MXPA99001736A - 7&agr;-(&xgr;-AMINOALKYL)ESTRATRIENES, PROCESS FOR PREPARING THE SAME, PHARMACEUTICAL PREPARATIONS CONTAINING SAID 7&agr;-(&xgr;-AMINOALKYL)ESTRATRIENES AND THEIR USE FOR PREPARING MEDICAMENTS - Google Patents

Abstract

The present invention describes new substituted 7&agr;-(&xgr;-aminoalkyl)-estratrienes of general formula (I), in which the side chain SK is a radical of partial formula (II), where m equals 4, 5 or 6;n equals 0, 1 or 2;x equals 0, 1 or 2;A is a hydrogen atom or a C1-5-alkyl group;B and D represent each a hydrogen atom, or A and B represent together an alkylene group -(CH2)p- where p=2, 3, 4 or 5 and D is a hydrogen atom, or A and D form together an alkylene group -(CH2)q- where q=2, 3 or 4 and B is a hydrogen atom;and E is a non-substituted ethyl radical or an ethyl radical fluorinated one to five times;or the terminal substituent -(CH2)3-E in the side chain is substituted by an optionally substituted aryl or heteroaryl radical bonded to the sulphur atom directly or by a mono-, di-or trimethylene group;R3 is a hydrogen atom, a hydrocarbon radical with up to 8 carbon atoms or a radical of partial formula R3'-C(O)-, where R3'is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms or a phenyl radical;R11 is a hydrogen atom, a halogen atom or a nitrooxy group -O-NO2, R14, R15&agr;, R15&bgr;, R16&agr;and R16&bgr;represent each a hydrogen atom or R14 and R15&agr;are an additional bond or a methylene bridge, or R15&bgr;is a methyl group and R15&agr;is a hydrogen atom, R15&agr;and R15&bgr;represent each a methyl group, or R15&bgr;and R16&bgr;form together a methylene bridge, or R16&agr;or R16&bgr;are a halogen atom or R16&agr;and R16&bgr;form together a methylidene group, and the remaining substitutents R14, R15&agr;, R15&bgr;, R16&agr;and R16&bgr;represent each a hydrogen atom, R17'at the&agr;- or&bgr;-position is a hydrogen atom, a C1-5 alkyl, C2-5 alkenyl or C2-5 alkinyl group or a trifluoromethyl group;and R17"is a hydrogen atom or a radical of partial formula R17'''-C(O)-, where R17'''is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms, or when R17'is at the&agr;-position, R17'forms together with R14 an ethano bridge, provided that when A and B do not stand together for -(CH2)p- or A and D stand together for -(CH2)q-, at least one of the substituents R11, R14, R15&agr;, R15&bgr;, R16&agr;and R16b be not a hydrogen atom. Also disclosed are the physiologically tolerable addition salts of these compounds with organic and inorganic acids. These new compounds have a very strong anti-estrogenic activity. Some of them are pure anti-estrogenes, others are anti-estrogenes with a partial estrogenic effect. Because of their spectrum of activity, these new compounds are most suitable for preparing medicaments for tumor therapy and hormone substitution therapy.

Description

7a- (? -AMINOALQUIL) -ESTRATRIENOS, PROCEDURE FOR YOUR PREPARATION, PREPARED PHARMACEUTICALS THAT CONTAIN THEM AND THE EMPLOYMENT OF THEM TO PREPARE MEDICINES The present invention relates to the substituted 7a- (α-aminoalkyl) tetratrienes of general formula I wherein the side chain SK represents a residue of formula - < CH2) m-N-CH-CH- (CH2) n-SO ^ -. { CH2) 3-E I I I A B D where m is 4, 5 or 6, n is 0, 1 or 2, x is 0, 1 or 2, A represents a hydrogen atom or an alkyl group (C1-5), B and D represent each a hydrogen atom or A and B together represent an alkylene group - (CH2) p- with p = 2, 3, 4 or 5 and D represents a hydrogen atom or A and D together represent an alkylene group - (CH2 ) q- with q = 2, 3 or 4 and B represents a hydrogen atom, and E represents an ethyl residue unsubstituted or substituted one to five times with fluorine, or the terminal substituent - (CH2) 3-E of the The side chain represents an optionally substituted aryl or heteroaryl radical, which is attached directly to the sulfur atom or through up to 3 methylene groups, R3 represents a hydrogen atom, a hydrocarbon radical of up to 8 carbon atoms or a rest of formula R3'-C (0) -, in which R3 'represents a hydrogen atom or a hydrocarbon radical of up to 8 carbon atoms or a phenyl residue, R <11> represents a hydrogen atom, a halogen atom or a group of nitrooxy -0-N02, R14, R15a, R15 [beta], R16 <t> and R <s> each represent a hydrogen atom or R14 and R15a represent an additional bond or a methylene bridge, or Ri5β represents a methyl group and R15a represents a hydrogen atom, or R15a and R1β represent in each case a methyl group, or R15β and R16β together represent a methylene bridge, or Rlda or R16β represents a halogen atom or R16a and R16β together represent a group of methylidene and the remaining R14, R15a, R15β, R16a and R16β substituents each represent a hydrogen atom, R17 'represents a hydrogen atom, a group of (C 1-5) alkyl, a (C2.5) alkenyl group, an alkynyl group (C2_s) or a trifluoromethyl group in the a or β position, and R17"represents a hydrogen atom or a radical of formula R17" ' -C (0) -, wherein R17 '"is a hydrogen atom or a hydrocarbon radical of up to 8 carbon atoms, or when R17' is in position a, then R17 'and R14 together represent a bridge of ethane , with the proviso that when A and B, together, do not represent - (CH2) p- or A and D, together, they do not represent - (CH2) q-, then at least one of the substituents R11, R14, R15a, R15ß, R16a and R1613 does not represent a hydrogen atom, and its salts by addition of organic and inorganic acids, acceptable from the point The present invention also relates to pharmaceutical preparations containing these compounds of general formula I and their salts by addition of organic and inorganic acids, physiologically acceptable, and the use thereof to prepare medicines. In the compounds of general formula I, the nitrogen atom of the side chain is preferably separated from carbon atom No. 7 of the steroid skeleton by 5 methylene groups. When A represents an alkyl group of up to 5 carbon atoms, this is usually a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, isopentyl or neopentyl group; for A, the methyl group is preferred.

The index n can take the values of 0, 1 or 2; but when A represents a hydrogen atom or an alkyl group of up to 5 carbon atoms, then the value of 1 is preferred for n so that the nitrogen atom is separated from the sulfur atom by means of 3 methylene groups .

The nitrogen atom can be part of a 4 to 7 or 5 to 7-membered heterocycle which is substituted in position 2 or 3 with the rest of the side chain - (CH2) n-SOx- (CH2) 3-E . A and B, together, preferably represent a group of trimethylene, that is to say, together with the nitrogen atom and its neighboring carbon atom form a pyrrolidine ring substituted in position 2.

Finally, the value of 0 is preferred for n and the value of 0 for x. The sulfur atom of the side chain can be found as a bridge of simple sulfur (sulfur), as a sulphone or as a sulfoxide. Sulfides are preferred. The residue E can be an ethyl residue which is unsubstituted or substituted one to one hundred times with fluorine; as residue E, the perfluorinated moiety is preferred. The substituent R3 of the oxygen atom in position 3 represents first a hydrogen atom. However, the hydroxyl group can be etherified with a straight or branched chain, saturated or unsaturated hydrocarbon radical and up to 8 carbon atoms such as, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl radical , terbutyl, pentyl, isopentyl, neopentyl, heptyl, hexyl or octyl, or esterified with an acyl residue R3'-C (0) -, wherein R3 'represents a hydrogen atom or a hydrocarbon radical of up to 8 carbon atoms or a phenyl radical. The substituent R11 may represent a hydrogen atom, a halogen atom (F, Cl, Br, I) or a nitrooxy group; the fluorine atom is preferred. When R11 represents a hydrogen atom or A and B, together, they do not represent - (CH2) p- or A and D, together, they do not represent - (CH2) q-, then ring D is substituted with a substituent selected from group formed by a double bond -14,15, 14a, 15a-methylene, 15β-methyl, 15, 15-dimethyl, 15β, 16β-methylene, 16a- or 16β-halogen and, in particular, 16 -fluoro, 16- methylidene or 14a, 17a-ethane. Among the named groups, the group of 15β-methyl and the fluorine atom in position 16a are preferred. R17 'may be in position a or ß. When it represents an alkyl group (C- ^), it is preferably a methyl, ethyl, propyl, isoproyl, butyl, isobutyl, terbutyl, pentyl, isopentyl or neopentyl group. As the alkenyl group (C2-s), for example, the vinyl or allyl radical can be named. The most common representatives of the alkynyl group (C2.5) are the ethynyl and 1-propynyl moiety. When R17 'is in position a, then it preferably represents a hydrogen atom, a methyl or trifluoromethyl group or together with R14 forms an ethane bridge. When R17 'is in the β position, then it represents first a hydrogen atom or a methyl group. In particular, those compounds of general formula I are preferred, wherein the side chain SK represents a radical of the formula - (CH 2) 5-N (CH 3) - (CH 2) 3-SO x - (CH 2) 3-C 2 F 5 with x = 0 , 1 or 2, or of the formula - (CH2) 5-N (A) - (CHB) -CH2-S- (CH2) 3-C2F5 with A + B = - (CH2) 3-. In the latter case, the compounds preferably have a hydrogen atom in position 17a. To form the acid addition salts, organic and inorganic acids which form physiologically acceptable salts and which are known to those skilled in the art are suitable. Among the acid addition salts, mention may be made, in particular, of the hydrochlorides and methanesulfonates. The following are particularly preferred compounds of the invention: 14, 17-ethane-7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; 14, 17-ethane-7a-. { 5 - [N-methyl-N- 3 - (4, 4, 5, 5, 5 -pentaf luoropentanesulf inyl) -propylamino] -pent il} -estra- 1,3,5 (10) -trien-3,17β-diol; 3, 17β-diacetoxy-14a, 17a-ethane-7a-. { 5- [N-methyl-N- 3- (4,4,5,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3.5 (10) -triene; 14, 17-ethane-7a-. { 5 - [N-met il-N- 3 - (4, 4, 5, 5, 5-pentafluoropentanesulfonyl) -propylamino] -pent il} -estra- 1,3,5 (10) -trien-3,17β-diol; 17 -trifluoromet il-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-penta-fluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trie -3,17ß-dÍ? l; s 15β, 16β-methano-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-l, 3,5 (10) -trien-3, 17ß-diol; 15β, 16β-methano-17-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentanesulf inyl) -propylamino] -pentyl} -estra- 1,3,5 (10) -trien-3, 17β-diol; 15β, 16β-methane-7a-. { 5- [N-methyl-N-3 - (4, 4, 5, 5, 5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; 15β, 16β-methane-7a-. { 5 - [N-methyl-N-3 - (4, 4, 5, 5, 5 -pentaf luoropentanesulf inyl) -propylamino] -pent il} -estra- 1,3,5 (10) -trien-3,17β-diol; 15β-methyl-7a-. { 5- [N-methyl-N- 3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; 15β, 17a-dimethyl-7a-. { 5- [N-methyl-N-3 - (4, 4, 5, 5, 5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro-7 -. { 5- [N-methyl-N- 3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra -1,3, 5 (10) -trien-3, 17β-diol; l l ß - f l uoro - 7a -. { 5 - [N-met i l -N- 3 - (4, 4, 5, 5, 5 -pentaf luoropentanesulf inyl) -propylamino] -pent il} -estra- 1,3,5 (10) -trien-3, 17β-diol; l l ß - f luoro - 7a -. { 5 - [N-met i l -N- 3 - (4, 4, 5, 5, 5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3,5 (10) -trien-3,17β-diol; 16a-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol; 16 -fluoro-17β-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-l, 3.5 (10) -trien-3, 17a-diol; 16a-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanosulfinyl) -propylamino] -pen il} -estra- 1,3,5 (10) -trien-3, 17β-diol; 16a-fluoro-17-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentanesulfonyl) -propylamino] -pen il} -estra- 1,3,5 (10) -trien-3,17β-diol; 16a-fluoro -la-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3.5 (10) -trien-3, 17β-diol; 16a-fluoro-7 -. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17a-diol; 16 -fluoro-7a-. { 5- [N-methyl-N-3 - (4, 4, 5, 5, 5-pentafluoropentanosulfinyl) -propylamino] -pent il} -estra- 1,3,5 (10) -trien-3, 17β-diol; 16a-fluoro-7a-. { 5- [N-methyl-N-3 - (4, 4, 5, 5, 5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra- 1, 3, 5 (10) -trien-3, 17β-diol; 7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10), 14-tetraen-3, 17β-diol; 7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentanesulf inyl) -pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol; llß-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3,5 (10) -trien-3, 17β-diol; llß-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra- 1,3,5 (10) -trien-3, 17β-diol; llß-fluoro-7a-. { 5- [N-methyl-N-2 - (4, 4, 5, 5, 5-pentafluoropentanesulfonyl) -ethylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3-hydroxy-estra-1, 3,5 (10) -trien-17-one; llß-fluoro-7a-. { 6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -hexyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro-7a-. { 6- [N-methyl-N-3 - (4, 4, 5, 5, 5-pentaf luoropentanesulf inyl) -propylamino] -hexyl} -estra- 1,3,5 (10) -trien-3, 17β-diol; llβ-f luoro-7a- (5- { [N-3- (f uran-2-i-lmet i 11 io) -propyl] -N-methylamino}. -pentyl) -estra-1,3, 5 (10) -trien-3, 17β-diol; llβ-f luoro-7a- (5- { N -methyl- [N-3- (thiof en-2-ylmethylthio) -pro-pyl] -amino.}. -pentyl) -estra-1,3, 5 (10) -trien-3, 17β-diol; llß-f luoro-7 -. { 5- [(2S) -2- (4 -trif luoromet-ilf-enylthiomethyl) -pyrrole-idin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro-17a-methyl-7a-. { 5- [(2S) -2- (4, 4, 5, 5, 5-propylamino] -pentyl.} .estra-1, 3,5 (10), 14-tetraen-3, 17β-diol; - { 5- [N-methyl-N-3- (4,4,5,5, 5-pentafluoropentanesulfonyl) -propylamino] -pentyl.} - -estra-1, 3, 5 (10), 14- tetraen-3, 17β-diol; la- { 5- [(2S) -2- (4,4,5,5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl.} -estra- 1,3, 5 (10) -trien-3, 17β-diol; 7a-. {5 - [(2R) -2- (4,4,5,5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl ] -pentyl.} -estra-1, 3, 5 (10) -trien-3, 17β-diol; 17a-methyl-7a- { 5- [2- (4,4,5,5, 5 -pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl.} -estra-1,3, 5 (10) -trien-3, 17β-diol; 11β-fluoro-7a- { 5- [2- ( 4,4,5,5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl.} .estra-1, 3, 5 (10) -trien-3, 17β-diol, 11β-fluoro-17a- methyl-7a-. {5- [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 ( 10) -trien-3, 17β-diol; 11β-fluoro-17a-methyl-7a- { 5- [(2S) -2- (4,4,5,5 , 5-pentafluoropentanosulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro-17a-methyl-7 -. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3.5 (10) -trien-3, 17β-diol; 7a-. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; 7a-. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17ß-diol; llß-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanosulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro-17a-methyl-7a-. { 5- [(2R) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -trien-3,17β-diol; llß-fluoro-7a-. { 5- [(2S) -2- (4, 4, 5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; l l ß - f l uo ro - 7 a -. { 5 - [(2 S) -2- (4, 4, 5, 5, 5-pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; l l ß - f l uoro - 7 a -. { 5 - [(2 S) -2- (4, 4, 5, 5, 5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol. The compounds of general formula I possess a very strong antiestrogenic activity. The compounds of the invention are, on the one hand, pure antiestrogens or, on the other hand, they are so-called partial antagonists, ie antiestrogens with a partial estrogenic activity such as tamoxifen or raloxifene. However, the estrogen agonist activity of the compounds of the invention is much weaker than that of tamoxifen. In contrast to tamoxifen, the partial antagonists of general formula I exhibit an estrogen agonist activity that is tissue-selective. The agonist action occurs, in particular, in the bones, in the cardiocirculatory system and in the central nervous system (CNS). Particularly in the uterus, no agonist activity is recorded. A large number of compounds with antiestrogenic properties, ie substances that have an inhibitory action against estrogens, have already been described. The compounds structurally closest to the compounds of general formula I of the present invention are the steroids described in EP-A 0 138 504, in particular 7 - [9- (4,4,5,5, 5-pentafluoropentylsulfinyl ) -n-nonyl] -estra-1,3,5 (10) -trien-3, 17β-diol (EP-A 0 138 504, page 58, second-to-last compound). This compound is currently in clinical development for the treatment of hormone-dependent tumors (breast cancer) and constitutes the most well-known compound for this purpose, that is, among the steroids mentioned there is the compound with the strongest anti-estrogenic activity. Pharmaceutical compositions containing sex steroid inhibitors having a steroid structure with a side chain in position 7a and at least another substituent in position 14, 15 or 16 are subject of EP-A 0 376 576 and are also considered as the state of the art closest. In WO 93/10741 a large number of compounds of different types are published, among them also the compounds of steroidal origin and those that have a basic structure of 2-phenylindol- that exert an antiestrogenic activity and / or that repress the estrogen biosynthesis. . EP-AS 0 384 842 and 0 629 635 disclose other steroidal antiestrogens which have a ll-phenyl radical. The compounds of the invention are antiestrogens with a stronger antiestrogenic activity and much higher than that of la- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) -n-nonyl] -estra-1, 3, 5 ( 10) -trien-3, 17β-diol already mentioned. Compared with the known steroids described in EP-A 0138 504 and EP-A 0 367 576, the compounds of general formula I of the invention stand out because in carbon 7 of the spheroid skeleton have novel side chains. By means of this structural modification, compounds with a particularly high antiestrogenic activity are obtained, as was found in the transactivation assays. The compounds of formula I of the invention also differ from the compounds of EP-A 0 138 504 by substitution at carbon 11 and / or by ring D (except in the case where A and B, together, represent - (CH2) p- or that A and D, together, represent - (CH2) q-). In comparison with the compounds of EP-A 0 367 576, the compounds of the general formula I can carry the same or different substituents on the carbon atom 11 and / or on the D ring. The general formula I has been defined in such a way as to exclude all those compounds that are covered by the German patent, unpublished, No. 19,622,457. The antiestrogenic activity of the compounds of the invention was determined by transactivation assays [Demirpence E., Duchesne M.-J., Badia E., Gagne Dy Pons M.: MVLN Cells: A Bioluminescent MCF-7-Derived Cell Line to study the Modulation of Estrogenic Activity; J. Steroid. Molec. Biol. Vol. 46, No. 3, 355-364 (1993) and Berry M., Metzger D. Chambón P .: Role of the two activating domains of the estrogen receptor in the cell-type and promoer-context dependent agonistic activity of the antiestrogen 4-hydoxytamoxifen; The EMBO Journal Vol.9, 2811-2818 (1990)]. Hela cells have been grafted with the expression vector of the human estrogen receptor (HEGO) and with the messenger gene Vit-TK-CAT, and in the MVLN cells the messenger gene Vit-TK-LUC has been stably transferred. Estrogen potency was determined in the presence of 0.1 nM estradiol. The IC50 values of the new compounds are given in nanomoles. Both the Hela cell line and the MVLN cell line are obtained for the compounds of examples 12, 15, 18, 25, 29, 31 and 36 and also for the 7a- [9- (4, 4, 5 , 5, 5-pentafluoropentyl-sulfinyl) -n-nonyl] -estra-1, 3, 5 (10) -trien-3,17β-diol the following IC50 values (the tests were carried out according to the indicated methods in the literature cited above): Compound IC50 [nM] Hela cells MVLN cells Example 12 0.06 2.4 Example 15 0.06 1.4 Example 18 0.05 0.13 Example 25 0.06 0.15 Example 29 0.13 0.2 Example 31 0.1 0.2 Example 36 0.05 0.4 Reference: 7a- [9- (4, 4, 5, 5, 5-pentafluoro- 0.5 6.0 pentanosulfinil ) -nonil] -estra-1,3,5 (10-trien-3,17β-diol) Test of the growth of the uterus in infant rats (antiestrogenic activity) Principle of the method The uterus of rodents reacts to the administration of estrogens with a increase in weight (both proliferation and storage of water), this growth must be inhibited in a dose-dependent manner by the simultaneous administration of compounds with antiestrogenic activity. Carrying out the test Animals At the beginning of the test the female infant rats had a weight of 35 to 45 g; 5 to 6 animals per dose. Formulation and administration of substances: For oral administration (p.o.) the substances were dissolved in one part of ethanol (E) and brought to volume with 9 parts of peanut oil (EO). Beginning of the trial The young newborn rats are delivered for acclimation one day before the start of treatment and are immediately provided - in the cage - with food. The treatment is carried out once a day for 3 days and in combination with 0.5 ug of estradiol benzoate (BE). The BE is always applied subcutaneously (s.c), while the test substance is administered orally (p.o.). After 24 hours have passed since the last application, the animals are weighed, killed and the uterus is removed. Wet weights (without content) are determined from the dissected uteri. Controls Negative control: vehicle (E / EO), 0.2 ml / animal / day Positive control: 0.5 ug BE / 0, lml / animal / day Analysis and assessment Based on the relative weights of the organs (mg / lOOg of body weight) the mean values are determined for each group with their standard deviation (X + SD) and the significance of the differences with respect to the control group (BE) in the Dunnett test (p <0.05). The calculation of the inhibition (in%) with respect to the control group BE is carried out with a program. The relative efficiencies of the test substances are determined by an analysis of covariance and regression. Antiuterotrophic activity in the rat Example 0.1 mg / kg p.o. IC50% inhibition 12 91 0.01 15 33 0.24 18 16 > 0.3 29 80 0.01 31 71 0.04 36 62 0.03 reference 8 0.39 The compounds act by inhibiting the growth of tumor cells dependent on hormones. In particular, they inhibit the growth of human breast and estrogen-dependent tumor cells (MCF-7). The antiproliferative activity of the new compounds in breast carcinoma cell lines is greater than that of 7a- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) -n-nonyl] -estra-1 , 3, 5 (10) -trien-3, 17β-diol. Accordingly, the compounds of the invention are suitable, in particular when they are pure antiestrogens, for the therapy of estrogen-dependent diseases such as, for example, breast carcinoma, endometrial carcinoma, prostatic hyperplasia, ovulatory infertility and melanoma. The pure antiestrogens of general formula I can also be used as components of the products described in EP 346 014 Bl containing an estrogen and a pure antiestrogen, and thus can be used simultaneously, successively or separately for the Selective estrogenic tetrapia in peri or postmenopausal women. The compounds of general formula I can be used, in particular when dealing with pure estrogens, in combination with antigestagens (competitive progesterone antagonists) for the treatment of hormone-dependent tumors (EP 310 542 A). Other indications for which the compounds of general formula I can be used, in particular when they are pure antiestrogens, are male-type alopecia, extended alopecia, alopecia induced by chemotherapy and hirsutism (Hye-Sun Oh and Robert C. Smart, Proc. Nati, Acad. Sci. USA, 93 (1996) pp. 12525 to 12530). The compounds of general formula I can also be used to prepare medicaments for the treatment of endometriosis and ovarian carcinomas. In addition, the compounds of general formula I can also be used to prepare pharmaceutical compositions for the control of male and female fertility (male fertility control: DE-A 195 10 862.0). Those compounds of general formula I which exhibit a partial estrogenic activity which is selective according to the tissue can be used, first of all, for the prophylaxis and therapy of osteoporosis and for the preparation of preparations intended for substitution therapy in the pre , peri and postmenopause (HRT). (Black, LJ, Sato, M., Rowley, ER, Magee, DE, Bekele, A., Williams, DC, Cullinan, GJ, Bendele, R., Kauffmann, RF, Bensch, WR, Frolik, CA, Complete, JD and Bryant, HU: Raloxifene [LY 139481 HCl] prevents bone loss and reduces blood serum without causing uterine hypertrophy in ovariectomized rats; J. Clin. Invest. 93, pp. 63-69, 1994). The partial estrogenic activity was checked exclusively in the desired recipient organ. The invention also relates to pharmaceutical preparations containing at least one compound of general formula I (or its salt by addition of organic and inorganic acids, physiologically acceptable), and the use of these compounds to prepare medicaments intended for , in particular, to the treatment of estrogen-dependent diseases and tumors and hormone replacement therapy (HRT). The compounds of the invention and their acid addition salts are suitable for preparing pharmaceutical compositions and preparations. The pharmaceutical compositions or medicaments contain as active substance one or more compounds of the invention or their compounds by the addition of acids, optionally together with other pharmacologically or pharmaceutically active substances. The medicaments are prepared in a known manner, optionally using known and customary auxiliary pharmaceutical substances and also customary excipients and diluents. Among the excipients and auxiliary substances can be mentioned, for example, those indicated or recommended in the bibliography cited below as auxiliary substances for pharmacy, cosmetics and other related items: Encyklopádie der technischen Chemie de Ullman, volume 4 (1953 ), pages 1 to 39; Journal of Pharmaceutical Sciences, volume 52 (1963), pp. 918 et seq., H. v. Czetsch-Lindenwald, Hifsstoffe für Pharmazie und angrenzende Gebiete; Pharm. Ind., Volume 2, 1961, p. 72 and following; Dr. H.P.Fiedler, Lexikon der Hílfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete Cantor KG. Aulendorf in Würtemberg 1971. The compounds can be administered orally or parenterally, for example, intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted in the tissue. The amount of the compounds that must be administered ranges over a wide range and can cover any amount that is effective. Depending on the condition of the patient to be treated and the type of administration, the amount of the compound administered can vary between 0.1 and 25 mg / kg of body weight, preferably between 0.5 and 5 mg / kg of body weight, per day. This represents in humans a daily dose of 5 to 1250 mg. The preferred daily dose in humans is 50 to 200 mg. For oral administration, capsules, pills, tablets, dragees, etc. are suitable. In addition to the active substance, the dosage units may also contain pharmaceutically acceptable excipients such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc. The individual dosage units intended for oral administration may contain, for example, between 5 and 500 mg of the active substance. To achieve improved bioavailability of the active substance, the compounds can be formulated as cyclodestrin clathrates. For this, the compounds are reacted with a-, β- or β-cyclodextrin or their derivatives (PCT / EP95 / 02656). For parenteral administration, the active substances can be dissolved or suspended in an acceptable diluent from the physiological point of view. As diluents, oils are commonly used, either with or without the addition of a dissolving agent, a surfactant, a suspending agent or an emulsifier. Examples of the oils used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil. The compounds can also be used in the form of a delayed-action injection or an implantable preparation, which can be formulated in such a way as to allow a sustained release of the active substance. As inert materials, the implants may contain, for example, biologically degradable polymers or synthetic silicones such as, for example, silicone rubber. The active substances intended for percutaneous application can be presented, for example, in the form of a plaster. The compounds of the invention can be prepared according to the methods described below. The following examples explain the invention in more detail. All compounds of general formula I can be obtained by means of similar procedures and by the use of reagents analogous to those of the indicated examples. Both the saponification of ester groups and the esterification and etherification of free hydroxyl groups are carried out according to known procedures of organic chemistry. Taking into account the difference in the reactivity of the free and esterified 3- and 17-hydroxyl group, the 3,17-diester can be selectively cleaved in position 3 and the 3-hydroxy-17-acyloxy compound thus obtained can be derivatized again in position 3; it is also possible to selectively esterify or etherify the 3,17-dihydroxyl compound only in position 3 and then incorporate in position 17 a residue different from that found in the 3-position. The acid addition salts of the compounds of general formula I they can also be prepared according to customary procedures and from the respective compounds of general formula I.

Example 1 14, 17-ethane-7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -estra-l, 3,5 (10) -trien-3, 17ß-diol a) 7a- (5-tert-butyldimethylsilyloxypentyl) -estr-4-en-3, 17-dione To prepare the Grignard reagent, 15.1 g of Mg chips are reacted in 70 ml of absolute tetrahydrofuran with 175.6 g of l-bromo-5-tert-butyldimethylsilyloxypentane [Tetrahedron Letters 23, 1982, 40, p. 4147 to 4150] dissolved in 600 ml of absolute tetrahydrofuran. To this solution cooled to -20 ° C, 59 g of copper iodide (I) are added under a nitrogen atmosphere and then, dropwise and in the course of one hour, 50 g of estra-4,6-dien-3. , 17-dione [Steroids Vol. 1, 1963, p. 233 to 249] dissolved in 300 ml absolute THF. To separate the product, 37.5 ml of acetic acid are added dropwise, the reaction mixture is diluted with ethyl acetate, washed with saturated ammonium chloride solution, water and sodium bicarbonate solution and dried . The residue which is obtained after concentration by evaporation is chromatographed on silica gel. 35.4 g of 7a- (5-tert-butyldimethylsilyloxypentyl) -estr-4-en-3,17-dione are obtained; [a] 22D = + 52.8 ° (c = 0.535% in chloroform). b) 7 a- (5-hydroxypentyl) -estr-4-en-3, 17-dione At 50 ° C a solution of 125.4 g of 7- (5-tert-butyldimethylsilyloxypentyl) ester is stirred for 2.5 hours. -4-in-3, 17-dione in 625 ml of methanol and 347 ml of water with 694 ml of glacial acetic acid. After evaporating at 60 ° C under vacuum, 94.1 g of crude 7- (5-hydroxypentyl) -estr-4-en-3,17-dione are obtained and in the oil state. c) 7 a- (5-acetoxy pentyl) -estr-4-en-3, 17-dione A solution of 94 g of 7 a- (5-hydroxypentyl) -estr-4-en-3,17-dione crude in 620 ml of pyridine is slowly mixed with 310 ml of acetic anhydride and stirred for 2 hours at 25 ° C. In an ice bath, 116 ml of water are added slowly, then it is diluted with 3 1 of diethyl ether, the organic phase is washed with sodium bicarbonate solution, dried and concentrated by evaporation. The residue is chromatographed on silica gel and 84.4 g of 7a- (5-acetoxypentyl) -estr-4-ene-3,17-dione are obtained at the oil state. d) 7a- (5-acetoxy-pentyl) -3-hydroxy-estra-1, 3, 5 (10) -trien-17-one To a solution of 82.3 g of 7a- (5-acetoxy-pentyl) -estr-4-en-3,17-dione in 936 ml of acetonitrile are added, in a bath at 80 ° C, 17.8 g. of lithium bromide and 92.83 g of copper (II) bromide. After standing in the bath at 80 ° C for 10 minutes, the reaction solution is cooled, extracted three times with ethyl acetate, washed with water and sodium bicarbonate solution and dried. The residue obtained after evaporation is chromatographed on silica gel and thus 60.4 g of 7- (5-acetoxypentyl) -3-hydroxy-estra-1, 3, 5 (10) -trien-17- are obtained. ona to the oil state. e) 3-acetoxy-7a- (5-acetoxy-pentyl) -estra-1, 3, 5 (10) -trien-17-one A solution of 60.4 g of 7a- (5-acetoxy pentyl) -3-hydroxy-estra-l, 3, 5 (10) -trien-17-one in 300 ml of pyridine is stirred with 150 ml of acetic anhydride during 1 hour at room temperature. The reaction mixture is then precipitated with a mixture of ice / water / sodium chloride / hydrochloric acid, the precipitate is taken up with ethyl acetate, washed until neutral with sodium bicarbonate solution and sodium chloride solution, dried on sodium sulfate and concentrated in vacuo. 63.9 g of 3-acetoxy-7- (5-acetoxypentyl) -estra-1,3,5 (10) -trien-17-one are obtained at the oil state. f) 3-acetoxy-7a- (5-acetoxy pentyl) -17, 17-ethylenedioxy-estra-1,3,5-10) -triene A solution of 63.9 g of 3-acetoxy-7a- (5) is stirred. -acetoxipentil) -estra-1, 3, 5 (10) -trien-17-one in 460 ml of dichloromethane with 460 ml of ethylene glycol, 155 ml of trimethyl ortho-formate and 1.2 g of para-toluene- sulphonic for 3 hours in a bath at 50 ° C. It is then diluted with dichloromethane, washed with sodium bicarbonate solution and sodium chloride solution, dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel with hexane / ethyl acetate. 63.2 g of 3-acetoxy-la- (5-acetoxypentyl) -17, 17-ethylenedioxy-tetra-1, 3,5 (10) -triene are obtained at the oil state. g) 3-acetoxy-7a- (5-acetoxy pentyl) -16a-bromo-17, 17-ethylene-dioxy-estra-1, 3, 5 (10) -triene To a solution of 63.2 g of 3-acetoxy -7a- (5-acetoxy-pentyl) -17, 17-ethylenedioxy-estra-l, 3,5 (10) -triene in 630 ml of tetrahydrofuran are added, in portions and at 0 ° C, 61,7g of perbromide pyridine bromohydrate and the mixture is stirred for 2 hours at 0 ° C. Then a solution of 15 g of sodium sulphide in 70 ml of water is added, diluted with ethyl acetate, washed with sodium bicarbonate solution and sodium chloride, dried over sodium sulfate and concentrated in vacuo. 74, 3-acetoxy-7a- (5-acetoxy-pentyl) -16-bromo-17, 17-ethylenedioxy-estra-l, 3,5 (10) -triene is obtained at the oil state. h) 17, 17-ethylenedioxy-7a- (5-hydroxypentyl) -estra-1, 3.5 (10), 15-tetraen-3-ol A solution of 74.1 g of 3-acetoxy-7a- is stirred (5-acetoxy pentyl) -16a-bromo-17, 17-ethylenedioxy-estra-l, 3,5 (10) -triene in 740 ml of dimethyl sulfoxide and 74 ml of methanol with 74 g of potassium hydroxide for 7.5 hours and in a bath at 85 ° C. The reaction mixture is then precipitated with a mixture of ice / water / sodium chloride, the precipitate is taken up with ethyl acetate, washed until neutral, dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel. silica with hexane / ethyl acetate. 36.12 g of 17, 17-ethylenedioxy-7a- (5-hydroxypentyl) -estra-1, 3, 5 (10), 15-tetraen-3-ol are obtained in the pure state and in the form of foam. i) 3-hydroxy-la- (5-h.-hydroxypentyl) -estra-1, 3,5 (10), 15-tetraen-17 -one A solution of 36.12 g of 17, 17-ethylenedioxy-7a- (5-hydroxypentyl) -estra-1, 3, 5 (10), 15-tetraen-3-ol in 958 ml of acetone and 111 ml of water is stirred with 2.76 g of para-toluenesulfonic acid for 2 hours at room temperature . It is then concentrated in vacuo to 1/3 of the original volume, the residue is taken up in ethyl acetate, washed until neutral, dried over sodium sulfate and concentrated in vacuo. 31.7 g of 3-hydroxy-la.- (5-hydroxypentyl) -estra-1, 3, 5 (10), 15-tetraen-17-one are obtained at the crystal stage and have a melting point of 194. -196 ° C. j) 3, 17-diacetoxy-7a- (5-acetoxy-pentyl) -estra-1, 3.5 (10), 14,16-pentane A solution of 15.7 g of 3-hydroxy-7a- (5-hydroxypentyl) ) -estra-1, 3, 5 (10), 15-tetraen-17-one in 330 ml of acetic anhydride is stirred with 4,6 g of paratoluenesulfonic acid for 4 hours at room temperature. The reaction mixture is then precipitated with a mixture of pyridine / water / sodium chloride, the precipitate is taken up in ethyl acetate, washed with sodium bicarbonate solution and sodium chloride, dried over sodium sulfate, Concentrate in vacuo and chromatograph on silica gel with hexane / ethyl acetate. 11, Ig of 3, 17-diacetoxy-7a- (5-acetoxypentyl) -estra-1, 3, 5 (10), 14, 16-pentaeno are obtained in the pure and oil state. k) 3, 17β-diacetoxy-7a- (5-acetoxy-pentyl) -14a, 17a-etheno-estra-1, 3, 5 (10) -triene. 11.0 g of 3,17-diacetoxy-7a- ( 5-acetoxy pentyl) -estra-1, 3, 5 (10), 14, 16-pentaene in 120 ml of benzene with ethene at a pressure of 300 bar, 175 ° C and for 6.5 days. The product is then taken with ethyl acetate, washed with sodium bicarbonate solution and sodium chloride, dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel with hexane / ethyl acetate. 8.4 g of 3, 17β-diacetoxy-7 - (5-acetoxypentyl) -14a, 17a-etheno-estra-1, 3, 5 (10) -triene are obtained at the foam state. 1) 3, 17β-diacetoxy-7a- (5-acetoxy pentyl) -14a, 17a-ethane-estra-1,3,5 (10) -triene A solution of 8.4 g of 3, 17β-diacetoxy-7 - (5-acetoxy pentyl) -14, 17a-etheno-estra-l, 3, 5 (10) -triene in 200 ml of ethyl acetate is stirred vigorously with 1.5 g of palladium (10%) on charcoal for one hour, at room temperature and under a hydrogen atmosphere. It is then filtered with suction on a celite bed, washed with ethyl acetate, concentrated in vacuo and purified by chromatography on silica gel with hexane / ethyl acetate. 6 are obtained, 0 g of 3, 17β-diacetoxy-7a- (5-acetoxypentyl) -14a, 17a-ethane-estra-1, 3,5 (10) -triene at the foam state. m) 14a, 17a-ethane-7a- (5-hydroxypentyl) -estra-1, 3, 5 (10) -trien-3,17β-diol A solution of 6.0 g of 3,17β-diacetoxy is allowed to rest. -7a- (5-acetoxy pentyl) -14a, 17a-ethane-estra-1, 3,5 (10) -triene in 100 ml of 1 molar solution of potassium hydroxide for 7.5 hours at room temperature. The solution is then poured into 1 molar hydrochloric acid, extracted three times with ethyl acetate, washed with sodium bicarbonate solution and sodium chloride, dried over sodium sulfate, concentrated in vacuo and recrystallized from acetone. / hexane. 4.57 g of 14a, 17a-ethane-7a- (5-hydroxypentyl) -estra-1,3,5 (10) -trien-3,17β-diol are obtained at the state of colorless crystals with a melting point of 63-65 °. n) 3-benzyloxy-14a, 17a-ethane-7a- (5-hydroxypentyl) -estra-1,3,5 (10) -trien-17ß-ol A solution of 4.5 g of 14a, 17a-ethano- 7a- (5-hydroxypentyl) -estra-1, 3, 5 (10) -trien-3, 17β-diol in 90 ml of acetonitrile is stirred with 1.91 g of potassium carbonate and 1.53 ml of bromide. Benzyl for 6.5 hours and in a bath at 80 ° C. It is then concentrated in vacuo to 1/3 of the original volume, the residue is poured into water, extracted three times with ethyl acetate, washed until neutral, dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel with dichloromethane / acetone. 4.8 g of 3-benzyloxy-14a, 17a-ethane-7a- (5-hydroxypentyl) -estra-1, 3, 5 (10) -triene-17β-ol are obtained at the foam state. o) 3-benzyloxy-14a, 17a-ethano-7a- (5-tosyloxypentyl) -estra-1, 3, 5 (10) -trien-17ß-ol A solution of 4.8 g of 3-benzyloxy-14, 17a-Ethane-7a- (5-hydroxypentyl) -estra-1,3,5 (10) -trien-17β-ol in 50 ml of pyridine is stirred at 0 ° C with 3.63 g of toluenesulfonic anhydride for 4 hours . It is then diluted with ethyl acetate, extracted with 2 molar hydrochloric acid, washed until neutral, dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel with hexane / ethyl acetate. 4.75 g of 3-benzyloxy-14a, 17a-ethano-7a- (5-tosyloxypentyl) -estra-1, 3, 5 (10) -trien-17β-ol are obtained at the foam state. p) 3-benzyloxy-14a, 17a-ethane-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-l, 3,5- (10) -trien-17ß-ol A solution of 4.7 g of 3-benzyloxy-14a, 17-ethane-7a- (5-tosyloxypentyl) -estra-1,3, 5 (10) -triene-17β-ol in 100 ml of dimethylformamide is stirred with 2.7 g of methyl- [3- (4,4,5,5,5-pentafluoropentylthio) -propyl] -amine for 4 hours and in a bath at 80 ° C. The reaction mixture is then poured into water, extracted three times with ethyl acetate, washed with sodium chloride, dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel with dichloromethane / methanol. 3.8 g of 3-benzyloxy-14a, 17a-ethane-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoro-pentylthio) -propylamino] -pentyl} -estra-1, 3, 5- (10) -trien-17ß-ol to the oil state. q) 14a, 17a-ethane-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3,5- (10) -trien-3,17β-diol A solution of 3.7 g of 3-benzyloxy-14a, 17a-ethane-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamine] -pentyl} -estra-1, 3, 5- (10) -trien-17ß-ol in 65 ml of dichloromethane is stirred at 0 ° C with 2.1 ml of N, N-dimethylaniline for 5 minutes, then 2.75 is added g of anhydrous aluminum chloride and stirred for an additional 3.5 hours at 0 ° C. Then add a saturated aqueous solution of sodium potassium tartrate, pour into water, extract three times with dichloromethane, wash until neutral, dry over sodium sulfate and concentrate in vacuo. 6.3 g of the crude product is obtained, which is purified by chromatography on silica gel with dichloromethane / methanol as eluent. 2.85 g of 14a, 17a-ethane-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5- (10) -trien-3, 17ß-diol at the state of pure crystals with a melting point of 63-67 ° C, [a] 22D = + 19.4 ° (c == 0.505% in chloroform).

Example 2 14, 17-ethane-7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentanesulf inyl) -propylamino] -pentyl} -estra-1,3,5 (10) -trien-3,17β-diol A solution of 1.0 g of 14a, 17a-ethane-7a- is stirred. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5- (10) -trien-3, 17β-diol in 37.5 ml of methanol and 1.78 ml of water for 5 hours with 381 mg of sodium periodate at room temperature. The mixture is then poured into water, extracted three times with dichloromethane, washed until neutral, dried over sodium sulfate and concentrated in vacuo. 985 g of the crude product are obtained, which is purified by chromatography on silica gel with dichloromethane / methanol as eluent. 514.3 mg of 14, 17-ethane-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17ß-diol at the state of pure crystals with a melting point of 84-86 ° C, [a] 2 D = + 13.0 ° (c = 0.5% in chloroform).

Example 3 3, 17β-diacetoxy-14a, 17a-ethane-7a-. { 5- [N-methyl-N- 3 - (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} - -1.3, 5 (10) -triene A solution of 600 mg of 14, 17 -ethane-7a- is stirred. { 5- [N-methyl-N-3 - (4,4,5,5,5-pentaf luoropentylthio) -propyl-amino] -pentyl} -estra-1, 3, 5- (10) -trien-3, 17β-diol in 2 ml of pyridine and 1 ml of acetic anhydride for 4.5 hours with 5 mg of dimethylaminopyridine at room temperature. It is then diluted with ethyl acetate, washed with water and with sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. 680 mg of 3, 17β-diacetoxy-14, 17a-ethane-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trieno to the state of oil.

Example 4 14, 17 - ethane - l -. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoro-pentanesulfonyl) -propylamino] -pentyl} -estra-1, 3,5 (10) -trien-3,17β-diol A solution of 650 mg of 3, 17β-diacetoxy-14a, 17-ethane-7a- is stirred. { 5- [N-methyl-N- 3 - (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3,5- (10) -triene in 15 ml of glacial acetic acid for 3 hours with 1.5 g of sodium perborate tetrahydrate at room temperature. The mixture is then poured into water, extracted three times with dichloromethane, washed until neutral, dried over sodium sulfate, concentrated in vacuo, the residue is taken up with 10 ml of 0.2 molar methanolic solution of potassium hydroxide. , it is stirred for 24 hours at room temperature, the mixture is poured into water, extracted three times with dichloromethane, washed until neutral, dried over sodium sulfate, concentrated in vacuo, the residue is suspended in 20 ml of acetate. of ethyl, take the suspension with 10 ml of tin (II) chloride solution, stir for 4 hours at room temperature, dilute with ethyl acetate, wash with sodium chloride solution, dry over Sodium sulfate, concentrated in vacuo and the product chromatographed on silica gel with hexane / ethyl acetate. 300 mg of pure crystals of 1,17-ethane-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propyl-amino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17ß-diol, with a melting point of 55-58 ° C, [a] 22D = + 19.4 ° (c = 0.51% in chloroform).

Example 5 17a-trifluoromethyl-7 -. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17ß-diol a) 17ß-acetoxy-7a- (5-tert-butyl-dimethylsilyloxypentyl) -estr-4-en-3 -one To prepare the Grignard reagent 22.9 g of Mg chips are reacted with 200 ml of absolute tetrahydrofuran with 261 g of l-bromo-5-tert-butyldimethylsilyl-oxypentane [Tetrahedron Letters 23, 1982, 40, p. 4147 to 4150] dissolved in 250 ml of absolute tetrahydrofuran. To this solution cooled to -20 ° C, 92.9 g of copper iodide (I) are added under a nitrogen atmosphere and then, dropwise and in the course of one hour, 73.5 g of 17β-acetoxiestra-4,6. -dien-3-one [J. Am. Chem. Soc. 80, 1958, pp. 2596 to 2597] dissolved in 300 ml absolute THF. To separate the product, 61.2 ml of acetic acid are added dropwise, the reaction mixture is diluted with ethyl acetate, washed with saturated ammonium chloride solution, water and sodium bicarbonate solution and dried . The residue which is obtained after concentration by evaporation is chromatographed on silica gel. 48 g of 17β-acetoxy-7α- (5-tert-butyldimethylsilyloxypentyl) -estr-4-en-3-one are obtained. b) 17β-acetoxy-7a- (5-hydroxypentyl) -estr-4-en-3-one A solution of 48 g of 17β-acetoxy-7a- (5-tert-butyldimethylsilyloxypentyl) -estr-4-en-3-one in 350 ml of methanol it is left to rest together with 35 ml of 8% by volume sulfuric acid for 30 minutes at room temperature. The solution is diluted with diethyl ether, washed with water until neutral and dried. After concentrating by evaporation, 31, 17β-acetoxy-7a- (5-hydroxypentyl) -estr-4-en-3-one is obtained at the oil state. c) 17β-Acetoxy-7a- (5-acetoxy-pentyl) -tr-4-en-3-one A solution of 37.7 g of 17β-acetoxy-7a- (5-hydroxypentyl) -estr-4-en-3 -one in 160 ml of pyridine is slowly mixed with 80 ml of acetic anhydride and stirred for 16 hours at 25 ° C. It is then diluted with ethyl acetate, the organic phase is washed with sodium bicarbonate solution, dried and concentrated by evaporation. The residue is chromatographed on silica gel and 26.6 g of 17β-acetoxy-7 - (5-acetoxypentyl) -estr-4-en-3-one are obtained at the oil state; [a] 22D = + 20.0 ° (c = 0.51% in chloroform). d) 17β-Acetoxy-7a- (5-acetoxy-pentyl) -estra-1, 3, 5 (10) -trien-3-ol To a solution previously heated to 80 ° C of 26.6 g of 17β-acetoxy-7a- (5-acetoxy pentyl) -tr-4-en-3-one in 260 ml of acetonitrile is added dropwise and over 30 minutes. minutes with stirring, a solution of 5.18 g of lithium bromide and 26.73 g of copper (II) bromide in 260 ml of acetonitrile. Once the addition is complete, allow the reaction mixture to cool, dilute with diethyl ether, wash with water and sodium bicarbonate solution and dry. The residue obtained after evaporation is chromatographed on silica gel and 21.3 g of 17β-acetoxy-7a- (5-acetoxy pentyl) -1, 3, 5 (10) -estratrien-3-ol are obtained at the oil state; [] 22D = + 28.9 ° (c = 0.535% in chloroform). e) 17β-Acetoxy-7a- (5-acetoxypentyl) -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene A solution of 21.3 g of 17β-acetoxy-7a- (5-acetoxy pentyl) -estra-1, 3, 5 (10) -trien-3-ol in 213 ml of tetrahydrofuran is allowed to rest with 21.3 ml of 3,4-dihydro-2H-pyran and 1.065 g of acid p-toluenesulfonic for 8 hours at room temperature. The reaction solution is then taken with 3 ml of pyridine, diluted with diethyl ether, washed with water and dried. The residue obtained after evaporation is chromatographed on silica gel and 24.3 g of 17β-acetoxy-7a- (5-acetoxypentyl) -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 ( 10) -trieno to the state of oil; [a] 22D = + 31.5 ° (c = 0.535% in chloroform). f) 17β-Acetoxy-7a- (5-hydroxypentyl) -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene A solution of 10.2 g of 17β-acetoxy-7 - (5-acetoxy pentyl) -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene in 205 ml of methanol is stirred with 33.7 ml of sodium hydroxide for 45 minutes at 15 ° C. It is then diluted with diethyl ether, washed with water, dried over sodium sulfate and concentrated in vacuo. 5.6 g of 17β-acetoxy-7a- (5-hydroxypentyl) -3- (tetrahydropyran-2-yl-oxy) -estra-1,3,5 (10) -triene are obtained; [a] 2 D = + 32.2 ° (c = 0.505% in chloroform). g) 17β-acetoxy-3 - (tetrahydropyran-2-yloxy) -7a- (5-p-toluenesulfonyloxypentyl) -estra-1, 3,5 (10) -triene A solution of 5.5 g of 17β-acetoxy- 7a- (5-hydroxypentyl) -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene in 47 ml of pyridine is allowed to rest with 5.5 g of p-toluenesulfonic acid anhydride for 45 minutes at room temperature. The reaction solution is then cooled in an ice bath, add 4 ml of water and stir for 45 minutes. It is then diluted with ethyl acetate, washed with water, dried and concentrated. 8.2 g of 17β-acetoxy-3- (tetrahydropyran-2-yloxy) -l a - (5-p-toluenesulfonyloxypentyl) -estra-1,3,5 (10) -triene are obtained at the oil state. h) 17β-acetoxy-7a- (5-methylanylpentyl) -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene In a solution of 8.2 g of 17β-acetoxy- 3- (tetrahydropyran-2-yloxy) -la- (5-p-toluenesulfonyloxypentyl) -estra-1,3,5 (10) -triene in 80 ml of tetrahydrofuran, 6.3 g of methylamine are condensed using a pressure tube and cooling with ice. The sealed pressure tube is then heated for 6 hours at 60 ° C. After cooling, it is evaporated in vacuo to dryness and the residue is chromatographed on silica gel. 5.1 g of 17β-acetoxy-7α- (5-methylaminopentyl) -3- (tetrahydropyran-2-yl-oxy) -estra-1,3,5 (10) -triene are obtained at the oil state; [] 22D = + 29.7 ° (c = 0.535% in chloroform). i) 17β-acetoxy-7a-. { 5- [N-methyl-N-3 - (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1, 3, 5 (10) -triene A solution of 1.64 g of 17β-acetoxy-7a- (5-methylaminopentyl) -3- (tetrahydropyran-2-) iloxy) -estra-1, 3,5 (10) -triene in 25 ml of absolute DMF is stirred with 159 mg of 80% sodium hydroxide under nitrogen, for 2 hours and at room temperature. Then, 43 g of 3-chloropropyl-4,4,5,5-pentafluoropentyl sulphide in 7 ml of absolute DMF is added dropwise and then it is stirred for 22 hours at 80 ° C. The reaction solution is then diluted with ethyl acetate, washed with water, dried, concentrated by evaporation and the residue chromatographed on silica gel. 820 mg of 17β-acetoxy-la- are obtained. { 5 - [N-methyl-N- 3 - (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1, 3, 5 (10) -triene at the oil state; [a] 22D = + 21.5 ° (c = 0.51% in chloroform). j) 7 -. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17β-ol A solution of 790 mg of 17β-acetoxy-7a-. { 5- [N-methyl-N-3 - (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (Tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene in 8 ml of methanol and 3 ml of THF is stirred with 430 g of potassium carbonate for 18 hours at room temperature. The reaction solution is diluted with diethyl ether, washed with water, dried and concentrated by evaporation. 750mg of 7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (Tetrahydropyran-2-yloxy) -estra-1, 3, 5 (10) -trien-17β-ol crude. k) 7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-l, 3, 5 (10) -trien-3, 17ß-diol A solution of 750 mg la. { 5- [N-methyl-N-3- (4, 4, 5, 5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (Tetrahydropyran-2-yloxy) -estra-1, 3, 5 (10) -trien-17β-ol in 28 ml of methanol and 2.8 ml of water is stirred with 350 mg of oxalic acid for 17 hours at room temperature. It is then diluted with ethyl acetate, washed with sodium bicarbonate solution and water, dried and concentrated by evaporation. The residue is chromatographed on silica gel and 640 mg of la- are obtained. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -estra-l, 3,5 (10) -trien-3, 17β-diol at the oil state; [a] 22D = + 24.0 ° (c = 0.515% in chloroform). 1) 7a-. { 5- [N-methyl-N- 3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one A solution of 900 mg of 7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17β-ol in 30 ml of toluene and 9.6 ml of cyclohexanone is mixed with a solution of 900 mg of isopropoxide of Aluminum in 16 ml of toluene and heated for 30 minutes with slow separation by distillation. The reaction solution is then diluted with ethyl acetate, washed with 20% sodium potassium tartrate solution, dried and concentrated by evaporation. The residue is chromatographed on silica gel with hexane / ethyl acetate. 715 mg of 7a- are obtained. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -3- (tetrahydroraniran-2-yloxy) -estra-1, 3, 5 (10) -trien-17-one at the oil state. ) 17a-trifluoromethyl-3- (tetrahydropyran-2-yloxy) -7a-. { 5- [N-methyl-N-3 - (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-l, 3,5 (10) -trien-17ß-ol A solution of 500 mg of la-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (tetra-hydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one in 5 ml of absolute tetrahydrofuran is mixed in a 0 ° C bath with 0.27 ml of (trifluoromethyl) -trimethylsilane. Then it is added slowly, dropwise, 0.2 ml of a 1.1 molar solution of tetrabutylammonium fluoride and stir for 45 minutes, add another 1 ml of the 1.1 molar solution of tetrabutylammonium fluoride and stir for another 30 minutes. minutes It is then diluted with ethyl acetate, washed with water, dried over sodium sulphate, evaporated in vacuo and chromatographed on silica gel with dichloromethane / methanol. 285 mg of 17a-tri-fluoromethyl-3- (tetrahydropyran-2-yloxy) -7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-17ß-ol to the oil state. n) 17a-trifluoromethyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-l, 3, 5 (10) -trien-3, 17β-diol A solution of 280 mg of 17-trifluoromethyl-3- (tetrahydropyran-2-yloxy) -7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-17ß-ol in 5.6 ml of methanol and 0.56 ml of water is stirred together with 140 mg of oxalic acid for 18 hours at room temperature. It is then diluted with ethyl acetate, washed with sodium bicarbonate and water, dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel with dichloromethane / methanol. 215 mg of 17a-trifluoromethyl-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-l, 3,5 (10) -trien-3, 17β-diol at the oil state.

Example 6 15β, 16β-methano-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3,17β-diol a) 3-benzyloxy-17, 17-ethylenedioxy-7a- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraene A solution of 32.7 g of 17, 17-ethylenedioxy-7a- (5-hydroxypentyl) -estra-1, 3, 5 (10), 15-tetraen-3-ol (see example lh) in 327 ml of dimethylformamide is mixed at room temperature with 5.73 g of lithium hydroxide and stirred with 15.1 ml of benzyl bromide for 2 hours at 60 ° C. The reaction mixture is then diluted with ethyl acetate, washed with water, dried over sodium sulfate, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel with dichloromethane / methanol. 32.8 g of 3-benzyloxy-17,17-ethylenedioxy-7- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraene are obtained. b) 3-benzyloxy -la- (5-hydroxypentyl) -estra-1, 3, 5 (10), 15-tetraen-17-one A solution of 32.8 g of 3-benzyloxy-17, 17-ethylenedioxy- 7oc- (5-hydroxypentyl) -estra-1, 3,5 (10), 15-tetra-ene in 328 ml of acetone and 32.8 ml of water is stirred for 2 hours and at room temperature with 1,033 g of paratoluenesulfonic acid . It is then diluted with diethyl ether, washed with sodium bicarbonate and water, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane / acetone. 25.4 g of 3-benzyloxy-7a- (5-hydroxypentyl) -estra-1, 3, 5 (10), 15-tetraen-17-one are obtained. c) 3-benzyloxy-7a- (5-hydroxypentyl) -15β, 16β-methano-estra-1,3,5 (10), 15-tetraen-17-one 2,861 g of trimethylsulfoxonium iodide are reacted in 65 ml of dimethyl sulfoxide with 345 mg of 80% sodium hydride for 2 hours and at room temperature. To this solution are added 4.44 g of 3-benzyloxy-7a- (5-hydroxypentyl) -estra-1, 3, 5 (10), 15-tetraen-17-one and then stirred at room temperature for 45 minutes. . The trained compound is filtered and washed with water. The precipitate is then taken up with ethyl acetate, washed with water, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane / acetone. 2.8 g of 3-benzyloxy-7a- (5-hydroxypentyl) -15β, 16β-methano-estra-1,3,5 (10), 15-tetraen-17-one; [a] 22D = + 13.1 ° (c = 0.525% in chloroform). d) 3-benzyloxy-15β, 16β-methano-7a- (5-tosyloxypentyl) -estra-1,3,5 (10), 15-tetraen-17-one A solution of 2.5 g of 3-benzyloxy- 7cc- (5-hydroxypentyl) -15β, 16β-methano-estra-1, 3,5 (10), 15-tetraen-17-one in 25 ml of pyridine is mixed at room temperature with 2.5 g of anhydride -Toluenesulfonic and the mixture is left to rest for 30 minutes. In an ice bath, add 1 ml of water and let it rest for another 45 minutes. It is then diluted with diethyl ether, washed with water, dried over sodium sulfate and concentrated by evaporation in vacuo. 3.4 g of crude 3-benzyloxy-15β, 16β-methano-7a- (5-tosyloxypentyl) -estra-1, 3, 5 (10), 15-tetraen-17-one are obtained. e) 3-benzyloxy-15β, 16β-methane-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-l, 3, 5 (10), 15-tetraen-17-one To a solution of 3.4 g of 3-benzyloxy-15β, 16β-methano-7a- (5-tosyloxypentyl) -estra-1, 3, 5 (10), crude 15-tetraen-17-one in 34 ml of dimethylformamide is added a solution of 2.1 g of methyl- [3- (4,4,5,5,5-pentafluoropentylthio) -propyl ] -amine in 1 ml of dimethylformamide and stirred for 3.5 hours at 100 ° C. It is then diluted with ethyl acetate, washed with water, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane / methanol. 2.6 g of 3-benzyloxy-15β, 16β-methane-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10), 15-tetraen-17-one at the oil state. f) 15β, 16β-methane-7a-. { 5- [N-me il-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3-hydroxy-estra-1,3,5 (10), 15-tetraen-17-one A solution of 2.3 g of 3-benzyloxy-15β, 16β-methano-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pent-fluoropentyl-thio) -propylamino] -pentyl} -estra-1, 3, 5 (10), 15-tetraen-17-one in 53 ml of dichloromethane is stirred for 4.5 hours and in a bath at 0 ° C with 1.12 ml of N, N-dimethylaniline and 1.64 g of aluminum chloride (anhydrous). It is then diluted with ethyl acetate, washed with 30% sodium and potassium tartrate solution and with water, dried over sodium sulfate, concentrated by evaporation in vacuo and chromatographed on silica gel with dichloromethane / methanol. L, 52g of 15β, 16β-methane-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3-hydro-xiestra-l, 3, 5 (10), 15-tetraen-17-one at the oil state; [] 22D = -2.5 ° (c = 0.505% in chloroform). g) 15β, 16β-methano-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-l, 3,5 (10) -trien-3, 17ß-diol To a solution of 515 mg of 15β, 16β-methane-7-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3-hydroxy-estra-l, 3, 5 (10), 15-tetraen-17-one in 10 ml of tetrahydrofuran is added, dropwise and in a bath at 0 ° C, 1.8 ml of a solution 3 molar of methyl magnesium bromide and stirred for 2 hours at room temperature. It is then diluted with ethyl acetate, washed with saturated ammonium chloride solution and with water, dried over sodium sulfate, concentrated by evaporation in vacuo and chromatographed on silica gel with dichloromethane / methanol. 395 g of 15β, 16β-methano-17a-methyl-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3,5 (10) -trien-3, 17β-diol at the oil state; [a] 22D = -5.1 ° (c = 0.52% in chloroform).

Example 7 15β, 16β-methano-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulf inyl) -propylamino] -pent il} -estra-1,3,5 (10) -trien-3,17β-diol A 115 mg solution of 15β, 16β-methano-17-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol (see example 6) in 5 ml of methanol is stirred for 3 hours and at room temperature with 80 mg of sodium periodate. It is then diluted with ethyl acetate, washed with water, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane / methanol. 65 mg of 15β, 16β-methano-17a-methyl-7 - are obtained. { 5- [N-methyl-N-3- (4, -4,5,5,5-pentaf luoropentanesulf inyl) -propylamino] -pent il} -estra-1,3,5 (10) -trien-3,17β-diol at the oil state; [a] 22D = -13, 3 ° (c = 0.27% in chloroform).

Example 8 15β, 16β-methane-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3, 5 (10) -trien-3, 17ß-diol A solution of 500mg of 15ß, 16ß-methane-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} 3-hydroxy-estra-1,3, 5 (10), 15-tetraen-17-one (see example 6f) in 10 ml of methanol and 1 ml of water is stirred for 3 hours and at room temperature with 100 mg of water. sodium borohydride. It is then diluted with ethyl acetate, washed with water, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane / methanol. 340 mg of 15β, 16β-methane-7- are obtained. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3,5 (10) -trien-3, 17β-diol at the oil state; [a] 22D = + 11.9 ° (c = 0.52% in chloroform).

Example 9 15β, 16β-methane-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl} -estra-1,3,5 (10) -trien-3, 17β-diol A solution of 100 mg of 15β, 16β-methane-7a-. { 5- [N-methyl-N-3 - (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol (see example 8) in 5 ml of methanol is stirred for 3 hours and at room temperature with 80 mg of sodium periodate. It is then diluted with ethyl acetate, washed with water, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane / methanol. 70 mg of 15β, 16β-methane-7- are obtained. { 5- [N-methyl-N-3- (4,4, 5, 5, 5-pentaf luoropentanosul f ini l) -propi lamino] -pent i l} - estra-1, 3, 5 (10) -trien-3, 17β-diol at the oil state; [] 22D = + 12, 2 ° (c = 0.515% in chloroform).

Example 10 15β-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentyl-thio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol a) 3-benzyloxy-7a- (5-hydroxypentyl) -15β-methyl-estra-l, 3, 5 (10) -trien- 17 -one To an ice-cold solution of 11.9 ml of a 3-molar solution of methylmagnesium bromide in 68 ml of tetrahydrofuran, 5.35 g of copper iodide are added under nitrogen.

(I) Then, a drop of 4.26 g of 3-benzyloxy-7a- (5-hydroxypentyl) -estra-1, 3,5 (10), 15-tetraen-17-one (see example 6b) is added dropwise. in 50 ml of tetrahydrofuran and stirred in a 0 ° bath for 30 minutes. The excess reagent is decomposed with saturated ammonium chloride solution, diluted with ethyl acetate, washed with ammonium chloride solution and with water, dried over sodium sulfate, concentrated by evaporation in vacuo and chromatographed on silica gel with hexane / acetone. 3.6 g of 3-benzyloxy-7a- (5-hydroxypentyl) -15β-methyl-estra-l, 3, 5 (10) -trien-17-one are obtained; [a] 22D = + 66.4 ° (c = 0.515% in chloroform). b) 3-benzyloxy-15β-methyl-7a- (5-tosyloxypentyl) -estra-1,3, 5 (10) -trien-17-one A solution of 3.6 g of 3-benzyloxy-7a- is tosylated (5-hydroxypentyl) -15β-methyl-estra-l, 3,5 (10) -trien-17-one analogously to that described in Example 6d. 4.9 g of crude 3-benzyloxy-15β-methyl-7a- (5-tosyloxy-pentyl) -estra-1, 3, 5 (10) -trien-17-one are obtained. c) 3-benzyloxy-15β-methyl-7a- (5-N-methylaminopentyl) -estra-1,3,5 (10) -trien-17-one 3.6 g is condensed in a pressure reactor under cooling of methylamine in a solution of 4.9 g of 3-benzyloxy-15β-methyl-7a- (5-tosyloxypentyl) -estra-1,3,5 (10) -trien-17-one in 30 ml of tetrahydrofuran, then the closed reactor is heated to 80 ° C for 5.5 hours, cooled and opened. It is then diluted with ethyl acetate, washed with water, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane / methanol / 1% triethylamine. 3.15 g of 3-benzyloxy-15β-methyl-7a- (5-N-methylaminopentyl) -estra-1,3,5 (10) -trien-17-one are obtained at the oil state. d) 3-benzyloxy-15β-methyl-7a-. { 5- [N-methyl-N- 3 - (4,4,5,5,5-pentafluoro-pentylthio) -propylamino] -pentyl} -estra-l, 3,5 (10) -trien-17 -one A solution of 3.15 g of 3-benzyloxy-15β-methyl-7a- (5-N-methylaminopentyl) -estra-1, 3, 5 (10) -trien-17-one in 31.5 ml of absolute dimethylformamide is mixed with 228 mg of 80% sodium hydride and the mixture is stirred for 5 hours at room temperature. 2.6 g of 3-chloropropyl-4,5,5,5,5-pentafluoropentyl sulphide in 2 ml of absolute dimethylformamide are added and stirred at 80 ° C for 24 hours. It is then diluted with ethyl acetate, washed with sodium bicarbonate and with water, dried over sodium sulfate, concentrated by evaporation in vacuo and chromatographed on silica gel with dichloromethane / methanol. 3.1 g of 3-benzyloxy-15β-methyl-7 - are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5,5-pentathio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-17-one to the oil state. e) 3-hydroxy-15β-methyl-7a-. { 5- [N-methyl-N- 3- (4, 4, 5, 5, 5-pentafluoro-pentylthio) -propylamino] -pentyl} -estra-l, 3,5 (10) -trien-17 -one A solution of 3.1 g of 3-benzyloxy-15β-methyl-7a-. { 5- [N-me-til-N-3- (4,4,5,5,5-pentaf luoro-pentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-17-one is debenzylated in a manner analogous to that described in example 6f. 830 mg of 3-hydroxy-15β-methyl-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-17-one to the oil state. f) 15β-methyl-7a-. { 5- [N-methyl-N-3 - (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -estra-l, 3,5 (10) -trien-3, 17ß-diol A solution of 460 mg of 3-hydroxy-15β-methyl-7- is reduced. { 5- [N-methyl-N-3- (4,4,5,5,5-pentathio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-17-one analogously to that described in example 8. 200 mg of 15β-methyl-7a- are obtained. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoro-pentylthio) -propylamino] -pentyl} -estra-1, 3,5 (10) -trien-3, 17b-diol at the oil state; [a] 22D = + 4.5 ° (c = 0.51% in chloroform).

Example 11 15β, 17a-dimethyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-l, 3,5 (10) -trien-3,17ß-diol In 15 ml of tetrahydrofuran, 1.44 g of anhydrous Ce (III) chloride is stirred for 2 hours at room temperature, then with cooling in a bath. 3.75 ml of 3 molar solution of methylmagnesium bromide is added, stirred for 15 minutes with cooling and for 30 minutes at room temperature, a solution of 650 mg of 3-hydroxy-15β- is added dropwise. methyl-7 -. { 5- [N-methyl-N-3 - (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-17-one (see example lOe) in 7 ml of tetrahydrofuran, is stirred for 2 hours at room temperature and the excess reagent is decomposed with saturated ammonium chloride solution . It is then diluted with ethyl acetate, washed with saturated ammonium chloride solution and with water, dried over sodium sulfate, concentrated by evaporation in vacuo and chromatographed on silica gel with dichloromethane / methanol. 145 mg of 15β, 17a-dimethyl-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17b-diol at the oil state; [] 22D = -7.3 (c = 0.505% in chloroform).

Example 12 llß-fluoro-7a-. { 5- [N-methyl-N- 3 - (, 4, 5, 5, 5 -pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17ß-diol a) llß-fluoro-estr-4-en-3, 17-dione A 5.0 g of lla-hydroxy-estr-4- in-3, 17-dione in 100 ml of toluene and 7.3 ml of 1,8-diazabicyclo [5, 4, 0] undec-7-ene are added, dropwise and at 0 ° C, 4.6 ml of per-fluorobutane-1-sulfonyl fluoride. After 30 minutes the solution is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in vacuo. After chromatographing the crude product on silica gel with a gradient of hexane-ethyl acetate, 3.8 g of llß-fluoro-estr-4-en-3,17-dione having a melting point of 173-174 are obtained. ° C. b) llß-fluoro-3-methoxy-estra-3,5-dien-17-one 7.8 g of llß-fluoro-estr-4-en-3,17-dione in 40 ml of 2, 2 are stirred. -dimethoxypropane with 780 mg of pyridinium toluene-4-sulphonate for 5 hours at 80 ° C. Then 1.5 ml of triethylamine is added, diluted with ethyl acetate and washed with saturated sodium chloride solution. After recrystallization from methanol, 5.3 g of llß-fluoro-3-methoxy-estra-3,5-dien-17-one of melting point 173 ° C are obtained. c) llß-fluoro-estra-4,6-dien-3,17-dione To 5.0 g of llß-fluoro-3-methoxy-estra-3,5-dien-17-one in 50 ml of DMF add, at 0 ° C, first 5 ml of a 10% solution of sodium acetate and then, in portions, 2.5 g of 1,3-dibromo-5,5-dimethylhydantoin. After 30 minutes, 2.3 g of sodium sulfite and then 2.5 g of lithium bromide and 2.0 g of lithium carbonate are added and the mixture is stirred for 2 hours at 100 ° C. The reaction mixture is introduced with stirring in ice-water. The formed precipitate is filtered off with suction, dissolved in ethyl acetate, washed with water, dried and concentrated by evaporation in vacuo. After recrystallization from ethyl acetate, 3.6 g of llß-fluoro-estra-4,6-dien-3,17-dione having a melting point of 198 ° C are obtained. d) llß-fluoro-7a- (5-butyl-dimethylsilyloxypentyl) -estr-4-en-3, 17-dione. To prepare the Grignard reagent, 7.9 g of magnesium are reacted in a nitrogen atmosphere in 40 ml of THF. with a solution of 95.3 g of 1-bromo-5-tert-butyldimethylsilyloxypentane [Tetrahedron Letters 1982, pp. 4147 to 4150] in 260 ml of THF. At -30 ° C, 32 g of copper iodide (I) are added and then, dropwise, 29 g of llß-fluoro-estra-4,6-dien-3,17-dione in 290 ml of THF. At the end of the reaction, 20.4 ml of glacial acetic acid are added and the reaction mixture is stirred into ice-water. The formed precipitate is filtered off with suction, dissolved with ethyl acetate, washed with water until neutral and dried. After chromatographing the crude product on silica gel with a gradient of hexane-ethyl acetate, 23, 9 g of llß-fluoro-la- (5-tert-butyl-dimethylsilyloxypentyl) -estr-4-en-3, 17-dione at the foam state. e) llß-fluoro-7a- (5-hydroxypentyl) -estr-4-en-3, 17-dione A solution of 23.1 g of llß-fluoro-7 - (5-tert-butyl-dimethylsilyloxypentyl) -estr-4 -in-3, 17-dione in 115 ml of THF and 64 ml of water is stirred with 128 ml of glacial acetic acid for 2.5 hours and at 50 ° C. The reaction mixture is concentrated by evaporation in vacuo, taken with ethyl acetate, washed with water and dried. 20.4 g of llß-fluoro-7a- (5-hydroxypentyl) -estr-4-en-3,17-dione are obtained as foam. f) 7a- (5-acetoxy-pentyl) -ll-fluoro-estr-4-en-3,17-dione For 20 hours 20 g of llß-fluoro-7a- (5-hydroxypentyl) are allowed to react at 25 ° C. estr-4-en-3, 17-dione in 100 ml of pyridine with 50 ml of acetic anhydride. At 0 ° C, 5 ml of water are added and the mixture is stirred for 45 min. It is extracted with diethyl ether, washed with 2N sulfuric acid, free of pyridine, and the solution is neutralized first with saturated sodium bicarbonate solution and then with water. After drying and concentrating in vacuo, the crude product is chromatographed on silica gel with a gradient of hexane-ethyl acetate. 17 g of 7a- (5-acetoxy-pentyl) -ll-fluoro-estr-4-en-3,17-dione are obtained with a melting point of 78.4 ° C. g) la- (5-acetoxypentyl) -ll-fluoro-3-hydroxy-estra-l, 3, 5 (10) -trien-17 -one A 16.5g of 7a- (5-acetoxypentyl) -ll-fluoro -estr-4-ene-3,17-dione in 190 ml of acetonitrile are added at 18 ° C 18.6 g of copper (II) bromide and 3.6 g of lithium bromide. After 15 minutes, the reaction mixture is stirred into an ice-water mixture containing sodium bicarbonate. The precipitate formed is filtered off with suction, dissolved in ethyl acetate, washed with water, dried and concentrated by evaporation in vacuo. After chromatographing the crude product on silica gel and with a gradient of hexane-ethyl acetate, 8.5 g of 7a- (5-acetoxypentyl) -ll-fluoro-3-hydroxy-tetra-1,3,5 ( 10) -trien-17-one to the state of foam. h) 7a- (5-acetoxypentyl) -ll-fluoro-3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one For 2.5 hours, stir at room temperature 8.2g of the- (5-acetoxy-pentyl) -ll-fluoro-3-hydroxy-estra-1, 3,5 (10) -trien-17-one in 86 ml of THF with 8.6 ml of 3, 4 -dihydro-2H-pyran and 820 mg of p-toluenesulfonic acid hydrate. Then 0.5 ml of triethylamine is added, diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in vacuo. After chromatographing the crude product on silica gel and with a gradient of hexane-ethyl acetate, 7.8 g of 7a- (5-acetoxy-pentyl) -ll-fluoro-3- (tetrahydropyran-2-yloxy) are obtained. -estra- 1,3, 5 (10) -trien-17-one at the foam state. i) llß-fluoro-la- (5-hydroxypentyl) -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one 7.4 g of la- (5- acetoxypentyl) -ll-fluoro-3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one in 370 ml of methanol and 37 ml of water are stirred at room temperature with , 8g of potassium carbonate. After 3 hours the reaction mixture is poured over ice-water. The precipitate formed is filtered off with suction, dissolved in ethyl acetate, washed with water until neutral, removed and concentrated by evaporation in vacuo. 7.0 g of llß-fluoro-7a- (5-hydroxypentyl) -3- (tetrahydropyran-2-yloxy) -estra-1, 3,5 (10) -trien-17 -one are obtained at the foam state. j) llß-fluoro-3- (tetrahydropyran-2-yloxy) -la- (5-p-toluene-sulfonyloxypentyl) -estra-1,3,5 (10) -trien-17-one For 3 hours, stir room temperature 6.7 g of llß-fluoro-7 - (5-hydroxypentyl) -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one in 70 ml of pyridine with 6.0 g of p-toluenesulfonic anhydride. The solution is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. The crude product is chromatographed on silica gel with a gradient of hexane-ethyl acetate. 5.7 g of llß-fluoro-3 - (tetrahydropyran-2-yloxy) -la- (5-p-toluenesul-foniloxypentyl) -estra-1,3,5 (10) -trien-17-one at foam state. k) llß-fluoro-7 -. { 5- [N-methyl-N-3 - (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (Tetrahydropyran-2-yloxy) -estra-1, 3, 5 (10) -trien-17-one At 80 ° C, 2.0 g of llß-fluoro-3- (tetrahydro-pyran-2) are stirred. - iloxy) - la- (5-p-toluenesulfonyloxypent-il) -estra-1,3,5 (10) -trien-17-one in 44 ml of DMF with 1.2 g of methyl- [3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propyl] -amine. After 6.5 hours, the reaction mixture is mixed with water. It is extracted with ethyl acetate, washed with saturated sodium chloride solution and concentrated by evaporation in vacuo. After chromatographing the crude product on silica gel with a gradient of methylene chloride-methanol, 1.3 g of llß-fluoro-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1, 3, 5 (10) -trien-17-one at the oil state. 1) llß-fluoro-7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1, 3, 5 (10) -trien-17ß-ol To 2.0 g of llß-fluoro-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (Tetrahydro-pyran-2-yloxy) -estra-1, 3, 5 (10) -trien-17-one in 17 ml of THF, 10 ml of ethanol and 4.2 ml of water are added, 0 ° C and portions, 350 mg of sodium borohydride. After 30 minutes the reaction mixture is stirred in ice-water, extracted with ethyl acetate, washed with saturated sodium chloride solution and concentrated in vacuo by evaporation. 1.7 g of llß-fluoro-la- are obtained. { 5- [N-methyl-N-3 - (4,4,5,5,5-pentafluoropentylthio) -propyl-amino] -pentyl} -3- (Tetrahydropyran-2-yloxy) -estra-1, 3, 5 (10) -trien-17ß-ol crude and in the state of foam. m) llß-fluoro-7a-. { 5- [N-methyl-N-3 - (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol A solution of 1.6 g of llß-fluoro-7 - is stirred. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (Tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17β-ol in 20 ml of methanol and 2 ml of water with 1.0 g of oxalic acid. After 3 hours the reaction mixture is poured over ice-water. It is extracted with methylene chloride, washed with saturated sodium chloride solution, dried and concentrated by evaporation in vacuo. After chromatographing the crude product on silica gel with a gradient of methylene chloride-methanol, 1.1 g of llß-fluoro-7a- is obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17ß-diol with a melting point of 95 ° C.

Example 13 llß-fluoro-7 -. { 5- [N-methyl-N-3 - (4, 4, 5, 5, 5-pentaf luoropentanosulfinyl) -propylamino] -pentyl} -estra-1,3,5 (10) -trien-3,17β-diol At room temperature 580 mg of llß-fluoro-7a- are stirred. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol in 24 ml of methanol and 1.1 ml of water with 350 g of sodium periodate. After 1.5 hours it is diluted with methylene chloride, washed with saturated sodium chloride solution, dried and concentrated by evaporation in vacuo. The crude product is chromatographed on silica gel with a gradient of methylene chloride-methanol. 287 mg of llß-fluoro-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanosulfinyl) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17ß-diol with a melting point of 87 ° C. Example 14 llß-fluoro-7a-. { 5- [N-methyl-N-3 - (4, 4, 5, 5, 5- pentaf luoropentanesulfonyl) -propylamino] -pent il} -estra-1,3,5 (10) -trien-3,17β-diol a) llß-f luoro-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentane-sulfonyl) -propylamino] -pentyl} -3- (Tetrahydropyran-2-yloxy) -estra-1, 3, 5 (10) -trien-17-one At 80 ° C, 2.0 g of llß-f luoro-3- (tetrahydro-pyran- 2-yloxy) -la- (5-p-toluenesulf onyloxypent-il) -estra- 1, 3, 5 (10) -trien-17-one in 40 ml of DMF with 2.1 g of methyl- [3- ( 4, 4, 5, 5, 5-pentaf luoro-pentanesulf onyl) -propyl] -amine. After 7 hours, the reaction mixture is poured onto ice-water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in vacuo. After chromatographing the crude product on silica gel and with a gradient of methylene chloride-methanol, 1.1 g of llß-f luoro-7a- is obtained. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pent af luoropent anosul f onyl) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1, 3, 5 (10) -trien-17 -one at the oil state. b) llß-fluoro-7a-. { 5- [N-methyl-N-3 - (4, 4, 5, 5, 5-pent af luorope t anosul f onyl) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1, 3, 5 (10) -trien-17ß-ol To 1.5 g of llß-f luoro-7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -3- (Tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one in a mixture of 13 ml of THF, 7.5 ml of ethanol and 3.2 ml of water are added. add, at 0 ° C and in portions, 270 mg of sodium borohydride. After 90 minutes, water is added, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in vacuo. 1.5 g of llß-f luoro-7a- are obtained. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pent af luoropent anosul f oni 1) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1, 3,5 (10) -trien-17β-ol as crude product. c) llß-fluoro-7a-. { 5- [N-methyl-N-3 - (4, 4, 5, 5, 5-pentaf luoropentanesulfonyl) -propylamino] -pentyl} -estra- 1,3,5 (10) -trien-3,17β-diol At room temperature 1.4 g of llß-f luoro-7- is stirred. { 5 - [N-methyl-N-3- (4,4,5,5,5-pentaf luoropent anosul f onyl) -propylamino] -pentyl} -3- (Tetrahydropyran-2-yloxy) -estra-1,3, 5 (10) -trien-17ß-ol in 18 ml of methanol and 1.8 ml of water with 900 mg of oxalic acid. After 4 h the reaction mixture is stirred into ice-water. The precipitated product is taken up with methylene chloride, washed with water, dried and concentrated by evaporation in vacuo. After chromatographing the crude product on silica gel and with a gradient of methylene chloride-methanol, 325 mg of llß-f luoro-7a- are obtained. { 5- [N-methyl-N- 3 - (4,4,5,5,5-pentaf luoropent ano-sulf onyl) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol with a melting point of 70 ° C.

Example 15 16-Fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol a) 7a- (5-chloropentyl) -estr-4-en-3,17-dione In 150 ml of anhydrous tetrahydrofuran are suspended., 6 g of magnesium shavings and the Grignard reagent is prepared with 58.8 ml of l-bromo-5-chloropentane in 40 ml of anhydrous tetrahydrofuran. It is stirred for 30 minutes at room temperature, diluted with an additional 100 ml of anhydrous tetrahydrofuran and cooled to -70 ° C. The solution of 3.04 g of a complex of copper bromide (I) -dimethyl sulphide in 72 ml of 1, 3- is then added dropwise and at an internal temperature between -65 and -70 ° C. dimethyltetrahydro-2 (1H) -pyrimidinone (DMPU) and 150 ml of tetrahydrofuran. Finally, the solution of 50 g of estra-4,6-dien-3,17-dione (Seroids Vol. 1, 1963, page 223) and 75 ml of trimethylchlorosilane in 700 ml of water is added over a period of 2.5 hours. anhydrous tetrahydrofuran. The solution is stirred in the cooling bath until it reaches room temperature, the next morning it is acidified in an ice bath with 48 ml of acetic acid and after stirring for 15 minutes it is mixed with ethyl acetate. The organic phase is extracted three times with saturated ammonium chloride solution, the aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with sodium bicarbonate solution, dried over magnesium sulphate and evaporated in vacuo. The residue of 53 g is chromatographed on silica gel with hexane / dichloromethane and ethyl acetate. The yield is 35 g of la- (5-chloropentyl) -estr-4-en-3, 17-dione. The same product is obtained by reaction for 3.5 hours and at room temperature of 8.05 g of la- (5-hydroxypentyl) -estr-4-en-3,17-dione (Example Ib) with 8.66 g of triphenylphosphine in 85 ml of carbon tetrachloride and 30 ml of acetonitrile. The reaction mixture is diluted with dichloromethane, stirred with saturated bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel with dichloromethane and ethyl acetate and 4.08 g of la- (5-chloropentyl) -estr-4-en-3,17-dione are obtained.; [a] 22D = + 68 ° (c = 0.5% in chloroform). b) 1- (5-Chloropentyl) -3-hydroxy-estra-1, 3, 5 (10) -trien-17-one 18.96 g of la- (5-chloropentyl) -estr-4-en are dissolved -3,17-dione in 350 ml of anhydrous acetonitrile, and in an inert gas atmosphere and at 80 C are mixed with a solution of 4.36 g of lithium bromide and 22.5 g of copper (II) bromide in 390 ml. of anhydrous acetonityl. The mixture is stirred for a further 5 minutes, the mixture is cooled in an ice bath and water and ethyl acetate are added. The organic phase is stirred with sodium bicarbonate solution, the aqueous phase is ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. 19.1 g of crude product are obtained, which are purified by chromatography on silica gel with hexane and ethyl acetate as eluents. 10.0 g of a la- (5-chloropentyl) -3-hydroxy-estra-l, 3, 5 (10) -trien-17-one oil which can be crystallized from hexane / dichloromethane are obtained. Melting point 143, 5 ° C; [a] 2D = + 112 ° (c = 0.5% in chloroform). c) Bis-3, 17-trimethylsilyloxy-7a- (5-chloropentyl) -estra-1,3,5 (10), 16-tetraene 5.65 g of la- (5-chloropentyl) -estra-1 are dissolved , 3, 5 (10) -trien-3-ol-17-one, 9 ml of triethylamine and 9 ml of trimethylsilyl trifluoromethanesulfonate in 75 ml of benzene and heated at reflux for 2 hours. After cooling, it is diluted with hexane, the upper phase is stirred with saturated sodium bicarbonate solution and with saturated sodium chloride solution, dried over sodium sulphate, concentrated by evaporation in vacuo and the bis- 3,17-trimethylsilyloxy-la- (5-chloropentyl) -estra-1, 3,5 (10), 16-tetraene at the oil state. d) la- (5-chloropentyl) -16a-fluoro-estra-l, 3,5 (10) -trien-3-ol-17-one The product of the previous test is dissolved in 150 ml of anhydrous dichloromethane and mixed with 14.2 g of N-fluorobenzenesulfonimide. After stirring for 2 hours at room temperature, 50 ml of 8% sulfuric acid are added, stirring vigorously for a further 3 hours and the phases are separated. The aqueous phase is extracted twice with dichloromethane, the organic phase is extracted first with saturated sodium bicarbonate solution and then with saturated sodium chloride solution, dried with sodium sulfate and concentrated in vacuo. The crude product of 15.3 g is chromatographed on silica gel with dichloromethane / diisopropyl ether and 2.92 g of la- (5-chloropentyl) -16a-fluoro-estra-1, 3, 5 (10) are obtained. -trien-3-ol-17-one at the oil state. The substance can be crystallized from diisopropyl ether, melting point 176 ° C; [a] 22D = + 114 ° (c = 0.5% in chloroform). e) la- (5-chloropentyl) -16a-fluoro-17a-methyl-estra-l, 3, 5 (10) -trien-3,17β-diol In an inert gas atmosphere, 3.0 g of lactide are dissolved. (5-Chloropentyl) -16a-fluoro-estra-1, 3,5 (10) -trien-3-ol-17-one in 300 ml of anhydrous toluene and at intervals of 15 minutes, 3 portions of the mixture are added at room temperature. 20 ml each of a 1.5 molar solution of methyllithium and lithium bromide in ether. After 30 minutes, the reaction mixture is stirred in a half-saturated solution of ammonium chloride in an ice bath, acidified with 8% sulfuric acid and extracted with ethyl acetate. The combined organic phases are stirred with sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. The 3.2 g crude product is chromatographed on silica gel with hexane and methyl tertiary butyl ether. The polar fraction of 1.21 g corresponds to la- (5-chloropentyl) -16a-fluoro-17-methyl-tetra-1,3,5 (10) -trien-3,17-diol, which is crystallized from diisopropyl ether / hexane, melting point 70 ° C; [a] 22D = + 7 ° (c = 0.5% in chloroform). f) 16a-fluoro-17a-methyl-7a-. { 5- [N-methyl-N- 3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3,17ß-diol 40.8 mg of la- (5-chloropentyl) -16a-fluoro-17a-methyl-estra-l, 3.5 ( 10) -trien-3, 17β-diol in 0.5 ml of dimethylformamide, the solution of 58 mg of 3- (N-methylamino) -propyl-4, 4, 5, 5, 5-pentafluoropentyl sulfide and 13 mg of lithium iodide is added and heated for 17 hours at 100 ° in an inert gas atmosphere. After cooling, ethyl acetate is added to the mixture, stirred first with saturated sodium bicarbonate solution and then with sodium chloride solution, dried over sodium sulfate and the solvent evaporated in vacuo. The residue is chromatographed on silica gel with ethyl acetate / methanol. The yield is 25 mg of 16-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3, 5 (10) -trien-3, 17ß-diol; [a] 22D = + 5.6 ° (c = 0.5% in chloroform); melting point 98.2 ° C. Example 16 16a-fluoro-17β-methyl-7 -. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3,5 (10) -trien-3, 17a-diol As a non-polar product of the chromatography of the example 15e) is obtained la- (5-chloropentyl) -16a-fluoro-17β-methyl-estra-1,3,5 (10) -trien-3,17a-diol in an amount of 0.48 g. Crystallization with diisopropylether / hexane gives crystals with a melting point of 65 ° C and [a] 22D = + 5 ° (c = 0.5% in chloroform). 41 mg of these crystals are taken and reacted as in example 15f). 23 mg of 16a-fluoro-17β-methyl-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17a-diol of melting point 103, 8 ° C and [a] 22D = + 3.1 ° (c = 0.5% in chloroform).

Example 17 16a-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentanesulf inyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3,17β-diol Analogously to that of example 2, 38 mg of 16a-f luoro-17-methyl-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentanesulf inyl) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol by oxidation of 72 mg of 16a-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3,5 (10) -trien-3, 17β-diol with sodium periodate.

Example 18 16a-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-penta-fluoropentanesulfonyl) -propylamino] -pentyl} -estra-1, 3,5 (10) -trien-3, 17β-diol Analogously to that described in Example 15f), 40.8 mg of la- (5-chloropentyl) -16a-fluoro- 17-methyl-1, 3, 5 (10) -trien-3, 17β-diol in dimethylformamide with 70 mg of 3- (N-methylamino) -propyl-4,4,5,5,5-pentafluoropentyl sulfide. After working the reaction mixture 21 mg of 16a-fluoro-17a-methyl-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5 -pentyl-fluoro-pentanesulfonyl) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol at the oil state; [a] 22D = + 2.4 ° (c = 0.5% in chloroform).

Example 19 16a-fluoro-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3,5 (10) -trien-3, 17β-diol a) la- (5-chloropentyl) -16a-fluoro-estra-1, 3, 5 (10) -trien-3, 17ß- diol and la- (5-chloropentyl) -16a-fluoro-estra-1, 3,5 (10) -trien-3,17a-diol 392 mg of 7a- (5-chloropentyl) -16a-fluoro-estra is dissolved -1, 3, 5 (10) -trien-3-ol-17-one (example 15d) in 2 ml of anhydrous tetrahydrofuran and 1.1 ml of a 1 molar solution of lithium hydride are added in an ice bath. triterbutoxyaluminum in tetrahydrofuran. It is stirred for 30 minutes at 0 ° C, mixed with water and with 8% sulfuric acid until weakly acidic reaction and extracted three times with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in vacuo to dryness. The crude product is chromatographed on silica gel with hexane / ethyl acetate and 118 mg of la- (5-chloro-pentyl) -16a-fluoro-estra-1,3,5 (10) -trien-3 are obtained, 17β-diol and 138 mg of la- (5-chloropentyl) -16a-fluoro-estra-1, 3, 5 (10) -trien-3,17a-diol, both at the state of solid foam. b) 16a-fluoro-7a-. { 5- [N-ethyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3,5 (10) -trien-3, 17β-diol Analogously to the one described in example 15f), 100 mg of la- (5-chloropentyl) -16a-fluorostra-1 are reacted, 3, 5 (10) -trien-3, 17β-diol with 3- (N-methylamino) -propyl-4, 4, 5, 5, 5-pentafluoropentyl sulfide. 83 mg of 16a-fluoro-l- are obtained. { 5- [N-methyl-N-3 - (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol at the state of solid foam; [a] 22D = + 15.2 ° (c = 0.5% in chloroform).

Example 20 16a-fluoro-7 -. { 5- [N-methyl-N- 3 - (4, 4, 5, 5, 5 -pentaf luoropentylthio) -propylamino] -pentyl} -estra- 1, 3, 5 (10) -trien-3, 17 -diol By analogous reaction of 100 mg of la- (5-chloropentyl) -12 16 -f luoro-estra-1, 3, 5 (10) -trien-3, 17a-diol 75 mg of 16a-fluoro-7a- are obtained. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17a-diol at the foam state; [a] 22D = + 6.9 ° (c = 0.5% in chloroform).

Example 21 16a-fluoro-7 -5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentanosulfinyl) -propylamino] -pentyl} -estra-1,3,5 (10) -trien-3, 17β-diol Analogously to that described in example 17, oxidation of 85 mg of 16a-f luoro-7a- is obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol with sodium periodate, 47 mg of 16a-f l or o - 7 a -. { 5 - [N - me t i l - N - 3 - (4, 4, 5, 5, 5 -pentaf luoropentanesulf inyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3, 17β-diol at the foam state.

Example 22 16a-f luoro-7 -. { 5 - [N-met il -N- 3 - (4, 4, 5, 5, 5 -pentaf luoropentanosulfonyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3,17β-diol Analogously to the one described in example 15f), 65 mg of la- (5-chloropentyl) -16a-f luoro-estra -1,3,5 (10) -trien-3,17ß-diol with 90 mg of 3- (N-methylamino) -propyl- 4, 4, 5, 5, 5 -pentaf luoropent i 1 sulfon and are obtained 53 mg of 16a-f luoro-7 -. { 5 - [N - me t i l - N - 3 - (4, 4, 5, 5, 5 -pentaf luoropentanesulfonyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3, 17β-diol at the oil state.

Example 23 7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10), 14-tetraen-3, 17β-diol a) la- (5-tert-butyldimethylsilyloxypentyl) -estr-4-en-3, 17-dione To prepare the Grignard reagent, react in 34 ml of absolute tetrahydrofuran 8.9 g of Mg chips with 103 g of 1-bromo-5-tert-butyldimethylsilyloxypentane dissolved in 110 ml of tetrahydrofuran. To this solution, cooled to a temperature between -70 ° C and -65 ° C, 2.5 g of a complex of copper bromide (I) and dimethyl sulfide and a mixture of 60 ml of 1,3 are added. -dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone and 70 ml of tetrahydrofuran. The suspension obtained is stirred for a further 30 minutes at -70 ° C and under an argon atmosphere. At a temperature between -70 ° C and -65 ° C, a solution of 50 g of estra-4,6-dien-3,17-dione is added drop by drop [Steroids Vol. 1, 1963, p. . 233 to 249] in 730 ml absolute THF and 62.7 ml of chlorotrimethylsilane. The mixture is stirred overnight at -70 ° C. To separate the product, 48 ml of acetic acid are added at a temperature of -15 ° C and after stirring for 15 minutes the reaction mixture is poured at the same temperature onto a mixture composed of a saturated solution of ammonium chloride and ethyl acetate. The organic phase is separated, washed first with saturated ammonium chloride solution, then with saturated sodium bicarbonate solution and finally with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with dichloromethane / acetone and 47 g of la- (5-tert-butyldimethylsilyloxypentyl) -estr-4-en-3,17-dione are obtained at the yellow oil state; [a] 22D = + 62.2 ° (c = 0.545% in chloroform). b) 3-hydroxy-la- (5-hydroxypentyl) -estra-1,3, 5 (10), 15-tetraen-17 -one 62,7g of 7a- (5-tert-butyldimethylsilyloxypentyl) -estr-4 are reacted -in-3, 17-dione in a manner analogous to that described in example Ib to li, and 15.8 g of 3-hydroxy-7a- (5-hydroxypentyl) -estra-1, 3, 5 (10 ), 15-tetraen-17-one. c) 3-benzyloxy-7a- (5-hydroxypentyl) -estra-1, 3, 5 (10), 15-tetraen-17 -one A solution of 2.85 g of 3-hydroxy-7a- (5-hydroxypentyl) ) -estra-1, 3.5 (10), 15-tetraen-17-one in 57 ml of acetone is mixed with 3.25 g of cesium carbonate and 1.14 ml of benzyl bromide. The mixture is heated for 1 hour at reflux. The reaction mixture is concentrated by evaporation, the residue is taken up with water, stirred with ethyl acetate, the organic phase is dried over sodium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane / ethyl acetate. 3.12 g of 3-benzyloxy-la- (5-hydroxy-penyl) -estra-1 are obtained., 3, 5 (10), 15-tetraen-17-one at the foam state. d) 17 -acetoxy-7a- (5-acetoxy-pentyl) -3-benzyloxy-tetra-1,3,5 (10), 14,16-pentane A solution of 6.12 g of methanol is stirred at room temperature for one hour. 3-benzyloxy-7a- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraen-17-one in 717 ml of acetic anhydride with 920 mg of p-toluenesulfonic acid. The reaction mixture is worked in a manner similar to that indicated in Example Ij and the crude product is chromatographed on silica gel with hexane / ethyl acetate. 4.6 g of 17-acetoxy-7a- (5-acetoxypentyl) -3-benzyloxy-estra-1, 3,5 (10), 14,16-pentane are obtained at the oil state. e) la- (5-acetoxy pentyl) -3-benzyloxy-estra-1, 3, 5 (10), 14-tetraen-17β-ol To a solution of 4.58 g of 17-acetoxy-7a- (5- acetoxypentyl) -3-benzyloxy-estra-l, 3, 5 (10), 14, 16-pentaene in 26.8 ml of tetrahydrofuran and 161 ml of ethanol is added, dropwise and at room temperature, a solution of 1, 25 g of sodium borohydride in 90 ml of ethanol and 18 ml of water, and the mixture is stirred for 1 hour. To the reaction mixture is added 4 ml of glacial acetic acid, it is concentrated by evaporation and the residue is taken up with ethyl acetate. The organic phase is washed with sodium bicarbonate, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane / ethyl acetate. 2.16 g of la- (5-acetoxy pentyl) -3-benzyloxy-estra-1, 3, 5 (10), 14-tetraen-17β-ol are obtained at the foam state. f) 3-benzyloxy-la- (5-hydroxypentyl) -estra-1,3, 5 (10), 14-tetraen-17β-ol. A total of 2.16 g of lactic acid are saponified at room temperature overnight. -acetoxipentil) -3-benzyloxy-estra-1, 3, 5 (10), 14-tetraen-17β-ol with 38 ml of IN methanolic solution of potassium hydroxide. The reaction mixture is poured into a saturated and ice-cold solution of sodium chloride, the precipitate is filtered off with suction, taken up with dichloromethane, washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. . 1.86 g of 3-benzyloxy-7a- (5-hydroxypentyl) -estra-1, 3, 5 (10), 14-tetraen-17β-ol are obtained at the foam state. g) 3-benzyloxy-1 - (5-tosyloxypentyl) -estra-1, 3,5 (10), 14-tetraen-17β-ol In the conditions described for the example, 3.03g of 3-benzyloxy are reacted -7a- (5-hydroxypentyl) -estra-1, 3, 5 (10), 14-tetraen-17β-ol with 2.31 g of p-toluenesulfonic anhydride in 58 ml of pyridine, the product is worked in an analogous manner to the one described there and chromatographed on silica gel. 3 g of 3-benzyloxy-7a- (5-tosyloxypentyl) -estra-1,3,5 (10), 14-tetraen-17β-ol are obtained at the foam state. h) 3-benzyloxy-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentathio) -propylamino] -pentyl} -estra-l, 3, 5 (10), 14-tetraen-17ß-ol A solution of 2 g of 3-benzyloxy-7a- (5-tosyloxypentyl) -estra-1, 3, 5 (10), 14- Tetraen-17ß-ol in 28 ml of ethylmethretone is stirred for 5 hours and in a bath at 80 ° C with 1.77 g of N-methyl-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamine in the presence of 950 mg of potassium carbonate and 230 mg of potassium iodide. The reaction mixture is poured into sodium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel and with hexane / ethyl acetate as eluent. 1.93 g of 3-benzyloxy-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3,5 (10), 14-tetraen-17ß-ol to the resin state; [a] 22D = + 47.3 ° (c = 0.505% in chloroform). i) 7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3, 5 (10), 14-tetraen-3, 17β-diol To a solution of 850 mg of 3-benzyloxy-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10), 14-tetraen-17β-ol in 10.2 ml of toluene are added, dropwise and at room temperature, 10.2 ml of a 1.2 molar solution of sodium hydride. diisobutylaluminum in toluene, and the mixture is stirred for 5 hours in a bath at 120 ° C. The reaction mixture is dripped, with stirring and under an argon atmosphere, into a mixture composed of a saturated solution of sodium chloride and 2N sulfuric acid. It is then extracted 3 times with ethyl acetate, the organic phase is washed twice with 2 N sulfuric acid and 3 times with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane / ethyl acetate / 0-30% methanol. 670 mg of la- are obtained. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10), 14-tetraen-3, 17β-diol at the foam state; [a] 22D = + 43 ° (c = 0.520% in chloroform / methanol).

Example 24 7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl} -estra-1, 3, 5 (10), 14-tetraen-3, 17β-diol Under the same conditions as those described for example 2, 400 mg of la- is reacted. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10), 14-tetraen-3, 17β-diol with 177 mg of sodium periodate, the mixture is worked up in the manner described in example 2 and the crude product is chromatographed on silica gel. silica with ethyl acetate / methanol. 287 mg of the title compound are obtained at the foam state; [a] 2 D = + 30.7 ° (c = 0.530% in chloroform / methanol).

Example 25 7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1, 3, 5 (10), 14-tetraen-3, 17β-diol a) 3-benzyloxy-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3, 5 (10), 14-tetraen-17β-ol Under the same conditions as in example 23h, 1 g of 3-benzyloxy-7a- (5-tosyloxypentyl) -estra-1 is reacted, 3, 5 (10), 14-tetraen-17β-ol with 990 mg of N-methyl-3- (4, 4, 5, 5, 5-pentafluoropentanesulfonyl) -propylamine. The reaction mixture is then treated in the same manner as in Example 23h and the crude product is chromatographed on silica gel with ethyl acetate / methanol. 960 mg of 3-benzyloxy-7a- are obtained. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentanesulfonyl) -propylamino] -pent il} -estra-1,3, 5 (10), 14-tetraen-17β-ol to the oil state; [a] 22D = + 48.5 ° (c = 0.535% in chloroform). b) 7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1, 3.5 (10), 14-tetraen-3, 17β-diol To a solution of 100 mg of 3-benzyloxy-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulonyl) -propylamino] -pentyl} -estra-l, 3, 5 (10), 14-tetraen-17β-ol in 1 ml of dichloromethane is added in an ice bath of 0.2 ml of dimethylaniline and 73 mg of aluminum chloride, and then stirred for 1 hour. hour at this temperature. The reaction mixture was poured into 1N hydrochloric acid, stirred with ethyl acetate, washed with sodium bicarbonate solution and with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. The crude product is chromatographed on silica gel with dichloromethane / methanol 0-10%. 74 mg of the title compound are obtained in the foam state; [a] 22D = + 36 ° (c = 0.525% in chloroform / methanol).

Example 26 7a-. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol a) l - (5-acetoxypentyl) -3-benzyloxystra-l, 3,5 (10) -trien-17-one To one solution of 6.5 g of the- (5-acetoxy-pentyl) -3-hydroxyestra-1, 3, 5 (10) -trien-17-one (example ld) in 65 ml of dimethylformamide is added 3.3 ml of benzoyl chloride , 8.7 g of cesium carbonate and 400 mg of sodium iodide, and stir overnight at room temperature. The reaction mixture is poured into water, stirred with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane / ethyl acetate. 7.26 g of la- (5-acetoxy pentyl) -3-benzyloxy-estra-1, 3,5 (10) -trien-17-one are obtained at the oil state. b) 3-benzyloxy-7a- (5-hydroxypentyl) -estra-1, 3, 5 (10) -trien-17-one A solution of 7.26 g of lactone is saponified at room temperature overnight. -acetoxy pentyl) -3-benzyloxy-estra-1, 3, 5 (10) -trien-17-one in 80 ml of methanol and 3 ml of tetrahydrofuran with 22.2 ml of 2N sodium hydroxide. The reaction solution is poured onto 2N hydrochloric acid, stirred with ethyl acetate, the organic phase is washed with saturated sodium chloro solution, dried over sodium sulfate and concentrated by evaporation. 6.7 g of 3-benzyloxy-7a- (5-hydroxypentyl) -estra-1, 3, 5 (10) -trien-17-one are obtained at the foam state. c) 3-benzyloxy-7a- (5-tosyloxypentyl) -estra-1, 3, 5 (10) -trien-17-one Under the same conditions as those in the example, 6.5 g of 3-benzyloxy-7a- (5-hydroxypentyl) -estra-1, 3, 5 ( 10) -triene with 7.14 g of p-toluenesulfonic anhydride, then work the reaction mixture as in example 1 and chromatograph the product on silica gel with hexane / ethyl acetate. 7.45 g of 3- benzyloxy-7cc- (5-tosyloxypentyl) -estra-1,3,5 (10) -trien-17-one are obtained at the foam state; [a] 22D = + 80.6 ° (c = 0.620% in chloroform). d) 3-benzyloxy-7a-. { 5 - [(2S) -2- (4, 4, 5, 5, 5 -pentaf luoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -trien-17-one Under the same conditions as those of example 23h, 4.58 g of 3-benzyloxy-7 - (5-tosyloxypentyl) -estra-1 are reacted, 3, 5 (10) -trien-17-one with 3.17 g of (2S) -2- (4, 4, 5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidine, then work the reaction mixture thereof so that in said example and the crude product is chromatographed on silica gel with hexane / ethyl acetate. 3.9 g of 3-benzyloxy-7a- are obtained. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-17-one to the oil state; [] 22D = + 32.5 ° (c = 0.117% in chloroform). e) 3-hydroxy-7a-. { 5- [(2S) -2 - (4, 4, 5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -trien-17-one Under the same conditions as those of Example 6f, 2.05 g of 3-benzyloxy-7cc- are debenzylated. { 5- [(2S) -2- (4, 4, 5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-17-one. 1.25 g of 3-hydroxy-7a- is obtained. { 5- [(2S) -2- (4,4,5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-17-one to the oil state; [] 22D = + 22.7 ° (c = 0.475% in chloroform). f) 7a-. { 5 - [(2S) -2- (4, 4, 5, 5, 5 -pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol Under the same conditions as those of example 8, 500 mg of 3-hydroxy-7a- are reduced. { 5- [(2S) -2- (4, 4, 5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-17-one with 100 mg of sodium borohydride. 325 mg of the title compound are obtained at the oil state; [a] 22D = + 8.7 ° (c = 0.510% in methanol).

Example 27 7a-. { 5- [(2R) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol Analogously to that described in Example 26d-f, 612 mg of the title compound are obtained at the oil state from 2.3 g. of 3-benzyloxy-7a- (5-tosyloxypentyl) -estra-1,3, 5 (10) -trien-17-one (example 26c) and of 1.6 g of (2R) -2- (4.4 , 5,5, 5-pentafluoropentylthiomethyl) -pyrrolidine.

Example 28 17a-methyl-7 -. { 5- [(2S) -2- (4,4, 5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol a) la- (5-chloropentyl) -17a-methyl-estra-l, 3, 5 (10) -trien-3, 17ß- diol A suspension of 5.21 g of anhydrous cerium (III) chloride in 53.2 ml of tetrahydrofuran is stirred at room temperature for 2 hours, and 7 ml of a solution of bromide is added dropwise and at 0 ° C. methylmagnesium (3M in diethyl ether) and the mixture is stirred for 30 minutes at 0 ° C and for 15 minutes at room temperature. Then a solution of 1 g of la- (5-chloropentyl) -3-hydroxy-estra-l, 3, 5 (10) -trien-17-one (example 15b) in 24 ml of tetrahydrofuran is added and stirred for 30 minutes more at room temperature. The reaction mixture is poured into saturated and ice-cold ammonium chloride solution, stirred with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane / ethyl acetate. 753 mg of 7a- (5-chloropentyl) -17a-methyl-tetra-1,3,5 (10) -trien-3, 17β-diol are obtained at the foam state; [a] 2D = + 27.3 ° (c = 0.515% in chloroform). b) la- (5-iodopentyl) -17a-methyl-estra-l, 3, 5 (10) -trien-3, 17β-diol A solution of 735 mg of la- (5-chloropentyl) -17a- is mixed methyl-estra-l, 3, 5 (10) -trien-3, 17β-diol in 4 ml of ethylmethyl ketone with 5.6 g of sodium iodide and heated at 80 ° C for 17 hours. The reaction mixture is poured into water, stirred with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. 834 mg of 7a- (5-iodopentyl) -17-methyl-estra-l, 3, 5 (10) -trien-3,17β-diol are obtained at the foam state; [a] 22D = + 20.2 ° (c = 0.500% in chloroform). c) 17a-methyl-7a-. { 5- [(2S) -2- (4, 4, 5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-3,17ß-diol A solution of 453 mg of la- (5-iodopentyl) -17a-methyl-estra-1,3,5 (10) -trien- 3, 17β-diol and 390 mg of (2S) -2- (4, 4, 5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidine in 8 ml of N-methyl-2-pyrrolidinone is heated at 80 ° C for 4 hours . After cooling the reaction mixture is poured into a saturated solution of sodium bicarbonate, stirred with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with dichloromethane / ethyl acetate. 413 mg of the title compound are obtained at the foam state; [a] 22D = -25.8 ° (c = 0.500% in chloroform).

Example 29 llß-fluoro-7a-. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17ß-diol a) 7a- (5-chloropentyl) -ll-fluorostr-4-en-3, 17-dione A solution of 78.7 g of llß-fluoro-7a- (5-hydroxypentyl) -estr-4-en-3,17-dione (example 12e) in 1.4 1 of carbon tetrachloride and 475 ml of acetonitrile is stirred for 8.5 hours and at room temperature environment with 71 g of triphenylphosphine. It is then extracted with water, an aqueous solution of sodium bicarbonate and sodium chlorine, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane / ethyl acetate. 48.0 g of la- (5-chloropentyl) -ll-fluorostr-4-en-3,17-dione crystals with a melting point of 51-53 ° C are obtained.; [cc] 22D = + 78.5 ° (c = 0.5% in chloroform). b) la- (5-chloropentyl) -ll-fluoro-3-hydroxy-estra-1, 3, 5 (10) -trien-17-one To a solution of 47g of la- (5-chloropentyl) -ll- Fluoroestr-4-en-3, 17-dione in 470 ml of acetonitrile is added, dropwise and in a bath at 80 ° C, a solution of 10.34 g of lithium bromide and 53.2 g of bromide of copper (II) in 280 ml of acetonitrile. After adding 20 ml, it is expected to discolor the solution and then the rest of the solution is added in a period of 12 minutes and finally it is stirred for a further 5 minutes at 80 ° C. It is then cooled to 0 ° C, sodium bicarbonate solution is added, it is poured into water, extracted 4 times with ethyl acetate, washed until neutral, dried over sodium sulfate, concentrated by evaporation under vacuum and chromatography on silica gel with hexane / ethyl acetate. 25.3 g of la- (5-chloropentyl) -ll-fluoro-3-hydroxyestra-1,3,5 (10) -trien-17-one are obtained; [a] 22D = + 115.4 ° (c = 0.5% in chloroform). c) llß-fluoro-3-hydroxy-1 -. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -trien-17-one To a solution of 785.9 mg of la- (5-chloropentyl) -ll-fluoro-3-hydroxy-estra-l, 3, 5 ( 10) -trien-17-one in 7 ml of N-methyl-2-pyrrolidone are added 535.5 mg of lithium iodide and 520 mg of (2S) -2- (4, 4, 5, 5, 5- pentafluoropentylthiomethyl) -pyrrolidine, and stirred for 2.5 hours in a bath at 100 ° C. The mixture is then poured into water, extracted 3 times with diethyl ether, washed until neutral, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane / methanol. 525 mg of llß-fluoro-3-hydroxy-7a- are obtained. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-17-one to the pure state; [a] 22D = + 29.3 ° (c = 0.5% in chloroform). d) llß-fluoro-7a-. { 5- [(2S) -2- (4, 4, 5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -trien-3,17-diol 500 mg of llß-fluoro-3-hydroxy-7a- are dissolved. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrole idin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-17-one in 5 ml of tetrahydrofuran, 2.75 ml of ethanol and 1.1 ml of water, add 100 mg of sodium borohydride in a 0-bath. ° C and stirred for 0.5 hour at room temperature. The mixture is then poured into water, extracted 3 times with ethyl acetate, washed until neutral with saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane / methanol. 441.3 mg of llß-fluoro-7a- are obtained. { 5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3,5 (10) -trien-3, 17β-diol at the state of crystals and with a melting point of 174-176 ° C; [a] 22 D = -14.9 ° (c = 0.5% in pyridine).

EXAMPLE 30 11-Nitroxy-7a- (9- [4,4,5,5,5-pentafluoropentanesulfonyl] -nonyl) -estra-1,3,5 (10) -trien-3,17-diol a) 3, 17β-diacetyloxy-7a- (9- [4, 4, 5, 5, 5-pentafluoropentanesulfonyl] -nonyl) -estra-1,3,5 (10) -triene 6.28 g of the- (9-) are dissolved [4, 4, 5, 5, 5-pentafluoropentanesulfonyl] -nonyl) -estra-1,3,5 (10) -triene-3,17-diol in 30 ml of pyridine, 15 ml of acetic anhydride are added while cool with water and finally stir at room temperature for 5 hours. To obtain the product, the reaction mixture is poured onto ice-water, the diacetate is extracted with ethyl acetate, the organic phase is washed with dilute sulfuric acid, water and saturated sodium chloride solution and dried over sodium sulfate. As crude product, an oil is obtained which is taken with 100 ml of acetic acid and mixed with 15 g of sodium perborate. The reaction is complete after stirring for 5 hours at room temperature.

The reaction mixture is poured into ice water and extracted with ethyl acetate. The organic phase is separated from the acidic residues with aqueous bicarbonate solution. After drying over sodium sulfate, it is filtered, concentrated by evaporation and chromatographed on silica gel (hexane / ethyl acetate, 7: 3). 6.83 g of the product are obtained at the foam state. b) 3,17β-diacetyloxy-11β-nitrooxy-7a- (9- [4,4,5,5,5-pentafluoropentanesulfonyl] -nonyl) -estra-1,3,5 (10) -trien-9-ol To a solution of 3.0 g of 3,17-diacetyloxy-7a- (9- [4,4,5,5,5-pentafluoropentanesulfonyl] -nonyl) -estra-1, 3,5 (10) -triene in 50 ml of aqueous acetic acid (90%) are added 18.6 g of cerium ammonium nitrate and stirred for 4 hours at room temperature. The reaction solution is poured onto ice-water, extracted with ethyl acetate and the organic phase is washed until neutral with aqueous bicarbonate solution. It is then washed with saturated sodium chloride solution and dried over sodium sulfate. The crude product is chromatographed on silica gel (hexane / ethyl acetate, 7: 3). 2.0 g of the product is obtained at the yellow foam state. c) 3, 17β-diacetyloxy-11b-nitrooxy-7a- (9- [4,4,5,5, 5-penta-fluoropentanesulfonyl] -nonyl) -estra-1, 3,5 (10) -triene To eliminate in reductive form the 9α-hydroxy group of 3,17β-diacetyloxy-11b-nitrooxy-7a- (9- [4,4,5,5,5-pentafluoropentanesulfonyl] -nonyl) -estra-1, 3, 5 (10). ) -trien-9-ol dissolve 2.0 g of the starting compound in 25 ml of dichloromethane, cool to -15 ° C and add 15 ml of triethylsilane and 2.2 ml of boron trifluoride etherate successively. After stirring for 1 hour at -15 ° C the cold bath is removed and allowed to reach room temperature. The reaction solution is poured onto ice-water, extracted with dichloromethane, the organic phase is washed with aqueous bicarbonate solution and with saturated sodium chloride solution and dried over sodium sulfate. The crude product is chromatographed on silica gel (hexane / ethyl acetate, 9: 1), yield: 1.3 g of foam. d) llß-nitrooxy-7a- (9- [4, 4, 5, 5, 5-pentafluoropentanesulfonyl] -nonyl) -estra-1, 3, 5 (10) -trien-3, 17ß-diol To carry out the saponification dissolves 1, 0g of 3, 17β-diacetyloxy-11β-nitrooxy-7a- (9- [4,4,5,5,5-pentafluoropentanesulfonyl] -nonyl) -estra-1, 3, 5 (10) -triene in 50 ml of methanol, add 20 ml of 3% methanolic potassium hydroxide and let it rest for 4 hours at room temperature. The reaction mixture is stirred into ice water acidified with citric acid and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution and dried over sodium sulfate.

The crude product is chromatographed on silica gel (hexane / ethyl acetate, gradient up to 3: 2), yield 0.53 g at the oil state.

Example 31 llß-fluoro-17-methyl-7a-. { 5- [(2 S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3,17β-diol a) 7a- (5-chloropentyl) -ll-fluoro-17a-methyl-is-1, 3, 5 (10) -trien-3, 17ß -diol Under the same conditions as in example 28a 750 mg of 7a- (5-chloropentyl) -ll-fluoro-3-hydroxyestra-1,3,5 (10) -trien-17-one (Example 29b) is reacted ) with 4.9 ml of methylmagnesium bromide solution (3M in diethyl ether), work the reaction mixture to obtain the product and chromatograph. 561 mg of la- (5-chloropentyl) -ll-fluoro-17a-methyl-estra-l, 3,5 (10) -trien-3, 17β-diol are obtained at the foam state; [a] 22D = + 51.6 ° (c = 0.515% in chloroform). b) llß-fluoro-17a-methyl-7a-. { 5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-3,17β-diol Under the same conditions as in example 15f, 408 mg of 7a- (5-chloropentyl) -ll-fluoro-17a-methyl-tetrahydrofuran are reacted. 1,3,5 (10) -trien-3, 17β-diol in 5 ml of N-methyl-2-pyrrolidinone and in the presence of 130 mg of lithium iodide with 606 mg of (2S) -2- (4, 4, 5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidine, then work the reaction mixture in the same manner as in the mentioned example and chromatograph. 326 mg of the title compound are obtained in the form of crystals of melting point 120-121 °; [a] 2D = -5.8 ° (c = 0.535% in chloroform).

Example 32 llß-fluoro-17a-methyl-7a-. { 5- [(2 S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol Under the same conditions as in example 13, 260 mg of llß-fluoro-17a-methyl-7a- are reacted. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol (example 31b) with 151 mg of sodium periodate, work the reaction mixture in the same manner as in example 31b and chromatograph. 129 mg of the title compound are obtained at the oil state.

Example 33 3,17β-diacetoxy-11β-fluoro-17-methyl-7a-. { 5- [(2S) -2- (4,4,5,5,5-pentaf luoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3,5 (10) -trien-3, 17β-diol Under the same conditions as in Example 3, 65 mg of llß-fluoro-17a-methyl-7a- are acetylated. { 5- [(2S) -2- (4, 4, 5,5, 5 -pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol (example 31b) with acetic anhydride and the crude product is oxidized with sodium periodate tetrahydrate in the same manner as in example 4. The mixture The reaction is worked in an analogous manner and chromatographed. 27 mg of the title compound are obtained at the oil state.

Example 34 7a-. { 5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17ß-diol By oxidation analogous to that of example 2 of 152 mg la. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol (example 26f) with sodium periodate gives 66 mg of the title compound at the oil state; [a] 22D = + 11.8 ° (c = 0.53% in methanol).

Example 35 7a-. { 5- [(2S) -2- (4,4,5,5,5-pentaf luoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol Under the same conditions as in Example 3, 76 mg of la- is acetylated. { 5 - [(2S) -2 - (4, 4, 5, 5, 5 -pentaf luoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol (example 26f) with acetic anhydride and the crude product is oxidized with sodium periodate tetrahydrate in the same manner as in example 4. The mixture The reaction is worked in an analogous manner and chromatographed. 31 mg of the title compound is obtained at the oil state; [a] 22D = + 30.6 ° (c = 0.515% in methanol).

Example 36 llß-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol a) llß-fluoro-3-hydroxy-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3,5 (10) -trien-17-one A solution of 2, Og of llß-fluoro-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (Tetrahydropyran-2-yloxy) -estra-1, 3,5 (10) -trien-17-one in 20 ml of methanol and 2 ml of water is stirred at room temperature with 1.2 g of oxalic acid. . After 2.5 hours the reaction mixture is poured onto ice water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on a gel. of silica with dichloromethane / methanol. 1.2 g of llß-fluoro-3-hydroxy-17a-methyl-7- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-17-one at the foam state; [a] 22D = + 69 ° (c = 0.5% in chloroform). b) llß-fluoro-17a-methyl-7a-. { 5- [N-methyl-N- 3 - (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3,17ß-diol To 5 g of llß-fluoro-3-hydroxy-17a-methyl-7 -. { 5- [N-methyl-N-3 - (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-17-one in 150 ml of tetrahydrofuran are added, dropwise and at room temperature, 33 ml of an ethereal solution and 1.6 molar of lithium methoxide. After 2.5 hours, a saturated solution of ammonium chloride is added in an ice bath.it is extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. After chromatography on silica gel containing 2% triethylamine, using dichloromethane / methanol as a diluent, 2.0 g of llß-fluoro-17a-methyl-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra- 1, 3,5 (10) -trien-3, 17β-diol in the form of crystals and with a melting point of 83 ° C.

Example 37 llß-fluoro-17a-methyl-7 -. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentanesulf inyl) -propylamino] -pentyl} -estra-1,3, 5 (10) -trien-3,17β-diol A solution of 500 mg of llß-f luoro-17a-methyl-7a- is stirred. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5- (10) -trien-3, 17β-diol in 20 ml of methanol and 0.9 ml of water for 3 hours with 355 mg of sodium periodate at room temperature. The mixture is then poured into ice water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane / methanol as eluent. . 216 mg of llß-f luoro-17a-methyl-7a- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol at the state of crystals with a melting point of 83.4 ° C.

Example 38 llß-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentanesulfonyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3, 17β-diol a) 11β-fluoro-3-hydroxy-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4, , 5, 5 -pentaf luoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3,5 (10) -trien-17-one A solution of 3 g of la- (5-chloropentyl) -ll-fluoro-3-hydroxyestra-1, 3, 5 (10) -trien- 17-one in 50 ml of dimethylformamide is stirred for 22 hours and at 100 ° C with 1.6 g of lithium iodide and 6.2 g of methyl- [3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propyl] -amine. It is then extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation in vacuo and chromatographed on silica gel with dichloromethane / methanol. 4.5 g of llß-f luoro-3-hydroxy-17a-methyl-7a- are obtained. { 5- [N-methyl-N-3 - (4,4,5,5,5-pentaf luoropentanesulfonyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-17-one at the foam state. b) llß-f luoro-17a-methyl-7a-. { 5- [N-methyl-N-3 - (4,4,5,5,5-pentaf luoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3,5 (10) -trien-3,17β-diol A suspension of 11.4 g of cerium chloride is stirred.

(III) anhydrous in 120 ml of tetrahydrofuran for 2 hours, at room temperature and under nitrogen, and then mixed, dropwise and at 0 ° C, with 17.5 ml of 3 molar etheral solution of methylmagnesium bromide. It is stirred for 30 minutes, then a solution of 3.5 g of llß-fluoro-3-hydroxy-17a-methyl-7a- is added. { 5- [N-methyl-N-3 - (4, 4, 5, 5, 5-pentafluoropentanesulfonyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-17-one in 24 ml of tetrahydrofuran and stirred for a further 30 minutes. Saturated ammonium chloride solution is then added, diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation in vacuo and chromatographed on silica gel with dichloromethane. methanol 2. 2g of llß-fluoro-17a-methyl-7a- are obtained. { 5- [N-methyl-N-3 - (4,4, 5, 5, 5- entaf luoropen- tanosulfonyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3, 17β-diol in the form of crystals with a melting point of 82.5 ° C.

Example 39 llß-fluoro-7a-. { 5- [N-methyl-N-2- (4, 4, 5, 5, 5-pentafluoropentanesulfonyl) -ethylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17ß-diol a) la- (5-bromopentyl) -ll-fluorostr-4-en-3, 17-dione A solution of 33 g of llß- fluoro-7 - (5-hydroxypentyl) -estr-4-en-3, 17-dione in 330 ml of dichloromethane is stirred at -5 ° C and for 0.5 hours with 28.9 g of triphenylphosphine and 36.7 g of carbon tetrabromide. Then dichloromethane is added and washed with water, saturated sodium bicarbonate solution and sodium chloride. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo. The crude product is chromatographed on silica gel with a gradient of hexane-ethyl acetate. 28.5 g of la- (5-bromopentyl) -ll-fluorostr-4-en-3,17-dione of melting point 75-76 ° C are obtained. b) la- (5-bromopentyl) -ll-fluoro-3-hydroxy-estra-l, 3, 5 (10) -trien-17 -one To a solution of 27.8 g of 7a- (5-bromopentyl) -llβ-fluoroestr-4-en-3, 17-dione in 190 ml of acetonitrile are added at 80 ° C 17.0 g of copper (II) bromide. After 8 hours the reaction mixture is stirred in water, extracted three times with ethyl acetate and twice with ammonium chloride, washed with sodium bicarbonate and sodium chloride, dried and concentrated by evaporation in vacuo. After chromatographing the crude product on silica gel and with a gradient of hexane-ethyl acetate, 20.4 g of la- (5-bromopentyl) -ll-fluoro-3-hydroxyestra-1,3,5 are obtained. ) -trien-17-one in the form of colorless crystals of melting point 178 ° C. c) 7a- (5-bromopentyl) -ll-fluoro-estra-1, 3, 5 (10) -trien-3, 17β-diol A solution of 16.2 g of la- (5-bromopentyl) -ll- fluoro-3-hydroxy-estra-l, 3, 5 (10) -trien-17-one in 162 ml of tetrahydrofuran, 90 ml of ethanol and 36 ml of water are mixed, in portions and at 0 ° C, with 4 , 7 g of sodium borohydride and stirred for 2 hours at 0 ° C. The mixture is then poured into water, extracted four times with ethyl acetate, washed with water and sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. 17.1 g of the crude product are obtained. After chromatography on silica gel with hexane / ethyl acetate, 15.6 g of la- (5-bromo-pentyl) -ll-fluoro-estra-1, 3,5 (10) -trien-3, 17ß are obtained. -diol to pure state. d) llß-fluoro-7a- [5- (methylamino) -pentyl] -estra-1, 3, 5 (10) -trien-3,17β-diol A solution of 2 g of la- (5-bromopentyl) - 11β-fluoro-estra-1, 3, 5 (10) -trien-3, 17β-diol in 20 ml of dimethylformamide is stirred for 3.5 hours and at 80 ° C with 8 ml of 40% aqueous solution of methylamine. The mixture is then poured into water, extracted three times with ethyl acetate, washed with water and sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in a vacuum. 1.77 g of llß-fluoro-l- [5- (methylamino) -pentyl] -estra-1,3,5 (10) -trien-3,17-diol are obtained. e) llß-fluoro-7a-. { 5- [N-methyl-N-2- (4,4,5,5,5-pentafluoropentanesulfonyl) -ethylamino] -pentyl} -estra-l, 3, 5 (10) -trien-3,17β-diol A solution of 440 mg of llß-fluoro-7 - [5- (methylamino) -pentyl] -estra-1, 3, 5 (10 ) -trien-3, 17β-diol in 15 ml of methanol is stirred for 1 hour at 90 ° C with 500 mg of 4,4,5,5,5-pentafluoropentylvinylsulfone. The mixture is then poured into water, extracted three times with ethyl acetate, washed with water and sodium chloride solution, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane. methanol 488 mg of 1-fluoro-la - are obtained. { 5 - [N-met il-N- 2 - (, 4, 5, 5, 5-pentafluoropentanesulfonyl) -ethylamino] -pentyl} -estra-1, 3,5 (10) -trien-3, 17β-diol in the form of crystals of melting point 74-76 ° C. Example 40 llß-fluoro-7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -3-hydroxyestra-l, 3,5 (10) -trien-17-one A solution of 1.6 g of llß-fluoro-7 -. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (Tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one in 20 ml of methanol and 2 ml of water is stirred with 1 g of oxalic acid. After 3 hours the reaction mixture is poured over ice-water. It is extracted with methylene chloride, washed with saturated sodium chloride solution, dried and concentrated by evaporation in vacuo. After chromatographing the crude product on silica gel with a gradient of methylene chloride-methanol, 1.1 g of llß-fluoro-7a- is obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3-hydroxy-estra-1,3, 5 (10) -trien-17-one; [a] 22D = + 69 ° (c = 0.5% in chloroform).

Example 41 llß-fluoro-7a-. { 6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -hexyl} -estra-1, 3,5 (10) -trien-3, 17β-dione a) la- (6-chlorohexyl) -ll-fluoro-estr-4-en-3, 17-dione A suspension of 6, 8 g of magnesium shavings in 100 ml of THF are first added under nitrogen to 30 ml of a 41 ml solution of 1-bromo-6-chlorohexane in 270 ml of THF. Once the reaction is started, the rest of the solution is added in drops so that the internal temperature does not exceed 35 C. In a second bath, 48.1 g of lithium bromide are added at 0 ° C. to a suspension of 26.4 g of copper iodide (I) in 120 ml of THF, whereby the internal temperature increases to 40 ° C. Without. After cooling, add 46.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro- (1H) -pyrimidin-2-one and stir for 30 minutes at 40 ° C. A clear solution is obtained which is added dropwise to the Grignard solution previously cooled to -40 ° C. It is then stirred for 30 minutes at -30 ° C and then a solution of 23.5 g of llß-fluoro-estra-4,6-dien-3, 17- is added dropwise and at -50 ° C. dione in 230 ml of THF, 24.6 ml of 1,3-dimethyl-3,4,5,6-tetrahydro- (1H) -pyrimidin-2-one and 55 ml of trimethylchlorosilane in such a way that the internal temperature does not exceed -40 ° C. It is stirred for 1 hour in cold, then 32 ml of glacial acetic acid are added, the cooling bath is removed and stirred for 1 hour at room temperature. To isolate the product, the reaction mixture is poured into 1.5 1 of water, diluted with the same amount of ethyl acetate, the precipitate is filtered on a celite bed, washed with ethyl acetate, the aqueous phase is extracted three times with ethyl acetate, washed with a solution of sodium bicarbonate and sodium chloride, dried over magnesium sulfate and concentrated by evaporation in vacuo. After chromatographing the crude product on silica gel with a gradient of hexane-ethyl acetate, 25.2 g of la- (6-chlorohexyl) -ll-fluoro-estr-4-en-3,17-dione are obtained. b) 7a- (6-chlorohexyl) -ll-fluoro-3-hydroxy-estra-l, 3, 5 (10) -trien-17-one To 25.2 g of la- (6-chlorohexyl) -ll- fluoro-estr-4-en-3, 17-dione in 175 ml of anhydrous acetonitrile are added at 80 ° C 28.1 g of copper (II) bromide and 5.4 g of lithium bromide in 105 ml of acetonitrile anhydrous. After 15 minutes the reaction mixture is cooled to 0 ° C and 250 ml of saturated sodium bicarbonate solution are added dropwise. The solution is then stirred in 1 liter of water, brought to pH = 6 with 2N hydrochloric acid, extracted 3 times with ethyl acetate, washed with sodium chloride solution, dried over magnesium sulfate and concentrated by Vacuum evaporation. The crude product is chromatographed on silica gel with a gradient of hexane-ethyl acetate and 5.7 g of 7a- (6-chlorohexyl) -ll-fluoro-3-hydroxy-estra-l, 3, 5 ( 10) -trien-17-one to the state of foam. c) llß-fluoro-3-hydroxy-la- (6-iodohexyl) -estra-1,3, 5 (10) -trien-17-one 2.7 g of 7a- (6-chlorohexyl) -llβ are dissolved -fluoro-3-hydroxy-estra-1, 3, 5 (10) -trien-17-one in 40 ml of ethylmethyl ketone, add 3.0 g of sodium iodide and stir overnight in a water bath. 90 ° C. To isolate the product, the reaction mixture is cooled to room temperature, stirred in water, extracted three times with ethyl acetate, washed with sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation under vacuum. . 3.4 g of llß-fluoro-3-hydroxy-7a- (6-iodohexyl) -estra-1,3,5 (10) -trien-17-one are obtained, which is used in the next step without purification later. d) llß-fluoro-3-hydroxy la. { 6- [N-methyl-N- 3 - (4,4,5,5,5-pentafluoropentylthio) -propylamino] -hexyl} -estra-l, 3, 5 (10) -trien-17-one 2.5 g of llß-fluoro-3-hydroxy-7a- (6-iodohexyl) -estra-1 are stirred in a bath at 100 ° C. , 3, 5 (10) -trien-17-one in 20 ml of anhydrous DMF with 2.0 g of methyl- [3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propyl] -amine. After two hours the reaction solution is poured over a semi-saturated solution of sodium bicarbonateIt is extracted three times with methylene chloride, dried over magnesium sulfate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel with a gradient of methylene chloride-methanol. 3.15 g of llß-fluoro-3-hydroxy-7a- are obtained. { 6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -hexyl} -estra-1, 3, 5 (10) -trien-17-one at the foam state. e) llß-fluoro-7a-. { 6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -hexyl} -estra-1, 3,5 (10) -trien-3,17-diol 250 mg of llß-fluoro-3-hydroxy-7a- are dissolved. { 6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -hexyl} -estra-1, 3, 5 (10) -trien-17-one in 4.5 ml of methanol and 60 mg of sodium borohydride are added portionwise and at 0 ° C.

After stirring for 3 hours at room temperature, the solvent is removed under vacuum, the residue is taken up in saturated sodium chloride solution, extracted 3 times with methylene chloride, dried over magnesium sulfate and concentrated by evaporation under vacuum. . After chromatography on silica gel with a gradient of methylene chloride-methanol, 165 mg of llß-fluoro-7a- are obtained. { 6- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -hexyl} -estra-1,3, 5 (10) -trien-3, 17-diol at the foam state; [a] D = + 37 ° (c = 1.01% in chloroform).

Example 42 llß-f luoro-7a-. { 6- [N-methyl-N-3 - (4, 4, 5, 5, 5-pentaf luoropentanesulf inyl) -propylamino] -hexyl} -estra-1,3,5 (10) -trien-3,17-diol a) llß-fluoro-3-hydroxy-7a-. { 6- [N-methyl-N- 3 - (4,4,5,5,5-pentafluoropentanosulfinyl) -propylamino] -hexyl} -estral, 3,5 (10) -trien-17-one 500 mg of llß-fluoro-3-hydroxy-7a- is dissolved. { 6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -hexyl} -estra-1, 3, 5 (10) -trien-17-one in 17 ml of methanol and 3.3 ml of water, add 262 mg of sodium periodate and stir for 2 hours at room temperature. To isolate the product, the reaction mixture is mixed with semi-saturated sodium chloride solution, extracted three times with methylene chloride, dried over magnesium sulfate and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel, using a gradient of methylene chloride-methanol. 149 mg of llß-f luoro-3-hydroxy-7a- are isolated. { 6 - [N-methyl-N-3 - (4, 4, 5, 5, 5 -pentaf luoropent anosul finí 1) -propylamino] -hexyl} -estra-1, 3, 5 (10) -trien-17-one at the foam state; [a] D = + 45 ° (c = 1.01% in chloroform). b) llß-fluoro-7a-. { 6- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentanesulf inyl) -propylamino] -hexyl} -estra-1,3,5 (10) -trien-3,17-diol 149 mg of llß-fluoro-3-hydroxy-7- is dissolved. { 6- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentanosulfinyl) -propyl-amino] -hexyl} -estra-1, 3, 5 (10) -trien-17-one in 3 ml of methanol and 35 mg of sodium borohydride are added portionwise. After stirring for 30 minutes at room temperature, the residue is taken up with water, extracted three times with methylene chloride, dried over magnesium sulphate and concentrated by evaporation in vacuo. Thin layer chromatography on a preparative scale and using methylene chloride / methanol = 9/1 as eluent gives 109 mg of llß-fluoro-7a-. { 6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -hexyl} -estra-1, 3, 5 (10) -trien-3, 17-diol at the foam state; [a] D = + 24 ° (c = 0.51% in chloroform). Example 43 llß-fluoro-7a- (5- { [N-3- (furan-2-ylmethylthio) -propyl] -N-methyl-amino.}. -pentyl) -estra-1,3, 5 ( 10) -trien-3, 17ß-diol a) la- (5-chloropentyl) -ll-fluoro-estr-4-en-3, 17-dione A suspension of 7.2 g of magnesium swarf in 100 ml of THF are first added in a nitrogen atmosphere to 20% of a solution of 39 ml of l-bromo-5-chloropentane in 300 ml of THF Once the reaction has begun (for which iodine and dibromomethane can be added), the rest of the solution is added dropwise in such a way that the internal temperature does not exceed 35 ° C. In a second balloon, 51.2 g of lithium bromide are added at 0 ° C to a suspension of 28.1 g of copper iodide.

(I) in 130 ml of THF, whereby the temperature increases to 40 ° C. Without cooling, 49.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro- (1H) -pyrimidin-2-one are added and the mixture is stirred for 15 minutes at 40 C. A clear solution is obtained. add, dropwise, to the Grignard solution previously cooled to -50 ° C. It is then stirred for 15 minutes at -30 ° C and then a solution of 25 g of llß-fluoro-estra-4,6-dien-3,17-dione in 260 drops is added dropwise and at -70 ° C. ml of THF, 26 ml of 1,3-dimethyl-3,4,5,6-tetrahydro- (1H) -pyrimidin-2-one and 59 ml of trimethylchlorosilane in such a way that the internal temperature does not exceed -65 ° C C. It is stirred for 30 minutes in cold, then 34.7 ml of glacial acetic acid are added, the cooling bath is removed and stirred for 1 hour at room temperature. To isolate the product, the reaction mixture is poured into 1.5 1 of water, diluted with the same amount of ethyl acetate, the precipitate is filtered on a celite bed, washed with ethyl acetate, the aqueous phase is extracted three times with ethyl acetate, washed with sodium bicarbonate solution and sodium chloride, dried over magnesium sulfate and concentrated by evaporation in vacuo. After chromatographing the crude product on silica gel with a gradient of hexane-ethyl acetate, 22 μg of la- (5-chloropentyl) -ll-fluoro-estr-4-en-3,17-dione are obtained. b) la- (5-chloropentyl) -ll-fluoro-3-hydroxy-estra-l, 3, 5 (10) -trien-17 -one A 22, lg of la- (5-chloropentyl) -ll-fluoro -estr-4-en-3, 17-dione in 160 ml of anhydrous acetonitrile, 25.4 g of copper (II) bromide and 4.9 g of lithium bromide in 95 ml of anhydrous acetonitrile are added at 80 ° C. After 20 minutes the reaction mixture is cooled to 0 ° C and 200 ml of saturated sodium bicarbonate solution are added dropwise. The solution is then stirred in 750 ml of water, brought to pH = 6 with 2N hydrochloric acid, extracted 3 times with ethyl acetate, washed with sodium chloride solution, dried over magnesium sulfate and concentrated by Vacuum evaporation. The crude product is chromatographed on silica gel with a gradient of hexane-ethyl acetate and 14.7 g of la- (5-chloropenthyl) -ll-fluoro-3-hydroxy-tetra-1,3 are obtained, 5 (10) -trien- 17 -one. c) llß-fluoro-3-hydroxy-la- (5-iodopentyl) -estra-1, 3, 5 (10) -trien-17 -one 5.0 g of la- (5-chloropentyl) -llβ are dissolved -fluoro-3-hydroxy-estra-1, 3, 5 (10) -trien-17-one in 80 ml of ethylmethyl ketone, 5.7 g of sodium iodide are added and the mixture is stirred overnight in a water bath. 90 ° C. To isolate the product, the reaction mixture is cooled to room temperature, stirred in water, extracted three times with ethyl acetate, washed with sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation under vacuum. . 6.8 g of llß-fluoro-3-hydroxy-7a- (5-iodopentyl) -estra-1,3,5 (10) -trien-17-one are obtained as crude product, which is used in the stage next without further purification. d) llß-fluoro-3-hydroxy-7a- [5- (methylamino) -pentyl] -estra-1,3,5 (10) -trien-17-one In a solution of 6.8 g of llß-fluoro 3-hydroxy-7a- (5-iodopentyl) -estra-1,3,5 (10) -trien-17-one in 35 ml of anhydrous tetrahydrofuran is condensed at -78 ° C to 5.1 g of methylamine, and The mixture is stirred inside the pressure reactor overnight at room temperature. After opening the reactor under pressure at -20 ° C, it is allowed to reach room temperature so that excess methylamine evaporates. Finally, the reaction mixture is poured into saturated sodium bicarbonate solution, extracted three times with ethyl acetate, dried over magnesium sulfate and concentrated by evaporation in vacuo. 6.7 g of llß-fluoro-3-hydroxy-la- [5- (methylamino) -pentyl] -estra-1, 3,5 (10) -trien-17-one are obtained as crude product. e) llß-fluoro-7 - (5- { [N-3- (furan-2-ylmethylthio) -propyl] -N-methylamino.} - pentyl) -3-hydroxy-estra-1, 3, 5 (10) -trien-17 -one 526 mg of llß-fluoro-3-hydroxy-7a- [5- (methylamino) -pentyl] -estra-1, 3, 5 (10) -trien-17- is dissolved One and 95 mg of 2- (3-chloro-propylthiomethyl) -furan in 5 ml of ethylmethyl ketone is mixed with 112 mg of sodium iodide and 104 mg of potassium carbonate and stirred for 3 hours in a water bath. 90 ° C. To isolate the product, the reaction mixture is poured into a half-saturated solution of sodium bicarbonate, extracted three times with methylene chloride, washed with sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. The crude product is chromatographed on silica gel with a gradient of methylene chloride-methanol and 229 mg of llß-fluoro-7a- (5- { [N-3- (furan-2-ylmethylthio) -propyl) are obtained. ] -N-methylamino.}. -pentyl) -3-hydroxy-estra-1, 3, 5 (10) -trien-17-one at the foam state. f) llß-fluoro-7a- (5- { [N-3- (furan-2-ylmethylthio) -propyl] -N-methylamino.} - pentyl) -estra-1,3,5 (10) -trien-3, 17ß-diol 217 mg of llß-fluoro-7a- (5- { [N-3- (furan-2-ylmethylthio) -propyl] -N-methylamino} -petyl) are dissolved. -3-Hydroxy-ses-1, 3, 5 (10) -trien-17-one in 6 ml of methanol and are mixed, in portions, with 44 mg of sodium borohydride. After stirring for 1 hour at room temperature, the solvent is removed in vacuo, the residue is taken up with sodium chloride solution, extracted three times with methylene chloride, dried over magnesium sulfate and evaporated in vacuo. By preparative-scale column chromatography and using a gradient of methylene chloride / methanol as the eluent, 146 mg of llß-fluoro-7a- (5- {[N-3- (furan-2-ylmethylthio)) are obtained. -propyl] -N-methylamino.} - pentyl) -estra-1,3, 5 (10) -trien-3, 17β-diol at the foam state.

Example 44 llß-fluoro-7a- (5- { N -methyl- [N-3- (thiophen-2-methylmethyl) -propyl] -amino}. -pentyl) -estra-1, 3, 5 ( 10) -trien-3, 17ß-diol a) llß-fluoro-3-hydroxy-7a- (5- { N-methyl- [N-3- (thiophen-2-yl-methylthio) -propyl] - amino.}. -pentyl) -estra-1, 3,5 (10) -trien-17-one Dissolve 526 mg of llß-fluoro-3-hydroxy-7a- [5- (methylamino) -pentyl] -estra-1, 3,5 (10) -trien-17-one and 103 mg of 2- (3-chloro-propylthiomethyl) -thiophene in 5 ml of ethylmethyl ketone is mixed with 112 mg of sodium iodide and 104 mg of potassium carbonate and stirred for 4.5 hours in a 90 ° C bath. . To isolate the product, the reaction mixture is poured into a half-saturated solution of sodium bicarbonate, extracted three times with methylene chloride, washed with sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. The crude product is chromatographed on silica gel with a gradient of methylene chloride-methanol and 191 mg of llß-fluoro-3-hydroxy-7a- (5- {N-methyl- [N- 1I2 3- (thiophen-2-ylmethylthio) -propyl] -amino.}. -pentyl) -estra-1, 3, 5 (10) -trien-17-one at the foam state. b) llß-fluoro-7a- (5- { N-methyl- [N-3- (thiophen-2-ylmethylthio) -propyl] -amino.}. -pentyl) -estra-1, 3, 5 ( 10) -trien-3, 17ß-diol 185 mg of llß-fluoro-3-hydroxy-7a- (5- { N-methyl- [N-3- (thiophen-2-ylmethylthio) -propyl] is dissolved. -amino.) -pentyl) -estra-1,3, 5 (10) -trien-17-one in 5 ml of methanol and mixed, in portions, with 28 mg of sodium borohydride. After stirring for 45 minutes at room temperature, a large part of the solvent is removed in vacuo, the residue is poured into sodium chloride solution, extracted three times with methylene chloride, dried over magnesium sulfate and evaporated in vacuo. By means of preparative-scale column chromatography and using a gradient of methylene chloride / methanol as eluent, 93 mg of llß-fluoro-7a- (5- {N-methyl- [N-3- (thiophene- 2-ylmethylthio) -propyl] -amino.}. -pentyl) -estra-1,3,5 (10) -trien-3, 17β-diol at the foam state.

Example 45 llß-f luoro-7a-. { 5- [(2S) -2- (4-trif luoromet ilf enyl t iomethyl) -pyrrole idin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17ß-diol a) llß-f luoro-3-hydroxy-7a-. { 5 - [(2S) -2 - (4-trifluoromethyl) enylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -trien-17-one A solution of 0.5 g of 7a- (5-chloropentyl) -ll-fluoro-3-hydroxy-estra-l, 3, 5 (10 ) -trien-17-one in 4 ml of dimethylformamide is stirred with 0.55 g of (2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidine and 0.32 g of lithium iodide for 2 hours and in a water bath. 100 ° C. The reaction mixture is then poured into sodium bicarbonate solution, extracted three times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on a gel. of silica with dichloromethane / acetone. 0.45 g of llß-fluoro-3-hydroxy-7a- are obtained. { 5 - [(2S) -2- (4-trifluoromethyl-phenyl-1-methyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-17-one; [a] 22D = + 32.7 ° (c = 0.51% in chloroform). b) llß-fluoro-7a-. { 5- [(2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol To a solution of 0.43 g of llß-fluoro-3-hydroxy-7a-. { 5- [(2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-17-one in 4 ml of tetrahydrofuran, 2.3 ml of ethanol and 1 ml of water are added, in portions and at 0 ° C, 111 mg of borohydride. Sodium and stirred for 2 hours. The mixture is then poured into ice water, extracted three times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel with dichloromethane / acetone. 0.32 g of llß-fluoro-7a- are obtained. { 5- [(2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estral, 3, 5 (10) -trien-3, 17β-diol; [a] 22D = +16, 2 ° (c = 0.51% in methanol).

Example 46 llß-fluoro-17a-metÍl-7a-. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17ß-diol A solution of 0.2 g of llß-fluoro-17a-methyl-7a-. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol in 5.8 ml of methanol and 2.9 ml of water is stirred with 82 mg of sodium periodate for 5 hours and at room temperature. The mixture is then poured into water, extracted three times with dichloromethane, washed until neutral, dried over sodium sulfate and concentrated by evaporation in vacuo. 210 mg of the crude product is obtained which is chromatographed on silica gel with dichloromethane / methanol. 105 mg of 14, 17-ethane-7oc- are obtained. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanosulfinyl) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol in its pure state, IR 1610 and 1190 [cm'1].

Example 47 llß-fluoro-17a-methyl-7a-. { 5- [(2R) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -trien-3,17β-diol The 11β-fluoro-17a-methyl-7 -. { 5- [(2R) -2- (4, 4, 5,5,5-pentaf luoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol is obtained analogously to that described in example 29; [a] 22D = + 68.7 ° (c = 0.74% in chloroform).

Example 48 l-f luoro-17a-methyl-7a-. { 5 - [(2S) -2 - (4, 4, 5, 5, 5 -pentaf luoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol A 100 mg solution of 3, 17β-diacetoxy-11β-fluoro-1 7 a-me t i-7-. { 5 - [(2 S) -2- (4, 4, 5, 5, 5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -triene in 1.3 ml of 0.2 M methanolic solution of potassium hydroxide is stirred for 2 hours at room temperature. The solution is then poured into water, extracted three times with dichloromethane, washed with sodium chloride solution, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane / acetone. 63 mg of 11-fluoro-17a-m e t i l-7 a- are obtained. { 5 - [(2 S) -2- (4, 4, 5, 5, 5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol; IR: 1710, 1660, 1610 [cm "1] Example 49 ll ß-fl uoro-7a -. {5 - [(2 S) -2 - (4, 4, 5, 5, 5 -pentafluoropentanosulfinylmethyl) - pyrrolidin-1-yl] -pentyl.} -estra-1,3, 5 (10) -trien-3, 17β-diol A solution of 300 mg of llß-fluoro-7a-. {5- [(2S ) -2- (4,4,5,5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol in 4 3 ml of methanol and 2.1 ml of water are stirred with 131 mg of sodium periodate for 4 hours at room temperature, then the mixture is poured into water, extracted three times with ethyl acetate, washed with Sodium chloride, dried over sodium sulfate, concentrated by evaporation in vacuo and chromatographed on silica gel with dichloromethane / ethyl acetate to obtain 203 mg of ll-fluorola-. {5 - [(2S)] ) -2- (4, 4, 5, 5, 5-pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] -pentyl.} -estra-1, 3, 5 (10) -trien-3, 17β-diol; a] 22D = + 11.8 ° (c = 0.53% in methanol).

Example 50 l l ß - f l uoro - 7 a -. { 5 - [(2 S) -2- (4, 4, 5, 5, 5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-3, 17ß-diol The llß-fluoro-7 -. { 5- [(2S) -2 - (4, 4, 5, 5, 5-pentaf luoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol is obtained analogously to that of example 48; [a] 2D = + 30.6 ° (c = 0.515% in methanol). Preparation of the starting compounds N-methyl- [3- (4,4,5,5,5-penta luoropentylthio) -propyl-aamine) 3-iodopropyl-4,4,5,5,5-pentafluoropentyl sulphide A solution of 22.8 g of 3-chloropropyl-4, 4, 5, 5, 5-pentafluoropentyl sulfide in 500 ml of ethylmethyl ketone is stirred with 40 g of sodium iodide for 5 hours in a bath at 100 ° C. and in a nitrogen atmosphere. It is then evaporated in vacuo to dryness, poured into water, extracted three times with ethyl acetate, washed until neutral, dried over sodium sulfate and concentrated by evaporation in vacuo. 30.6 g of 3-iodopropyl-4,4,5,5,5-pentafluoropentyl sulfide are obtained. b) N-methyl- [3- (4,4,5,5, 5-pentafluoropentylthio) -propyl] -amine In a solution of 30.6 g of 3-iodopropyl-4,4,5,5,5-pentafluoropentyl sulfide in 200 ml of absolute tetrahydrofuran, 45 g of methylamine are condensed in a -78 ° C bath and stirred 1.5 hours at room temperature and 4 hours at 60 ° C in a pressure reactor. To open the reactor, let it reach room temperature overnight and then cool to -78 ° C. Then it is allowed to reach room temperature, the methylamine is allowed to evaporate in excess, diluted with ethyl acetate, washed until neutral, dried over sodium sulfate, concentrated by evaporation in vacuo and chromatographed on silica gel with dichloromethane / methanol. 15.7 g of N-methyl- [3- (4,4,5,5,5-pentafluoropentylthio) -propyl] -amine are obtained at the oil state. N-methyl-T3- (4,4,5,5, 5-pentafluoropyntanesulfonyl) -prop-l-amine) 3-chloropropyl-4, 4,5,5, 5-pentafluoropentanesulfone A solution of 23 g of 3-sulfur Chloropropyl-4,4,5,5,5-pentafluoropentyl in 230 ml of chloroform is mixed, at portions and at 0 ° C, with 41.8 g of m-chloroperbenzoic acid at 70 and is stirred for 1.5 hours at room temperature. It is then diluted with dichloromethane, washed with sodium bisulfite solution, sodium bicarbonate and sodium chloride, dried over sodium sulphate and evaporated in vacuo. 23.8 g of pure crystals of 3-chloropropyl-4, 4, 5, 5, 5-pentafluoropentanesulfone of melting point 74-76 ° C are obtained. b) 3-iodopropyl-4,4,5,5,5-pentafluoropentanesulfone A solution of 23.5 g of 3-chloropropyl-4, 4, 5, 5, 5-pentafluoropentanesulfone in 500 ml of ethylmethyl ketone is stirred with 40 g of sodium iodide for 5 hours, in a bath at 100 ° C and under a nitrogen atmosphere. It is then evaporated in vacuo to dryness, poured into water, extracted three times with ethyl acetate, washed until neutral, dried over sodium sulfate and concentrated by evaporation in vacuo. 30.6 g of 3-iodopropyl-4,4,5,5,5-pentafluoropentanesulfone are obtained in the form of crystals with a melting point of 88-89 ° C. c) N-methyl- [3- (4,4,5,5, 5-pentafluoropentanesulfonyl) -propyl] -amine In a solution of 23.5 g of 3-iodopropyl-4, 4, 5, 5, 5- Pentafluoropentanesulfone in 200 ml of absolute tetrahydrofuran condenses 44 g of methylamine in a bath at -78 ° C, and is stirred for 1.5 hours at room temperature and 4 hours at 60 ° C in a pressure reactor. To open the reactor, let it reach room temperature overnight and then cool to -78 ° C. Then it is allowed to reach room temperature, the methylamine is allowed to evaporate in excess, diluted with ethyl acetate, washed until neutral, dried over sodium sulfate, concentrated by evaporation in vacuo and chromatographed on silica gel with dichloromethane / methanol. 14.8 g of N-met il - [3 - (4, 4, 5, 5, 5-pentafluoropentanesulfonyl) -propyl] -amine are obtained in the form of crystals with a melting point of 55-57 ° C. l-bromo-5-t-butyldimethylsilyloxypentane a) 5-bromo-1-pentanol To a solution of 50 g of 5-bromopentyl acetate in 1.6 l of methanol are added dropwise 50 ml of concentrated sulfuric acid and the The mixture is stirred for 30 hours at room temperature. The methanol is removed in vacuo, the residue is taken up in diethyl ether, washed with saturated sodium chloride solution until neutral, dried over sodium sulfate and concentrated by evaporation. 28 g of 5-bromo-1-pentanol are obtained as crude product. b) l-bromo-5-tert-butyldimethylsilyloxypentane A solution of 28 g of crude 5-bromo-1-pentanol in 144 ml of tetrahydrofuran is mixed with 24 g of imidazole. Then a solution of 30.3 g of tert-butyldimethylchlorosilane in 46 ml of tetrahydrofuran is added dropwise and stirred for 4 hours at room temperature. The reaction mixture is poured into water, stirred with diethyl ether, the organic phase is washed 4 times with water, dried over sodium sulphate and concentrated by evaporation. The crude product is chromatographed on silica gel with hexane / diethyl ether. 42 g of the title compound are obtained in the state of colorless liquid. (2S) -2- (4, 4,5,5,5-ßntaf luoropenti 11iomethyl) -pyrrolidine a) N-tert-butyloxycarbonyl-L-prolinol p-tosylate To a solution of 10 g of N-tert-butyloxycarbonyl-L-prolinol in 170 ml of pyridine are added, in portions and at 0 ° C, 24.2 g of p-toluenesulfonic anhydride and the mixture is stirred at 0 ° C for 5 hours. The reaction mixture is then poured onto 2N hydrochloric acid, extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. 17.7 g of N-tert-butyloxycarbonyl-L-prolinol p-tosylate are obtained as oily crude product; [] D22 = -28.0 ° (c = 0.545% in chloroform). b) N-tert-butyloxycarbonyl- (2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidine To a solution of 3.93 g of 4,4,5,5,5-pentafluoropentyl thioacetate in 18 ml of methanol is added 2.94 ml of a solution of sodium methoxide (30% in methanol) and stirred for 30 minutes at room temperature. This reaction solution is added to a solution of 3.0 g of N-tert-butyloxycarbonyl-L-prolinol tosylate and the mixture is stirred for 3 hours at room temperature and for 3 hours at 50 ° C. The reaction mixture is then poured into water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane / ethyl acetate. 2.59 g of N-tert-butyloxycarbonyl- (2S) -2- (4,4,5,5,5,5-pentafluoropentylthiomethyl) -pyrrolidine are obtained at the oil state; [a] D22 = -41.3 ° (c = 0.530% in chloroform). c) (2S) -2- (4,4,5,5, 5-pentafluoropentylthiomethyl) -pyrrolidine To 5.4 ml of trifluoroacetic acid previously cooled to 0 ° C is added 2.55 g of N-tert-butyloxycarbonyl- (2S) ) -2- (4, 4, 5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidine and the mixture is stirred for 1.5 hours at 0 ° C and for 16 hours at room temperature. The reaction mixture is then poured into a 10% solution of sodium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. L, 8g of the title compound is obtained as oily crude product. (2R) -2- (4,4,5,5, 5-pentafluoropentylthiomethyl) -pyridinidine Analogously to the preparation of (2S) -2- (4, 4, 5, 5, 5-pentafluoropentylthiomethyl) - pyrrolidine 9.69 g of the title compound is obtained as an oily crude product by reacting 10 g of N-tert-butyloxycarbonyl-D-prolinol. (4,4,5,5,5-pentafluoropentyl) -vinylsul na a) 4, 4, 5, 5, 5-pentafluoropentyl sulfide A solution of 40 g of 4,4,5,5,5-pentafluoropentyl thioacetate in 200 ml of methanol it is stirred for 1 hour and at 25 C with 34 ml of a 30% solution of sodium methoxide. Then, dropwise, 21 ml of 1,2-dibromomethane is added, stirring is continued for 2 hours at room temperature, a further 70 ml of 30% sodium methoxide are added dropwise and the mixture is stirred for 3 hours. more at 25 ° C. The methanol is then evaporated in vacuo, poured into water, extracted three times with ethyl acetate, washed with water and sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. 34 g of 4,4,5,5,5-pentafluoro-pentyl sulfide are obtained. b) (4,4,5,5, 5-pentafluoropentyl) -vinylsulfone A solution of 34 g of 4,4,5,5,5-pentafluoropentyl sulfide in 74 ml of glacial acetic acid is mixed, dropwise, with 59 ml of 30% hydrogen peroxide in such a way that the reaction temperature does not exceed 70 ° C. It is then stirred for one hour in a bath at 70 ° C. It is then poured into water, extracted three times with ethyl acetate, washed with sodium thiosulfate solution, water and sodium chloride solution, dried over sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on a gel. of silica with hexane / ethyl acetate. 12.3 g of (4, 4, 5, 5, 5-pentafluoropentyl) -vinylsulfone are obtained at the oil state. 2- (3-chloropropylthiomethyl) -furan A 1.77 ml of furan-2-yl-methanethiol in 18 ml of anhydrous acetonitrile are added, dropwise and at 0 ° C, 3.3 ml of a 30% solution of sodium methoxide in methanol. After 5 minutes, 2.6 ml of l-bromo-3-chloropropane are added dropwise. The reaction solution is then stirred for 5 hours at room temperature. To isolate the product, it is diluted with ethyl acetate, washed with water and with sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. By chromatography of the crude product on silica gel and with a gradient of hexane-ethyl acetate, the, lg of 2- (3-chloro-propylthiomethyl) -furan to the oil state. 2- (3-Chloro-propylthiomethyl) -thiophene To 1.0 g of thiophene-2-yl-methanethiol in 8 ml of anhydrous acetonitrile are added, dropwise and at 0 ° C, 1.5 ml of a 30% solution. % of sodium methoxide in methanol. After 5 minutes, 1.1 ml of l-bromo-3-chloropropane are added dropwise. The reaction solution is then stirred for 5 hours at room temperature. To isolate the product, it is diluted with ethyl acetate, washed with water and with sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. By chromatography of the crude product on silica gel and with a gradient of hexane-ethyl acetate, 1.3 g of 2- (3-chloropropylthiomethyl) -thiophene is obtained at the oil state. (2S) -2- (4-trifluoromethyl-enylthiomethyl) -pyrrolidine a) N-tert-butyloxycarbonyl- (2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidine To a solution of 1.65 g of 4-trifluoromethylthiophenol in 18 ml 3 g of cesium carbonate and 3 g of N-terbutyloxycarbonyl-L-prolinol tosylate are added to the dimethylformamide and the mixture is stirred at room temperature for 8 hours. The reaction mixture is poured into water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane / ethyl acetate. 2.59 g of N-tert-butyloxycarbonyl- (2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidine are obtained at the oil state. b) (2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidine A solution of 2.55 g of N-tert-butyloxycarbonyl- (2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidine in 5.64 ml of trifluoroacetic acid is stirred for 1 hour at 0 ° C and then for 3.5 hours at room temperature. The reaction mixture is poured into a 10% solution of sodium bicarbonate, extracted with ethyl acetate, washed twice with 2M hydrochloric acid, the aqueous phase is extracted with ether, brought to alkaline pH with sodium bicarbonate. sodium, extracted three times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. 557 mg of (2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidine are obtained.

Claims (42)

1. CLAIMS 1. substituted la- (? -aminoalkyl) -trtratrienes corresponding to the general formula I wherein the side chain SK represents a residue of formula
2. ACH2) m-N-CH-CH-CCH2) n-SO ^ -. { CH2) 3-E I I I A B D where m is 4, 5 or 6, n is 0, 1 or 2, x is 0, 1 or 2, A represents a hydrogen atom or an alkyl group (C1-5), B and D represent each a hydrogen atom or A and B together represent an alkylene group - (CH2) p- with p = 2, 3, 4 or 5 and D represents a hydrogen atom or A and D together represent an alkylene group - (CH2 ) q- with q = 2, 3 or 4 and B represents a hydrogen atom, and E represents an ethyl residue unsubstituted or substituted one to five times with fluorine, or the terminal substituent (CH2) 3- E of the chain The lateral represents an aryl or optionally substituted heteroaryl radical, which is attached directly to the sulfur atom or through up to 3 methylene groups, R3 represents a hydrogen atom, a hydrocarbon radical of up to 8 carbon atoms or a radical of the formula R 3 -C (0) - in which R 3 'represents a hydrogen atom or a hydrocarbon radical of up to 8 carbon atoms or a radical of phenyl, R11 represents a hydrogen atom, a halogen atom or a group of nitrooxy -0-N02, R14, R15a, R15p, R16a and R16ß each represent a hydrogen atom or R14 and R15a represent an additional bond or a methylene bridge, or R15β represents a methyl group and R15a represents a hydrogen atom, or R15a and R15β represent in each case a methyl group, or R15β and R16β together represent a methylene bridge, or RlAa or R16β represents a Halogen atom or 1 R16a and R16β together represent a group of methylidene and the remaining substituents R14, R15a, R15β, R16a and R16ß each represent a hydrogen atom, R17 'represents a hydrogen atom, an alkyl group (C1-) 5), a group of alkenyl (C2.5), a group of alkynyl (C2_5) or a group of trifluoromethyl in position a or β, and R17"represents a hydrogen atom or a radical of formula R17 '" - C (0) ) -, where R17 '"is a hydrogen atom or a hydroxyl residue with up to 8 carbon atoms, or when R17 'is in position a, then R17' and R14 together represent a bridge of ethane, with the proviso that when A and B, together, do not represent - (CH2) p - or A and D, together, do not represent - (CH2) q-, then at least one of the substituents R11, R14, R15a, R15β, Rlsa and R16β does not represent a hydrogen atom, and their salts by the addition of organic acids and inorganic, acceptable from the physiological point of view. 2. Estratrienes according to claim 1, wherein m is 5.
3. 3. Estratrienes according to claim 1, wherein n is O.
4. 4. Estratrienes according to claim 1, wherein n is 1.
5. 5. Estratrienes according to claim 1, wherein n is 2.
6. 6. Estratrienes according to claim 1, wherein A is a methyl group.
7. 7. Estratrienes according to claim 1, wherein x is 0.
8. 8. Estratrienes according to claim 1, wherein x is 1.
9. 9. Estratrienes according to claim 1, wherein x is 2.
10. 10. Estratrienes according to claim 6, wherein n is 1.
11. 11. Estratrienes according to claim 1, wherein A and B together represent - (CH2) 3-.
12. 12. Estratrienes according to claim 11, wherein n is 0.
13. 13. Estratrienes according to claim 12, wherein x is 0.
14. 14. Estratrienes according to claim 1, wherein E represents a perfluoroethyl residue.
15. 15. Estratrienes according to claim 1, wherein R 3 represents a hydrogen atom.
16. 16. Estratrienes according to claim 1, wherein R 3 represents a methyl group.
17. 17. Estratrienes according to claim 1, wherein R 3 represents an acetyl group.
18. 18. Estratrienes according to claim 1, wherein R11 represents a hydrogen atom.
19. 19. Estratrienes according to claim 1, wherein R 11 represents a fluorine atom.
20. 20. Estratrienes according to claim 1, wherein R 11 is a nitrooxy group.
21. 21. Estratrienes according to claim 1, wherein R 14 is a hydrogen atom.
22. 22. Estratrienes according to claim 1, wherein R14 forms together with R15a an additional bond.
23. 23. Estratrienes according to claim 1, wherein R15β represents a methyl group.
24. 24. Estratrienes according to claim 1, wherein R15 and R16β together form a methylene bridge.
25. 25. Estratrienes according to claim 1, wherein Rlsa is a halogen atom (F, Cl, Br, I).
26. 26. Estratrienes according to claim 25, wherein R16a is a fluorine atom.
27. 27. Estratrienes according to claim 1, wherein R16a and R16ß together form a methylidene group.
28. 28. Estratrienes according to claim 1, wherein R 17 is in position
29. 29. Estratrienes according to claim 28, wherein R 17 represents a trifluoromethyl group.
30. 30. Estratrienes according to the re-excitation 28, in which R 17 represents a methyl group.
31. 31. Estratrienes according to claim 28, wherein R 17 represents a hydrogen atom.
32. 32. Estratrienes according to claim 1, wherein R17ß is in the β position.
33. 33. Estratrienes according to claim 32, wherein R17 represents a methyl group.
34. 34. Estratrienes according to claim 32, wherein R 17 represents a hydrogen atom.
35. 35. Estratrienes according to claim 28, wherein R 14 and R 17 together form an ethane bridge.
36. 36. Estratrienes according to claim 1, wherein SK is a residue of formula (CH2) 5-N- (CH2) 3-SOx- (CH2) 3-C2F5, with X = 0, 1 or 2 CH3
37. 37. Estratrienes according to claim 13, wherein m = 5, E represents a perfluoroethyl residue and the conformation of the n 2 carbon atom of the heterocycle is R.
38. 38. Estratrienes according to claim 13, wherein m = 5 , E represents a perfluoroethyl residue and the conformation of carbon atom 2 of the heterocycle is S.
39. 39. Estratrienes according to claim 37, wherein R 17 is in position a and represents a hydrogen atom.
40. 40. Estratrienes according to claim 1, with the following designations: 14, 17-ethane-7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -estra-l, 3,5 (10) -trien-3,17β-diol; 14, 17 - ethane - 7a -. { 5 - [N-met i l -N- 3 - (4, 4, 5, 5, 5 -pentaf luoropentanosulf inyl) -propylamino] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol; 3, 17β-diacetoxy-14a, 17a-ethano-7a-. { 5- [N-methyl-N- 3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3.5 (10) -triene; 14, 17-ethane-7a-. { 5 - [N-methyl-N-3 - (4, 4, 5, 5, 5 -pentaf luoropentanesulfonyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3,17β-diol; 17 -trifluoromethyl-7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3.5 (10) -trien-3, 17β-diol; 15β, 16β-methano-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; 15β, 16β-methane-17a-methyl-7a-. { 5 - [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanosulfinyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3, 17β-diol; 15β, 16β-methane-7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; 15β, 16β-methane-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol; 15β-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3.5 (10) -trien-3, 17β-diol; 15β, 17a-dimethyl-7a-. { 5- [N-met il-N-3 - (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro- la-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro-7a-. { 5- [N-methyl-N-3 - (4, 4, 5, 5, 5-pentafluoropentanosul finyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3, 17β-diol; llß- fluoro-7a-. { 5- [N-methyl-N-3 - (4, 4, 5, 5, 5-pentaf luoropentanesulfonyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3, 17β-diol; 16 -fluoro-17a-methyl-7 -. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3.5 (10) -trien-3, 17β-diol; 16a-fluoro-17β-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-l, 3.5 (10) -trien-3, 17a-diol; 16a-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentanesulf inyl) -propylamino] -pentyl} -estra- 1,3, 5 (10) -trien-3,17β-diol; 16a-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentanesulfonyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3,17β-diol; 16a-fluoro-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3,5 (10) -trien-3, 17β-diol; 16a-fluoro-7 -. { 5- [N-methyl-N- 3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17a-diol; 16a - f luoro - 7 -. { 5 - [N-met i l -N- 3 - (4, 4, 5, 5, 5 -pentaf luoropentanesulf inyl) -propylamino] -pent il} -estra- 1,3, 5 (10) -trien-3,17β-diol; 16 - f luoro - 7a -. { 5 - [N-met i l -N- 3 - (4, 4, 5, 5, 5 -pentaf luoropentanosul f onyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3, 17β-diol; 7a-. { 5- [N-methyl-N-3- (4, 4, 5, 5, 5-pentaf luoropentylthio) -propylamino] -pentyl} -estra-1, 3.5 (10), 14-tetraen-3, 17β-diol; the- . { 5- [N-methyl-N-3 - (4,4,5,5,5-pentaf luoropentanesulf inyl) -propylamino] -pentyl} -estra-1, 3.5 (10), 14-tetraen-3, 17β-diol; the- . { 5- [N-methyl-N- 3- (4,4,5,5,5-pentaf luoropentanesulfonyl) -propylamino] -pentyl} -estra-1, 3, 5 (10), 14-tetraen-3, 17β-diol; 7 -. 7 -. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; 7a-. { 5- [(2R) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; 17a-methyl-7a-. { 5- [2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro - la-. { 5- [2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro-17a-methyl-7a-. { 5- [(2 S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol; llß-fluoro-17a-methyl-7a-. { 5- [(2 S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro-17a-methyl-7 -. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; 7a-. { 5- [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; 7a-. { 5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro-17 -metl-7 -. { 5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3.5 (10) -trien-3, 17β-diol; llß-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentanesulf inyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3, 17β-diol; llß-fluoro-17a-methyl-7a-. { 5- [N-methyl-N-3- (4,4,5,5,5-pentaf luoropentanesulfonyl) -propylamino] -pent il} -estra-1,3, 5 (10) -trien-3, 17β-diol; l lß - f luoro - 7a-. { 5 - [N-methyl-N-2 - (4, 4, 5, 5, 5-pentaf luoropentanesulfonyl) -ethylamino] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro-7a-. { 5- [N-methyl-N- 3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -pentyl} -3-hydroxy-estra-l, 3,5 (10) -trien-17-one; llß-fluoro-7a-. { 6- [N-methyl-N- 3- (4,4,5,5,5-pentaf luoropentylthio) -propylamino] -hexyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; l l ß - f luoro - 7a -. { 6 - [N-met i l -N- 3 - (4, 4, 5, 5, 5 -pentaf luoropentanosulf inyl) -propylamino] -hexyl} -estra-1,3,5 * (10) -trien-3,17β-diol; llβ-f luoro-7a- (5-. {[[N-3- (f uran-2-i-lmet-11-io) -propyl] -N-methylamino] -pentyl) -estra-1,3, 5 (10) -trien-3, 17β-diol; llß-f luoro-7a- (5- { N -methyl- [N-3- (thiofen-2-ylmethylthio) -propyl] -amino.}. -pentyl) -estra-1, 3, 5 ( 10) -trien-3, 17β-diol; llß-fluoro-7 -. { 5- [(2S) -2- (4-trif luoromet ilf enylthiomethyl) -pyrrole idin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17ß-diol; llß-fluoro-17a-methyl-7a-. { 5- [(2S) -2 - (4, 4, 5, 5, 5-pentaf luoropentanesulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; llß-fluoro-17a-methyl-7a-. { 5- [(2R) -2- (4, 4, 5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol; llß-fluoro-7 -. { 5- [(2S) -2- (4, 4, 5, 5, 5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3, 17β-diol; l l ß - f l uoro - 7 a -. { 5 - [(2 S) -2- (4, 4, 5, 5, 5-pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1, 3, 5 (10) -trien-3,17β-diol; l l ß - f l uoro - 7a -. { 5 - [(2 S) -2- (4, 4, 5, 5, 5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -trien-3, 17β-diol.
41. 41. Pharmaceutical preparations containing at least one compound of general formula I, according to claim 1, and a pharmaceutically acceptable excipient.
42. 42. Use of the compounds of general formula I, according to claim 1, for preparing medicaments. SUMMARY The present invention relates to the new substituted la- (? -aminoalkyl) tetratrienes of general formula I wherein the side chain SK represents a residue of formula ACH2) m-N-CH-CH- (CH2) n-SOxACH2) 3: - E I I i A B D where m is 4, 5 or 6, n is 0, 1 or 2, x is O, 1 or 2, A represents a hydrogen atom or an alkyl group (C1.5), B and D represent each a hydrogen atom or A and B together represent an alkylene group - (CH2) P- with p = 2, 3, 4 or 5 and D represents a hydrogen atom or A and D together represent an alkylene group - (CH2 ) q- with q = 2, 3 or 4 and B represents a hydrogen atom, and E represents an ethyl residue unsubstituted or substituted one to five times with fluorine, or the terminal substituent - (CH2) 3-E of the The side chain represents an optionally substituted aryl or heteroaryl radical, which is attached directly to the sulfur atom or through up to 3 methylene groups, R3 represents a hydrogen atom, a hydrocarbon radical of up to 8 carbon atoms or a rest of formula R3'-C (0) -, in which R3 'represents a hydrogen atom or a hydrocarbon radical of up to 8 carbon atoms or a phenyl radical, R11 represents a hydrogen atom, a halogen atom or a group of nitrooxi 0N02, R14, R15a, R15β, R16a and R16β each represent a hydrogen atom or R14 and Rlsa represent an additional bond or a methylene bridge, or R15β represents a group of methyl and R15a represents a hydrogen atom, or R15a and R15β represent in each case a methyl group, or RX5β and Rlsβ together represent a methylene bridge, or R16a or R16β represents a halogen atom or R16a and R16β represent together a group of methylidene and the remaining substituents R14, R15a, Rlsß, R16a and R? sß each represent a hydrogen atom, R17 'represents a hydrogen atom, an alkyl group (C15), an alkenyl group (C25) ), a group of alkynyl (C25) or a group of trifluoromethyl in position a or β, and R17"represents a hydrogen atom or a radical of formula R17" 'c (0), wherein R17' "is a hydrogen atom or a hydrocarbon residue of up to 8 carbon atoms, or When R17 'is in position a, then R17' and R14 together represent a bridge of ethane, with the proviso that when A and B, together, do not represent (CH2) po A and D, together, they do not represent (CH2) ) q, then at least one of the substituents R11, R14, Rlsa, Rlsβ, R16a and R16β does not represent a hydrogen atom, and its salts by the addition of organic and inorganic acids, acceptable from the physiological point of view. It also relates to pharmaceutical preparations containing the compounds of general formula I and to the use of the latter to prepare medicaments. The new compounds have a very strong anti-estrogenic effect. They constitute, on the one hand, pure antiestrogens or, on the other hand, antiestrogens with a partial estrogenic action. Due to this spectrum of action, the new compounds are particularly suitable for preparing drugs for the therapy of tumors and hormone replacement.