Патент USA US2116454код для вставки
2,116,454 Patented May 3, 1938 umrso STATES‘ PATENT OFFICE HIGHLY ACTIVE PREPARATION OF E'RGOT ' AND PROCESS FOR MAKING SAME - "Marvin R. Thompson, Baltimore, Md. No Drawing. ’ Application August 16, 1934, Serial No. 740,199 40mins. (CI. 87-28) dampened and alkaline drug is then exhaustively The present invention provides a hitherto un extracted with ethyl ether, benzol, acetone, chlor known component of ergot and process for mak ing the same. ‘ - This component, henceforth called Ergostetrine, 5 is a substance exhibiting alkaloidal properties, but differs greatly from all of the hitherto un known alkaloids of ergot, in that its physiologi cal, therapeutic or oxytocic activity develops with remarkable promptness when compared with any 10 of the other hitherto known alkaloids or com‘ ponents of ergot. , The known therapeutically significant com ponents of ergot are “Ergotoxine”, “Ergotamine" and “Sensibamine”. These components of ergot or alkaloids are possessed of oxytocic activity, but this activity manifests itself only in an erratic and much delayed manner following dosage by mouth. Even when administered subcutaneously or intramuscularly the uterine activity of these 20 alkaloids or components of ergot develop very slowly and feebly compared to Ergostetrine, the subject of the present invention. Brie?y stated, the instant invention provides a hitherto unknown component of ergot, called Er gostetrine whose physiological, therapeutic or 2 oxytocic activity develops with a marked degree of quickness when compared with-other known alkaloids, and consists of the “residual alkaloid” as a‘ single chemical entity which remains after 30 the chemical removal of all of the other hitherto known alkaloidal substances. Ergostetrine differs from all other hitherto known alkaloids or components of ergot in that ethylenes, the chlor-methanes, or any one of the common organic solvents. The solution of the total alkaloidal bases in the organic solvent is concentrated in vacuo with or without the aid of a slight amount of heat. The amount of con centration necessary depends of course upon the particular organic solvent used, and the acid em ployed to convert the free bases to their corre sponding salts. An acid is then added, such as 10' sulphuric, hydrochloric, or phosphoric acid, to 7 convert the alkaloidal bases to their correspond ing salts. This causes a substantially complete precipitation of all alkaloids except Ergostetrine, the latter alkaloidal salts remaining in solution because of its greater solubility in all organic solvents. After removal of the other alkaloids by ?ltra tion, Ergostetrine is obtained in amorphous, im 20 pure form from the clear ?ltrate by evaporating to dryness in vacuo. By leaching the residue with small portions of water and ?ltering, until ap proximately 100 CC ot' the aqueous solution of Ergostetrine sulphate is obtained, the Ergostetrine 25 can then be obtained as the dry amorphous base by (a) precipitating the base from the aqueous solution by partial saturation with sodium bi carbonate, collecting the Ergostetrine base on a filter and drying to constant weight in vacuo 30 over a suitable dehydrating agent; or (b) by slightly alkalinizing the aqueous solution of Er gostetrine sulphate and shaking out with several it is considerably more soluble in water as the‘ small portions of ether or other immiscible or free base or its salts than the hitherto known ganic solvent. The Ergostetrine base passes into 35 35 alkaloids or their salts. Its most readily apparent the layer of immiscible solvent, and can be ob and therapeutically all important diiierence lies in the fact that its oxytocic action develops with a marked degree of rapidity and intensity fol 40 lowing either oral, or parenteral administration, as compared by actual test with any of the other hitherto known alkaloids or puri?ed preparations of ergot. . tained as the dry substance by removal of the volatile solvent in vacuo, or (c) by obtaining the total alkaloids in ethereal solution by direct alka line extraction of ergot or its aqueous extract, 40 removing the ether in vacuo and drying. and re dissolving the total alkaloids in the smallest nec essary amount of acetone, adding water to the ,The new component, Ergostetrine as such can , acetone which causes all other alkaloids to pre 45 45 be obtained as a dry powder, either from crude cipitate. After discarding the precipitate the ergot or from crude ergot extracts in various ways, ‘amorphous Ergostetrine base is obtained by re moval of the solvent. ' and for-illustrative purposes I hereinafter de scribe several preferred methods of making the same. 50 From crude ergot , In accordance with one procedure I mix 1 kilo gram of ?nely powdered ergot, preferably de iatted with benzine, with a su?icient quantity of 55 anv aqueous solution or mixture of any alkali, such as hydroxides, carbonates or bicarbonates of sodium, potassium, ammonium, lithium, stron tium, calcium, magnesium, etc. to render it evenly and distinctly damp, and to impart a slightly but 60 de?nitely alkaline reaction to the mixture. The From crude ergot extracts Crude aqueous or hydro-alcoholic extracts 50 (liquid, semi-solid or, solid) prepared by simple procedures such as described by the U. S. Phar macopoeia, the British Pharmacopoeia or the National Formulary can serve as a convenient starting point for the preparation of Ergostet 55 rine. An amount of such extracts representing 1 kilo gram of original ergot, is preferably de-alcohol ized in the conventional manner, alkalinized to litmus by the addition ‘of any one of the alkalies 2 8,1 16,154 above mentioned. and exhaustively shaken out with immiscible solvent such as ether, bensol chloroform etc. The total alkaloids pass into the layer of the immiscible solvent. From this point the lt'rgostetrlne can be obtained as the base or its corresponding salts as above indicated. It is understood that the Ergostetrine so ob tained may be further puri?ed as desired by con ventional alkaloldal puri?cation procedures, such as repeating the steps above mentioned. What is claimed is: 1. A process for obtaininga hitherto unknown component of ergot, consisting of mixing a pre determined quantity of powdered ergot with aqueous solution oi! alkali, extracting the damp ened and alkaline drug with an organic solvent, and then concentrating and reducing the volume of the solution of the total alkaloidal bases in the organic solvent, adding an acid of the group con 20 sisting of sulphuric, hydrochloric and phosphoric acids, causing the conversion of the total alka loids to theirv corrmponding sulphates, hydro . chlorides or phosphates and resulting in a sub 25 stantially complete precipitation or all the alka loids except the desired component. 2. A process for obtaining a hitherto unknown component of ergot, consisting oi’ mixing a pre determined quantity oi.’ powdered ergot‘with an aqueous solution of alkali, exhaustively extract 30 ing the dampened and alkaline drug with an or ganic solvent, concentrating the solution oi.’ the total alkaloidal bases in vacuo and reducing the volume, adding an acid of the group consisting of sulphuric, hydrochloric and phosphoric acids, 35 causing the conversion 01' the total alkaloids to determined quantity of de-iatted powdered ergot with an aqueous solution of alkali, exhaustively extracting the dampened and alkaline drug with an organic ‘solvent, then concentrating the solu tion of the total alkaloidal bases in vacuo and reducing the volume, adding an acid oi’ the group consisting oi’ sulphuric, hydrochloric and phos phoric acids, causing the conversion or the total alkaloids to their corresponding sulphates. hy drochlorides or phosphates and resulting in a substantially complete precipitation oi’ all the alkaloids except the desired component, remov ing said alkaloids by ?ltration, then evaporating the ?ltrate to dryness in vacuo and leaching the residue with small portions of water to obtain an aqueous solution oi’ the component salt, precipi tating the base of the component from the aque. ous sulphate solution by alkalinizing to litmus with alkaline substances, collecting the base oi’ the component on a ?lter, and drying to con stant weight in vacuo over a dehydrating agent. 4. A process for obtaining a hitherto unknown component of ergot, consisting of mixing a pre determined quantity oi de-tatted powdered ergot with an aqueous solution oi alkali, exhaustively 26 extracting the dampened and alkaline drug with an organic solvent, then concentrating the solu tion of the total alkaloidal bases in vacuo, and reducing the volume, adding an acid of the group consisting of sulphuric, hydrochloric and phos phoric acids, causing the conversion of the total alkaloids to their corresponding sulphates, hy drochlorides or phosphates and resulting in a substantially complete precipitation of all the alkaloids except the desired component, remov~ 35 their corresponding sulphates, hydrochlorides or phosphates and resulting in a substantially com ingsaid alkaloids by ?ltration, then evaporating plete precipitation of all the alkaloids except the desired component, removing said alkaloids by residue with small portions of water to obtain an 1 40 ?ltration, and then obtaining an aqueous solution _ of the component salt from the clear ?ltrate by evaporating to dryness in vacuo, and leaching the residue with small portions 01' water. ' 3. A process for obtaining a hitherto unknown 45 component of ergot, consisting of mixing a pre the ?ltrate to dryness in vacuo and leaching the aqueous solution of the component salt, then ob taining the component as a dry amorphous base 40 by slightly alkalinixing the component salt solu tion and shaking out with several small portions of immiscible organic solvents, and ?nal removal of the volatile solvent in vacuo. _ MARVIN R. THOMPSON.