3,445,461 United States Patent Office Patented May 20, 1969 2 3,445,461 and STEROD DAZARINES AND OAZRD NES AND A PROCESS FOR PRODUCING SAME /S Poul Borrevang and Peter Faarup, Copenhagen, Denmark, RN-NR; assignors to Novo Terapeutisk Laboratorium A/S, wherein each of the symbols R and R2 means hydrogen, Copenhagen, Denmark, a Danish company 5 alkyl, cycloalkyl, hydroxyalkyl, aralkyl, aryl or halogen No Drawing. Filed Aug. 5, 1965, Ser. No. 477,602 aryl, R3 means hydrogen or methyl, R4 means hydrogen, Claims priority, application Great Britain, Aug. 12, 1964, methyl, or halogen, R5 means two hydrogen atoms, hy 32,814/64; May 25, 1965, 22,075/65 drogen and methyl, hydrogen and hydroxyl, or a methyl Int. C. C07c 173/10, 167/00 U.S. C. 260-239.5 13 Claims O ene group, and X means CR CH do ABSTRACT OF THE DESCLOSURE --R or C--Rs Derivatives of the pregnane series and of 17,17-lower dialkyl steroids which carry a spiro- group, a 5 the compounds having, when X means spiro-diaziridine group or substituted spiro-diaziridine C group in the 3-position are disclosed. These compounds (-R, may be prepared by reaction of chloramine in the pres a A13 double bond and no group Rs, while R means ence of with the corresponding steroid which 20 lower alkyl, preferably methyl or ethyl, whereas when has in the 3-position a carbonyl group, an imino group X is or a group convertible to an imino group under the con ditions of the reaction. The new compounds show anti CHR androgenic properties and compounds may be obtained O with gestagenic effect. 25 --Rs the compounds have no A13 double bond, while Rs means lower alkyl, preferably methyl, Ra means hydrogen, alkyl, The present invention relates to new and useful steroid hydroxyl or an ester group, for example an acetate group compounds and to a process for preparing such com or a higher ester group, e.g. a caproate group, and Rg pounds, 30 means hydrogen or halogen, with the addition that when The new compounds of the invention have in 3-position R5 is hydrogen and hydroxy, and R8 is hydroxy, the two in the steroid molecule a 3-membered ring system con hydroxy groups may together form a ketal or acetal taining two atoms and one carbon atom, the structure as shown by the below partial formula latter being carbon atom number 3 in the A-ring of the CHR steroid molecule. Thus, the new compounds of the inven tion may be defined as steroids carrying in 3-position a spiro-diazirine or a spiro-diaziridine ring, which latter may carry substituents. It has been found that by the introduction of the spiro diaziridine or spiro-diazirine ring system into 3-position 40 of certain classes of steroids as defined below there may wherein each of the groups R10 and R11 means hydrogen, be obtained compounds of pharmacological value. For lower alkyl, phenyl, or substituted phenyl. example, there may be obtained compounds showing anti Concerning the meaning of the symbols R1 and R2, androgenic properties (in the pregnane series there may 1(2) - methyl-diaziridines and 1’ (2) - ethyl-diaziridines be obtained compounds showing antiandrogenic proper 45 may be mentioned as examples of compounds wherein ties with no demonstrable gestagenic effect), further, R1 and R2 mean hydrogen and alkyl, 1(2)-3-hydroxy there may be obtained compounds with gestagenic effect, ethyl-diaziridines may be mentioned as examples of com and in the pregnane series it has been found possible to pounds wherein R1 and R2 mean hydrogen and hydroxy obtain no androgenic effect at all, but very interesting alkyl, 1'(2)-benzyl-diaziridines may be mentioned as ex anabolic properties. 50 amples of compounds wherein R1 and R2 mean hydrogen It has further been found that the new steroid com and aralkyl, and 1,2'-dimethyl-diaziridines may be men pounds of the invention are useful as intermediates for tioned as examples of compounds wherein both R1 and the preparation of other steroid compounds. R2 mean alkyl. More specifically, the compounds of the invention 55 Concerning the meaning of the symbol R8, caproates have the general Formula I and valerates may be mentioned as examples of com pounds wherein Rs means a higher ester group. An important class of the compounds of the invention are steroids of the general Formula IV 60

C N/NA : 65 R4 (I) in which Y means one of the groups 70 (IV) 3,445,461 3 4 wherein Y means or m c C N4 N HN4 NH C and R4 is as defined above, are of special interest, as, among these compounds, there are some showing a very C strong antiandrogenic effect. HN4 NH A further very important class of the compounds of the and R R5, Ra and Rs are as defined above, and among invention are steroids of the general Formula VIII these, the steroids of the general Formula V O C Cls CH3 --R

(H,C scO CE --OOCC 5 r N/ (VIII) wherein Y means 20 C R (W) N4N wherein Y means O C C N4N 25 HN4 NH O and R is as defined above. Also among these compounds, C there are some showing a very strong antiandrogenic effect. HN4 NH 30 As specific examples of interesting compounds of the and R4 is as defined above, are of special interest. invention there may be mentioned Another very important class of the compounds of the 5o-pregnane-20-one-3-spiro-3'-diazirine and -diaziridine, invention are steroids of the general Formula VI 17a-acetoxy-5a-pregnane-20-one-3-spiro-3'-diazirine and -diaziridine, 35 17c-acetoxy-56-pregnane-20-one-3-spiro-3'-diazirine and -diaziridine, CE 60-methyl-17a-acetoxy-5oz-pregnane-20-one-3-spiro-3'- diazirine and -diaziridine, 40 60-methyl-17 oz-acetoxy-58-pregnane-20-one-3-spiro-3'- diazirine and -diaziridine, 6a-chloro-17 oz-acetoxy-5c-pregnane-20-one-3-spiro-3'- diazirine and -diaziridine, 6a-chloro-17a-acetoxy-56-pregnane-20-one-3-spiro-3'- 45 diazirine and -diaziridine, (VI) 21-fluoro-17a-acetoxy-5b-pregnane-20-one-3-spiro-3'- diazirine and -diaziridine, wherein Y means 21-fluoro-6c-methyl-17 oz-acetoxy-55-pregnane-20-one-3- spiro-3'-diazirine and -diaziridine, 50 6-methyl-17a-acetoxy-A-pregnene-20-one-3-spiro-3'- diazirine and -diaziridine, o 6-chloro-17c-acetoxy-A5-pregnene-20-one-3-spiro-3'- C diazirine and -diaziridine, HN4 NH 21-fluoro-17a-acetoxy-A5-pregnene-20-one-3-spiro-3'- 55 diazirine and -diaziridine, and R, R, R and R are as defined above, and of these, 6-methyl-17a-acetoxy-A-pregnene-20-one-3-spiro-3'- the steroids of the general Formula VII diazirine and -diaziridine, 17 oz-acetoxy-16a-methyl-5a-pregnane-20-one-3-spiro-3'- C diazirine and -diaziridine, CBs 60 17a-acetoxy-16cy-methyl-56-pregnane-20-one-3-spiro-3'- (=o diazirine and -diaziridine, CE --OOCCH 17 oz-acetoxy-16-methylene-5,3-pregnane-20-one-3-spiro-3'- diazirine and -diaziridine, 6a, 16o-dimethyl-17a-acetoxy-56-pregnane-20-one-3- 65 spiro-3'-diazirine and -diaziridine, 6oz,16cy-dimethyl-17 oz-acetoxy-5a-pregnane-20-one-3- spiro-3'-diazirine and -diaziridine, 16oz,17a-isopropylidenedioxy-5o-pregnane-20-one-3- spiro-3'-diazirine and -diaziridine, R (VII) 70 16oz,17a-isopropylidenedioxy-56-pregnane-20-one-3- spiro-3'-diazirine and -diaziridine, wherein Y means 160,17a-isopropylidenedioxy-6a-methyl-58-pregnane-20 C one-3-spiro-3'-diazirine and -diaziridine, Z N 160,17a-isopropylidenedioxy-6a-chloro-58-pregnane-20 75 one-3-spiro-3'-diazirine and -diaziridine, 3,445,461 5 6 16oz,17a-dihydroxy-56-pregnane-20-one-3-spiro-3'-dia means a hydrogen atom or a methyl group, or, when the zirine or -diaziridine benzaldehyde acetal and the cor A6 double bond is not present, A means responding 5oz-pregnane compounds, 16oz,17a-dihydroxy-5B-pregnane-20-one-3-spiro-3'-dia CHR zirine or -diaziridine methyl phenyl ketal and the cor & HoH responding 5a-pregnane compounds, --R 21-fluoro-160,17a-isopropylidenedioxy-5o-pregnane-20 in which R8 and R9 have the meanings defined above, and one-3-spiro-3'-diazirine and -diaziridine, R13 has the same meaning as defined above for Rs (in 17a-hexanoyloxy-5oz-pregnane-20-one-3-spiro-3'-diazirine cluding the ketal or acetal formation with Ra), while Z. and -diaziridine, O in the above Formulas II and III is a carbonyl or imino 17 oz-hexanoyloxy-58-pregnane-20-one-3-spiro-3'-diazirine group or a derivative thereof which is convertible into an and -diaziridine, imino group, with a reactive derivative such as 6a-methyl-17a-hexanoyloxy-5o-pregnane-20-one-3-spiro NHR or R'NHR wherein R is an acid residue and R' 3'-diazirine and -diaziridine, has the same meaning as defined above for R1 and R2 60-methyl-17 oz-hexanoyloxy-56-pregnane-20-one-3-spiro 15 (other than hydrogen), in the presence of NH3 and/or 3'-diazirine and -diaziridine, and another basic-reacting agent, 17,17-dimethyl-18-nor-5a-A13-androstene-3-spiro-3'- If desired oxidizing a diaziridine group resulting from diazirine and -diaziridine. the above treatment to form a diazirine group, The process of the invention is in principle character If using as starting steroid a compound of the Formula ized by introducing into 3-position of a steroid of the 20 III oxidizing (if necessary) the product resulting from partial formula one of the aforementioned operations to form a 3-spiro 3'-diazirine steroid comprised by the general Formula I, If desired esterifying a 17a-hydroxy-containing 3-spiro 3'-diazirine steroid obtained in one of the above manners 25 to form a 17 oz-ester, ?N/ If desired converting a 16c.,17a-dihydroxy-3-spiro-3'- diazirine obtained into a ketal or acetal of the partial a group of the formula formula indicated above, and If desired converting a diazirine group obtained into a 30 monosubstituted diaziridine group. By the term "imino group” is meant as well an unsub O stituted as a substituted imino group. It will be understood that the reactive group in the steroid may not only be a carbonyl group or an imino QN4 NQ group, but also a derivative thereof which is convertible wherein Q and Q are hydrogen or substituents. into an imino group. Without limiting the scope of the More specifically, the process of the invention for the invention to any theory it is believed that an imino group, preparation of steroids of the general Formula I is charac if not present in the starting steroid, is formed inter terized by treating a steroid of the general Formula II mediately during the reaction. As illustrating examples 40 of suitable steroid starting materials may be mentioned R 3-keto steroids, steroids carrying in 3-position an unsub X stituted imino group. Schiff's bases and steroids carrying in 3-position a hydrazone group which may be sub R3 t stituted. 45 Examples of reactive amine derivatives are hydroyl amine-O-sulfonic acid, chloramine, N-alkyl-hydroxyl Z N a. amine-O-sulfonic acid, and N-alkyl-chloramine. It will be recognized that these illustrating examples of reactive N/ y amine derivatives correspond to the general formulas R (II) 50 NH2R and R'NHR, the acid residue R being OSOOH or chlorine. wherein the symbols X and R3, R1, R5 and Rs have the The process of the invention may be carried out for meanings defined above, or of the general Formula III instance from -30 to -40° C. up to room temperature or even higher. Sometimes it is preferred to carry out 55 main part of the reaction at about 0 to 5 C. and let the reaction complete at room temperature. As solvent medi um may be used various commonly used solvents with the proviso that the solvent used must not be one which reacts with the reactants used. As illustrating examples of 60 suitable solvents may be mentioned methanol and dioxane. Though the use of dry solvents is often preferred, the process may also be carried out in the presence of water, especially when using a reactive amine derivative (III) containing the group OSOOH. 65 When the desired reaction product is a 3-spiro-3'-dia wherein the symbols Ra, Ra and Rs have the meanings ziridine steroid in which the diaziridine group is unsub defined above, and wherein, when the A6 double bond is stituted, suitable embodiments of the process of the in present, A means vention comprise treating a steroid of the general Formula II wherein Z is as defined above, with hydroxylamine-O- (H.R. 70 sulfonic acid or chloramine in the presence of NH3, chlor =Ria amine being used in the proportion of one mole of chlor amine to one mole of the steroid. Examples of suitable steroid starting materials are 3-keto steroids, steroids in which R has the meaning defined above and R1a means carrying in 3-position an unsubstituted imino group, an oxygen atom or hydrogen and hydroxy, while R13 75 Schiff's bases, and steroids carrying in 3-position a hydra 3,445,461 7 8 zone group. When using as starting compounds steroids If a steroid of the general Formula III is used as starting carrying in 3-position an unsubstituted imino group, an material, an oxidation is necessary to convert the product other basic-reacting agent, for instance potassium hy obtained in the main reaction into a desired end product. droxide, may be used instead of NH, though NH3 is if, for example, the starting material is a steroid of the preferred. general Formula III containing a 20-hydroxy-group, the When the desired reaction product is a 3-spiro-3'-dia 20-hydroxy-group must be oxidized to form a 20-keto zirine steroid, suitable embodiments of the process of the group. In some cases, this oxidation may be carried out invention comprise treating a steroid of the general For simultaneously with a possible conversion of a diaziridine mula II wherein Z is as defined above, with an excess of group into a diazirine group. chloramine in the presence of NH3. It is believed that in 160,17a-dihydroxy-3-spiro-3'-diazirine steroids in which this process, which provides a most simple way of produc O no A13 double bond is present may readily be prepared ing the , the chloramine itself acts as an oxidiz using as starting material a 160,17a-dihydroxy steroid ing agent for the diaziridine group. Examples of suitable corresponding to the general Formula II, but they may steroid starting materials are 3-keto steroids, steroids car also be prepared from steroids of the general Formula III rying in 3-position an unsubstituted imino group, Schiff's 5 wherein the A16 double bond is present, the hydroxy groups bases, and steroids carrying in 3-position a hydrazone in the 16oz- and 17 oz-positions being introduced by oxida group. When using as starting compounds steroids carry tion subsequently to the main reaction. ing in 3-position an unsubstituted imino group, another Also, 17cc - hydroxy-16-methylene-3-spiro-3'-diazirine basic-reacting agent may be used instead of NH3, though steroids in which no A13 double bond is present may be NH is preferred. 20 prepared as well from starting materials corresponding to According to the invention, a further suitable method the general Formula II as from starting materials of the of preparing 3-spiro-3'-diazirine steroids is by oxidizing a general Formula III. In the latter case, a starting material 3-spiro-3'-diaziridine steroid in which the diaziridine group containing a A16 double bond and a 16-methyl group is is unsubstituted, by means of an oxidizing agent, for used, and Subsequently to the main reaction an oxidizing example bromine, silver oxide, tertiary butyl hypochlorite 25 and dehydrating is performed. or chromium trioxide. Further, 16oz,17a-dihydroxy-3-spiro-3'-diazirine ketals It is often preferred to use bromine as the oxidizing or acetals corresponding to the general Formula I may be agent, because in most cases bromine has been found to prepared as well by introducing the diazirine group into react selectively with the diaziridine group, without affect a steroid already containing the ketal or acetal group de ing the remaining constitution of the steroid treated. 30 sired as by reacting a 160,17a-dihydroxy-3-spiro-3'-di When the desired reaction product is a 1(2)-substi azirine steroid corresponding to the general Formula II tuted 3-spiro-3'-diaziridine steroid, suitable embodiments with the appropriate carbonyl compound in the presence of the process of the invention comprise treating a of an acidic catalyst. steroid of the general Formula II wherein Z means a The following examples illustrate the invention. carbonyl group, with hydroxylamine-O-sulfonic acid or 35 chloramine in the presence of R'NH2 wherein R is as EXAMPLE 1. defined above. Other suitable embodiments comprise treat 17 oz-acetoxy-5g-pregnane-20-one-3-spiro-3'-diazirine ing steroids of the general Formular II, wherein Z means an amino group substituted with R', with hydroxylamine (1) 17 or - acetoxy-5B - pregnane-20-one-3-spiro-3'-di O-sulfonic acid or chloramine in the presence of a basic 40 aziridine-2.7 g. of 17a-acetoxy-5g-pregnane-3,20-dione reacting agent other than NH3, preferably an amine. Fur were dissolved in 250 ml. of dry methanol. The solution ther suitable embodiments comprise treating a steroid was cooled in a mixture of ice and water, and 19.0 ml. of the general Formula II wherein Z means a carbonyl of methanolic ammonia (3.8 molar) were added. 0.95 g. group, with R'NHOSOOH or R'NHCl in the presence of hydroxylamine-O-sulfonic acid (96%) was added por of NH3. Still further suitable embodiments comprise treat tionwise with stirring. The reaction mixture was stirred ing a steroid of the general Formula II wherein Z. means 45 and cooled for a couple of hours and was then allowed an unsubstituted imino group, with R'NHOSOOH or to stand at room temperature for about 14 hours. There RNHCl in the presence of a basic-reacting agent, pref after the reaction mixture was evaporated almost to erably NH3. dryness in vacuo, methylene chloride was added, the mix A diazirine group may be converted into a monosub ture was shaken out three times with water, and the stituted diaziridine group for instance by Grignard syn 50 methylene chloride phase was dried over NaSO and thesis. evaporated to dryness in vacuo. The resulting residue When the desired reaction product is a 1,2'-disub (weighing 2.6 g.) consisted of 17a-acetoxy-5B-pregnane stituted 3-spiro-3'-diaziridine steroid, suitable embodi 20-one-3-spiro-3'-diaziridine. The infrared spectrum ments of the process of the invention comprise treating (KBr) showed characteristic bands at 1245 cm. a steroid of the general Formula II wherein Z means a 55 carbonyl group, with R'NHOSOOH or RNHCl in the (C-O-C) presence of R'NH2, in which formulas each R is one of 1712 cm. (C=O), 1731 cm. (C=O, acetate), and the groups R and R2 as defined above (other than hydro 3180, cm. - (NH). gen). Other suitable embodiments comprise treating a 60 (2) 17 oz-acetoxy-5-6-pregnane-20-one-3-spiro-3-diazir steroid of the general Formula II wherein Z. means an ine-2.4 g. of the above 3-diazirdine (crude) were dis R-substituted imino group, with R'NHOSOOH or solved in 100 ml. of chloroform. The solution was cooled RNHCl, wherein each R is one of the groups R1 and R2 as defined above (other than hydrogen), in the presence in a mixture of ice and water, and 5.0 ml. of triethylamine of a basic-reacting agent other than NH3, preferably an were added. A solution of 1.0 g. of Br in 20.0 ml, of 65 chloroform was added dropwise with stirring in the e course of about 4 hour. After stirring for additionally While steroids of the general Formula I wherein R is 2 hour the reaction mixture was shaken out three times an ester group can be prepared from a starting material with water, dried over Na2SO4 and evaporated to dryness already containing the desired ester group, using as re in vacuo. The residue was treated with methanol, which active amine derivative for example NHCl or R'NHCl, a O caused the residue to crystallize, and after separation by further suitable method for the preparation of 17 oz-ester filtration and recrystallization from methanol there was 3-spiro-3'-diazirine steroids is by treating a 17a-hydroxy obtained 1.3 g of the 17c-acetoxy-56-pregnane-20-one-3- 3-spiro-3'-diazirine steroid with an acid anhydride or spiro-3'-diazirine with a melting point of 140-141 C. mixed anhydride in the presence of p-toluene sulfonic The infrared spectrum (KBr) showed characteristic acid. 75 bands at 1249 cm. (C-O-C), 1568 cm. and 1583 3,445,461 9 10 cm. - (N-N), 1715 cm.-1 (C=O), and 1730 cm Analysis.--Calculated for CHNO: N=8.48%. (CFO, acetate). Found: N-8.55%. Analysis.-Calculated for C2H8N2O3: C=71.47%; EXAMPLE 5 H=8.87%; N=7.25%. Found: C=71.66%; H=8.69%; N-7.44%. 5o-pregnane-20-one-3-spiro-3'-diazirine In biological tests, 17a-acetoxy-58-pregnane-20-one-3- 5 The residue obtained after working up as described in spiro-3'-diazirine showed antiandrogenic effect. Example 4 was admixed with 10.0 ml. of triethylamine and treated in the same manner as described in Example EXAMPLE 2 1(2), adding dropwise a solution of 2.5 g. of Br in 50 6a-methyl-17a-acetoxy-58-pregnane - 20 - one - 3 - spiro ml. of chloroform. After working up the residue was 3'-diaziridine dissolved in benzene and chromatographed over silica gel (40 g.). After eluation with benzene and evaporation to 4.0 g. of 6a-methyl-17a-acetoxy-56 - pregnane - 3,20 dryness in vacuo the resulting residue was recrystallized dione were dissolved in 200 ml. of dry methanol. There from methanol, yielding 1.6 g. of 5oz-pregnane-20-one-3- after the procedure described in Example 1, 1 was foll 15 spiro-3-diazirine with a melting point of 141-142 C. lowed, adding 20.0 ml. of methanolic ammonia (5.0 mo From the mother liquor additional 1.0 g. of the substance lar) and 1.3 g. of hydroxylamine - O -sulfonic acid was obtained. (97.5%). After recrystallization of the residue from The infrared spectrum (KBr) showed characteristics methanol there was obtained 2.4 g. of 60-methyl-17 oz bands at 1576 cm. (N=N) and 1700 cm. (C=O). acetoxy-56-pregnane - 20 - one-3-spiro - 3 - diaziridine 20 Analysis.-Calculated for C2H2N2O: C-76.78%; with a melting point of 198-205 C. (Heating of the H-9.82%; N=8.53%. Found: C-76.77%; H-9.70%; sample started at 190° C.) The infrared spectrum (KBr) N8.8%. showed characteristic bands at 1243 cm.1 (C-O-C), 1706 cm. (C=O), 1734 cm. l (C=O, acetate), and EXAMPLE 6 3240 cm. - (NH). 17a-acetoxy-5a-pregnane-20-one-3-spiro-3'-diaziridine Analysis.-Calculated for C2H8N2O: C=71.60%; 25 H-9.51%; N=6.96%. Found: C=71.63%; H-9.53%; 10.3 g. of 17 oz-acetoxy-5oz-pregnane-3,20-dione were dis N-7.00%. solved in 1000 ml. of dry methanol and treated in the same In biological tests, 60-methyl-17c-acetoxy-56-pregnane manner as described in Example 1 (1), adding 36.0 ml. of methanolic ammonia (6.8 molar) and 3.7 g of hydroxyl 20-one-3-spiro-3'-diaziridine showed antiandrogenic effect. 30 amine-O-sulfonic acid (97%). After working up the re EXAMPLE 3 sulting residue was treated with acetone, which caused it to crystallize, and on separation by filtration there was ob 60-methyl-17a-acetoxy-5oz-pregnane-20-one-3-spiro tained 6.8 g. of 17 oz-acetoxy-5a-pregnane-20-one-3-spiro 3'-diazirine 35 3'-diaziridine. After recrystallization from acetone a melt To 1.0 g. of the 3-diaziridine compound described in ing point of 217-221 C. was obtained. Example 2 were added 100 ml. of ether and 0.7 ml. of The infrared spectrum (KBr) showed characteristic triethylamine. The resulting suspension was cooled in bands at 1245 cm. l (C-O-C), 1705 cm. (C=O), ice-water and while stirring a solution of 0.4 g. of Bra 1735 cm.-1 (C=O, acetate), and 3260 cm.1 (NH). in 15.0 ml. of carbon tetrachloride was added in the 40 Analysis.--Calculated for C3H8N2O3: C=71.10%; course of 30 minutes. After further stirring for 4 hour H=9.34%; N=7.21%. Found: C=71.00%; H-9.23%; ethyl acetate was added and washing once with a NaHCO N=7.17%. solution and twice with water was performed. After dry In biological tests, 17c-acetoxy-5oz-pregnane-20-one-3- ing over Na2SO4 the solution was evaporated to dryness spiro-3'-diaziridine showed gestagenic effect. in vacuo. EXAMPLE 7 The resulting residue was recrystallized from methanol, 45 and in this manner there was obtained 0.7 g. of 6cy 17a-acetoxy-5a-pregnane-20-one-3-spiro-3'-diazirine methyl - 17 c. - acetoxy - 58 - pregnane - 20 - one - 3 3.7 g. of the 3-diaziridine compound described in Exam spiro-3-diazirine with a melting point of 145-149 C. ple 6 were dissolved in 100 ml. of chloroform and treated (Heating of the sample started at 140° C.) The infrared 50 in the same manner as described in Example 1(2), adding spectrum (KBr) showed characteristic bands at 1246 7.0 ml. of triethylamine and dropwise a solution of 1.5 g. cm.1 (C-O-C), 1568 cm.1 and 1582 cm.1 (NEN), of Br2 in 25.0 ml. of chloroform. After working up the 1711 cm.1 (C=O), and 1728 cm. (C=O, acetate). residue was treated with methanol, which caused it to Analysis.-Calculated for C2H86N2O3: C=71.97%; crystallize. After separation by filtration and recrystalliza H=9.06%; N=6.99%. Found: C=71.93%; H=9.11%; 55 tion from methanol there was obtained 2.05 g. of 17a-ace N-6.98%. toxy-5a-pregnane-20-one-3-spiro-3'-diazirine with a melt In biological tests, 6cy-methyl-17 oz-acetoxy-5g-pregnane ing point of 183-187° C. (by slow heating of the sample). 20-one-3-spiro-3'-diazirine showed a very strong anti The infrared spectrum (KBr) showed characteristic bands androgenic effect and no demonstrable gestagenic effect. at 1243 cm.-1 (C-O-C), 1572 cm. -1 (N=N), 1708 60 cm. l (C=O), and 1737 cm.-1 (C=O, acetate). EXAMPLE 4 Analysis.-Calculated for CH4NO3: C=71.47%; 5cz-pregnane-20-one-3-spiro-3'-diaziridine H=8.87%; N=7.25%. Found (after drying in vacuo at 25 C. for 48 hours): C-71.63%; H=8.71%; 5.0 g. of 5o-pregnane-3,20-dione were admixed with N-7.24%. 250 ml. of dry methanol and treated as described in Ex 65 In biological tests, 17a-acetoxy-5a-pregnane-20-one-3- ample 1 (1), adding 35.0 ml. of methanolic ammonia spiro-3'-diazirine showed no androgenic effect at all, but (4.6 molar) and 2.1 g. of hydroxylamine-O-sulfonic very interesting anabolic properties. acid (98%). After working up the residue was treated with ethyl acetate, which caused the residue to crystallize, EXAMPLE 8 and on separation by filtration there was obtained 3.7 g. of 5cy-pregnane-20-one-3-spiro-3'-diaziridine. After re 70 17,17-dimethyl-18-nor-5oz-A13-androstene-3-spiro-3'- crystallization from ethyl acetate a melting point of diaziridine 181-182° C. was obtained. The infrared spectrum (KBr) (A) 2.8 g. of 17,17-dimethyl-18-nor-5oz-A13-androstene showed characteristic bands at 1703 cm. (C=O) and 3-one were dissolved in 350 ml. of dry methanol and treat 3205 cm. -1 (NH). 75 ed in the same manner as described in Example 1 (1), 3,445,461 11 12 adding 8.7 ml. of methanolic ammonia (4.6 molar) and R is a member selected from the group consisting of 1.4 g. of hydroxylamine-O-sulfonic acid (98%). After hydrogen, methyl, and chlorine, when the A5-double working up, acetone was added to the residue, and on bond is present, and R4 is a member selected from separation by filtration 0.4 g. of 17,17-dimethyl-18-nor-5a the group consisting of two hydrogen atoms, hydro A18-androstene-3-spiro-3'-diaziridine was obtained. After gen and methyl, hydrogen and chlorine, when the recrystallization from 80% ethanol a melting point of 131 5 A5-double bond is not present, and 133 C. was obtained. The infrared spectrum (KBr) R5 is a member selected from the group consisting of showed a characteristic band at 3175 cm.-1 (NH). hydrogen and methyl. Analysis.-Calculated for C20H2N2, 2 H2O: C= 2. 17,17-dimethyl - 18 - nor-5a-A8-androstene-3-spiro 77.61%; H-10.75%; N=9.05%. Found: C=77.55%; 10 3'-diaziridine. H=10.63%; N=9.06%. 3. Steroid compounds of the formula (B) 2.9 g, of 17,17-dimethyl-18-nor-5oz-A13-androstene 3-one were dissolved in 275 ml. of dry methanol. The solu tion was cooled in a mixture of ice and water. Thereafter 10.5 ml. of methanolic ammonia (3.8 molar) were added, and in the course of 2 hour 43 ml. of a solution of chlor amine in ether (0.248 molar) was added dropwise while stirring. The solution was kept cool for a couple of hours and then allowed to stand at room temperature for about 15 hours. Thereafter there was evaporated to dryness in 20 vacuo, methylene chloride was added, and the mixture was shaken out three times with water. The methylene chloride phase was dried over Na2SO4 and evaporated to dryness in vacuo. By addition of ethyl acetate to the residue and separation by filtration there was obtained 0.5 g. of the 3 25 in which the dotted line between positions 5 and 6 denotes diaziridine compound corresponding to the substance ob the optional presence of a double bond, tained by method A. Y is a member selected from the group consisting of In biological tests, 17,17-dimethyl-18-nor-5a-A13-andro C stene-3-spiro-3'-diaziridine showed a very strong anti N4 SN androgenic effect. 30 and EXAMPLE 9 C 17,17-dimethyl-18-nor-5oz-A13-androstene-3-spiro-3'- RN4 NR, diazirine 35 wherein each of R1 and R2 is a member selected from 2.9 g, of 17,17-dimethyl-18-nor-5oz-Al3-androstene-3-one the group consisting of hydrogen, lower-alkyl, and were dissolved in 275 ml. of dry methanol and treated as benzyl, described in Example 8, method B, adding 6.0 ml. of R4 is a member selected from the group consisting of methanolic ammonia (6.7 molar) and in one portion 189 hydrogen, methyl, and chlorine, when the A5-double ml. of a solution of chloramine in ether (0.212 molar). 40 bond is present, and R4 is a member selected from After working up, 99% ethanol was added to the residue, the group consisting of two hydrogen atoms, hydro which caused the latter to crystallize, and after separation gen and methyl, hydrogen and chlorine, when the A5 by filtration there was obtained 1.5 g. of 17,17-dimethyl double bond is not present, 18-nor-5oz-Ai3-androstene-3-spiro-3'-diazirine with a melt R5 is a member selected from the group consisting of ing point of 67-69 C. hydrogen and methyl, and The infrared spectrum (KBr) showed a characteristic 45 R is a member selected from the group consisting of band at 1572 cm. - (N=N). hydroxyl and hydroxyl esterified with a carboxylic Analysis.-Calculated for C2H8N2: C=80.48%; H= acid containing up to 6 carbon atoms. 10.13%; N-9.39%. Found: C=80.37%; H=9.89%; 4. 6oz - methyl - 17 oz - acetoxy-56-pregnane-20-one-3- N-9.69%. spiro-3'-diazirine. What we claim is: 50 5. 17c. - acetoxy - 5oz - pregnane-20-one-3-spiro-3'-di 1. Steroid compounds of the formula azirine. CH 6. 17c. - acetoxy - 56 - pregnane - 20 - one-3-spiro-3'- CH k-CH, diaziridine. --Rs 55 7. 17 or - acetoxy - 56 - pregnane - 20 - one-3-spiro-3'- diazirine. 8. 6oz - methyl - 17a-acetoxy-5B - pregnane-20-one-3- spiro-3'-diaziridine. 9. 17a-acetoxy - 5oz - pregnane - 20 - one-3-spiro-3'- C a 60 dialziridine. : 10. 3-spiro-3'-dialziridine derivatives of the pregnanese R ries having the formula: in which the dotted line between positions 5 and 6 denotes C the optional presence of a double bond, CE: Y is a member selected from the group consisting of 65 (=o C N4 N CE: --OOCCH and C 70 RN4 SNR, wherein each of R1 and R is a member selected from the group consisting of hydrogen, lower-alkyl, and N adRs benzyl, 5 3,445,461 3 14 in which R is a member selected from the group consist 13. A process of making steroids of the formula ing of two hydrogen atoms, hydrogen and methyl, and hydrogen and chlorine. CH3 11. 3-spiro-3'-diazirine derivatives of the pregnane series having the formula CE3 CH3 &=o CH3 r () / R N in which the dotted line between positions 5 and 6 denotes the optional presence of a double bond, lvi R4 is a member selected from the group consisting of R4 hydrogen, methyl, and chlorine, when the A5-double bond is present, and R4 is a member selected from in which Ra is a member selected from the group consist 20 the group consisting of two hydrogen atoms, hydro ing of two hydrogen atoms, hydrogen and methyl, and gen and methyl, hydrogen and chlorine, when the A5 hydrogen and chlorine. double bond is not present, 12. A process of making steroids have the formula R5 is a member selected from the group consisting of hydrogen and methyl, and CEI R is a member selected from the group consisting of CH k-CHs hydroxyl and hydroxyl esterified with a carboxylic acid containing up to 6 carbon atoms, --Rs which comprises reacting a molar excess of chloramine in the presence of ammonia with a steroid of the formula /N/ 30 CH Dy CI3 in which the dotted line between positions 5 and 6 denotes the optional presence of a double bond, R4 is a member selected from the group consisting of hydrogen, methyl, and chlorine, when the A5-double 40 bond is present, and R4 is a member selected from the group consisting of two hydrogen atoms, hydro gen and methyl, hydrogen and chlorine, when the A-double bond is not present, and in which R4, R5 and R are as defined above and R5 is a member selected from the group consisting of 45 Z is a member selected from the group consisting of a hydrogen and methyl carbonyl group, an imino group and a derivative which comprises reacting a molar excess of chloramine thereof convertible into an imino group under the re in the presence of ammonia with a steroid of the formula action conditions.

CH3 50 References Cited

Cs k-CH UNITED STATES PATENTS --Rs 3,264,331 - 8/1966 Robinson et al. --- 260-397.5 OTHER REFERENCES 55 Schmitz et al.: Chemische Berichte, vol. 94, No. 8, 1961, pp. 2166-2173. Church et al.: Journ. Amer. Chem. Soc., vol. 87, No. 12, 1965, pp. 2665-2671. 60 LEWIS GOTTS, Primary Examiner. in which R and R5 are as defined above and Z is a member selected from the group consisting of a ETHEL G. LOVE, Assistant Examiner. carbonyl group, an imino group and a derivative thereof convertible into an imino group under the U.S. C. X.R. reaction conditions. 65 260-239.55,999