HK1079215B - 17α-ALKYL-17β-OXY-ESTRATRIENES, USES THEREOF AND PHARMACEUTICAL PREPARATIONS - Google Patents

Description

17 alpha-alkyl-17 beta-oxy-estratrienes, use thereof and pharmaceutical preparations

This patent application is a divisional application of chinese patent application No. 02827583.7 filed on 27/11/2002.

Technical Field

The invention relates to 17 alpha-alkyl-17 beta-oxy-estratrienes, to the use of the 17 alpha-alkyl-17 beta-oxy-estratrienes for producing medicaments and to pharmaceutical preparations containing these compounds. The invention also relates to intermediates for the preparation of 17 alpha-alkyl-17 beta-oxy-estratrienes.

Background

The compounds according to the invention have an antiestrogenic action, i.e. these substances exert an inhibitory effect on estrogens. Such substances have been widely described.

For example, compounds having an antiestrogenic effect are disclosed in EP 0138504B 1. These compounds are essentially estra-1, 3, 5(10) -triene derivatives substituted in the 3-position, for example by hydroxy or alkoxy, in the 17 β -position by hydroxy, and in the 17 α -position, for example by hydrogen or alkyl. At the 7 α -position, these compounds also have an alkyl side chain which may be partially fluorinated and may be interrupted, for example, by an amide group, an amino group, an amine N-oxide, an oxy group, a thio group, a sulfinyl group and/or a sulfonyl group.

In WO 99/33855A1, 11 β -halo-7 α -substituted estra-1, 3, 5(10) -trienes are described that can have hydroxyl groups in the 3-and 17-positions. The 7 α -side chain is a partially fluorinated, optionally unsaturated, hydrocarbon chain, to which an amine nitrogen atom or a thio (sulfeny), sulfinyl or sulfonyl group may be inserted.

Other compounds are also described in WO98/07740 a 1. In this aspect, these compounds are substituted 7 α - (ξ -aminoalkyl) -estra-1, 3, 5(10) -trienes. These compounds preferably have a hydroxyl, methoxy or acetyloxy group in the 3-position and preferably a methyl or trifluoromethyl group in the 17 alpha-and/or 17 beta-position. Preferably having a fluorine atom in the 11 beta-position and preferably having an alkyl side chain at the 7 alpha-position which is at least fluorinated in the terminal position and interrupted by an amine nitrogen atom, a thio group, a sulfinyl group or a sulfonyl group.

In WO 97/45441A 1, 7 α - (5-methylaminopentyl) -estra-1, 3, 5(10) -trienes are disclosed, which have hydroxyl groups in the 3-and 17 β -positions. In the 17 α -position, there may be a methyl or ethynyl group. The estratriene skeleton may also be substituted in the 2-position by a fluorine atom.

It has now been shown that the known compounds in this application form various metabolites which are very biologically active. The formation of these metabolites leads to undesirable and uncontrollable effects. In particular, due to the simultaneous formation of these metabolites, the regulatory side effects or the desired primary effect (antiestrogenic effect) are not controllable. In addition, the compliance of these known compounds is not satisfactory when administered orally. In particular, these known compounds were found to promote alveolar macrophage formation.

Disclosure of Invention

It was therefore an object of the present invention to find antiestrogenic compounds which are able to control their metabolism and thus form little or no bioactive metabolites. In addition, it is desirable that the compliance of the compounds sought upon oral administration is satisfactory and that, upon dispensing administration, alveolar macrophages are not formed, or at least are formed only to a very small extent.

This object is achieved by the novel 17 α -alkyl-17 β -oxy-estratrienes. The 17 α -alkyl-17 β -oxy-estratrienes according to the invention have the following general formula I:

wherein:

hal represents F or Cl; the group is attached to the 11 beta-position of the estratriene skeleton;

R³represents hydrogen, C₁-C₄Alkyl radical, C₁-C₄Alkanoyl or forming a ring C with O atom₃-C₇(ii) an ether, in particular a polyether,

R^17’represents hydrogen, C₁-C₄Alkyl and C₁-C₄An alkanoyl group;

R^17”represents C₁-C₄Alkyl radical, C₁-C₄Alkynyl and at least partially fluorinated alkyl, wherein R^17’

represents-O in the 17 beta-position and R in the 17 alpha-position^17”Linked to the estratriene backbone;

SK stands for-U-V-W-X-Y-Z-E, whereby the radical is attached to the 7 alpha position of the estratriene skeleton via U.

In the side chains, the symbols U, V, W, X, Y, Z and E have the following meanings:

u represents a linear or branched C₁-C₁₃Alkylene radical, C₁-C₁₃Alkenylene or C₁-C₁₃Alkynylene or a group A-B, wherein

A is attached to the estratriene skeleton and represents the bond via-CH₂Benzylidene, phenylene attached to the estratriene skeleton or C attached to the estratriene skeleton via an alkyl group₁-C₃An alkylaryl group;

b represents a linear or branched C₁-C₁₃Alkylene radical, C₁-C₁₃Alkenylene or C₁-C₁₃Alkynylene, and

a and B may also be linked to each other via an O atom,

v represents CH₂Or a C (O) group.

W is N (R)⁶) Or N⁺(O^-)(R⁶) The radicals being either pyrrolidinylidene (azolidinylene) rings or pyrazinylidenesA pyrrolidinyl N-oxide ring wherein the pyrrolidinylidene ring or pyrrolidinyl N-oxide ring includes at least one carbon atom of the X group wherein

R⁶Or may be H or CH₂-R⁷Or C (O) -R⁷Wherein R is⁷Represents the following meanings:

a) hydrogen, or

b) Straight or branched, unfluorinated or at least partially fluorinated C₁-C₁₄Alkyl radical, C₁-C₁₄Alkenyl or C₁-C₁₄Alkynyl which may be hydroxylated in one or more positions and may be interrupted by 1 to 3 heteroatoms-O-and-S-and/or groups-NR⁹-, wherein R⁹Represents hydrogen or C₁-C₃Alkyl, or

c) Substituted or unsubstituted aryl or heteroaryl, or

d) Substituted or unsubstituted C₃-C₁₀Cycloalkyl radicals, or

e) Substituted or unsubstituted C₄-C₁₅Cycloalkylalkyl, or

f) Substituted or unsubstituted C₇-C₂₀Aralkyl, or

g) Substituted or unsubstituted heteroaryl C₁-C₆Alkyl, or

h) A substituted or unsubstituted aminoalkyl group or a biphenyl group,

x is preferably a straight or branched chain C₁-C₁₂Alkylene radical, C₁-C₁₂Alkenylene or C₁-C₁₂Alkynylene radical.

Y may be a direct bond between X and Z. However, Y may also have the following meaning:

a)SO_n-R¹⁰group, if W is N⁺(O^-)(R⁶) Radical or pyrrolidinylidene N-oxidationCyclic and not N (R)⁶) A radical or a pyrrolidinylidene ring, wherein n is 0, 1 or 2, and R¹⁰Represents SO_nAnd Z, a direct bond or a straight or branched C₁-C₆Alkylene radical, C₁-C₆Alkenylene or C₁-C₆Alkynylene, or

b) Radical R¹¹Or O-R¹¹Wherein R is¹¹Represents:

i) straight or branched C₁-C₅Alkylene radical, C₁-C₅Alkenylene or C₁-C₅Alkynylene, or

ii) substituted or unsubstituted aryl or heteroaryl, or

iii) substituted or unsubstituted C₃-C₁₀Cycloalkyl radicals or

iv) substituted or unsubstituted C₄-C₁₅Cycloalkylalkyl or

v) substituted or unsubstituted C₇-C₂₀Aralkyl or

vi) substituted or unsubstituted heteroaryl-C₁-C₆Alkyl, or

c) The group CH ═ CF, or

d) The group HN-C (O) -NH-R¹²Wherein R is¹²Represents a substituted or unsubstituted arylene group and R¹²Bonded to Z.

Z represents a direct bond between Y and E or a linear or branched C₁-C₉Alkylene radical, C₁-C₉Alkenylene or C₁-C₉Alkynylene, these groups may be partially or fully fluorinated.

E is CF₃A radical or an at least partially fluorinated aryl group, in particular a phenyl group.

Furthermore, the hydrogen atoms are preferably bonded to the 1, 2, 4, 6-9 and 11-16 positions of the estratriene skeleton. In principle, however, the estratriene skeleton can be modified, for example, by hydrocarbon bridges (for example 15 β, 16 β -methylene bridges).

Hal represents in particular fluorine.

R³Can be hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl, the corresponding alkanoyl (acetyl, propionyl, butyryl) or cyclic ether. R³In particular hydrogen, CH₃、CH₃CO or C₅H₁₀O。

R^17’And R^17”In particular methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl, where R is^17’Further, hydrogen, acetyl, propionyl, and butyryl groups may be mentioned, and in this case, the corresponding isomers may be included. In addition, R^17”There may be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl as well as trifluoromethyl, pentafluoroethyl, heptafluoropropyl and nonafluorobutyl, and in this case, the corresponding isomers may be included. R^17’In particular hydrogen, CH₃Or CH₃CO。R^17”Preferably represents methyl, ethynyl and trifluoromethyl.

U may be in particular a straight-chain or branched alkylene group and is, in particular, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene or tridecylene. U preferably represents (CH)₂)_pWherein p is an integer from 2 to 10. Specifically, U is preferably a butylene group, a pentylene group, a hexylene group or a heptylene group. U is very particularly preferably n-butylene, for example of the formula (CH)₂)_pRepresents U, wherein p ═ 4.

In particular, V represents CH₂. In a quite preferred embodiment, the group U-V may thus be n-pentylene.

In particular, W represents amine N-oxide N⁺(O^-)(R⁶) Or represents an amineN(R⁶) Wherein R is⁶Preferably hydrogen or CH₂-R⁷Wherein R is⁷In particular hydrogen or methyl or ethyl. R⁶Thus preferably being hydrogen or C₁-C₃Alkyl, in particular methyl, ethyl, n-propyl or iso-propyl. In a particularly preferred embodiment, W represents N⁺(O^-)(CH₃) The group (N-methylamine N-oxide).

X preferably represents (CH)₂)_qWherein q is 0 or an integer from 1 to 12, thereby representing a direct bond between W and Y, or a linear or branched methylene group, ethylene group, propylene group, butylene group, pentylene group, hexylene group, heptylene group, octylene group, nonylene group, decylene group, undecylene group or dodecylene group. In a particularly preferred embodiment, X is ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, n-heptylene or n-octylene.

Drawings

FIG. 1 is a reaction scheme for preparing compounds of the present invention.

FIGS. 2a-2f are the concentrations of the test substances at each LC/MS/MS measurement and the resulting 17-keto product.

Detailed Description

In particular, Y may represent a direct bond between X and Z. If so, X represents a longer alkylene chain, in particular X represents n-hexylene, n-heptylene or n-octylene. In a particularly preferred embodiment, Y may also be SO_nWhere n is 0, 1 or 2, thus being thio, sulfinyl or sulfonyl. If Y is SO_nThe radical, X then represents a shorter alkylene chain, in particular an n-propyl chain.

Z is preferably a direct bond between Y and E or a straight or branched chain C₁-C₇Alkylene group ofAre less partially fluorinated. In particular, Z may be methylene, ethylene, propylene or butylene, which may be at least partially fluorinated. In particular, Z is difluoromethylene or a linear alkylene group fluorinated at one end, such as 1, 1-difluoroethylene, 1, 2, 2-tetrafluoro-n-propylene or 1, 1, 2, 2, 3, 3-hexafluoro-n-butylene. Alkylene radicals carrying only 2 fluorine atoms on the terminal carbon atom are particularly advantageous, where the CF₂The group is attached to E. In this case, the side chain SK is C₂F₅And (4) end capping.

In particular, E represents CF₃Or a pentafluorophenyl group. The group Z-E thus preferably represents one of the groups selected from the following group: c₂F₅、C₃F₇And C₄F₉And C₆F₅。

Pharmacologically compatible acid addition salts and esters of 17 α -alkyl-17 β -oxy-estratrienes are also included according to the invention. Addition salts are the corresponding salts formed with inorganic and organic acids. As addition salts there come into consideration in particular the hydrochloride, hydrobromide, acetate, citrate, oxalate, tartrate and methanesulfonate salts. If R is³And R^17’Is hydrogen, so that in the presence of 3, 17 β -diols, esters of these hydroxy compounds can also be formed. These esters are preferably formed with organic acids, where the same acids as those forming acid addition salts are suitable, in particular acetic acid, but may also be higher carboxylic acids such as propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid or pivalic acid.

The novel 17 α -alkyl-17 β -oxy-estratrienes have several chiral centers, for example on the nitrogen atom which is optionally oxidized to the N-oxide. Thus, each compound has in each case several stereoisomeric forms. The compounds of formula I may exist as tautomers, stereoisomers, or geometric isomers. The invention also includes all possible isomers, such as E-and Z-isomers, S-and R-enantiomers, diastereomers, racemates and mixtures including tautomeric compounds. All of these isomeric compounds are integral to the invention, even if not explicitly stated in each case. The isomer mixtures can be separated into the enantiomers or E/Z-isomers according to conventionally used methods such as crystallization, chromatography or salt formation.

Particularly suitable compounds in the present invention are estratrienes having the general formula I, i.e.:

1)11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 9-heptafluorononyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide

2)11 β -fluoro-7 α - {5- [ methyl (8, 8, 9, 9, 10, 10, 10-heptafluorodecyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide

3) (RS) -11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] -pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide

4)11 β -fluoro-7 α - {5- [ methyl (8, 8, 9, 9, 9-pentafluorononyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide

5)11 β -fluoro-7 α - {5- [ methyl (9, 9, 10, 10, 10-pentafluorodecyl) amino ] pentyl-17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide

6)11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 9-pentafluorononyl) amino ] pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol

7)11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol

8)11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 9-heptafluorononyl) amino ] pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol

9)17 α -ethynyl-11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) -amino ] pentyl } -estra-1, 3, 5(10) -triene-3, 17 β -diol

10)17 α -ethynyl-11 β -fluoro-3- (2-tetrahydropyranyloxy) -7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -estra-1, 3, 5(10) -trien-17 β -ol

11)11 β -fluoro-3- (2-tetrahydropyranyloxy) -7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -trien-17 β -ol

12)11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -17 α -trifluoromethylestra-1, 3, 5(10) -triene-3, 17 β -diol

13)11 beta-fluoro-7 alpha- {5- [ methyl (6, 6, 7, 7, 8, 8, 8-heptafluorooctyl) amino ] pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol

14)11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 10, 10, 10-heptafluorodecyl) amino ] pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol

15)11 β -fluoro-7 α - {5- [ methyl (6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 10-undecafluorodecyl) amino ] -pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol

16)11 β -fluoro-7 α - {5- [ methyl (5, 5, 6, 6, 7, 7, 8, 8, 8-nonafluorooctyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol

17)11 β -fluoro-7 α - {5- [ methyl (9, 9, 10, 10, 11, 11, 11-heptafluoroundecyl) amino ] -pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol

18)11 beta-fluoro-7 alpha- {5- [ methyl (9, 9, 10, 10, 10-pentafluorodecyl) amino ] pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol

The physical properties of some of these compounds are shown in table 1.

The main distinguishing feature of the 17 α -alkyl-17 β -oxy-estratrienes according to the invention from known compounds is that the halogen atom is attached in the 11 α -position and/or the alkyl group is attached in the 17 α -position. In addition, preferred compounds have an amine N-oxide group in the 7 α -side chain.

In contrast to 3, 17 β -dihydroxy-estratrienes, which are unsubstituted in the 17 α -position, little metabolite is formed from the 17 α -alkyl-17 β -oxy-estratrienes according to the invention. The metabolite may also be biologically active. It has also been found that estratriene derivatives prepared by oxidation of the hydroxyl group attached at the 17 β -position, thereby forming 17-oxo derivatives, have very strong biological activity.

With alkyl radicals, especially C₁-C₄Blocking the 17 alpha-position by alkyl groups can stop the oxidation reaction, so that metabolite changes can also be inhibited. Accordingly, the estratrienes to be used as active ingredients according to the invention have a species-independent effect and activity. The advantage of these compounds is thus that the complete action of the active ingredients can be achieved in a single compound.

For this reason, advantageous effects have been developed as drugs, since the lack of formation of biologically active metabolites, the effect can be attributed more simply to certain structural factors, making it possible to target studies on active ingredients.

In addition, 17 α -alkyl-17 β -oxy-estratrienes according to the invention inhibit the action of estradiol by about 100%. Therefore, they represent antiestrogens.

To investigate the effect of the compounds of the invention, in vivo tests were performed on young mice. For this purpose, uterine development experiments (tests for antiestrogenic action) were carried out by oral administration (p.o.) of the drug.

The principle of the method consists in examining how the administration of a compound having an antiestrogenic action has an effect on the concurrent administration of estrogen. In rodents, the uterus responds to the administration of estrogen, i.e., weight gain (by proliferation and retention of water ). This development can be inhibited in a dose-dependent manner by the simultaneous administration of compounds having an antiestrogenic action.

For this test, female pups weighing 35-45g were studied at the beginning of the test. 5-6 animals were tested per dose. For p.o. administration, the material was dissolved in 1 part of ethanol (E) and then 9 parts of peanut oil (E oil) was added. For acclimatization, the day before the start of treatment, young rats which had just been discarded by the mother rats were removed and immediately fed food in a cage. These animals were then treated once daily for 3 days in combination with 0.5 μ g Estradiol Benzoate (EB). EB was always administered subcutaneously (s.c.) and the test substance was administered orally 24 hours after the last dose, animals were weighed, sacrificed and uterus was removed. Wet weight (lower content) was determined from the prepared uterus. The following control studies were performed: for the negative control, each animal was supplemented with 0.2ml of an E/E oil per day. For the positive control study, each animal was dosed daily with 0.5. mu.g EB/0.1 ml.

For each group, the significance of the mean and standard deviation (X + -SD) from the relative organ weights (mg/100g body weight) and the difference relative to the control group (EB) was determined in Dunnett's test (p < 0.05). The inhibition (%) relative to the EB control group was determined by a computer program. The relative potency of the test substances was calculated by covariance and regression analysis.

The results of the tests on the selected compounds are reproduced in table 2. The results of tests of uterine development carried out with simultaneous administration of 0.5. mu.g EB/0.1ml s.c. and oral dispensing of compounds having an antiestrogenic action in amounts ranging from 0.03mg/kg body weight to 0.3mg/kg body weight are reproduced there as well.

As can be seen from Table 2, the antiestrogenic effect is almost 100% when a dose of about 0.3mg/kg is added when administered orally.

The compounds according to the invention are equally effective or even more effective than the corresponding compounds unsubstituted in the 17 alpha position. The estratrienes according to the invention are also more compliant and therefore preferred than the compounds unsubstituted in the 17 alpha position. The better compliance is due in particular to the fact that the formation of metabolites is greatly limited.

Determination of metabolic stability: in vitro 17 beta-HSD assay

17 β -HSD2 mediates the intestinal enzymatic dehydrogenation of the OH group at the 17-position of the prednisolone backbone to a keto group.

For this experiment, the following materials were used:

sodium phosphate buffer: 100mmol of Na₂HPO₄×2H₂O and 100mmol of NaH₂PO₄×H₂O

Solutions of the following test substances:

11 β -fluoro-7 α - {5- [ methyl (8, 8, 9, 9, 9-pentafluorononyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol (compound 1, representative of compounds of formula I) and

11 β -fluoro-7 α - {5- [ methyl (8, 8, 9, 9, 9-pentafluorononyl) amino ] pentyl-estra-1, 3, 5(10) -triene-3, 17 β -diol (compound 2): 15 μmol in MeOH (0.3 μmol in the test patch).

Cofactor solution: 2ml of glucose-6-phosphate (160mmol)/MgCl were added₂(80mmol) of the mixture was added to 400. mu.l of a glucose-6-phosphate dehydrogenase solution, followed by addition of 15.6mg of NADP and 13.4mg of NAD.

Microsome solution: intestinal microsomes (InVitro technologies; protein content: 24 mg/ml; CYP450 content: 0.058nmol/mg protein)

Thawed in a water bath at 37 deg.C (about 60 seconds) and then diluted with sodium phosphate buffer to a concentration of 5mg/ml protein.

In each case, 170. mu.l/well of buffer and 5. mu.l/well of test substance solution were introduced into the respective wells, whereby two values were tested for each test time point (0, 10, 20, 30, 45 and 60 minutes).

In each case, to the 0 minutes value added 250 u l ice cold MeOH. Then 25. mu.l of microsome solution and 50. mu.l of cofactor solution were immediately added to each well. Samples with a value of 0 minutes were stored at about-20 ℃ for 24 hours without incubation. The other samples were incubated at 37 ℃ for 10, 20, 30, 45 and 60 minutes, respectively, and the dehydrogenation reaction was stopped after these times by adding 250. mu.l of ice-cold MeOH, respectively. The samples were stored at-20 ℃ for about 24 hours until each LC/MS/MS measurement was made and centrifuged at 3000rpm before analysis, whereby the supernatant was measured.

The concentration of the test substance at each LC/MS/MS measurement and the resulting 17-ketone product are shown in FIGS. 2a-2 f.

Compound 1 is metabolically stable in intestinal microsomes but not in liver microsomes, indicating that different phase 1 reactions occur in these two tissues. However, the putative product of the 17 β HSD reaction, 11 β -fluoro-7 α - {5- [ methyl (8, 8, 9, 9, 9-pentafluorononyl) amino ] pentyl } -estr-1, 3, 5(10) -trien-3-ol-17-one (Compound 3), was not present in any of these tissues. In contrast, compound 2, which does not have any 17-methyl groups, is decomposed in intestinal microsomes and thus produces the corresponding 17-ketone. Thus, the high metabolic stability of compound 1 may be explained by the complete blockage of the 17 β HSD reaction by the 17 β -methyl group. It can thus be hypothesized that an alkyl group (such as methyl) or other alkenyl or alkynyl group (such as ethynyl) near 17-OH is sufficient to surprisingly prevent its oxidation to ketones by the intestine (not the liver), which should have the consequence of higher oral bioavailability.

In addition, the compounds according to the invention are characterized by exceptionally high bioavailability, such that high serum concentrations can be achieved upon administration of the compounds of the invention to a patient. In respect of the high compliance already mentioned, successful and reliable treatment is thereby possible, since with the compounds according to the invention it is possible to set the serum concentration of the active compound sufficiently apart from the effective concentration of the corresponding compound. By effective concentration is meant that the serum concentration of the active ingredient must be such that at least the desired effect is achieved in the corresponding indication.

The 17 α -alkyl-17 β -oxy-estratrienes of the general formula I according to the invention are particularly suitable for the production of medicaments. The invention therefore also relates to a pharmaceutical composition comprising, in addition to at least one 17 α -alkyl-17 β -oxy-estratriene of the general formula I, wherein the substituents Hal, R³、R^17’、R^17”U, V, W, X, Y, Z and E are as defined above) and at least one pharmaceutically compatible carrier.

Pharmaceutical formulations or compositions according to the invention are prepared in a manner known per se in the art using commonly used solid or liquid carriers or diluents and commonly used pharmaceutical and technical auxiliaries, depending on the desired dosage form and the appropriate dosage. Preferred formulations include dispensing forms suitable for oral, enteral or parenteral administration, such as i.p. (intraperitoneal), i.v. (intravenous), i.m. (intramuscular) or transdermal administration. Such dispensing forms are, for example, tablets, film tablets, coated tablets, pills, capsules, powders, creams, ointments, lotions, liquids such as syrups, gels, liquids for injection such as i.p., i.v., i.m., or transdermal injections, etc. In addition, long acting dosage forms such as implants and suppositories are also suitable. In this case, depending on their form, the individual preparations release the estratrienes according to the invention into the body gradually or in a short time at once.

For oral administration, the pharmaceutical preparations may be capsules, pills, tablets, coated tablets and liquids or other known oral dispensing forms. In this case, the drug may be formulated to release the active ingredient in a short period of time and reach the body, or have a long-lasting effect, so that long-lasting, slow supply of the active ingredient to the body can be achieved. In addition to the at least one estratriene, the dosage unit may contain one or more pharmaceutically compatible carriers, such as substances that modify the rheological properties of the drug, surfactants, solubilizers, microcapsules, microparticles, granulating agents, diluents, binders, such as starch, sugar, sorbitol and gelatin, fillers, such as silicic acid and talc, lubricants, dyes, flavors and other substances.

Corresponding tablets may be obtained, for example, by bringing into association the active ingredient with known auxiliaries, such as inert diluents (e.g. glucose, sucrose, sorbitol, mannitol, polyvinylpyrrolidone), disintegrating agents (e.g. corn starch or alginic acid), binding agents (e.g. starch or gelatin), lubricating agents (e.g. carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate). The tablet may consist of multiple layers.

The coated tablets may be prepared accordingly as follows: cores prepared similarly to tablets are coated with materials commonly used in the coating of coated tablets, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. In this case, the shell of the coated tablet may also consist of a plurality of layers, whereby the auxiliaries mentioned above in the tablets may be used.

Capsules containing active ingredients can be prepared, for example, as follows: the active ingredient is mixed with an inert carrier, such as lactose or sorbitol, and then encapsulated in a gelatin capsule.

The estratrienes according to the invention can also be formulated in the form of solutions for oral administration which, in addition to the active estratriene, comprise as constituents a pharmaceutically compatible oil and/or a pharmaceutically compatible lipophilic surfactant and/or a pharmaceutically compatible hydrophilic surfactant and/or a pharmaceutically compatible water-miscible solvent.

To achieve a higher bioavailability of the active ingredients according to the invention, the compounds of the invention can also be formulated in the form of cyclodextrin inclusion compounds. For this purpose, the compounds are reacted with alpha-, beta-or gamma-cyclodextrins or derivatives thereof.

If creams, ointments, lotions and liquid preparations which can be applied topically are used, they must be composed such that the compounds of the invention can be delivered to the body in sufficient quantities. In these dispensing formulations, for example, the following adjuvants are included: substances which modify the rheological properties of the drugs, surfactants, preservatives, solubilizers, diluents, substances which increase the skin penetration of the estratrienes according to the invention, dyes, fragrances and skin protection agents such as conditioners and moisturizers. Other active ingredients may also be included in the medicament, together with the compounds of the invention [ Ullmann Enzyklopadie der technischen Chemie (Ullmann encyclopedia of chemical industry), Vol.4 (1953), pages 1-39; j.pharm.sci., 52, 918 ff. (1963); consumed by Czetsch-Lindenwald, Hilfsstuffe fur Pharmazieund and grenzede Gebiete (pharmaceutical and related field adjuvants), pharm. Ind., 2, 72 ff (1961); Dr.H.P.Fiedler, Lexikon der Hilfsstuffe fur Pharmazie, Kosmetikond and grenzende Gebiete (adjuvant dictionary for pharmaceuticals, cosmetics and related fields), CantorAG, Aulendorf/Huntt., 1971).

The substances according to the invention can also be used in suitable solutions, such as physiological saline solutions, infusion or injection solutions. For parenteral administration, the active ingredient may be dissolved or suspended in a physiologically compatible diluent. As diluents, particularly preferred are oily solutions, such as solutions in sesame oil, castor oil and cottonseed oil. To increase solubility, a solubilizing agent such as benzyl benzoate or benzyl alcohol may be added.

For the preparation of injectable preparations, any liquid carrier may be used in which the compounds of the present invention are soluble or emulsifiable. These liquids often also contain substances to adjust viscosity, surfactants, preservatives, solubilizers, diluents and other additives to adjust the osmotic pressure of the solution. Other active ingredients may also be administered with the estratriene.

The estratrienes according to the invention can also be administered in the form of long-acting injectable preparations or implants, for example subcutaneously. Such formulations may be formulated to achieve delayed release of the active ingredient. For this purpose, known techniques, such as dissolving or membrane-working depot preparations, can be used. The implant may comprise, for example, a biodegradable polymer or a synthetic silicone (e.g., silicone rubber) as an inert material. Estratrienes can also be incorporated into patches, for example, for transdermal administration.

The substances according to the invention can also be incorporated into transdermal systems, whereby transdermal administration takes place.

To achieve a higher transdermal flux to produce therapeutically effective blood concentrations, the compounds according to the invention may also be incorporated in transdermal systems similar to those used in WO 01/76608 for other antiestrogens. These transdermal systems are characterized by a specific ratio of penetration enhancers, in particular of lauric acid and propylene glycol, of 2.

The dosage of the substances of the general formula I according to the invention is determined by the hospitalization physician and depends, for example, on the substance to be administered, on the method of administration, on the illness to be treated and on the severity of these illnesses. The amount of compound administered can vary over a wide range and can cover any effective amount. The amount of the compound to be administered may be 0.1 to 25mg/kg body weight, preferably 0.5 to 5mg/kg body weight per day, depending on the condition to be treated and the type of administration. In humans, this corresponds to a daily dose of 5-1250 mg. The preferred daily dosage in humans is 50-200 mg. This applies in particular to the treatment of tumours. The dose may be administered in a single dose or divided into two or more daily doses.

As mentioned above, the compounds of formula I represent compounds with very strong antiestrogenic action.

The compounds of the invention are useful in the treatment of estrogen-dependent diseases such as breast cancer (second-line therapy for breast cancer resistant to tamoxifen; adjuvant therapy for breast cancer in place of tamoxifen), endometrial cancer, prostatic hyperplasia, anovulatory infertility and melanoma.

The compounds of formula I may also be used as components of a product as described in EP 346014B 1, whereby the product comprises an estrogen and a pure antiestrogen, and is for simultaneous, sequential or separate use in selective estrogen therapy in pre-or post-menopausal women. The compounds of formula I can be used together with antiprogestins (competitive progesterone antagonists) for the treatment of hormone-dependent tumors (EP 310542 a).

Other indications for which the compounds of formula I may be used are male pattern baldness, diffuse alopecia, alopecia due to chemotherapy, and hirsutism (Hye-Sun Oh, and Robert C.Smart, Proc. Natl. Acad. Sci. USA (93/1996) 12525-12530).

In addition, the compounds of the general formula I can be used for preparing medicaments for treating endometriosis.

The compounds of the general formula I can also be used for the production of medicaments for male and female fertility control (male fertility control: DE 19510862.0A).

The estratrienes according to the invention can be prepared analogously to known methods:

in fig. 1, a reaction scheme is shown, according to which the compounds according to the invention can be prepared. In this reaction scheme, the 17 α -alkyl-17 β -oxy-estratrienes according to the invention are denoted by "17 α -methyl-amine" and "17 α -methyl-amine oxide". However, compounds having a "17 α -methyl" group at the 7 α -position have side chains that do not contain an amine group. Compounds carrying a hydroxyl or alkoxy group in the 17 β -position, an alkyl group in the 17 α -position and an amine group in the 7 α -side chain are all referred to as "17 α -methylamines". In a corresponding manner, the compound referred to as "17 α -methyl-amine oxide" is the amine N-oxide according to the invention previously referred to as "17 α -methylamine" compound.

If R is³Not equal to H, it is possible to use reagents R in which X represents a leaving group³And (4) carrying out etherification reaction.

The compound referred to as "17 β -OH" is also an estratriene having a hydroxyl or alkoxy group in the 17 β -position, but no 17 α -alkyl or amine group in the side chain in the 7 α -position. The compounds referred to as "17-ketones" are estratrienes carrying an oxo group in the 17-position but not an amine group in the side chain in the 7 alpha-position. Other compounds referred to as "17 β -OH-amine", "17-keto-amine", "17 β -OH-amine oxide" and "17-keto-amine oxide" have corresponding substitution patterns.

In principle, all the mentioned compounds can be prepared starting from 17-oxo compounds. The preparation of 17-oxo compounds is described, for example, in WO 99/33855A 1. Derivatives having the same substitution pattern as those explicitly disclosed in the document can be prepared analogously in addition to the compound. According to the same process, the estratrienes according to the invention can also be prepared starting from 17 β -hydroxy compounds or 17 β -alkoxy compounds ("17 β -OH"). The preparation of these derivatives is also described, for example, in WO 99/33855A 1. In the same way, the preparation of 17 β -hydroxy compounds or 17 β -alkoxy compounds having an amine group in the side chain in the 7 α -position and 17-oxo compounds is disclosed in this document. If the preparation of the starting compounds is not described, the starting compounds are known and commercially available, or the compounds can be synthesized analogously to known methods. The preparation of some precursors, intermediates and products is described below by way of example.

In the preparation of the substances according to aspects, the following processes may be used, for example (see, for example, EP 0138504B 1, WO 97/45441A 1, WO 98/07740A 1, WO 99/33855A1 in this respect):

the 17 α -alkyl-17 β -oxy-estratrienes according to the invention can be prepared starting from the corresponding 17 β -oxy-estratrienes ("17 β -OH"). The synthesis of these starters is also described, for example, in WO 97/45441A 1 and WO 98/07740A 1. The side chain in the 7 alpha-position can be constructed, for example, according to the method described in WO 98/07740A 1.

The resulting 17 β -hydroxy compound or 17 β -alkoxy compound having an amine group in the side chain at the 7 α -position is then oxidized to the corresponding 17-oxo compound ("17-keto-amine") by oxidation. For this purpose, the conventionally used oxidizing agents can be used, for example chromium (VI) compounds (Jones oxidation), nitric acid, manganese dioxide, selenium dioxide and SO in pyridine₃. The ketone compounds can also be prepared by the following method: catalytic dehydrogenation reactions are carried out with copper, silver, copper chromate and zinc oxide at high temperatures, or dehydrogenation reactions are carried out with ketones (e.g. cyclohexanone), or by Oppenauer oxidation. If the side chain-reduced groups contain, for example, S or SO groups, the latter can be subjected to selective reduction again after over-oxidation.

In another method embodiment, 17 β -oxy-estratrienes without an amine group in the 7 α -side chain can be directly oxidized to 17-oxo-estratrienes ("17-ketones") and the latter can be aminated in the 7 α -side chain in a known manner.

Next, an alkyl group may be introduced at the 17 α -position. For this purpose, the nucleophilic alkylating agents usually used, such as Grignard reagents or alkyllithium compounds, can be used. In this reaction, the desired 17 α -alkyl-17 β -oxy-estratriene is produced ("17 α -methyl", if initiated by the corresponding 17 β -hydroxy-estratriene [ "17 β -OH" ] without an amine group in the side chain at the 7 α -position, or "17 α -methyl-amine", if initiated by the corresponding 7-hydroxy-estratriene [ "17 β -OH-amine" ] with an amine group in the side chain at the 17 α -position). Alternatively, the 17-oxo-estratrienes obtained as intermediates can first be alkylated in a known manner and then aminated in the 7 α -side chain.

If amine N-oxide compounds ("17 β -OH-amine oxide" or "17-keto-amine oxide" or "17 α -methyl-amine oxide") are to be prepared, the corresponding estratrienes having an amine group in the 7 α -side chain ("17 β -OH-amine" or "17-keto-amine" or "17 α -methyl-amine") can be oxidized, for example, with hydrogen peroxide. In this reaction, the secondary OH group in the 17 β -position is not oxidized.

In another embodiment of the preparation of 17 α -alkyl-17 β -oxy-estratrienes according to the invention, a previously substituted 17 β -hydroxy-estratriene ("17 β -OH-amine") having an amine group in the side chain in the 7 α -position can also be used as starting material.

The material is first reacted to form the corresponding amine N-oxide compound ("17 β -OH-amine oxide"), as described above, using a conventionally used oxidizing agent such as hydrogen peroxide.

The amine N-oxide compound formed ("17 β -OH-amine oxide") can be oxidized to the corresponding ketone ("17-keto-amine oxide"), where the same oxidizing agents as described above can be used. In this case, a 17-oxo compound having an amine N-oxide group in the 7 α -side chain was prepared.

To prepare the 17 α -alkyl-17 β -oxy-estratrienes according to the invention, the keto group is reacted with a suitable nucleophilic alkylating agent according to the above description. In this case, a 17 α -alkyl-17 β -oxy-estratriene ("17 α -methyl-amine oxide") with an amine N-oxide group in the 7 α -side chain was produced.

To prepare the 17 α -alkyl-17 β -oxy-estratrienes according to the invention, it is also possible, for example, to form intermediates of the following general formula II, which are also subject matter of the invention:

wherein:

hal represents F or Cl, which is attached in the 11 beta-position of the estratriene skeleton;

R³represents hydrogen, C₁-C₄Alkyl radical, C₁-C₄Alkanoyl or forming a ring C with O atom₃-C₇(ii) an ether, in particular a polyether,

R^17’represents hydrogen, C₁-C₄Alkyl and C₁-C₄Alkanoyl radicals, in which R is in the 17 beta-position^17’Linked to the estratriene backbone;

SK represents-U-V-W-X-Y-Z-E, wherein the radical is attached via U in the 7 alpha position of the estratriene skeleton and U, V, X, Y, Z and E have the meaning given above, and W represents N⁺(O^-)(R⁶) Or represents a pyrrolidinylidene N-oxide ring, wherein the pyrrolidinylidene N-oxide ring comprises at least one C atom of the X group, R⁶As defined above.

The estratriene skeleton is preferably bonded to hydrogen atoms in positions 1, 2, 4, 6-9 and 11-16. In principle, however, the estratriene skeleton can also be modified, for example by means of a hydrocarbon bridge, such as 15 β, 16 β -methylene.

Particularly preferred 17 α -alkyl-17 β -oxy-estratrienes of the general formula II having an amine N-oxide group in the 7 α -side chain are the following compounds:

x1)11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 9-pentafluorononyl) amino ] pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide

X2)11 beta-fluoro-7 alpha- [5- (methyl {3- [ (2, 3, 4, 5, 6-pentafluorophenyl) thio ] propyl } -amino) pentyl ] estra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide

X3)11 β -fluoro-7 α - [5- (methyl {3- [ (4, 4, 5, 5, 5-pentafluoropentyl) thio ] -propyl } amino) pentyl ] estra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide

X4)11 β -fluoro-7 α - [5- (methyl {3- [ (4, 4, 5, 5, 5-pentafluoropentyl) sulfinyl ] -propyl } amino) pentyl ] estra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide

X5)11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } estra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide

X6) (S) -11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide

X7) (R) -11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide

X8)11 β -fluoro-7 α - {5- [ methyl (9, 9, 10, 10, 10-pentafluorodecyl) amino ] pentyl } estra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide.

The physical properties of the compounds are shown in table 3.

In addition, 17-oxo-estratrienes having an amine N-oxide group in the 7 α -side chain, which are formed as intermediates in the preparation of 17 α -alkyl-17 β -oxy-estratrienes according to the invention, are also subject matter of the present invention. These compounds have the general formula III:

wherein:

hal represents F or Cl, which is attached in the 11 beta-position of the estratriene skeleton;

R³represents hydrogen, C₁-C₄Alkyl radical, C₁-C₄Alkanoyl or forming a ring C with O atom₃-C₇(ii) an ether, in particular a polyether,

SK-U-V-W-X-Y-Z-E, in which the radical is attached via U in the 7 alpha position of the estratriene skeleton, and U, V, X, Y, Z and E are as defined above, and W represents N⁺(O^-)(R⁶) Or represents a pyrrolidinylidene N-oxide ring, wherein the pyrrolidinylidene N-oxide ring comprises at least one C atom of the X group, R⁶As defined above.

Furthermore, it is preferable to link hydrogen at the 1, 2, 4, 6-9 and 11-16 positions of the estratriene skeleton. In principle, the estratriene skeleton can also be modified, for example, by a hydrocarbon bridge, such as 15 β, 16 β -methylene.

Particularly preferred 17-oxo-estratrienes of the general formula III having an amine N-oxide group in the 7 α -side chain are the following compounds:

y111 β -fluoro-7 α - [5- (methyl {3- [ (4, 4, 5, 5, 5-pentafluoropentyl) sulfinyl ] propyl } -amino) pentyl ] estra-1, 3, 5(10) -trien-3-ol-17-one N-oxide

Y211 β -fluoro-7 α - [5- (methyl {3- [ (4, 4, 5, 5, 5-pentafluoropentyl) thio ] propyl } -amino) pentyl ] estra-1, 3, 5(10) -trien-3-ol-17-one N-oxide

Y311 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -estra-1, 3, 5(10) -trien-3-ol-17-one N-oxide.

The physical properties of these compounds are shown in table 4.

The compounds of the formula II and the compounds of the formula III are also compounds having an antiestrogenic action. They can therefore be used in principle for the type of indications for which the compounds of the general formula I mentioned above are suitable.

The process steps for preparing the compounds according to the invention are described in more detail below.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are in uncorrected degrees Celsius and all parts and percentages are by weight unless otherwise indicated.

Method example 1.1

(preparation of 17-oxo-estratrienes having amine N-oxide groups in the side chains from the corresponding 17-oxoestratrienes starting from 17 beta-hydroxy-estratrienes having amine groups in the side chains)

a)11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]-pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one (rotation angle α of this compound (No. Z14))_DShown in Table 5)

1.5ml of ethyldiisopropylamine are added dropwise at 10 ℃ to a solution of 1.23g of pyridine sulfur trioxide complex in 10ml of anhydrous dimethyl sulfoxide. Followed by the addition of 1.72g of 11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } -estra-1, 3, 5(10) -triene-3, 17. beta. -diol (compound Z9) and a further 10ml of anhydrous dimethyl sulfoxide and stirring at room temperature for 30 minutes. Diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and sodium chloride solution, dried over sodium sulfate, evaporated to dryness in vacuo and then dried over silica gel with dichloro-benzeneThe methane/methanol is purified by chromatography. To give 11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one, [ alpha ]]_D+58.2 ° in chloroform.

b)211 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] -pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one N-oxide

0.5g of 11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]A solution of pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one in 11ml methanol and 11ml chloroform was mixed with 3.5ml of 30% hydrogen peroxide solution and stirred at room temperature for 5 days. Then mixed with sodium thiosulfate, added to water, extracted three times with dichloromethane, washed to neutrality, dried over sodium sulfate, evaporated to dryness in vacuo, and then chromatographed on silica gel with dichloromethane/methanol. 401mg of 11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino are obtained]Pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one N-oxide solid having a melting point of 84-86 ℃; [ alpha ] to]_D+53.6 ° in chloroform.

c)11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] -pentyl }17 β -methylestra-1, 3, 5(10) -triene-3, 17-diol N-oxide

A suspension of 2.3g of cerium (III) chloride in 23ml of tetrahydrofuran is mixed at 0 ℃ with 3.19ml of a 3M solution of methylmagnesium bromide in diethyl ether and stirred for 30 minutes. A solution of 250mg of 11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one N-oxide in 5ml of tetrahydrofuran is added dropwise thereto, stirred at room temperature for 24 hours, then mixed at 0 ℃ with 10ml of ammonium chloride solution, extracted with ethyl acetate, washed with water, dried over sodium sulfate, concentrated by evaporation in vacuo, dissolved with 5ml of methanol and 5ml of chloroform, mixed with 2ml of 30% hydrogen peroxide solution, mixed at room temperature and stirred for 5 days. Then with mixed sodium thiosulfate, added to water, extracted three times with dichloromethane, washed to neutrality, dried over sodium sulfate, evaporated to dryness in vacuo, and then chromatographed on silica gel with dichloromethane/methanol. 165mg of 11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide are obtained, whose melting point is 122 ℃.

Method example 1.2:

(17-oxo-estratrienes having an amine N-oxide group in the side chain are prepared starting from 17 β -hydroxy-estratrienes having an amine group in the side chain by the corresponding 17 β -hydroxy-estratrienes having an amine N-oxide group in the side chain):

a)11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) -amino ] pentyl } -estra-1, 3, 5(10) -triene-3, 17-diol N-oxide

A solution of 50g of 11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -estra-1, 3, 5(10) -triene-3, 17 β -diol in 500ml of methanol and 500ml of chloroform was mixed with 7.3g of sodium bicarbonate and 45ml of 30% hydrogen peroxide solution and stirred at room temperature for 3 days. Then mixed with sodium thiosulfate, added to water, extracted three times with dichloromethane, washed to neutrality, dried over sodium sulfate, evaporated to dryness in vacuo, and then precipitated by adsorption with diethyl ether. 48.3g of 11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -estra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide are obtained, whose melting point is 131.7 ℃.

b)11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) -amino ] pentyl } -estra-1, 3, 5(10) -trien-3-ol-17-one N-oxide

1.5ml of ethyldiisopropylamine are added dropwise at 10 ℃ to a solution of 1.23g of pyridine sulfur trioxide complex in 10ml of anhydrous dimethyl sulfoxide. 1.62g of 11. beta. -fluoro-7. alpha. {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) was added) Amino group]Pentyl } -estra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide and a further 10ml of anhydrous dimethyl sulfoxide and stirred at room temperature for 30 minutes. It is subsequently diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and sodium chloride solution, dried over sodium sulfate, evaporated to dryness in vacuo and then chromatographed on silica gel using dichloromethane/methanol. 1.32g of 11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8.9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } -estra-1, 3, 5(10) -trien-3-ol-17-one N-oxide solid having a melting point of 84-86 ℃; [ alpha ] to]_D+53.6 ° in chloroform.

Method example 2.1:

(preparation of 17 a-methyl-estratrienes having amine N-oxide groups in the side chains starting from 17-oxo-estratrienes having amine groups in the side chains by the corresponding 17-oxo-estratrienes having amine N-oxide groups in the side chains):

a)11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] -pentyl } -17 α -methylestra-1, 3, 5(10) -trien-3, 17 β -diol (physical properties of this compound (No.7) are shown in Table 1)

A suspension of 230g of cerium (III) chloride in 2.31 g of tetrahydrofuran is mixed with 320ml of a 3M solution of methylmagnesium bromide in diethyl ether at 0 ℃ and stirred for 30 minutes. 25g of 11. beta. -fluoro-7. alpha. {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino group was added dropwise thereto]Rotation Angle alpha of pentyl [ estra-1, 3, 5(10) -trien-3-ol-17-one (Compound (No. Z14) ]_DShown in table 5) in 250ml of tetrahydrofuran, then stirred at room temperature for 24 hours, mixed with ammonium chloride solution at 0 ℃, extracted with ethyl acetate, washed with water, dried over sodium sulfate, concentrated by evaporation in vacuo and then chromatographed on silica gel with dichloromethane/methanol. 19.1g of 11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino are obtained]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol having a melting point of 82-85 ℃, and [ alpha ] - [ alpha ]]_D+21.8 ° (in chloroform).

b)11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) -amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide

A solution of 18g of 11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol in 180ml of chloroform and 180ml of methanol was mixed with 2.57g of sodium bicarbonate and 16.2ml of a 30% hydrogen peroxide solution and stirred at room temperature for 48 hours. It is subsequently diluted with dichloromethane, washed with water and sodium thiosulfate solution, dried over sodium sulfate, evaporated to dryness in vacuo and then precipitated by absorption with diethyl ether. 18.4g of 11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol N-oxide are obtained, whose melting point is 122 ℃.

Method example 2.2:

(17 α -methyl-estratrienes having an amine group in the side chain are prepared starting from 17-oxo-estratriene by 17 α -methyl-estratriene):

a)7 alpha- (5-bromopentyl) -11 beta-fluoro-17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol

A suspension of 46.8g of cerium (III) chloride in 0.471 tetrahydrofuran is mixed at 0 ℃ with 63.8ml of a 3M solution of methylmagnesium bromide in diethyl ether and then stirred for 1 hour. To this was added dropwise a solution of 25g of 7 α - (5-bromopentyl) -11 β -fluoro-estra-1, 3, 5(10) -trien-3-ol-17-one in 200ml of tetrahydrofuran, then stirred at room temperature for 28 hours, mixed with ammonium chloride solution at 0 ℃, extracted with ethyl acetate, washed with water, dried over sodium sulfate, concentrated by evaporation in vacuo, and then chromatographed on silica gel with dichloromethane/methanol. 15.1g of 7 α - (5-bromopentyl) -11 β -fluoro-17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol are obtained, the melting point of which is 48.6 ℃.

b)11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] -pentyl } -17 α -methylestra-1, 3, 5(10) -trien-3, 17 β -diol (physical properties of this compound (No.7) are shown in Table 1)

A solution of 18g of 7 α - (5-bromopentyl) -11 β -fluoro-17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol in 180ml of dimethylformamide was mixed with 15.9g of (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) -methylamine and 5g of sodium carbonate and stirred in a water bath at 80 ℃ for 8.5 hours. Added to water, extracted with ethyl acetate, washed with water and saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation in vacuo, and then chromatographed on silica gel with dichloromethane/methanol. 22.9g of 11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino are obtained]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol having a melting point of 82-85 ℃, and [ alpha ] - [ alpha ]]_D+21.8 ° (in chloroform).

Other compounds according to the invention can be prepared analogously. For this purpose, further intermediates are listed in table 5. In addition, the physical properties of these compounds are also partially shown.

Table 1:

		melting Point [. degree.C. ]]	Rotation angle alphaD 1)
				1	11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 9-heptafluorononyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide	152-154
2	11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 10, 10, 10-heptafluorodecyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide	137.7	+31°
				3	(RS) -11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide	122	+29.6°
4	11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 9-pentafluorononyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide	148.5	+25.3°
				5	11 beta-fluoro-7 alpha- {5- [ methyl (9, 9, 10, 10, 10-pentafluorodecyl) amino]Pentyl-17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide	118-120	+26°
6	11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 9-pentafluorononyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol	68-71	+32°
				7	11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol	82-85	+21.8
8	11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 9-heptafluorononyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol	138	+29.8°
				9	17 α -ethynyl-11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } -estra-1, 3, 5(10) -triene-3, 17 beta-diol	128-130	+13.1°
10	17 α -ethynyl-11 β -fluoro-3- (2-tetrahydropyranyloxy) -7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } -estra-1, 3, 5(10) -trien-17 beta-ol		+18.1°
				11	11 β -fluoro-3- (2-tetrahydropyranyloxy) -7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -trien-17 beta-ol		+26.9°
12	11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } -17 alpha-trifluoromethyl-estra-1, 3, 5(10) -triene-3, 17 beta-diol		+24.6°
				13	11 beta-fluoro-7 alpha- {5- [ methyl (6, 6, 7, 7, 8, 8, 8-heptafluorooctyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol	96.3	+38.8°
14	11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 10, 10, 10-heptafluorodecyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol	137	+24.6°
				15	11 beta-fluoro-7 alpha- {5-[ methyl (6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 10-undecafluorodecyl) amino group]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol	112.6	+21.3°
16	11 beta-fluoro-7 alpha- {5- [ methyl (5, 5, 6, 6, 7, 7, 8, 8, 8-nonafluorooctyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol
				17	11 beta-fluoro-7 alpha- {5- [ methyl (9, 9, 10, 10, 11, 11, 11-heptafluoroundecyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol
18	11 beta-fluoro-7 alpha- {5- [ methyl (9, 9, 10, 10, 10-pentafluorodecyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol	88-90	+32.5°

¹)[α]_DIn chloroform

Table 2:

		anti-uterotrophic effect
								s.c.	% inhibition	p.o.	% inhibition
3	(RS) -11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } -17 alpha-methylestra-13, 5(10) -triene-3, 17 beta-diol N-oxide			0.3	76
						7	11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol	0.03	59
8	11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 9-heptafluorononyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol			0.3	94

Table 3:

		melting Point [. degree.C. ]]	Rotation angle alphaD 1)
				X1	11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 9-pentafluorononyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide	158-160	+33.6°
X2	11 beta-fluoro-7 alpha- [5- (methyl {3- [ (2, 3, 4, 5, 6-pentafluorophenyl) thio group]Propyl } amino) -pentyl]Estra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide
				X3	11 beta-fluoro-7 alpha- [5- (methyl {3- [ (4, 4, 5, 5, 5-pentafluoropentyl) thio]Propyl } amino) -pentyl]Estra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide	114-116
X4	11 beta-fluoro-7 alpha- [5- (methyl {3- [ (4, 4, 5, 5, 5-pentafluoropentyl) sulfinyl group]Propyl } -amino) pentyl group]Estra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide	103-105
				X5	11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide	147-150	+30.2°
X6	(S) -11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide	128.5	+32.5°
				X7	(R) -11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide	144.0	+31.3°
X8	11 beta-fluoro-7 alpha- {5- [ methyl (9, 9, 10, 10, 10-pentafluorodecyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol N-oxide	99-101	+28.5°

¹)[α]_DIn chloroform

Table 4:

		melting Point [. degree.C. ]]	Rotation angle alphaD 1)
				Y1	11 beta-fluoro-7 alpha- [5- (methyl {3- [ (4, 4, 5, 5, 5-pentafluoropentyl) sulfinyl group]Propyl } amino) -pentyl]Estra-1, 3, 5(10) -trien-3-ol-17-one N-oxide		+45.6°
Y2	11 beta-fluoro-7 alpha- [5- (methyl {3- [ (4, 4, 5, 5, 5-pentafluoropentyl) thio]Propyl } amino) -pentyl]Estra-1, 3, 5(10) -trien-3-ol-17-one N-oxide		+52.8°
				Y3	11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl [ estra-1, 3, 5(10) -trien-3-ol-17-one N-oxide	84-86	+53.6°

¹)[α]_DIn chloroform

Table 5:

		melting Point [. degree.C. ]]	Rotation angle alphaD 1)
				Z1	11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 9-pentafluorononyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol
Z2	11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 9-pentafluorononyl) amino]Pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one
				Z3	11 beta-fluoro-7 alpha- {5- [ methyl (3, 3, 4, 4, 5, 5, 6, 6, 7, 7, 8, 8, 8-tridecafluorooctyl) amino]Pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one
Z4	11 beta-fluoro-7 alpha- {5- [ methyl (9, 9, 10, 10, 10-pentafluorodecyl) amino]Pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one		+48.4°
				Z5	11 beta-fluoro-7 alpha- {5- [ methyl (9, 9, 10, 10, 10-pentafluorodecyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol
Z6	11 beta-fluoro-7 alpha- {5- [ methyl (3, 3, 4, 4, 5, 5, 6, 6, 6-nonafluorohexyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol
				Z7	11 β -fluoro-7 α - {5- [ methyl (4, 4, 5, 5, 6, 6, 7, 7, 8, 8, 9, 9, 9-tridecafluorononyl) amino]Pentyl } -estra-1, 3, 5(10) -triene-3, 17 beta-diol
Z8	11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 8-pentafluorooctyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol
				Z9	11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol
Z10	11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 11, 11, 12, 12, 12-tridecafluorododecyl) amino]-pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol
				Z11	11 β -fluoro-7 α - {5- [ methyl (4, 4, 5, 5, 6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 11, 11, 11-heptadecafluoroundecyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol

		Melting Point [. degree.C. ]]	Rotation angle alphaD 1)
				Z12	11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 11, 11, 12, 12, 13, 13, 14, 14, 14-heptadecafluorotetradecyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol
Z13	11 β -fluoro-7 α - {5- [ methyl (5, 5, 6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 10-tridecafluorodecanyl) amino]Pentyl } -estra-1, 3, 5(10) -triene-3, 17 beta-diol
				Z14	11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one		+58.2°
Z15	11 beta-fluoro-3-methoxy-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]-pentyl } estra-1, 3, 5(10) -trien-17 beta-ol		+39.2°
				Z16	11 beta-fluoro-3-methoxy-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]-pentyl } estra-1, 3, 5(10) -trien-17-one		+55.9°
Z17	17 beta-acetyloxy-11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]-pentyl } estra-1, 3, 5(10) -trien-3-ol		+21.0°
				Z18	11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3- (2-tetrahydropyranyloxy) -17-one		+66.1°
Z19	3-tert-Butyloxy-11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) -amino]Pentyl } estra-1, 3, 5(10) -trien-17 beta-ol		+31.2°
				Z20	3-Acetyloxy-11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino]-pentyl } estra-1, 3, 5(10) -trien-17 beta-ol		+33°

		Melting Point [. degree.C. ]]	Rotation angle alphaD 1)
				Z21	11 beta-fluoro-7 alpha- {5- [ methyl (6, 6, 7, 7, 8, 8, 9, 9, 9-nonafluorononyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol
Z22	11 beta-fluoro-7 alpha- {5-[ methyl (8, 8, 9, 9, 10, 10, 11, 11, 11-nonafluoroundecyl) amino group]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol
				Z23	11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 9-heptafluorononyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol	125.0
Z24	11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 9-heptafluorononyl) amino]Pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one		+70.2°
				Z25	11 beta-fluoro-7 alpha- {5- [ methyl (6, 6, 7, 7, 8, 8, 8-heptafluorooctyl) amino]Pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one		+71.6°
Z26	11 beta-fluoro-7 alpha- {5- [ methyl (6, 6, 7, 7, 8, 8, 8-heptafluorooctyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol	112.8	+42.6°
				Z27	11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 10, 10, 10-heptafluorodecyl) amino]Pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one		+56.2°
Z28	11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 10, 10, 10-heptafluorodecyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol	104	+34.9°
				Z29	11 β -fluoro-7 α - {5- [ methyl (6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 10-undecafluorodecanyl) amino]-pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one		+64.6°
Z30	11 β -fluoro-7 α - {5- [ methyl (6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 10-undecafluorodecanyl) amino]-pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol	94-96	+36.8°
				Z31	11 beta-fluoro-7 alpha- {5- [ methyl (5, 5, 6, 6, 7, 7, 8, 8, 8-nonafluorooctyl) amino]Pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one
Z32	11 beta-fluoro-7 alpha- {5- [ methyl (5, 5, 6, 6, 7, 7, 8, 8, 8-nonafluorooctyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol
				Z33	11 beta-fluoro-7 alpha- {5- [ methyl (9, 9, 10, 10, 11, 11, 11-heptafluoroundecyl) amino]Pentyl } estra-1, 3, 5(10) -trien-3-ol-17-one
Z34	11 beta-fluoro-7 alpha- {5- [ methyl (9, 9, 10, 10, 11, 11, 11-heptafluoroundecyl) amino]Pentyl } estra-1, 3, 5(10) -triene-3, 17 beta-diol

¹)[α_D]In chloroform

Claims (15)

1. 17 α -alkyl-17 β -oxy-estratrienes having the following general formula I:

wherein:

hal represents F or Cl, which is attached in the 11 beta-position of the estratriene skeleton;

R³represents hydrogen, C₁-C₄Alkyl radical, C₁-C₄Alkanoyl or forming a ring with an O atomC₃-C₇(ii) an ether, in particular a polyether,

R¹⁷' represents hydrogen, C₁-C₄Alkyl and C₁-C₄An alkanoyl group;

R¹⁷"represents C₁-C₄Alkyl radical, C₁-C₄Alkynyl and at least partially fluorinated C₁-C₄Alkyl, wherein R is in the 17 beta-position¹⁷' -O and R in the 17 alpha-position¹⁷"attached to the estratriene skeleton;

SK represents-U-V-W-X-Y-Z-E, in which the radical is attached to the 7 alpha position of the estratriene skeleton via U, and

u represents a linear or branched C₁-C₁₃Alkylene radical, C₁-C₁₃Alkenylene or C₁-C₁₃An alkynylene group which is a substituent of a heterocyclic ring,

v represents CH₂A group;

w is N (R)⁶) The group is either a pyrrolidinylidene ring, wherein the pyrrolidinylidene ring includes at least one carbon atom of the X group, wherein

R⁶Is H or CH₂-R⁷Or C (O) -R⁷Wherein R is⁷Represents the following meanings:

a) hydrogen, or

b) Straight or branched, unfluorinated or at least partially fluorinated C₁-C₁₄Alkyl radical, C₁-C₁₄Alkenyl or C₁-C₁₄Alkynyl, or

c) Unsubstituted aryl or heteroaryl, or

d) Unsubstituted C₃-C₁₀Cycloalkyl radicals, or

e) Unsubstituted C₄-C₁₅Cycloalkylalkyl, or

f) Unsubstituted C₇-C₂₀Aralkyl, or

g) Unsubstituted heteroaryl C₁-C₆An alkyl group, a carboxyl group,

x is straight or branched C₁-C₁₂Alkylene radical, C₁-C₁₂Alkenylene or C₁-C₁₂An alkynylene group;

y is a direct bond between X and Z,

z represents a direct bond between Y and E or a linear or branched C₁-C₉Alkylene radical, C₁-C₉Alkenylene or C₁-C₉Alkynylene groups, these groups being partially or fully fluorinated; and E is CF₃A group or an at least partially fluorinated aryl group;

and their pharmaceutically compatible acid addition salts and esters.

2. The estratriene of claim 1 wherein R³Represents hydrogen, CH₃、CH₃CO or C₅H₁₀O。

3. The estratriene of claim 1 wherein R¹⁷' represents hydrogen, CH₃Or CH₃CO, and R¹⁷"represents methyl, ethynyl or trifluoromethyl.

4. Estratrienes according to claim 1 wherein Hal represents fluorine.

5. Estratrienes according to any of claims 1 to 4 wherein U represents (CH)₂)_pWherein p is an integer from 2 to 10.

6. The estratriene of claim 5 wherein p ═ 4.

7. Estratrienes according to any of claims 1 to 4 wherein W represents N (R)⁶) -, and R⁶Is hydrogen or C₁-C₃An alkyl group.

8. The estratriene of claim 7 wherein R⁶Represents a methyl group.

9. As claimed in claim1-4, wherein X represents (CH)₂)_qWherein q is an integer of 1 to 12.

10. The estratriene of any of claims 1 to 4 wherein Z is an at least partially fluorinated linear or branched C₁-C₇An alkylene group.

11. Estratrienes according to any of claims 1 to 4 wherein E represents CF₃Or represents pentafluorophenyl.

12. Estratrienes according to any of claims 1 to 4 wherein Z-E represents C₂F₅、C₃F₇、C₄F₉Or C₆F₅。

13. The estratriene of claim 1 which is:

11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 9-pentafluorononyl) amino ] pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol

11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol

11 beta-fluoro-7 alpha- {5- [ methyl (7, 7, 8, 8, 9, 9, 9-heptafluorononyl) amino ] pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol

17 α -ethynyl-11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) -amino ] pentyl } -estra-1, 3, 5(10) -triene-3, 17 β -diol

17 α -ethynyl-11 β -fluoro-3- (2-tetrahydropyranyloxy) -7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, -10, 10-nonafluorodecyl) amino ] pentyl } -estra-1, 3, 5(10) -trien-17 β -ol

11 β -fluoro-3- (2-tetrahydropyranyloxy) -7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -trien-17 β -ol

11 β -fluoro-7 α - {5- [ methyl (7, 7, 8, 8, 9, 9, 10, 10, 10-nonafluorodecyl) amino ] pentyl } -17 α -trifluoromethylestra-1, 3, 5(10) -triene-3, 17 β -diol

11 beta-fluoro-7 alpha- {5- [ methyl (6, 6, 7, 7, 8, 8, 8-heptafluorooctyl) amino ] pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol

11 beta-fluoro-7 alpha- {5- [ methyl (8, 8, 9, 9, 10, 10, 10-heptafluorodecyl) amino ] pentyl } -17 alpha-methylestra-1, 3, 5(10) -triene-3, 17 beta-diol

11 β -fluoro-7 α - {5- [ methyl (6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 10-undecafluorodecyl) amino ] -pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol

11 β -fluoro-7 α - {5- [ methyl (5, 5, 6, 6, 7, 7, 8, 8, 8-nonafluorooctyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol

11 β -fluoro-7 α - {5- [ methyl (9, 9, 10, 10, 11, 11, 11-heptafluoroundecyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol or

11 β -fluoro-7 α - {5- [ methyl (9, 9, 10, 10, 10-pentafluorodecyl) amino ] pentyl } -17 α -methylestra-1, 3, 5(10) -triene-3, 17 β -diol.

14. Use of 17 α -alkyl-17 β -oxy-estratrienes of general formula I according to any of claims 1 to 13 for the preparation of a medicament.

15. Pharmaceutical composition comprising at least one 17 α -alkyl-17 β -oxy-estratriene of general formula I according to any of claims 1 to 13 and at least one pharmaceutically compatible carrier.