MXPA00007351A - Combination preparation of estrogen and anti-estrogen - Google Patents

Abstract

The invention relates to a combination preparation containing an estrogen and an anti-estrogen, characterized in that the estrogen is chosen from the group consisting of 17-&bgr;-estradiol, 17-&agr;-ethinyl estradiol, estriol, estrone, estrone sulfate, estrogen sulfamate, 17-&agr;-estradiol, mestranol, stilbestrol and natural conjugated estrogens, and in that the anti-estrogen is a substituted 7&agr;-(&xgr;-aminoalkyl)-estratriene of the general formula (I). The combination preparation provided for in the invention can be used for hormone replacement therapy.

Description

COMBINED PREPARATION OF ESTROGEN AND ANTI-ESTROGEN AND Sü EMPLOYMENT DESCRIPTIVE MEMORY The invention relates to a combined preparation of estrogen and to 11 estrogen. During the climacteric and after menopause, many women suffer from acute discomfort that requires treatment, such as heat waves, sudden exudations, tachycardia and other vasomotor symptoms, as a consequence of decreased estrogen production. In the long term, the loss of endogenous estrogen can lead to an increased loss of bone mass (or steroids) and to an increase in cardiovascular diseases. New epidemiological studies showed that senile physiological and psychological central nervous system affections can also be attributed to the loss of estrogen. Examples of this include: limitation of the ability to recall recent events (SM Phillips, BB Sher in, 1992, P syc ho neuroendocri no 1 ogy 17, 485) and Morbus Alzheimer (A. Paganini -Hl 11, VW Henderson , 1994, Am. J. Epidemiol 140, 256).

The aim of hormone replacement therapy is to replace the endogenous estrogen losses that occur with menopause and, thus, avoid both acute and chronic symptoms. At present, the therapy is carried out as a monotherapy of estrogen or as a combination therapy with gestogen. A disadvantage of monotherapy is the strong effect of estrogen on the endometrium, which can lead to hyperplasia of the endometrium and to non-cancers. In combination therapy, sudden and intermediate hemorrhages are reached that markedly limit therapy and often lead to the interruption of therapy. The negative effects of gestagen on the central effects of estrogen are also discussed.

Another possibility of hormone replacement is the combination of a estrogen with an a n 11 e s t r ogen. Here the protective effects of estrogen on the bones are maintained, while the undesired effect on the endometrium is antagonized (EP 0346014). However, it is disadvantageous that the an t i e s t oge does not access the central nervous system and antagonizes the positive properties of estrogen. For example, to Tamofixen is reported to produce acute discomfort typical of the climacteric, such as heat waves (S. Litherland, M. Jackson, 1987, Cancer Treat, Rev. 15, 183). It can be seen that the substance accesses the central nervous system, where it acts as an estrogen antagonist (A. Biegon et al., 1996, Cancer Research 56, 4328). It is also not to be expected that the a n t i e s t r ogen will act against the protective effect of estrogen in the Morbus Al z he íme r. The technical problem lies, then, in finding a combined preparation of estrogen and a n t i e s t r oge not in which the a n t i e s t r og e does not access the central nervous system and, at the same time, act n 11 p r or 11 f e r a 11 vamen t e on the endometpo. The problem is solved because a combined preparation was found in which the estrogen is selected from the group consisting of 17-ß-estradiol 1, 17-a and 11 or 1-adi ol, stupor, stuppa, estrione sulfate, sulfamate estrogen, 17 - - estr adi or 1, mestranol, is 11 lbe stro 1, estrogen esters of 17-ß-estradiol such as, for example, estradiol valerate, and natural conjugated estrogens, and the 11 estrogen is not a 7 a- (? - ami noa 1 qu 11) - unsubstituted estratrie that responds to the formula (1) where the side chain SK represents a residue with the subformula - (CH2) mK-CH-CH- (CH2) n-SO .- [CH2) 3-E lll ABD where m represents 4, 5 or 6, n represents 0, 1 or 2, x represents 0, 1 or 2, A represents a hydrogen atom or a C1-C5 alkyl group, B and D each represent a hydrogen atom, A and B represent, together, a alkylene group - (CH2) p-, with p = 2, 3, 4 or 5, and D a hydrogen atom, or A and D represent, together, an alkylene group - (CH; |, -, with q = 2, 3 or 4, and B an atom of hydrogen, and E represents an ethyl moiety unsubstituted or fluorinated one to five times, or the terminal substituent - (CH 2) 3-E is replaced on the side chain by an aryl or heteroaryl moiety, also substituted, attached directly or through a mono-, di- or t -methylene group to the sulfur atom, R3 represents a hydrogen atom, a hydrocarbon radical with up to 8 carbon atoms or a radical with the subformula R3 -C (O) -, in which R3 represents a hydrogen atom, a hydrocarbon radical with up to 8 carbon atoms or a radical residue 11 or, R 11 represents a hydrogen atom, a halogen atom or a nitrooxy group -0-N02-, R1 R1 represent, each, a hydrogen atom Rx "and R1 additional bond bridge me 111 ene, group me tilo hydrogen, together, methylene bridge, or R1 a halogen atom, or R16"and R16P, taken together, a methylidene group, and the remaining substituents R14 R15", R1D ", R -" and R "" each, a hydrogen atom, R17 represents a hydrogen atom, an alkyl group C1-C5, a C2-Cs alkenyl group, a C2-C5 alkynyl group or a tr1 f1 or ome 111 or ß-position group, and R17 represents a hydrogen atom or a residue with subformula R17-C ( 0) -, wherein R17 represents a hydrogen atom or a hydrocarbon residue with up to 8 carbon atoms, when R is in position a, R17 configures an ethane bridge in conjunction with R14, with the indication that, when A and B do not represent, together, - (CHJ p-, or A and D do not represent, as a whole , - (CH2) s-, at least one of its 111 uyen te s R15 R15", R15p, R" "and Rlo | i does not represent a hydrogen atom, as well as its addition salts with organic and inorganic acids physiologically compatible, in addition, a contoured preparation is made available in which the estrogen is selected from the group consisting of 17-ß- estradiol, 17-and 11 or 1 estri or 1, strio !, estpona, estrione sulfate, estrogen sulfamate, 17-a-estriol, mestranol, stilbestrol, estrogen esters of 1 - ß- estradi o 1 as, for example, estradiol valerate, and conjugated natural estrogens, and the antiestroge is not an 11 ß-ha 1 oge non-7 a - unsubstituted estratrie that responds to the formula where R3 represents a hydrogen atom, a hydrocarbon residue with up to 8 carbon atoms or a residue of subformula R3 -C (0) -, where R3 represents a hydrogen atom or a hydrocarbon residue with up to 8 carbon atoms or a phenyl residue, R7 represents a residue with the formula -ABZ -R °, where A is shown for a direct bond or a benzylidene radical, where the methylene group is linked to the carbon atom 7 of the steroid, or a phenylene moiety, B to an alkylene, alkenylene or alkynylene group with 3 to 14 carbon atoms, linear or branched, and Z to a group -NR21, and Rzl to an alkyl group C1-C3, where, then, R represents a hydrogen atom, an alkyl, alkenyl or alkyl group with up to 10 carbon atoms, linear or branched, or one of the D-CnF n +? Aggregates, where D represents an alkylene, alkenylene or alkylene group with up to 8 carbon atoms, linear or branched, and n an integer from 1 to 8, L - CH = C F - CpF2p +? , where L represents an alkylene, alkenylene or alkynylene group with 2 to 7 carbon atoms, linear or branched, and p represents an integer from 2 to 7, DO- (CH2) q- ar 11 o, where D represents the same as what is already indicated, qa 0, 1, 2 or 3 and aplo figure for a phenyl or 1- or 2-naphthyl moiety, in given cases, substituted once or twice, or a hetero-active moiety, D-0- (C H2) r-CnF2n +? , where D and n represent the same as that already indicated, and r figure for an integer from 1 to 5, or R and R 1, together with the nitrogen to which they are bound, form a saturated or saturated heterocycle with 5 or 6 members of chain that, in given cases, contains one or two neteroatomes selected from nitrogen, oxygen and sulfur and, in given cases, is substituted, or Z is for -SOx- and x for 0, 1 or 2, where, then, R20 represents a group of alkyl, alkenyl or alkynyl with up to 10 carbon atoms, linear or branched, or one of the additives D-CnF n + i / where D represents an alkylene, alkenylene or alkynylene group with up to 8 carbon atoms, linear or branched, and n an integer from 1 to 8, L- CH = C F- CpF2p +? , where L represents an alkylene, alkenylene or alkynylene group with 2 to 7 carbon atoms, linear or branched, and p represents an integer from 2 to 7, D-0- (CH?) q-ar? lo, where D represents the same as what is already indicated, qa 0, 1, 2 or 3 and aryl Figure for a phenyl or 1- or 2-naphthyl moiety, in given cases, substituted once or twice, or a hetero-optional moiety, D-0 - (C H2) r "CnF2nt i, where D and n represent the same as what is already indicated, and r figures for an integer from 1 to 5, or Z figures for -NR31, where, then, R20 represents an alkyl, alkenyl or alkynyl residue with up to 14 carbon atoms, linear or branched, in given cases, partially fluorinated and / or interrupted by one to three heteroatoms -0- and -S- and a g r up ami n t o s -NR32, where R3 'represents a hydrogen atom or a C-CJ alkyl radical, a hetero or heteroaryl radical, in certain cases, substituted once or twice, a cycloalkyl radical C3-C10, in given cases, substituted once or twice, a residue c 1 c 1 or a 1 qu 11 a 1 qu 11 or C-C13, in given cases, substituted once or twice, a C7-C2o aralkyl residue, in certain cases, substituted one or two times, a heteroaryl Cl-C6 radical, in some cases, substituted once or twice, or an amino radical 1 qu or, in some cases, substituted, and R31 represents a radical with the formula -C (0) RJ -CH - RJ where, then, R represents an alkyl, alkenyl or alkynyl moiety with up to 14 carbon atoms, linear or branched, in some cases, fluorinated and / or interrupted by one to three heteroatoms -0- and -S- yagr upami tos - NR 32, where R 32 represents a hydrogen atom or a C 1 -C 3 alkyl radical, an aplo or heteroaryl radical, in certain cases, substituted once or twice, a C 3 -C 10 cycloalkyl radical, in certain cases, substituted once or twice, a residue c 1 c 1 or 1 qu 11 a 1 qu 11 or C4-C15, in given cases, substituted once or twice, a C-C20 aralkyl radical in given cases, substituted once or twice, a heteroaryl radical Ci- Cß, in given cases, substituted once or twice, a amine residue 1 qu 11 or, in given cases, substituted, or a biphenyl residue, except for the compounds 11β-fluor-7a-. { 5- [N-met lN-3- (4,4,5,5,5-pentafluor-penththio) -propylammo] -pentyl 1 -estra-1, 3, 5 (10) -tr? En-3, 17ß-d? Ol 7a-. { 5- [(2S) -2- (4, 4, 5, 5, 5-pentafluorpentylthiomethyl) -p? Rrol? Dm-1-? L] -pentyl) -estra-1, 3, 5 (10) -tr ? en-3, 17ß-d? ol 7a-. { 5- [(2R) -2- (4, 4, 5, 5, 5-pentafluorpentylthiomethyl) -p? Rrol? D? N-1-? L] -pentyl} -estra-1, 3, 5 (10) -tr? en-3, 17β-d? ol ll? -fluor-7a-. { 5- [2- (4-4-5,5,5-pentafluorpentylthio-methyl) -p? Rrol? D? N-1-? L] -pentyl) estra-1, 3, 5 (10) -tr? en-3, 17β-d? ol llβ-fluor-7a-. { 5- [N-met? L-N-3- (4, 4, 5, 5, 5-pentafluor-pentthio) -propylamino] -pentyl} - 3-h? Drox? -estra-1, 3, 5 (10) -tr? En-17-one llß-fluor-7a- (6- [N-met? LN-3- (4,4,5 , 5,5-pentafluor-pentthio) -propylamino] -hex? L.] .estra-1, 3, 5 (10) -tr? En-3, 17β-d? Ol ll? -fluor-7a-. { 5- [(2S) -2- (4-trifluoromethylphenylthio-methyl) -pyrrolid-1-yl] -pentyl} -estra-1, 3, 5 (10) -tr? en-3, 17β-d? ol llß-fluor-7a- { 5- [(2S) -2- (4,4,5,5,5-pentafluor-pentylthiomethyl) -p? rrol? dm-1 -? l] -pentyl.} estra-1, 3, 5 (10) -tr? en-3, 17β-d? ol ll? -fluor-7 - (5 - [(2S) -2- (4, 4,5,5,5-pentafluorpentan-sulfylmethyl) -p? Rrol? Dm-1-? L] -pent? L.} -estra-l, 3, 5 (10) -tr? En-3, 17ß -d? ol llß-fluor-7 - { 5- [(2S) -2- (4,4,5,5,5-pentafluorpentan-sulfonylmethyl) -p? rrol? d? n-1-? ] -pent?) -estra-l, 3, 5 (10) -tr? en-3, 17β-d? ol R11 represents a fluorine or chlorine atom, and R a hydrogen atom or a moiety with the ubu or rmu 1 to R -C (0) -, where R17 represents a hydrogen atom or a hydrocarbon moiety with up to 8 carbon atoms. With a combined preparation it is understood that estrogen and a n t i e s t r egen can be disposed in the same or in different forms of application in a package of medicines and be used simultaneously or in successive times. With a n t i e s t r og e a material that does not have any or very low estrogen activity is not understood, it binds to the estrogen receptor and inhibits the effect of estrogen. An antitumor agent acts against the increase in uterine weight and / or the increase in the height of the epithelium of the uterus in castrated female rats or mice substituted with estradiol benzoate. The unique treatment of castrated rats with the a n t i e s t r ogeno does not lead to the stimulation (increase) of the weight of the uterus or of the epithelial height, in comparison with untreated rats. The compounds that respond to the formulas (I) and (II) have an an t i e s t r e e not very strong effect and do not access the central nervous system. That is why they are particularly suited to be combined with a estrogen, since they do not inhibit the positive properties of estrogen in the brain. The ratio of the dose of estrogen to the dose of antiestrogen is from 1: 5 to 1: 500, preferably from 1:20 to 1,200 and, more preferably, from 1:50 to 1: 100. The combination of a estrogen with a n 11 e s t rgenogen 11 ß- f 1 uor-7 a- is preferred. { 5 - [N -me 111 -N-3 - (4, 4, 5, 5, 5-penta-fluorpentyl) -propylammo] -pentyl} -estra-1, 3, 5 (10) -tr? en-3, 17β-d? ol. Also preferred is the combination of an estrogen with an antiestr oge not selected from the group consisting of: llß-fluor-7a- (5- [N-met? L- (8,8,9,9,9-pentafluornonil) -ammo) ] -pent? ll-estra-1, 3, 5 (10) -tr? en-3, 17? -d? ol ll? -fluor-7a- (6- [N-methyl- (8, 8, 9, 9) , 9-pentafluornonyl) -arrimo] -hex? L.] -estra-l, 3, 5 (10) -tr? En-3, 17β-d? Ol ll? -fluor-7a- (5- [met? l- (7, 7, 8, 8, 9, 9, 10, 10, 10-nona-fluorodec?) -amino] -pent? ll-estra-1, 3, 5 (10) -tr? en- 3, 17β-d? Ol ll? -fluor-7a- [5- (methyl-nonyl-amino) -pent ll] -estra-1, 3, 5 (10) -tr? En-3, 17? -d? Ol llß-fluor-7a-. { 5- [(3,4,4,5,5,5-hexafluoro-pent-2-en? L) -methylammo] -pentyl} -estra-1, 3, 5 (10) -tr? en-3, 17β-d? ol ll? -fluor-7a-. { 5- [N-meth? N-3- (4, 4, 5, 5, 5-pentafluor-pentyloxy) -propylamino] -pent? L) -estra-1, 3, 5 (10) -tr? En- 3, 17ß-d? Ol 4-b? Phen? L-. { 6- [llß-fluor-3,17β-d? H? Drox? -estra-1,3,5 (10) -tpen-7a-? L] -hex? L} -N- (3-phenol-propyl) -acetamide. The antigen can be delivered orally, transdermally, intravenously or as an implant. The estrogen can be supplied orally, transdermally, intravenously or as an implant. All possible combinations of the forms of application for estrogen and antiestrogen are practicable here. Furthermore, the invention relates to the use of the combined preparation of estrogen and to n t i e s t r og e not in the preparation of a medicament for replacement therapy of male and female hormones. It can be used in the prevention and therapy of osteoporosis po s tme nopau s i ca, climacteric discomfort and Alzheimer's disease. Other indications are the therapy of heat waves, dislikes Depressive disorders conditioned by the climacteric, improvement of gnosis, cardiovascular therapy and protection, immunotherapy, therapy of discomfort caused by dysmenorrhoea, uterine hemores di sf une 1 ona, acne, restenosis, h ip er col estero 1 emi a, and de hi pe r 1 ípidemí a, the prevention and treatment of arteriosclerosis, the tendency to the loss of bone mass in histerect women omitted if they were treated with LHRH agonists or antagonists, the treatment of the dome in triosisy myomas in combination with LHR analogs, and the inhibition of the proliferation of arterial smooth muscle cells. The invention also relates to pharmaceutical preparations or media containing, in certain cases, the combined preparation according to the invention, together with additional materials and formulations customary in pharmacy. Graphic Graphics l Graph 1 shows the effect of different combinations of estradiol and llß-fluor-7a-. { 5- [N-met? N-3- (4, 4, 5, 5, 5-pentafluoropentyl) -propylamine] -pentyl) -estra-1, 3, 5 (10) -tr? En- 3, 17 ß -diol (test substance) on the bone trabecular of the proximal tibia of the rat or va r i e c t omi z a da. In the graph they mean, 1: control (solvent only), 2: 0.3 g of estradiol, 3:75 μg of test substance, 4:75 μg of test substance + 0.03 g of estradiol, 5:75 μg of test substance + 0.1 g of estradiol, 6:75 μg of test substance + 0.3 g of estradiol, 7:75 μg of test substance + 1.0 g of estradiol, 8:75 μg of Test substance + 3.0 g of estradiol. Graph 2 Graph 2 shows the effect of different combinations of estradiol and 11 ß- f 1 uo r - 7 a-. { 5 - [N -met? LN-3- (4, 4, 5, 5, 5-pentafluoropentyl) -propylamino] -pentyl) -estra-l, 3, 5 (10) -tr? En- 3, 17 ß-diol (test substance) on the weight of the uterus of female rats or va r te ct omiz es. In the Graph they mean, 1: control (solvent only), 2: 0.3 g of estradiol, 3:75 μg of test substance, 4:75 μg of test substance + 0.03 g of estradiol, 5:75 μg of test substance + 0.1 g of estradiol, 6:75 μg of test substance + 0.3 g of estradiol, 7:75 μg of test substance + 1.0 g of estradiol, 8:75 μg of Test substance + 3.0 g of estradiol. Graphic 3 Graph 3 shows the effect of different combinations of estradiol and 11 ß- f 1 uo r - 7 a- (5 - [N -met? LN-3- (4,4,5,5,5-pentafluorpent? Lt? o) -propylamine] -pentyl.} -estra-l, 3, 5 (10) -tr? en-3, 17? -diol (test substance) on the height of the epithelium of the luminal uterus. Graph means, 1: control (solvent only), 2: 0.3 g of estradiol, 3:75 μg of test substance, 4:75 μg of test substance + 0.03 g of estradiol, 5:75 μg of test substance + 0.1 g of estradiol, 6:75 μg of test substance + 0.3 g of estradiol, 7:75 μg of test substance + 1.0 g of estradiol, 8:75 μg of substance of test + 3.0 g of estradiol Graph 4 Graph 4 shows that 11 ß - f 1 uor - 7 -. {5- [N-met? N-3- (4, 4, 5, 5, 5-pentafluoropentyl) -propylamine] -pent? L) -estra-l, 3, 5 (10) -tr? En-3, 17? -diol does not access the central nervous system. The tissue distribution is represented by llß-fluor-7a- (5- [N-meth? N-3- (4, 4, 5, 5, 5-pentaf luorpen-tiltio) -propylamino] -pent?]. -estra-l, 3, 5 (10) -trien-3,17ß-d? ol marked with 14C, after one application? .v., at 30 minutes (a) and at 180 minutes (b). For comparative purposes, the tissue distribution with 17 - ß - e s t r a di o 1 at 30 minutes (c) and at 180 minutes (d) of the application i.v. The following examples serve for further clarification of the invention.

EXAMPLES Example 1: Synthesis of 11 ß- f 1 uor - 7 a-. { 5 - [Methyl- (8, 8, 9, 9, 9-pentafluor-non? L) -amino] -pentyl) -estra-1, 3, 5 (10) -tr? En-3, 17β-d? ol a) llß-fluor-estr-4-en-3, 17-dαone To 5.0 g of 1 la-hl dr ox i-estr-4-en-3, 17-di nase in 100 ml of toluene and A3 ml of 1,8-diaz ab icic 1 or [5, 4, 0] unde c-7-ene are dripped, at 0 ° C, 4.6 ml of acid fluoride pe r - f 1 uo r bu tan -1-sulfon? co. After 30 minutes the solution is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. After triturating the crude product on silica gel with an eluent of ethyl non-ethyl acetate, 3.8 g of 11 ß-f 1 or r-estr-4-en-3, 17- are obtained. diona, with a melting point of 173-174 ° C. b) llß-fluor-3-methox? -estra-3, 5-d? en-17-one 7.8 g of 1 Iß-f luor-is t-4-in-3, 17 -dione in 40 ml of 2,2-d-t-oxo-p-phenyl are stirred for 5 hours at 80 ° C. 780 mg of 1 to n-4 - its 1 pyridinium phase. Then add 1.5 ml of t r i e t i 1 amine, dilute with ethyl acetate and wash with saturated sodium chloride solution. After crystallization from methanol, 5.3 g of 11β-f-1-or-3 -rae t ox i -e s t r a -3, 5-d i e n-17-one are obtained, with a melting point of 173 ° C. c) 1 lß- f luor-es tra-4, 6-d? en-3, 17 -dione A 5.0 g of 11 ß- f 1 uo r - 3 -me t oxy-estra-3, 5 - d? en-17-one in 50 ml of 1 ml of the same is added, at 0 ° C and successively, 5 ml of a solution of sodium acetate (10%) and, in portions, 2, 5 g of 1, 3-d ibr orno - 5, 5-d ime 111 h idan toi na. After 30 minutes, 2.3 g of sodium sulfite are added, followed by 2.5 g of lithium bromide and 2.0 g of lithium carbonate, followed by stirring for 2 hours at 100 ° C. The reaction mixture is poured into negated water. The precipitated product is aspirated, dissolved in ethyl acetate, washed with water, dried and concentrated in vacuo. After crystallization from ethyl acetate, 3.6 g of 11β-f-1-o-r-e-t-a-4,6-di-3,1-dione are obtained, with a melting point of 198 ° C. d) 1 lß-f luor-7a- (5- tert-butyl-dimethylsilyloxypentyl) -estr-4-en-3,17-dione One reacts under a nitrogen atmosphere with 1.9 g of magnesium in 40 ml of tetrahi dr ofur anus with a solution of 95.3 g of 1-bromo-5-ter-but? Ld? Met? L? L? Lox? -pentane [Tetrahedron Letters 1982, 4147 - 4150] in 260 ml from tetr ah i dr ofur anus, to obtain the Grignard reagent. 32 g of copper iodide (I) are added at -30 ° C and, then, by drip, 29 g of llß-f 1 uo r-e s t r a - 4, 6 -di en-3, 17 -di ona in 290 ml of t e t r a r i i f or a f or a. After the reaction is completed, 20.4 g of glacial acetic acid are added and the reaction mixture is poured into ice water. The precipitated product is aspirated, dissolved in ethyl acetate, washed neutral with water and dried. After decorating the crude product on silica gel with an eluent of hexane-ethyl acetate, 23.9 g of 11 ß-f 1 or r-7 a- (5-tert-butyl-dimethylsilylaxypentyl) -estr are obtained. -4-in-3, 17-d? Ona, in the form of foam. e) llß-fluoro-7a- (5-hydroxentin) -estr-4-en-3, 17-dione. A solution of 23 hours is stirred for 2.5 hours at 50 ° C. , 1 g of 11 ß - f 1 uor - 7 - [5 - ter - or 111 - dime t i 1 s i 1 i loxipent i 1) -e s t r- 4 -en- 3, 17 -dione in 115 ml of t e t r a h i dr o f ur anus and 64 ml of water with 128 ml of glacial acetic acid. The reaction mixture is concentrated in vacuo, taken with ethyl acetate, washed with water and dried. 20.4 g of llß-fluoro-7a- (5-hydroxentinyl) -estr-4-ene-3,17-dione are obtained in the form of a foam. f) 7a- (5-acetoxy-pentyl) -ll-fluor-estr-4-en-3,17-dione. Reacted for 2 hours at ° C, 20 g of 11 ß- f 1 uo r - 7 a- (5-hir ox i pen 111) - estr -4 - en - 3, 17 - di ona dissolved in 100 ml of pipdin with 50 ml of aceta nh idr i do. Then add 5 ml of water at 0 ° C and stir for 45 minutes. It is extracted with diethyl ether, washed with 2N sulfuric acid until pipdma-free and the solution is neutralized with saturated sodium bicarbonate solution and water. After drying and concentrating under vacuum, the product is chromatographed on silica gel with a solvent eluent of ethyl acetate. 17 g of 7a- (5-a c e t or x i pen 111) -lll-f 1 uor-s t r -4-e n-3, 17-di nase are obtained, with a melting point of 78.4 ° C. g) 7a- (5-acetoxy-pentyl) -ll-fluoro-3-hydroxy-ester-l, 3,5 (10) -tr? en-17-one To 16.7 g of 7 a- (5-acetoipen 111) -11 ß-f 1 uor-estr-4-e n-3, 17-di none dissolved in 190 ml of acetonitrile are added, at 80 ° C. , 18.6 g of copper bromide | II) and 3.6 g of lithium bromide. After 15 minutes, the reaction mixture is poured into ice water containing sodium bicarbonate. The precipitated product is aspirated, dissolved in ethyl acetate, washed with water, dried and concentrated in vacuo. After When the product was added on silica gel with an eluent of hexane-ethyl acetate, 8.7 g of 7 a- (5-acetoxypen-111) -11 ß-f-1-or-3-hiroxy-estra is obtained. -1, 3, 5 (10) -tr? En-17-one, in the form of foam. h) 7a- (5-acetoxy pent? l) -ll-fluoro-3-15 (tetrah? drop? rau-2-? lox?) -estra-1, 3, 5 (10) -trien-Donate Moves , for 2.5 hours at room temperature, 8.2 g of 7 a- (5 -aceto ipen 111) - 11 ß- f 1 uo r - 3 - hi dr oxy-estra - 1, 3, 5 (10) - tri-en-17-one dissolved in 86 ml of THF with 8.6 ml of 3, 4 - d i h i d r o - 2 H - p i r a n o and 820 mg of acid p - t ol ol s ul f on i c o. Then add 0.5 ml of saturated sodium chloride solution, dry and concentrate in vacuo. After c oma t og r a f i a r the raw product on gel silica with an eluent of hexane-ethyl acetate 7.8 g of 7 - (5 - a ce t ox ipe n 111) - 11 ß-fluor-3- (tetrah? drop? ran-2-? lox?) -estra-1, 3, 5 ( 10) -trien-17-one, in the form of foam i) llß-fluor-7a- (5-h? Drox? Pent? L) -3- (tetrah? Drop? Ran-2-? Lox?) -estra -1, 3, 5 (10) -tr? En-17- At room temperature, 7.4 g of 7a- (5-acetoxy-pentyl) -ll-fluoro-3- (tetrahydro-p-ran-2-ylox) -estra-l, 3 are stirred. 5 (10) -tpen-17-one dissolved in 370 ml of methanol and 37 ml of water with 1.8 g of sodium carbonate. After three hours, the reaction mixture was poured into ice water. The precipitated product is aspirated, dissolved in ethyl acetate, washed neutral with water, dried and concentrated in vacuo. 7.0 g of llß-fluor-7a- (5-hydrox? -pent? L) -3- (tetrahydro-p? Ran-2? Lox?) - estra-l, 3.5 ( 10) -tpen-17-one, in the form of foam j) llß-fluor-3- (tetrah? Drop? Ran-2-? Lox?) -la- (5-p-toluolsulfon? Lox? Pent? L) -estra-1, 3, 5 (10) -tr? en-17-one Stir, for 3 hours at room temperature, 6.7 g of 11 ß-f 1 uor-7 - (5-hydroxypen 111) - 3- (tetrah? Drop? Ran-2-? Lox?) -estra-1, 3, 5 (10) -trien-17-one dissolved in 70 ml of pyridine with 6.0 g of anhydride p - to 1 uen s u 1 f óni co. The solution is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. After hardening the crude product on silica gel with an eluent of hexane-ethyl acetate, 5.7 g of llß-fluoro-3- (tetrah? drop? ran-2-α-lox?) - la - (5-p-toluolsulfonyloxy-pentyl) -estra-1, 3, 5 (10) are obtained -tpen-17-one, in the form of foam. k) llß-f lúor-7a-. { 5- [N-met? L-N-3- (4, 4, 5, 5, 5-pentafluorpentylthio) -propylamino] -pent? L} -3- (tetrah? Drop? Ran-2-? Lox?) -estra-1, 3, 5 (10) -tr? En-17-one 2.0 g of llß- are stirred at 80 ° C. fluorine-3- (tetrah? drop? ran-2-? lox?) - l -. { 5-p-toluenesulfonyloxypentyl) -estra-1, 3, 5 (10) -tr? En-17-one dissolved in 44 ml of THF with 1.2 g of methyl- [3- (4, 4, 5, 5 , 5-pentafluoropentyl) -propyl] -amine. After 6.5 hours the reaction mixture is combined with water. It is extracted with ethyl acetate, washed with saturated sodium chloride solution and concentrated in vacuo. After centrifuging the crude product on silica gel with an eluent of methylene chloride and no methanol, 1.3 g of llß-fluoro-7a- are obtained. { 5- [N-met? L-N-3- (4, 4, 5, 5, 5- pentafluorpentylthio) -propylamine] -pentyl} - 3 - (tetrah? Drop? Ran-2-? Lox?) -estra-1, 3, 5 (10) -tpen-17-one, in the form of oil. 1) llß-fluor-7a- (5- [N-meth? N-3- (4, 4, 5, 5, 5-pentaf luorpentylthio) -propylammo] -pentyl.} - 3 - (tetrah? Drop? ran-2-? lox?) -estra-1, 3, 5 (10) -trien- 17ß-ol A 2.0 g of 11 ß- f 1 uo r - 7 a- { 5 - [-me 111 - N - 3 - (4, 4, 5, 5, 5-pentafluorpent? Lt? O) -propylammo] -pentyl) -3- (tetrah? Drop? Ran-2-? Lox?) -estra- 1, 3, 5 (10) - tr? In-17 -one dissolved in 17 ml of THF, ml of ethanol and 4.2 ml of water are added, in portions and at 0 ° C, 350 mg of sodium borohydride. After 30 minutes, the reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution and concentrated in vacuo. 1.7 g of llß-fluoro-7a- (5- [N-meth? N-3- (4,4,5,5,5-pentafluorpentylthio) -propylammo] -pentyl.) - 3 - ( tetrah? drop? ran-2-? lox?) -estra-1, 3, 5 (10) -tpen-17ß-ol crude, in the form of foam m) llß-fluor-7a-. { 5- [N-met? L-N-3- (4, 4, 5, 5, 5-pentafluorpentylthio) -propylamino] -pentyl} -estra-1, 3, 5 (10) -tr en-3, 17ß-d? ol A solution of 1.6 g of llß-fluor-7a- (5- [N-meth? N-3- (4, 4, 5, 5, 5-pentafluorpent? Lt? O) -propylamino] -pent is stirred. ? l.]. -3- (tetrah? drop? ran-2-? lox?) -est ra-1, 3, 5 (10) - tri en-17 ß-ol in 20 ml of ethanol and 2 ml of Water with 1.0 g of oxalic acid After 3 hours, pour the reaction mixture into ice water, extract with methylene chloride, wash with saturated sodium chloride solution, dry and concentrate in vacuo. When the crude product is evaporated on silica gel with an eluent of methylene chloride, the result is 1.1 g of 11-fluoro-7a-. {5- [N-met? IN-3- (4, 4, 5, 5, 5-pentafluorpentyl-thio) -proprilam no] -pentylj-estra-l, 3,5 (10) -tr? en-3,17β-d? ol, with a melting point of 95 ° C. Example 2: Effect of the combined preparation of estrogen and antstr oge not on the uterus and on the bones The dosages to be used of the estrogen and the anasthetrose for the selective effect test on bones should be previously established with pre-tests. The dose of a n t i e s t r egen to be used is determined in a test of a uterus in the rat or in a substitute estradiol. The dose to be selected must decrease the weight of the uterus exactly at the level of that of female rats or untreated t rats. The dose of estrogen to be used is determined in a test of uterine growth in the female rat ova r i e c omitted. A dose is selected which, in this model, produces a uterine weight stimulation such as that found in untreated test animals. In the combination to be tested, the anchor is not delivered in the doses defined above. The estrogen is applied in different combinations with the 11 estrogen, from a dose 10 times smaller to 100 times larger than that determined in the test. of uterine growth of each estrogen. In the selective effect test on bones, female rats or 3-month old female rats are treated for 28 days with the combinations of active drugs defined above, for which the treatment is possible to be carried out orally. , subcutaneous or a combination of both. After 28 days the animals are killed and the weight of the uterus is measured, as well as the density trabecular bone of the proximal tibia. The weight of the uterus is determined by weighing the wet uterus immediately after removal of the organ. The trabecular bone density is determined ex vivo by means of measurements of bone density in the second spongiosa of the proximal tibia with a QCT (Stratec XCT 960A). A typical example of a combination of a non-selectively effective estrogen with antiestr oge is shown in Figures 1 to 3 for the active substances 17 ß-estr ad io 1 and 11 ß- f 1 uor - 7 a - (5 - [N -met? lN-3- (4,4,5,5,5-pentafluorpentyl? t) -prop lamino] -pentyl) -estra-1, 3, 5 (10) -tr? en-3, 17 β -diol (substance of example 1).

Example 3: Verification that the antigen does not access the central nervous system. Female rats (approximately 180 g) are treated once with 1 mg / kg of test substance labeled with 1A (2 MBq / kg). The test substance is dissolved in p r op i 1 eng 1 i co 1 / ag ua and is applied intravenously. One test animal is killed at a time at 0.5 and 3.0 hours after application and whole body sagittal sections are prepared. The determination of the distribution of Tissues are carried out by means of a full-body adductor. A typical example is represented in figure 4, for llß-fluor-7a-. { 5- [N-met? L-N-3- (4, 4, 5, 5, 5-pentafluor-pen-tiltio) -propylamino] -pentyl} -estra-l, 3, 5 (10) -trien-3,17ß-d? ol (substance of example 1).

Example 4: 11 ß - f 1 uo r - 7 a -. { 5 - [me 111 - (8, 8, 9, 9, 9-pentafluor-non? L) -ami] -pent? L) -estra-1, 3, 5 (10) -tr? En-3, 17β-dα ol a) llß-fluor-estr-4-en-3, 17-d ?ane A 5.0 g of 11 a - hydr ox i - estr - 4 - en - 3, 1 - dione in 100 my toluene and 7.3 ml of 1,8-diazabicic 1 or [5, 4, 0] unde c-7-ene are dripped, at 0 ° C, 4.6 ml of acid fluoride pe rf 1 uo r bu tan - 1 -sulfonic. After 30 minutes the solution is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. After centrifuging the crude product on silica gel with an eluent of hexane-ethyl acetate, 3.8 g of 11 ß-f 1 or r-estr-4-en-3, 17-di are obtained. ona, with a melting point of 173-174 ° C. b) llß-fluor-3-methox? -estra-3, 5-d? en-17-one 7.8 g of llß-f luor-estr-4-en-3, 17-d-one are stirred for 5 hours at 80 ° C in 40 ml of 2,2-d isopropy not with 780 g. mg of 1 to n - 4 - its 1 pyridinium phase. Then add 1.5 ml of t r i e 111 amine, dilute with ethyl acetate and wash with saturated sodium chloride solution. After crystallisation from methanol, 5.3 g of 11β-f-1-or-3-methyl-oxy-estra-3,5-di-en-17-one was obtained, with a melting point of 173 ° C. . c) 1 Iß- f luor-is tra-4, 6-d? en-3, 17 -dione A 5.0 g of 11 ß- f luo r - 3 -me toi-estra-3, 5 -d? At -17-one in 50 ml of dime ti 1 f ormami da are added, at 0 ° C and successively, 5 ml of a solution of sodium acetate (10%) and, in portions, 2.5 g of 1,3-dibrino-5, 5-dime 111 -nidantoma. After 30 minutes, add 2.3 g of sodium sulphite and then 2.5 g of lithium bromide and 2.0 g of lithium carbonate, stirring for 2 hours at 100 ° C. The reaction mixture is poured into ice water. The precipitated product is sucked off, dissolved in ethyl acetate, washed with water, dried and concentrated in vacuo. After crystallization from ethyl acetate, 3.6 g of 11 ß-f luo r-e s t r a-4, 6-d i e n-3, 17-dione are obtained, with a melting point of 198 ° C. d) llß-f luor-7a- (5-tert-butyl-dimethylsilyloxypentyl) -estr-4-en-3,17-dione. 7.9 g of magnesium are reacted under nitrogen. 40 ml of tetr ah i dr of ur ano with a solution of 95.3 g of 1-bromo-5-ter-but? Ld? Met? Ls? L? Lox? -pentane [Tetrahedron Letters 1982, 4147-4150] in 260 ml of tetrahydrurase, not to obtain the Gpgnard reagent. 32 g of copper iodide (I) are added at -30 ° C and then, dropwise, 29 g of llß-f 1 uo r-estra-4, 6-di en-3, 17-di ona in 290 ml of tetrahydrofura no. After the reaction is completed, 20.4 g of glacial acetic acid are added and the reaction mixture is poured into ice water. The precipitated product is aspirated, dissolved in ethyl acetate, washed neutral with water and dried. After centrifuging the crude product on silica gel with an eluent of hexane-ethyl acetate, 23.9 g of 11β-f-1-or -7- (5-tert-butyl-dimethylsilyloxypentyl) ester are obtained. -4-in-3, 17-d? Ona, in the form of foam. e) llß-fluoro-7a- (5-hydroxentin) -estr-4-en-3, 17-dione. A solution of 23 hours is stirred for 2.5 hours at 50 ° C. , 1 g of 11 ß- f 1 uo r - 7 a- [5 - ter -bu 111 - d 111 111 1111 or 111 111) - e s r - 4 - en - 3, 17 -di ona in 115 mi of t e t r a n i f r o f a r a r and 64 ml of water with 128 ml of glacial acetic acid. The reaction mixture is concentrated in vacuo, taken with ethyl acetate, washed with water and dried. 20.4 g of llß-fluoro-7a- (5-hydroxentinyl) -estr-4-ene-3,17-dione are obtained in the form of a foam. f) - (5-bromopentyl) -ll-fluor-estr-4-en-3,17-d-one A solution of 33 g of llß-fluor-7a- (5 g) is mixed at 5 ° C. -h? drox? pent? l) -estr-4-en-3, 17-d? ona in 330 ml of dicone or omene with 28.9 g of triphen 11 phosphine and 36.7 g of tetra- br or carbon, stirring for 0.5 hour. The mixture is then added and washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. The crude product is then chromatographed on silica gel with an eluent of hexane-ethyl acetate. 28.5 g of 7a- (5-b romope n 111) -11 ß- f luo r -e s t r -4-e n-3, 17-di nase are obtained, with a melting point of 75-76 ° C. g) 7 a - (5-bromopent? l) -ll-fluoro-3-hydrox? -estra-l, 3,5 (10) -tpen-17-d? ona To 27.8 g of 7 a- (5-br omopen 111) -11 ß- f 1 uor -estr-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 was poured into water, extracted three times with ethyl acetate, washed twice with ammonium chloride solution, with sodium bicarbonate solution and with sodium chloride solution, dried and dried. concentrate with vacuum. After chromatography on silica gel with an eluent of hexane-ethyl acetate, 20.4 g of 7 a- (5-br omope n 111) -11 ß-fluoro-3-hydroxyl are obtained? -estra-l, 3,5 (10) -tpen-17-d ?one, in the form of colorless crystals with a melting point of 178 ° C. h) 7 a- (5 -br omopen 111) - 11 ß- f 1 uo r - estra - 1, 3, 5 (10) -tr? en-3, 17β-d? ol A solution of 16.2 g of 7a- (5-bromopentyl) -ll-fluoro-3-hydroxyl-tra-l, 3, 5 (10) -tri in-17 -dione in 162 mi of tetr ahdr ofur, as well as 90 ml of ethanol and 36 ml of water are mixed, 0 ° C and in portions, with 4.7 g of sodium borohydride and stirred for 2 hours at 0 ° C. It is then poured into water, extracted four times with ethyl acetate, washed with water and sodium chloride solution, dried over sodium sulfate and it concentrates with emptiness. 17.1 g of crude product are obtained. After chromatography on silica gel with an eluent of hexane-ethyl acetate, 15.6 g of 7 a- (5-br omope n 111) -11β are obtained. -fluor-estra-l, 3.5 (10) -tr? en-3,17β-d? ol pure. i) llß-fluor-7a- [5- (methylene-amine) -pent? l] -estra-1, 3, 5 (10) -tr? en-3, 17β-d? ol Stirred , for 3.5 hours at 80 ° C, a solution of 2 g of 7 a- (5 -br omopen 111) - 11 ß- f 1 uo r -estra-1, 3, 5 (10) -tpen-3 , 17ß-d-ol in 20 ml of dimethylammonium oxide with 8 ml of 40% aqueous solution of methylamine. It is then poured into water, extracted three times with ethyl acetate, washed with water and with chloride solution. sodium, dried over sodium sulfate and concentrated in vacuo. 1.77 g 11β-fluoro-7a- [5- (metho-ammo) -pent ?l] -estra-1, 3, 5 (10) -trα in-3, 17β-dαol are obtained . j) llß-fluor-7a-. { 5- [met? L- (8,8,9,9,9-pentafluor-nonyl) -amino] -pentyl} -estra-1, 3, 5 (10) -tr? en-3,17β-d? ol A solution of 1.77 g 11 ß - f 1 uor is stirred for 1 hour in a bath at 80 ° C. - a - [5 - (me 111 -amino) -pen ti 1] -estra-1, 3, 5 (10) -tr? en-3, 17ß-d? ol in 18 mi of íme ti 1 fo rmami da with 1.4 g of tosylate of 8,8,9,9,9, -pentafluor-non? lo. Then pour in Water is extracted three times with ethyl acetate, washed with water and with sodium chloride solution, dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel with an eluent of 1% strength. no-me ta no 1. You get llß-fluor-7a-. { 5- [me til- (8, 8, 9, 9, 9-pentafluor-non? L) -amino] -pentyl) -estra-1, 3, 5 (10) -tr? En-3, 17? -d? Ol, in the form of crystals and with a fusion of 110 A. Preparation of the starting compounds tosylate of 8,8,9,9,9-pentafluor-non? Lo a) 4 -be nc 11 oxy -bu tan-1 - or 1 Incorporate, in portions and at room temperature, 42 g of sodium hydride (60%) in 900 ml of absolute diammonium. To the suspension cooled to -20 ° C, 88.6 ml of 1, 4 -bu t a n od 1 are dripped into 450 ml of dime t i 1 -f or absolute rmamide so as not to exceed an internal temperature of -15 ° C. After the addition is complete, a solution of 121 ml of benzyl bromide in 870 ml of absolute dimethanol is discharged and interrupted, and the reaction mixture is then stirred for 30 minutes at room temperature. The reaction is terminated by the careful addition of 315 ml of water. To conclude pour the mixture The reaction mixture was 1.5 l of water and extracted three times with 1 l of ether each time. The ether phases were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. By means of chromatography on silica gel with an eluent of hexane-ethyl acetate gives 105 g of 4-benzyl-11-oxoxy-1-o-1, in the form of oil b) 4-be nc 11 oxy-1-br omo-bu ta no To the solution of 105 g of 4-benzyl-1-butan-1-ol and 191 g of triphenylphosphide in 1: 1 methylene chloride cooled to -15 ° C are added, in portions, 239 g of tetrameromer and, After the addition is complete, it is stirred for 1 hour at 0 ° C. After concentrating the reaction mixture with vacuum, purification is carried out by chromatography on silica gel with an eluent of hexane-ethyl acetate. 133 g of 4-benz 11 oi-1 -b-blubber are obtained, in the form of oil c) l-benzylx -8,8,9,9,9-pentafluor-nonane to a suspension of 2 g. , 23 g of magnesium chips in 58 ml of tetr ah not absolute irofura are added, initially at room temperature, 10% of a solution of 20 g of 4-benzyl-l-bromo-butane in 20 ml of tetrahydrofuran. Dr ofura not absolute. After starting the reaction, what can be done by adding iodine, the rest of the solution is dripped in order to maintain an internal temperature of 40 ° C. After the addition is complete, it is still stirred for 1 hour at room temperature, before the excess magnesium ecantaf, transferring the solution to a loading ampoule. Now this solution is dripped, together with a solution of 21 g of 1, 1, 1, 2, 2 -pe ntaf 1 uor - 5 - and odo-pentane in 97 mi of tetr ah i dr o - f ur to not absolute , to a solution of 555 mg of copper (II) chloride and 350 mg of lithium chloride in 58 ml of non-absolute tetrahydrofure at 0 ° C. It is still stirred for 1 hour at room temperature, then the reaction mixture is added in saturated ammonium chloride solution, extracted three times with ether, the organic phase is dried over magnesium sulfate and concentrated in vacuo. A preparative column chromatography on silica gel with an eluent of hexane-acetate or ethyl gives 22 g of 1-benzyl-1-oxy-8, 8, 9, 9, 9-pe ntaf 1 u-r -nonman widely purified, in the form of oil, d) 8,8,9,9,9-pentafluor-nonan-l-ol 16 g of l-benzol is dissolved -8,8,9,9,9-pe ntaf 1 uo r - nona not in 700 ml of absolute methylene chloride, mixed with 18.4 ml of N, N- dime 11 I landed 11 na at 0 ° C and stirred for 5 minutes. Then, 26.4 g of aluminum trichloride are added in portions and the reaction mixture is heated for 45 minutes at 50 ° C. To conclude, the mixture is cooled to room temperature, poured into 2N hydrochloric acid, extracted three times with methylene chloride, dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel with an eluent of hexane-ethyl acetate. 8.6 g of 8,8,9,9,9-pentafluor-nonan-1-ol are obtained in the form of an oil. e) 8,8,9,9,9-pentafluor-non-la tosylate 3.0 g of 8, 8, 9, 9, 9 -pe ntaf 1 u or r -nonan-1-ol are dissolved in 26 ml of absolute pyridine and, at 0 ° C, 3.1 g of chloride of pt or 1 ue nsu 1 f on 11 o, and stir in the cold for 1.5 hours. The reaction mixture is then poured into water, extracted three times with ether, dried over magnesium sulfate and concentrated in vacuo. Preparative column chromatography on silica gel with an eluent of hexane-ethyl acetate provides 4.1 g of tosylate of 8, 8, 9, 9, 9 -pen taf 1 or r or n 11, as an oil. limpid.

Tosylate 9, 9, 10, 10, 10 - pe taf 1 uor -de c 11 o a) 5 -be c 11 exi -pen tan - 1 - o 1 Incorporate, at room temperature and in portions, 31.5 g from sodium hydride (60%) to 900 ml of di me 111 absolute foaming. To the suspension cooled to -20 ° C are added, drip, 104.8 g of 1, 5 - pen t a nodi or 1 in 450 ml of dime t i 1 f or absolute temperature, so as not to exceed an internal temperature of -15 ° C. After the addition is complete, a solution of 121 ml of benzyl bromide in 870 ml of absolute diammonium is added dropwise, and then the reaction mixture is stirred for 30 minutes at room temperature. . The reaction is terminated by the careful addition of 315 ml of water. To conclude, the reaction mixture was poured into 1.5 1 of water and extracted three times with 1 1 of ether each time. The ether phases are combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. By chromatography on silica gel with an eluent of hexane-ethyl acetate, 85 g of 5-benzyl-11-oxypen t-1-o-1 are obtained in the form of an oil. b) 5 -be nc i lox i - 1 -br ornope n t a no To the solution of 85 g of 5-benzyl? -pentan-1-ol and 143 g of trif in 11-phosphine in 720 ml of methylene chloride cooled to -15 ° C are added, in portions, 179 g of tetr ab r omome ta no, and after the addition is complete, stir for 3 hours at 0 ° C. After concentrating the reaction mixture with a vacuum, the purification is carried out by chromatography on silica gel with an eluent of hexane 1 or methanol or methylene chloride. 71 g of 5-oe nc 11 or i-1-b are obtained as-oil, in the form of an oil. c) l-benz? lox? -9,9,10,10,10-pentafluor-de ca no To a suspension of 2.23 g of magnesium swarf in 58 ml of tetrahydrate of absolute water are added, micially to At room temperature, 10% of a solution of 21.5 g of 5-benzyl-1-methyl-pen is not in 20 ml of non-absolute tetrahydration. After starting the reaction, which can be done by adding iodine, the rest of the solution is dripped in order to maintain an internal temperature of 40 ° C. After the addition is complete, it is still stirred for 1 hour at room temperature, before decanting the excess magnesium, transferring the solution to a loading ampoule. Now this solution is dripping, together with a solution of 21 g of 1,1,1,2,2-pentaf 1 uo r - 5 - and odo -pen t anus in 97 ml of absolute tetrahydrofuran, to a solution of 555 mg of copper chloride (II) and 350 mg of lithium in 58 ml of non-absolute tetrahydrous at 0 ° C. It is stirred for 1 hour at room temperature, then the reaction mixture is poured into saturated ammonium chloride solution, extracted three times with ether, the organic phase is dried over magnesium sulfate and concentrated in vacuo. 26.8 g of crude product are obtained, which can be used without purification in the next step. d) 9, 9, 10, 10, 10-pentafluor-decan-l-ol 26 g of 1-benzyl-9, 9, 10, 10, 10-pentaf luor-decane are dissolved in 1000 ml of chloride of absolute methylene are mixed with 28.9 ml of N, N-d, 111 to 11 at 0 ° C and stirred for 5 minutes. Then, 41.4 g of aluminum tetrachloride are added in portions and the reaction mixture is heated for 45 minutes at 50 ° C. To conclude, allow the mixture to cool to room temperature, pour into 2N hydrochloric acid, extract three times with methylene chloride, wash the organic phase with sodium chloride solution, dry over magnesium sulfate and concentrate. with emptiness The crude product is chromatographed on silica gel with an eluent of hexane-ethyl acetate. 7.8 g of 9,9,10,10,10-pen t a f 1 úo r - of ca n-1-ol are obtained in the form of an oil. e) tosylate 9, 9, 10, 10, 10 - pe ntaf 1 uo r -de c 11 o Dissolve 1.0 g of 9,9,10,10,10-pen taf 1 úo r -de ca n - 1 - or 1 in 8 ml of absolute pipdam and add, at 0 ° C, 985 mg of chloride of pt or 1 uens ul f on 11 o, and stir in the cold for 2 hours. The reaction mixture is then poured into water, extracted three times with ether, dried over magnesium sulfate and concentrated in vacuo. Preparative column chromatography on silica gel with an eluant of ethyl acetate-ethyl acetate provides 1.5 g of tosylate of 9, 9, 10, 10, 10 -pe ntaf lúo r - of c 11 o, in form of oil. N-methyl- [3- (4, 4, 5, 5, 5-pentafluor-pe n 11111 o) - pr op 11] - amine a) sulfide 3 - and odop r op 11 - 4, 4, 5 , 5, 5 -pentafluor-pentyl A solution of 22.8 g of sulfur of 3-c 1 or op rop 11-4, 4 is stirred for 5 hours in a bath at 100 ° C and under a nitrogen atmosphere. 5, 5, 5 - pe n t a f 1 uo r - pen 111 or in 500 ml of e 11 lme 111 ce tone with 40 g of sodium iodide. It is then concentrated to dryness, poured into water, extracted three times with ethyl acetate, washed neutral, dried over sodium sulfate and concentrated in vacuo. 30.6 g of 3-iodopropyl-4, 4, 5, 5, 5-pentafluor-pentyl sulfide are obtained. b) N-met? l- [3- (4, 4,5,5, 5-pentafluor-pentylthio) -propyl] -amine In a solution of 30, 6 g of 3-and odop sulfide or op 11 - 4, 4, 5, 5, 5 -pen taf luo r - pe n 111 or in 200 ml of tetr ah irofur absolute are condensed, at a bath temperature of -78 A, 45 g of methylamine and stirred 1.5 hours at room temperature, as well as 4 hours at 60 ° C in a pressurized reactor. To open the reactor, it is cooled to room temperature overnight and then cooled to 78 ° C. It is then brought to room temperature, the excess of tin is evaporated, diluted with ethyl acetate, washed neutral , dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel with an eluent of di-1-one or thomethymol. 15.7 g of N-methyl- [3- (4, 4, 5, 5, 5-pentafluor-pent? Lt? O) -propyl] -amine are obtained in the form of an oil.

N-met l- [3- (4, 4, 5, 5, 5-pentafluor-pentanesulfonyl) -propyl] -amine a) 3-chloropropyl-4, 4,5,5, 5-pentafluor-pentansulfone mix, in portions and at 0 ° C, a solution of 23 g of 3-c 1 or op r or 11-4,4,5,5,5-pentafluor-pentyl sulfide in 230 ml of chloroform with 41, 8 g of acid m-pe rc 1 or oben zoi co (to 70%) and stir for 1.5 hours at room temperature. Then it is diluted with di c 1 or r ome t or not, washed with solutions of sodium bisulfite, sodium bicarbonate and sodium chloride, dried over sodium sulfate and concentrated in vacuo. 23.8 g of 3-chloropropyl-4,4,5,5,5-pe ntaf 1 uo r -pe ntan its 1 ph ona, in the form of crystals with a melting point of 74-76 ° are obtained. C. b) 3-iodopropyl-4, 4,5,5, 5-pentafluor-pentansulfone A solution of 23.5 g of 3% is stirred for 5 hours at 100 ° C in the year and under nitrogen atmosphere. - c 1 or op r opi 1 - 4, 4, 5, 5, 5 - pen taf 1 uo r -pen tans ul f ona in 500 ml of 11 lite 111 ce t ona with 40 g of sodium iodide. It is then concentrated to dryness, poured into water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate and concentrated in vacuo. 30.6 g of 3-iodopropl-4,4,5,5,5-pentaf 1 uor-pentnsu 1 f on a, in the form of crystals with a fusion of 88-89 ° C. 5 c) N-me 111- [3 - (4,, 5, 5, 5 -pen taf 1 uor- pentanesulfonyl) -propyl] -amine In a solution of 23.5 g of 3 - and odop r opi 1 - 4, 4, 5, 5, 5 - pe ntaf 1 uo r -pen t ans u 1 f ona in 200 mi of tetr ah i dr of ur not absolute are condensed, with a bath temperature of -78 ° C, 44 g of methylamma and stir 1.5 hours at room temperature, as well as 4 hours at 60 ° C in a budget reactor. To open the reactor it is allowed to cool to room temperature overnight and then cooled to .78 ° C. It is then brought to room temperature, the excess methylamine is evaporated, diluted with ethyl acetate, washed neutral, dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel with a eluent ae dic 1 or ome ta non-methane 1 14.8 g of N-methyl- [3- (4, 4, 5, 5, 5-pentafluor-pentansulfon? L) - pr op 11] - amine is obtained , in the form of crystals with a melting point of 55-57 ° C. l-bromo-5-tert-but? ld? met? ls? l? lox? pentane a) 5 - b r orno - 1 -pen t anol 50 ml of concentrated sulfuric acid are added dropwise to a solution of 50 g of 5-b r omopen 111 or 1.6 1 of methanol and the mixture is stirred for 30 hours at room temperature. The methanol is then removed in vacuo, the residue is taken up in diethyl ether, washed neutral with saturated sodium chloride solution, dried over sodium sulfate and concentrated. 28 g of 5-b roneno-1 -pe n t a no 1 are obtained as a crude product. b) 1-boron-5-t e r-bu 111 dime 111 s 1111 -oxypentane A solution of 28 g of 5-bromo-1-pentanol in 144 ml of t e t r a h i d r o f u r a n o with 24 g of i idazole are mixed. Subsequently, a solution of 30.3 g of t rbu 11 Id 1 1 to 1 or r 11 s is added dropwise to 46 ml of water and the mixture is stirred for 4 hours at room temperature. The reaction mixture is poured into water, stirred with diethylether, the organic phase is washed four times with water, dried over sodium sulfate and concentrated. The crude product is chromatographed on silica gel with an eluent of hexa no-di e 111 e t e r. 42 g of 1-boron-5-t are obtained in the form of a colorless liquid.

Example 5: 11 ß- f 1 uo r - 7 - [5 - (me 111 - non 11 -amino) -pent 11] -estra-1, 3, 5 (10) -tr? En-3, 17β-d (a) l - (5-chloropentyl) -ll-fluor-estr-4-en-3,17-dione On a suspension of 7.2 g of magnesium chips in 100 ml of tetr ah i At the same time, under a nitrogen atmosphere, 20% of a solution of 39 ml of 1-bromo-5-methane in 300 ml of tetrahydrofuran is added, initially and under a nitrogen atmosphere. After the start of the reaction, which can be achieved by adding iodine and dib r omome t a no, drip the rest of the solution, so as not to exceed an internal temperature of 35 ° C. In a second balloon 51.2 g of lithium bromide are added to a suspension of 28.1 g of copper iodide (I) in 130 ml of tetrahydric acid at 0 ° C, whereby the internal temperature increases to 40 ° C. 49.4 ml of 1,3-d? Met? L-3,4,5,6-tetrahydro- (lH) -p? Pm? Dm-2-one are added and stirred. for 15 minutes at 40 ° C. A limpid solution is obtained which is dripped onto the Grignard solution cooled to -50 ° C. It is then stirred for 15 minutes at -30 ° C and mixed, with dripping and at -70 ° C, with a solution of 25 g of llß-fluor-e stra-4, 6-diethylene-3, 17-diol. in 260 mi of tetrahydrofuran, 26 ml of 1, 3-d? met? -l-3, 4,5,6-etrahi dr o - (1 H) -pyrmidiin-2-one and 59 ml of trime 111 c 1 gold 11 year, so that the internal temperature does not exceed -65 ° C. The mixture is stirred for 30 minutes in the cold, then 34.7 ml of glacial acetic acid are dripped, the cooling bath is stirred and stirred for one hour at room temperature. To conclude, the reaction mixture was poured into 1.5 1 of water, diluted with the same amount of ethyl acetate, the precipitate was separated with Celite, washed with ethyl acetate, and the aqueous phase was extracted three times with ethyl acetate. ethyl, washed with sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and concentrated in vacuo. After centrifuging the crude product on silica gel with an eluent of hexane-ethyl acetate, 22.1 g of the - (5-chloropentyl) -ll-fluor-estr-4-enol are obtained. 3, 17-d? Ona. b) 7a- (5-chloropentyl) -ll-fluoro-3-hydroxyl-tra-1, 3, 5 (10) -tpen-17-one A 22.1 g of 7 a- ( 5 - c 1 or op in 111) - 11 ß - f 1 uor -estr-4-en-3, 17-dione in 160 g water-free acetonitrile are added, at 80 ° C, 25.4 g of bromide of copper (II) and 4.9 g of lithium bromide in 95 ml of water-free acetonitoplo. After 20 minutes, cool the reaction mixture to 0 ° C and drip 200 ml of saturated sodium bicarbonate solution. The solution is then poured into 750 ml of water, brought to pH 6 with 2 N hydrochloric acid, extracted three times with ethyl acetate, washed with sodium chloride solution, dried over magnesium sulfate, and it concentrates with emptiness. Chromatography of the crude product on silica gel with an eluent of hexane-ethyl acetate affords 14.7 g of 7a- (5-chloropentyl) -ll-fluoro-3-hydroxy? -estra-l, 3, 5 (10) -tpen-17-one. c) llß-fluoro-3-hydroxy? -7a- (5-iodopent? l) -estra-1, 3, 5 (10) -tpen-17-one 5.0 g of 7 a- ( 5-c 1 or ope n 111) -ll-fluoro-3-hydroxyl -estra-l, 3, 5 (10) -ppen-17-one in 80 ml of 11 lme 111-ce tone, they are mixed with 5.7 g of sodium iodide and stirred overnight at a bath temperature of 90 ° C. To conclude, the reaction mixture was cooled to room temperature, poured into water, extracted three times with ethyl acetate, washed with sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. 6.8 g of llß-fluoro-3-hydrox -7a- (5- (iodopentyl) -estra-1, 3, 5 (10) - are obtained. t r i e n - 17 - on a, in the form of crude product, which is used, without purification, in the next stage. d) llß-fluor-3-h? drox? -7 (l- [5- (methyl-ammo) -pentyl] -estra-1, 3, 5 (10) -tr? en-17-one In a solution of 6.8 g of llß-fluoro-3-hydrox -7a- (5- (iodopentyl) -estra-1, 3, 5 (10) -trien-17-one in 35 ml of tetr ah i dr of water not condensed, at -78 ° C, 5.1 g of methylamine are condensed and stirred overnight at room temperature in a pre-set reactor After opening the reactor at -20 ° C it is allowed to arrive At room temperature, in order to allow the excess methylamma to evaporate, the reaction solution is poured into saturated sodium bicarbonate solution, extracted three times with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. obtain 6.7 g of 1 lß-f luor-3-hydr oxy -7a- [5 - (methyl-ammo) -pentyl] -estra-1,3,5 (10) -tr? en-17-one, in the form of crude product e) llß- f luor-3-h drox? -7a- [5- (metil-nonyl-ami no) -pentyl] -estra-1, 3, 5 (10) -ppen- 17-one Dissolve 526 mg of 11 ß- f 1 uo r - 3 - h i dr oxy -7 a- [5- (methyl-amino) -pentyl] -estra-1, 3, 5 (10) -trien-17-one and 127 mg of iodononane in 5 ml of dime 111 free-form of water and stirred for 4 hours in a bath at 100 ° C. To conclude, pour the mixture into a half-saturated solution of sodium bicarbonate, extract three times with methylene chloride, dry over magnesium sulfate and concentrate in vacuo. A preparative column chromatography provides 85 mg of 11 ß-f 1 or r-3-h i dr ox i-7 a- [5- (methyl-nonyl-ammo) -pentyl] -estra-1, 3, 5 (10) -t r i e - 17 - on a, in the form of foam. f) llß-fluoro-3-hydroxy? -7a- [5- (met? l-non? l-amino) -pentyl] -estra-1, 3, 5 (10) -tr? en-3, 17β-dαol 85 mg of 11β-f-1-or-3-hydroxy-1 - [5- (methyl-nonyl-amino) -pentyl] -estra-1,3,5 (10) is dissolved. ) -tr? in-17-one in 3 ml of methanol and mixed with 25 mg of sodium borohydride. After stirring for 30 minutes at room temperature, the majority of the solvent is removed in vacuo, the residue is mixed with sodium chloride solution, extracted three times with methylene chloride, dried over magnesium sulfate and concentrated in vacuo. . A preparative thin-layer chromatography with methylene chloride 1 ene-me ta nol 9: 1 + 0.5% triet l-amine supplies 33 mg of 11 ß- f 1 uor-3 -hi dr ox i-7 a - [5 - (Methyl-nonyl-a mo) -pentyl] -estra-1, 3, 5 (10) -trien-3,17ß-ol, in the form of foam.

Example 6: 11 ß - f 1 u or r - 7 a -. { 6 [me t _ 1 - (8, 8, 9, 9, 9-pentafluornon? L) -amino] -hexyl) -estra-1, 3, 5 (10) -tr? En-3, 17? -d? ol a) 7 a- (6-chlorohex? l) -llß-fluor-estr-4-en-3,17-d? ona To a suspension of 6.8 g of magnesium chips in 100 ml of tetr ah idr Of course, 30 ml of a solution of 41 ml of 1 - br or - 6 - c 1 oohexane in 270 ml of tetr ahdr or fu ano is added initially and under a nitrogen atmosphere. After the start of the reaction, the rest of the solution is dripped, so as not to exceed an interior temperature of 35 ° C. In a second balloon, 48.1 g of lithium bromide are added to a suspension of 26.4 g of copper iodide (I) in 120 ml of e t r a h i dr or f u r a n at 0 ° C, whereby the internal temperature increases to 40 aC. Now, without cooling, 46.4 ml of 1, 3-d? Met? L-3, 4,5,6-tetr ah i dr o- (1 H) -pyrimmi-n-2 -one and it is stirred for 30 minutes at 40 ° C. A clear solution is obtained which is dripped on the Gpgnard solution cooled to -40 ° C. It is then stirred for 15 minutes at -30 ° C and mixed, with dripping and at -50 ° C, with a solution of 23.5 g of llß-fluor-es-ra -4,6-d-en-3 , 17 -diona in 230 mi of tetr ah i dr ofura no, 24.6 mi of 1, 3 - ime 111 - 3, 4, 5, 6 -tetrah ídr o- (1 H) -pyrmidiin- 2 -one and 55 mi of trime 111 c 1 oros 11 anus, so that the internal temperature does not exceed -40 ° C. The mixture is stirred for 30 minutes in the cold, then 34 ml of glacial acetic acid are dripped, the cooling bath is stirred and stirred for one hour at room temperature. To conclude, the reaction mixture was poured into 1.5 1 of water, diluted with the same amount of ethyl acetate, the precipitate was separated with Celite, washed with ethyl acetate, and the aqueous phase was extracted three times with ethyl acetate. ethyl, washed with sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and concentrated in vacuo. After centrifugation of the crude product on silica gel with an eluent of hexane-ethyl acetate, 25.2 g of the - (6-chlorohexyl) -ll-fluoro-estr-4-enol are obtained. 3, 17-d? Ona. b) 7o- (6-chlorohex? l) -ll-fluoro-3-hydrox? -estra-1, 3, 5 (10) -tpen-17-one To 25.2 g of 7 to- (6 - (c 1 gold and 11) - 11 ß - f 1 uor -estr-4-en-3, 17-di none in 175 g water-free acetonitrile are added, at 80 ° C, 28.1 g of bromide copper (II) and 5.4 g of lithium bromide in 105 ml of water-free acetonitrile, after 15 minutes cool the reaction mixture to 0 ° C and drip 250 ml of saturated sodium bicarbonate solution. The solution is then poured into 1 liter of water, brought to pH 6 with 2N hydrochloric acid, extracted three times with ethyl acetate, washed with sodium chloride solution, dried over magnesium sulfate and concentrate with vacuum. Chromatography of the crude product on silica gel with an eluent of hexane-ethyl acetate provides 5.7 g of 7α- (6-chlorohexyl) -llβ-fluoro-3-hydroxy? -estra-l, 3, 5 (10) -tri in-17-one, in the form of foam. c) llß-fluoro-3-hydroxy -7a- (6-iodohexyl) -estra-1, 3, 5 (10) -tr? en-17-one 2.7 g and 7 a are dissolved - (6 - c 1 or ohe 11) -llß-fluor-3-h? Drox? -estra-l, 3,5 (10) -tr? En-17-one in 40 ml of e 11 lme 111 ce t One is mixed with 3.0 g of sodium iodide and stirred overnight at a bath temperature of 90 ° C. To conclude, the reaction mixture was cooled to room temperature, poured into water, extracted three times with sodium acetate, washed with sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. 3.4 g of llß-fluoro-3-hydroxyl-7a- (6-iodohexyl) -estra-1, 3, 5 (10) - are obtained t r i e n - 17 - on a, in the form of crude product, which is used, without purification, in the next stage. d) llß-fluor-3-h? drox? -7u- [6- (methyl-amino) -hexyl] -estra-1, 3, 5 (10) -tr? en-17-one In a solution of 960 mg of llß-fluor-3-h? drox? -7a- (6-iodohex? l) -estra-1, 3, 5 (10) -tpen-17-one in 9 ml of water and water-free solvent are condensed, at -78 ° C, 718 mg of methylamine and stirred overnight, at room temperature, in a budget reactor. After opening the reactor at -20 ° C it will reach room temperature, in order to allow excess methylamine to evaporate. The reaction solution is then poured into saturated sodium bicarbonate solution, extracted three times with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. 763 mg of 11 ß-f 1 or r-3-hydroxy-7 a- [6 - (methyl-ammo) -hexyl] -estra-1,3,5 (10) -tr? En-17-one are obtained , in the form of raw product. e) llß- f luor-3-n? drox? -7u- (6- [me t íl- (8, 8, 9, 9, 9-pentafluornon? l) -amino] -hexill-estra-1, 3 , 5 (10) -tr? En-17-one A solution of 381 mg of llß-fluoro-3-hydroxyl-7a- [6- (methyl-ammo) -hexyl] -estra-1 is stirred, 3, 5 (10) - tri en - 17 - one in 5 mi of dime 111 fo rmami da with 200 mg tosylate of 8, 8,9,9,9-pe n t a f 1 uo r non 11 o, for 2 hours at a bath temperature of 100 ° C. It is then poured into a semisaturated solution of sodium bicarbonate, extracted three times with methylene chloride, dried over magnesium sulfate, concentrated in vacuo and chromatographed on silica gel with an eluent. t 1. The 90 mg of llß-fluor-3-h? drox? -7a- is obtained. { 6- [methyl- (8, 8, 9, 9, 9-pentafluor-non-11) -amino] -hexyl) -estra-1, 3, 5 (10) -tr? En-17-one, in the form of foam. f) llß-fluor-7a- (6- [met? l- (8,8,9,9,9-pentafluor-nonyl) -arrimo] -hex? l) -estra-l, 3, 5 (10) -tr? en-3, 17β-d? ol 89 mg of 11 ß- f luor-3-idr ox i -l- are dissolved. { 6- [methyl- (8, 8, 9, 9, 9-pentafluor-non? L) -arrimo] -nex? L} -estra-l, 3.5 (10) -tpen-17-one in 2 ml of methanol and mixed with 22 mg of sodium borohydride. After stirring for 1 hour at room temperature, the majority of the solvent is removed in vacuo, the residue is mixed with sodium chloride solution, extracted three times with methylene chloride, dried over magnesium sulfate and concentrated in vacuo. . A preparative thin-layer chromatography with methylene chloride and methylene chloride 9: 1 provides 53 mg of 11β-f-1-or-3-hydroxy-7-a- (6 - [methyl- (8, 8, 9, 9, 9-pentaf-lauryl-nonyl) -amino] -hexyl. .estra-l, 3,5 (10) -tr? en-3,17β-d? ol, in the form of foam; [< x] D = + 32 ° (c = 1.0 in chloroform).

Example 7 ß- f lúor-7 a-. { 5 - [me 111 - (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluor-dec? L) -animo] -pentyl} -estra-1, 3, 5 (10) -tr? en-3, 17β-d? ol A solution of 466 mg of 7a- (5-) is stirred for 3 hours at a bath temperature of 80 ° C. bromopentyl) -ll-fluoro-estra-1, 3, 5 (10) -tr? en-3, 17-ol in 10 ml of 1-methyl 111-2-pyrrione di none with 1.0 g of methyl - (7, 7, 8, 8, 9, 9, 10, 10, 10-nonaf lúor-decil) -amina. To conclude, pour the mixture into saturated sodium chloride solution, extract with ether, dry over sodium sulfate, concentrate in vacuo and chromatograph on silica gel with an eluent of e 111 or -methodium acetate. 1. 546 rp.g of llß-fluorine-7a- are obtained. { 5- [met? L- (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluor-dec? L) -amino] -pen 1111 -estr a- 1, 3, 5 (10) - trien- 3, 17 ß-diol, in the form of foam; [a] D = + 39 ° (c = 0.5 in CHC13).

Example 8: 11 ß - f 1 uo r - 7 a-. { 5 - [3, 4,, 5, 5, 5-hexafluoro-pent-2-en? L) -methyl-amino] -pentyl} -estra-1, 3, 5 (10) -tr? en-3, 17? -d? ol a) ll? -fluor-7a- (5- [3,4,4,5,5,5-hexafluor-pent -2-in? L) -methyl-amino] -pent? L} -3-h? Drox? -estra- 1, 3, 5 (10) -tpen-17-one 880 mg of 11 ß- f 1 úo r - 3 - hi dr oxi -7a- (5-iodopent? l) -estra-l, 3.5 (10) -tpen-17-one and 1.26 g of (3,4,4,5,5,5-hexafluor-pent-2-en? l) -methyl -amine in 20 ml of N -me 111 -pirro 11 donates and is heated for 3 hours in a bath at 80 ° C. After cooling the reaction mixture to room temperature, it is poured into saturated sodium chloride solution, extracted with diethylether, dried and concentrated in vacuo. 1.86 g of llß-fluoro-3-hydroxyl-7a- (5- [3,4,4,5,5,5-hexafluor-pent-2-in-1-methoxyl] are obtained. am? no] -pent?) -3-h? drox? -estra-1, 3, 5 (10) - tri-en-17-one, in the form of crude product, which is used, without purification, in the next stage. b) llß-fluorine-7a-. { 5- [3,4,4,5,5,5-hexafluor-pent-2-en? L) -methyl-ammo] -pentyl} -estra-1, 3, 5 (10) -tr? en-3, 17 ß-di ol Dissolve 1.86 g of 11 ß - f 1 ú or r - 3 - h i d r or x 1 -7a-. { 5- [3, 4, 4, 5, 5, 5-hexaf lúor-pent-2-en? L) -met ll- amino] -pent? l} -3-h? Drox? -estra-l, 3, 5 (10) -trien-lione in 15 ral of methanol and mix carefully with 222 mg of sodium borohydride. After stirring for 15 minutes at room temperature, the mixture is poured into saturated sodium chloride solution, extracted with methylene chloride, dried over magnesium sulfate and concentrated in vacuo. After centrifuging the crude product on silica gel with an eluent of hexane-ethyl acetate and another of e-111 o-acetone acetate, 241 mg of llß-fluor-7a- (5- [3, 4,4,5,5,5-hexafluor-pent-2-enyl) -methyl-ammo] -pentyl) -estra-1, 3, 5 (10) -tr? En-3, 17β-d? Ol, with a melting point of 122 ° C; [CI] D = + 47 ° (c = 0.5 in CHC13A Example 9: 11 ß- f luor-7a- (5 - [N-me 111 - - 3 - (4, 4, 5, 5, 5-pentafluorpent? Lox?) -propylamine] -pent? L) -estra- l, 3,5 (10) -tpen-3,17β-dα ol a) llβ-fluoro-7a- (5-bromopentyl) -3- (tetrah? drop? ran-2-? lox) - estra-1, 3, 5 (10) -tpen-17- They are reacted at room temperature 8.4 g of 11 ß - f 1 ú or - 7 a - (5 - br omope n 111) - 3 - h 1 drox 1 -estra-1, 3, 5 (10) -tpen-17-one in 90 my tetrah 1 drofura not with 9.0 mi of 3, 4 - d 1 h 1 dr op 1 ranoy 805 mg of hydrate of p-t acid or 1 uen s ul f on i co. After 7 hours add 1 ml of t r i e t i 1 amine, dilute with ethyl acetate, wash neutral with saturated sodium chloride solution and dry over sodium sulfate. Chromatography on silica gel with an eluent of hexane-ethyl acetate provides 7.6 g of 11β-fluoro-7a- (5-methyl) 1 - 3 - (tetrahydrofuran-2? ?) -estra-1, 3, 5 (10) -tr? en-17-one, in the form of foam. b) llß-fluor-7a- (5- [(3-tert-butyl-dimethylsilyloxy-propyl) -methylammo] -pentyl) -3- (tetrah? drop? ran-2-? lox?) -estra- 1, 3, 5 (10) -trien-lione 6.0 g of llß-fluorine- (5-bromopentyl) -3- (tetrah? Drop? Ran-2) are reacted at 100 ° C. - 11 or <i) - estra - 1, 3, 5 (10) - trien - 17 - on a in 130 ml of dime ti 1 f ormami da with 5.7 g of 1-N-me ti lamino- 3 -te r-bu 111 -dime 111 s 111 loxprim (prepared from 1-r omo-3-hrdr oxpr opane, by a reaction with terbu-111 chloride -dime 111 s 1111 or to obtain 1-br omo-3-ter-bu 111 -dime 111 s 1111 ox ipr opa, and the next reaction with methylamma). After 7 hours it is diluted with ethyl acetate, washed with saturated sodium chloride solution and concentrated in vacuo. After c og r a f i a r Crude product on silica gel with an eluent of methylene chloride 1 gives 4.5 g of lipofluoride (5- [(3-tert.-ld? met? ls? ? lox? prop?) -methylamine] -pentyl) -3- (tetrahydropyran 2-? lox?) -estra-1, 3, 5 (10) -tri-en-17 -one, in the form of oil ) llß-fluor-7a-. { 5- [(3-hydroxy? Prop?) -met lammo] -pentyl} -estra-l, 3, 5 (10) -tpen-17-one 2.3 g of 11 ß-f 1 uo r - 7 «- (5 - [(3 - ter -) - are reacted at room temperature. bu 111 -dimethylsilyloxypropyl) -methylamino] -pentyl) -3- (tetrah? drop? ran-2? -lox?) -estra-1, 3, 5 (10) -tpen-17-one in 23 ml of tetr ahydr ofur anus with 6 ml of tetrbu-111-fluoride solution (1 M in tetrahydrofuran) After 2 hours it is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. Cr oma t og raffinate the crude product on silica gel with an eluent of methylene chloride-methanol to obtain 1.5 g of llß-fluor-7a-. { 5- [(3-hydroxypropyl) -methylamino] -pent.l) -estra-1, 3, 5 (10) -trien-17-one, in the form of foam d) llß-fluor-3- (tetran? Drop ? ran-2-? lox?) -the-. { 5- [N-met? L-N-3- (4, 4, 5, 5, 5-pentafluorpent? L-oxy) -propylamino] -pent? L} -estra-l, 3, 5 (10) -tpen-17-one To 710 mg of 11 ß - f 1 uo r - 7 a-. { 5 - [(3-Hydroxypropyl) -methylamino] -pentyl} -estra-1, 3, 5 (10) -tr? en-17-one in 10 ml of toluene are added, at room temperature, 1.8 g of petent iodide 1 or r 111 n, 10 ml. of sodium hydroxide (at 40%) and 465 mg of bisulfate of tetr abu 111 ammonium. After 6 days, the reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. After stirring the crude product on a Silica with an eluent of methylene chloride-methanol gives 123 g of llß-fluoro-3- (tetrahydrofuran-2-ylox?) -7a- (5- [N-met? N-3- ( 4, 4, 5, 5, 5-pentafluorpent? L-ox?) -oropylammo] -pent? L) -estra-l, 3,5 (10) -tpen-17-one, in the form of oil. e) llß-fluor-3- (tetrah? drop? ran-2? lex?) -l a -. { 5- [N-met? N-3- (4, 4, 5, 5, 5-pentafluorpent? Lo < i) -propylamino] -pent? L) -estra-l, 3, 5 (10) -trien -17ß-ol It is reduced, at room temperature, 120 mg of llß-fluor-3- (tetrah? Drop? Ran-2-? Lox?) - 7a-. { 5- [N-met? L-N-3- (4,4,5,5,5-pentafluorpent? L-ox?) - propylamino] -pentyl} -estra-1, 3, 5 (10) -tr? en-17-one with 20 mg of sodium borohydride in a mixture of 1 ml of tetrahydrofuran, 0.6 ml of ethanol and 0.3 ml of water. After 1 hour, it is diluted with ethyl acetate, washed neutral with water, concentrated in vacuo and dried. 76 mg of llß-fluoro-3- (tetrah? Drop? Ran-2-? Lox?) - 7 a- are obtained. { 5 - [N-methyl-N-3- (4, 4, 5, 5, 5-pentafluorpent? Lox?) -propylamine] -pent? L) -estra-l, 3,5 (10) -tr? In -17ß-ol, in the form of crude product. f) 1 lß-f luor-la-. { 5- [N -me 111 -N-3 - (4, 4, 5, 5, 5-penta-fluorpentyl-oxy) -propylamino] -pent? L} -estra-1, 3, 5 (10) -tr? en-3, 17β-d? ol 75 mg of llß-fluor-3- (tetrah? drop? ran-2) are reacted at room temperature. lloxy) -7a- (5- [N-meth? N-3- (4, 4, 5, 5, 5-pentafluorpent.l-ox?) -propylammo] -pentyl.}. -estra-l, 3, 5 (10) -tr? En-17ß-ol with 50 mg of oxalic acid in 1 ml of methanol and 0.1 ml of water After two hours it is diluted with methylene chloride, washed neutral with saturated aqueous solution. Sodium chloride, dried and concentrated in vacuo After cracking the crude product on silica gel with an eluent of methylene chloride and no methyl ester, 25 mg of 11 ß-f 1 r - 7 - { 5 - [N -me 111 - N - 3 - (4, 4, 5, 5, 5-pentafluorpent? l-ox?) -propylamine] - Pen 111 } -e s t ra- 1, 3, 5 (1 O) - t r len- 3, 17 ß-diol, in the form of foam Example 10: 11 ß- f 1 uo r - 7 a- (5 - [me 111 - (2-p-5 tol? L-et? L) -am? No] -pent? L.}. l, 3,5 (10) -tpen-3, 17β-d? ol Dissolve 660 mg of 7 a- (5 -br omope n 111) -1 lß-f luor-estra-1, 3, 5 (10 ) -tr? en-3, 17ß-d? ol in 10 ml of N -me 111 - pyrrole 11 dona, mixed with 1.2 g of 10 me 111 - (2 - - to 111 - e 111) - ami Finally, the mixture is poured into saturated sodium chloride solution, extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. column chromatography on silica gel and an eluant of e 111 o -meta-ammonia acetate and a subsequent crystallisation in acetate of 11 lo / c 1 or ur or of me 111 e no / he xa do not provide 277 mg of 11 ß- f 1 uo r - 7 a- (5 - [me 111 - (2-p-20 tolyl-ethyl) -arrimo] -pent? l.} -estra-l, 3, 5 (10 ) -trien- 3,17ß-d? ol, with a melting point of 142-143 ° C. starting positions a) tosylate of 2 -p - t or 111 - e 111 o 2.8 ml of 2 - p - t or 111 - e t ano 1 are present in 25 40 ml of pipdma, cooled in a water bath frost, they are mixed with 4.96 g of p-toluenesulfonyl chloride and stirred 30 minutes at 0 ° C and 2 hours at room temperature. The reaction mixture is then slowly poured into approximately 150 g of water / ice. The precipitated product is sucked off, washed several times with water, dissolved in methylene chloride, dried over magnesium sulfate and concentrated in vacuo. 5.8 g of 2-p-t or 111-e 111 tosylate is obtained, which is used, without purification, in the next step. b) me 111 - (2-p - to 111 - e 111) - amine In a solution of 5.8 g of cough of 2-o - or 111-e 111 or in 15 ml of tetrahydride of non-absolute 9.2 g of me 111 amine are condensed at -20 ° C and stirred at room temperature overnight in a pressurized reactor. After opening the pressurized reactor at -20 ° C, it is allowed to reach room temperature, in order to let excess methylamine evaporate. The reaction solution is taken up with ether, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. 5.39 g of me 111 - (2-p-t or 11-e 111) -amino are obtained, which is further processed as a crude product.

Described that it has been the nature of the present invention and the manner of carrying it out, it is declared that what is claimed as the exclusive property and invention of the applicant

Claims (6)

CLAIMS 1. Combined preparation of estrogen and antiestrogen, characterized in that the estrogen is selected from the group consisting of 17-ß-estradiol, 1-α t-traol, estriol, stupor, sulphate of stupor, sulfamate of estrogen, 17-a- estradiol, mestranol, stilbestrol, estr oge noe steres of 17-ß-estr adi ol as, for example, estradiol valerate, and natural conjugated estrogens, and the 11 estrogen is a 7 a- (? -ami noa 1 qu 11) - substituted stratri ene responding to the formula (I) where the side chain SK represents a residue with the s ub f or rmu 1 a (CH2) m-N-CH-CH- (CH2) n-S0, - (CH2) 3-E
1. A B D where m represents 4, 5 or 6, n represents 0, 1 or 2, x represents 0, 1 or 2, A represents a hydrogen atom or a C1-C5 alkyl group, B and D each represent a hydrogen atom, A and B represent, together , an alkylene group - (CH) p-, with p = 2, 3, 4 or 5, and D a hydrogen atom, or A and D represent, together, an alkylene group - (CH-> g); , with q = 2, 3 or 4, and B a hydrogen atom, and E represents an ethyl moiety unsubstituted or fluorinated one to five times, or the terminal substituent - (CH) 3-E is replaced in the side chain by an aryl or heteroaryl residue, also substituted, attached directly or through a mono-, di- or trimethylene group to the sulfur atom, R3 represents a hydrogen atom, a hydrocarbon radical with up to 8 carbon atoms or a radical with the subformula RJ -C (O) -, in which R3 represents a hydrogen atom, a hydrocarbon radical with up to 8 carbon atoms carbon or a phenyl residue, R 11 represents a hydrogen atom, a halogen atom or a nitrooxy group -O-NOj-, represent, each one, a hydrogen atom or me 111 e no, g r upo met 11 o de hidrogen, Y A conjunto, a methylene bridge, R "or R 'a halogen atom, or R16 ° or R16", together, a methylidene group, and the remaining R14 substitutes R15', R15p, R16"and R16f3 each, a hydrogen atom, R, represents a hydrogen atom, a C1-C5 alkyl group, a C2-C5 alkenyl group, an C2-C5 alginyl group or a trif1 or ome 111 group or in a or β position, and R17 represents a hydrogen atom or a residue with the subformula R17 -C (O) -, wherein R17 represents a hydrogen atom or a hydrocarbon residue with up to 8 carbon atoms. when R17 is in position a, R17 configures an ethane bridge in conjunction with R, with the indication that, when A and B do not represent, as a whole, - (CHJ p-, or A and D do not represent, together, - (CH2) "- at least one of the substituents R14 R15 °, RA A0 'and A6"does not represent a hydrogen atom, as well as its addition salts with organic and inorganic acids physiologically compacts.
2. 2. Combined preparation of estrogen yantiestr oge no, characterized in that the estrogen is selected from the group consisting of 17 - ß - estradi or 1, 17 - - 11 n 11 estradiol 1, estriol, estrione, sulfate of stuppa, sulfamate of estrogen, 17 -a estradiol, mestranol, stilbestrol, estr oge noe steres of 17-ß-estradiol such as, for example, estradiol valerate, and natural conjugated estrogens, and the antiestrogen is a substituted β-halogeno-7u-estratpene that responds to the formula (II) where OR ' R represents a hydrogen atom, a hydrocarbon radical with up to 8 carbon atoms or a radical of the subformula R -C (0) -, where R3 represents a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms or a phenyl residue, R7 represents a residue with the formula -ABZ-RA where A is for a direct bond or a benzylidene moiety, where the methylene group is linked to the carbon atom of the steroid, or a phenylene moiety, B is shown for a linear or branched alkylene, alkenylene or alkynylene group with 3 to 14 carbon atoms, and Z is for a group -NR21, and R21 for a C1-C3 alkyl group, where, then, R20 represents a hydrogen atom, a group alkyl, alkenyl or alkynyl with up to 10 carbon atoms, linear or branched, or one of the agr above ami ests D-CnF-n + x, where D represents an alkylene, aikylene or alkylene group with up to 8 carbon atoms, linear or branched, and n an integer from 1 to 8, L - CH = C F - CpF2p + 1, where L represents an alkylene, alkenylene or alkynylene group with 2 to 7 carbon atoms, linear or branched, and p represents an integer from 2 to 7, D-0- (C H2) qa r 11 o, where D represents the same as what is already indicated, qa 0, 1, 2 or 3 and aril is for a phenyl residue or 1- or 2-naft it, in given cases, substituted once or twice, or a neteroaryl residue, DO- (C H2) r-Cn F2n +? i where D and n represent the same as what has already been indicated, and r figures for an integer from 1 to 5, or R20 and R21 together with the nitrogen to which they are. united, they form a saturated or more saturated heterocycle with 5 or 6 chain members which, in given cases, contains one or two heteroatoms selected from nitrogen, oxygen and sulfur and, in given cases, is substituted, or Z is included for -S0X- and x for 0, 1 or 2, where, then, R20 represents an alkyl, alkenyl or alkyloyl group with up to 10 carbon atoms, linear or branched, or one of the agr upami D-CrF2ntl, where D represents an alkylene, alkenylene or alkylenylene group with up to 8 carbon atoms, linear or branched , and n an integer from 1 to 8, L - CH = C F - CpF2p +? , where L represents an alkylene, alkenylene or alkynylene group with 2 to 7 carbon atoms, linear or branched, and p represents an integer from 2 to 7, D- O- (CH2) q- ar 11 o, where D represents same as already indicated, qa 0, 1, 2 or 3 and aryl is for a phenyl or 1- or 2-naphthyl radical, in some cases, substituted once or twice, or a heteroaryl radical, DO- (CHJ rC "R2lt?, Where D and n represent the same as already indicated, and r figure for an integer from 1 to 5, or Z figure for -NR31, where, then, R20 represents an alkyl, alkenyl or alkyloxy moiety with up to 14 atoms carbon, linear or branched, in some cases, partially fluorinated and / or interrupted by one to three heteroatoms -O- and -S- yagr upami entos -NR32, where R32 represents a hydrogen atom or a C C-C3 alkyl, an aplo or heteroaplo moiety, in some cases, substituted once or twice, an i-this cycloalkyl C3 Cío / in given cases, substituted one or two times, a residue cyc 1 or 1 qui the 1 qui 1 or C4-C 5, in given cases, substituted once or twice, an aralkyl residue in given cases, substituted once or twice , a C? -C0 heteroaryl moiety, in given cases, substituted once or twice, or an amino-aikyl moiety, in given cases, substituted, and R31 represents a moiety with the formula where, then, R33 represents an alkyl moiety, alkenyl or alkynyl with up to 14 carbon atoms, linear or branched, in some cases, fluorinated and / or interrupted by one to three heteroatoms -O- and -S- and ag r up ami ests -NR32, where R32 represents a hydrogen or a C1-C3 alkyl radical, an aryl or heteroaryl radical, in certain cases, substituted once or twice, a C3-C10 cycloalkyl radical, in certain cases dice, substituted one or two times, an iste cyclo-a 1 qu 11 to 1 qu 11 or C4-C15, in given cases, substituted once or twice, a C7-C aralkyl residue or, in cases dies, substituted once or twice, a heteroaryl residue C, -C6, in given cases, substituted once or twice, a residue aminoa 1 qu 11 or, in given cases, substituted, or a biphenyl residue, except for the compounds llß-fluor-7a-. { 5- [N-met? N-3- (4, 4, 5, 5, 5-pentafluor-pentthio) -propylamine] -pentyl) -estra-1, 3, 5 (10) -tr? En-3, 17ß-d? Ol 7a-. { 5- [(2S) -2- (, 4, 5, 5, 5-pentafluorpentylthiomethyl) -p? Rrol? D? N-1-? L] -pentyl) -estra-1, 3, 5 (10) - tr? en-3, 17β-d? ol 7a- (5- [(2R) -2- (4, 4, 5, 5, 5-pentafluorpentylthiomethyl) -p? rrol? d? n-1-? l] -pentyl) -estra-1, 3, 5 (10) -tr? en-3, 17β-d? ol? -fluor-7a- [5- [2- (4,4,5,5,5-pentafluorpentylthio -met l) -p? rrol? dm-1-? l] -pentil} -estra-1, 3, 5 (10) -tr? en-3, 17β-d? ol ll? -fluor-7a-. { 5- [N-met? L-N-3- (4, 4, 5, 5, 5-pentafluor-pentthio) -propylamino] -pentyl} - 3-h? Drox? -estra-1, 3, 5 (10) -tpen-17-one llß-fluor-7a-. { 6- [N-met? N-3- (4, 4, 5, 5, 5-pentafluor-pentthio) -propylamino] -hexyl) -estra-1, 3, 5 (10) -tr? En-3, 17ß-d? Ol 11β-fluoro-7a- (5- [(2S) -2- (4-trifluoromethylphenylthio-methyl) -pyrrolidin-1? l] -pentyl.] -estra-l, 3 , 5 (10) -tpen-3, 17β-d? Ol ll? -fluor-7a- {5 - [(2S) -2- (4,4,5,5,5-pentafluorpentyl-thiomethyl) -p ? -rolid-1-? l] -pentyl) -estra-1, 3, 5 (10) -tr? en-3, 17? -d? ol ll? -fluor-7a-. { 5 - [(2S) -2- (4,4,5,5,5-pentafluorpentan-sulfylmethyl) -p? Rrol? Dm-1-? L] -pent? L} -estra-l, 3, 5 (10) -tr? en-3, 17β-d? ol ll? -fluor-7a-. { 5- [(2S) -2- 14,4,5,5, 5-pentafluorpentan-sulfonylmethyl) -p rrol? D? N-1-? L] -pent? L} -estra-l, 3, 5 (10) -tr? en-3, 17β-d? ol R11 represents a fluorine or chlorine atom, and R17 a hydrogen Stoma or a residue with the ubu mumu 1 to R1 -C (O) -, where Rl7 represents a hydrogen atom or a hydrocarbon residue with up to 8 carbon atoms.
3. 3. Combined preparation according to claims 1 and 2, characterized in that the ratio of the dose of estrogen to the dose of antiestrogen is from 1: 5 to 1: 500, preferably from 1:20 to 1: 200 and, with greater Prerequisite, 1:50 to 1: 100.
4. 4. Combined preparation according to one of claims 1 and 3, characterized by the fact that the 11th odor is not 11 ß- f 1 uor-7 a- (5 - [N -me 111 -N- 3 - (4, 4, 5 , 5, 5-pentafluorpentyl) -propylamine] -pentyl.}. -estra-1, 3, 5 (10) -tr? En-3, 17β-d? Ol
5. The combined preparation according to one of claims 2 and 3, characterized in that the antiestr oge is not selected from the group consisting of llß-fluor-7a- (5- [N-methyl- (8, 8, 9, 9, 9- pentafluornonyl) -ami no] -pent? l) -estra-l, 3, 5 (10) -tr? en-3, 17? -diol ll? -fluor-7a-. { 6- [N-methyl- (8, 8, 9, 9, 9-pentafluornonyl) - ami no] -hex? L} -estra-l, 3, 5 (10) -tr? eu-3, 17β-d? ol ll? -fluor-7a-. { 5- (meth- (7, 7, 8, 8, 9, 9, 10, 10, 10-nona-fluorodecyl) -amino] -pentyl.}. -estra-1, 3, 5 (10 ) -tr? en-3, 17β-d? ol ll? -fluor-7a- [5- (met? l-non? l-ammo) -pentyl] -estra-1, 3, 5 (10) -tr? en-3, 17β-d? ol? -fluor-7a- (5- [(3,4,4,5,5,5-hexafluor-pent-2-en? l) -methylammo] -pentyl) -estra -1, 3, 5 (10) -tr? En-3, 17? -diol llß-fluor-7a-. { 5- [N-met? L-N-3- (4, 4, 5, 5, 5-pentafluoropentyloxy) -propylamino] -pentyl} -estra-1, 3, 5 (10) -tpen-3, 17β-d? ol 4-b? phen? l-. { 6- [llß-fluoro-3,17β-d? H? Drox? -estra-1, 3, 5 (10) -tnen-la-il] -hex? L) -N- (3-phen? L- propyl) -acetamide.
6. 6. Use of a combined preparation according to one of the indications 1-5, characterized by the preparation of a medicament for hormone replacement therapy.