical, in which the alkylene chain has 1 to 6 carbon atoms; R _{1 is} hydrogen, an aliphatic acyl radical having 1 to 6 carbon atoms or an aromatic acyl radical; R- hydrogen, an aliphatic acyl radical with 1 to 6 Carbon atoms, or an aromatic acyl radical * or the radicals R, together form an isopropylidene chain; for the manufacture of pharmaceutical products with anti-inflammatory, analgesic and antipyretic effectiveness. 13. Use according to claim 12, characterized in that in the general formula (I) R and R ~ are hydrogen, R _{3 is} the methyl radical and η 0. 14. Use according to claim 12, characterized in that in the general formula (I) R. and R _? Hydrogen, R denotes the methyl radical and η denotes the number 1.