. Patented June 1.6, 71953 2,642,427

. . , weer ~ - " 1.11.rename-emits 10F CYGLQPENTANQ POLYHYDROBHENANTHRENE- 3"-_'MONO- .

‘ ' 1? 7Richard Bl‘vHasbrouck, Waukegan, ‘11],, assignior , ‘ ~to.AbbottrLaboratories, North qhieaaol 111-’. pa ‘ *- - ,corporation bflllinois; ~ ' 'No'?ravv ' ‘ Application‘v'Aug-ust 1 , 1951, .91" ">S’rialNo.239,857_ . I (o1. zen-239.5)

' Thisin-vention relates to therapeutic prepara ring, to‘ about? 95-1005 0., andvthe heating is con- tions having hormone"activi_ty,"~ and 'lIlCllldElS tin-uedefor about one and one-quarter hours. »'At among its objects‘ and advantages, compounds of the end'of‘the heatingperiod the reaction massis increased‘ stability,- and‘method's- for producing cooled .to: about-room‘ temperature and about, 7 the same. Speci?cally, the‘ invention relatesnto. 5 parts *ofianhydrous ether is added. The dense, ' piperazine salts ‘of the half acid sulfate esters of pinkggr‘anular solid which forms is ?ltered and cyclopentanopolyhydrophenanthrenes..‘ -‘ " ' , washed with anhydrous ether. The solid, which Thewcompo'unds of the present-invention-are is amixture of ammoniumestrone-3 -..monosulfate derived. from hormone typesteroidsknownl'as and'pyridine.sulfamatais dried.v , ,, .. the Vcyclopentanopolyhydrophenanthrene . series; m About 24 parts of piperazine hexahydratelor whichkincludes-estr'ogenic Steroids, such as'ese. an equivalent amount of anhydrous piperazine) trone‘; estradiol, eq'uilin; and equilenin; androster dissolved in afsolutionof'about 125~parts of meth ones} pregnenolones; ‘stereo-isomerides and-de anol "and40parts-of wateni‘s added to. thecrude rivatives thereof, etc‘. - - .. ~ I 1 . . ammonium estrone-3emono'sulfate.7:. The" pH is‘ According to the invention, stable organic salts adjusted to 87-85. with morerof the piperazine, and of the cyclopentancpolyhydrophenanthrenesI are the ' mixture is gently, heated until solution is" ef produced, which are. particularly, suitable .for oral fected. The solution is eva'porated'to dryness, administration.v ‘The salts are‘ odorless, or practi to. remove; the...last traces of water. The dried cally so,.and inoffensive to the user. The salts residueiis extracted with about. 200 parts of meth are solublerinwaqueous émedia and are stable ~ , anol; byslurrying'the solid'inthe methanolaand' ?ltering.,-_;The.methanol extract is clari?ed with therein.Butenandt, ;, ' Z.‘ Physiol.2 Chem. 259,. y 222—3,¢l,;(1,9_3p9;),l ,_ decolorizing charcoal, and partially concentrated. during an investigation of estrone, prepared sev-l' About 400 parts of anhydrous ether are added eral alkaloidvsalts of estrone sulfate. The salts with stirring to the concentrated methanol S0111? , are quite insoluble in aqueous solutions and are 25 tion, precipitating the piperazine estrone-3-imono- ' not, therefore, particularly adaptedf-or human sulfate as light tan crystals. The crystals are consumption. A further disadvantage of these dried invacuum. When recrystallized from meth estrone salts if used for medication, is the fact anol the product melts at 193-195° C. that if any dissociation takes place in the solu In the example the sulfamic acid is used in a tion, the alkaloids thus liberated from the com 3-molar excess to the estrone, to insure a high pounds produce the general alkaloid effects, which yield of the ammonium estrone sulfate. The ex are undesirable. Some of the alkaloids used to cess sulfamic acid is converted to pyridinesul produce the salts are extremely toxic or poisonous famate. and therefore, impractical for use. The ammonium estrone sulfate is a very desir Generally, the compounds of my invention may 7 35 able intermediate in the process, as the ammoni be prepared from the known naturally ‘occurring um group may be replaced by the piperazine ‘ sodium steroid3-monosulfates or from thester- », group.‘ Itis important that the basic group of ‘ oids per se. The steroids may be sulfonated ac- ' r the intermediatesalt of the estrone sulfate be, less ' cording to known procedures'wi'th such sulfonat basic than the piperazine, otherwise no reaction ing agents as sulfur trioxide, chlorosulfonic acid, will occur between the two compounds. _ sulfamic acid, etc., and recovered, as water-soluble 40 salts, such as, sodium, a- monium, or other alkali , Example I_ I or alkali metal salts. The salt is then reacted“ with piperazine (or a piperazinesalt) to produce the desired piperazine 'cyclopentanopolyhydro— To asolution of 0.650 gm. of piperazine hexa phenanthrene-3-monosulfate. 45 hydrate in 5 cc. of methanol is added 0.275‘ gm. ‘of ammonium estradiol-3-monosulfate. The mix The following examples illustrate in detail the _ ture is warmed gently to dissolvethe solids. It present invention. is then concentratedto dryness in vacuum. The Example I residue is stirred with about 10 cc. of methanol at ' 60 40--50° for about one hour. The solution is ?l About 10 parts (by weight) of estrone and about tered and the residue washed with a small amount 10.8 parts of sulfamic acid are placed in a suitable of methanol. 'About 30 cc. of-anhydrous ether reaction vessel such as an ordinary round is added gradually to the methanol solution. The bottomed glass ?ask, with about 40 parts of py ‘product, piperazine estradiol-3-monosulfate, pre- ' ridine. Dimethylaniline may be substituted for ' cipitates as light tan crystals, melting point is ' the pyridine. ‘The mixture is heated, with stir 65 188° C,‘ or y 2,642,427 4 Example III This application is a continuation-impart of my copending application Serial No. 103,968, ?led Piperazine estradiol-B-monosulfate may also be July.9, 1949, now abandoned, entitled “Thera prepared by the hydrogenation of piperazine peutic Compounds.” estrone sulfate as follows; Others may readily adapt the invention for use A solution‘ of 0.9 gm. of piperazine estrous-3 under various conditions of service, by employing monosulfate and 0.750 gm. of piperazine hexa one or more of the novel features disclosed or hydrate dissolved in '70 cc. of methanol is hydro ‘ equivalents thereof. As at present advised with genated at 20 lbs. hydrogen pressure in the pres- ‘ ence of 0.15 gm. of prehydrogenatedeplatinmn ox respect to the apparent scope of my invention, ide catalyst. After the hydrogen adsorption-‘is 10 , I ,de'sireto claim the -f ollowing subject matter. complete, the catalyst is removed "by ?ltration, 1 Iclaim: . ' and the ?ltrate is concentrated under reduced 1. A therapeutic compound selected from the pressure until crystallization starts. ~About ‘10 group‘ consisting of piperazine estrone-3-mono volumes of anhydrous ether is then'slowl'y added . sulfate; Ipiperazine estradiol-3 -monosulfate, pi to complete the crystallization. The resulting 15 perazine- equilin-S-monosulfate and piperazine piperazine estradiol-3-monosulfate, is recovered equilenin-B-monosulfate. by ?ltration, washed with ether and dried; 2.’ Piperazine estrone-B-monosulfate. 3. Piperazine estradiol-3-monosuliate. Example IV 4. wPiperazine equilin-{i-monosulfate. To a solution of 0.500 gm. of piperazine hexa 20 5. Piperazine equileniii-S-monosulfate. hydrate in 5 cc. ofmethanol is added‘ 0.200 gm. 6. The process which comprises reactinga salt of ammonium equilin-B-monosulfate‘. The mix of a member of, the group-consisting of estrone ture, is warmed gently to e?ect solution and then B-monosulfate, estradiol-3-monosulfate, equilin concentrated to dryness in vacuum. The residue 3-monosulfate and equilenin-3-monosulfate with is extracted with 10 cc. of methanol at 40-50“ 25 piperazine. for about one hour, and then ?ltered. ‘The ?l 7. The process which comprises, reacting am trate is treated with about 30 cc. of ether, added , monium estrone-3-monosulfate with piperazine gradually. The product, piperazine equilin-3 to produce piperazine estrone-3-monosulfate. monosulfate, precipitates as a light tan powder. 8. The process ‘which comprises, reacting am monium estradiol-B-monosulfate with piperazine Example ‘V to produce piperazine estradiol-3-monosulfate. To a solution of 0.600 gm._ piperazine hexa 9. The process which comprises, reacting am hydrate in 5 cc. of methanol is'added 0.225 gm. monium equilin-3-monosulfate with piperazine to of ammonium equilenin-Ii - monosulfate. ‘ The produce piperazine equilin-B-monosulfate. mixture is warmed gently to cause solution to 10. The process which comprises, reacting am take place. It is then concentrated to dryness in monium equilenin-3-monosulfate with piperazine vacuum. The residue is stirred with about 10 to produce piperazine equilenin-3-monosulfate. cc. of methanol for about an hour and then ?l RICHARD B. HASBROUCK. tered. To the ?ltrate is added gradually about 30 cc. of ether. The product, piperazine equilenin 40 References Cited in the ?le of _ this patent 3-monosulfate, precipitates as nearly white, small Butenandt, Zeit. Physiol. Chem. 259, pp. 222' crystals. ‘ 234 (1939). '