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United States Patent Office 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-diazirine 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 ammonia 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 nitrogen 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 amine 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.
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