FI70227C - ADJUSTMENT OF THERAPEUTIC ADJUSTMENT - Google Patents

Description

70227

The invention relates to a process for the preparation of novel useful adenosine derivatives of the formula (I) and their acid addition salts, The invention relates to a process for the preparation of therapeutically useful adenosine derivatives and their acid addition salts.

NH-R

10 sjL '(?) N (I)

ςΗ -S-R

b OR 2 OR 2 wherein R is a straight or branched C 1-6 alkyl radical or a phenylalkylene radical having 1-6 C atoms in the alkylene chain, R 1 is hydrogen, an aliphatic C 1-6 acyl radical or an aromatic acyl radical, R 2 is an aliphatic C 1-8 acyl radical or an aromatic acyl radical, wherein the substituents R 1 and, in the case of acyl R 1 = R 2, or the substituents R 2 together form an isopropylidene chain and n is O or 1. These compounds have anti-inflammatory, analgesic and antipyretic activity.

In formula (I), R is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, hexadecyl, octadecyl or benzyl.

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

R2 is preferably acetyl, propionyl, butyryl, benzoyl or tosyl.

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

The compounds of formula (I) and their acid addition salts can be prepared by reacting adenosine with thionyl chloride in hexamethylphosphoramide to give 51-chloro-5'-deoxyadenosine, followed by reacting 5'-chloro-5'-deoxyadenosine with mercaptan. with 2N sodium hydroxide solution at 80 ° C to give a compound of formula (I) wherein and R 2 represent hydrogen and n is 0, and a) reacting the resulting compound with acyl chloride in anhydrous pyridine to give a compound of formula (I) wherein R 1 and R 2 are the same and represent aliphatic C 1-6 acyl or aromatic acyl and n is O, or b) the resulting compound is reacted with acetone in the presence of Z 1 C 6 J to give a compound of formula (I) wherein the substituents R 1 together form an isopropylidene chain and n is 0, and if desired c) the compound obtained is oxidized with bromine or hydrogen peroxide in aqueous solution, already thereby obtaining a compound of formula (I) wherein n is 1, and / or d) converting the obtained compound into an acid addition salt.

In the preparation of the compounds of formula (I) the so-called The Legraverand method (Legraverand, M., Ibanez S., et al. (1977) Eur. J. Med. Chem. 12, 105-108), in which adenosine is converted to 5'-chloro-5'-deoxyadenosine by reaction with thionyl chloride in hexamethylphosphoramide .

5'-Chloro-51-deoxyadenosine is then converted to the desired thioether by reaction with the corresponding mercaptan in 2N sodium hydroxide solution at 80 ° C.

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

The resulting compounds of formula (I) wherein R 1 and R 2 represent hydrogen and n is O are subjected to Satom and Makino

II

3 70227 (Satom K, Makino K (1951) Nature 167, 238) to react with acyl chloride in anhydrous pyridine to give compounds of formula (I) in which and are the same and represent aliphatic C 1-6 acyl or 5 aromatic acyl and n is O. The products are preferably recrystallized from a 1: 1 chloroform / petroleum ether mixture.

Alternatively, compounds of formula (I) wherein and R 2 represent hydrogen and n is 0, 10 NH-R 1 N'ri \ U>

15 CH -S-R

O

TV

o o / \, is reacted with acetone in the presence of ZnCl 2 using the method of Satom and Makon (ref. above) to give compounds of formula (I) in which the substituents R 2 together form an isopropylidene chain. The products obtained are preferably purified by crystallization from a 1: 1 mixture of chloroform / petroleum ether. If desired, the thioethers of formula (I) obtained are oxidized with 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.

The compounds of formula (I) may be converted into a salt form using a stoichiometric amount of the desired acid.

The compounds of formula (I) have potent anti-inflammatory activity with analgesic and antipyretic activity.

Anti-inflammatory activity was demonstrated in a carrageenan-induced rat schema test, in which percent protection was determined by the method of Winter (J.Pharm.exper.

5 Therap. 141, 369, 1963). The values obtained are shown in Table I.

Table I

Compound of formula (I) Oral Percentage of oral dose calculated on 1 q mg / kg of edema development n = OR = -CH3, R1 = R2 = -CO-CH3 114 47 n = 0 R = -CH3, R R2 = tosyl 204 15 n = OR = -CH ,, R. = R_ = -CO-C, Hc 164 10 - | 5 3 1 2 6 5 n = O R = -CH_, R = H, R_-R1 = isopropyl 91 20

Indimethacin 9 50

The following examples illustrate the invention.

20

Example 1 Preparation of 5'-deoxy-51-ethylthioacenosine 1 kg of adenosine is dissolved in 10 liters of hexamethylphosphoramide under a nitrogen atmosphere and 7.5 liters of thionyl chloride are added under cooling.

The mixture is allowed to react at room temperature for 20 hours.

10 L of water are added and the mixture is neutralized with 2N NaOH. The 5'-deoxy-5'-chloroadenosine thus formed is allowed to crystallize overnight at 3 ° C and then filtered. 0.950 kg of 5'-deoxy-5'-chloroadenosine are obtained (yield 89%).

0.950 kg of 5'-deoxy-51-chloroadenosine are dissolved in 10 liters of 2N NaOH, and 200 ml of atanethiol are added. The mixture is heated to 80 ° C and allowed to react for 1 hour, after which it is neutralized with glacial acetic acid. The 5'-deoxy-5'-35 ethylthioadenosine thus formed is allowed to precipitate overnight at 3 ° C and then filtered and recrystallized from water.

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0.830 kg of product is obtained (yield 80% calculated from the previous step).

The procedure described above is repeated, but using propanethiol, butanethiol, isobutanethiol, pentanethiol, hexanethiol and benzylthiol instead of ethanethiol, respectively.

Example 2 Preparation of 5'-deoxy-5'-methylthioadenosine (^) 0.950 kg of 5'-hydroxy-51-chloroadenosine obtained as described in Example 1 (first step) are dissolved in 10 liters of 2N NaOH, followed by 150 ml liquid methane-thiol is added, the mixture is heated to 80 ° C and allowed to react for 1 hour, after which it is neutralized with glacial acetic acid.

The 5'-deoxy-5'-methylthioadenosine formed is allowed to precipitate overnight at 3 ° C and then filtered and recrystallized from water. 0.790 kg of product (yield 90%, calculated on 5'-deoxy-5'-chloroadenosine)

Example 3 Preparation of 6 N, 2 ', 31-tributyryl-51-deoxy-5'-methylthioadenosine 1 kg of MTA is suspended in 10 liters of anhydrous pyridine and 3.3 liters of butyryl chloride are added. The mixture is allowed to react for 4 hours, which is added and 20 liters of water are added and the mixture is concentrated in vacuo to give an oily mass which does not contain pyridine. The mass is dissolved in a hot petroleum ether / chloroform mixture (1: 1, 10 liters) and then allowed to crystallize. The product is recrystallized from petroleum ether / chloro-2Q form mixture (1: 1) to give 1.33 kg of product (76% yield).

Example 4 Preparation of N, 2 ', 31-tribenzoyl-5'-deoxy-5-methylthioadenosine 1 kg of MTA is suspended in 10 liters of anhydrous pyridine and 3.7 liters of benzoyl chloride are added. The mixture is allowed to react for 4 hours. 20 liters of water are added and the mixture is concentrated in vacuo to give an oily mass which does not contain pyridine. The mass is dissolved in hot petroleum ether / chloroform (1: 1, 10 liters) and then allowed to crystallize. The product is recrystallized from petroleum ether / chloroform (1: 1) to give 1.68 kg of product (yield 82%).

Example 5 Preparation of 1 q of 51-deoxy-21,3'-isopropylidene-5'-methylthioadenosine 1 kg of MTA is suspended in 25 liters of anhydrous acetone and 2.5 kg of molten ZnCl 2 are added. The reaction is carried out under reflux for 5 hours. The mixture is then concentrated in vacuo to 1/3 of 15 of its original volume and 7.5 kg of barium hydroxide octahydrate in aqueous suspension are added. Carbon dioxide is then passed through until the reaction is neutral. 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 mixture of chloroform / petroleum ether (10 L) and filtered and left to crystallize. The product is recrystallized from 1: 1 chloroform / petroleum ether to give 0.795 kg of product (70% yield).

The procedure described above is repeated, but starting from the corresponding 25 adenosine derivatives instead of MTS.

Example 6 Preparation of MTA sulfoxide 1 kg of MTA is suspended in 10 liters of water and bromine is added under cooling.

The aqueous solution containing bromine immediately loses color when the MTA is oxidized to the sulfoxide.

The addition of bromine is continued until the color of the solution no longer disappears.

35 Decolorize the solution by adding small amounts of MTA.

70227

The aqueous solution is treated with Amber Lite IRA 9 3 resin 'Ro hr. and Haas is a registered trademark of a weakly alkaline ion exchange resin in a polystyrene matrix) until the bromine ion reaction disappears.

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

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

The procedure described above is repeated, but starting from the corresponding 10 adenosine derivatives instead of MTA.

Claims (3)

A process for the preparation of therapeutically useful adenosine derivatives of the formula (I) and their acid addition salts, NH-R 1 -n \ / M n (I) 10 CH - SR f / oj 2 V-r4 or2 or2 1 5 in which R is a straight-chain or branched C. A 10-alkyl radical or a phenylalkylene radical having 1 to 6 carbon atoms in the alkylene chain, R 1 is hydrogen, an aliphatic C a .beta.-acyl radical or an aromatic acyl radical, R is an aliphatic C 1-4 acyl radical or an aromatic acyl radical, wherein the substituents R. 20. 1 and R 2 for acyl R 1 = R 2, or the substituents R 2 together form an isopropylidene chain and n is O or 1, characterized in that adenosine is reacted with thionyl chloride in hexamethylphosphoramide to give 5'-chloro-5'-deoxyadenosine, followed by 5 '-chloro-5'-deoxyadenosine is reacted with mercaptan in 2N sodium hydroxide solution at 80 ° C to give a compound of formula (I) wherein R 1 and R 2 are hydrogen and n is O, and a) the resulting compound is reacted with acyl chloride in anhydrous pyridine to give a compound of formula (I) wherein R 1 and R 2 are the same and represent aliphatic C 1-6 acyl or aromatic acyl and n is O, or b) the resulting compound is reacted with acetone ZnCl 2 in the presence of to give a compound of formula (I) wherein the substituents R n together form an isopropylidene chain and n is 35 2 O, and if desired c) the compound obtained is an acid with bromine or hydrogen peroxide in aqueous solution to give a compound of formula (I) wherein n is 1, and / or d) the compound obtained is converted into an acid addition salt. Figure 9 Patent claims 7 0 2 2 7 For use in the formulation of therapeutic adenosine derivatives of formula (I) and the addition of hydrogen, 5 fH-R1 Li / n (I) CH2-SR V / OR2 or2 15. a valenic form of a radical or a alkyl radical having a phenyl alkyl radical having 1 to 6 carbon atoms in the alkyl chain, a radical of an aliphatic C. - acyl radical or an aromatic acyl radical, R 2 is an aliphatic C 1-4 acyl radical or an aromatic acyl radical, the colors R 1 = R 2, the substituent R 1 and R 2 are acyl, or the 20 substituents R 2 are bisyl equivalents and are optionally substituted with 0 or 1, the first of which is meant, thionyl chloride and hexamethylphosphoramide, 5'-chloro-5'-deoxyadenosine, 5'-chloro-5'-deoxyadenosine are added with mercaptan and 2N sodium hydroxide solution at a temperature of 80 ° C, 25 colors are obtained from the formulation ( I), wherein R 1 and R 2 are used in the form of 0, and a) are given in the form of a mixture of acyl chloride and a watt-pyridine, colors of which are given in the form of formula (I), aliphatic C. -acyl or aromatic z Ί - o 30 acyl and is 0, or (b) in the case of compounds of formula (I), the color is in the form of the compounds of formula (I), the substituent R2 being a mixture of isomers or isopropylidenes and having 0, and, in particular, 35 c) oxides of the same The bromine or hydrogen peroxide is enriched in the form of a solution of form (I), as defined in paragraph 1, and / or (d) the addition of a separate account.