NL8502994A - 6-Desoxy-6-azido-7,8-dihydro-isomorphines - with cardiac sedative activity and low addictive potential - Google Patents

Abstract

6-Desoxy-6-azido-14-hydroxy-7, 8-dihydroisomorphine and its salts, 3-O-acyl-6-desoxy-6-azido-7, 8-dihydroiso morphine, 6-desoxy-6-azido-3-O-ethyl-7, 8-dihydro-isomorphine, and 3-O-acetyl-6-desoxy-6-azido-14-hydroxy-7, 8-dihydroisomorphine have cardiac sedative activity with low addictive potential. The cpds. are prepd. by protection of hydroxy gps. of 7, 8-dihydro-morphine and its 14-hydroxy dediv. with acyl. alkyl, aralkyl or aryl gps, then treating the prods. with metallic azides or sources of the azido gp, opt. removing the protecting gpds. during or after azidolysis.

Description

A method of preparing a medicament having an anti and analgesic action based on a 3- (O-alkyl) -6-dei azido-7,8-dihydroisomorphine, and a method of preparing such a compound.

The invention relates to a method of preparing a medicament with anti-intermediate and analgesic activity by introducing a 3- (O-alkyl) -6-deoxy-6-azido-7,8-dihydro into a medicinal product. The preparation of the compound 3- (0-methyl) -6-deso: 6-azido-7,8-dihydroisomorphine (azidocodeine) is known from an article by R. Bognar and S. Makleit in Acta Chim. Acad. S Hung. 58, 203 (1968). The effects of this and related ver are described in an article by J. Knoll, Z. Fürst and 10 K. Kelemen in Qrvostudomany 22, 265 (1971). These known things have narcotic and analgesic properties. Said known 3- (0-methyl) compound also has an intermediate action.

It has now been found that the new compound 3- (Q 15 6-deoxy-7,8-dihydroisomorphine has a strong analgesic wex and can be used both alone and together with other morphines or other compounds for medicinal purposes. Moreover, this compound is distinguished oc has a very pronounced antitussive effect Also the physiol-acceptable salts of the present compound exhibit said favorable properties.

The invention is therefore characterized in that the method as described in the opening paragraph as active substance 3- (O-ethyl) -6-deoxy-6-azido-7,8-dihydroisomorphine, or a physiologically acceptable salt thereof, is used.

The invention 3- (O-ethyl) -6-deoxy-6-azido-7,8-dihydroisomino (hereinafter referred to as azidoethylisomorphine for short) is distinguished by a particularly strong anti-intermediate action: "" ** "** · *» ν ' ** - 2 - Experimentally induced coughing with very good long-term tolerance, as shown in the following tables of comparative test values: When used in anti-tensive doses, the compound does not cause respiratory depression.

However, it is also a strong analgesic, whose analgesic activity when administered intravenously to rats is 7.8 times that of codeine.

The one compared with the compound of the invention to codeine and the one from Acta Chim. Acad. Sci. Hung _58 203-205 (1968) 10 known 3- (O-methyl) -6-deoxy-6-azido-7,8-dihydroisomorphine & zidocodeine) achieved antitussive activity was observed both in rats / method of Gösswald, Arzneimittel-Forschung 8, 550 (1958) J as to cats / Domenjoz's method, Naunyn-Schmiedebergs Arch, exp. Path. Pharmak. 125, 19-24 (1952) 7 ”determined.

In the Gösswald method, a cough was induced in rats weighing 100-150 g by treatment with citric acid aerosol for 3 minutes and the dose of test compound determined, with which the cough could be completely quenched for a predetermined time when administered orally or subcutaneously. (AtD ^^, AtD = antitussive 20 dose). From the determined AtD ^^^ values, the AtD ^ value was calculated according to the method of Litchfield and Wilcoxon.

In the Domenjoz method, in cats vein 2.5-4.0 kg electrical stimulation vein strength of the upper laryngeal nerve, a cough stimulus was generated and the cumulative dose of test compound was determined, thereby completely suppressing the cough when administered intravenously. This dose is the effective antitussive dose (AtD ^^).

The values obtained in these tests are summarized in Table A.

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It can be deduced from Table A that the azidoethyl isomorphine of the invention has a stronger action than codeine and azidocodeine both by the method of Domenjoz (intravenous administration in the cat) and by the method of Gösswald (subcutaneous or oral administration in the rat). and that activity when administered orally in the rat is 60 times greater than that of codeine.

In order to determine the effect of the compounds to be tested on respiration, cats were administered the AtD 2 dose of the test substance concerned either in a single dose or in multiple increasing single doses intravenously and the ratio of the respiratory rate and minute volume, respectively. determined before and after administration of the AtD ^^ dose according to the Krogh method. The results obtained are summarized in Table B.

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Table B shows that when administered in a single injection, codeine and azidocodeine decrease the respiratory parameter, whereas azidoethyl isomorphine of the invention, independently, whether administered cumulatively or in a single dose, does not significantly decrease the respiratory function or the minute volume. .

Table C shows the results obtained in a long-term test.

The study was conducted on groups of 20 rats each IQ, receiving once a day the AtD2 dose of the compound under test. The aim of the study was to determine the transferability of the compounds to be tested when administered over a longer period of time. The survival rate was determined.

15

Table C

Compound survival rate at AtD ^^ dose (rat) thing 4 8 12 16 20 24 weeks weeks weeks weeks weeks weeks 20 _% _% _% _% _% __%

Codeine 100 100 80 50 40 20

Azido- 100 80 60 60 60 40 codeine

Azido- 100 100 100 100 90 25 ethyliso-morphine

Table C shows that when used over a long period of time the azidoethyl isomorphine of the invention is very much better tolerated than codeine and azidocodeine. While the percentage of surviving rats had decreased to about 20% with codeine at 24 weeks and with azidocodeine with approximately 40%, the proportion of surviving rats was 1.

Sp · ..........., "- 7" in the azidoethyl isomorphine of the invention after 20 weeks about 90%.

The invention also relates to a process for the preparation of a medicinal compound, suitable for use in the above-mentioned process for the preparation of a medicament, characterized in that 3- (O-ethyl) -6-deoxy-6-azido- 7,8-dihydroisomorphine, or a physiologically acceptable salt thereof, is prepared in a manner known for analogous compounds. To this end, the hydroxyl group 10 in the 6-position of 3- (O-ethyl) -7,8-dihydromorphine with an arylsulfonic acid group or alkylsulfonic acid group is esterified in a known manner and the resulting 7,8-dihydromorphine derivative is reacted with a metal azide. the product obtained as base or as salt wins.

In the esterification of the hydroxyl group in the 6-position 15 with the aryl or alkyl sulfonic acid or a derivative thereof, it is expedient to use the corresponding tosyl, brosyl, nosyl, mesyl or mesysyl derivative.

The reaction with the metal azide, the azidolysis, is expediently carried out with sodium, potassium or lithium azide or with a compound which releases azido groups during the reaction under decomposition.

The salts obtained in the reaction can be converted into salts which are more physiologically tolerable or which give better physical chemical properties. Examples of these are tartrates, acetates, salicylates, benzoates, hydrochlorides and formates.

The preparation of the active substance is illustrated in the following example.

Example 30 a. 14.85 g of 3-o-ethyl-7,8-dihydromorphine are dissolved in 60 ml of anhydrous pyridine and a solution of 6.014 g is added dropwise to the solution cooled to 0-5 ° C with stirring for about 20 minutes. (4.06 ml) methanesulfonic acid chloride in 60 ml anhydrous pyridine.

* τ- - 8 -

The resulting reaction mixture is stirred for an additional 2 hours, then left at room temperature for 24 hours and then poured into 1.5 liters of saturated aqueous sodium hydrogen carbonate solution. The aqueous solution is shaken out 3 times, each time with 200 ml of chloroform. The combined chloroform phases are washed twice with 100 ml of water each time, dried over magnesium sulfate and filtered. The filtrate is evaporated to dryness. The resinous mass obtained is taken up in warm absolute ether. Crystallization starts quickly. 11.86 g (64%) are obtained

10 3- (O-ethyl) -6-O-mesyl) -7,8-dihydromorphine, which is at 135-136 ° C

melt.

"/" W »-96, °, (C = 0.52, CHCl3).

b). 11.0 g of 3- (O-ethyl) -6- (0-mesyl) -7,8-dihydro-15-morphine are dissolved in 330 ml of dimethylformamide and the solution is mixed with 18.19 g of sodium azide in 51.2 ml. water. The resulting homogeneous reaction mixture is kept at 100 ° C for 24 hours, cooled, poured into 1.65 liters of water and the aqueous solution thus obtained is extracted 4 times, each time with 200 ml of chloroform. The combined chloroform phases are washed twice, each time with 110 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to a temperature below 50 ° C. The resinous residue is taken up in absolute ether and the precipitated flaky precipitate is filtered off. The filtrate is evaporated to dryness to give 6.8 g of the purified resinous mass as a residue, which is dissolved in 102 ml of anhydrous ethyl alcohol and mixed with a hot solution of 3 g of D-tartaric acid in 30 ml of ethyl alcohol. The tartrate separates in the form of yellow, petal-shaped crystals. It is recrystallized twice from water. The resulting 3- (O-ethyl) -6-deoxy-6-azido-7,8-dihydroisomorphine bitartrate melts at 55-56 ° C.

/ α = -192 °, (c = 0.5 chloroform).

the free base can be obtained from the aqueous solution of the bitartrate by treatment with sodium carbonate.

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Claims (2)

A method of preparing a medicament having an anti-intermediate and analgesic activity by introducing a 3- (O-alkyl) -6-deoxy-6-azido-7,8-dihydroisomorphine into a dosage form suitable for medical purposes, with characterized in that the active substance used is 3- (O-ethyl) -6-deoxy-6-azido-7,8-dihydroisomorphine, or a physiologically acceptable salt thereof. 2. Process for preparing a medicinal compound suitable for use in the process according to claim 1, characterized in that 3- (O-ethyl) -6-deoxy-6-azido-7,8-10-dihydroisomorphine, or a physiologically acceptable salt thereof, prepared in a manner known for analogous compounds.