CA1209915A - Adenosine derivatives of antiinflammatory and analgesic activity, and therapeutic compositions which contain them as their active principle - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Therapeutic composition of antiinflammatory, anal-gesic and antipyretic activity comprising as its active principle at least one compound of general formula (I)

Description

~2~ 5 This invention relates to therapeutic compositions which contain andenosine derivatives of anti-inflammatory, analgecis and antipyretic activity, as their active principleO

This application is a divisional application of copending application No. 375,784 filed April 21, 1981.

According to the present invention there is pro-vided a therapeutic composition of anti-inflammatory, anal-gesic and antipyretic activity, comprising as its active principle at least one compound of general formula . N~-R1 ~ (Il)n (I) L/\l ~ I

2 2 in which R is a linear or branched alkyl radical of 1 to 18 C atoms, or phenyl-alkylene in which the alkylene chain has 1 to 6 C atoms and n is 0 or 1 or a pharmaceutically accep-table acid addition salt thereof and a pharmaceutically acceptable carrier or dilent therefor.

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

~g ,_ ~O9~L5 The preferred acid addition salts of the compounds of formula (I) are: chloride, sulphate, phosphate, formate, acetate, citrate, tartara-te, methanesulphonate or p-toluene-sulphonate.

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

For preparing the group of compounds of formula:

~ ~ . (I3) ~\1 OH OH

. ~. .
. . .: .

~2~ S

in which R has the aforesaid meanings, the Legraverand method (Legraverand M.Ibanez S., et al (1977) Eur. J. Med. Chem.
12, 105-108) has been followed, in which andenosine is con-verted 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 correspon-ding mercaptan in a 2N sodium hydroxide solution at 80C.

The thioethers obtained are purified by recrys-tal1isation from water or from lower aliphatic alcohols.

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

..--.

~20~1~

The compounds of formula ~12 I

~ ~ O (Ib) ~\1 ' ' 1~
OH H
in which R, Rl, R2 are as heretofore defined, are prepared by oxidation of the corresponding thioethers, obtained by the methods heretofore indicated, by means of bromine or hydrogen peroxide in aqueous solution (Green Stein J.P., Winitz M. (l961)-Chemistry of the amino acids John Wiley & Sons Inc. 2146). The products obtained are purified by recrystallisation from water.

~O Of all the products prepared, the one which has proved particularly interesting for the purpose of the pre-sent invention is 5'-deoxy-5l-methylthioadenosine (MTA) of formula NH

~ ~ (II) ¦ ~ CH2 S-CH3 H

~2Q~15 which is a physiological compound already present in living organisms.

The method has been found for preparing this pro-duct which is particularly simple and economical from an industrial viewpoint. The process which is the subject matter of copending application No. 375,874 consists essen-tially of carrying out hydrolysis of the S-adenosylmethionine (SAME) under strictly controlled critical conditions, which lead to practically total hydrolysis and complete crystal-lisation of the MTA

.. ' NH2 I N
~ ~

NH C~ ~2 . ~ CH3 \ _ /

OH OH

N~

c}l2 ~3 cll3 N~12 HO-CH2-CH2-CH-COOH ~ H
OH OH

~zo9~s The controlled hydrolysis process can be 2pplied to SAi~
prepared in any mamler, However, the method of preparation of the SA~ 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 embodiment of the process:
a) Normal bread yeast is enriched in SAME by treatment with methionine in accordance with the ~chlenk method (Schlenk F.
(1965) Enzymologie 29~ ~83) b) The yeast cells suspended in water are lysised by treatment with eth~l or methyl acetate at ambient tempe,ature (DT-OS P23 36401.4).
By adjusting the pH to between 4 and 6 and filtering, an aqueous solution is obtained containing practically 811 the S~E present in the ~nitial yeast c) The so ution is concentrated under vacuum at 35_40C to about 1/10 cf its initial volume d) The concentrate is boiled u~der 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 practicaily completely and at good purity. -The stages cq d and et which as stated are critically necessary for obtaini~g complete selective hydro ysis of SAi~E to ~A without formstion of by-products~ are new.
The preparstion of some products used according to the present invention are de.scribed hereinafter.
EX~i_LE 1 Preparation of 5'-deo~y-5'-methylthioadenosine (~

12~ r9~ 5 .

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 SA~ content is 6.88 ~ kg.
4fter energetic stirring for 30 minutes, the pH is adjusted to 4.5 with dilute H2S04, the mixture is filtered ~nd the residue is ~lashed ~ith water io give 140 litres of solution with a SAME
content of 4.~0 ~/1, equal to 99.5,~ of the SA~E present in the initial material.
The lysate thus obtained is concentrated under vacuum (30 mm Hg;
35_40C) to 3 volume cf about 14 litres. The concentrated solution is boiled under reflux at normal pressure for 30 minutes. It is cooled to 20~, the pH adjusted to 7 with 40,' ~oda, and left over-night in a refrigeration cell (+3C).
A white precipitate is formed which is ~iltered5 dissolved in 10 litres of boiling distilled water and crystallised by cooling this solutio~.
410 g of crystalline i~A of high purity are obtained, equal to a yield of gOc,/ with respect to the SAi~ subjected to hydrolysis.
The characteristics of the product obtained coincide ~ith those of pure li~A obtsined by other means.
E~AI~LE 2 Preparation of 5'-deox-J-5'-e-thylthioadenosine 1 kg of adenosine is dissol-~ed under a nitrogen atmosphere in 10 1 of hexamethylphosphoramide, and 705 1 of thionyl chloride are added unàer cooling.
The mixture is left to react at ambient temperature for 20 hours.
10 1 of water are added, and the mixture neutralised with 2N NaOH.

S
g The 5~-deoxy-5~-ch;oroadenosine which thus forms is allowed to crystallise overnight at ~C. It is filtered off. 0~950 kg of 5'-deoxy_5'-chloroadenosine are obtained (yield ~9%~.
0.950 kg of 5'-deoxy-5'-chloroadenosine are dissolved -.n 10 1 of 2N NaOH, and 200 ml of ethanethiol are added. The mixture is heated to 80C 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 3 C. It is filtered off and recrystallised from water.
0.830 kg of product are obtained (yield 80% with respect to the preceding stage).
E~MPLE ~
Preparation of other compounds of class Ia The method as described in example 2 is carried out~ but using propanethiol,b~tanethiol, isobutanethiol, pentanethiol~ hexanethiol and benzylthiol respectively~ in place of the ethanethiol~
EXA~LE 4 Preparation of N ~ 2', 3'-triacetyl-5'-deoxy-5'-thioadenosine.
1 kg of l~rA is suspended in 10 1 of anhydrous pyridine, and 3 1 of acetic ~nhydride 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 (10 1) and left to crystsllise. The product is recrystallised from a i:l petroleum ether/chloroform mixture. 1.140 kg of product are obtained (yield 80',').
EXAl`IPL~ 5 Preparation of other compounds of class Ib The method described in example 4 is carried out~ but using other ~2~9~L5 thioethers or propionic anhydride, butyric anhgdride, benzoy~
chloride or tosyl chloride instea~ of I~

Preparation of 51-deoxy-2'~3'-isopropylidene-5'-methylthioadenosine.
l kg of I~A are suspended in 25 l of anhydrous acetone~ and 2.5 kg of molten ZnCl2 are added. Reaction is carried out under reflux for 5 hours. The mixture is then concentrated under vacuum to l/3 of its initial volume~ ar.d 7.5 kg of barium hydroxide octahydrate in aqueous suspension are added. Carbon dioxide is then bubbled through until neutral. The mixture i5 filtered and the residue washed with acetone. The filtrate is concentrated under vacuum to give a syrupy residue~ It is taken up in 3 hot l:l chloroform/
petroleum ether mixture (lO l)~ filtered and left to crystallise.
The product is recrystallised from l:l chloroform~petroleum ether~
to give 0.795 kg of product (yield 70%).
EXAIvlPLE 7 Prepara~ion of other compounds of class Ic.
The method as described i~ example 6 is carried out~ but s~arting from the corresponding adenosine derivatives instead of l~A.

Preparation of l~iTA sulphoxide.
l kg of lviTA are suspended in lO l of water~ and bromine is added under cooling~
The aqueous solution containing bromine is immediately decoloured by the oxidation of the ~A to sulphoxide.
Addition of bromine is continued until the solution does not decolourise furthe .
The solution is decolourised by further addition of small quantities of ~iTA.

2~9~15 The aqueous solution is treated with ~mberlite IRA 9~ resin (registered trademark cf 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 1, trested with activsted carbon (100 g) and lyophilised.
0.950 kg of product are obtained (yield 90~).
EXA~PLE 9 Preparation of other compounds of class Id The method described in example 8 is followed, but starting from the corresponding adenosine derivatives instead of ~ITA.
As initially stated~ it has been found that the co~pounds of formula I possess strong antiinflammatory activity, accompanied by analgesic and antipyretic action.
The antiinflammatory activity was demonstrated initially for some terms of the class by the test of experimental adema in the rat bycarragen9 by determining the percentage protection by the Winter method (J. Pharm. exper. Therap. 1411 369 1963). The values obtained are shown in Table 1.

12~9~5 T A B L E
Compound of formula (I) Dosa ad.min- Percent protec-~stered tion calculated on orally edema development m~/kg n = 0 R = -CH2, ~1 = R2 = H 37 5

3 1 Z 23 (a) 50 n = 0 R = -CH2-c~H5~ R1 R2 lO

n = 0 R = -CH2-CH ' 1 2 5 62 ~ CH3 n = 0 R = -(CH2)6~cH3~ R1 R2 20 n = 0 R - -(CH2)ll~cH3' R1 R2 112 10 n = 0 R = -(CH2)4-CH3- Rl R2 25 n = O R = -CH2-cH3~ Rl R2 80 44 n = Q R = -(CH2)2~cH3~ R1 R2 80 53 n = 0 R = -CH , R1 = R2 = H 80 45 ~3 n = 0 R = -(CH2)3~cH3 ' R1 2 85 39 n = 0 R = C1H~CH2~CH3 ' R1 R2 85 35 n = 0 R = -(CH2)7~cH3~ Rl R2 100 l~7 n = 0 R = -(CH2)9-cH3~ Rl-R2 106 33 3' 1 2 8.6 (a) 50 3' 1 2 3 714 47 12(~9~S

n = 0 R = -CH3, R1 = R2 = tosyl 204 15 n = 0 R = -CH3, R1 = R2 = -C-c6 5 164 10 n - 0 R = -CH3, R1 = H, R2-R1 = isopropyl 91 20 Indo~ethacine 9 50 (a) signifies that the product was ad~inistered intramuscularly.

.4s can be seen from this table, the ~D50 of the ~A is 37 mg/kg, and is thus the lowest of those of tne compound~ tested when administered orally.
In the same test, the ED50 of indomethacine is 9 mg/kg. At tkese doses, there is the appearance of serious gastric lesions, whereas at the ED50 doses the ~A gives rise to no seeondary effect on the gsstro-intest-nal system. It should also be noted that the LD of indomethacine in the rat is 12 m ~kg (Martelli A. in Aspetti di farmacologia dell'infiammazione, page 73, published by Tamburini - Milan 1973), whereas the LD50 of MTA in the rat is > 200 m~k ~ oa.
The following therapeutical indices are therefore obtained:
Indomethacine TI = 1.3 MTA TI = ~ 54.05 The compounds according to the invention were also subjected to a series of pharmacological tests for the purpose of confirming their antiinflammator~ 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 ~09'.9~5 - 14 _ certainly the safest as it is a compound physiologically present in the organism, as alregdy stated.
Again from the industrial production viewpoint, the method for producing i~A from SA~ 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 dats of table 1~ methylthioadenosine sulphoxide is particularly active when administered intrgmuscularly.
The g~eater activity of said compound on intramuscular administration ~as confirmed in all the tests carried out. Some significsnt dsta regarding ~A sulphoxide are also given, however it should be noted that all the compounds tested were in all cOsses shown to be active, although at different levels, A - Antiinflammatory activity ~he products were tested by pleuritis induced in the rat by carragan in accordance with the Velo method (Velo G.P., DUNN
C~J. et al. (1973) J. Path. 111, 149).
~TA at a dose of 75 mg/kg by oral administration gave a protection of 42.4,S calculated on the volume of the exu~ate~
and 48.8% calculated on the total number of cells present in the exudate, A comparable protection wa,s obtained with 10 mg/kg of indomethacine, i~e. with a dose much closer to the LD50. In the same test~
the MTA sulphoxide givss a protection of 75.3C,S calculated on the volume of the exudate, and 76~4~o calculated on the total number of cells present in the exudate when administered intramusculsrly at a dose of 80 m~kg.
B _ Antiinflammatory activity In the granuloma test in the rat by cotton pellets (~inter C.A., ,, . ~

126~9~J 5 Riseley E.A. et al ~1963) J. Pharm. Exper. Ther. 141, 369), which is significant for chronic inflammation~ the ~TA gave a protection of 30,~ with an oral dose OI 9 mg/kg, with a TI of 222.
C - The analgesic activity of the products was tested by two tests considered very significant.
- In the hot plate test on the mouse according to Roberts (Roberts E. Simonsen D~Go (1966) Biochem. Pharmac. 15, 1875) the MT~ gives a protection of 50C,' with an oral dose of 37 m~kg. An approx-imately equivaler.t protection of 58,' is o~tzined with 100 mg/kg of amidopyrine admin-stered orally.
In the same test MTA sulphoxide gives a protection of 50,' at a dose of 20 m~kg when administered intramuscularly, and at a dose of 100 mg/kg when administered orally.
- In the stretching test by phenylquinone (Siegmund ~., Cadmus R., GO_LU (1957) Proc. Soc. Exp. Biol. Med. 951 729), the ~A gives a protection of 51% at an oral dose of 37 m~kg.
In the same test~ M~A sulphoxide has an ED50 of 10 mg/kg when administered intramuscularly.
D _ Antipyretic activity.
This was measured ror the new products by means of fever induced in the rat by beer yeast (Winder C.U. et al (1961) J. Pharmacol.
Exp. Ther. 133~ lI7).
The antipyretic effect evaluated one hour after oral administration of r~TA at a dose of 300 mg/kg gave a temperature reduction of

4 .59C~ with respect to the controls~ which were treated only with yeast. This percentage corresponded to a temperaturs lowering from 38.8C to 37~4 C.
By comparisor.~ amidopyrine administered orally at a dose of 200 m~ kg produced a temperatu~e reduction of 4069i~, and intramuscular 9~5 administration of MTA at a dose of 80 mg/Kg gave a tem-perature reduction of 2.35%.
E- Platelet antiaggregation activity.
The compounds of the invention have also been evaluated with respect to their possible platelet antiaggregat on 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 di-phosphate, i.e. ADP, or epinephrin) and a secondary stage due to the aggregation induced by a 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 wa~e of platelet aggregation. The fol-lowing tests wexe carried out in order to evaluate the antiaggregation effect of the new compounds:l) "in vitro"
tests on platelet aggregation induced by ADP and collagen, in the presence 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 ob-tained 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 anti-coagulant (3.8% sodium citrate) was added to give a blood:
citrate ratio of 9:1. Plasma rich in plateletes and plasma poor in platelets were obtained by centrifuging at ambient temperature. The platelet aggregation was estimated using , ~ 16 -~, ~209~5 the Born & Cross method (G.V.R. Born and M.~. 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 ~M; collagen (Horn)

5 ~g/ml; arachidonic acid 4xlO 4M.

Adenosine at a concentration of lxlO 5M was used as the antiaggragation activity reference substance.
The results obtained with ADP are shown on the graphs of Fig. 1, in which the abscissa indicates the time in minu-tes and the ordinate the precentage aggregation.

Curve 1 relates to the controls, curve 2 to the samples treated with lxlO 5 adenosine, and curve 3 to the samples treated with 5xlO M MTA.

From the curve pattern it is apparent that MTA
strongly reduces primary platelet aggregation due to ADP, and as a consequence inhibits the 2nd aggregation wave.
The same tests carried out with collagen gave negative results, i.e. MTA showed no inhibiting power towards platelet aggregation induced by collagen which was worthy of note.

2) Fig. 2 shows the effects of various MTA concentrations on platelet aggregation induced by AA at a concentration of 4.xlO M. Curve 1 relates to the controls, curve 2 to MTA
at a concentration of 2.5xlO 4M, curve 3 to MTA a~ a concen-tration of 5xlO 4M, and curve 4 to MTA at a concentration of 10 3M. As is apparent, the platelet aggregation inhibiting effect of the MTA is proportional to its concentration. The capacity of MTA to increase the inhibiting effect of pros-tacyclin (PGI2) in aggregation induced by AA was also inves-tigated. In Fig. 3, curve 1 relates to the controls, curve 2 to MTA at a concentration of 5xlO 4M, curve 3 to PGI2 at a concentration of 5xlO 9M, and curve 4 to a mixture consist-;~ ~ - 17 -~ .~

1209~5 ing of SxlO 4M MTA and 5xlO 9M PGI2. It ls 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 not taken any drug for at least 15 days, were submitted to aggregation tests before and after consuming the new products at a dose of 100 mg every 8 hours for 3 days, these tests then being evaluated. The blood sample for the determination of the platelet aggregation was taken 2 hours before consuming the last dose of product under test.

Fig. 4 shows the results obtained with MTA.

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

It is apparent that MTA strongly inhibits platelet aggregation induced by ADP (l~M) "in vivo". The same tests repeated on adding 5~g/ml of collagen to the blood demon-strated that MTA is not effective in inhibiting platelet aggregation induced by collagen, but only lengthens the latency time of the phenomenon.

The fact that MTA (and in a more or less compar-able manner the other products of the same class) strongly inhibits platelet aggregation induced by ADP, whereas it has practically no effect on aggregation induced by collagen, indicates that MTA inhibits the 1st aggregation wave, whereas it has a negligible direct effect on the 2nd aggregation wave.

~2Q9!~L5 Its use in association with other known antiaggre-gation drugs which are yenerally active towards the 2nd wave whereas are only poorly effective towards the 1st wave is therefore particularly interesting.
s 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 pla-telets and vasal walls also plays a primary role in atherosclerotic illness.

~209!~.5 Sleep inducing activity.
The ~lorris test was used (Morris R.W.(1966) Arch. int. Pharmacodyn 161, ~o. 2, 380~
In this test, the MTA increased by 8~' the duration of the sleep induced by pentobarbital in the mouse~ at an intramuscular dose of 20 mg/kg.
Acute toxicity.
The compounds of the present invention are practically free from acute toxicity when administered orally. They are practically free from toxicity st therapeutic doses for any method of sdministration, The following values are obtained for MTA and MTA sulphoxide~
M~A - DL50 in the mouse orally ~ 2000 mg/kg intravenously 360 mg/kg MTA sulphoxide - DL50 in the mouse orally > 2000 mg/kg intravenously 400 m~kg The adenosine derivatives of formula (I) can be administered, diluted with suitable pharmacologically acceptaole excipients, in any therapeutically useful form, orally, parenterally or by venous or rectal means~ They can also be used in products for external use by topical application.
Some examples of typical pharmaceutical compositions with ~ITA
are given hereinafter by way of example:

..

~209~LS
_ 21 -100 mg capsules ~A 100.2 mg Mannitol 195.0 mg Magnesium stearate5.0 mg 300.2 mg 50 mg capsules MTA 50.1 mg Mannitol 100~0 mg Magnesium stearate3.0 mg 153.0 mg 100 mg tablets I`~A 100.2 mg Starch 100.0 mg ~iagnesium stearate15.0 mg Lactose 85.o mg 3.Z mg 50 mg tablets MTA 50.1 mg Starch 120.0 mg Magnesium stearate15.0 mg Lactose 115.0 mg 300~1 mg 100 mg sup~ositories MTA 100~2 mg Suppository mass1,700.0 mg 1,800.2 ~g ~0~5 2~ -50 m~ su~ositories ~TA 50.1 mg Suppository mass1,450.0 mg 1,500.1 mg _0 mg injactable_phial MTA . HCl (56.15 mg basically equiv31ent) 50 mg Lidocain HCl 25 mg l~ater to make up to 3 ml 25 mg in,iectable phial MTA ~ HCl (28.07 mg basically equivalent) 25 mg 1idocai.n HCl20 mg :~ater to ma~e up to 2 ml 100 mg oral dose MTA . HCl (112.3 mg bas.ically equivalent) 100 mg Citrus flavouring0.025 mg Sugar 1 g Antifermenting agent 50 mg Water to make up to 5 ml 50 mg oral dose i~lTA , ~Cl (56,15 mg basically equivalent) 50 mg Citrus flavouring0.015 mg Sugar -5 g Antifermenting agent 30 mg Water to ma~e up to 5 ml O~ S
. ~ 23 -- 100 g ointment ~A 5 g Base for water-soluble ointment, to make up to 100 g Antioxid~nt 0.1 g , .

Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A therapeutic composition of anti-inflamma-tory, analgesic and antipyretic activity, comprising as its active principle at least one compound of general formula (I) in which R is a linear or branched alkyl radical of 1 to 18 C atoms, or phenyl-alkylene in which the alkylene chain has l to 6 C atoms and n is o or 1 or a pharmaceutically accep-table acid addition salt thereof and a pharmaceutically acceptable carrier or diluent therefor.

2. A composition according to claim 1, in which R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.
butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, hexa-decyl, octadecyl or benzyl.

3. A therapeutic composition according to claim 1, in which R is CH3 and n is 0.

4. A therapeutic composition according to claim 1, in which R is CH3 and n is 1.

5. A therapeutic composition according to claim 1, in which R is a linear or branched alkyl of 1 to 12 C
atoms and n is 0.

6. A therapeutic composition according to claim 1 in which R is benzyl and n is 0.