US2758113A

US2758113A - The like

Info

Publication number: US2758113A
Authority: US
Publication date: 1956-08-07
Anticipated expiration: 1973-08-07

Description

United States Patent NEW ESTERS 0F STRYCHNIC ACID N-OXIDE AND THE LIKE, AND A PROCESS OF MAKING SAME Hugo Zellner, Linz A. D. Donau, Austria, assignor to Douau-Pharmazie Gesellschaft m. b. H., Linz A. D. Donau, Austria, a firm No Drawing. Application July 20, 1954, Serial No. 444,667

oxide compounds, especially to esters of brucinic acid -ox1de and more particularly to esters of strychnic acid N-oxide and brucinic acid N-oxide with amino alcohols,

and to a process of making such esters.

Strychnine is the principal alkaloid isolated from the nuts of the tropical tree Strychnos nux-vomica. Strychnine has found therapeutical use as an effective agent for stimulating the central nervous system and the vital medul lary centers when they are in a depressed state. On account of said action strychnine is employed, for instance, to strengthen the circulatory system impaired by infections diseases and by serious injuries, for collapse prophylaxis and therapy especially after surgical operations, loss of blood and the like, to restore motoric functions in cases of paralysis or paresis due to poliomyelitis, apoplexy and the like, for sensitization of the uterus in cases of primary atony of the uterus in labor, to arouse a person from barbiturate sleep or poisoning, and generally, as an analeptic. Strychnine, however, causes very serious side eifects. It produces excessive irritability of the spinal cord resulting in convulsions. Therefore, this drug, in spite of its excellent analeptic properties, is no longer extensively used by the medical profession.

Attempts have been made, by modifying the strychnine molecule, to moderate and mitigate the sudden convulsant action of strychnine without impairing its basic pharmacological properties and to prolong its action. For instance, mixtures of strychnine and strychnine oxide, and strychnine derivatives with an opened lactame ring, such as strychnic acid, are used therapeutically as preparations having a prolonged strychnine eflect and a more moderate onset of action. Pharmacological studies of said strychnine oxide and strychnic acid showed that their strychnine action is markedly improved. Such compounds are somewhat less toxic and are effective for a prolonged period of time. This, probably, is due to a gradual reduction of strychnine oxide to strychnine or respectively, to a gradual ring closure of the lactame ring of strychnic acid. See, for instance, A. Amann, K. H. Jaeger, and A. Jarisch in Archiv fuer Experimentelle Pathologie and Pharmakologie, vol. 201, page 161 (1943), referring to Comparative Investigations of Strychnine and Strychnine Derivatives.

Preparations containing strychnic acid, however, must be used in alkaline solution. They have the disadvantage that, on standing with access of air, the lactame ring is again closed thereby forming the considerably more toxic strychnine. This ring closure proceeds especially rapidly in acid medium, even by the action of atmospheric carbon dioxide.

Strychnine oxide preparations also tend to split oif oxygen, especially in the presence of reducing agents and are thereby reconverted into the more toxic strychnine.

To improve the therapeutic usefulness of strychnine, attempts have been made to combine the detoxifying ac- 2,758,113 Patented Aug. 7, 1956 tion of the amine oxide formation with the simultaneous opening of the lactame ring of the strychnine molecule. The production of such strychnic acid N-oxide compounds, however, is quite difiicult because the opened lactame ring is apt to be readily closed, thus, reforming the strychnine ring. The formation of strychnine N-oxide has previously been described by Pictet. It is readily reduced by the action of reducing agents to strychnine.

Splitting up the lactame ring in strychnine N-oxide has heretofore been effected by means of alcoholic alkali hydroxide as described by Oesterlin in Berichte der Deutschen Chemischen Gesellschaft, vol. 76, pages 224 and S74. Strychnic acid N-oxide can be isolated, according to Oesterlin, in the form of its sodium salt which, by careful acidifying, is converted into the free acid and can be isolated as such. While strychnic acid in acetic acid solution rapidly re-forms strychnine by ring closure, strychnic acid N-oxide does not exhibit such a pronounced tendency to ring closure and reconversion into strychnine -oxide. Therefore, said acid can be isolated in its free form from acetic acid. However, strychnic acid N oxide is also gradually reconverted into strychnine N- oxide on standing in aqueous solution or in more strongly acid solution.

It is one object of the present invention to provide new derivatives of strychnic acid N-oxide and also of its methoxy substitution products, especially of the corresponding brucinic acid N-oxide, which derivatives are stable even on prolonged storage in aqueous solution and which are of sufficiently reduced toxicity and of considerably prolonged activity so that they can advantageously be used in therapy.

Another object of the present invention is to provide therapeutically useful preparations containing such new derivatives of strychnic acid N-oxide and its methoxy substitution products, such as brucinic acid N-oxide.

A further object of the present invention is to provide a simple and effective process of producing such new and therapeutically useful derivatives of strychnic acid N- oxide and its methoxy substitution products, such as brucinic acid N-oxide.

Other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.

The new derivatives of strychnic acid N-oxide and of its methoxy substitution products, especially of brucinic acid N-oxide according to the present invention are their esters with amino alcohols. Said esters are stable compounds which are of low toxicity and have a considerably prolonged activity and which, therefore, are especially suitable for therapeutic administration.

The new esters with amino alcohols cannot be prepared by using conventional esterification methods since the acid medium usually employed thereby causes ring closure of the opened lactame ring.

The present invention, however, provides a very effective process of making such esters. Said process consists in principle in carrying out esterfication in alkaline medium until the opened lactame ring is protected by complete esterification of the carboxyl group and in acidifying the reaction mixture only when ring closure is prevented by such complete esterification of the carboxyl group.

Thus, the process according to the present invention is characterized by the feature that first the alkali salts of strychnic acid N-oxide or its methoxy substitution products and especially of brucinic acid N-oxide, and preferably the sodium salts of said acids are produced by alkaline cleavage of the lactame ring of the corre sponding strychnine N-oxide or its methoxy substitution products and especially of brucine N-oxide and that thereafter said alkali salts are esterified with amino alkyl halogenides or acid addition compounds thereof, also in alkaline medium. Said esterification is preferably carried out by first isolating the alkali salts of said acids and especially the sodium salts and then reacting said isolated salts with amino alkyl halogenides and preferably with dialkylamino alkyl halogenides.

The resulting esters are advantageously isolated in the form of their acid addition compounds, preferably in the form of their hydrohalogenides.

The following examples serve to illustrate the present invention without, however, limiting the same thereto.

Example I 84 parts by weight of strychnine base are dissolved in 1000 parts by weight of an aqueous 3% hydrogen peroxide solution while heating on the water bath and stirring vigorously. After complete solution has taken place, excess hydrogen peroxide is destroyed in a customary manner, for instance, by the addition of freshly precipitated manganese dioxide. The resulting solution, after filtering off the manganese dioxide, is concentrated by evaporation and yields about 80 parts by weight of pure strychnine N-oxide.

50 parts by weight of said strychnine N-oxide are heated on the water bath, while stirring vigorously, in 500 parts by weight of water to which 20 parts by weight of sodium hydroxide were added. Heating is continued until complete solution has taken place. The hot solution is purified by treatment with activated charcoal and with bentonite and, after cooling, is carefully acidified with acetic acid.

The precipitated crude strychnic acid N-oxide is dried in a vacuum over sodium hydroxide and the dry acid is suspended in 300 parts by weight of 96% ethanol. 6 parts by weight of sodium hydroxide dissolved in parts by weight of water are added to said solution. On gently heating the mixture on the water bath a reddish solution is obtained. On cooling said solution in a freezing mixture, the sodium salt of strychnic acid N-oxide precipitates in hard crystalline needles.

The diethylamino ethyl ester of said strychnic acid N-oxide is prepared from said known sodium salt in the following manner:

28 parts by weght of said sodium salt of strychnic acid N-oxide, carefully dried over sodium hydroxide, aredissolved in 200 parts by weight of absolute ethanol. 10 parts by weight of freshly distilled diethylamino .ethylchloride are added thereto and the mixture is. heated under reflux on the water bath. The solution becomes rapidly turbid due to precipitating sodium chloride.

Heating is continued for 2 hours, the reaction mixture 1 is allowed to stand overnight, and is again heated on the water bath for 3 hours. The precipitated granular sodium chloride is filtered off by suction, is treated with decolorizing carbon, and is filtered while still hot.

24 cc. of a 6 N solution of hydrochloric acid in absolute ethanol are added to the resulting faintly yellowish clear solution while well cooling. After standing for minutes in the refrigerator, the precipitated hydrochloride of the diethylamino ethyl. ester of strychnic acid N-oxide is filtered off by suction and is washed with absolute ethanol. The mother liquor is concentrated by evaporation in a vacuum and yields a small additional amount of crystalline material. Said hydrochloride of the diethylamino ethyl ester of strychnic acid'N-oxide is recrystallized from absolute ethanol and is obtained thereby in the form of fine white needles which decompose (with darkening) on heating at 250 C. without definite melting point. The hydrochloride is readily soluble in water. Its aqueous solutions are stable and can be sterilized at 100 C.

Example 2 parts by weight of strychnine N-oxide areadded to a solution of 5 parts by: weight of'metallic sodium-in 500 parts by weight of absolute ethanol. The mixture is heated on the water bath under reflux for 6 hours while stirring vigorously. As soon as the strychnine N-oxide is completely dissolved, 14.5 parts by weight of the hydrochloride of dimethylamino ethyl chloride are added to the cooled solution by flushing, said hydrochloride with absolute ethanol into the reaction vessel. The mixture is heated on the water bath for 4 hours, allowed to stand overnight, again heated on the water bath for 2 hours, and the precipitated granular sodium. chloride is filtered off by suction.

The solution, while still hot, is purified by repeated filtration over decolorizing carbon and is cooled. 33.3 cc. of a 6 N solution of hydrochloric acid in absolute ethanol are carefully added to the filtrate while cooling and stirring. The mixture is allowed to stand for 20 minutes in the refrigerator and the hydrochloride of the dimethylamino ethyl ester of strychnic acid N-oxide which precipitates thereby in the form of fine needles, is filtered off by suction.

Example 3 Brucine N-oxide, brucinic acid N-oxide, and the sodium salt of brucinic acid N-oxide are prepared in the same manner as described in the preceding examples for the production of the corresponding strychnine derivatives.

48 parts by weight of the carefully dried sodium salt brucinic acid N-oxide are dissolved in 350 parts by weight of absolute ethanol. 15 parts by weight of freshly distilled diethylamino ethylchloride are added to said solution and the mixture is heated under reflux on the water bath. The, solution rapidly becomes turbid due to precipitating sodium. chloride. Boiling under reflux is continued for 1 hour. The reaction mixture is allowed to stand for several hours and the precipitated sodium chloride which by then has become granular, is filtered off by suction. 36 cc. of a 6 N solution of hydrochloric acid in absolute ethanol is added to the clear filtrate while vigorously stirring and cooling. The mixture is then kept in a refrigerator for a short period of time. The precipitated hydrochloride of the diethylamino ethyl ester of brucinic acid N-oxide is filtered off by suction and washed with absolute ethanol. The mother liquor is concentrated by evaporation in a vacuum to half its initial volume and: yields an additional crystalline fraction.

The hydrochloride of the diethylamino ethyl ester of brucinic, acid N-oxide can be recrystallized from absolute ethanol. It forms white needles which start to decompose at C- without a definite-melting point.

In place of the sodium salts of strychnic acid N-oxide and; brucinic acid N-oxide, there may be used equimolecular amounts of other alkali metal salts, such as the, potassium and lithium salts. Other metal salts, such as the alkaline, earth metal salts, for instance, the calcium and. the barium salts, or'the lead, silver and the like salts of said acidsmay also be used. However, the sodium saltshave proved to be the most suitable salts since they are directly obtained on splitting up the lactame ring of strychnine N-oxide and brucine N-oxide.

In. place of diethylamino ethylchloride and dimethylamino ethylchloride and their hydrochlorides, as used in the preceding examples, there may be'used equimolecular amounts of the corresponding bromides and the iodides and also other monoand dialkylamino alkyl halogenides and especially of compounds with a lower alkyl radical, such as dipropylamino ethylhalogenides, di-isopropylamino ethylhalogenides, dibutylamino ethylhalogenides, methyl ethylamino ethylhalogenides, monomethylamino ethylhalogenides, monoethylamino ethylhalogenides, monopropylamino ethylhalogenides, monoisopropylamino ethylhalogenides, amino ethylhalogenides and the like. However, the diethylamino ethylchloride and the dimethylamino ,ethylchloride. have provedto be the most suitable reactioncomponents yielding very valuable and effective new strychnine derivatives and, therefore, are the preferred' reaction components.

In'place of the hydrochlorides of said amino alcohols,

as used in Example 2, there may, of course, be used other corresponding acid addition compounds of said amino alcohols, such as the hydrobromides, hydroiodides, sulfates, nitrates, phosphates and others. The hydrochlorides, however, are the most preferred salts of said amino alcohols since they yield sodium chloride during reaction which can readily be converted into a granular, well filterable form.

The new esters of strychnic acid N-oxide and brucinic acid N-oxide with amino alcohols may be isolated not only in the form of their hydrochlorides as described in the examples but also in the form of their hydrobromides, hydroiodides, sulfates, phosphates, nitrates, or as salts with organic acids, such as the citrates, tartrates, oxalates, mandelates, malates, benzoates, salicylates and others. Any inorganic or organic acid is suitable for combining with said new strychnine and brucine derivatives, provided the acid is compatible to the human body. It is, of course, also possible to use acids which are not compatible to the human body, such as picric acid and others, but which form with said new esters acidaddition compounds that can be used for purifying said esters.

Esterification is preferably carried out, as shown in the preceding examples, in anhydrous ethanol wherein the alkali salts of strychnic acid N-oxide and brucinic acid N-oxide are readily soluble. In place of anhydrous ethanol, there may be used other anhydrous alcohols, such as methanol, propanol and the like. If the acid addition compounds of the amino alkyl halogenides, such as their hydrochlorides, are used as the one reaction component, it is, of course, necessary to provide sufficient amounts of alkali so as to at least completely neutralize the acid component of said amino alkyl halogenide. Such alkali is preferably supplied in the form of the corresponding alkali metal alcoholate as shown in Example 2.

The acid addition compounds of the new esters and especially of the dialkylamino alkyl esters of strychnic acid N-oxide and brucinic acid N-oxide can also be produced by adding a solution of the corresponding acid in another anhydrous alcohol than ethanol, for instance, in methanol, propanol, isopropanol and the like to the ester solution.

Other changes and variations in the starting materials employed, the amino alcohol derivatives and the solvents used for esterification, the esterification conditions, temperature and duration, the methods of working up the reaction mixture and of isolating and purifying the new esters and their acid addition compounds, and the like may be made by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.

As stated hereinbefore, the new esters and especially the new dialkylamino alkyl esters of strychnic acid N-oxide are superior to any of the heretofore known strychnine derivatives by their very advantageous therapeutic properties, such as gentle onset of strychnine action, low acute toxicity, and considerably prolonged activity. Said new esters, and especially the diethylamino ethyl ester of strychnic acid N-oxide are administered perorally as well as parenterally. Injectable preparations are obtained, for instance, by dissolving the hydrochloride of the diethylamino ethyl ester of strychnic acid N-oxide in distilled water or isotonic saline solution, filling the resulting solution into ampoules, and sterilizing the sealed ampoules. Such ampoules usually contain between mg. and 40 mg. per cc. and preferably mg. per cc. of said esters or their addition compounds. The solutions are stable at least for a period of several years and can even be kept open in contact with air for a certain period of time.

The average dose is between 40 mg. to 60 mg. daily given subcutaneously or, preferably, intramuscularly, i. e. 2 to 3 ampoules, each ampoule containing 20 mg. of the hydrochloride of the diethylamino ethyl ester of strychnic acid N-oxide. Higher doses should be given only in exceptional cases, such as malignant diphtheria and the like. Generally one ampoule is administered and administration is repeated every 12 hours since the strychnine efiect is prolonged to at least 12 hours.

The new esters may also be administered perorally in the form of tablets, dragees, pills, or in other solid shaped form or as powders, preferably enclosed in gelatin capsules. They are preferably diluted with a suitable solid pharmaceutical carrier as they are employed in making such tablets, pills, dragees and the like preparations. Such commonly used diluting agents are, for instance, sugar, lactose, talcum, starch, bolus alba, talcum and, as binders, gelatin, gum arabic, methyl cellulose, yeast extract, agar, tragacanth, and others. Such tablets, pills and the like solid preparations contain between about 10 mg. and about 50 mg. and, preferably, 20 mg. of the new esters per tablet unit. The average daily dose is between 40 mg. and. mg. and, preferably, 60 mg., subdivided in 4 to 6 equal doses given in intervals of 6 to 4 hours. These dosages, of course, may be varied in accordance with the requirements in each case.

According to a further embodiment of the present invention it is also possible to open the lactame ring of strychnine N-oxide or brucine N-oxide by means of alkali hydroxide and simultaneously to cause esterification of the intermediately formed strychnic acid N-oxide or brucinic acid N-oxide in said alkaline medium.

The present invention is, of course, not limited to esters with amino ethanols. Esters with (3- or -amino propanols, butanols or the like amino alkanols may also be produced in the same manner as described in the preceding examples whereby the corresponding amino propyl or butyl halogenides are used as reaction components.

In place of the dialkylamino alkyl halogenides there may be used amino alkyl halogenides in which the amino nitrogen atom is a member of a five to six-membered heterocyclic nucleus. Such amino alkyl halogenides are, for instance, B-N-piperidino ethylchloride, fl-N-pyrrolidino ethylbromide, B-N-morpholino ethylchloride, ,B-N-piperazino ethyliodide and others. The esters of strychnic acid N-oxide and brucinic acid N-oxide with said amino alkanols are also highly effective.

Reaction of the new amino alkyl esters of strychnic acid N-oxide and brucinic acid N-oxide with quaternizing agents, such as alkyl halogenides, for instance, methyl bromide, methyl iodide, ethyl bromide, ethyl iodide, butyl bromide, butyl iodide and others, or dialkyl sulfates, for instance, dimethyl sulfate or diethyl sulfate, or the like yields compounds of reduced toxicity and increased solubility which can advantageously be used for therapeutic purposes.

I claim:

1. An ester compound selected from the group consisting of an ester of an acid selected from the group consisting of strychnic acid N-oxide and brucinic acid N-oxide, with an alkanol amine, and an acid addition compound of said ester.

2. A new ester compound selected from the group consisting of an ester of an acid selected from the group consisting of strychnic acid N-oxide and its methoxy substitution products having not more than two methoxy groups in the aromatic ring A of the strychnic acid N-oxide molecule, with an alkanol amine, and an acid addition compound of such an ester.

3. The diethylamino ethyl ester of strychnic acid N oxide.

4. The dimethylarnino ethyl ester of strychnic acid N- oxide.

5. The diethylamino ethyl ester of brucinic acid N- oxide.

6. The hydrochloride of the diethylamino ethyl ester of strychnic acid N-oxide.

7. The hydrochloride of the dimethylamino ethyl ester of strychnic acid N-oxide.

8. A dialkylamino alkyl ester of strychnic acid N- oxide.

9. A dialkylamino alkyl ester of brucinic acid N-oxide.

10. An acid addition compound of a dialkylamino alkyl ester of strychnic acid N-oxide.

11. In a process of producing an ester of an acid selected from the group consisting of strychnic acid N-oxide and its methoxy substitution products, the steps comprising esterifying an alkali metal salt of an acid selected from the group consisting of strychnic acid N-oxide and its methoxy substitution products having not more than two methoxy groups in the aromatic ring A of the strychnic acid N-oxide molecule, in weakly alkaline medium with an amino alkyl compound selected from the group consisting of an amino alkyl halogenide, the halogen atom of said halogenide having an atomic weight of at least that of chlorine, and its acid addition compounds, and isolating the resulting ester from the reaction mixture.

12. In a process of producing an ester of an acid selected from the group consisting of strychnic acid N-oxide and its methoxy substitution products, the steps comprising esterifying a sodium salt of an acid selected from the group consisting of strychnic acid N-oxide and its methoxy substitution products having not more than two methoxy groups in the aromatic ring A of the strychnic acid N-oxide molecule, in weakly alkaline medium with an amino alkyl compound selected from the group consisting of an amino alkyl halogenide, the halogen atom of said halogenide having an atomic weight of at least that of chlorine, and its acid addition compounds, and isolating the resulting ester from the reaction mixture.

13. In a proees of producing an ester of an acid selected from the group consisting of strychnic acid N-oxide and its methoxy substitution products, the steps comprising esterifying an alkali metal salt of an acid selected from the group consisting of strychnic acid N-oxide and its methoxy substitution products having not more than two methoxy groups in the aromatic ring A of the strychnic acid N-oxide molecule, in weakly alkaline medium with a dialkyl amino alkyl halogenide, the halogen atom of said halogenide having an atomic weight of at least that of chlorine, and isolating the resulting ester from the reaction mixture.

14. In a process of producing an ester of an acid selected from the group consisting of strychnic acid N-oxide and its methoxy substitution products, the steps comprising esterifying an alkali metal salt of an acid selected from the group consisting of strychnic acid N-oxide and its methoxy substitution products having not more than two methoxy groups in the aromatic ring A of the strychnic acid N- oxide molecule, in weakly alkaline medium with an amino alkyl compound selected from the group consisting of an amino alkyl halo-genide, the halogen atom of said halogenidc having an atomic weight of at least. that of chlorine, and its acid addition compounds, and isolating the resulting ester in the form of its acid addition compound.

15. In a process of producing an ester of an acid selected from the group consisting of strychnic acid N-oxide and its methoxy substitution products, the steps comprising esterifying an alkali metal salt of an acid selected from the group consisting of strychnic acid N-oxide and its methoxy substitution products having not more than two methoxy groups in the aromatic ring A of the strychnic acid N-oxide molecule, in weakly alkaline medium with an amino alkyl compound selected from the group consisting of an amino alkyl halogenide, the halogen atom of said halogenide having an atomic weight of at least that of chlorine, and its acid addition compounds, and isolating the resulting ester in the form of: its addition compound with hydrogen halide.

16. In a process of producing an ester of strychnic acid N-oxide, the steps comprising dissolving the sodium salt of strychnic acid N-oxide in absolute ethanol, adding to the resulting solution diethylamino ethylchloride, heating the reaction mixture under reflux until esterification is complete, filtering off the precipitated sodium chloride, adding a concentrated solution of hydrochloric acid in absolute ethanol to the resulting filtrate, cooling the reaction mixture, and filtering off the precipitated hydrochloride of the diethylamino ethyl ester of strychnic acid N-oxide.

17. In a process of producing an ester of strychnic acid N-oxide, the steps comprising dissolving the sodium salt of strychnic acid N-oxide in absolute ethanol containing sodium alcoholate, adding to the resulting solution the hydrochloride of dimethylamino ethylchloride, heating the reaction mixtureunder reflux until esterification is complete, filtering oh the precipitated sodium chloride, adding a concentrated solution of hydrochloric acid in absolute ethanol to the resulting filtrate, cooling the reaction mixture, and filtering oif the precipitated hydrochloride of the dimethylamino ethyl ester of strychnic acid N-oxide.

18. In a process of producing an ester of brucinic acid N-oxide, the steps comprising dissolving the sodium salt of brucinic acid N-oxide in absolute ethanol, adding to the resulting solution diethylamino ethylchloride, heating the reaction mixture under reflux until esterification is complete, filtering off the precipitated sodium chloride, adding a concentrated solution of hydrochloric acid in absolute ethanol to the resulting filtrate, cooling the reaction mixture, and filtering off the precipitated hydrochloride of the diethylamino ethyl ester of brucinic acid N-oxide.

19. In a process of producing an ester of an acid selected from the group consisting of strychnic acid N-oxide and brucinic acid N-oxide, the steps comprising dissolving an alkali metal salt of said acid in an anhydrous alcohol, adding to the resulting solution an amino alkyl halogenide, the halogen atom of said halogenide having an atomic weight of at least that of chlorine, heating the reaction mixture under reflux until esterification is complete, filtering off the precipitated alkali halogenide, adding a concentrated solution of an acid in anhydrous alcohol to the resulting filtrate, cooling the reaction mixture, and separating the resulting acid addition compound of the amino alkyl ester of said acid from the reaction mixture.

References Cited in the file of this patent UNITED STATES PATENTS 2,619,485 Chabrier et al Nov. 25, 1952

Claims

1. AN ESTER COMPOUND SELECTED FROM THE GROUP CONSISTING OF AN ESTER OF AN ACID SELECTED FROM THE GROUP CONSISTING TO STRYCHNIC ACID N-OXIDE AND BRUCINIC ACID N-ODIDE, WITH AN ALKONOL AMINE, AND AN ACID ADDITION COMPOUND OF SAID ESTER.