EP1622924A2 - 8$g(b)-vinyl-11$g(b)-( g(v)-substituted)alkyl-estra-1,3,5(10)-trienes - Google Patents

Abstract

The invention relates to 8beta-vinyl-11beta-(omega-substituted)alkyl-estra-1,3,5(10)-trienes of general formula (I), which have ERbeta-antagonistic activity, methods for the production thereof, the intermediate products thereof, pharmaceutical preparations containing the inventive compounds, and the use thereof for producing medicaments. The novel compounds can be used for contraceptive purposes in men and women without influencing other estrogen-sensitive organs such as the uterus or the liver and while also being suitable for the treatment of benign or malignant proliferous ovarian diseases, such as ovarian carcinoma and granulosa cell tumors.

Description

 8β-vinyl-11β- (ω-substituted) alkyl-estra-1,3,5 (10) -trienes

The present invention relates to 8β-vinyl-11β- (ω-substituted) alkyl-estra-1,3,5 (10) -trienes having ERβ-antagonistic activity, processes for their preparation, their intermediates, pharmaceutical preparations containing the compounds according to the invention , as well as their use for the production of medicaments. The compounds according to the invention are those steroidal tissue-selective estrogens which have a higher affinity for estrogen receptor preparations of rat prostate than rat estrogen receptor preparations in vitro, and have a contraceptive action in vivo by virtue of their preferential effect on the ovary, and can develop through a characterized by an improved physicochemical profile.

Contraceptive methods with chemical compounds are widely used in women who do not want to get pregnant. The following chemical methods of female contraception are currently available:

1) suppression of ovulation by inhibition of gonadotropin release and thus of ovulation (the endocrine principle); 2) Prevention of sperm ascension by the female

Reproductive tract to the fallopian tube where fertilization takes place;

3) prevention of implantation or nidation of a fertilized embryo into the uterus;

4) spermicides; 5) Abort-inducing agents.

Oral contraceptives, which consist of various combinations of an estrogen with a progestin, are the most commonly used contraceptives in women. They work according to the endocrine principle. Although such contraceptives are very effective, undesirable side effects such as: irregular bleeding, nausea, vomiting, depression, weight gain or headache may occur. Occasionally, more severe conditions are observed, such as thromboembolism, stroke, liver adenomas, gall bladder disease or high blood pressure. These unwanted side effects of the oral contraceptives used today make clear the medical need for a new contraceptive method without side effects. An ideal contraceptive method is a method that attaches directly to the ovarian follicle without affecting the endocrine hypothalamic-pituitary-ovarian axis.

This could be achieved with a chemical compound that interferes with folliculogenesis, for example, by destroying a paracrine

Interaction between the oocyte and the granulosa cells, and thus ensures that a) the follicular program can not run adequately, so that an incompetent

Ovulation, which is indeed ovulated but can not be fertilized, or b) the follicle program can not run adequately, so that an incompetent

Ovulation, which is ovulated and fertilized, but does not lead to a preimplantation development, or c) folliculogenesis is limited and no ovulation occurs.

Follicular growth is the development of an ovarian follicle from the primordial stage to the large ankyardous, proliferating follicle. Only an optimally constructed antral follicle has the potential to ovulate a mature egg. Patients with ovarian infertility, e.g. PCOS (= Policystic Ovary Syndrome) Patients with impaired folliculogenesis associated with hormonal and ovulatory disorders as well as insufficiently mature oocytes (Franks et al., Mol. Cell Endocrinol 2000, 163, 49-52). There is increasing evidence that the early stages of folliculogenesis, i. the developmental steps from the primordial follicle to the early onset follicle are gonadotropin-independent, but it has not yet been conclusively clarified which of the identified autocrine or paracrine factors (Elvin et al., Mol. Cell, Endocrinol 1999, 13, 1035-1048; McNatty et al., J. Reprod. Fertil. Suppl., 1999, 54, 3-16) are the most important in early folliculogenesis. Gonadotropins, e.g. the follicle stimulating hormone (FSH), on the other hand, are mainly involved in the late stages of folliculogenesis, i. development from the early onset to the large ovulatory follicle. However, additional modulators of folliculogenesis are also discussed in late folliculogenesis (Elvin et al., Mol Cell Cell Endocrinol 1999, 13, 1035-1048).

Recently, estrogen receptor β (ERβ) has been discovered as the second subtype of the estrogen receptor (Kuiper et al., Proc Natl Acad Sci 1996, 93, 5925-5930, Mosselman, Dijkema, FEBS Letters 1996, 392, 49-53 Tremblay et al., Molecular Endocrinology 1997, 11, 353-365). The expression pattern of ERβ differs from that of ERα (Kuiper et al., Endocrinology 1996, 138, 863-870). Whereas an expression of ER was detectable in nearly old organs examined, the highest expression of ERβ was found in ovarian females, in male animals in the prostate (Couse et al., Endocrinology 1997, 138, 4613-4621). In the ovary, a clear ERß expression in follicles of almost all stages of development shows. While in the follicles ERα is only expressed in the outer follicle cells (the the the Aca cells), there is a strong expression of ERβ in the oestradiol-producing granulosa cells. Due to the different cell distribution of ERα and ERβ in the ovarian follicle, it is to be expected that the interaction of a ligand with ERα or ERβ will lead to different cellular responses. That ERα and ERβ are functionally different has recently been confirmed by the successful production of ERα and ERβ knockout mice (Couse et al., Endocrine Reviews 1999, 20, 358-417). Consequently, ERα is significantly involved in the function of the uterus, the mammary gland, the control of the sexual endocrine axis, whereas ERβ is predominantly involved in the processes of ovarian physiology, in particular folliculogenesis, and ovulation.

Another organ system with high ERβ expression is the testis (Mosselmann et al., FEBS Lett. 1996, 392, 49-53) including the spermatids (Shugrue et al., Steroids 1998, 63, 498-504). That ERβ is functional in the male animal is also evident from studies on ERα (ERKO) and ERβ (BERKO) knockout mice: male ERKO mice (RA Hess et al., Nature 1997, 390, 509-512 ) show marked fertility disorders. This demonstrates the important role of estrogens in maintaining fertility testis function. ERα and ERβ have significantly different amino acid sequences in their ligand binding and transactivation domain. This suggests that (1) ER subtypes with different affinity bind their ligands, and

(2) ligands have different agonistic and / or antagonistic potential over the two receptor subtypes.

Patent Applications WO 00/47603, WO 00/63228, WO 01/32680, WO 01/77138, US 60 / 207,370 and publications (Sun et al., Endocrinology 1999, 140, 800-804; Stauffer et al., J. Comb Chem. 2000, 2, 318-329) show that steroidal and nonsteroidal ligands with high affinity to ERα and ERβ were found. Some compounds were considerably stronger agonists / antagonists on ERα, whereas other compounds were stronger agonists / antagonists on ERβ. In WO 00/31112 new steroidal compounds are described based on the base of the 8-position unsubstituted estradiol, which carry in 11 ß position a hydrocarbon radical containing a single linear chain with a length of 5 to 9 carbon atoms. These compounds have an ERα- agonistic / ERβ antagonistic profile of action. Because of this mixed estrogen receptor profile, these compounds are useful as improved estrogens for the treatment of estrogen-related disorders and for contraception with a progestin.

In WO 02/068548 findings are shown for the first time in vivo demonstrating that ERβ-selective agonists lead to an improvement in folliculogenesis, whereas ERβ-selective antagonists increase fertility, i. reduce the ovulation rate.

WO 01/77138 discloses 11β-n-pentyl and 11β-n-hexyl-8β-substituted estra-1,3,5 (10) -trienes having ERβ-antagonistic activity. However, 11β- / --alkyl substitution leads to a further reduction of the polarity and thus also to the poorer water solubility of such compounds.

The object of the present invention is to provide compounds with improved physicochemical properties which have a dissociation in vitro of binding to estrogen receptor preparations of rat prostate Ge025 and rat uterus and in vivo by their preferential effect on the ovary have a contraceptive effect, without other estrogen-sensitive organs such eg affecting the uterus or the liver. Furthermore, these compounds should be used for contraception in men and for the treatment of benign or malignant proliferative diseases of the ovary.

This object is achieved by providing the compounds of general formula I.

The present invention relates to compounds of general formula I.

wherein

R ^{3 is} a group R ¹ -O-, R ^u SO ₂ -O-, -OC (O) R 321 ¹ .; n 3, 4, 5: X is a group of the formula II

z

II in which

Z and W are independently R ¹⁹ , or

Z and W together represent an oxygen atom,

Y is -OR ¹⁹ , -CN, -SCN, a halogen atom, R ²⁰ , R ²⁰ SO ₂ -O-; or YR ¹⁹ or R ²⁰ when Z and W together represent an oxygen atom;

R ¹⁷ and R ¹⁷ 'together represent an oxygen atom, a group = CR ²³ R ²⁴ , wherein

R ²³ and R ²⁴ independently represent a hydrogen atom or a halogen;

or

R ^{17 is} hydrogen, -OR ¹⁹ or halogen;

R ^{17 '} R ¹⁹ , -OR ¹⁹ , halogen, R ² ° SO ₂ -O-, -C (O) R ²¹ or

-OC (O) R ²¹ ;

R ^{19 is} a hydrogen atom, a radical of the formula C _p F _q H _r with p = 1, 2, 3, 4, 5, 6, 7, 8, 9; q> 1 and q + r = 2p + 1; a straight-chain C ₁ -C ₄ -alkyl group or branched C ₃ -C ₆ -alkyl group, a C ₃ -C ₆ -cycloalkyl group optionally substituted by a phenyl radical, a (C ₁ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkylene group, a branched or unbranched C ₂ -C ₅ alkenyl group, a C ₂ -C ₅ -

alkynyl; or an unsubstituted or substituted aryl, heteroaryl, heterocyclyl, aryl-C 1 -C -alkylene, heteroaryl-C 1 -C ₄ -alkylene group; ^{20 is} an R ²¹ R ²² N group, a group -C (NOR ¹⁹ ) H, or a group of the general formula III

wherein

V is -CH ₂ -, an oxygen atom or a sulfur atom, or = NR 25. M is 0, 1, 2, 3, 4, 5, 6, 7 or 8; o is 0, 1, 2, 3, 4, 5, 6, 7 or 8, the sum of which is m + o 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12;

R ²¹ and R ^{22 are} independently R ¹⁹ ; R ²⁵ R ¹⁹ , R ²⁰ SO ₂ - or an acyl group -C (O) R ²¹

represent.

The present invention also encompasses the pharmaceutically acceptable salts of the compounds of general formula I according to the invention.

At the unbranched it may be, for example, a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, π-heptyl, n-octyl; and the branched C ₃ -C ₈ alkyl groups a / ^'so-propyl, / so-butyl, sec-butyl, te / f-butyl, / so-pentyl, neo-pentyl, 2-methylpentyl , 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylhexyl, 2,2-dimethylpentyl, 2,2,3-trimethylbutyl, 2,3,3-trimethylbutyl group.

The optionally substituted with a phenyl radical C ₃ -C ₆ -cycloalkyl groups may be consistently a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenylcyclopropyl, phenylcyclobutyl, phenylcyclopentyl, Phenylcyclohexyl- group act. The (C ₃ -C ₆ -cycloalkyl) -CC-C ₄ -alkylene groups may be, for example, a cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopropylpropyl, Cyclobutylpropyl, cyclopentylpropyl, cyclohexylpropyl, cyclopropylbutyl, cyclobutylbutyl, cyclopentylbutyl and cyclohexylbutyl groups, respectively.

The branched or unbranched C ₂ -C ₅ -alkenyl groups may be, for example, a vinyl, trifluorovinyl, allyl, homoallyl, (ε) -but-2-enyl, (Z) -but-2-enyl , (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-S- enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, ()) -pent-1-enyl, (Z) -penem-enyl, 2-methylvinyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, 3-methylbut-2 act enyl group.

The C ₂ -C ₅ -alkynyl groups may be, for example, an ethynyl, prop-1-inyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-one. inyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 1-methylprop-2-ynyl, 1-methylbut-3-ynyl, 1 -Ethylprop-2-inyl group act.

Accordingly, it may be in the R ⁹ O groups, for example, methoxy, ethoxy, n-propoxy, / ^'so-propoxy, n-butoxy, sec-butoxy, / so-butoxy, tert- Butoxy group act.

The aryl groups may be, for example, a phenyl, naphthalen-1-yl, naphthalen-2-yl, [1, 1'-biphenyl] -2-yl, [1, 1'-biphenyl] -3 -yl- or a [1, 1'-biphenyl] -4-yl group.

The heteroaryl groups can be a pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, 1,3-benzodioxolyl, 2,1,3-benzothiadiazolyl, indolyl- , Furanyl, thienyl,

Oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl or a

Imidazolyl group act.

The heterocyclyl groups for the radicals Z and Z 'may be a piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl or pyrrolidinyl group linked via one of the substitutable sites. The substituents of the aryl, heteroaryl, heterocyclyl radicals may be, inter alia, unbranched or branched C 1 -C ₄ -alkyl groups (methyl, ethyl, n-propyl, n-propyl, n-butyl, sec-butyl). , / so-butyl and tert-butyl) and / or C ₂ -C ₆ -alkenyl groups (vinyl, allyl, homoallyl, (E) -but-2-enyl, (Z) -but-2 -enyl,

Pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl- , 2-methylvinyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, 2-Ethylprop-2-enyl, Hex-5-enyl, (£) hex-4-enyl, (Z) -hex-4-enyl, (£) -hex-3-enyl, ( Z) -hex-S-enyl, (£) -hex-2-enyl, (Z) -hex-2-enyl, 1-methylpent-4-enyl, (E) -1-methylpent-3 -enyl-, (Z) -1-methylpent-3-enyl-, 1-

Ethyl but-3-enyl, (ε) -1-methylpent-2-enyl, (Z) -1-methylpent-2-enyl-) and / or

C ₃ -C ₆ -cycloalkyl groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), and / or

Halogen (fluorine, chlorine, bromine, iodine), and / or

-OH, -O- (C ₁ -C ₄ -alkyl), formyl, -CO ₂ H, -CO ₂ (C ₁ -C ₄ -alkyl), -NO ₂ , -N ₃ , -CN,

Ci-Cs-acyl, d-Cs-acyloxy, trifluoromethyl-pentafluoroethyl, methylthio, trifluoromethylthio, and / or amino, mono (C ₁ -C ₈ alkyl) amino or di (C -C ₈ Alkyl) amino, both being

Alkyl groups are identical or different, act.

The aryl-C 1 -alkylene groups for the radicals Z and Z 'may be a combination of the previously defined aryl and C 1 -C ₄ -alkyl groups, for example: a

Phenylmethyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-1-phenylethyl, 3-phenylpropyl-4-phenylbutyl, (naphthalen-1-yl) methyl, 1- (naphthalen-1-yl) ethyl, 2- (naphthalen-1-yl) ethyl, (naphthalen-2-yl) methyl, 1- (naphthalen-2-yl) ethyl, 2- (naphthalen-2-yl) ethyl, ([1, 1'-biphenyl] -2-yl) methyl, ([1, 1'-biphenyl] -3-yl) methyl or a ([1, 1'-biphenyl] -4-yl) methyl group act.

The heteroaryl-C 1 -C ₄ -alkylene groups for the radicals Z and Z 'may be a combination of the previously defined heteroaryl and dd-alkylene groups, for example a (pyridin-2-yl) methyl-, (pyridine) 3-yl) methyl, (pyridin-4-yl) methyl, (furan-2-yl) methyl, (furan-3-yl) methyl, (thien-2-yl) methyl, (thien) 3-yl) methyl, 2- (thien-2-yl) ethyl or a 2- (thien-3-yl) ethyl group. In the rest of the formula C _p F _q H _r with p = 1, 2, 3, 4, 5, 6, 7, 8, 9; q> 1 and q + r = 2p + 1 may be monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, perfluoropropyl, perfluorobutyl, 2,2,2-trifluoroethyl, 5,5,5,4 , 4-pentafluoropentyl, 6,6,6,5,5,4,4,3,3-nonafluorohexyl, 9,9,9,8,8-pentafluorononyl, or 9,9,9,8,8 7,7-heptafluomonyl group.

It is inventively the halogen to fluorine, chlorine, bromine or iodine.

For the formation of pharmaceutically acceptable salts of the compounds of the general formula I according to the invention, according to the methods known to those skilled in the inorganic acids, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, nitric acid, as carboxylic acids, inter alia, acetic acid, propionic acid, hexanoic acid, Octanoic acid, decanoic acid, oleic acid, stearic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, ascorbic acid, oxalic acid, salicylic acid, tartaric acid, citric acid, lactic acid, glycolic acid malic acid, mandelic acid, cinnamic acid, glutamic acid, aspartic acid, sulfonic acids including methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid and naphthalenesulfonic acid into consideration.

Preferred according to the present invention are those compounds of general formula I wherein

Y is -OH, -CN, -SCN, a halogen atom, R ²⁰ ; or

YR ²⁰ , when Z and W together represent an oxygen atom

means.

Particularly preferred according to the present invention are those compounds of general formula I wherein

Y is -OH, -CN, -SCN, a halogen atom, R ²⁰ ; or YR ²⁰ , when Z and W together represent an oxygen atom,

and

R ¹⁷ and R ^{17 '} together represent an oxygen atom, or

R ^{17 is} hydrogen, -OH;

R ^{17 'represent} hydrogen, -OH, -CC ₄ -alkyl group, C ₂ -C ₅ -alkenyl group, a C ₂ -C ₅ - alkynyl group, or a trifluoromethyl group.

The compounds according to the invention named below are very particularly preferred. In the case of epimeric alcohols, both possible diastereomers are also very particularly preferred.

1 1 β - [(R) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1), 11β - [(S) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

1 1β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2),

1 1 β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol,

(Diastereomer 1),

1 1 β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2), 1-1β- [6,6,6-trifluoro-5-hydroxy-5- (trifluoromethyl) hexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β - diol,

11β- [7,7,7-trifluoro-6-hydroxy-6- (trifluoromethyl) heptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol,

11β- [8,8,8-trifluoro-7-hydroxy-7- (trifluoromethyl) octyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol 11β- [7,7,7,6,6-pentafluoro-5-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

11β- [7,7,7,6,6-pentafluoro-5-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2),

11β- [8,8,8,7,7-pentafluoro-6-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

11β- [8,8,8,7,7-pentafluoro-6-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2), 11β- [9,9,9,8,8-pentafluoro-7-hydroxynonyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

11β- [9,9,9,8,8-pentafluoro-7-hydroxynonyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

11β- [8,8,8,7,7,6,6-heptafluoro-5-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 1) .

11β- [8,8,8,7,7,6,6-heptafluoro-5-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

11β- [9,9,9,8,8,7,7-heptafluoro-6-hydroxynonyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1), 11β- [9,9,9,8,8,7,7-heptafluoro-6-hydroxynonyl] -8-vinyl-estra-1, 3,5 (10) -triene-3,17β- diol

(Diastereomer 2)

11β- [10,10,10,9,9,8,8-heptafluoro-7-hydroxydecyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

11β- [10,10,10,9,9,8,8-heptafluoro-7-hydroxydecyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2 )

11β- (5-bromopentyl) -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol,

11β- [5- (methylamino) pentyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- [5- (dimethylamino) pentyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- [5- (pyrrolidin-1-yl) pentyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- [5- (1-piperidyl) pentyl] -8 -vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- (5-morpholinopentyl) -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- {5- [methyl (9,9,9,8,8-pentafluorononyl) amino] pentyl} -8-vinylestra-1, 3,5 (10) -triene

3,17ß-diol,

11β- {5 - [(9,9,9,8,8,7,7-heptafluorononyl) methylamino] pentyl} -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- {5- [methyl (octanoyl) amino] pentyl} -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol, 11β- (6-chlorohexyl) -8-vinyl estra-1, 3,5 (10) -triene-3,17β-diol, 11β- [6- (methylamino) hexyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol , 11β- [6- (dimethylamino) hexyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- [6- (pyrrolidin-1-yl) hexyl] - 8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- [6- (1-piperidyl) hexyl] -8-vinylestra-1, 3,5 (10) -triene-3 , 17β-diol, 11β- (6-morpholinohexyl) -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- {6- [methyl (9,9,9, 8,8-pentafluomonyl) amino] hexyl} -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- {6 - [(9,9,9,8,8, 7,7-heptafluorononyl) methylamino] hexyl} -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- {6- [methyl (octanoyl) amino] hexyl} -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol, 11β- (7-bromoheptyl) -8-vinyl estra-1, 3,5 (10) -triene-3,17β-diol, 11β- [7- (methylamino) heptyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β- diol, 11β- [7- (dimethylamino) heptyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- [7- (pyrrolidin-1-yl) heptyl] - 8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- [7- (1-piperidyl) heptyl] -8-vinylestra-1, 3,5 (10) -triene-3 , 17β-diol, 11β- (7-morpholinoheptyl) -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- {7- [methyl (9,9,9, 8,8-pentafluorononyl) amino] heptyl} -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- {7 - [(9,9,9,8,8,7,7-heptafluorononyl) methylamino] heptyl} -8-vinylestra-1, 3,5 (10) -triene

3,17ß-diol,

11β- {7- [methyl (octanoyl) amino] heptyl} -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol,

Λ / -n-butyl-Λ / -methyl-5- [3,17β-dihydroxy-8-vinylestra-1, 3,5 (10) -triene-11β-yl] valeramide, Λ / -r-butyl / V -methyl-6- [3,17β-dihydroxy-8-vinylestra-1, 3,5 (10) -trien-11β-yl] capronamide, Λ / -n-butyl-Λ / -methyl-7- [3,17β -dihydroxy-8-vinylestra-1, 3,5 (10) -triene-11β-yl] oenanthamide, 11β- (5-thiocyanatopentyl) -8-vinylestra-1, 3,5 (10) -triene-3 , 17β-diol, 11β- (6-thiocyanatohexyl) -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- (7-thiocyanatoheptyl) -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

6- [3,17β-dihydroxy-8-vinylestra-1, 3,5 (10) -trien-11β-yl] capronitrile,

7- [3,17β-Dihydroxy-8-vinylestra-1, 3,5 (10) -triene-11β-yl] oenanthenitrile, 17β-hydroxy-11β - [(R) 6,6,6-trifluoro- 5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 1),

17β-hydroxy-11β - [(S) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 2) .

17β-hydroxy-11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 1),

17β-hydroxy-11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 2),

17β-hydroxy-11β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate, (diastereomer 1), 17β -Hydroxy-11β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 2),

17β-hydroxy-11β- [6,6,6-trifluoro-5-hydroxy-5- (trifluoromethyl) hexyl] -8-vinyl-estrone

1, 3,5 (10) -trien-3-yl-sulfamate,

17β-Hydroxy-11β- [7,7,7-trifluoro-6-hydroxy-6- (trifluoromethyl) heptyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate .

17β-Hydroxy-11β- [8,8,8-trifluoro-7-hydroxy-7- (trifluoromethyl) octyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate .

17β-hydroxy-11β- [7,7,7,6,6-pentafluoro-5-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3-yl-sulfamate (diastereomer 1 ), 1β-hydroxy-11β- [7,7,7,6,6-pentafluoro-5-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3-yl-sulfamate (Diastereomer 2),

17β-hydroxy-11β- [8,8,8,7,7-pentafluoro-6-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (diastereomer 1 )

17β-hydroxy-11β- [8,8,8,7,7-pentafluoro-6-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (diastereomer 2 )

1β-hydroxy-11β- [9,9,9,8,8-pentafluoro-7-hydroxynonyl] -8-vinyl-estra-1,3,5 (10) -triene-3-yl-sulfamate (diastereomer 1 ),

17β-hydroxy-11β- [9,9,9,8,8-pentafluoro-7-hydroxynonyl] -8-vinyl-estra-1,3,5 (10) -triene-3-yl-sulfamate (diastereomer 2 ) 11β- [5- (Dimethylamino) pentyl] -17β-hydroxy-8-vinylestra-1, 3,5 (10) -trien-3-yl-sulphamate, 17β-hydroxy-11β- [5- (pyrrolidine-1 -yl) pentyl] -8-vinylestra-1, 3,5 (10) -trien-3-yl-sulphamate, 17β-hydroxy-11β- [5- (1-piperidyl) -pentyl] -8-vinylestra-1 , 3,5 (10) -trien-3-yl-sulfamate, 17β-hydroxy-11β- (5-morpholinopentyl) -8-vinylestra-1, 3,5 (10) -trien-3-yl-sulfamate, 11β- [6- (dimethylamino) hexyl] -17β-hydroxy-8-vinylestra-1, 3,5 (10) -trien-3-yl-sulphamate, 17β-hydroxy-11β- [6- (pyrrolidine) 1 -yl) hexyl] -8-vinylestra-1, 3,5 (10) -trien-3-yl-sulfamate, 17β-hydroxy-11β- [6- (1-piperidyl) hexyl] -8-vinylestra- 1, 3,5 (10) -trien-3-yl-sulfamate, 17β-hydroxy-11β- (6-morpholinohexyl) -8-vinylestra-1, 3,5 (10) -trien-3-yl-sulfamate , 11β- [7- (Dimethylamino) heptyl] -17β-hydroxy-8-vinylestra-1, 3,5 (10) -trien-3-yl-sulphamate, 17β-hydroxy-11β- [7- (pyrrolidine 1 -yl) heptyl] -8-vinylestra-1, 3,5 (10) -trien-3-yl-sulphamate, 17β-hydroxy-11β- [7- (1-piperidyl) heptyl] -8-vinylestra -1, 3,5 (10) -trien-3-yl-sulfamate, 17β-hydroxy-11β- (7 -morpholinoheptyl) -8-vinylestra-1, 3,5 (10) -trien-3-yl-sulfamate,

11β- [7,7,6-trifluoro-5-hydroxyhept-6-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

11β- [7,7,6-trifluoro-5-hydroxyhept-6-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

11β- [8,8,7-trifluoro-6-hydroxyoct-7-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 1),

11β- [8,8,7-trifluoro-6-hydroxyoct-7-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

11β- [9,9,8-trifluoro-7-hydroxynon-8-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1), 11β- [9,9,8-trifluoro-7-hydroxynon-8-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

11β- [5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 1),

11β- [5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2),

11β- [6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 1), 11β- [6-hydroxyheptyl] -8-vinyl-estrone 1, 3,5 (10) -triene-3,17β-diol (diastereomer 2),

11β- [7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 1),

11β- [7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2),

11β- [5-methyl-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol, 11β- [6-methyl-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol,

11β- [7-methyl-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol,

17α-methyl-11β - [(R) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 1) .

17α-methyl-11β - [(S) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2) .

17α-Methyl-11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1), 17α-methyl-11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

17α-methyl-11β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

17α-methyl-11β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2),

17β-hydroxy-11β- [8,8,8,7,7,6,6-heptafluoro-5-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene

3-yl-sulfamate (diastereomer 1),

17β-hydroxy-11β- [8,8,8,7,7,6,6-heptafluoro-5-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene

3-yl-sulfamate (diastereomer 2), 17β-hydroxy-11β- [9,9,9,8,8,7,7-heptafluoro-6-hydroxynonyl] -8-vinyl-estra-1, 3,5 (10) -triene

3-yl-sulfamate (diastereomer 1),

17β-hydroxy-11β- [9,9,9,8,8,7,7-heptafluoro-6-hydroxynonyl] -8-vinyl-estra-1,3,5 (10) -triene

3-yl-sulfamate (diastereomer 2),

17β-hydroxy-11β- [10,10,10,9,9,8,8-heptafluoro-7-hydroxydecyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl sulfamate (diastereomer 1),

17β-hydroxy-11β- [10,10,10,9,9,8,8-heptafluoro-7-hydroxydecyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl sulfamate (diastereomer 2),

17β-hydroxy-11β- [7,7,6-trifluoro-5-hydroxyhept-6-enyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (diastereomer 1 ), 17β-Hydroxy-11β- [7,7,6-trifluoro-5-hydroxyhept-6-enyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate ( Diastereomer 2),

17β-hydroxy-11β- [8,8,7-trifluoro-6-hydroxyoct-7-enyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (diastereomer 1 ) 17β-hydroxy-11β- [8,8,7-trifluoro-6-hydroxyoct-7-enyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (diastereomer 2 )

17β-Hydroxy-11β- [9,9,8-trifluoro-7-hydroxynon-8-enyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (Diastereomer 1 )

17β-hydroxy-11β- [9,9,8-trifluoro-7-hydroxynon-8-enyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (diastereomer 2 )

17β-Hydroxy-17α-methyl-11β - [(R) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (Diastereomer 1), 17β-hydroxy-17α-methyl-11β - [(S) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene 3-yl-sulfamate (diastereomer 2),

17β-hydroxy-17α-methyl-11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 1 )

17β-hydroxy-17α-methyl-11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 2 )

17β-hydroxy-17α-methyl-11β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene

3-yl-sulfamate (diastereomer 1),

17β-hydroxy-17α-methyl-11β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene

3-yl sulfamate (diastereomer 2).

The compounds according to the invention are suitable for inhibiting folliculogenesis and ovulation, for male contraception and for the treatment of benign and malignant proliferative disorders of the ovary. Unlike the estrogen ethinylestradiol commonly used for hormonal contraception or even in the case of the compounds to be used for contraception according to WO 00/31112, the compounds of the general formula I according to the invention alone, d. H. be used without the additional administration of progestins for contraception.

The ester derivatives of the estratrienes according to the invention can have as prodrug advantages over the unesterified active compounds with respect to their mode of application, their mode of action, potency and duration of action. Pharmacokinetic and pharmacodynamic advantages are also exhibited by the sulphamate derivatives of estratrienes according to the invention. These effects have already been described in other steroid sulfamates (Steroid Biochem Molec Biol 1995, 55, 395-403, Exp Opinion Invest Drugs 1998, 7, 575-589).

The present invention describes 8β-vinyl-11β- (TO-substituted) alkyl-estra-1,3,5 (10) -trienes, the in vitro dissociation for binding to estrogen receptor preplarations of rat prostate and rat uterus, and those in vivo preferably have an inhibition of folliculogenesis and ovulation. The compounds of the invention have a contraceptive effect over a wide dose range, without other estrogen-sensitive organs, e.g. affecting the uterus or the liver. In addition, these compounds can be used for male contraception and for the treatment of benign or malignant proliferative diseases of the ovary.

The present invention therefore relates to pharmaceutical preparations containing at least one compound of general formula I and their physiologically acceptable salts; the use of the compounds of general formula I for the manufacture of a medicament for male and / or female contraception, for the treatment of benign and malignant proliferative diseases of the ovary.

The compounds according to the invention, both after oral and parenteral administration, can be used for the following indications.

The compounds of the general formula I according to the invention can be employed as individual components in pharmaceutical preparations or in combination, in particular, with GnRH antagonists, progesterone receptor antagonists, mesoprogestins, gestagens or tissue-selective gestagens (action via type A / B form).

The compounds according to the invention and the preparations containing them are particularly suitable for ovarian contraception, for the treatment of benign or malignant proliferative diseases of the ovary, such as e.g. Ovarian carcinomas, granulosa cell tumors.

In addition, the compounds may find use in the treatment of male fertility disorders and prostatic diseases. The amount of a compound of general formula I to be administered will vary within a wide range and may cover any effective amount. Depending on the condition to be treated and the mode of administration, the amount of compound administered may be 0.01 μg / kg-100 mg / kg body weight, preferably 0.04 μg / kg-1 mg / kg body weight, per day. In humans, this corresponds to a dose of 0.8 μg to 8 g, preferably 3.2 μg to 80 mg, _r daily.

A dosage unit according to the invention contains 1, 6 μg to 2000 mg of one or more compounds of general formula I.

The compounds of the invention and their acid addition salts are suitable for the preparation of pharmaceutical compositions and preparations. The pharmaceutical compositions or medicaments contain as active ingredient one or more of the compounds according to the invention or their acid addition salts, optionally mixed with other pharmacologically or pharmaceutically active substances. The preparation of the drug is carried out in a known manner, wherein the known and customary pharmaceutical excipients and other conventional carriers and diluents can be used.

As such carriers and excipients are, for example, those recommended or indicated in the following references as adjuvants for pharmacy, cosmetics and related fields: Ullmans Encyklopadie der technischen Chemie, Vol. 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), page 918 et seq., H. v. Chr. Czetsch-ündenwald, adjuvants for pharmacy and adjacent areas; Pharm. Ind., Issue 2, 1961, page 72 u. ff. H. P. Fiedler, Lexicon of excipients for pharmacy, cosmetics and adjacent areas, Cantor KG. Aulendorf in Württemberg 1971.

The compounds according to the invention can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously, or else be implanted in the tissue.

For oral administration capsules, pills, tablets, dragees, etc. are suitable.

The dosage units may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier, such as starch, sugar, sorbitol, gelatin, lubricant,

Silica, talc, etc included. For parenteral administration, the active ingredients may be dissolved or suspended in a physiologically acceptable diluent. As diluents, oils are often used with or without the addition of a solubilizer, surfactant, suspending or emulsifying agent. Examples of oils used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

The compounds may also be used in the form of a depot injection or an implant preparation, which may be formulated to allow sustained release of active ingredient.

Implants may contain as inert materials, for example, biodegradable polymers or synthetic silicones such as silicone rubber. The active ingredients can also be incorporated for percutaneous administration, for example in a plaster.

For the preparation of intravaginal (e.g., vaginal rings) or intrauterine systems (e.g., pessaries, spirals, lUSs) loaded with active compounds of general formula I for local administration, various polymers such as silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene are suitable.

To achieve better bioavailability of the drug, the compounds may also be formulated as cyclodextrin clathrates. For this purpose, the compounds with α-, ß- or γ-cyclodextrin or derivatives of these are implemented (PCT / EP95 / 02656). The compounds of the general formula I according to the invention can also be encapsulated with liposomes.

Pharmacological examinations

Estrogen receptor binding studies

The binding affinity of the compounds of the invention was tested in competition experiments using 3H-estradiol as a ligand on estrogen receptor preparations of rat prostates and rat uteri. The preparation of the prostate cytosol and the estrogen receptor test with the prostate cytosol was performed as described by J. Testas et al. in Endocrinology 1981, 109, 1287-1289. The preparation of rat uterus cytosol, as well as the receptor assay with the ER-containing cytosol were carried out in principle as described by Stack and Gorski in Endocrinology 1985, 117, 2024-2032, with some modifications according to U. Fuhrmann et al. in Contraception 1995, 51, 45-52).

The compounds of the invention have higher binding affinity for estrogen receptor from rat prostate than for estrogen receptor from rat uterus (Tables 1 and 2). It is assumed that ERβ predominates over ERα in the rat prostate and in rat uterus ERα over ERβ. Table 1 shows that the ratio of prostate and uterine receptor binding qualitatively agrees with the relative binding affinity (RBA) ratio of rat human ERβ and rat ERα (according to Kuiper et al., Endocrinology 1996, 138, 863-870) (Table 1) ).

Table 1

Table 1 (continued)

cited from: Kuiper et al. Endocrinology 1996. 138. 863-870

Transactivation test for estrogen agonists and antagonists

Cultivation of the cells:

U-2 OS cells are grown in Dulbecco ^'s medium (DMEM) without phenol red (Gibco BRL; # 11880-028) + 5% fetal calf serum (FKS) (Seromed; # S 0115) + 100 units / ml penicillin / 100 μg / ml Streptomycin (Seromed, #A 2213), 4 mM L-glutamine (Gibco BRL; # 25030-024) (PSG) was cultured at 37 ° C and 8.5% CO ₂ .

Cells maintained in D-MEM with 5% charcoal-treated FBS (CCS) + PSG for at least 24 hours are washed with PBS "Dulbecco ^'s (Gibco BRL; # 14190-094) and trypsinized (trypsin / EDTA (0, 05 / 0.02%); Seromed; #L 2153) Resuspend the cells in 10 ml D-MEM + 5% CCS + PSG Dilute 8x10 ⁶ cells to 80 ml with D-MEM + 5% CCS + PSG for Eight 96 well plates (Packard, CulturePlate-96, # 6005180) Saw 100μl of cell suspension (1x1 O cells) per well, 6h after sowing, transfection. Transfection using FuGENE 6:

The ERβα expression plasmid (HEGO) used was amplified in E. coli DH5α (from Invitrogen). The ERβ expression plasmid (ERβO) used was produced in house and amplified in E. coli DH5α. As in the case of ERα, the expression plasmid pSG5 was used. As a reporter plasmid, the vector pBL-LUC ^{+ was provided} with two tandem EREs (estrogen-responsive elements of the vitellogenin promoter) and amplified in E. coli (XL1-Blue, Fa. Stratagene). Plasmid DNA is prepared using the NucleoBond Plasmid Maxi Kit (CLONTECH; # K3003-2) and FuGENE 6 Reagent (Boehringer Mannheim, # 1 814 443). These are first diluted separately in a suitable volume of DMEM and incubated before combining the solutions and incubating again. Approaches for 96-well plates:

DNA mixture (A) in the 50 ml β / ueMax (Falcon; # 2070) tube pSG5-ERα / βFL (HeqO / ERβO) 2ng / well (estrogen receptor expression plasmid) p (ERE) 2 ~ luc ⁺ 100ng / well (luciferase reporter plasmid)

Transfection reagent (B): in 14 ml polypropylene tube (Falcon; # 2059)

DMEM o. Serum (to be submitted) 9,7μl / well

FuGENE 6 (directly into the medium) 0.3μl / well

Incubate solutions A and B for 5 min at room temperature (RT). Then add solution B dropwise to solution A, mix. Incubate solution AB for 15 min at RT.

Dilution of transfection mixture AB for 4 plates with 22.5 ml D-MEM + 5%

CCS + PSG. 100 μl of this dilution are added to the cells per well and incubated overnight (16-18 hours) at 8.5% CO2 and 37 ° C. There are only 60 per plate

Wells transfected; the outer wells receive only medium. Hormone replacement therapy:

For dose-response curves, 10 " ³ M stock solutions are prepared in 96 well plates (Costar; # 3595) starting from dimethylsulfoxide (DMSO, Sigma; # D-2650),

Serial dilutions prepared for reference and test substances. The 10 "" ³ M DMSO

Solutions are stored at -20 ° C and must be well resolved before removal

(15 min, 37 ° C).

The dilution stages are chosen such that the final concentrations on the test plate for agonism in the range of 10 - ¹² M ^"7 10" (for E2: 10 ^-8 - 10 ^_13 M) lie.

All dilution steps thus contain 1% DMSO.

After transfection, the transfection medium is replaced by 180 μl D-MEM + 5% CCS +

PSG per well replaced.

To test for antagonism, the cells are additionally treated with estradiol. Subsequently, 20 μl of the substance dilutions are added by pipette. The negative controls receive 20 μl DMEM + 1% DMSO per well. The final test substance concentrations are 3x10 ^_1 M for ERα and 3x10 ^{_ 0} M for ERβ, respectively. The reference substance used is the known antiestrogen fulvestrant (AstraZeneca) in the same concentrations (Table 2).

Incubation takes place overnight (16-18h) at 8.5% CO2 and 37 ° C.

Lysis of cells and determination of luciferase activity:

After aspirating the medium, in each case 30 μl of lysis 1x reagent (Promega;

# E1531) on the cells and for ¹ -1h at RT with vigorous shaking (IKA

VIBRAX-VXR, 600 rpm).

Subsequently, the lysates are mixed with 30 μl of luciferase substrate A (PharMingen, # 556867) and 30 μl of luciferase substrate B (PharMingen, # 556869). The measurement of the luciferase activity takes place 30 seconds after the addition of substrate B in the cycle mode of

Luminometer (DYNATECH, ML3000).

The evaluation of the measured data takes place by means of the device manufacturer

Software (BioLinx). The presentation of the results as dose-response curves for

Agonism and antagonism is performed in the Sigma P / of program with means (n = 3) and standard deviation. A calculation of the EC ₅₀ , the efficacy and the EMR

Value for the agonism, or the IC ₅₀ and the efficacy for the antagonism is possible by means of S "software (Table 2). Physicochemical profile:

In comparison with compounds from WO 01/77138, an improvement of the physicochemical profile, with regard to the distribution coefficient [logD (HPLC method, pH: 7.0, 25 ° C.)] and / or the solubility [Sw (turbidimetry, pH 7.4 at 25 ° C)], the compounds of the invention achieved (Table 2).

Surprisingly, it was also possible to increase the potency at the ERβ (EMR value) and / or the selectivity in favor of the ERβ.

Table 2

Investigative examples of the contraceptive effect

Early Folliculogenesis Study: Immature female rats are treated from day 1 to day 4 with a combination of cetrorelix and the ERβ selective estrogen 8β-vinylestra-1, 3,5 (10) -triene-3,17β-diol (25 mg / ml). kg, sc). In addition, from day 1 to day 4, the vehicle or the active substance is administered in various dosages (1, 3, 10, 30 mg / kg, s.c.). The animals are autopsied on day 5. The ovary is harvested and macroscopically, e.g. Organ weights, and microscopic, e.g. histological evaluation of the follicles, so-called follicle staging, analyzed.

Investigation of late folliculogenesis / ovulation

Immature female rats are hypophysectomized. This tag is defined as day 0. From Day 1 - Day 4, treatment, subcutaneous and / or oral, is with the active substance in combination with 17β-oestradiol. On day 5, a subcutaneous injection with PMSG (pregnant mare serum gonadotropin) is performed. On day 7, hCG is administered intraperitoneally to induce ovulation. On day 8, the ovary is harvested and analyzed macroscopically (e.g., ovary weights) and / or microscopically (e.g., follicular histological evaluation, so-called follicle staging). The tubes are rinsed and examined for the presence of egg cells.

Examination of ovulation

Immature female rats are subcutaneously treated with PMSG (pregnant mare serum gonadotropin) at day 23 (day 1). On the same day, as well as 24 and 48 hours later, the animals receive the active substance administered subcutaneously or orally. 54 hours after the PMSG injection, the animals are given an intraperitoneal injection of hCG to induce ovulation. Autopsy is performed 16 hours after hCG administration. The tubes are rinsed and examined for the presence of oocytes.

Another possibility for detecting the dissociated estrogen effect of the substances according to the invention in vivo is, after single application of the substances in rats, to measure effects on the expression of 5HT2a receptor and serotonin transporter protein and mRNA levels in ERβ-rich brain areas. Compared to the effect on serotonin receptor and transporter expression, the effect on LH secretion is measured. Substances with higher binding to the rat prostate compared to the rat uterine estrogen receptor are more potent as regards Increasing the expression of serotonin receptor and transporter, compared to their positive effect on LH secretion. The density of serotonin receptor and transporter is determined by radioactive ligands, and the corresponding mRNA by in situ hybridization. The method is described in the literature: G. Fink & BEH Sumner 1996 Nature 383: 306; BEH Sumner et al. 1999 Molecular Brain Research, in press.

Production process for the compounds of the invention

The present invention also relates to the intermediates of general formula VI

Intermediates of the general formula VII

Intermediates of the general formula VIII

as well as intermediates of general formula IX

wherein the radicals X, R ³ , R ¹⁷ , R ^{17 '} and n have the same meaning as in the general formula I. Compounds of the general formulas IV to X are used as intermediates in the preparation process for the compounds of the general formula I

VII

VI

VIII IX

i) trifluoromethanesulfonic anhydride / pyridine ii) compound of general formula X, palladium (II) acetate / triphenylphosphine / copper (I) iodide / piperidine / 50 ° C. iii) palladium / magnesium carbonate (10%) / 1 bar hydrogen / tetrahydrofuran / Methanol iv) diisobutylaluminum hydride / toluene / 0 ° C v) protecting group manipulation vi) a) protecting group manipulation, b) Pd / C (10%) / 10Obar hydrogen / tetrahydrofuran / methanol vii) Wittig olefination with Ph ₃ P = CH

Compounds of general formula IV are available to those skilled in the art according to WO 01/77139, the intermediate of general formula V is also known from PCT / EP / 02/11533.

The present invention further relates to processes for the preparation of the compounds of general formula I, and in each case a process for the preparation of the individual intermediates VI to IX.

The compounds of general formula I according to the invention can be prepared as described in the examples. By analogous procedure using homologous reagents to the reagents described in the examples, the other compounds of general formula I can be obtained.

Etherification and / or esterification of free hydroxy groups takes place by methods familiar to the person skilled in the art.

The compounds according to the invention can be present at the carbon atom 17 as α, β-stereoisomers. In the preparation of the compounds according to the described method, the compounds are usually obtained as mixtures of the corresponding α, ß-isomers. The mixtures can be separated, for example, by chromatographic methods. Substituents which are possible according to the general formula I may already be present in the starting form or in the form of a precursor in the starting product, an estron already corresponding to the desired end product.

17-Substituents are, also by known methods, introduced by nucleophilic addition of the desired substituent or a reactive precursor thereof, and optionally further developed.

The estratriene carboxylic acid esters according to the invention are prepared analogously to likewise known processes from the corresponding hydroxysteroids (see, for example, Pharmaceutical Active Ingredients, Syntheses, Patents, Applications, A. Kleemann, J. Engel, Georg Thieme Verlag, Stuttgart 1978. Arzneimittel, Fortschritt 1972 to 1985 A. Kleemann, E. Lindner, J. Engel, VCH 1987, pp. 773-814).

The estratriene sulfamates according to the invention are obtainable in a manner known per se from the corresponding hydroxy steroids by esterification with sulfamoyl chlorides in the presence of a base (Z. Chem., 1975, 15, 270-272, Steroids 1996, 61, 710-717). Subsequent acylation of the sulfamide group leads to the (N-acyl) sulfamates according to the invention, for which pharmacokinetic advantages have already been demonstrated in the absence of an 8-substituent (compare WO 97/14712).

The regioselective esterification of polyhydroxylated steroids with N-substituted and N-unsubstituted sulfamoyl chlorides takes place after partial protection of those hydroxyl groups which are to remain unesterified. Silyl ethers have proven to be protective groups with selective reactivity suitable for this purpose, since they are stable under the conditions of sulfamate formation and the sulfamate group remains intact when the silyl ethers are again split off for regeneration of the remaining hydroxyl group (s) present in the molecule (Steroids 1996, 61 , 710-717).

The preparation of the sulfamates according to the invention with one or more additional hydroxyl groups in the molecule is also possible by starting from suitable hydroxy-steroid ketones. First, depending on the objective, one or more hydroxyl groups are subjected to sulfamoylation. Then the sulfamate groups can optionally be converted with a desired acyl chloride in the presence of a base in the respective / N-acyl) sulfamates. The now present oxosulfamates or oxo (N-acyl) sulfamates are converted by reduction into the corresponding hydroxysulfamates or hydroxy- (N-acyl) sulfamates (Steroids 1996, 61, 710-717). Suitable reducing agents are sodium borohydride and the borane-dimethyl sulfide complex.

However, substituents according to the general formula I can also be introduced at the stage of the estratrienes already substituted in the 8-position. This can be useful or necessary in particular in the case of multiple substitution of the desired end compound.

The following examples serve to illustrate the invention.

The starting material for such syntheses are 11-keto-estratetraene derivatives (US Pat. No. 3,491,089, Tetrahedron Letters, 1967, 37, 3603), which are stereoselectively substituted in position 8β in the reaction with diethyl aluminum cyanide. The synthesis of compound (1) is described (WO 01/77139). By conversion into a Δ-9,11-enol triflate and subsequent Sonogashira coupling one arrives at 8β-substituted 11-alkyl-estra-1, 3,5 (10), 9 (11) -tetraenen. The 8β-cyano moiety can then be converted to the 8β-aldehyde. Functionalization (e.g., by Wittig reactions) following hydrogenation of the C (9) -C (11) double bond results in the 8β, 11β-disubstituted steroids of the present invention (Scheme 1).

The 8β-substituted 11-alkyl estrone initially obtained in this sequence

1, 3,5 (10), 9 (11) -tetraenes can be, as well as the 8ß-substituted 11 ß-alkyl estraene

1, 3,5 (10) -trienes according to methods known to those skilled in further implement to various substitution patterns on the steroid.

Common Abbreviations:

THP = tetrahydropyran-2-yl;

Me = methyl;

Bn = benzyl;

Tf = trifluoromethanesulfonyl; TBS = tert-butyldimethylsilyl;

TMS = trimethylsilyl;

Equiv. = Equivalents Synthesis of 5-benzyloxypent-1-in

To a suspension of 17.4 g of sodium hydride (55%) in 200 ml of DMF are added dropwise at 0 ° C 15 ml of 4-pentin-1-ol and it is stirred for 1 hour at 0 ° C. Subsequently, 30 ml of benzyl bromide are added dropwise at this temperature and it is stirred for a further 2 hours at 0 ° C. Then the reaction is carefully neutralized with 1N hydrochloric acid. The phase separation is carried out between diethyl ether and water and the aqueous phase is extracted several times with diethyl ether. The combined organic phases are washed with water, sat. Sodium bicarbonate and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is distilled in an oil pump vacuum, giving 22.7 g of 5-benzyloxypent-1-yn as a colorless oil. '

Synthesis of aldehyde 9a (Scheme 1)

3-Methoxy-17β- (tetrahydropyran-2-yloxy) -11-trifluoromethanesulfonyloxy-estra-1, 3,5 (10), 9, (11) -tetraene-8-carbonitrile (2)

To a solution of 20 g of ketone 1 in 490 ml of pyridine 16 ml trifluoromethanesulfonic anhydride are added dropwise at 0 ° C and it is stirred until complete reaction at room temperature. Pyridine is distilled off with toluene as co-solvent, the residue taken up in ethyl acetate, washed with 1 N hydrochloric acid, water, sat. Sodium bicarbonate and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is filtered through silica gel (cyclohexane / ethyl acetate) to give 18.12 g of triflate 2 as a light yellow foam, which is used without further purification in the next step.

11 - [5- (Benzyloxy) -pent-1 -inyl] -3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10), 9 (11) -tetraene-8- carbonitrile (3)

0.75 g of palladium (II) acetate (47%), 1.8 g of triphenylphosphine and 1.28 g of copper (I) iodide are added successively to a solution of 18.1 g of triflate 2 in 170 ml of piperidine, followed by a solution of 11.66 g of 5-benzyloxypent Added dropwise in 50 ml of piperidine. The reaction solution is heated to 50 ° C and stirred until complete reaction. For workup, a phase separation between diethyl ether / water and the aqueous phase is extracted several times with diethyl ether. The combined organic phases are neutralized with 1 N hydrochloric acid, washed with sat.

Sodium bicarbonate and sat. Sodium chloride solution washed over

Dried magnesium sulfate and concentrated. The residue is purified by column chromatography (cyclohexane / ethyl acetate) to give 15.26 g of alkyne 3 as a light brown foam [LC-MS: m / z theor .: 565, practical: 566 (M + H) *].

11 - [5- (Benzyloxy) pentyl] -3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1, 3,5 (10), 9 (11) -tetraene-8-carbonitrile (4)

A solution of 15.26 g of alkyne 3 in 300 ml of tetrahydrofuran / methanol (3: 1) is treated with 2.7 g of palladium (10% on magnesium carbonate) and stirred under a hydrogen atmosphere (1 bar) until complete reaction at room temperature. For workup, it is filtered through Celite and concentrated in vacuo. There are obtained 15.4 g of a colorless foam 4, which is used without further purification in the next stage (GC-MS: m / z theor .: 569, practical: 569).

11 - [5- (Benzyloxy) pentyl] -17β-hydroxy-3-methoxyestra-1, 3,5 (10), 9 (11) -tetraene-8-carbaldehyde (5)

A solution of 28 ml of diisobutylaluminum hydride in 83 ml of toluene is added dropwise at -10 ° C. to a solution of 15.4 g of nitrile 4 in 280 ml of toluene. The reaction solution is stirred until complete reaction at 0 ° C, successively with 460 ml of toluene, 92 ml of sat. Sodium bicarbonate solution and 9 ml of 2-propanol and stirred for several hours at room temperature. It is then filtered through Celite and the filtrate is concentrated. The colorless foam thus obtained is dissolved in 280 ml of ethanol / water (5: 1), 28.75 g of p-toluenesulfonic acid are added, and the reaction solution is heated to 60 ° C. and stirred until complete reaction. Subsequently, a large portion of the ethanol is removed on a rotary evaporator, the residue diluted with ethyl acetate, washed with water, sat. Sodium bicarbonate and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography (cyclohexane / ethyl acetate) and gives 12.49 g of aldehyde 5 as a light brown viscous mass (GC-MS: m / z theor .: 488, practical: 488). 11- [5- (Benzyloxy) pentyl] -17β- (tert -butyldimethylsilyloxy) -3-methoxyestra-1,3,5 (10), 9 (11) -tetraene-8-carbaldehyde (6)

4.46 g of imidazole and 9.66 g of tert-butyldimethylsilyl chloride are added successively at 0.degree. C. to a solution of 12.49 g of alcohol 5 in 160 ml of N, N-dimethylformamide, and the mixture is stirred until complete reaction at room temperature. For workup, the aqueous phase is mixed with water and extracted several times with diethyl ether. The combined organic phases are washed with water and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography (cyclohexane / ethyl acetate) and gives 14.36 g of silyl ether 6 as a yellow viscous mass (GC-MS: m / z theor .: 602, practical: 602).

17β- (tert-butyldimethylsilyloxy) -11β- (5-hydroxypentyl) -3-methoxyestra-1, 3,5 (10) -triene-8-carbaldehyde (7)

A solution of 14.36 g of tetraene 6 in 400 ml of tetrahydrofuran / methanol (3: 1) is mixed with 2.8 g of palladium (10% on carbon) and stirred under a hydrogen atmosphere (100 bar) for two days at room temperature. This reaction is repeated twice. For workup, it is filtered through Celite and concentrated in vacuo. The residue is purified by column chromatography (cyclohexane / ethyl acetate) to give 8.25 g of 7 as a colorless foam (GC-MS: m / z theor .: 514, practical: 514).

General procedure for the Wittiq olefination of estratriene-8-carbaldehvden

A suspension of sodium hydride (80%, 15 equiv.) In dimethyl sulfoxide (0.5 ml / mmol) is heated to 70 ° C for 1 hour. Subsequently, at room temperature, a solution of the corresponding Alkyltriphenylphosphoniumbromids (15 equiv.) Was added dropwise in dimethyl sulfoxide (2 ml / mmol). The reaction solution turns yellow-green and is stirred for a further hour at room temperature.

A solution of the corresponding 8-carbaldehyde in dimethyl sulfoxide (5 ml / mmol) is added dropwise at room temperature to the solution of the ylide. The reaction solution is stirred until complete reaction at 40 ° C, cooled to 0 ° C and treated with water. It is then extracted several times with diethyl ether, the combined organic phases with water and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatographic purification (cyclohexane / ethyl acetate) gives the corresponding olefins. 17β-tert-butyldimethylsilyloxy-11β- (5-hydroxypentyl) -3-methoxy-8-vinyI-estra-1,3,5 (10) -triene (8)

4 g of aldehyde 7 give in the reaction with Methyltriphenylphosphoniumbromid analogous to the general Olefinierungsvorschrift 3.62 g of olefin 8 as a colorless foam (GC-MS: m / z theor .: 512, practical: 512).

5- [17β- (tert-butyldimethylsilyloxy) -3-methoxy-8-vinylestraι-1,3,5 (10) -triene-11β-yl-jaleraldehyde (9a)

1.24 g of pyridinium chlorochromate are initially charged in 9 ml of dichloromethane, a solution of 1.5 g of alcohol 8 in 15 ml of dichloromethane is added dropwise, and then 940 mg of Celite are added. The reaction mixture is stirred at room temperature until complete reaction, concentrated on a rotary evaporator, then taken up in diethyl ether and filtered through silica gel. This gives 1.41 g of aldehyde 9a as a light yellow, viscous mass (GC-MS: m / z theor .: 510, practical: 510) which is used in the subsequent reaction without further purification.

Synthesis of Aldehyde 9b (Scheme 2)

11β- (5-bromopentyl) -17β-tert-butyldimethylsilyloxy-3-methoxy-8-vinyl-estra-1,3,5 (10) -triene (10)

1.62 g of triphenylphosphine and 420 mg of imidazole are added successively to a solution of 2.11 g of alcohol 8 in 41 ml of dichloromethane. The solution is cooled to 0 ° C and 2.05 g of tetrabromomethane are added. The reaction mixture is warmed to room temperature and stirred until complete. For workup is diluted with dichloromethane, the organic phase with water and sat. Washed sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatographic purification (cyclohexane / ethyl acetate) gives 2.3 g of bromide 10 as a colorless viscous mass (GC-MS: m / z theor .: 574, practical: 574). 6- [17β- (tert-butyldimethylsilyloxy) -3-methoxy-8-vinylestra-1, 3,5 (10) -trien-11β-yl] capronitrile (11a)

To a solution of 2.3 g of bromide 10 in 20 ml of N, N-dimethylformamide are added 295 mg of sodium cyanide and a catalytic amount of sodium iodide. The reaction mixture is stirred until complete reaction at room temperature. For workup is diluted with diethyl ether, the organic phase with water and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. This gives 1.97 g of cyanide 11a as a colorless foam which is used in the next step without further purification (GC-MS: m / z theor .: 521, practical: 521).

6- [17β- (tert -butyldimethylsilyloxy) -3-methoxy-8-vinylestra-1, 3,5 (10) -triene-11β-yl] capronaldehyde (9b)

A solution of 1 ml of diisobutylaluminum hydride in 1 ml of toluene is added dropwise at -10 ° C. to a solution of 1.16 g of cyanide 11a in 23 ml of toluene. The reaction solution is stirred until complete reaction at -10 ° C, successively with 17 ml of toluene, 6 ml of sat. Sodium bicarbonate solution and 0.7 ml of 2-propanol and stirred for several hours at room temperature. It is then filtered through Celite and the filtrate is concentrated. Column chromatographic purification (cyclohexane / ethyl acetate) gives 1.13 g of aldehyde 9b as a colorless foam (GC-MS: m / z theor .: 524, practical: 524).

Synthesis of bromide 13 (Scheme 2)

17β-tert-butyldimethylsilyloxy-11β- (6-hydroxyhexyl) -3-methoxy-8-vinyl-estra-1,3,5 (10) -triene (12)

To a solution of 1.95 g of aldehyde 9b in 37 ml of tetrahydrofuran / methanol (1: 1) are added at 0 ° C 282 mg of sodium borohydride. The reaction solution is stirred until complete reaction at room temperature. For workup is diluted with diethyl ether, the organic phase with 1 N hydrochloric acid, water, sat. Sodium bicarbonate and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatographic purification (cyclohexane / ethyl acetate) gives 1.06 g of alcohol 12 as a colorless viscous mass (GC-MS: m / z theor .: 526, practical: 526). 11β- (6-bromohexyl) -17β-tert-butyldimethylsilyloxy-3-methoxy-8-vinyl-estra-1,3,5 (10) -triene (13)

The reaction of 930 mg of alcohol 12 is carried out analogously to the experimental procedure for the conversion of alcohol 8 in bromide 10. In this way 975 mg of bromide 13 are obtained as a colorless viscous oil (GC-MS: m / z theor.: 588, prakt .: 588). Synthesis of Aldehyde 9c (Scheme 3)

7- [1β- (tert-butyldimethylsilyloxy) -3-methoxy-8-vinylestra-1, 3,5 (10) -trien-11β-yl] heptanitrile (11b)

The synthesis of (cyanomethyl) trimethylphosphonium iodide is carried out in complete analogy to that in the literature [J. Org. Chem. 2001, 66, 2518-2521] described trimethylphosphine and iodoacetonitrile.

2.42 g (cyanomethyl) trimethylphosphonium iodide are added to a solution of 1 g of alcohol 8 in 18 ml of propionitrile and then 2.1 ml of diisopropylethylamine are added dropwise. The reaction mixture is stirred for 14 hours at 97 ° C. After cooling to room temperature, the mixture with 10 ml of water and 1 ml of conc. Hydrochloric acid added. The phase separation takes place between ethyl acetate / water. The organic phase is washed with water and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatography (cyclohexane / ethyl acetate) gives 480 mg of cyanide 11b as a colorless foam (GC-MS: m / z theor .: 535, practical: 535).

7- [17β- (tert-butyldimethylsilyloxy) -3-methoxy-8-vinylestra-1, 3,5 (10) -trien-11β-yl] heptanal (9c)

A solution of 0.4 ml of diisobutylaluminum hydride in 0.4 ml of toluene is added dropwise at -10 ° C. to a solution of 480 mg of cyanide 11b in 10 ml of toluene. The reaction solution is stirred until complete reaction at -10 ° C, successively with 8 ml of toluene, 3 ml of sat. Sodium bicarbonate solution and 0.3 ml of 2-propanol and stirred for several hours at room temperature. It is then filtered through Celite and the filtrate is concentrated. Column chromatography (cyclohexane / ethyl acetate) gives 361 mg of aldehyde 9c as a colorless foam (GC-MS: m / z theor .: 538, practical: 538). example 1

General © Working instructions for the reaction of aldehydes 9a-c with (perfluoroalkvO-trimethylsilanes and subsequent cleavage of the trimethylsilyl ether with tetrabutylammonium fluoride trihydrate (Schemes 4-5)

To a solution of the corresponding carbonyl compound (1 equiv.) In tetrahydrofuran (2 ml / mmol) is added a catalytic amount of tetrabutylammonium fluoride trihydrate, the solution cooled to -20 ° C and the (perfluoroalkyl) trimethylsilane (15 equiv.) Added dropwise. The cooling bath is removed and the reaction solution is stirred until complete reaction at room temperature. For workup is diluted with diethyl ether, the organic phase with water and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. The resulting trimethylsilyl ether proves to be partially unstable during subsequent purification by column chromatography and is reacted in a mixture with its corresponding alcohol. For this purpose, the mixture is dissolved in tetrahydrofuran (10 ml / mmol), treated at room temperature with tetrabutylammonium fluoride trihydrate (1.5 equiv.) And stirred until complete reaction at room temperature. For workup is diluted with diethyl ether, the organic phase with water and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatographic purification (cyclohexane / ethyl acetate) gives the corresponding perfluoroalkyl-substituted alcohols as colorless foams.

17β-tert-butyldimethylsilyloxy-3-methoxy-11β - [(R / S) -6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene (14a)

900 mg of aldehyde 9a give in the reaction with (trifluoromethyl) trimethylsilane analogous to specification 1.1 804 mg of alcohol 14a as colorless foam (GC-MS: m / z theor .: 580, practical: 580) and mixture of its diastereomers. General procedure for simultaneous cleavage of tert-butyldimethylsilyl and methyl ethers by means of boron trichloride /

Tetrabutylammonium iodide (Schemes 2-8)

To a solution of the corresponding steroid and tetrabutylammonium iodide cooled to -78 ° C (1.5 equiv. Of ether to be cleaved, an additional equiv. For each basic moiety) in dichloromethane (5 ml / mmol) is added an appropriate amount of boron trichloride (1.5 equiv to be cleaved ether, an additional equiv. for each basic grouping). The reaction solution is slowly warmed to 0 ° C and stirred until complete reaction. For workup, the mixture is mixed with ice water and stirred for about 30 minutes, then with sat. Sodium bicarbonate solution and extracted several times with dichloromethane. The combined organic phases are dried with magnesium sulfate and concentrated. The residue obtained is purified by column chromatography to give the corresponding estradiols.

11β - [(R / S) -6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (15a D1 / 2 )

100 mg of steroid 14a result in the reaction analogous to Regulation 1.2 78 mg of a slightly yellow viscous mass which turned out to be 3-methyl ether. Then the 3-methyl ether is dissolved in 2.7 ml of toluene, the solution is cooled to 0 ° C and added dropwise 0.5 ml of diisobutylaluminum hydride. The reaction solution is heated to reflux until complete. For workup, the solution is cooled to 0 ° C and successively ethanol (1 ml), ethanol / water (1: 1, 2 ml), half conc. Hydrochloric acid (2 ml) was added dropwise. The phase separation is carried out between diethyl ether / water and the aqueous phase is extracted several times with diethyl ether. The combined organic phases are washed with water and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatographic purification (cyclohexane / ethyl acetate) gives 62 mg Estratriendiol 15a as a colorless viscous mass (GC-MS: m / z theor .: 452, practical: 452) and mixture of its diastereomers D1 / D2. Diastereomer separation is carried out by means of preparative HPLC (Chiralpak AD 250 × 10, n-heptane / 2-propanol 9/1 v / v, 4.7 ml / min) and gives in each case 16 mg of the two diastereomers 15a D1 ([] _D = 66 °, chloroform) and 15a D2 ([α] _D = 33 °, chloroform).

By X-ray diffraction analysis, the diastereomer 15aD1 was assigned the R configuration and diastereomer 15aD2 the S configuration at the epimeric center. Example 2

17β-tert-butyldimethylsilyloxy-3-ethoxy-11β - [(RS) -7,7,7-trifluoro-6-hydro-sheptyl] -8-vinyl-estra-1,3,5 (10) -triene (14b)

500 mg of aldehyde 9b give in the reaction with (trifluoromethyl) trimethylsilane analogously to Regulation 1.1 292 mg of alcohol 14b as a colorless foam (GC-MS: m / z theor .: 594, practical: 594) and mixture of its diastereomers.

11β - [(R / S) -7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (15b D1 / 2)

In the reaction analogous to procedure 1.2, 90 mg of steroid 14b give 56 mg of estratriene diol 15b as a colorless foam (GC-MS: m / z theor .: 466, practical: 466) and a mixture of its diastereomers D1 / D2. Diastereomer separation is carried out by preparative HPLC (Chiralcel OD 250x51, n-hexane / 2-propanol 9/1 v / v, 100 ml / min) to give 9 mg diastereomer 15b D1 and 7 mg diastereomer 15b D2.

Example 3

17β-tert-butyldimethylsilyloxy-3-methoxy-11β - [(RS) -8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene ( 14c)

360 mg of aldehyde 9c give in the reaction with (trifluoromethyl) trimethylsilane analogous to specification 1.1 370 mg of alcohol 14c as a colorless foam (GC-MS: m / z theor .: 608, practical: 608) and mixture of its diastereomers.

11β - [(RS) -8 _L 8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (15c D1 / 2)

90 mg of steroid 14c give in the reaction analogous to Regulation 1.2 78 mg Estratriendiol 15c as a colorless foam (GC-MS: m / z theor .: 466, practical: 466) and mixture of its diastereomers D1 / 2. Diastereomer separation is carried out by preparative HPLC (Chiralpak AD 250x60, n-hexane / ethanol 95/5 v / v, 80 ml / min) to give 23 mg diastereomer 15c D1 and 17 mg diastereomer 15c D2. Example 4

general procedure for the oxidation of the trifluoroethyl-substituted alcohols (Scheme 4)

To a suspension of Dess-Martin periodinane (6 equiv.) In dichloromethane (5 ml / mmol) is added dropwise at room temperature a solution of the corresponding alcohol (1 equiv.) In dichloromethane (15 ml / mmol) and stirred until complete , Subsequently, the reaction mixture is mixed with water and stirred for about 30 min. The phase separation is carried out between diethyl ether / water and the aqueous phase is extracted several times with diethyl ether. The combined organic phases are washed with sat. Sodium thiosulfate, sat. Sodium bicarbonate solution, water and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatographic purification (cyclohexane / ethyl acetate) gives the corresponding ketones.

6- [17β- (tert -butyldimethylsilyloxy) -3-methoxy-8-vinylestra-1, 3,5 (0) -trien-11β-yl] -1,1,1-trifluorohexan-2-one (16a )

312 mg of alcohol 14a give in the reaction analogous to regulation 4.1 252 mg of ketone 16a as a yellow viscous mass (GC-MS: m / z theor .: 578, practical: 578).

17β-tert-butyldimethylsilyloxy-3-methoxy-11β- [6,6,6-trifluoro-5-trifluoromethyl-5- (trimethylsilyloxy) hexyl] -8-vinyl-estra-1, 3,5 (10) -trien (17a)

200 mg of alcohol 16a give in the reaction with (trifluoromethyl) trimethylsilane analogous to regulation 1.1 200 mg of the column-chromatographically stable trimethylsilyl ether 17a as a pale yellow viscous mass (GC-MS: m / z theor .: 720, practical: 720). This is used in the next step without carrying out the reaction with tetrabutylammonium fluoride trihydrate. 11ß- [6,6,6-trifluoro-5-hydroxy-5- (trifluoromethyl) ^j he yl] -8-vinyl-estra-1, 3,5 (10) -triene-3,1-diol ß (18a )

200 mg of steroid 17a give in the reaction analogous to Regulation 1.2 19 mg Estratriendiol 18a as a colorless foam (GC-MS: m / z theor .: 520, practical: 520) together with 46 mg of the by-produced unreacted trimethylsilyl ether, which by reaction with Tetrabutylammonium fluoride trihydrate in tetrahydrofuran (see procedure 1.1 / trimethylsilyl ether cleavage) is converted into compound 18a (33 mg).

Example 5

7- [17β- (tert -butyldimethylsilyloxy) -3-methoxy-8-vinylestra-1,3,5 (10) -trien-11β-yl] -1,1,1-trifluoroheptan-2-one (16b )

182 mg of alcohol 14b give in the reaction analogous to Regulation 4.1 131 mg of ketone 16b as a yellow viscous mass (GC-MS: m / z theor .: 592, practical: 592).

17β-tert-butyldimethylsilyloxy-3-methoxy-11β- [7,7,7-trifluoro-6-trifluoromethyl-6- (trirnethylsyloxy) heptyl] -8-vinyl-estra-1, 3,5 (10) -tria (17b)

131 mg of alcohol 16b give, in the reaction with (trifluoromethyl) -trimethylsilane analogous to specification 1.1,162 mg of trimethylsilyl ether 17b as a yellow viscous mass (GC-MS: m / z theor .: 734, practical: 734). This is used in the next step without carrying out the reaction with tetrabutylammonium fluoride trihydrate.

11β-ϊ7,7,7-trifluoro-6-hydroxy-6- (trifluoromethyl) heptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (18b)

161 mg steroid 17b give in the reaction analogous to regulation 1.2 57 mg of the unreacted trimethylsilyl ether. 37 mg of the trimethylsilyl ether give in the reaction with tetrabutylammonium fluoride trihydrate in tetrahydrofuran (cf regulation 1.1 / trimethylsilyl ether cleavage) 20 mg of estratriene diol 18b as a colorless foam (GC-MS: m / z theor .: 534, practical: 534). Example 6

8- [17β- (tert -butyldimethylsilyloxy) -3-methoxy-8-yinylestra-1, 3,5 (10) -trien-11β-yl] -1,1,1-trifluoro-octan-2-one ( 16c)

200 mg of alcohol 14c give in the reaction analogous to Regulation 4.1 138 mg of ketone 16c as a yellow viscous mass (GC-MS: m / z theor .: 606, practical: 606).

17β-tert-butyldimethylsilyloxy-3-methoxy-11β- [8,8,8-trifluoro-7-trifluoromethyl-7- (trimethylsiloxy) octyl] -8-vinyl-estra-1, 3,5 (10) - triennial (17c)

135 mg of alcohol 16c give in the reaction with (trifluoromethyl) trimethylsilane analogous to specification 1.1 159 mg of trimethylsilyl ether 17c as a yellow viscous mass (GC-MS: m / z theor .: 748, practical: 748). This is used in the next step without carrying out the reaction with tetrabutylammonium fluoride trihydrate.

11β- [8,8,8-Trifluoro-7-hydroxy-7- (trifluoromethyl) octyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (18c )

155 mg of steroid 17c give, in the reaction analogous to procedure 1.2, 57 mg of the unreacted trimethylsilyl ether which, in the reaction with tetrabutylammonium fluoride trihydrate in tetrahydrofuran (cf., regulation 1.1 / trimethylsilyl ether cleavage), contains 45 mg of estratriene diol 18c as a colorless foam (GC-MS: m / z theor .: 548, practical: 548).

Example 7

General procedure for the reaction of aldehydes 9a-b with pentafluoroethyllithium (Scheme 5)

To a 1M solution of pentafluoroethyl iodide (10 equiv with respect to carbonyl compound) in tetrahydrofuran is added dropwise nButyllithium (1.6M in hexanes, 1 equiv.) At -78 ° C and the solution is stirred at -78 ° C for 1 hour. Subsequently, a solution of the corresponding carbonyl compound in tetrahydrofuran (5 ml / mmol) is added dropwise at this temperature. The reaction solution is slowly warmed and stirred until complete conversion. For workup, the reaction solution with ioo Δmmnπii nei inn πnH mohrmalc with PYtrnhiört The combined organic phases are washed with water and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatographic purification (cyclohexane / ethyl acetate) gives the corresponding pentafluoroethyl-substituted alcohols.

1β-tert-butyldimethylsilyloxy-3-methoxy-11β - [(RS) -7,7,7,6,6-pentafluoro-5-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10 ) -trien (19a)

55 mg of aldehyde 9a give in the reaction analogous to Regulation 7.1 61 mg of alcohol 19a as a colorless foam (GC-MS: m / z theor .: 630, practical: 630) and mixture of its diastereomers.

11β - [(R / S) -7,7,7,6,6-pentafluoro-5-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (20a D1 / 2)

60 mg steroid 19a give in the reaction analogous to 1.2 1.2 26 mg Estratriendiol 20a D1 / 2 as a colorless foam (GC-MS: m / z theor .: 502, practical: 502) and mixture of its diastereomers.

Example 8

17β-tert-butyldimethyl isilyloxy-3-methoxy-11β - [(R / S) -8,8,8,7,7-pentafluoro-6-hydroxyoctyl] -8-vinyl-estra-1, 3.5 (10) -tria (19b)

45 mg of aldehyde 9b give in the reaction analogous to Regulation 7.1 47 mg of alcohol 19b as a colorless foam (GC-MS: m / z theor .: 644, practical: 644) and mixture of its diastereomers.

11β - [(R / S) -8,8,8,7,7-pentafluoro-6-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (20b D1 / 2)

45 mg of steroid 19b give in the reaction analogous to Regulation 1.2 16 mg Estratriendiol 20b D1 / 2 as a colorless foam (GC-MS: m / z theor .: 516, practical: 516) and mixture of its diastereomers. Example 9

1β-tert-butyldimethylsilyloxy-11β - [(R / S) -8,8,8,7,7,6,6-heptafluoro-5-trimethylisilyloxyoctyl] -3-methoxy-8-vinyl-estrone 1, 3.5 (10) -tria (21 a)

60 mg of aldehyde 9a give in the reaction with (heptafluoropropyl) -trimethylsilane analogous to specification 1.1 81 mg of the stable trimethylsilyl ether 21a as colorless foam (GC-MS: m / z theor .: 752, practical: 752) and mixture of its diastereomers. This is used in the next step without carrying out the reaction with tetrabutylammonium fluoride trihydrate.

11β - [(RS) -8,8,8,7,7,6,6-heptafluoro-5-hydroxyoctyl] -8-vinyl-estra-1, 3,5 (10) -triene-3,17β- diol (22a D1 / 2)

80 mg steroid 21a give in the reaction analogous to 1.2 1.2 27 mg Estratriendiol 22a D1 / 2 as a colorless foam (GC-MS: m / z theor .: 552, practical: 552) and mixture of its diastereomers.

Example 10

17β-tert-butyldimethylsilyloxy-11β - [(R / S) -9,9,9,8,8,7,7-heptafluoro-6-trimethylsilyloxynonyl] -3-methoxy-8-vinyI-estra-1, 3.5 (10) -tria (21b)

70 mg of aldehyde 9b give in the reaction with (heptafluoropropyl) trimethylsilane analogous to specification 1.1 94 mg of the stable trimethylsilyl ether 21b as a colorless foam (GC-MS: m / z theor .: 766, practical: 766) and mixture of its diastereomers. This is used in the next step without carrying out the reaction with tetrabutylammonium fluoride trihydrate.

11β - [(R / S) -9,9,9,8,8,7,7-heptafluoro-6-hydroxynonyl] -8-vinyl-estra-1, 3,5 (10) -triene-3, 17β-diol (22b D1 / 2)

94 mg steroid 21b give in the reaction analogous to 1.2 1.2 mg Estratriendiol 22b D1 / 2 as a colorless foam (GC-MS: m / z theor .: 566, practical: 566) and mixture of its diastereomers. Example 11

17β-tert-Bufyldimethylsilyloxy-3-methyl-11β - [(R / S) -7,7,6-trifluoro-5-trimethylsilyloxyhept-6-enyl] -8-vinyI-estra-1,3 , 5 (10) -tria (23a)

The synthesis of 1, 1, 2-trifluoro-2-trimethylsilylethylene is carried out in complete analogy to that in the literature [J. Fluorine Chem. 2003, 121, 75-77] described procedure of 1-bromo-1, 2,2-trifluoroethene, zinc and trimethylsilyl chloride. 60 mg of aldehyde 9a give in the reaction with 1, 1, 2-trifluoro-2-trimethylsilylethylene analogous to Regulation 1.1 77 mg of trimethylsilyl ether 23a as a colorless foam (GC-MS: m / z theor .: 664, practical: 664) and mixture its diastereomers. This is used without further purification in the next stage.

11β - [(R 7 S) -7,7,6-trifluoro-5-hydroxyhept-6-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (24a D1 / 2)

0.16 ml of 10% hydrochloric acid are added at room temperature to a solution of 77 mg of silyl ether 23a in 4 ml of acetone. The reaction solution is stirred until complete reaction at room temperature and washed with sat. Sodium bicarbonate solution. The phase separation takes place between ethyl acetate / water. The organic phase is washed with sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. The residue thus obtained is filtered through silica gel (cyclohexane / ethyl acetate) and concentrated again. The colorless foam obtained is dissolved in 1 ml of toluene, added dropwise at 0 ° C 0.15 ml of diisobutylaluminum hydride and the reaction solution heated to reflux until complete. After cooling to 0 ° C, the reaction mixture is successively with 0.5 ml of ethanol, 0.5 ml of ethanol / water (1: 1) and 0.5 ml semicon. Hydrochloric acid and stirred for about 30 minutes. The phase separation takes place between diethyl ether / water. The organic phase is washed with sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatography (cyclohexane / ethyl acetate) gives 14 mg Estratriendiol 24a D1 / 2 as a colorless foam (GC-MS: m / z theor .: 464, practical: 464) and mixture of its diastereomers. Example 12

17-tert - ButyldimethylsMyIo. y-3-methoxy-yl-11β - [(/ S) -8,8,7-trifluoro-6-trimethylsilyloxyoct-7-enyl] -8-vinyl-estra-1,3,5 (10) -triene (23b)

80 mg of aldehyde 9b give in the reaction with 1, 1, 2, -Trifluor-2-trimethylsilylethylene analogous to Regulation 1.1 95 mg of trimethylsilyl ether 23b as a colorless foam (GC-MS: m / z theor .: 678, practical: 678) and Mixture of its diastereomers. This is used without further purification in the next stage.

11β - [(R / S) -8,8,7-trifluoro-6-hydroxyoct-7-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (24b D1 / 2)

95 mg of aldehyde 23b give in the reaction analogous to Regulation 11.2 22 mg of trimethylsilyl ether 24b D1 / 2 as a colorless foam (GC-MS: m / z theor .: 478, practical: 478) and mixture of its diastereomers.

Example 13

General working instructions for the reaction of an aldehyde or ketone with methyllithium

To a cooled to -78 ° C solution of the corresponding carbonyl compound (1 equiv.) In tetrahydrofuran (10 ml / mmol) is added an excess of methyllithium (5-10 equiv., 1.6M in diethyl ether) is added dropwise and the reaction solution until complete reaction at stirred at this temperature. For workup, the reaction solution with sat. Ammonium chloride solution / water / diethyl ether, the organic phase with water and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatographic purification (cyclohexane / ethyl acetate) gives the corresponding methyl-substituted alcohols as colorless foams.

17β-tert-butyldimethylsilyloxy-11β - [(R / S) -5-hydroxyhexyl] -3-methoxy-8-vinyl-estra-1,3,5 (10) -triene (25a)

200 mg of aldehyde 9a give in the reaction analogous to Rule 13.1 120 mg of alcohol 25a as a colorless foam (GC-MS: m / z theor .: 526, practical: 526) and mixture of its diastereomers. 11β-ϊ (R / S) -5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,1β-diol (26a D1 / 2)

25 mg steroid 25a give in the reaction analogous to 1.2 1.2 mg Estratriendiol 26a D1 / 2 as a colorless foam (GC-MS: m / z theor .: 398, practical: 398) and mixture of its diastereomers.

Example 14

17β-tert-butyldimethylsilyloxy-11β - [(R / S) -6-hydroxyheptyl] -3-methoxy-8-vinyl-estra-1,3,5 (10) -triene (25b)

155 mg of aldehyde 9b give in the reaction analogous to Rule 13.1 100 mg of alcohol 25b as a colorless foam (GC-MS: m / z theor .: 540, practical: 540) and mixture of its diastereomers.

11β - [(R / S) -6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (26b D1 / 2)

25 mg steroid 25b give in the reaction analogous to 1.2 1.2 10 mg Estratriendiol 26b D1 / 2 as a colorless foam (GC-MS: m / z theor .: 412, practical: 412) and mixture of its diastereomers.

Example 15

6- [17β- (tert -butyldimethylsilyloxy) -3-methoxy-8-vinylestra-1, 3,5 (10) -triene-11β-yl] -hexan-2-one (27a)

58 mg of pyridinium chlorochromate and 58 mg of Celite are initially charged in 0.5 ml of dichloromethane, a solution of 95 mg of alcohol 25a in 0.9 ml of dichloromethane is added dropwise and the reaction mixture is stirred at room temperature until complete reaction. The reaction mixture is then filtered through Celite and silica gel, and the filtrate is concentrated. This gives 81 mg of ketone 27a as a light yellow, viscous mass (GC-MS: m / z theor .: 524, practical: 524), which is used without further purification in the subsequent reaction. 17β-tert-butyldimethylsilyloxy-3-methoxy-11β-ϊ5-methyl-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene (28a)

75 mg of ketone 27a give in the reaction analogous to Regulation 13.1 45 mg of alcohol 28a as a colorless foam (GC-MS: m / z theor .: 540, practical: 540).

11β- [5-methyl-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (29a)

40 mg steroid 28a give in the reaction analogous to Regulation 1.2 22 mg Estratriendiol 29a as a colorless foam (GC-MS: m / z theor .: 412, practical: 412).

Example 16

7- [17β- (tert -butyldimethylsilyloxy) -3-methoxy-8-vinylestra-1,3,5 (10) -trien-11β-yl] -heptan-2-one (27b)

70 mg of alcohol 25b give in the reaction analogous to Regulation 15.1 56 mg of ketone 27b as a yellow foam (GC-MS: m / z theor .: 538, practical: 538), which is used without further purification in the subsequent reaction.

17β-tert-butyldimethylsilyloxy-3-methoxy-11β- [6-methyl-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene (28b)

53 mg of ketone 27b give in the reaction analogous to Regulation 13.1 30 mg of alcohol 28b as a colorless foam (GC-MS: m / z theor .: 554, practical: 554).

11β- [6-methyl-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (29b)

26 mg steroid 28b give in the reaction analogous to Regulation 1.2 9 mg Estratriendiol 29b as a colorless foam (GC-MS: m / z theor .: 426, practical: 426).

Example 17

11β- (5-bromopentyl) -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (30a)

1.55 g of steroid 10 result in the reaction analogous to specification 1.2 836 mg Estratriendiol 30a as a colorless foam (GC-MS: m / z theor .: 446, practical: 446). General working procedure for the introduction of an aminoganga

(Scheme 7)

An appropriate amount of bromide is dissolved in N, N-dimethylformamide (5 ml / mmol), treated with an excess of the corresponding amine and stirred at room temperature (optionally at 40 ° C) until complete reaction. The phase separation is carried out between ethyl acetate / water and the aqueous phase is extracted several times with ethyl acetate. The organic phase is washed with water and sat. Washed with sodium chloride solution, dried with magnesium sulfate and concentrated. The column chromatographic purification is carried out on silica gel with an ethyl acetate / methanol mixture as eluent and gives the corresponding amines.

11β- [5- (methylamino) pentyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol (31a)

258 mg of bromide 30a give in the reaction with methylamine (40% in water, 2 ml / mmol) analogously to Regulation 17.2 161 mg of amine 31a as a colorless solid (GC-MS: m / z theor .: 397, practical: 397).

Example 18

11β- [5- (dimethylamino) pentyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol (32a)

30 mg of bromide 30a give in the reaction with dimethylamine (2M in tetrahydrofuran, 10 equivalents) analogous to Regulation 17.2 12 mg of amine 32a as a colorless foam (GC-MS: m / z theor .: 411, practical: 411).

Example 19

11β- [5- (pyrrolidin-1-yl) pentyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol (33a)

30 mg of bromide 30a give in the reaction with pyrrolidine (10 equivalents) analogous to Regulation 17.2 23 mg of amine 33a as a colorless foam (GC-MS: m / z theor .: 437, practical: 437). Example 20

11β- [5- (1-piperidyl) pentyl] -8-vinylestra-1, 3,5 (10) -riene-3,1β-diol (34a)

50 mg of bromide 30a give in the reaction with piperidine (10 equivalents) analogously to Regulation 17.2 41 mg of amine 34a as a colorless foam (GC-MS: m / z theor .: 451, practical: 451).

Example 21

11β- (5-morpholinopentyl) -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol (35a)

30 mg of bromide 30a give in the reaction with morpholine (10 equivalents) analogously to Regulation 17.2 10 mg of amine 35a as a colorless foam (GC-MS: m / z theor .: 453, practical: 453).

Example 22

General procedure for introducing a polyfluorinated alkyl chain into amines 31a-b (Scheme 7)

An appropriate amount of amine is dissolved in N, N-dimethylformamide (5 ml / mmol), a solution of the corresponding tosylate (1.5 equivalents) in N, N-dimethylformamide (5 ml / mmol) added dropwise and 20 equivalents of sodium carbonate added. Subsequently, the reaction mixture is stirred for 8 hours at 40.degree. For workup, a phase separation between ethyl acetate / water and the aqueous phase is extracted several times with ethyl acetate. The organic phase is washed with water and sat. Washed with sodium chloride solution, dried with magnesium sulfate and concentrated. The column chromatographic purification is carried out on silica gel with a chloroform / methanol mixture as eluent and results in unreacted starting material, the corresponding tertiary amines. 11β- {5- [methyl (8,8,9,9,9-pentafluoronyl) amino] pentyl} -8-vinylestra-1, 3,5 (10) -triene-3,1β-diol (36a )

32 mg of amine 31a give in the reaction with 8,8,9,9,9-Pentafluornonyltosylat analogous to Regulation 22.1 16 mg of amine 36a as colorless crystals (GC-MS: m / z theor .: 613, practical: 613).

Example 23

11β- {5 - [(7,7,8,8,9,9,9-Heptafluorononyl) methylamino] pentyl} -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol (37a )

31 mg of amine 31a give in the reaction with 7,7,8,8,9, 9,9-Heptafluornonyltosylat analogous to Regulation 22.1 22 mg amine 37a as colorless crystals (GC-MS: m / z theor .: 649, practical: 649).

Example 24

General procedure for the acylation of amines 31a-b (Scheme 7)

An appropriate amount of amine is dissolved in ethanol (5 ml / mmol), a solution of the N-succinimide ester of the corresponding carboxylic acid (2 equivalents) in ethanol (5 ml / mmol) added dropwise and 4 equivalents of sodium bicarbonate added. Subsequently, the reaction mixture is stirred until complete conversion at room temperature. For workup, a phase separation between ethyl acetate / water and the aqueous phase is extracted several times with ethyl acetate. The organic phase is dried with magnesium sulfate and concentrated. The column-chromatographic purification is carried out on silica gel with a cyclohexane / ethyl acetate mixture as eluent and gives the corresponding amides.

11β- {5- [ethyl (octanoyl) amino] pentyl} -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (38a)

9 mg of amine 31a gives, in the reaction with octanoic acid N-succinimidyl ester analogous to procedure 24.1, 10 mg of amine 38a as colorless crystals [LC-MS: m / z theor .: 523, practical: 524 (M + H) ⁺ ]. Example 25

11β- (6-chlorohexyl) -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (30b)

975 mg of steroid 13 result in the reaction analogous to 1.2 1.224 mg of a colorless foam which, in addition to the chlorine compound (GC-MS: 81%, m / z theor .: 416, practical: 416), the corresponding bromine compound (GC-MS: 17%, m / z theor .: 460, practical: 460).

11β- [6- (methylamino) hexyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol (31b)

155 mg of product mixture 30b give in the reaction with methylamine (40% in water, 3 ml / mmol) with the addition of sodium carbonate analogously to Regulation 17.2 152 mg of amine 31b as a colorless solid (GC-MS: m / z theor .: 411, practical: 411).

Example 26

11β- [6- (dimethylamino) hexyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol (32b)

33 mg of mixture 30b give in the reaction with dimethylamine (2M in tetrahydrofuran, 10 equivalents) with the addition of sodium carbonate analogously to Regulation 17.2 30 mg of amine 32b as a colorless foam (GC-MS: m / z theor .: 425, practical: 425) ,

Example 27

11β- [6- (pyrrolidin-1-yl) hexyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol (33b)

32 mg of mixture 30b give in the reaction with pyrrolidine (10 equivalents) with addition of sodium carbonate analogous to Regulation 17.2 33 mg of amine 33b as a colorless foam (GC-MS: m / z theor .: 451, practical: 451). Example 28

11β- [6- (1-piperidyl) hexyl] -8-vinylestra-1, 3,5 (10) -triene-3,1β-diol (34b)

34 mg of mixture 30b give in the reaction with piperidine (10 equivalents) with addition of sodium carbonate analogous to Regulation 17.2 40 mg of amine 34b 'as a colorless foam (GC-MS: m / z theor .: 465, practical: 465).

Example 29

11β- (6-Morpholinohexyl) -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol (35b)

32 mg of mixture 30b give in the reaction with morpholine (10 equivalents) with addition of sodium carbonate analogous to Regulation 17.2 32 mg of amine 35b as a colorless foam (GC-MS: m / z theor .: 467, practical: 467).

Example 30

11β- {6- [methyl (8,8,9,9,9-pentafluoronyl) amino] hexyl} -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol (36b)

39 mg of amine 31b give in the reaction with 8,8,9,9,9-Pentafluomonyltosylat analogous to Regulation 22.1 22 mg of amine 36b as a colorless foam (GC-MS: m / z theor .: 627, practical: 627).

Example 31

11β- {6 - [(7,7,8,8,9,9,9-Heptafluorononyl) methylamino] hexyl} -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol ( 37b)

39 mg of amine 31b give in the reaction with 7,7,8,8,9,9,9-heptafluomonyl tosylate analogous to Regulation 22.1 21 mg of amine 37b as a colorless foam (GC-MS: m / z theor .: 663, practical: 663 ). Example 32

11β- {6-pethyl (ocanoyl) amino] hexyl} -8-vinyl-estra-1,3,5 (10) -triene-3,1β-diol (38b)

10 mg of amine 31b give, in the reaction with octanoic acid N-succinimidyl ester analogous to Regulation 24.1, 10 mg of amine 38b as colorless crystals [LC-MS: m / z theor .: 537, practical: 538 (M + H) ⁺ ].

Example 33

General Procedure for the Oxidation of Aldehydes 9a-b (Scheme 8)

An appropriate amount of aldehyde is dissolved in tert-butanol (5 ml / mmol). 2-Methylbut-2-ene (1 ml / mmol) and a solution of sodium chlorite (1.1 equiv.) And sodium dihydrogen phosphate dihydrate (1.1 equiv.) In water (1 ml / mmol) are added dropwise in succession. Subsequently, the reaction mixture is stirred until complete conversion at room temperature. For workup, a phase separation between diethyl ether / water, the aqueous phase is adjusted to pH ~ 2 with 5% hydrochloric acid, saturated with sodium chloride and extracted several times with diethyl ether. The organic phase is washed with water and sat. Washed sodium chloride solution, dried over magnesium sulfate and concentrated. The column-chromatographic purification is carried out on silica gel with a cyclohexane / ethyl acetate mixture as eluent and gives the corresponding carboxylic acids.

5- [17β- (tert-butyldimethylsilyloxy) -3-methoxy-8-vinylestra-1, 3,5 (10) -trien-11β-yl] valeric acid (39a)

195 mg of aldehyde 9a give in the reaction analogous to procedure 33.1 136 mg of carboxylic acid 39a as colorless crystals [LC-MS: m / z theor .: 526, practical: 527 (M + H) ⁺ j. General procedure for the conversion of the carboxylic acids 39a-b into the amides 40a-b (Scheme 8)

An appropriate amount of carboxylic acid is dissolved in dichloromethane (10 ml / mmol) and cooled to -10 ° C. N-methylmorpholine (4 equiv.), Isobutylchloroformate (4 equiv.) And, after a further 30 minutes, n-butylmethylamine (6 equiv.) Are added dropwise in succession. Subsequently, the reaction mixture is stirred until complete conversion at room temperature. For workup, a phase separation between dichloromethane / sat. Sodium bicarbonate solution. The aqueous phase is extracted several times with dichloromethane, the combined organic phases with sat. Washed sodium chloride solution, dried over magnesium sulfate and concentrated. The column-chromatographic purification is carried out on silica gel with a cyclohexane / ethyl acetate mixture as eluent and gives the corresponding amides.

N-n-butyl-N-methyl-5- [17β- (tert-butyldimethylsilyloxy) -3-methoxy-8-vinylestra-1, 3,5 (10) -triene-11β-yl] valeramide (40a)

130 mg of carboxylic acid 39a in the reaction analogous to procedure 33.2 give 81 mg of amide 40a as a colorless foam [LC-MS: m / z theor .: 595, practical: 596 (M + H) "].

N-n-butyl-N-methyl-5- [3,17β-dihydroxy-8-vinylestra-1, 3,5 (10) -triene-11β-yl] valeramide (41a)

80 mg of amide 40a give in the reaction analogous to 1.2 1.2 31 mg Estratriendiol 41a as a colorless foam [LC-MS: m / z theor .: 467, practical: 468 (M + H) ⁺ ].

Example 34

6- [17β- (tert-butyldimethylsilyloxy) -3-methoxy-8-vinylestra-1, 3,5 (10) -triene-11β-yl] caproic acid (39b)

150 mg of aldehyde 9b give in the reaction analogous to procedure 33.1 108 mg of carboxylic acid 39b as colorless crystals [LC-MS: m / z theor .: 540, practical: 541 (M + H) ⁺ ]. N-n-butyl-N-methyl-6- [17β- (tert-butyldimethylsilyloxy) -3-methoxy-8-vinylestra-1, 3,5 (10) -triene-11β-yl3capronamide (40b)

In the reaction analogous to procedure 33.2, 105 mg of carboxylic acid 39b give 63 mg of amide 40b as a colorless foam [LC-MS: m / z theor .: 609, practical: 610 (M + H) ⁺ ].

N-n-butyl-N-methyl-6- [3,17β-dihydroxy-8-vinylestra-1, 3,5 (10) -triene-11β-yl] capronamide (41b)

60 mg of amide 40b give in the reaction analogous to procedure 1.2 28 mg Estratriendiol 41b as a colorless foam [LC-MS: m / z theor .: 481, practical: 482 (M + H) ⁺ j.

Example 35

11β- (5-thiocyanatopentyl) -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol (42) (Scheme 7)

8.4 mg of potassium thiocyanate and 32 mg of tetrabutylammonium iodide are added in succession to a solution of 13 mg of bromide 30a in 0.3 ml of N, N-dimethylformamide, and the reaction solution is subsequently stirred until complete reaction. For working up, a phase separation by means of ethyl acetate / water and the aqueous phase is extracted several times with ethyl acetate. The organic phase is washed with water and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography (cyclohexane / ethyl acetate) and gives 9 mg of rhodanide 42 as a colorless foam [LC-MS: m / z theor .: 425, practical: 426 (M + H) ⁺ ].

Example 36

6- [3,17β-Dihydroxy-8-vinylestra-1, 3,5 (10) -triene-11β-yl] capronitrile (43a) (Scheme 2)

16 mg of steroid 11a give in the reaction analogous to Regulation 1.2 7 mg estratriendiol 43a as a colorless foam (GC-MS: m / z theor .: 393, practical: 393). Example 37

7- [3,17β-Dlhydroxy-8-vinylestra-1,3,5 (10) -trien-11β-yl] heponitrile (43b)

22 mg of steroid 11b give in the reaction analogous to Regulation 1.2 12 mg Estratriendiol 43b as a colorless foam (GC-MS: m / z theor .: 407, practical: 407).

Example 38

General procedure for Oppenauer oxidation of 17ß-hydroxy group

To a solution of the corresponding alcohol (1 equiv.) In toluene (20 ml / mmol) is added sequentially cyclohexanone (50 equiv.) And aluminum isopropylate (10 equiv.). The reaction solution is then heated to reflux until complete. For workup, the reaction solution is acidified at room temperature with 1 N hydrochloric acid and the phases are separated by means of diethyl ether / water. The organic phase is washed with water and sat. Washed sodium chloride solution, dried over magnesium sulfate, the diethyl ether and toluene removed on a vacuum rotary evaporator and the remaining amount of solvent distilled off azeotropically with water. The residue thus obtained is purified by column chromatography (cyclohexane / ethyl acetate) and the corresponding 17-ketones are obtained.

3-Hydroxy-11β - [(R) -6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-17-one (44a D1)

50 mg of alcohol 15a D1 give in the reaction analogous to Regulation 38.1 40 mg of ketone 44a D1 as a colorless foam (GC-MS: m / z theor .: 450, practical: 450).

17α-Methyl-11β - [(R) -6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (45a D1)

39 mg of ketone 44a D1 give in the reaction analogous to procedure 13.1 30 mg of alcohol 45a D1 as a colorless foam (GC-MS: m / z theor .: 466, practical: 466). Example 39

3-Hydroyl-11β - [(S) -6,6,6-trifluoro-5-hydrox yhexyl] -8-vinyl-estra-1,3,5 (10) -trien-17-one (44a D2)

50 mg of alcohol 15a D2 give in the reaction analogous to Regulation 38.1 42 mg of ketone 44a D2 as a colorless foam (GC-MS: m / z theor .: 450, practical: 450).

17α-Wiethyl-11β - [(S) -6,6, ^β- trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (45a D2)

28 mg of ketone 44a D2 give in the reaction analogous to Regulation 13.1 19 mg of alcohol

45a D2 as a colorless foam (GC-MS: m / z theor .: 466, practical: 466).

Example 40

3-hydroxy-11β- (7,7,7-trifluoro-6-hydroxyheptyl) -8-vinyl-estra-1,3,5 (10) -trien-17-one

(44b D1)

35 mg of alcohol 15b D1 give in the reaction analogous to Regulation 38.1 27 mg of ketone 44b D1 as a colorless foam (GC-MS: m / z theor .: 464, practical: 464).

17α-methyl-11β- (7,7,7-trifluoro-6-hydroxyheptyl) -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (45b D1)

25 mg of ketone 44b D1 give in the reaction analogous to Regulation 13.1 20 mg of alcohol 45b D1 as a colorless foam (GC-MS: m / z theor .: 480, practical: 480). Example 41

3-Hydroxy-11β- (7,7,7-trifluoro-6-hydroxyheptyl) -8-vinyl-estra-1,3,5 (10) -trien-17-one (44b D2)

35 mg of alcohol 15b D2 give in the reaction analogous to Regulation 38.1 25 mg of ketone 44b D2 as a colorless foam (GC-MS: m / z theor .: 464, practical: 464).

17α-Methyl-11β- (7,7,7-trifluoro-6-hydroxyheptyl) -8-vinyl-estra-1,3,5 (10) -triene-3,1β-diol (45b D2)

23 mg of ketone 44b D2 give in the reaction analogous to Regulation 13.1 18 mg of alcohol

45b D2 as colorless foam (GC-MS: m / z theor .: 480, practical: 480).

Claims

claims

Compounds of the general formula

wherein

R ^{3 is} a group R ¹⁹ -O-, R ²⁰ SO ₂ -O-, -OC (O) R ²¹ ; 3, 4, 5

X is a group of the formula II

wherein

Z and W are independently R ¹⁹ , or

Z and W together represent an oxygen atom,

Y -OR ^ιa, -CN, -SCN, a halogen atom, R ^υ, R ^'u SO ₂ -O-; or YR ⁹ or R ²⁰ when Z and W together represent an oxygen atom;

R and R together represent an oxygen atom, a group = -C / -Rθ23 R _D2 wherein

R ²³ and R ²⁴ independently represent a hydrogen atom or a halogen;

or

R ^{17 is} hydrogen, -OR ¹⁹ or halogen;

R ^{17 '} R ¹⁹ , -OR ¹⁹ , halogen, R ² ° SO ₂ -O-, -C (O) R ²¹ or

-OC (O) R ²¹ ;

R ^{19 is} a hydrogen atom, a radical of the formula C _p F _q H _r with p = 1, 2, 3, 4, 5, 6, 7, 8, 9; q> 1 and q + r = 2p + 1; an unbranched d-Cs-alkyl group or branched C ₃ -C ₆ -alkyl group, an optionally substituted with a phenyl radical C ₃ -C ₆ -cycloalkyl group, a (Cs-Ce-Cycloalky -C ^ C ^ alkylene group, a branched or unbranched C ₂ -C ₅ alkenyl group, a C ₂ -C ₅ alkynyl group, or an unsubstituted or substituted aryl, heteroaryl, heterocyclyl, Heteroaryl-C 1 -C ₄ -alkylene group;

R ^{20 is} an R ²¹ R ²² N group; a group -C (NOR ⁹ ) H, or a group of general formula III

wherein

V is -CH ₂ -, an oxygen atom or a sulfur atom, or = NR ²⁵ ; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; o 0, 1,

2, 3, 4, 5, 6, 7 or 8, the sum of which is m + o 2,

3, 4, 5, 6, 7, 8, 9, 10, 11, 12; R ²¹ and R ^{22 are} independently R ¹⁹ ;

.21

R ^Zb R, R ^Λ SO ₂ - or an acyl group -C (O) R

represent.

Compounds of general formula I according to claim 1, characterized in that Y = -OH, -CN, -SCN, a halogen, or R ²⁰ means.

Compounds of general formula I according to claim 1, characterized in that Y = R ²⁰ , when Z and W together represent an oxygen atom.

4. Compounds of general formula I according to claim 1, characterized in that

Y is -OH, -CN, -SCN, a halogen atom, or R ²⁰ ; and

R ¹⁷ and R ^{17 '} together represent an oxygen atom, or

R ^{17 is} hydrogen, -OH;

R ^{17 'represents} hydrogen, -OH, dC ^ allyl group, C ₂ -C ₅ alkenyl group, a C ₂ -C ₅ alkynyl group, or a trifluoromethyl group.

5. Compounds of general formula I according to claim 1, characterized in that YR ²⁰ , when Z and W together represent an oxygen atom, and R ¹⁷ and R ^{17 '} together represent an oxygen atom, or

R ^{17 is} hydrogen, -OH;

R ^{17 'represents} hydrogen, -OH, C ₁ -C ₄ alkyl group, C ₂ -C ₅ alkenyl group, a C ₂ -C ₅ alkynyl group, or a trifluoromethyl group.

6. Compounds according to claim 1, namely

11β - [(R) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 1),

11β - [(S) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1), 11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

11β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol,

(Diastereomer 1),

11β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2),

11β- [6,6,6-trifluoro-5-hydroxy-5- (trifluoromethyl) hexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol,

11β- [7,7,7-trifluoro-6-hydroxy-6- (trifluoromethyl) heptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol, 11β- [8,8,8-trifluoro-7-hydroxy-7- (trifluoromethyl) octyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

11β- [7,7,7,6,6-pentafluoro-5-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

1, 1β- [7,7,7,6,6-pentafluoro-5-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2),

11β- [8,8,8,7,7-pentafluoro-6-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

11β- [8,8,8,7,7-pentafluoro-6-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2), 11β- [9,9,9,8,8-pentafluoro-7-hydroxynonyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

11β- [9,9,9,8,8-pentafluoro-7-hydroxynonyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2), 11β- [8,8,8,7,7,6,6-heptafluoro-5-hydroxyoctyi] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

11β- [8,8,8,7,7,6,6-heptafluoro-5-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

11β- [9,9,9,8,8,7,7-heptafluoro-6-hydroxynonyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

11β- [9,9,9,8,8,7,7-heptafluoro-6-hydroxynonyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2)

11β- [10,10,10,9,9,8,8-heptafluoro-7-hydroxydecyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

11β- [10,10,10,9,9,8,8-heptafluoro-7-hydroxydecyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

11β- (5-bromopentyl) -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol,

11β- [5- (methylamino) pentyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- [5- (dimethylamino) pentyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- [5- (pyrrolidin-1-yl) pentyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- [5- (1-piperidyl) pentyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- (5-morpholinopentyl) -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- {5- [methyl (9,9,9,8,8-pentafluorononyl) amino] pentyl} -8-vinylestra-1, 3,5 (10) -triene

3,17ß-diol,

11β- {5 - [(9,9,9,8,8,7,7-heptafluorononyl) methylamino] pentyl} -8-vinylestra-1, 3,5 (10) -triene

3,17ß-diol,

11β- {5- [methyl (octanoyl) amino] pentyl} -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol,

11β- (6-chlorohexyl) -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol,

11β- [6- (methylamino) hexyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- [6- (dimethylamino) hexyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- [6- (pyrrolidin-1-yl) hexyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- [6- (1-piperidyl) hexyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- (6-morpholinohexyl) -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- {6- [methyl (9,9,9,8,8-pentafluorononyl) amino] hexyl} -8-vinylestra-1, 3,5 (10) -triene

3,17ß-diol,

11β- {6 - [(9,9,9,8,8,7,7-heptafluomonyl) methylamino] hexyl} -8-vinylestra-1, 3,5 (10) -triene

3,17ß-diol, 1 1 β- {6- [methyl (octanoyl) amino] hexyl} -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol, 11β- (7-bromoheptyl) -8 -vinyl-estra-1, 3,5 (10) -triene-3,17β-diol, 11β- [7- (methylamino) heptyl] -8-vinylestra-1, 3,5 (10) -triene-3 , 17β-diol, 11β- [7- (dimethylamino) -heptyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 1,1-β- [7- (pyrrolidin-1-yl ) heptyl] -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- [7- (1-piperidyl) heptyl] -8-vinylestra-1, 3.5 (10 ) -triene-3,17β-diol, 11β- (7-morpholinoheptyl) -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- {7- [methyl (9 , 9,9,8,8-pentafluorononyl) amino] heptyl} -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- {7 - [(9,9,9 , 8,8,7,7-heptafluomonyl) methylamino] heptyl} -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol,

11β- {7- [Methyl (octanoyl) amino] heptyl} -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol, Λ / -n-butyl-Λ / -methyl-5 - [3,17β-dihydroxy-8-vinylestra-1, 3,5 (10) -triene-11β-yl] valeramide, Λ / -n-butyl-Λ / -methyl-6- [3,17β-dihydroxy-8 -vinylestra-1, 3,5 (10) -trien-11β-yl] capronamide, Λ / -Λ ⁾ butyl-Λ / -methyl-7- [3,17β-dihydroxy-8-vinylestra-1, 3.5 (10) -trien-11β-yl] oenanthamide, 11β- (5-thiocyanatopentyl) -8-vinylestra-1, 3,5 (10) -triene-3,17β-diol, 11β- (6-thiocyanatohexyl ) -8-vinytestra-1, 3,5 (10) -triene-3, 17β-diol, 11β- (7-thiocyanatoheptyl) -8-vinylestra-1, 3,5 (10) -triene-3,17β -diol, 6- [3,17β-dihydroxy-8-vinylestra-1, 3,5 (10) -trien-11β-yl] capronitrile, 7- [3,17β-dihydroxy-8-vinylestra-1, 3 , 5 (10) -triene-11β-yl] oenanthenitrile,

17β-hydroxy-11β - [(R) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 1) .

17β-hydroxy-11β - [(S) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 2) 17β-hydroxy-11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 1),

17β-hydroxy-11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 2), 17β-hydroxy-11β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 1),

17β-hydroxy-11β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 2),

17β-hydroxy-11β- [6,6,6-trifluoro-5-hydroxy-5- (trifluoromethyl) hexyl] -8-vinyl-estrone

1, 3,5 (10) -trien-3-yl-sulfamate,

17β-hydroxy-11β- [7,7,7-trifluoro-6-hydroxy-6- (trifluoromethyl) heptyl] -8-vinyl-estra

1, 3,5 (10) -trien-3-yl-sulfamate, 17β-hydroxy-11β- [8,8,8-trifluoro-7-hydroxy-7- (trifluoromethyl) octyl] -8-vinyl-estra -1, 3,5 (10) -trien-3-yl-sulfamate,

17β-hydroxy-11β- [7,7,7,6,6-pentafluoro-5-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3-yl-sulfamate (diastereomer 1 )

17β-hydroxy-11β- [7,7,7,6,6-pentafluoro-5-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3-yl-sulfamate (diastereomer 2 )

17β-hydroxy-11β- [8,8,8,7,7-pentafluoro-6-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (diastereomer 1 )

17β-hydroxy-11β- [8,8,8,7,7-pentafluoro-6-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (diastereomer 2 ), 17β-hydroxy-11β- [9,9,9,8,8-pentafluoro-7-hydroxynonyl] -8-vinyl-estra-1,3,5 (10) -triene-3-yl-sulfamate ( Diastereomer 1),

17β-hydroxy-11β- [9,9,9,8,8-pentafluoro-7-hydroxynonyl] -8-vinyl-estra-1,3,5 (10) -triene-3-yl-sulfamate (diastereomer 2 )

11β- [5- (dimethylamino) pentyl] -17β-hydroxy-8-vinylestra-1, 3,5 (10) -trien-3-yl-sulphamate, 17β-hydroxy-11β- [5- (pyrrolidine) 1-yl) pentyl] -8-vinylestra-1, 3,5 (10) -trien-3-yl-sulphamate,

17β-hydroxy-11β- [5- (1-piperidyl) pentyl] -8-vinylestra-1, 3,5 (10) -trien-3-yl-sulphamate,

17β-hydroxy-11β- (5-morpholinopentyl) -8-vinylestra-1, 3,5 (10) -trien-3-yl-sulphamate,

11β- [6- (dimethylamino) hexyl] -17β-hydroxy-8-vinylestra-1,3,5 (10) -trien-3-yl-sulfamate,

17β-hydroxy-11β- [6- (pyrrolidin-1-yl) hexyl] -8-vinylestra-1, 3,5 (10) -trien-3-yl-sulphamate, 17β-hydroxy-11β- [6 (1-piperidyl) hexyl] -8-vinylestra-1, 3,5 (10) -trien-3-yl-sulphamate,

17β-hydroxy-11β- (6-morpholinohexyl) -8-vinylestra-1, 3,5 (10) -trien-3-yl-sulphamate,

11β- [7- (dimethylamino) heptyl]] -17β-hydroxy-8-vinyleslra-1,3,5 (10) -trien-3-yl-sulfamate,

17β-hydroxy-11β- [7- (pyrrolidin-1-yl) heptyl] -8-vinylestra-1, 3,5 (10) -trien-3-yl-sulphamate,

17β-hydroxy-11β- [7- (1-piperidyl) heptyl] -8-vinylestra-1,3,5 (10) -trien-3-yl-sulphamate, 17β-hydroxy-11β- (7-morpholinoheptyl) -8-vinylestra-1,3,5 (10) -trien-3-yl-sulphamate,

11β- [7,7,6-trifluoro-5-hydroxyhept-6-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 1),

11β- [7,7,6-trifluoro-5-hydroxyhept-6-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

11β- [8,8,7-trifluoro-6-hydroxyoct-7-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1), 11β- [8,8,7-trifluoro-6-hydroxyoct-7-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

11β- [9,9,8-trifluoro-7-hydroxynon-8-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1),

11β- [9,9,8-trifluoro-7-hydroxynon-8-enyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2),

11β- [5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 1),

11β- [5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2),

11β- [6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 1),

11β- [6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2), 11β- [7-hydroxyoctyl] -8-vinyl-estra -1, 3,5 (10) -triene-3,17β-diol (diastereomer 1),

11β- [7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2),

11β- [5-methyl-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol,

11β- [6-methyl-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol,

11β- [7-methyl-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol, 17α-methyl-11β - [(R) 6,6 , 6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1, 3,5 (10) -triene-3, 17β-diol (diastereomer 1),

17α-methyl-11β - [(S) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2) .

17α-methyl-11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 1),

17α-methyl-11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 2),

17α-Methyl-11β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

(Diastereomer 1), 17α-methyl-11β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (diastereomer 2).

17β-Hydroxy-11β- [8,8,8,7,7,6,6-heptafluoro-5-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -trienyl-3-yl sulfamate (diastereomer 1),

17β-hydroxy-11β- [8,8,8,7,7,6,6-heptafluoro-5-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl sulfamate (diastereomer 2),

17β-hydroxy-11β- [9,9,9,8,8,7,7-heptafluoro-6-hydroxynonyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl sulfamate (diastereomer 1), 17β-hydroxy-11β- [9,9,9,8,8,7,7-heptafluoro-6-hydroxynonyl] -8-vinyl-estra-1, 3,5 (10) trienyl 3-yl sulfamate (diastereomer 2),

17β-hydroxy-11β- [10,10,10,9,9,8,8-heptafluoro-7-hydroxydecyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl sulfamate (diastereomer 1),

17β-hydroxy-11β- [10,10,10,9,9,8,8-heptafluoro-7-hydroxydecyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl sulfamate (diastereomer 2),

17β-hydroxy-11β- [7,7,6-trifluoro-5-hydroxyhept-6-enyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (diastereomer 1 )

17β-hydroxy-11β- [7,7,6-trifluoro-5-hydroxyhept-6-enyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 2 ), 17β-Hydroxy-11β- [8,8,7-trifluoro-6-hydroxyoct-7-enyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate ( Diastereomer 1),

17β-hydroxy-11β- [8,8,7-trifluoro-6-hydroxyoct-7-enyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (diastereomer 2 )

17β-Hydroxy-11β- [9,9,8-trifluoro-7-hydroxynon-8-enyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (Diastereomer 1 )

17β-hydroxy-11β- [9,9,8-trifluoro-7-hydroxynon-8-enyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (diastereomer 2 )

17β-Hydroxy-17α-methyl-11β - [(R) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (Diastereomer 1), 17β-hydroxy-17α-methyl-11β - [(S) 6,6,6-trifluoro-5-hydroxyhexyl] -8-vinyl-estra-1,3,5 (10) -triene 3-yl-sulfamate (diastereomer 2),

1β-hydroxy-17α-methyl-11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (diastereomer 1 ),

17β-hydroxy-17α-methyl-11β- [7,7,7-trifluoro-6-hydroxyheptyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulfamate (diastereomer 2 ) 17β-Hydroxy-17-methyl-11β- [8,8,8-trifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (Diastereomer 1 )

17β-hydroxy-17α-methyl-11β- [8,8,8-irifluoro-7-hydroxyoctyl] -8-vinyl-estra-1,3,5 (10) -trien-3-yl-sulphamate (diastereomer 2 ).

7. Pharmaceutical compositions containing at least one compound according to any one of the preceding claims and a pharmaceutically acceptable excipient and / or carrier.

8. Pharmaceutical compositions containing at least one compound according to one of the preceding claims, which contain in addition to at least one compound of the general formula I according to claim 1 at least one compound selected from the group of GnRH antagonists, progesterone receptor antagonists, mesoprogestins, gestagens or tissue-selective gestagens.

9. Use of the compounds of general formula 1 according to any one of claims 1 to 6 for the manufacture of a medicament.

10. Use of the compounds of general formula 1 according to claim 9 for contraception in women.

11. Use of the compounds of general formula 1 according to claim 9 for contraception in men.

12. Use of the compounds of general formula 1 according to claim 9 for the treatment of benign or malignant proliferative diseases of the ovary.

13. Use according to claim 12 for the treatment of ovarian carcinomas.

14. Use according to claim 12 for the treatment of granulosa cell tumors.

15. Use according to one of claims 9 to 14, characterized in that the function of other estrogen-sensitive organs such as uterus, liver is not impaired.

16. Intermediates of the general formula VI

in which the radicals X, R ³ , R ¹⁷ , R ^{17 '} and n have the same meaning as those in the general formula I.

17. Intermediates of the general formula VII

in which the radicals X, R ³ , R ¹⁷ , R ^{17 '} and n have the same meaning as those in the general formula I.

18. Intermediates of the general formula VIII

in which the radicals X, R ³ , R ¹⁷ , R ^{17 '} and n have the same meaning as those in the general formula I.

19. Intermediates of the general formula IX

in which the radicals X, R ³ , R ¹⁷ , R ^{17 '} and n have the same meaning as those in the general formula I.