Патент USA US3092653код для вставки
i@ 3,92,643 Patented June 4, 1963 1 2 3,092,643 After complete extraction of the plant with one of PREPARATION 0F ALLOPREGNANE - 20 - HY these solvents or a mixture thereof, the extracts are DROXY-3-0NE AND OF ALLGPREGNANE 3-20-DIONE Jean Louis Paul Mainil, Boitsfort, Belgium, assignor to stirred with a solution of acetic, hydrochloric, oxalic or other ‘acid sufficiently strong to displace the principles combined with the rubber and with the chlorophyll. It Societe Anonyme Oletta, Luxembnrg is generally desirable to use concentrations of at least No Drawing. Original application Sept. 26, 1958, Ser. 25%, ‘depending upon the acids. No. 763,431. Divided and this application June 12, The solvent and the acid .are separated, if necessary 1962, Ser. No. 201,791 with ?ltration. The aqueous part is added to any solid Claims priority, application Belgium Sept. 27, 1957 10 part remaining on the ?lter. 3 Claims. (Cl. 260-3973) The principles in acid solution are made alkaline with The present invention relates to ‘the preparation of ammonia or by :a sodium carbon-ate solution so as to allopregnane-20-hydroxy-3-one and of allopregnane-S dissociate the principles A and C from the other prin ZO-dione. ciples. The alkaloid is then extracted by means of a The invention is characterized in that respectively 15 solvent or a mixture of solvents immiscible with Water, amino-3a-allopregnane-20-ol (Funtumidine: C21H37ON) and amino - 3oz - 'al-lopregnane - 20 _ one (Funtumine: such as ether ‘or chloroform, or miscible with Water, such as ethyl or methyl alcohol. On distillation, ‘a residue is obtained and is dried, the residue consisting of the alka C21H35ON) are caused to react with hypochlorous acid, the chloramine obtained is treated by means of sodium 20 loids or bases mixed with other substances and resins heretofore regarded as impurities. ethylate so as to obtain the corresponding ketamine and These substances A and C are taken up individually ‘the latter is hydrolized. in methanol and, if desired, recrystallized several times. The present invention is based on alkaloids and prin The substance having a melting point of 260° C. can ciples isolated from plants of the genus Funtumia (Apoc also be obtained by distilling or otherwise treating the yn-aceae) and more particularly from the species F. 25 extraction solvents ‘after elimination of the basic prin substance ciples and ?rom, of the‘for chlorophyll example, methanol and by recrystallizin-g or ethyl acetate. This application is a divisional based on my earlier Latifolia. application, Serial No. 763,431, ?led September 26, ~l958. Investigations have shown that crystallizable alkaloids Experience shows ‘that the product obtained is a sapo genin which ‘is positive to Liebermann’s reaction. Its ‘and principles, combined with the latex of this plant, can 30 infra-red spectrum shows an OH band at about 3 Ill/.0 and be isolated in an advantageous and economic yield from a C—-O band at about 6 my. This substance contains no nitrogen. this species of the genus Funtumi-a and from any part of the plant. The crude residual mixture of alkaloids and bases can These ‘alkaloids and bases are useful in veterinary ther 35 also be obtained by extraction with acid water or neutral or acid alcohol by concentrating and extracting the resi apy and as an intermediary product (raw product) for due by means of a solvent immiscible in the alkaline synthesis of other steroids. More particularly, the al phase. kaloids are useful in controlling respiratory action and The residual mixture can be directly treated by ‘suc the nervous systems of animals. They are two in num cessive recrystallizatious until pure principles are obtained. ber, and are hereinafter called alkaloids A and C, re 40 The chemical characteristics of bases A and C are as spectively. The physiological properties of alkaloids A and C have been the subject of experiments and more detailed par ticulars will hereinafter be ‘given. For the isolation of these products, use is made of of alkalids from the plants, account being taken ‘of one of the methods generally employed for the isolation the fact that each fraction is combined with the latex and/or the chlorophyll ‘of the plant. The plants or parts thereof, such as the leaves, trunk bark or roots, depending on the season ‘at which the crop is taken, are crushed and then Washed in petroleum ether. ‘follows. Alkaloid (principle) A: Empirical formula: C21H37ON. Developed formula: 3-a-amino-allopregnane-ZO-ol. Infra-red spectrum: OH, NH bands at about 3”; no (‘:0 bands; its chloro'hydrate has a 2080 cm.-1 'a band NHs‘l". Melting point: 182° C. (0013:: 0 in methanol. Gives a hydrochloride of MP. 290° C. Alkalcid (principle) C: The cells are burst by a current of steam or by other Empirical formula: C21H35ON. Developed formula: B-a-aminO-alIOpregnane-ZO-one. chemical or physical means. The plants are then made 55 ‘Melting point: 123 ° C. alkaline with ‘a solution either of 20% ammonia or of 10% or 5% sodium carbonate, or with milk of lime or It gives a hydrochloride of M1’. 280° C. having a of magnesia, or they are moistened with water. rotatory power of +60 in methanol and the infra-red spec~ After contact for several hours with the ‘alkaline me trum of which exhibits NH bands in the region of 3/1, a dium, the plant is extracted in a Soxhlet apparatus, a 60 NH3+ band at 4.9”, a 0:0 hand at ‘about 5.9/1. and mixer, a percolator or a rotative extractor, with petroleum another band at about 6.2,u, which may correspond Ito ether, ether, benzene, chloroform, ethyl acetate or other a C=C vibration. solvents polar or non-polar chlorinated or non-chlori These reactions and identi?cations show that it is a nated, alone or in admixture. ‘ketonic alkaloid. aooaeas Toxicity DL5U Action on the central nervous system. 5 times more anaes- thetic than cocaine sulphate so as to avoid the presence of Water. 5 times more anaes‘ thetic than cocaine on the cornea of the on the cornea of the rabbit; Temperature ture reducer and reducer and anti~ Gardiotonlc _________ _- On the isolated auri- cle; On the rabbit’s heart in situ. Respiratory analeptic. On the normal rabbit pyretic. 0n the rabbit’s heart in situ. phinized rabbit. phinized rabbit. tension. 10 is boiled under re?ux for 40 minutes with a solution of On the normal rabbit and on the mor Diuretic _____________ -_ by the method of Wohl and Goldschmidt, Ber. 46; 2731 (1913). After agitation for one hour, the ethereal solu tion is ?ltered to separate the sodium sulphate, and is evaporated to dryness in vacuo. The crystalline residue On the isolated auricle: and on the mor- Cardiovascular ...... _. Vasodllatation hypo- The ethereal hypochlorous acid solution is prepared 5 rabbit; Tempera- antipyretic. Kidney _____________ -. of alkaloid C (Furltumine) in solution in ethereal solu tion cooled to 10° C., with agitation. The entire opera tion is carried out in the presence of anhydrous ‘sodium Alkaloid A, 28 mgJkg. Alkaloid C, 30 rug/kg. sodium ethylate in 50 ml. of absolute ethanol. The solu rtion is thereafter poured into 300 ml. of water slightly acidi?ed with sulphuric acid. The mixture is allowed Vasodilatation hypo tension. to stand for 24 hours and the precipitate formed is suc No action. Anabolic ____________ __ Slightly per os nil by tion filtered and dissolved in chloroform. The chloro No oestrogenic action; No oestrogenic action; 15 formic solution is Washed with water, dried and evapo injection. Hormonal and metabolic action. No androgenic action; No folliculinostimulant action. Suprarenal __________ ._ Weight unchanged after 40 days as com- No folllculino-stim ulant action. rated to dryness in vacuo. mg. is obtained. Weight unchanged af pared with controls. Ascorbic acid and _ Ascorbic acid and cholesterol content cholesterol content unchanged as com- unchanged as com- 1 pared with controls. pared with controls. Liver ________________ _. Slight increase in dry Prevents glycogen de-V weight; Prevents glycogen depletion After recrystallization from hexane and alcohol, allo prognane-3,20-dione, M.P. ZOO-202° C. and (a)D-|-128 (CHCls), is obtained. By the same method, alkaloid A or its ZO-position cp'i ter 40 days as com pared with controls; mer can be converted into the two sterolic alcohols 20 pletion of the liver liydroxy-allopregnanc-3-one. (like cortisone). . Alkaloid A is advantageously oxidized to give alkaloid C in ketonic form by the use of chromic acid in acetic ' of the liver (like _ A residue weighing 1:800 cortisone). Trauquilizing Action- 25 mg./kg. per day reduces the motility of rats by changing the number of movements recorded in 6 hours from 16,500 to 2,500. ‘acid solution or by any other method. Injectable solutions containing 5 rug/cc. of the hydro chloride of alkaloid A or C can be prepared by dis 30 solving it in propylene glycol (30 parts) diluted with dis tilled water (70 parts). Other injectable solvents such as methyl acetamide, etc., may be employed. Concen trations of 1 mg./cc. of hydrochloride can be obtained 35 in distilled water alone. It is also possible to prepare tablets for therapeutic use by using, vfor example, the following recipe: [Hydrochloride of alkaloid A or O 10 mg. or 25 mg.] 40 Lactose.-.__ Rice starch Magneisum stearate _____________________________________ _. Talc 71 80 56 80 2 2 37 37 The invention also concerns the production of deriva tives of alkaloid C (Funtumine) preserving the amino function in the 3-p-osition, as follows. , (1) Reduction of the ketone function of alkaloid C For example, the alkaloid and the lactose are granu 45 into an alcohol function (Funtumidine) : _ 3-u-rzmino-ZO-o-hydraxy-all0pregnane: Fzmtum‘ia‘ina lated. After drying, the other ingredients are added to Funtumidine is advantageously obtained by reduction of enable ready dis-solution in the stomach and lubricants Funtumine by means of sodium in ‘alcohol. to enable ready compression of the tablets. 7 200 mg. of Funtuniine are dissolved in 20 cc. ‘of abso Principals A and C may be converted into mineral salts, such as vsulphates, hydrochlorides, nitrates or hy 50 lute alcohol. To this solution, maintained at boiling point, are added in small fractions, over the course of 1 drobromides, or into organic salts, such as tartrates, ci ‘hour, 3 times the calculated quantity of sodium. The trates, gluconates, camphorates, camphosulfonates and alcohol is driven oil by distillation in vacuo and the acetates. residue is taken up in Water ‘and extracted with methylene For the production of hydrochlorides ‘of bases A and C, the puri?ed base in suspension in very hot water may be 55 chloride. The organic solution is dried ’over "anhydrous. sodium sulphate, ?ltered “and distilled to dryness. The employed as starting material. The pH value is adjusted residue (200 mg.) is crystallized from ethyl acetate and to 4 with a mixture of methanol and hydrochloric acid gives the 'dihydrogenated derivative of Funtumine, which and the white hydrochloride is allowed to cool. They are is identical with Funtumidine: M.P. 178° (MD-H0 very sparingly soluble in the cold. ' The alkaloids A and C, hereinafter called Funtumidine 60 (CHCl3). ' ' 3~u-amino-ZO-B-hya’roxy-all0pregnane: ZO-epi-Funtum‘i and Funtumine respectively, may be used as starting ma dine.—T-he epimer of 'Funtumidine is obtained by: the reduction of Funturnine by means of potassium b‘orohy drid'e in solution in methyl alcohol. terials for the production of other steriods, particularly for obtaining dihydro-progesteronc in an advantageous yield (allopregnane-3-20-dione) . It is particularly advantageous to obtain these sub 65 stances by preparing the chloramine by action of hypo chlorous acid in ethereal solution. This chloramine is 200 mg. of Funtumine are dissolved in 10 cc. of methanol. To solution ‘are added 200 mg. of potas sium borohydride. The mixture is constantly stirred for dechlorinated by means of sodium ethylate and [the ket 5 hours at room temperature. The excess of horohydride amine obtained is hydrolized in sulphuric acid solution is them entirely ‘consumed. The solution is poured into 7 to give allopregnanc-S-ZO-dione in a good yield. . Example The calculated quantity of hypochlorous acid in ethereal solution, cooled. to —20° C. (the quantityis ‘calculated mol. per mol.) is added dropwise to 1 ‘gram 70 100 cc. of water and the precipitate is extracted with an organic solvent such as other or methylene chloride. The organic solution is dried and evaporated to dryness. The crystalline residue is recrystallized from ethyl acetate. 180 mg. of 20~epi-Funtumidine: M.P. 167° C.,' are ob tained. 3,092,643 5 6. (2) Production of 3-amino derivatives of androstane from Funtumine: 3-a-amino-androstane-17-B-ol.—-The 17 ?-hydroxy com pound of 3-a-amino-androstane can be ‘obtained by the action of peracids with the retention of the con?guration in the 17-position. In this reaction, using peracetic ‘acid, What is claimed is: [1. A process for the preparation of allopregnane-ZO hydroxy-3-one and of allopregnane-3-20-dione, said proc ess comprising reacting 'amino-3wallopregnane-20-‘ol and iamino-3wal1opregnane-20-one with ‘hypochlorous acid, treating the chloramine thus obtained with sodium ‘eth ylate ‘to ‘obtain the corresponding 'ketamine, and hydro 17?aacetoxy-3-a-arninoaandrostane is obtained, ‘together with 21-acetoXy-Funtumine. The latter product consti lyzing the latter. rtutes a -by-product of the reaction. These ‘operations are summarized as follows: OH; / 2. The process according to claim 1 wherein the reac 10 rtion with hypochlomus acid takes place in ethereal solu rtion. 3. The process according to claim 1 wherein the hy OHIOAC :aa drolysis takes place in sulfuric solution. 15 No references cited.