United States Patent Office Patented June 20, 1967

3,326,758 United States Patent Office Patented June 20, 1967

1. 2 3,326,758 Ro represents any of methyl, ethyl, or isopropyl; CHOLESTEROL DERVATIVES n is 0, 1, 2 or 3; Klaus Irmscher, Darmstadt, Klaus Brickner, Darmstadt n2 is 0, 1 or 2; and Eberstadt, Josef Krämer, Darmstadt, Karl-Heinz Bork, n3 is 2 or 3; Griesheim, near Darmstadt, Rudolf Watzel, Nieder Ramstadt-Trautheim, and Hans-Otto Voge, Ober and where a double bond can occur in the 5-position. Ramstadt, Germany, assignors to E. Merck Aktienge The new compounds can be produced in various ways. sellschaft, Darmstadt, Germany For example, conventional hydrogenation techniques can No Drawing. Filed Mar. 23, 1964, Ser. No. 354,158 be employed starting with steroids of the above formula Claims priority, application Germany, Mar. 21, 1963, having a chlorine atom or a free or functionally altered M 56,198; Apr. 1, 1963, M 56,329 O hydroxyl group in the 3-position, and in the R1 residue 18 Claims. (CI. 167-65) next to an NH- group, a CO- or CS - group, or in This invention relates to cholesterol derivatives and par place of a -CH-NH- or >CH-NH- group a ticularly to those derivatives having a therapeutic activity. -CHFN- or >CFN group. Alternatively, in a steroid It has been found that certain cholesterol derivatives 5 of Formula I, wherein R1 has in place of the isoalkylamino Substituted by nitrogen and/or oxygen in the side chain group, an aryl-CHFN-group, the latter can be con attached to the 17-position, have a retarding effect on the verted into the desired isoalkylamino group by treatment physiological synthesis of cholesterol. These compounds with a corresponding isoalkylhalide and subsequent hy are also physiologically compatible, and are therefore drolysis. It is additionally possible in the corresponding suitable for the treatment of hypercholesteremia. 20 primary steroid amine or isoalkyl amine to introduce the The new compounds are of the following formula: missing isoalkyl- or steroid-residue by known alkylating methods. It is also possible in a corresponding steroid of Formula I whose residue R1 has an N-isoalkyl-N-acyl amino group (where acyl designates the acid residue of 25 a carboxylic or sulfonic acid), in place of an isoalkyl amino group, to liberate the isoalkyl amino group by the usual hydrolytic or alcoholytic methods. Those cholesterol derivatives which have oxygen-con taining side chains in the 17-position can be produced, O 30 e.g. by the usual etherizing methods. For example, a com pound of Formula I which in the 3-position has a chlorine and its 5-dehydro derivatives and its acid-addition salts atom or a functionally altered hydroxyl group and in the wherein: 17, 20, 22 or 23-position has an alcoholic group, can R represents any of halo, preferably chloro, hydroxy-O- be etherized with the corresponding alcohol of the for alkyl of 1-4 carbon atoms or O-acyl having 1-18 car 35 mula (CH3)2-CH-(CH2)n-OH or bon atoms, R represents any of Rs O (CH3)2-CH-O-(CH2)2-OH, where R3, R6 and 23 have the previously indicated meanings. This etherization 40 is preferably performed in the presence of a condensation having a total of 6 to 10 carbon atoms, agent such as an alcoholate producer or a dehydrating Ca agent. Instead of the alcohol, a reactive ester of such alcohol can sometimes be used for the etherization. Fur thermore, a steroid of Formula I which has a carbonyl having a total of 6 or 7 carbon atoms, 45 or thiocarbonyl group next to an oxygen atom in a side chain can be reduced by treatment with a borane. pH, The teritary amines of Formula I (where R3 is methyl -N-(CH2)-Rs or ethyl) can be produced from the corresponding sec ondary amines by introducing the missing radical by the pH, i. 50 usual alkylating method, if necessary with intermediate -N-(CH2)-N-CH-(CH3)2 blocking of a hydroxyl group in the 3-position of the pH, steroid, or by converting a carbonyl or thiocarbonyl -N-(CH2)-O-CH-(CH3) group, in the residue R1 of a steroid of Formula I next to a nitrogen atom into a methylene group by the usual -O-(CH2)n-CH-(CH3)2 hydrogenation process. i. In a steroid which has been produced by one of the -O-(CH2)-N-Rs methods described above, a functionally modified hy having a total of 4 to 7 carbon atoms, or droxyl group in the 3-position can, if desired, be set free, and/or a free or functionally altered hydroxyl group in -O-(CH2)2-O-CH-(CH3)2 60 this position can be converted into an O-acyl group with R2 represents any of methyl, ethyl, isopropyl, isobutyl, iso 1 to 18 carbon atoms by the usual acylation process, or pentyl, 1-methyl-propyl, 1-ethyl-propyl, 2-methylbutyl, by a conventional chlorination process, can be substituted 2-ethylbutyl; by a chlorine atom and/or by known alkylating methods Ra represents any of hydrogen, methyl or ethyl; can be converted into an O-alkyl group with 1 to 4 car R4 represents any of isopropyl, isobutyl, isopenty or di 65 bon atoms. A double bond in the 5,6-position of the methylaminoethyl; steroid thus produced can, if desired, be hydrogenated by R5 represents any of isopropyl, isobutyl, 1-methylpropyl or known methods, and any of the steroids thus produced 1-ethylpropyl; can be converted into acid-addition salts.

3,326,758 5 6 CH CH3 20-oxa-21,24-bis-nor-cholestane-3,6-ol 22-oxa-cholestane-3,6-ol - H-NH-OH)-off 22-oxa-24-nor-cholestane-3,6-ol YoH, (42) 23-oxa-cholestane-3,6-ol CH3 23-oxa-24-nor-cholestane-3-ol -bH-CH-NH-CH-(C.H.), (43) 24-oxa-cholestane-3,6-ol CH3 CH3 22-aza-24-nor-cholestane-3,6-ol 23-aza-24-nor-cholestane-3,6-ol -b H-CH-NH-off 24-nor-25-aza-cholestane-3,6-ol Yo2Es (44) 10 CH3 As stated previously, the compounds of Formula I -bH-NH-C H-CH-(CH), (45) can be produced by the hydrogenation of those original steroids which have a carbonyl or thiocarbonyl group in CH3 CEI the residue Ri next to a nitrogen atom. The reduction of -: H-NH-C-C such a carbonyl or thiocarbonyl group can be accom CEIs. (46) plished, e.g. wtih lithium aluminum hydride or with a -O-(CH2)3-CH(CH3)2 (47) mixture of boron trifluoride and lithium aluminum hy dride. Suitable solvents for this reaction are ethers such -O-(CH2)2-CH(CIda)2 (48) as tetrahydrofuran, dioxane, diethylene-glycol-diethyl -O-(CH2)-O-CH(CH3) (49) 20 ether or dibutyl ether, possibly in the presence of dry -O-(CH2)3-N(CH3)2 (50) pyridine to facilitate solution. The hydrogenation can also -O-(CH2)9-N(CH3)2 (51) be performed in the presence of catalysts such as plati -O-(CH2) -N (C2H5)2 (52) num oxide, Raney-nickel, Raney-cobalt or nickel-Sulfide/ CH3 molybdenum-sulfide. In this case, suitable solvents are, -O-(CH)--CHCH). (53) 25 e.g. dioxane, alcohol or glacial acetic acid. The carbonyl group can be in blocked form as an imide-chloride group, C25 and in the presence of a palladium or a palladium/bar -O-(CH2) --CHCH), (54) ium-carbonate catalyst can likewise be converted into a CH3 methylene group. For this reduction, use can be made of 30 practically any of the methods which are described in -O-(CH2) -N Houben-Weyl's "Methoden der Organischen Chemie,” C2H5 (55) published by George Thieme, Stuttgart, (1957), vol. XI/I, With respect to R1, the cholesterol and cholestanol de pages 574-600. rivatives of Formula I esterified in the 3-position are pref As a starting material for hydrogenation, use can also erably the formate, acetate, propionate, n-butyrate, iso 35 be made of compounds which instead of a -CH-NH butyrate, n-valerate, isovalerate, trimethylacetate, capro or >CHNH- group, have a -CH=N or >C=N- ate, cyclopentyl carbonate, oenanthate, caprylate, pelar group. Such Schiff bases can, e.g. by the use of a complex gonate, caprate, laurate, myristate, palmitate, Stearate, metal hydride such as lithium-aluminum hydride or so undecylenate, oleate, cyclopenty1 acetate, cyclopentyl dium-boron hydride be converted into secondary amino propionate, cyclohexyl acetate, cyclohexyl propionate, groups. As a solvent for such hydrogenation, ether, tetra benzoate, substituted benzoates, phenyl acetate, phenyl hydrofuran, dioxane or dibutyl ether can be used. The propionate and nicotinate. On the other hand, compounds reduction can be performed by the use of an alkali met of Formula I with a 3-O-alkyl group are preferably the all or alkali metal amalgam such as, e.g. sodium or so corresponding 3 - methoxy-, 3 - ethoxy-, 3-n-propoxy, 3 dium amalgam in alcohol, or zinc in the presence of isopropoxy-, 3-n-butoxy-, 3-isobutoxy, 3-sec.-butoxy- and alkali. The hydrogenation can also be performed catalyt 3-tert-butoxy-cholesterol or cholestanol derivatives. It is ically in the presence of Raney-nickel, platinum oxide, also preferred for R to be either chloro or hydroxy. palladium-black or nickel/kieselguhr as a catalyst, prefer The preceding preferred specific identities of R1 and R ably in the presence of a suitable solvent such as metha yield preferred compounds of the present invention, it nol, glacial acetic acid, benzene, toluene or decahydro 50 naphthalene. If as a starting material for such a reduc being noted that any R1 can be employed with any R, tion, a steroid of Formula I is selected wherein R is chlo and that a large but finite group of compounds is thus rine, then the conditions for hydrogenation must be such embraced. Consequently, to present a large list of these that the halogen atoms will not be attacked. When a 3 compounds would be merely redundant. chlorosteroid is used as the starting material, it is best In any event, the most highly preferred compounds to avoid acalytic hydrogenation but instead to use com are: plex metal hydrides for hydrogenation. It is generally pos 22-oxa-25-aza-cholesterol sible, however, to use any of the hydrogenation methods 20-oxa-21-nor-25-aza-cholesterol described in Houben-Weyl's loc. cit. on pages 618 to 631 22-aza-cholestane-3,6-ol and 665 to 669. N-ethyl-22-aza-24-nor-cholesterol 60 It is also possible to produce the secondary amines of Formula I by commencing with those steroids which 20-oxa-21,24-bis-nor-25-aza-cholesterol have in the residue R1 an aryl-CH=N group instead N-ethyl-20-oxa-21,26-bis-nor-24-aza-cholesterol of the isoalkyl-amino group. Such initial steroids can be 20-aza-24-nor-cholesterol36-chloro-22-oxa-25-aza-5-cholestene - converted into the desired secondary isoalkyl-amino-ste 65 roids by treatment with a corresponding isoalkylhalide, 20-aza-24-oxa-cholestane-3,6-olN-ethyl-20-oxa-21-nor-24-aza-cholesterol e.g. with isopropyl-, isobutyl-, isoamyl-, Sec.-butyl-, ox 20-aza-24-oxa-cholesterol ethyl-n-propyl-, 2-ethyl-n-butyl- or 2-methyl-n-butyl bromide, -chloride or -iodide. During this reaction there 22-oxa-25-aza-cholestane-3,6-ol will first be a formation of the corresponding quaternary 20-oxa-21-nor-25-aza-cholestane-3,6-ol 70 ammonium salts which produce on hydrolysis besides the 20,24-diaza-cholestane-3,6-ol corresponding aldehyde of Formula aryl-CHO, also the 20-aza-cholestane-3,6-ol desired secondary amine of Formula I. The reaction is 24-aza-cholestane-3,6-ol advantageously performed in the presence of a suitable N-ethyl-26-nor-24-aza-cholestane-3,6-ol solvent, e.g. methanol, ethanol, or in the same alkyl halide 20-oxa-21-nor-cholestane-3,6-ol 75 that is used as a reaction component. The term “aryl' 3,326,758 7 8 is here understood to mean especially a phenyl or tolyl concentrated sulfuric acid. The carboxylic acid amide can residue (see Houben-Weyl, loc. cit., page 108). also be split by alkalies, e.g. by sodium or potassium The secondary amines of Formula I can also be ob hydroxide in aqueous alcoholic solution or in ethylene tained by the usual alkylation of the corresponding glycol or ethylene-glycol-monomethylether as solvents, primary steroids with isoalkylamines, For example, the 5 or can be split alcoholytically, e.g. by a solution of a steroid-amines can be alkylated by reaction with the cor hydrohalide or boron trifluoride in absolute ethanol or responding halide, e.g. with an isopropyl-, isobutyl, iso methanol at boiling temperature of the alcohol. The split amyl-, 1-ethyl-n-propyl-, 1-methyl-n-propyl-, 2-ethyl-n- ting of sulfonic acid amides can be similarly done in an butyl-, or 2-methyl-n-butyl-halide. Alkylation by the re acid or alkaline medium. Sulfonic acid amides can also verse method is also possible, namely by reaction of the O be split effectively with zinc and acid, with sodium in corresponding amines with their respective steroid-alkyl-, liquid ammonia, or with sodium alcoholates. The libera steroid-oxyalkyl- or steroid-methyl-aminoethyl-halide. Ha tion of the secondary amine from acyl-amines can more lides suitable for such alkylations are especially the bro over occur under all reaction conditions as described in mides, chlorides and iodides. The primary amine is Houben-Weyl, loc. cit., pages 98-100 and 926-948. preferably used in excess and for absorbing the hydro The cholesterol derivatives of Formula I which contain halide that is formed, a strong base such as sodium or oxygen or oxygen and nitrogen in the 17-side-chain in potassium hydroxide, potassium carbonate, certain silver stead of carbon atoms can be produced by known meth salts, alkali hydride or alkali amide is added. Neutral salts ods. In each case, the synthesis is commenced either with and ammonium salts can also be added as condensation two alcohols or with one alcohol and a reactive ester of agents, such as lithium bromide or sodium bromide, so 20 the other alcohol. In that manner, the steroid-17-alcohols dium nitrate, ammonium chloride, calcium nitrate, stron can be reacted with their respective isoalkyl- or isoalkoxy tium nitrate or copper salts. It is also advantageous to alkyl- or alkylaminoalkyl-alcohols. Steroid-20-alcohols can add sodium iodide or potassium iodide if an isoalkyl bro be reacted with their respective isoalkyl- or dialkyl-amino mide or isoalkyl chloride is used as the organic halide. In alkyl-alcohols, steroid-22-alcohols with secondary butanol this case, the respective iodides which react more quickly 25 or isopropanol, and steroid-23-alcohols with isopropanol. than the corresponding bromides or chlorides will be In these reactions, one of the alcoholic reaction part formed as intermediaries. As a solvent for such an alkyla ners can be substituted by a reactive ester thereof, e.g. tion, benzene, toluene, petroleum ether, acetone or alcohol a halide such as chloride, bromide or iodide, or a sulfuric can be used. It may also be possible to work without any or sulfonic acid ester such as methane sulfonate or p-tolu added solvent. The required reaction temperatures range 30 ene sulfonate. from -30° C. to -- 160° C. The conditions can vary The etherification is preferably performed in the pres widely (see Houben-Weyl, loc. cit., pages 108-112). ence of a condensing agent. Suitable condensation agents The alkylation can also be performed by reacting the are, e.g. alkali hydroxide, alcoholate producers such as corresponding primary steroid- or isoalkylamine with its alkali metals, alkali hydrides, alkali amides or metal respective carbonyl compound in the presence of a hydro 35 organic compounds such as lithium-methyl. Suitable con genation catalyst. The work is preferably done by dis densation agents also include halide-ion acceptors such solving the primary amine and the carbonyl compound as lead salts or certain silver compounds, e.g. silver oxide, in a suitable solvent and then adding the hydrogenation silver carbonate, silver acetate, silver nitrate, silver per catalyst. Suitable solvents are methanol, ethanol, tetra chlorate or silver fluoroborate. If the work is commenced hydrofuran, dioxane, and benzene. The carbonyl com 40 with two alcohols, the condensation agent is in the form pound can also be added gradually to a mixture of primary of a dehydrating agent such as aluminum oxide, sulfuric amine, hydrogen and hydrogenation catalyst. As hydro acid or one of its acid salts, boric acid, or organic sul genation catalysts for such a reaction, platinum, platinum fonic acids such as p-toluene sulfonic acid. It is advan oxide, palladium-black, Raney-nickel and nickel/kiesel tageous to perform the Teaction in the presence of an guhr should be given special consideration. As carbonyl organic solvent. Suitable solvents are hydrocarbons such compounds corresponding to the respective steroid-amines, as cyclohexane, benzene, toluene or xylene, ethers such as consideration should be given to acetone, isobutyralde tetrahydrofuran and dioxane, also acetonitrile, acetone, hyde, isovaleraldehyde, diethyl ketone, methyl-n-propyl nitromethane, and also liquid ammonia. If the work is ketone, 2-ethyl-n-butyraldehyde and 2-methyl-n-butyral done under dehydrating conditions, then suitable solvents dehyde. The reaction conditions for these special alkyla 50 are those which would permit the water that is formed tions are described in Houben-Weyl, loc. cit., pages 618 during the reaction to be removed by azeotropic distill 639. lation, for which benzene and toluene are well adapted. Another special alkylation process for the production The alcoholate formation can also occur in liquid am of secondary amines of Formula I consists in reacting the monia. The latter can then be removed and the reaction corresponding primary amines with reactive esters. In that 5 5 then performed in the presence of one of the above manner, a primary steroid amine can be reacted with a mentioned solvents with a higher boiling point. suitable ester of the corresponding alcohol, namely of the If a steroid alcohol is used as one of the reaction com isopropanol, isobutanol, isoamyl alcohol, 2-ethyl-n-pro ponents for etherification, then care should be taken that panol, 2-methyl-n-propanol, 2-ethyl-n-butanol or 2-methyl a Walden inversion occurs at the steroid-C-atom which n-butanol. Suitable esters are those of sulfurous acid, phos 60 carries the reactive group, e.g. a halogen atom or a p phorous, acid, phosphoric acid, alkyl- or aryl-sulfonic toluene-sulfonic acid residue. For the production of 20 acids, sulfuric acid or 2,4-dinitrobenzene-sulfonic acid. oxa-compounds, the work is commenced with 17,3-hy In the selection of a solvent, care should be taken to select droxy steriods if a free steroid alcohol is to be reacted one in which both components are soluble. with a reactive ester of another corresponding alcohol. The final products of Formula I can also be produced If, on the other hand, a reactive ester of the steroid alco from those steroids which have in the residue R1 in place hol is used, then the work is commenced with the cor of the isoalkylamino group, an N-isoalkyl-N-acyl-amino responding 17 oz-Steroid. Similarly for the production of group where "acyl” denotes the acid residue of a carbox 22-Oxa-compounds, use is made of 20of-hydroxy-steroids, ylic or sulfonic acid. The acyl group of such an N-iso and also 20,3F-halogen-steroids and 20.3F-hydroxy-steriod alkyl-N-acylamino-steroid can be substituted by hydrogen sulfonic acid esters. by the usual hydrolytic or alcoholytic methods. For the The etherification step can be performed by practical hydrolytic splitting of carboxylic acid amides, the hy ly all the methods described in Houben-Weyl, loc. cit., drolysis can be performed in an acid medium, e.g. with vol. 3, pages 132-169. aqueous hydrohalide acid or with dilute or semi According to this invention, the new compounds can 3,326,758 9 10 also be produced by commencing with steroids cor benzene, toluene, petroleum ether, acetone or alcohol. responding the Formula I, but which have a carbonyl or In some cases the work can be done without solvents. thiocarbonyl group next to an oxygen atom in the side The required reaction temperatures lie between about chain. Such steroid esters can be reduced to the desired -30° C. and -- 160° C. end products by treatment with a borane, preferably di 5 If a reactive ester, e.g. a halide or a p-toluene-sulfonic borane. The borane is generally produced in the reaction acid ester of a steroid alcohol is used for the alkylation, solution itself, in which, e.g. a mixture of borontrifluoride then care should be taken that a Walden inversion will with lithium-aluminum hydride or sodium-boron hydride occur at the steroid-C-atom which carries the reactive is used as the reducing agent. It is, however, possible to group. For the production of 20-aza-compounds, the work conduct the borane into the reaction solution which pre is therefore commenced with the reactive esters of the ferably contains some additional boron trifluoride. The O respective 17a-hydroxy-steroids. reaction is preferably performed in the presence of a The alkylation can also be performed by reacting a solvent, e.g. an ether such as diethylether, tetrahydro corresponding secondary steroid or isoalkylamine with furan, dioxane or dithylene-glycol-dimethyl-ether. The a respective carbonyl compound in the presence of a hy required reaction temperatures lie between -30° C. and drogenation catalyst. The work is preferably done in such --150° C. A hydroxyl group, for instance, in the 3-posi a manner that the secondary amine and the carbonyl tion does not need to be protected in this reaction. compound are dissolved in a suitable solvent and the Obviously, howexer, the work can also be commenced hydrogenation catalyst is then added. Suitable solvents with the corresponding i-steroids or steroids with an acetal for this reaction are especially the lower aliphatic alco group in the 3-position, e.g. a tetrahydro-pyranyl-ether. 20 hols such as methanol and ethanol. Suitable carbonyl All tertiary amines of Formula I can be produced from compounds are, according to the initial steroids, acetone, the respective secondary amines by introducing the miss isobutyraldehyde, isoamylaldehyde, c-methyl or ot-ethyl-n- ing residue by the usual alkylation method, and if neces butyraldehyde, 3-methyl- or b-ethyl-n-valeraldehyde, sary with a preliminary blocking of a hydroxyl group in methyl-ethyl-ketone or diethylketone. This method of alky the 3-position of the residue. For example, a secondary 25 lation can be performed with all the variations previously steroid-amine can be reacted in that manner with an alkyl described where at any time, instead of the halide, the halide which may carry substituents. Suitable for substi corresponding carbonyl compound can be used. tution in the 17-side-chain of the selected initial steroid, Another alkylation process for the production of the the respective halides are used for arriving at the desired desired tertiary amines comprises the reaction of the cor end-product of Formula I. For this purpose, use can be 30 responding secondary steroid-or isoalkylamine with re made, for example, of isopropyl halide, isobutyl halide, active esters other than the halides, namely with esters isoamyl halide, isohexyl halide, 2-(N-methyl-N-isopropyl of sulfurous acid, phosphorous acid, orthophosphoric acid, amino)-ethyl-halide, 2-(N - ethyl- N - isopropylamino)- alkyl- or aryl-sulfonic acid, sulfuric acid, or also the 2,4- ethyl halide, 2-(isopropoxy)-ethyl - halide, 2-ethyl - n dinitrobenzene-sulfonic acid. butyl-halide, 2-methyl-n-butyl-halide, 1-ethyl-n-propyl For the production of the tertiary amines of Formula I, halide, sec.-butyl halide, or 3-ethyl or 3-methyl-n-phenyl it is generally possible to use any of the alkylation methods halide. Substituted secondary 20-, 22-, 23-, 24- and 25 that are described in Houben-Weyl, loc. cit., pages 108 azasteroid corresponding to Formula I can be methylated, 112 and 618-639. while corresponding secondary 22-, 23- and 24-azasteroids The initial steroids can have in their 3-position either can be ethylated. 40 a chlorine atom or a free or functionally modified hy For the production of the tertiary steroidamines-amines droxyl group. The hydroxyl group can, for example, be in of Formula I, it is also possible to proceed alternatively the form of an ester group or as a readily separable ether from the corresponding secondary aliphatic amines and group (like an acetal group), e.g. a tetrahydride-pyranyl to alkylate these with the respective steroid-halides. The ether or an ox-ethoxyethyl-ether group. If the initial steroid selection of the amine is determined by the substituents already present in the 17-side-chain of the steroid-halide. has a 5,6-double bond, then this, together with a 3-hy Amines that would be particularly suitable for producing droxyl group, can exist as an i-steroid grouping. As a the various possible side-chains in Formula I are dimethyl starting material, a 3c,5a-cyclo-6-ol-steroid can therefore amine, diethyl amine, N-isopropyl-N-methyl-amine N be used, in which the hydroxyl group in the 6-position can isopropyl-N-ethyl-amine, N-methyl-N-ethyl-amine, N be likewise esterified or etherized. methyl-N-isobutyl-amine, N-ethyl-N-isobutyl-amine, N 50. In a steroid that has been produced according to this methyl-N-isoamyl-amine, N-ethyl-N-isoamyl-amine, N invention, and which has in the 3-position a functionally methyl-N-isohexyl-amine, N-methyl - N - (3 - isopropyl altered hydroxyl group, the latter can be set free in the amino)-ethyl amine, N-methyl-N-6-(N'-methyl-N'-isopro usual manner, e.g. by hydrolysis which with an ester group pylamino)-ethyl amine, N-methyl-N-6-(N'-ethyl-N'-iso can be either alkaline or acid, but with an ether group propylamino)-ethyl amine, N-methyl-N-6-(isopropoxy 55 or an i-steroid group, is generally only acid. For alkaline ethyl)-amine, N-methyl-N-(y-ethyl-n-pentyl)-amine, N hydrolysis, alkali hydroxides are especially suitable. For methyl-N-(y-methyl-n-pentyl)-amine, N-methyl- or N acid hydrolysis, alcoholic or aqueous-alcoholic mineral ethyl-N-(8-ethyl-n-butyl)-amine, N-methyl- or N-ethyl acids can be used. N-(6-methyl-n-butyl)-amine, N-methyl- or N-ethyl-N-(o- A hydroxyl group in the 3-position of the synthesized ethyl-n-propyl)amine, N-methyl- or N-ethyl-N-sec.-butyl 60 steroid which has been liberated or functionally altered afe. can be converted by known acylation methods into an O For alkylations of this kind, the bromides, chlorides acyl group with 1 to 18 carbon atoms. As steroids with and iodides are generally used as the organic halides. functionally altered 3-hydroxyl groups which are to be The secondary amine is generally used in excess. For 65 esterified, consideration should be given especially to i capturing the hydrogen halide that is liberated, a strong steroids or 3-hydroxy-steroid-sulfonic-acid esters. With base such as sodium or potassium hydroxide, potassium the secondary amines of Formula I, the esterification is carbonate, certain silver salts, alkali hydrides or alkali preferably performed under mild conditions, so that the amides can be added. As condensation agents neutral salts secondary amino group of the side-chain will not also be and ammonium salts are suitable, such as lithium bromide, 70 acylated. For the esterification, the halides and anhydrides sodium bromide, sodium nitrate, ammonium chloride, of the acids here named, or the acids themselves, are calcium nitrate, strontium nitrate or copper salts. If a bro particularly suitable: formic, acetic, propionic, n-butyric, mide or chloride has been introduced, the reaction can isobutyric n-valeric, iso-valeric, trimethylacetic, caproic, be accelerated by the addition of sodium iodide or po cyclopentylcarboxylic, oenanthic, caprylic, pelargonic, tassium iodide. As solvents, use can be made, e.g. of 75 capric, lauric, myristic, palmitic, stearic, undecylenic, oleic, 3,326,758 2 cyclopentyl-acetic, cyclopentylpropionic, cyclohexylacetic, chain-lengthening according to Arndt-Eistert method with cyclohexylpropionic, benzoic, substituted benzoic, phenyl subsequent reduction. acetic, phenyl-propionic and nicotinic acid. The reactive esters of the steroid alcohols are prefer A hydroxy group which is present or has been set ably produced from the alcohols themselves, during which free in the 3-position of a synthesized steroid can be a Walden inversion occurs with hydrohalide acids, so converted by the usual acylation methods into an O-alkyl that 176-hydroxy-steroids give 17 oz-halogen-steroids and group with 1 to 4 carbon atoms. Such etherification or 200-hydroxy-steroids give 20,3F-halogen steroids. In the alkylation is accomplished by the usual methods. As Suit case of sulfur-containing esters it is necessary to begin able etherifying agents, methyl-, ethyl-, n-propyl-, iso with the 17a-hydroxy- or 20,3-hydroxy-steroids, which can propyl-, n-butyl-, sec.-butyl-, iso-butyl- or tert-butyl-bro O be obtained by hydrolysis of the sulfonic acid esters of mide, -chloride or -iodide are preferred. For the etherifi their epimers. The 206F-steroid-alcohols can also be ob cation, a corresponding alkanol with 1 to 4 carbon atoms tained from the corresponding 20-keto-steroids by re can also be used by condensing it with the appropriate 3 duction with complex metal hydrides. chloro-steroid, or under dehydrating conditions with the The production of secondary 20-aza-cholesterol-or corresponding 3-hydroxy-steroid. Instead of a 3-hydroxy -nor-cholesterol-derivatives for use as a starting material steroid, a steroid with a functionally altered 3-hydroxy can be accomplished by condensation of a correspond group can also be used. For example, a 3-hydroxy-ster ing primary amine with a 17-keto-steroid and reduction of oid-sulfonic-acid-ester or an i-steroid; hence a 30,50-cyclo the resulting Schiff base with a complex metal hydride to 6-ol-steroid or a 30,5a cyclo-6-alkoxy-steroid can be used. 20-aza-21-nor-cholesterol derivatives (J. Med. Pharma As a solvent, use can be made of the alcoholic reaction 20 ceut. Chem., vol. 5 (1962), page 1224). It is also possible component itself. Sometimes it is also advantageous to to commence with a 1713-methylamino-steroid (produced use a condensing agent such as an alcoholate former, or a from a 17-keto-steroid with methylamine and subsequent catalyst such as p-toluene-Sulfonic acid. reduction of the 17 (20)-double-bond by a process similar In the synthetically produced steroid of Formula I, to that of the Belgian Patent 586,621), which is convert a free or functionally altered hydroxyl group can also 25 ed into the acid-amide by chloro-acetamide, is then alky be substituted by a chlorine atom by the usual chlorina lated, and is reduced by a complex metal hydride whereby tion methods. For such chlorination, use can be made of substituted 17.6-methyl-amino-steroids are obtained. hydrochloric acid, thionyl chloride, or phosphorus penta The secondary 23-aza-steroids of the cholesterol and chloride. The 3-hydroxy-steroids can also be converted nor-cholesterol series which are used as starting materials into the chloroformates and the latter then decomposed 30 are obtained by alkylation of the corresponding bis-nor thermally into the 3-chloro-steroids. In another method cholenic-acid-chlorides (Med. u. Chem., vol. 4 (1942), for the production of the 3-chloro-steroids, the correspond 327; cited from Zentralblatt, vol. 1943, 2689, and Chem ing i-steroids, that is the i-steroid-6-ethers, can be em ical Abstracts, 1944, 4954) with the required primary ployed as starting materials by reacting them with hydro amines and reduction of the resulting acid amines with a chloric acid or acetyl chloride. Also, from the steroid-3- complex metal hydride. ethers of the steroid-3-sulfonic acid esters, the respective Starting compounds with a secondary nitrogen atom in steroid-3-chlorine compounds can be obtained by treat position 24 of the cholesterol or nor-cholesterol side ment with hydrochloric acid or a chloride. The reaction chain can be produced by reaction of 20-keto-compounds is preferably performed in the presence of a suitable sol with cyano-acetic ester (J. Chem. Soc., 1952, p. 161), fol vent such as benzene, dioxane or pyridine. 40 lowed by partial hydrogenation of the 20(22)-double If a steroid of this invention contains a double bond bond (see Helv. Chim. Acta, 1962, page 1939), saponi in the 5,6-position, the latter can be hydrogenated by the fication and decarboxylation and reduction of the cyano usual methods, preferably in the presence of noble metal group to a primary amino group. The latter can then be catalysts such as finely divided palladium or platinum ox converted into the corresponding secondary amine by ide. For use as solvents, the lower carboxylic acids such 45 known alkylation methods, or the cyano group can be as acetic acid, or esters such as methyl or ethyl acetate converted into the acid amide by treatment with hydro are suitable. gen peroxide, and is then mono-alkylated and converted Those end-products of this invention which in the side into the corresponding secondary amine by treatment with chain contain a nitrogen atom can be converted into acid lithium-aluminum-hydride. addition salts by treatment with an acid in the usual man 50 For the production of such starting materials of the ner. For this conversion, use should be made of those cholesterol or nor-cholesterol series which have a second acids whose salts are not physiologically dangerous. They ary nitrogen atom in position 22, the work is advantage can be either organic or inorganic acids, such as aliphatic, ously commenced with 20c -amino-pregnane derivatives alicyclic, araliphatic, aromatic or heterocyclic mono- or (J. Am. Chem. Soc., 1948, page 888 and 1960, page polyvalent carboxylic or sulfonic acids, e.g. formic, acetic, 55 5688), which are converted into the corresponding acyl propionic, diethylacetic, oxalic, malonic, succinic, pimeli compounds and are then reduced by lithium-aluminum nic, fumaric, maleic, lactic, aminocarboxylic, sulfaminic, hydride to the secondary amines. benzoic, phenylpropionic, citric, ascorbic, isonicotinic, sul The starting compounds with the side-chains furic, hydrohalide such as hydrochloric or hydrobromic, or phosphorus-containing such as orthophosphoric acid. 60 The 176-steroid-alcohols which are required as start ing materials can be obtained from the corresponding 17-keto-steroids by catalytic hydrogenation with Raney nickel in alcoholic solution or by reduction with complex metal hydrides, while the 20of-steroid-alcohols can be ob tained from the 20-keto-steroids by reduction with sodium in alcohol or by catalytic hydrogenation with Raney can be produced as follows: The work is commenced nickel in alcoholic solution, whereby the separation of the with 5-androstene-3,6-ol-17-one or 5-pregnene-3,6-ol-20 206F-isomers is accomplished by chromatography and/or one or derivatives thereof which are saturated in the 5,6- crystallization. The 22-steroid-alcohols can be obtained 70 position. The 3(3-hydroxyl group is protected by the for from A-sterols, as e.g. stigmasterol, by the action of mation of the tetrahydro-pyranyl-ether or ox-ethoxy-ethyl ozone and subsequent reduction, wherein the 5-double ether. The keto group in the 17- or 20- position is then bond is protected, if necessary by the addition of a halo converted into a hydroxyl group by a complex metal gen or hydrohalide to form an intermediate. The 23-ste hydride, an alkali metal in alcohol, or by hydrogen in alco roid-alcohols can be obtained, e.g. from the 22-acids by 75 holic solvents in the presence of Raney-nickel. The 17- or 3,326,758 13 4. 20-alcohols thus obtained, which are protected in the 3 to the reaction mixture which then is thoroughly shaken. position, are converted by the required w-halogen-car The ethereal layer is separated and the aqueous layer boxylic acid ester into compounds with a side-chain is extracted with ether. The combined extracts are washed -O-(CH2)COOR and dried over sodium sulfate. The amine is precipitated by addition of gaseous HCl and filtered off. The pre (where n=1 or 2 and R is a hydrocarbon radical), which cipitate is dissolved in methanol. The thus obtained solu are then converted by the required primary amine into tion is made strongly alkaline by addition of 1 N-sodium acid amines with a side-chain hydroxide and poured into 1 liter water. The precipitated 22-aza-cholesterol is recrystallized from methanol. M.P. (wherein R=H, CH, CH5 or CH (CH3)2 and n=1. 10 133-139 C., oil?3 -20° (chloroform). or 2). These are then reduced to secondary amines by In analogy the following compounds may be prepared: lithium-aluminum hydride. 22-aza-24 - ethyl-27 - norcholesterol from 20-(2?-ethyl)- The steroid-amines or thio-amines which are required butylimino-5-pregnene-3,6-ol, and as starting materials can be produced by reacting the re 22-aza-24-methyl-27-norcholesterol from 2013-(2-methyl)- spective steroid esters with the corresponding aliphatic 15 butylimino-5-pregnene-3,6-ol. amines. The steroid-thioamides can also be obtained by coupling the corresponding metal-organic compounds to EXAMPLE 2 their respective isothiocyan-acid-esters. The Schiff bases 23-aza-cholesterol which can also be used as starting materials are obtain 20 2 g. 36-hydroxybisnor-cholenic-acid-isobutylamide are able from the parent steroid-keto-compounds and the dissolved in 70 ml. anhydrous dioxane and added to a respective aliphatic amines. Comounds of Formula I in suspension of 1.0 g. lithium aluminum hydride in 35 ml. which R contains an aryl-CH=N-group instead of the anhydrous dioxane. The mixture is refluxed for 18 hours, isoalkylamino group can be obtained by reacting the cor then the excess of the hydride is destroyed by addition responding primary steroid-amines with an aromatic alde 25 of aqueous dioxane. The solution is heated with 0.8 ml. hyde, e.g. benzaldehyde. The primary steroid-amines of 20% sodium hydroxide. After addition of some water, which are used for the alkylation reactions can be ob the precipitated salts are filtered off in the hot and washed tained by reduction of the corresponding steroid-oximes, with dioxane. The crude 23-aza-cholesterol is isolated nitriles or mono-substituted steroid-carboxylic acid from the organic layer, dissolved in methanol and pre amides. Starting materials of Formula I in which R1 has 30 cipitated with ethereal hydrogen chloride. The free base an N-acyl-isoalkylamino group can be produced by alkyla may be obtained by addition of 1 N-sodium hydroxide tion of the parent N-acylamino compounds. until a strongly alkaline reaction and subsequent addi From the foregoing discussion, it is evident that a tion of water. In analogy the following compounds may large number of novel and unobvious starting materials be obtained. and intermediates are covered by this invention. ... These new compounds are valuable therapeutic agents, 23-aza-24-ethyl-27-nor-cholesterine from 33-hydroxy-bis and can be employed in admixture with the usual phar norcholenic-acid-1'-ethyl propylamide; maceutical carriers. As carriers, there can be used those 23-aza-24-methyl-27-norcholesterine from 36-hydroxy-bis organic and inorganic substances which are suitable for norcholenic-acid-1'-methyl propylamide. parenteral or enteral application and which do not react EXAMPLE 3 with the new compounds, as for example, water, vegeta 40 ble oils, polyethylene glycol, gelatin, lactose, starch, mag 24-aza-chiolesterol nesium stearate, talcum, etc. For enteral application tab A solution of 3 g. 3,3-hydroxy-nor-cholenic-acid-iso lets, dragees or solutions can be used which can be steri propylamide in 100 ml. anhydrous dioxane is added slow lized if necessary or mixed with ancillary materials such ly to a suspension of 1.5 g. LiAlH4 in 50 ml. of anhydrous as preservatives, stabilizers or wetting agents, or with 45 dioxane. The mixture is refluxed for 18 hours. The ex salts for influencing the osmotic pressure, or with buffer cess of the hydride is destroyed by addition of aqueous substances. dioxane. Then it is heated to the boiling point with 1.2 The new compounds are preferably used in oral dosage ml. of 20% sodium hydroxide. After addition of a small units of 2 to 300 mg., but it is also possible to administer amount of water, the precipitate is filtered off in the them parenterally when necessary. 50 hot and washed with dioxane. The combined filtrates are The investigations to evaluate the activity of the new evaporated to dryness. The residue of 24-aza-cholesterol compounds were conducted according to the test method is recrystallized from acetone. as described in Journal med, pharm. Chem, vol. 5, page 1224, 1962. EXAMPLE 4 The substances to be tested were administered ten times 55 22-aza-24-norcholesterol to normally fed rats. The animals were sacrificed after 9.3 g of the benzylidene derivative of 20c -amino-5- 10 days and the cholesterol level in the blood serum was pregnene-3,6-ol are refluxed for 4 hours with 5 ml, iso determined. butylbromide in 150 ml. anhydrous ethanol. After addi Without further elaboration, it is believed that one 60 tion of 15 ml. 5 N-hydrochloric acid the solution is re skilled in the art can, using the preceding description, fluxed for another 15 minutes and then concentrated to utilize the present invention to its fullest extent. The about 50 ml. Upon addition of 50 ml, water it is extracted following preferred specific embodiments are, therefore, with ether and the organic layer is separated. to be construed as merely illustrative, and not limitative The aqueous suspension is treated with 2 N-sodium hy of the remainder of the specification and claims in any droxide until an alkaline reaction. The mixture is allowed way whatsoever. 65 to stand overnight, then the 22-aza-24-norcholesterol is EXAMPLE 1 filtered off and recrystallized from methanol, M.P. 130 22-aza-cholesterol 131 C.; al?? -41 (dioxane). EXAMPLE 5 7 g. 20-isoamyl-imino-5-pregnene-3,6-ol are dissolved 70 in 75 ml. of anhydrous tetrahydrofuran and are added 23-aza-24-norcholesterol slowly to a suspension of 5 g. sodium borohydride in 200 A suspension of 3.1 g. 23 - aza-24 - norcholesterol-N- ml. of anhydrous ether. The mixture is refluxed for 90 acetate in 130 ml. anhydrous methanol which contains minutes. The excess of hydride is destroyed by addition 1.15 g. HCl is refluxed for four hours. The solvent is of aqueous methanol. Sodium potassium tartrate is added 75 evaporated and the residue is dissolved in methanol. The 3,326,758 5 6 obtained solution is made alkaline by addition of 2 N In analogy the following compounds are prepared: NaOH and then poured into water. The precipitate is 23-aza-cholestanol filtered off and recrystallized from methanol. 24-aza-cholestanol EXAMPLE 6 22-aza-24-norcholestanol 5 22-aza-24-ethyl-27-norcholestanol 20,24-diazacholesterol 22-aza-24-methyl-27-norcholestanol A solution of 3 g. 17-(N-methyl-N(3-chloroethyl) 23-aza-24-norcholestanol amino-5-androstene-3,6-ol in 150 ml. ethanol is treated 23-aza-24-ethyl-27-norcholestanol with a fivefold excess of isopropylamine for 16 hours in 23-aza-24-methyl-27-norcholestanol a bomb tube to 100° C. The reaction mixture is concen O 20,24-diaza-cholestanol trated and extracted with ether upon addition of water. 3-chloro-22-aza-cholestane The extract is washed with water and dried over sodium 3-chloro-23-aza-cholestane sulfate. The solvent is evaporated and the residue chro 3-chloro-24-aza-cholestane matographed through silica gel. The 20,24-diazacholes 3-chloro-22-aza-24-norcholestane terol is eluated with chloroform and recrystallized from 3-chloro-23-aza-24-norcholestane methanol. 3-chloro-20,24-diaza-cholestane3-chloro-22-aza-24-ethyl-27-norcholestane EXAMPLE 7 3-chloro-22-aza-24-methyl-27-norcholestane 20-Oxa-21-nor-24-aza-cholesterol 3-chloro-23-aza-24-ethyl-27-norcholestane 5 g. 5 - androstene-3,3 - 176-diol-3-tetrahydropyranyl 20 3-chloro-23-aza-24-methyl2-7-norcholestane ether-17 - (3 - (para-toluene-sulfonyloxy)-ethylether) are EXAMPLE 11 dissolved in 50 ml. dioxane and heated in a bomb tube for five hours to 100° C. with 10 ml. isopropylamine. 22-aza-cholesterol-3-acetate Upon cooling, the mixture is diluted with 500 ml. water 3 g. 20-isoamylimino-5-pregnene-3,6-ol-acetate are dis and extracted with chloroform. The chloroform solution solved in 50 ml. anhydrous tetrahydrofuran and dropped is dried and concentrated. The crude 20-oxa-21-nor-24 slowly to the suspension of 2.2 g. sodium borohydride in aza-cholesterol-3-tetrahydropyranylether is dissolved in 90 ml. anhydrous ether. After having refluxed the mix 100 ml. ethanol and then refluxed for three hours with ture for 90 minutes, the excess of hydride is destroyed 5 ml. concentrated hydrochloric acid. The solution is by addition of aqueous methanol. The reaction mixture is cooled and filtered through a basic ion exchanger. The 30 treated with potassium sodium ?tartrate and extracted with eluate is evaporated whereby the 20-oxa-21-nor-24-aza ether. From the washed and dried ether extracts the 22 cholesterol is obtained. aza-cholesterol-3-acetate is obtained. EXAMPLE 8 In analogy the 22-aza-cholesterol-3-propionate and the esters of 23-aza-cholesterol, 24-aza-cholesterol, 22-aza 38-chloro-20-Oxa-21-nor-24-aza-5-cholestene 24-nor-cholesterol, 23-aza-24-nor-cholesterol, 20-oxa-21 5 g. 20-Oxa-21-nor-24-aza-cholesterol-24-N-acetate are nor-24-aza-cholesterol and the corresponding cholestane heated in a bomb tube for 24 hours to 170° C. with 100 36-ol derivatives are prepared. ml. concentrated HCl. The suspension is made alkaline with sodium hydroxide and extracted with chloroform. EXAMPLE 1.2 The crude 3(3-chloro-20-oxa-21-nor-24-aza-5-cholestene is 40 22-aza-cholesterol-3-propylether purified by chromatography over neutral AlO3. In analogy to Example 11, 2.8 g. 20-isoamylimino-5- In analogy, 3 (3 - chloro-20-oxa-21-nor-24-aza-5-choles pregnene-3,6-ol-propyl ether are reacted with 2 g. sodium tane is obtained. borohydride. The 22-aza-cholesterol-3-propylether is ob EXAMPLE 9 45 tained from aqueous acetone. 36-chloro-22-aza-5-cholestene EXAMPLE 13 1.5 g. of dry CaCO3 and subsequently 30 ml, thionyl 20-oxa-21-nor-25-aza-cholesterol and its hydrochloride chloride are added at 15° C. to a solution of 1.5 g. 22 aza-cholesterol in 60 ml. anhydrous ether. The solution 5 g. 5-androstene-3,6,176-diol-3-tetrahydropyranylether 50 are dissolved in 180 ml. anhydrous xylene and treated is allowed to stand for four hours at room temperature. with 12.2 g. of a 20% suspension of sodium borohydride The solvent is evaporated under reduced pressure and the in paraffin oil, which is diluted with 150 ml. anhydrous residue is chromatographed over basic AlO3, whereby xylene. The mixture is refluxed for 90 minutes under 3,3-chloro-22-aza-5-cholesteneIn analogy the following compounds is obtained. may be prepared: nitrogen. Upon cooling, 12.5 g. ?y-bromopropyl dimethyl 55 ammonium bromide are added slowly with stirring. Then 3-chloro-23-aza-5-cholestene the reaction mixture is refluxed for 150 minutes, cooled 3-chloro-24-aza-5-cholestene and poured into 500 ml. ice water and extracted with chloroform. The extract is washed with water, dried and 3-chloro-22-aza-24-nor-5-cholestene3-chloro-22-aza-24-ethyl-27-nor-5-cholestene evaporated and chromatographed over 150 g. basic Al2O3. 3-chloro-22-aza-24-methyl-27-nor-5-cholestene 60 The 20 - oxa-21-nor-25-aza-cholesterol-3-tetrahydropyra 3-chloro-23-aza-24-nor-5-cholestene nylether is eluated with benzene and recrystallized from 3-chloro-23-aza-24-ethyl-27-nor-5-cholestene acetone, M.P. 66-71 C.; or 24-38 (chloroform). 3-chloro-23-aza-24-methyl-27-nor-5-cholestene 5 g. 20 - oxa - 21 - nor-25-aza-cholesterol-3-tetrahydro 3-chloro-22,24-diaza-5-cholestene pyranylether are refluxed with 100 ml. 5% aqueous alco 65 holic HC1. The mixture is cooled, poured into 500 ml. EXAMPLE 10 water and extracted with 250 ml. chloroform. The extract is washed with water and the latter one combined with 22-aza-cholestane-3,6-ol the aqueous layer. The chloroform extract is evaporated. 2.5g, 22-aza-cholesterol are dissolved in 50 ml. methyl The 20-oxa-21-nor-25-aza-cholesterol-hydrochloride is re acetate and hydrogenated at room temperature in the 70 crystallized from methanol/acetone. M.P. 275-282 C. presence of 250 mg. PtCl2. After addition of the calculated (decomposition). amount of hydrogen the catalyst is filtered off and the The aqueous layers are made alkaline with NaHCO3 filtrate is evaporated to dryness. The 22-aza-cholestanol and extracted once more with chloroform to obtain 20 is rescrystallized from acetone. M.P. 144-145° C., c.22 oxa-21-nor-25-aza-cholesterol, M.P. 149-150° C.; ox? --20 (chloroform). 75 -48 (chloroform). 3,326,758 17 18 The free base may also be obtained from the hydro solution of NaHCO3. The 22-oxa-25-aza-cholesterol is ex chloride when it is filtered over a strongly basic ion ex tracted with chloroform and purified by chromatography changer in methanol. over basic AlOs. M.P. 158-160° C. (acetone). EXAMPLE 14 EXAMPLE 1.8 22-oxa-25-aza-cholesterol Small particles of potassium are added to 30 ml. liquid 22-oxa-cholesterol ammonia until the blue color does no longer disappear. 1 g. 5-pregnene-3,6,20op-diol-3-tetrahydropyranyl ether Then a trace of ferric nitrate and another 500 mg. potas is dissolved in 150 ml. xylene. Subsequently, 10 ml. of the sium are added and the solution is stirred for 30 minutes obtained solution are distilled off. The solution dried in at -70° C. After addition of 5 g. 5-pregnene-36,200 O this manner is added under nitrogen to a suspension of diol-3-tetrahydropyranylether the solution is stirred for 72 mg. sodium hydride in 15 ml. anhydrous xylene and another 30 minutes. The ammonia is evaporated by intro refluxed for one hour with stirring. 2.66 g. isoamyl chlo ducing nitrogen and the residue is dissolved in 15 ml. an ride in 20 ml. xylene are dropped into the boiling solu hydrous dioxane and treated with a solution of 1.8 g. 6 5 tion which is continued to boil for another five hours. chloro-ethyldimethylamine in 5 ml. anhydrous dioxane. After being cooled, 10 ml. water and dilute hydrochloric The mixture is refluxed under nitrogen for 10 hours di acid are added. The solution is extracted with ether, luted with 30 ml. dioxane and evaporated to dryness. washed to neutrality and worked up in the usual way to After having filtered off the formed KCl the crude prod form 22-oxa-cholesterol-3-tetrahydropyranylether. uct is chromatographed over 150 g. basic AlO. The 22 20 To split this ether partially, the obtained compound is oxa-25-aza-cholesterol-3-tetrahydropyranylether is eluated dissolved in dioxane and heated on the steam bath for with benzene. M.P. 102-104°C. (acetone). two hours with 3% of 2 N aqueous solution of oxalic 1.36 g. 22-oxa-25-aza-cholesterol-3-tetrahydropyranyl acid. The reaction mixture is diluted with water and ex ether are refluxed for 3 hours with 27 ml. 5% aqueous tracted with ether whereby the 22-oxa-cholesterol is ob alcoholic HCl (prepared by diluting concentrated hydro 25 tained. chloric acid with ethanol). After cooling, the solution is In analogy, 5 - androstene-3,6,17(3-diol - 3-(o-ethoxy poured into 100 ml. ice water, made alkaline with 150 ethyl)-ether is reacted with isohexyl chloride and Subse ml. 7% aqueous NaHCO3 and extracted 3 times with quently hydrolyzed to form 20-oxa-21-nor-cholesterol. In 150 ml. chloroform. The combined extracts are washed addition, the following compounds may be obtained in a with water, dried, filtered, and evaporated to dryness. 30 similar manner: The crude 22-oxa-25-aza-cholesterol is recrystallized from acetone. M.P. 157-160° C. (155° sintering); (c.24 -30° N-ethyl-20-oxa-21,26-bisnor-24-aza-cholesterol20,24-dioxa-21-nor-cholesterol (chloroform). N-methyl-20-oxa-21-nor-24-aza-cholesterol fromIn analogy,5a-pregnane-36,20op-diol-3-tetrahydropyranylether, 22-oxa-25-aza-cholestane-3,6-ol is obtained N-ethyl-20-oxa-21-nor-24-aza-cholesterol The intermediate 22-oxa-25-aza-cholestane-3,6-ol-3-tetra hydropyranylether melts at 83-85 (acetone); c.20 EXAMPLE 19 - 160 (chloroform). 23-oxa-cholesterol EXAMPLE 1.5 40 0.5 g. potassium are dissolved with cooling to about 20-oxa-21,24-bisnor-25-aza-cholesterol -70° C. in 300 ml. liquid anhydrous ammonia after ad A solution of 10 ml. boron trifluoride etherate and 800 dition of a trace ferric nitrate. The solution is stirred with mg. 5-androstene-3 (3,176-diol-17-dimethylamino acetate exclusion of moisture until the blue color disappears. in 25 ml. tetrahydrofuran are added slowly under nitro Then a solution of 2 g. 5-bisnorcholene-36,22-diol-3- gen to an ice cooled suspension of 400 mg. LiAlH4 in 25 45 tetrahydropyranyl-ether in 20 ml. dioxane is added drop ml. tetrahydrofuran. The mixture is stirred for one hour wise. After stirring for another 1–2 hours, 1.75 g. isobutyl with ice cooling and then refluxed for one hour. After bromide in 10 ml. dioxane are added and the solution is cooling the ethyl acetate and 50 ml. 2 NHCl are added. stirred for 5-6 hours. The amonia is evaporated and the The solution is made alkaline with NaHCO and extracted solution is poured into ice, acidified and extracted with with chloroform. The obtained 20-oxa-21,24-bisnor-25 50 ether. By working up the reaction mixture in the usual aza-cholesterol is purified by chromatography over basic way, the 23-oxa-cholesterol-3-tetrahydropyranyl ether is Al2O3. M.P. 158-161° C. (acetone); ox4 -52 obtained which may be split according to the method de (chloroform). scribed in Example 18 to form 23-oxa-cholesterol. EXAMPLE 16 In a similar manner, 5-androstene-3,6, 17(3-diol-3- 55 tetrahydropyranylether is reacted with isoamyl bromide 20-aza-24-oxa-cholesterol-3-acetate and hydrolyzed subsequently to form 20-oxa-21,24 3.9 g, 176 (N-methyl-N-6-hydroxyethyl)-amino-5- bisnor-cholesterol. In analogy, the following compounds androstene-3,6-ol-3-acetate, 0.75 g. isopropanol, 2.66 g. may be prepared: para-toluene-sulfonic-acid-monohydrate and 150 ml. an hydrous toluene are refluxed in an apparatus with water 60 20-oxa-21-nor-cholestanol separator. After three hours, 0.45 ml. water have sepa 20-oxa-21,24-bisnor-cholestanol rated. The solution is allowed to cool, washed with aque 20,24-dioxa-21-nor-cholestanol ous NaHCO3 and water, dried with sodium sulfate and 20-oxa-21-nor-25-aza-cholestanol evaporated. The obtained 20 - aza-24-oxa-cholesterol-3- 20-oxa-21-nor-24-aza-cholestanol acetate is purified by chromatography over basic Al2O3. 65 N-ethyl-20-oxa-21,26-bisnor-24-aza-cholestanol20-oxa-21,24-bisnor-25-aza-cholestanol EXAMPLE 17 N-methyl-20-oxa-21-nor-24-aza-cholestanol 22-oxa-25-aza-cholesterol N-ethyl-20-oxa-21-nor-24-aza-cholestanol 22-oxa-cholestanol According to the method described in Example 14, 2 g. 70 22-Oxa-24-nor-cholestanol 3a,5o-cyclo-pregnane-63,20op-diol-6-methyl ether are re 22-Oxa-25-aza-cholestanol acted to form 22-oxa-25-aza-i-cholesterol-6-methyl ether. 23-oxa-cholestanol This 6-methyl ether is dissolved in 30 ml. dioxane and re 23-oxa-24-nor-cholestanol fluxed for one hour with 5 ml. 5% sulfuric acid. The solu 24-oxa-cholestanol tion is allowed to cool and made alkaline with an aqueous 75 20-aZo-24-oxa-cholestanol 3,326,758 9 20 EXAMPLE 20 20-oxa-21,24-bisnor-25-aza-cholestanolN-ethyl-20-oxa-21,26-bisnor-24-aza-cholestanol 24-oxa-cholesterol N-methyl-20-oxa-21-nor-24-aza-cholestanol 21 g. boron trifluoride etherate and 2 g. 3 (3-hydroxy-A- N-ethyl-20-oxa-21-nor-24-aza-cholestanol nor-cholenic acid isopropyl ester are dissolved in 100 ml. 22-oxa-cholestanol tetrahydrofuran. The solution is added slowly with stir 22-oxa-24-nor-cholestanol ring at 0° C. under nitrogen to a mixture of 0.37 g. 23-oxa-cholestanol sodium borohydride in 25 ml. diethylene glycol dimethyl 23-oxa-24-nor-cholestanol ether. The reaction mixture is allowed to stand for three 24-oxa-cholestanol hours with cooling and then is refluxed for one hour. Up 20-aza-24-oxa-cholestanol on cooling methanol is added to the solution which then 10 3-chloro-20-oxa-21-nor-cholestane is acidified with dilute HC1, and diluted with water. It is 3-chloro-20-oxa-21,24-bisnor-cholestane extracted with ether, washed to neutrality, dried and chro 3chloro-20,24-dioxa-21-nor-cholestane matographed over silica gel. Elution with petroleum ether 3-chloro-20-Oxa-21-nor-25-aza-cholestane yields 24-oxa-cholesterol which is recrystallized. 15 3chloro-20-oxa-21-nor-24-aza-cholestane In a similar way 20,24-dioxa-21-nor-cholesterol is ob 3-chloro-20-oxa-21,24-bisnor-25-aza-cholestane tained by reduction of 5-androstene-3 (3,17f8-diol-17 3-chloro-N-ethyl-20-oxa-21,26-bisnor-24-aza-cholestane (isopropyloxy)-acetate and 20-Oxa-nor-24-aza-cholesterol 3-chloro-N-methyl-20-oxa-21-nor-24-aza-cholestane by reduction of 5-androstene-3 (3,176-diol-17-isopropyla 3-chloro-N-ethyl-20-oxa-21-nor-24-aza-cholestane minoacetate. 20 3-chloro-22-oxa-cholestane 3-chloro-22-oxa-24-nor-cholestane EXAMPLE 21 3-choloro-22-oxa-25-aza-cholestane 22-oxa-24-nor-cholesterol 3-chloro-23-oxa-cholestane 30 g. isobutanol are added dropwise to a boiling solu 3-chloro-23-oxa-24-nor-cholestane tion of 2 g. 5-pregnene-3,6-203F-diol-3-acetate-20-p- 25 3-chloro-24-oxa-cholestane toluene sulfonate in 100 ml. benzene with stirring and 3-chloro-20-aza-24-oxa-cholestane under nitrogen. The mixture is refluxed for 1/2 hours and is diluted with ether after being cooled and washed to EXAMPLE 25 neutrality with aqueous Na2CO3 and water. From the 36-chloro-22-oxa-25-aza-5-cholestene residue of the dry solution 22-oxa-24-nor-cholesterol-3- 30 acetate is obtained which is saponified with methanolic 3 g. 22-oxa-25-aza-cholesterol are dissolved in 120 ml. potassium hydroxide at room temperature to form 22-Oxa ether. 3 g. dry and freshly prepared CaCO3 and 60 ml. 24-nor-cholesterol. thionyl chloride are added with stirring at 15° C. The reaction mixture is allowed to stand for four hours at EXAMPLE 22 35 room temperature and then is evaporated. The residue is 23-oxa-24-nor-cholesterol-3-acetate chromatographed over basic AlO3 to form the pure 3 (3- 2.4 g. sodium hydride are added to a mixture of 6 g. chloro-22-oxa-25-aza-5-cholestene. M.P. 97-98 (ace isopropanol and 200 ml. dry xylene. The suspension is tone); a)20-22 (chloroform). refluxed under nitrogen for one hour. 3.9 g. 3,3-acetoxy In analogy, the following compounds may be pre 22-chloro-A5-bisnorcholen in 50 ml. dry xylene are added 40 pared: with stirring to the boiling mixture which is refluxed for 3-chloro-20-oxa-21-nor-5-cholestene another 7 hours. Upon cooling, methanol and dilute hy 3-chloro-20-oxa-21,24-bisnor-5-chloestene drochloric acid are added until the reaction is slightly 3-chloro-20,24-dioxa-21-nor-5-cholestene acidic. It is worked up in the usual way to form 23-oxa 3-chloro-20-oxa-21-nor-25-aza-5-chloestene 24-nor-cholesterol-3-acetate. 45 3-chloro-20-oxa-21-nor-24-aza-5-cholestene 3-chloro-20-oxa-21,24-bisnor-25-aza-5-cholestene EXAMPLE 23 3-chloro-N-ethyl-20-oxa-21,26-bisnor-24-aza-5-cho 20-oxa-21,24-bisnor-25-aza-cholesterol lestene In accordance with the method described in Example 3-chloro-N-methyl-20-oxa-21-nor-24-aza-5-cholestene 14, 20-oxa-21,24-bisnor-25 - aza-cholesterol - 3-tetrahy 50 3-chloro-N-ethyl-20-oxa-21-nor-24-aza-5-cholestene dropyranyl-ether is obtained from 5-androstene-3,3,17B 3-chloro-22-oxa-5-cholestene diol-3-tetrahydropyranyl ether. M.P. 98-102° C. (ace 3-chloro-22-oxa-24-nor-5-cholestene tone); (c.24 31 (CHC13). This ether is split to form 3-chloro-23-oxa-5-cholestene 20-oxa-21,24-bisnor-25-aza-cholesterol. M.P. 158-161 3-chloro-23-oxa-24-nor-5-cholestene (acetone); (c.24 52 (chloroform). 3-chloro-24-oxa-5-cholestene EXAMPLE 24 3-chloro-20-aza-24-oxa-5-cholestene 22-oxa-25-aza-cholestane-3,6-ol EXAMPLE 26 5 g. 22-oxa-25-aza-cholesterol are dissolved in 100 ml. 60 22-Oxa-25-aza-cholesterol-3-acetate methyl acetate and hydrogenated in the presence of 500 ml. PtC). When the calculated amount of hydrogen has 1 g. 22-Oxa-25-aza-cholesterol is refluxed with 10 ml. been absorbed, the catlyst is filtered off and the filtrate acetic acid anhydride and 10 ml. pyridine for 2 hours. evaporated to dryness. The obtained 22-oxa-25-aza-cho The mixture is evaporated to dryness and the residue lestane-38-ol is recrystallized from acetone. Double M.P. 65 is worked up in the usual way with chloroform and water 135-136 and 144-145; (c) 20 +34 (chloroform). to form 22-oxa-25-aza-cholesterol-3-acetate. In analogy the 20-oxa-21-nor-25-aza-cholestanol, M.P. 137-138; a 20 --8 (chloroform), is obtained from EXAMPLE 27 20-Oxa-21-nor-25-aza-cholesterol. 22-oxa-25-aza-cholesterol-3-methyl ether In analogy the following compounds may be prepared: 70 2 g. 22-Oxa-25-aza-cholesterol are reacted with tosyl 20-oxa-21-nor-cholestanol chloride to form the corresponding 3-p-toluene sulfonic 20-oxa-21,24-bisnor-cholestanol acid ester. The ester is refluxed in 30 ml. methanol for 20,24-dioxa-21-nor-cholestanol 45 minutes and then worked up in the usual way to 20-oxa-21-nor-24-aza-cholestanol 75 form 22-Oxa-25-aza-cholesterol-3-methyl-ether. 3,826,758 21 If instead of methanol ethanol, isopropanol, n, iso- or 22 tert-butanol is used, the corresponding 3-ethyl-, 3-pro 104-107 (acetone); c.120 -34 (chloroform). Acid pyl-, or 3-butyl ether is obtained. hydrolysis yields N-ethyl-20-oxa-21-nor-24-aza-choles All compounds which may be prepared corresponding terol. M.P. 87-89° C. (acetone); ox20 - 45° (chloro to the present invention having a hydroxy group in the form). 3-position may be etherified in this way. It has to be EXAMPLE 33 noted, however, that in the case of secondary amines N-methyl-20-oxa-21-nor-24-aza-cholesterol the p-toluene sulfonic acid ester has to be prepared under In accordance with Example 14, 5-androstene-3,6,176 acidic reaction conditions. diol-3-tetrahydropyranyl-ether is reacted with 6-(methyl EXAMPLE 28 0. isopropyl-amino)-ethyl bromide to form N-methyl-20 oXa-21-nor-24-aza-cholesterol - 3-tetrahydropyranyl-ether. 20-oxa-21-nor-25-aza-cholestanol M.P. 131-133° C. (acetone); ox20 -36 (chloroform). In accordance with the method decribed in Example Acid hydrolysis yields N-methyl-20-oxa-21-nor-24-aza 13, 20-oxa-21-nor-25-aza-cholesterol-3-tetrahydropyranyl cholesterol. M.P. 117-119 (acetone); or 20 -51 ether is obtained by reaction of androstane 3,3,176-diol 5 (chloroform). 3-tetrahydropyranyl-ether with y-bromopropyl dimethyl EXAMPLE 34. ammonium bromide. M.P. 63-65 (acetone); a)20 - 4.4 (chloroform). Hydrolysis yields 20-oxa-21-nor-25 20-aza-24-nor-cholesterol-propionate aza-cholestanol. M.P. 137-138 (acetone); ox20 --8 (chloroform). 20 The solution of 7 g. 5 - androstene - 36-ol-17-on-3-pro In analogy, the following compounds may be prepared: pionate in 100 ml. benzene and 30 ml. isoamyl amine is distilled azeotropically after addition of 1. g. p-toluene 20-oxa-21,24-bisnor-25-aza-cholestane-3,6-ol sulfonic acid. After four hours, the mixture is washed to 22-oxa-25-aza-cholestane-3,6-ol neutrality with water and the dried benzene solution is N-ethyl-20-oxa-21,27-bis-nor-24-aza-cholestane-3,6-ol 25 concentrated. The crude crystallized 17-(3'-methyl)- EXAMPLE 29 butylamino-5-androstene-3,6-ol-propionate is dissolved in 200 ml. anhydrous tetrahydrofuran. The solution is added 20-aza-24-oxa-cholestanol dropwise to a boiling suspension of 5 g. NaBH4 in 200 ml. 20-aza-24-oxa-cholesterol anhydrous ether. The reaction mixture is refluxed for an In accordance with the method described in Example 30 other 2 hours, then the excess of the hydride is destroyed by addition of methanol and water. 14 g. sodium potassium 176-(N-methyl16,20-aza-24-oxa-cholestanol-3-acetate - N - B - hydroxyethyl)-aminol-andro is obtained from tartrate are added and the separated aqueous layer is ex stane-3,6-ol-3-acetate. M.P. 65-69 C. (acetone). tracted with ether. From the extracts, the 20-aza-21,24 By saponification with 5% methanolic potassium hy bisnor-cholesterol-propionate is obtained by evaporation. droxide, the 20-aza-24-oxa-cholestane-3,6-ol is obtained 35 1.9 g. 20-aza-21,24-bisnor-cholesterol-propionate, 2.4 g. which is purified by recrystallization from petroleum 90% formic acid and 2 g. 35% aqueous formaldehyde ether, M.P. 101-104° C. are heated on a steam bath for 18 hours. The reaction mix In a similar manner, the 20-aza-24-oxa-cholesterol-3- ture is diluted with water, acidified with hydrochloric acid acetate is obtained. According to Example 16, it is con to pH 3 and extracted with ether. The aqueous layer is verted into 20-aza-24-oxa-cholesterol by saponification 40 made alkaline with NaOH and the separated 20-aza-24 with methanolic KOH. The crude product recrystallizes nor-cholesterol-propionate is filtered off and recrystallized from petroleum ether. M.P. 87-89 C.; a)2 -59 from petroleum ether. (chloroform). To obtain the corresponding hydrochloride, 0.1 g, of EXAMPLE 30 the base thus obtained are dissolved in methanol and this 45 solution is treated with an excess of ethereal hydrochloric 36-chloro-20-aza-24-oxa-5-cholestene acid. The separating salt recrystallizes from methanol. 3 g. 20-aza-24-oxa-cholesterol are dissolved in 120 ml. ether and reacted with 3 g. dry CaCO3 and 16 ml. thionyl EXAMPLE 35 chloride at 15° C. with stirring. The reaction mixture is allowed to stand for four hours at room temperature. 50 20-aza-24-nor-cholestane-butyrate Then the solvent is evaporated under reduced pressure. The residue is chromatographed over basic AlO3. The In analogy to Example 34, 20-aza-24-nor-cholestane obtained product is dissolved in ethereal hydrochloric acid butyrate.butyrate is obtained from androstane - 36 - ol - 17 - on and recrystallized from chloroform/ether. The 33-chloro 20-aza-24-oxa-5-cholestene melts at 239-240° C.; oz)20 55 EXAMPLE 36 -33 (chloroform). 20-aza-cholesterol EXAMPLE 31 2.5 g. 20-aza-21-nor-cholesterol are heated overnight on N-ethyl-20-oxa-21,26-bisnor-24-aza-cholesterol the steam bath with 3.1 g. 90% formic acid and 2.6 g. 60 35% aqueous formaldehyde. The reaction mixture is In accordance with Example 14, 5-androstene-3,3,176 filtered with water, acidified with hydrochloric acid and diol-3-tetrahydropyranyl ether is reacted with (8-chloro extracted with small amounts of ether. The aqueous layer ethyl diethyl amine to form N-ethyl-20-oxa-21,26-bisnor is made alkaline with NaOH and the separated 20-aza 24-aza-cholesterol-3-tetrahydropyranyl-ether. M.P. 100 cholesterol is filtered off, dried, and recrystallized from 103 C. (acetone); oz)? -29 (chloroform). Acid hy 65 acetOne. drolysis yields N-ethyl-20-oxa-21,26-bisnor-24-aza-cho In analogy, N-methyl-22-aza-cholestanol hydrochloride, lesterol. M.P. 100-103 (acetone); c.20 -51 (chloro M.P. 263 (decomposition, from ether) and 20-aza-24 form). nor-cholesterol-hydrochloride, M.P. 251-252 (decom EXAMPLE 32 position, methanol/acetone) are prepared. N-ethyl-20-oxa-21-nor-24-aza-cholesterol 70 In a similar manner, N-methyl-22-aza-cholesterol is obtained from 22 - aza - cholesterol, N-methyl - 23 - aza In accordance with Example 14, 5-androestene-3,6,17B cholesterol is obtained from 23-aza-cholesterol, N-methyl diol-3-tetrahydropyranyl-ether is reacted with 6-(ethyl 24-aza-cholesterol is obtained from 24-aza-cholesterol, and isopropyl-amino)-ethyl chloride to form N-ethyl-20-oxa N-methyl-20,24-diaza-cholesterol is obtained from 20,24 21-nor-24-aza-cholesterol-3-tetrayhdropyranyl-ether, M.P. 75 diaza-cholesterol. 3,326,758 23. 24 EXAMPLE 37 EXAMPLE 41 N-methyl-20-Oxa-21-nor-24-aza-cholesterol 20-aza-cholestanol 2.5 g. 20-aza-cholesterol are hydrogenated in a solution In accordance with the method described in Example of 60 ml. methyl acetate in the presence of 0.25 g. PtCl2. 36, 7.2 g. 20-oxa-21-nor-24-aza-cholesterol are reacted to 5 When the reaction is terminated, the catalyst is filtered off form N-methyl-20-oxa-21-nor-24-aza-cholesterol. M.P. and the filtrate is evaporated to dryness. The 20-aza 117-119 C. (acetone); ox20 -51 (chloroform). cholestane-3-3-ol is recrystallized from acetone. EXAMPLE 38 EXAMPLE 42 20-aza-24-oxa-cholesterol and its hydrochloride O 6.5 g. 176-N-methylamino-5-androstene-3,6-ol are dis 20-aza-24-Oxa-cholestane-3,6-ol solved in 40 ml. anhydrous benzene and 4.2 g. triethyl According to the method described in Example 24, 20 amine. 11.3 g. isopropoxy acetylchloride in 10 ml. an aza-24-oxa-cholestane-3,6-ol is obtained by hydrogenation hydrous benzene are added dropwise with ice cooling. of 20-aza-24-oxa-cholesterol at 62° C. and a pressure of The mixture is heated for 2 hours on the steam bath, 6 atm. M.P. 101-104 (petroleum ether). cooled and poured into 500 ml. 5% aqueous NaHCO3 EXAMPLE 43 and extracted with chloroform. The extract is washed with water, dried and evaporated. The crude product is chro 3{3-chloro-20-aza-5-cholestene matographed in benzene over 170 g. silica gel. The 176 30 ml. thionyl chloride are added dropwise at about 15 N - methyl - amino - 5 - androstene - 36 - ol - 3,17-di 20 C. to a mixture of 1.5 g. 20-aza-cholesterol in 60 ml. ether (isopropoxy)-acetate is eluated with benzol/chloro and 1.5 g. dry CaCO3. The mixture is allowed to stand form 7:3 and 1:1 and is recrystallized from acetone, M.P. for 5 hours at room temperature and then is evaporated. 124-126; ox24 - 102 (chloroform). The residue is chromatographed over basic Al2O3 where 3. g. of this ester are dissolved in 45 ml. anhydrous by 36-chloro-20-aza-5-cholestene is obtained. ether and dropped with ice cooling into a suspension of 25 In analogy the following compounds may be prepared 700 mg. LiAlH4 in 30 ml. anhydrous ether. The mixture is refluxed for 3 hours and the excess of hydride is then 36-chloro-20-oxa-21-nor-25-aza-5-cholestene decomposed by addition of 10 m. water. It is poured 36-chloro-20-oxa-21,24-bisnor-25-aza-5-cholestene36-chloro-N-ethyl-20-oxa-21,27-bisnor-24-aza-5- into 60 ml. 20% NaOH and extracted with ether. By working it up in the usual way, the 20-aza-24-Oxa-choles 30 36-chloro-N-methyl-20-Oxa-21-nor-24-aza-5-cholestenecholestene terol is obtained M.P. 87-89° C.;c.22 -59 (choro 36-chloro-N-ethyl-20-oxa-21-nor-24-aza-5-cholestene form).To prepare the corresponding hydrochloride, the ob. EXAMPLE 44. tained product is dissolved in 50 ml. anhydrous ether. 38-chloro-20-aza-24-nor-5-cholestene Dry gaseous HCl is introduced into the solution with stir The solution of 8 g. 36-chloro-5-androstene-17-one in ring and under nitrogen. The crystalline hydrochloride 100 ml. benzene and 20 ml. isoamyl amine is distilled separates. Io D24 -35 (methanol). azeotropically with 1. g. p-toluene sulfonic acid. After 2% In analogy, 20-aza-24-oxa-cholestane-3,6-ol may be hours, another 20 ml, isamyl amine are added. The cold prepared. M.P. 101-104° C. 40 reaction mixture is washed with water to neutrality. The EXAMPLE 39 benzene solution is dried over CaCO3 and concentrated. N-ethyl-20-oxa-21-nor-24-aza-cholesterol The amorphous residue of 36-chloro-17-(3-methyl)-butyl imino-5-androstene is dissolved in 100 ml. anhydrous tetra 3.9 g. 20-oxa-21-nor-24-aza-cholesterol are refluxed hydrofuran without further purification and is added drop with 80 ml. ethanol and 1.2 g. ethyl bromide for 5 hours. wise into a suspension of 7.5 g. NaBH4 into 200 ml. ether. The mixture is evaporated to dryness and the obtained N 45 The mixture is stirred for 30 minutes at room temperature ethyl-20-oxa-21-nor-24-aza-cholesterol is purified by and then is refluxed for 2 hours. After cooling, the excess chromatography over basic Al-O. M.P. 87-89 (ace of NaBH4 is decomposed with methanol and is extracted tone); (c.20 - 45° (chloroform). with ether after addition of 20 g., sodium potassium tar EXAMPLE 40 trate. From the dried extracts 36-chloro-20-aza-21,24-bis 50 nor-5-cholestene is isolated. N-ethyl-22-aza-cholesterol 3.1 g. of 36-chloro-20-aza-21,24-bisnor-5-cholestene, 2 g. 22-aza-cholesterol are refluxed for 3 hours with 10 2.6 g. 90% formic acid and 2 g. 35% aqueous formalde ml. pyridine and 10 ml. acetic acid anhydride. The mix hyde are heated on the steam bath for 20 hours. The reac ture is poured into ice water, the precipitate is filtered tion mixture is diluted with water, acidified to pH 2 with off and dried. The crude 3,22-diacetyl compound is re HCl and extracted with ether. The aqueous layer is made duced with LiAlH4 as described in Example 35 to form alkaline with NaOH and the 36-chloro-20-aza-24-nor-5- N-ethyl-22-aza-cholesterol. cholestene is filtered off and recrystallized from acetone. In analogy the following compounds may be pre In analogy, 36-chloro-20-aza-24-nor-cholestane is ob pared 60 tained from 3-chloro-androstane-17-one. N-ethyl-22-aza-cholestanol-hydrochloride, M.P. 260 EXAMPLE 45 (decomp.), 20-aza-cholesterol-3-propionate N-ethyl-22-aza-24-nor-cholesterol, M.P. 140-142 1.5 g. 20-aza-cholesterol are allowed to stand overnight (methanol), at room temperature with 7.5 ml. propionic acid anhy ol--16 (dioxane) hydrochloride: M.P. 254 (decomp. 65 dride and 7.5 ml. pyridine. The reaction mixture is poured from methanol/ether), into water and the separated 20-aza-cholesterol-3-propio N-ethyl-22-aza-24-nor-cholestanol, M.P. 148-150 nate is filtered off and recrystallized from petroleum ether. (methanol), ox)--66 (chloroform), hydrochloride: M.P. EXAMPLE 46 250-253 (acetone), 70 22-aza-24-nor-cholesterol N-ethyl-24-aza-26-nor-cholestan-36-ol,(a)--17 (chloroform), 22-aza-24-nor-cholestanol N-ethyl-23-aza-cholesterol, 7 ml. isobutyric acid chloride are added with stirring at 24-ethyl-24-aza-cholesterol, 0 C. to a solution of 7 g. 20c -amino-allopregnane-3,6-ol N-ethyl-20,24-diaza-cholesterol. 75 in 70 ml. pyridine. The reaction mixture is allowed to stand 8,826,758 25 26 for 2 hours at room temperature, then is diluted with wa ter and the separated 20a-amino-allopregnane-3,6-ol-di II, DRAGEES (COATED TABLETS) isobutyrate is filtered off. After recrystallization (M.P. The compressed cores contain 228-229 from methanol) it is dissolved in 320 ml. di Mg. oxane and refluxed for 18 hours with a suspension of 5.8 N-ethyl-22-aza-24-nor-cholesterol ------40 g. LiAlH4 in 100 ml. dioxane. 5 ml. water are added after Lactose ------80 cooling, then the mixture is heated to the boiling point Potato starch ------10 with 4.5 ml. 20% NaOH. The precipitate is filtered off The cores were then coated, according to conventional after addition of 30 ml. water. The filtrate is concentrated methods, with a mixture of wheat starch, sugar, talc and and the residue consisting of 22-aza-24-nor-cholestane tragacanth. 36-ol is crystallized from methanol. M.P. 161-162, 10 old +24 (alcohol). III. TABLETS With ethereal hydrochloric acid, the hydrochloride of Kg. 22-aza-24-nor-cholestanol is precipitated from the meth 22-Oxa-25-aza-cholestanol ------0.100 anolic solution, M.P. 335-336 (decomp., from meth Lactose ------0.500 anol). 15 Corn starch ------0.200 In analogy, the 22-aza-24-nor-cholesterol (M.P. 130 Tale ------0,150 131, methanol) is obtained from 20oz-amino-5-pregnene Magnesium stearate ------0.050 36-ol; the hydrochloride melts at >280. The ingredients were mixed and stamped into 10,000 EXAMPLE 47 20 tablets so that the dosage unit is 10 mg/tablet, 23-aza-24-nor-cholestane-39-ol IV. DRAGEES (COATED TABLETS) The solution of 3.1 g. of the 3-acetate of bisnor cholenic The core contains acid isopropyl amide in 60 ml. anhydrous ether is dropped Mg. into a suspension of 1 g. LiAlH4 in 50 ml. ether. The 25 22-Oxa-25aza-cholesterol ------20 mixture is refluxed overnight and decomposed after cool Lactose ------100 ing with aqueous NaOH. By working up the reaction mix Starch ------50 ture in the usual way, the 23-aza-24-nor-cholestane-3,6-ol is obtained in crystalline form. Tale ------10 EXAMPLE 48 30 The cores were then coated with a tinted sugar solution. 25-aza-cholesterol W. TABLETS Each tablet contains 3 g. 3,3-hydroxy-5-cholenic acid dimethyl amide dis Mg. solved in 100 ml. anhydrous dioxane are dropped into a 35 suspension of 1.5 g. LiAHlH4 and the mixture is refluxed 20-Oxa-21-nor-25-aza-cholesterol ------25 for 18 hours. The excess of hydride is decomposed with a Lactose ------120 mixture of dioxane and water. 1-2 ml. 20% NaOH are Corn starch ------25 added to the reaction mixture which is heated to the boil Magnesium stearate ------5 ing point and filtered in the hot after addition of small 40 WI. TABLETS amounts of water. There were mixed The residue is washed with dioxane and the combined Kg. filtrates are concentrated. The obtained 25-aza-cholesterol 22-aza-cholestanol ------3.0 is recrystallized from acetone. actose ------8.0 45 Corn starch ------2.0 EXAMPLE 49 Tale ------1.0 20-aza-24-oxa-cholestanol-3-acetate Magnesium stearate ------0.6 1 g. 20-aza-24-oxa-cholestanol is refluxed with 10 ml. The mixture was then formed into 100,000 tablets so pyridine and 10 ml. acetic acid anhydride. The mixture 50 that the dosage unit is 30 mg/tablet. is evaporated and the residue is worked up in the usual VII. TABLETS way with chloroform and water. The 20-aza-24-Oxa , cholestanol-3-acetate melts at 65-69. Each tablet contains In a similar manner, all compounds obtainable accord Mg. ing to the present invention may be acylated if they do 55 20-aza-24-Oxa-cholesterol ------40 not contain a secondary nitrogen atom. For an acylation Starch ------20 with acids of longer chain length preferably the acid actose ------100 chlorides are used instead of the anhydrides, e.g. tri T ------8 methylacetyl chloride, caprylic chloride, undecylenic acid chloride, stearylic chloride, benzoyl chloride. 60 WIII. TABLETS The acid addition salts of the cholesterol derivatives Each tablet contains containing nitrogen are obtained by dissolving the bases Mg. in ethanol and adding the corresponding acid, e.g. hydro 20-Oxa-21-nor-25-aza-cholestanol ------15 chloric acid in ether. actose ------120 The following examples relate to preferred pharma 65 Potato starch ------60 ceutical compositions: Magnesium stearate ------3 I, TABLETS From the foregoing description, one skilled in the art Each tablet contains can easily ascertain the essential characteristics of this 70 invention, and without departing from the spirit and Scope Mg. thereof, can make various changes and modifications of 20-aza-24-Oxa-cholestanol ------50 the invention to adapt it to various usages and conditions. Lactose ------120 Consequently, such changes and modifications are Corn starch ------30 properly, equitably, and intended to be, within the full Tale ------2 75 range of equivalence of the following claims. 3,326,758 28 27 is selected from the group consisting of isopropyl, What is claimed is: isobutyl, 1-methylpropyl, and 1-ethylpropyl; 1. A member of the group consisting of a compound R8 is selected from the group consisting of methyl, of the formula ethyl and isopropyl; n1 is an integer in the range of 0-3; 122 is an integer in the range of 0-2; and n3 is an integer in the range of 2-3. 20-oxa-21-nor-25-aza-cholesterol. 20-oxa-21,24-bis-nor-25-aza-cholesterol.N-ethyl-20-oxa-21,26-bis-nor-24-aza-cholesterol. 10 33-chloro-22-oxa-25-aza-5-cholestene. 20-aza-24-oxa-cholestane-3,6-ol.N-ethyl-20-oxa-21-nor-24-aza-cholesterol. and the 5-dehydro-derivatives and the acid-addition salts 20-aza-24-oxa-cholesterol. thereof, wherein: 20-oxa-21-nor-25-aza-cholestane-3,6-ol. R is selected from the group consisting of: chloro, hy 0. 20-oxa-21-nor-cholestane-3,6-ol. droxy, O-alkyl of 1-4 carbon atoms, and O-acyl of 1. 20-oxa-21,24-bis-nor-cholestane-3,6-ol. 1-18 carbon atoms; 2. 22-Oxa-cholestane-3,6-ol. R1 is selected from the group consisting of: 3. 22-oxa-24-nor-cholestane-3,6-ol. 20 14. 23-oxa-cholestane-3,6-ol. 15. 23-oxa-24-nor-cholestane-33-ol. 16. 24-oxa-cholestane-3,6-ol. 17. A pharmaceutical composition in dosage unit form having a total of 6-7 carbon atoms, comprising a pharmaceutically acceptable carrier and 2 CH3 300 mg. of a compound in accordance with claim 1. 18. A method of treating a mammal having hyper -N-(CH)-o-CH-(CH), cholesteremia, which method comprises administering to -O-(CH2)3-CH-(CH3)2 Said mammal an effective dosage of a compound in ac R3 cordance with claim 1. -O-(CH) --R, References Cited having a total of 4-7 carbon atoms, and UNITED STATES PATENTS -O-(CH2)2-O-CH-(CH3)2 3,013,008 12/1961 Counsell ------260-239.5 3,038,912 6/1962 Nysted ------260-397.1 R2 is selected from the group consisting of methyl, 3 5 ethyl, isopropyl, isobutyl, isopenty, 1-methylpropyl, 3,084,156 4/1963 Counsell et al. ---- 260-239.5 1-ethylpropyl, 2-methylbutyl, and 2-ethylbutyl; 3,097,200 7/1963 Kincl ------260 239.5 R3 is selected from the group consisting of hydrogen, 3,144,471 8/1964 Nelson ------260-397.5 methyl and ethyl; LEWIS GOTTS, Primary Examiner. R4 is selected from the group consisting of isopropyl, 40 isobutyl, and isopentyl; HENRY A. FRENCH, Assistant Examiner.