DE102004032674A1 - New 2-substituted Estra-1,3,5 (10) -triene-17-ones as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 - Google Patents

Abstract

The invention relates to novel 2-substituted Estra-1,3,5 (10) -triene-17-ones of the general formula I, DOLLAR F1 wherein DOLLAR AR · 2 · a saturated or unsaturated C¶1¶-C¶8¶- Alkyl group, a C¶1¶-C¶5¶-alkyloxy, an aralkyl or alkylaryl radical, a radical -OC¶n¶F¶m¶H¶¶¶, where n = 1, 2, 3, 4, 5 or 6, m> = 1 and m + o = 2n + 1, DOLLAR A or a group CH¶2¶XY in which X is an oxygen atom and Y is an alkyl radical having 1 to 4 carbon atoms, DOLLAR A and a halogen atom or a nitrile group, DOLLAR AR · 13 · a hydrogen atom or a methyl group, DOLLAR AR · 16 · a hydrogen or a fluorine atom, DOLLAR AZ an oxygen or sulfur atom, DOLLAR AR · 3 · and R · 5 · each independently alpha or beta hydrogen, DOLLAR AR 4 and R 6 are each independently an alpha or beta hydrogen, a C 1 to C 5 5 alkyl, a C 1 to C 4 alkyl, C¶5¶-alkyloxy-, a C¶1¶-C¶5 ¶-acyl or a hydroxy group or an aralkyl or alkylaryl radical, DOLLAR AR * 3 * and R * 4 together form an oxygen atom, DOLLAR AR * 5 * and R * 6 together form an oxygen atom, DOLLAR AR * 7 * and R * 8 each represents a hydrogen atom or, together, a CH¶2¶ group, DOLLAR A and their pharmaceutically acceptable salts, DOLLAR A their preparation and use as medicaments for the prophylaxis and therapy of estrogen-dependent diseases which are influenced by inhibition of 17beta hydroxysteroid dehydrogenase type 1 to let.

Description

The present invention relates to novel 2-substituted Estra-1,3,5 (10) -triene-17-ones, their preparation and use as medicaments for treatment estrogen-dependent diseases, characterized by inhibition of 17β-hydroxysteroid dehydrogenase Influence type 1 and pharmaceutical compositions, containing these compounds.

sex hormones control the proliferation and function of steroid sensitive normal as well as malignant tissue [E. E. Baulieu, Hormones, a complex communication network. In Hormones, eds. E.E. Baulieu and P.A. Kelly, Herman Publisher Paris and Chapman and Hall New York, 1990, pp. 147-149; D. D. Thomas, Cancer 53 (1984) 595-601].

estradiol is the most active female sex hormone except the known effects on the reproductive system more functions in bone and lipid metabolism, in the cardiovascular system as well exerts regulatory effects in the central nervous system. It will in premenopausal Women primarily in produced by the ovaries. Another big part of the active estrogens is formed in the peripheral tissue from inactive steroid precursors, which in humans in the adrenal glands are released in large quantities into the blood.

To Menopause decreases the estradiol level in the blood to about 1/10 of the Salary of premenopausal women [T.Thorsten, M.Tangen, K.F. Stoa, Eur. J. Cancer Clin. Oncol. 18 (1982) 333-337; A.A. van Landeghem et al., Cancer Res. 45 (1985) 2900-2906]. From this point on, estrogens are mainly involved in peripheral biosynthesis Tissue available [F. Labrie, Intracrinology. Mol. Cell. Endocrinol. 78 (1991) C113-C118].

estrogens be over The blood is absorbed by the tumor tissue and stimulates its growth.

The Concentration of the intratumoral estradiol, however, also remains Menopause obtained at a high level, comparable to that in premenopausal Women [A. A. van Landeghem et al., Cancer Res. 45 (1985) 2900-2906]. The high estradiol concentration in tumor tissue in postmenopausal Women are caused by biosynthesis of estrogens in tumor tissue.

estradiol (E2) is expressed in breast cancer tissue via either the aromatase or the Sulphatase path formed [Y. J. Abul-Hajj, R. Iverson, D.T. Kiang, Steroids 33 (1979) 205-222; A. Lipton et al., Cancer 59 (1987), 779-782; E. Perel et al., J. Steroid Biochem. 29 (1988) 393-399]. Androstenedione is taken up by the blood from the tumor tissue, too Estrone (E1) flavored and then reduced to estradiol (E2) (Aromatase method). In the sulfatase pathway, estrone sulfate is produced by steroid sulfatase converted to E1 and then reduced to E2.

Of the crucial final step in steroid synthesis is by 17β-hydroxysteroid dehydrogenases (17β-HSD), belonging to the Family of 17β-hydroxysteroid dehydrogenases / 17-ketosteroid reductases catalyzed. These enzymes convert less active 17-ketosteroids in their active 17β-hydroxysteroids around and vice versa. Both estrogens and androgens show the highest affinity to the corresponding receptors in the 17β-hydroxy form, i. the 17β-HSD enzymes control the biological activity Sex Hormones [H. Peltoketo et al., J. Mol. Endocrinol. 23 (1999), 1-11; P. Vihko et al., Mol. Cell. Endocrinol. 171 (2001) 71-76].

Certain Extragonadal tissues such as breast and prostate tissues express reductive 17-HSD's and walk so the circulating in the blood precursors with less activity in the Target tissues into the more active forms around [F. Labrie et al., Steroids 62 (1997) 148-158; H. Peltoketo et al., Horm. 55 (1999) 353-398].

To date, 11 different 17β-HSD's are known. They differ in their tissue distribution, catalytic activity, substrate specificity, subcellular localization, and regulatory mechanism. For a large number of hydroxysteroid dehydrogenases their involvement in the pathogenesis of human diseases has been demonstrated, bsplw. for pseudohermaphroditism [17β-HSD 3, WM Geissler et al., Nat. Genet. 7 (1994) 34-39], bifunctional enzyme deficit [17β-HSD 4, EG van Grunsven et al., Proc. Natl. Acad. Sci. USA 95 (1998) 2128-2133], polycystic kidney disease [17β-HSD 8, MM Maxwell et al., J. Biol. Chem. 270 (1995) 25213-25219] and Alzheimer's disease [17-HSD 10, SD Yan et al., Nature 389 (1997) 689-695; XY He et al., J. Biol. Chem. 274 (1999) 15014-15019].

The human placental 17β-hydroxysteroid dehydrogenases Type 1 and Type 2 belong of the same steroid dehydrogenase reductase protein family (SDR). They differ from each other, inter alia, by the reaction direction, which is catalyzed by the enzymes.

17β-HSD 1 controls especially the reduction of estrone to estradiol [T. Puranen et al., Endocrinology 138 (1997) 3532-3539] involving NADPH as co-factor [J. Z. Jin, S. X. Lin, Biochem. Biophys. Res. Commun. 259 (1999) 489-493].

In cultured cells supported the HSD 1 partly the reduction of androstenedione and Androstandion. However, it could be clearly shown that phenolic substrates preferred are [M. Poutanen et al., Endocrinology 133 (1993) 2639-2644]. In comparison with 17β-HSD 1 catalyzes the 17β-HSD 2, however, the opposite reaction, namely the conversion of estradiol to Estrone and Androstenedione and Dihydrotestosterone to Androstandion [L. Wu et al., J. Biol. Chem. 268 (1993) 12964-12969] and is preferred in the presence of the non-phosphorylated form of the co-factor NAD [F. Labrie et al., Steroids 62 (1997) 148-158].

17β-HSD 1 and 2 are in normal mammary tissue expressed [G. Söderqvist, J. Clin. Endocrinol. Metab. 83 (1998) 1190-1193; M. Miettinen, Breast Cancer Res, Treat. 57 (1999) 175-182].

in the Unlike normal breast tissue, one finds in malignant mammary epithelial cells the reductive activity (by 17β-HSD 1) opposite oxidative (by 17β-HSD 2) increased [M. Miettinen, M. et al., Biochem. J. 314 (1996) 839-845; V. Speirs, J. Steroid Biochem. Mol. Biol. 67 (1998) 267-274]. It it was observed that estradiol accumulates in malignant breast cells which also indicates an activity of 17β-HSD 1 [A. Vermeulen et al., Eur. J. Cancer Clin. Oncol. 22 (1986) 515-525]. It was also found that in the presence of 17β-HSD 1 administration of Estrone in the same way to a growth of breast cancer cells leads like the administration of estradiol alone. In contrast, causes administration of estrone alone without 17β-HSD 1 does not have this effect [M. M. Miettinen et al., Int. J. Cancer 68 (1996) 600-604].

The Dominance of 17β-HSD 1 in malignant tissue leads to a reinforced Estrogen-dependent growth and progress of tumors while the oxidative 17β-HSD 2 normal breast tissue cells protect against excessive estradiol effect [P. Vihko et al. Mol. Cell. Endocrinol. 171 (2000) 71-76].

in the Case of endometriosis plays the balance between the 17β-HSD 1 and 2 a role. 17β-HSD 1 is expressed in eutopic tissue, the hormone-inactivating Enzyme 17β-HSD 2 is missing completely [S. E. Bulun et al. J. Mol. Endocrinol. 25 (2000) 35-42.

Also prostate carcinoma is 17β-HSD 2 lowers [J. P. Elo et al., Endocrinol. Metab. 88 (2003) 705-712].

Under the previously developed 17β-HSD 1-inhibitors distinguish the irreversible from the reversible Inhibitors. The irreversible inhibitors contain a reactive functional group formed by formation of a covalent bond with an amino acid residue of the enzyme inactivates this. Well-known representatives of the mentioned Group are 16-methylene-estradiols, acetylene-substituted 16-seco-estradiol [R. J. Auchus, D.F. Covey, Biochemistry 25 (1983) 7295-7300; J. Thomas, Thomas et al., J. Biol. Chem. 258 (1983) 11500-11504; B. Tobias et al., J. Biol. Chem. 257 (1982) 2783-2786] or else 16α-haloalkyl estradiols [K. M. Sam et al., Drug Des. Discov. 15 (1997) 157-180; M.R. Tremblay, D. Poirier, J. Steroid Biochem. Mol. Biol. 66 (1998) 179-191]. To the reversible inhibitors belong 16,17-pyrazole or 16,17-isoxazole-estrone derivatives [F. Sweet et al. Biochem. Biophys. Res. Commun. 180 (1991), 1057-1063], Estradiolderivate with a long 7α-undecanamide [C. Labrie et al. Cancer Res. 52 (1992), 610-615; S.J. Santner, R.J. Santen, J. Steroid Biochem. Mol. Biol. 45 (1993) 383-390] or with a 6β-thiaheptanamide side chain [D. Poirier, P. Dionne, S. Auger, J. Steroid Biochem. Mol. Biol. 64 (1998), 83-90].

One Special case as 17β-HSD 1-inhibitor is the 16-oxoestron: it counts at neutral pH 7.2 to the reversible, under basic conditions at pH 8.5 to the irreversible inhibitors [H. Inano, B. Tamaoki, Eur. J. Biochem. 129 (1983) 691-695].

The previously known both reversible and the irreversible inhibitors have only a moderate activity as a 17β-HSD 1 inhibitor.

Recently, the first hybrid inhibitor was found by modeling studies [M. Tremblay, D. Poirier et al., FASEB 13 (2002) 1829-1831]. The hybrid inhibitor, in which estradiol is linked to adenosine via a spacer of 8 methylene groups at the 16-position, inhibits 17β-HSD 1 as the best inhibitor with an IC ₅₀ value of 52 nM.

by virtue of the size of this molecule might This compound would be difficult to be orally bioavailable. It is not unlikely that the molecule with other NAD (P) (H) -dependent Enzyme cross-reacts.

The 17β-HSD 1 is a target for the local prior art Inhibition of estradiol biosynthesis. Accompanying the treatment with Antihormones that bind the active steroid to the corresponding Can prevent receptor 17β-HSD 1 - inhibitor supportive for the treatment of estrogen-dependent Diseases are used.

task The present invention is therefore to provide further compounds, the selective inhibition of 17β-HSD 1 effect. These compounds are intended for the treatment of estrogen-dependent diseases as well as hormone dependent Tumors that are characterized by inhibition of 17β-hydroxysteroid dehydrogenase Influence type 1.

Further objects present invention are the production and use of these Compounds as a medicament for the treatment of estrogen-dependent diseases as well as hormone dependent Tumor diseases characterized by inhibition of 17β-hydroxysteroid dehydrogenase Influence type 1.

worin
R² eine gesättigte oder ungesättigte C₁-C₈-Alkylgruppe, eine C₁-C₅-Alkyloxygruppe, ein Aralkyl- oder Alkylarylrest, ein Rest -O-C_nF_mH_o, wobei n = 1, 2, 3, 4, 5 oder 6, m ≥ 1 und m + o = 2n + 1 ist, oder eine Gruppe CH₂XY, in der X für ein Sauerstoffatom und Y für einen Alkylrest mit 1 bis 4 Kohlenstoffatomen steht, sowie ein Halogenatom oder eine Nitrilgruppe
R¹³ ein Wasserstoffatom oder eine Methylgruppe
R¹⁶ ein Wasserstoff- oder ein Fluoratom
Z ein Sauerstoff- oder ein Schwefelatom
R³ und R⁵ jeweils unabhängig voneinander ein α- oder β-ständiges Wasserstoffatom
R⁴ und R⁶ jeweils unabhängig voneinander ein α- oder β-ständiges Wasserstoffatom, eine C₁-C₅-Alkyl-, eine C₁-C₅-Alkyloxy-, eine C₁-C₅-Acyl- oder eine Hydroxygruppe oder ein Aralkyl- oder Alkylarylrest,
R₃ und R₄ zusammen ein Sauerstoffatom
R₅ und R₆ zusammen ein Sauerstoffatom
R⁷ und R⁸ jeweils ein Wasserstoffatom oder zusammen eine CH₂-Gruppe
bedeuten, wobei die gestrichelten Linien im B-, C- und D-Ring des Steroidgerüstes zusätzlich bis zu zwei Doppelbindungen sein können,
sowie ihre pharmazeutisch annehmbaren Salze.The object is achieved according to the present invention by the provision of new 2-substituted Estra-1,3,5 (10) -triene-17-one of the general formula I.

wherein
R ^{2 is} a saturated or unsaturated C ₁ -C ₈ -alkyl group, a C ₁ -C ₅ -alkyloxy group, an aralkyl or alkylaryl radical, a radical -OC _n F _m H _o , where n = 1, 2, 3, 4, 5 or 6, m ≥ 1 and m + o = 2n + 1, or a group CH ₂ XY in which X is an oxygen atom and Y is an alkyl radical having 1 to 4 carbon atoms, and a halogen atom or a nitrile group
R ^{13 is} a hydrogen atom or a methyl group
R ^{16 is} a hydrogen or a fluorine atom
Z is an oxygen or a sulfur atom
R ³ and R ^{5 are} each independently an α- or β-position hydrogen atom
R ⁴ and R ^{6 are} each independently an alpha or beta hydrogen, a C ₁ -C ₅ alkyl, a C ₁ -C ₅ alkyloxy, a C ₁ -C ₅ acyl or a hydroxy group, or an aralkyl or alkylaryl radical,
R ₃ and R ₄ together represent an oxygen atom
R ₅ and R ₆ together represent an oxygen atom
R ⁷ and R ⁸ each represent a hydrogen atom or together a CH ₂ group
in which the dashed lines in the B, C and D ring of the steroid skeleton can additionally be up to two double bonds,
and their pharmaceutically acceptable salts.

Furthermore, the present invention comprises the new compounds as pharmaceutical active ingredients, their preparation, their therapeutic application and pharmaceutical dosage forms containing the new Contain substances.

The Compounds of the invention of general formula (I) or their pharmaceutically acceptable Salts can for the Production of a medicament, in particular for the treatment of estrogen-dependent diseases as well as hormone dependent Tumor diseases characterized by inhibition of 17β-hydroxysteroid dehydrogenase Type 1 can be used.

It it was found that the low molecular weight 2-substituted invention Estra-1,3,5 (10) -trien-17-one stronger as previously known 17β-HSD 1 inhibitors a selective inhibition of 17β-HSD 1 enzyme activity in vitro cause.

If not closer defined, it is within the meaning of the present invention an aryl radical which may optionally be substituted to a Phenyl, 1- or 2-naphthyl radical, wherein the phenyl radical is preferred. Unless specifically stated, aryl excludes always include a heteroaryl radical. Examples of one Heteroaryl are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl.

Examples of suitable substituents for an aryl or heteroaryl radical are a methyl, ethyl, trifluoromethyl-pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine), Hydroxy, amino, mono (C _1-8 alkyl) or di (C _1-8 alkyl) amino, where both alkyl groups are identical or different, di (aralkyl) amino, where both aralkyl groups are identical or different, mentioned.

The C ₁ -C ₈ alkyl groups for R ² may be saturated or unsaturated and partially or fully substituted. Representative of the saturated alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n, iso or tert-butyl, n, iso or neo-pentyl or n-hexyl and n To call Heptyl. Methyl, ethyl and propyl are preferred.

When Representative for unsaturated Alkyl radicals are allyl, vinyl and ethynyl.

For the partially or completely fluorinated alkyl radical in the substituent R ³ is, for example, a trifluoromethyl, pentafluoroethyl or 2,2,2-trifluoroethyl in question.

For the C ₁ -C ₅ -alkoxy radical R ² , a methoxy, ethoxy, n-propoxy, iso-propoxy, n, iso or tert-butoxy, n, iso or neo-pentoxy group stand.

In the case of R ^2, a halogen can be a chlorine, iodine or bromine atom.

By a C ₁ -C ₅ acyl radical is meant a formyl, acetyl, propionyl, butyryl or pentanoyl radical.

Preferred according to the present invention are compounds of the general formula I in which R ^{2 is} a C ₁ -C ₅ -alkoxy, C ₁ -C ₅ -alkyl or C ₂ -C ₃ -alkenyl or C ₂ -C ₃ -alkynyl or bromine , Iodine or chlorine or a nitrile radical and R ^{13 is} a hydrogen atom.

• 1) 2-Chlor-3-hydroxy-18a-homoestra-1,3,5(10)-trien-17-on 1
• 2) 3-Hydroxy-2-pentanoyl-estra-1,3,5(10)-trien-17-on 2
• 3) 2-Chlor-16α-fluor-3-hydroxy-estra-1,3,5(10)-trien-17-on 3
• 4) 2-Chlor-16β-fluor-3-hydroxy-estra-1,3,5(10)-trien-17-on 4
• 5) 3-Hydroxy-2-methoxy-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on 5
• 6) 3-Hydroxy-2-methoxy-estra-1,3,5(10)-trien-17-thion 6
• 7) 3-Hydroxy-2-methoxymethyl-estra-1,3,5(10)-trien-17-on 7
• 8) 3-Hydroxy-2-methyl-estra-1,3,5(10)-trien-17-on 8
• 9) 2-Ethyl-3-hydroxy-estra-1,3,5(10)-trien-17-on 23
• 10) 3-Hydroxy-2-propyl-estra-1,3,5(10)-trien-17-on 9
• 11) 3-Hydroxy-2-(prop-2'-enyl)-estra-1,3,5(10)-trien-17-on 10
• 12) 2-Chlor-3-hydroxy-estra-1,3,5(10)-trien-17-on 11
• 13) 2-Brom-3-hydroxy-estra-1,3,5(10)-trien-17-on
• 14) 2-Cyano-3-hydroxy-estra-1,3,5(10)-trien-17-on 12
• 15) 3-Hydroxy-2-iod-estra-1,3,5(10)-trien-7,17-dion 13
• 16) 3-Hydroxy-2-methoxy-estra-1,3,5(10)-trien-6,17-dion 14
• 17) 3,7β-Dihydroxy-2-iod-estra-1,3,5(10)-trien-17-on 15
• 18) 7β-Acetoxy-3-hydroxy-2-iod-estra-1,3,5(10)-trien-17-on 16
• 19) 2-Chlor-3-hydroxy-7α-methyl-estra-1,3,5(10)-trien-17-on 17
• 20) 3-Hydroxy-2-methoxy-estra-1,3,5(10),6-tetraen-17-on 18
• 21) 3-Hydroxy-2-phenylethinyl-estra-1,3,5(10)-trien-17-on 19
• 22) 2-Hexyl-3-hydroxy-estra-1,3,5(10)-trien-17-on 20
• 23) 3-Hydroxy-2-(2'-phenyl-ethyl)estra-1,3,5(10)-trien-17-on 21
• 24) 3-Hydroxy-2-(3'-phenyl-propyl)-estra-1,3,5(10)-trien-17-on 22
• 25) 3-Hydroxy-2-pentanoyl-estra-1,3,5(10)-trien-17-on
• 26) 2-Brom-3-hydroxy-estra-1,3,5(10)-trien-6,17-dion
• 27) 2-Chlor-3-hydroxy-estra-1,3,5(10)-trien-6,17-dion
• 28) 2-Brom-3-hydroxy-estra-1,3,5(10)-trien-7,17-dion
• 29) 2-Chlor-3-hydroxy-estra-1,3,5(10)-trien-7,17-dion
• 30) 2-Cyano-3-hydroxy-estra-1,3,5(10)-trien-6,17-dion
• 31) 2-Cyano-3-hydroxy-estra-1,3,5(10)-trien-7,17-dion
• 32) 2-Brom-3-hydroxy-estra-1,3,5(10)-trien-17-thion
• 33) 2-Chlor-3-hydroxy-estra-1,3,5(10)-trien-17-thion
• 34) 2-Cyano-3-hydroxy-estra-1,3,5(10)-trien-17-thion
• 35) 3-Hydroxy-2-iod-estra-1,3,5(10)-trien-17-thion
• 36) 3-Hydroxy-2-iod-estra-1,3,5(10)-trien-6,17-dion 24
• 37) 2-Chlor-3-hydroxy-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on
• 38) 3-Hydroxy-2-iod-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on
• 39) 2-Brom-3-hydroxy-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on
• 40) 2-Cyano-3-hydroxy-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on
• 41) 3-Hydroxy-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on
• 42) 3-Hydroxy-2-propyl-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on
• 43) 7β-Acetoxy-2-chlor-3-hydroxy-estra-1,3,5(10)-trien-17-on
• 44) 7β-Acetoxy-2-cyano-3-hydroxy-estra-1,3,5(10)-trien-17-on
• 45) 7β-Acetoxy-2-brom-3-hydroxy-estra-1,3,5(10)-trien-17-on
• 46) 3-Hydroxy-2-methyl-estra-1,3,5(10)-trien-6,17-dion
• 47) 3-Hydroxy-2-propyl-estra-1,3,5(10)-trien-6,17-dion
• 48) 3-Hydroxy-2-(prop-2'-enyl)-estra-1,3,5(10)-trien-6,17-dion
• 49) 3-Hydroxy-2-methyl-estra-1,3,5(10)-trien-7,17-dion
• 50) 3-Hydroxy-2-propyl-estra-1,3,5(10)-trien-7,17-dion
• 51) 3-Hydroxy-2-(prop-2'-enyl)-estra-1,3,5(10)-trien-7,17-dion
• 52) 7β-Acetoxy-3-hydroxy-2-methyl-estra-1,3,5(10)-trien-17-on
• 53) 7β-Acetoxy-3-hydroxy-2-propyl-estra-1,3,5(10)-trien-17-on
• 54) 7β-Acetoxy-3-hydroxy-2-(prop-2'-enyl)-estra-1,3,5(10)-trien-17-on
• 55) 2-Brom-3-hydroxy-18a-homoestra-1,3,5(10)-trien-17-on
• 56) 3-Hydroxy-2-iod-18a-homoestra-1,3,5(10)-trien-17-on
• 57) 2-Cyano-3-hydroxy-18a-homoestra-1,3,5(10)-trien-17-on
• 58) 2-Brom-3-hydroxy-7α-methyl-estra-1,3,5(10)-trien-17-on
• 59) 2-Cyano-3-hydroxy-7α-methyl-estra-1,3,5(10)-trien-17-on
• 60) 3-Hydroxy-2-iod-7α-methyl-estra-1,3,5(10)-trien-17-on
• 61) 3-Hydroxy-2-iod-estra-1,3,5(10)-trien-17-on
• 62) 3-Hydroxy-2-methoxy-estra-1,3,5(10),14-tetraen-17-on
• 63) 16α-Fluor-3-hydroxy-2-(2'-phenyl-ethyl)-estra-1,3,5(10)-trien-17-on
• 64) 16β-Fluor-3-hydroxy-2-(2'-phenyl-ethyl)-estra-1,3,5(10)-trien-l7-on
• 65) 3-Hydroxy-2-(2'-phenyl-ethyl)-18a-homoestra-1,3,5(10)-trien-17-on
• 66) 16α-Fluor-3-hydroxy-2-(2'-phenyl-ethyl)-18a-homoestra-1,3,5(10)-trien-17-on
• 67) 16β-Fluor-3-hydroxy-2-(2'-phenyl-ethyl)-18a-homoestra-1,3,5(10)-trien-17-on
• 68) 16α-Fluor-3-hydroxy-2-phenylethinyl-estra-1,3,5(10)-trien-17-on
• 69) 16β-Fluor-3-hydroxy-2-phenylethinyl-estra-1,3,5(10)-trien-17-on
• 70) 2-Chlor-16α-fluor-3-hydroxy-18a-homoestra-1,3,5(10)-trien-17-on
• 71) 2-Chlor-16β-fluor-3-hydroxy-18a-homoestra-1,3,5(10)-trien-17-on
• 72) 2-Cyano-16α-fluor-3-hydroxy-estra-1,3,5(10)-trien-17-on
• 73) 2-Cyano-16β-fluor-3-hydroxy-estra-1,3,5(10)-trien-17-on
• 74) 2-Cyano-16α-fluor-3-hydroxy-18a-homoestra-1,3,5(10)-trien-17-on
• 75) 2-Cyano-16β-fluor-3-hydroxy-18a-homoestra-1,3,5(10)-trien-17-on
• 76) 2-Chlor-16α-fuor-3-hydroxy-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on
• 77) 2-Chlor-16β-fluor-3-hydroxy-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on
• 78) 2-Cyano-16α-fluor-3-hydroxy-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on
• 79) 2-Cyano-16β-fluor-3-hydroxy-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on
• 80) 3-Hydroxy-2-(2'-phenyl-ethyl)-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on
• 81) 16α-Fluor-3-hydroxy-2-(2'-phenyl-ethyl)-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on
• 82) 16β-Fluor-3-hydroxy-2-(2'-phenyl-ethyl)-14α,15α-cyclopropa[a]estra-1,3,5(10),8-tetraen-17-on
• 83) 2-Chlor-3-hydroxy-14α,15α-cyclopropa[a]estra-1,3,5(10)-trien-17-on
• 84) 2-Chlor-16β-fluor-3-hydroxy-14α,15α-cyclopropa[a]estra-1,3,5(10)-trien-17-on
• 85) 2-Cyano-3-hydroxy-14α,15α-cyclopropa[a]estra-1,3,5(10)-trien-17-on
• 86) 2-Cyano-16β-fluoro-3-hydroxy-14α,15α-cyclopropa[a]estra-1,3,5(10)-trien-17-on
• 87) 3-Hydroxy-2-(2'-phenyl-ethyl)-14α,15α-cyclopropa[a]estra-1,3,5(10)-trien-17-on
• 88) 16β-Fluor-3-hydroxy-2-(2'-phenyl-ethyl)-14α,15α-cyclopropa[a]estra-1,3,5(10)-trien-17-on

The compounds mentioned below and their use are preferred according to the invention:

• 1) 2-Chloro-3-hydroxy-18a-homoestra-1,3,5 (10) -trien-17-one 1
• 2) 3-hydroxy-2-pentanoyl-estra-1,3,5 (10) -trien-17-one 2
• 3) 2-chloro-16α-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one 3
• 4) 2-Chloro-16β-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one 4
• 5) 3-hydroxy-2-methoxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one 5
• 6) 3-hydroxy-2-methoxy-estra-1,3,5 (10) -triene-17-thione 6
• 7) 3-hydroxy-2-methoxymethyl-estra-1,3,5 (10) -trien-17-one 7
• 8) 3-hydroxy-2-methyl-estra-1,3,5 (10) -trien-17-one 8
• 9) 2-ethyl-3-hydroxy-estra-1,3,5 (10) -trien-17-one 23
• 10) 3-hydroxy-2-propyl-estra-1,3,5 (10) -trien-17-one 9
• 11) 3-Hydroxy-2- (prop-2'-enyl) -estra-1,3,5 (10) -trien-17-one 10
• 12) 2-chloro-3-hydroxy-estra-1,3,5 (10) -trien-17-one 11
• 13) 2-bromo-3-hydroxy-estra-1,3,5 (10) -trien-17-one
• 14) 2-cyano-3-hydroxy-estra-1,3,5 (10) -trien-17-one 12
• 15) 3-hydroxy-2-iodo-estra-1,3,5 (10) -triene-7,17-dione 13
• 16) 3-hydroxy-2-methoxy-estra-1,3,5 (10) -triene-6,17-dione 14
• 17) 3,7β-Dihydroxy-2-iodo-estra-1,3,5 (10) -trien-17-one 15
• 18) 7β-Acetoxy-3-hydroxy-2-iodo-estra-1,3,5 (10) -trien-17-one 16
• 19) 2-chloro-3-hydroxy-7α-methyl-estra-1,3,5 (10) -trien-17-one 17
• 20) 3-hydroxy-2-methoxy-estra-1,3,5 (10), 6-tetraen-17-one 18
• 21) 3-hydroxy-2-phenylethynyl-estra-1,3,5 (10) -trien-17-one 19
• 22) 2-hexyl-3-hydroxy-estra-1,3,5 (10) -trien-17-one 20
• 23) 3-hydroxy-2- (2'-phenylethyl) estra-1,3,5 (10) -trien-17-one 21
• 24) 3-hydroxy-2- (3'-phenyl-propyl) -estra-1,3,5 (10) -trien-17-one 22
• 25) 3-hydroxy-2-pentanoyl-estra-1,3,5 (10) -trien-17-one
• 26) 2-bromo-3-hydroxy-estra-1,3,5 (10) -triene-6,17-dione
• 27) 2-chloro-3-hydroxy-estra-1,3,5 (10) -triene-6,17-dione
• 28) 2-bromo-3-hydroxy-estra-1,3,5 (10) -triene-7,17-dione
• 29) 2-chloro-3-hydroxy-estra-1,3,5 (10) -triene-7,17-dione
• 30) 2-cyano-3-hydroxy-estra-1,3,5 (10) -triene-6,17-dione
• 31) 2-cyano-3-hydroxy-estra-1,3,5 (10) -triene-7,17-dione
• 32) 2-bromo-3-hydroxy-estra-1,3,5 (10) -triene-17-thione
• 33) 2-chloro-3-hydroxy-estra-1,3,5 (10) -triene-17-thione
• 34) 2-cyano-3-hydroxy-estra-1,3,5 (10) -triene-17-thione
• 35) 3-hydroxy-2-iodo-estra-1,3,5 (10) -triene-17-thione
• 36) 3-hydroxy-2-iodo-estra-1,3,5 (10) -triene-6,17-dione 24
• 37) 2-chloro-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraene-17-one
• 38) 3-hydroxy-2-iodo-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one
• 39) 2-bromo-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraene-17-one
• 40) 2-cyano-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraene-17-one
• 41) 3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraene-17-one
• 42) 3-hydroxy-2-propyl-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraene-17-one
• 43) 7β-acetoxy-2-chloro-3-hydroxy-estra-1,3,5 (10) -trien-17-one
• 44) 7β-acetoxy-2-cyano-3-hydroxy-estra-1,3,5 (10) -trien-17-one
• 45) 7β-acetoxy-2-bromo-3-hydroxy-estra-1,3,5 (10) -trien-17-one
• 46) 3-hydroxy-2-methyl-estra-1,3,5 (10) -triene-6,17-dione
• 47) 3-hydroxy-2-propyl-estra-1,3,5 (10) -triene-6,17-dione
• 48) 3-hydroxy-2- (prop-2'-enyl) -estra-1,3,5 (10) -triene-6,17-dione
• 49) 3-hydroxy-2-methyl-estra-1,3,5 (10) -triene-7,17-dione
• 50) 3-hydroxy-2-propyl-estra-1,3,5 (10) -triene-7,17-dione
• 51) 3-hydroxy-2- (prop-2'-enyl) -estra-1,3,5 (10) -triene-7,17-dione
• 52) 7β-acetoxy-3-hydroxy-2-methyl-estra-1,3,5 (10) -trien-17-one
• 53) 7β-acetoxy-3-hydroxy-2-propyl-estra-1,3,5 (10) -trien-17-one
• 54) 7β-acetoxy-3-hydroxy-2- (prop-2'-enyl) -estra-1,3,5 (10) -trien-17-one
• 55) 2-bromo-3-hydroxy-18a-homoestra-1,3,5 (10) -trien-17-one
• 56) 3-hydroxy-2-iodo-18a-homoestra-1,3,5 (10) -trien-17-one
• 57) 2-cyano-3-hydroxy-18a-homoestra-1,3,5 (10) -trien-17-one
• 58) 2-bromo-3-hydroxy-7α-methyl-estra-1,3,5 (10) -trien-17-one
• 59) 2-cyano-3-hydroxy-7α-methyl-estra-1,3,5 (10) -trien-17-one
• 60) 3-hydroxy-2-iodo-7α-methyl-estra-1,3,5 (10) -trien-17-one
• 61) 3-hydroxy-2-iodo-estra-1,3,5 (10) -trien-17-one
• 62) 3-hydroxy-2-methoxy-estra-1,3,5 (10), 14-tetraene-17-one
• 63) 16α-fluoro-3-hydroxy-2- (2'-phenyl-ethyl) -estra-1,3,5 (10) -trien-17-one
• 64) 16β-fluoro-3-hydroxy-2- (2'-phenyl-ethyl) -estra-1,3,5 (10) -triene-17-one
• 65) 3-hydroxy-2- (2'-phenyl-ethyl) -18a-homoestra-1,3,5 (10) -trien-17-one
• 66) 16α-fluoro-3-hydroxy-2- (2'-phenyl-ethyl) -18a-homoestra-1,3,5 (10) -trien-17-one
• 67) 16β-fluoro-3-hydroxy-2- (2'-phenyl-ethyl) -18a-homoestra-1,3,5 (10) -trien-17-one
• 68) 16α-fluoro-3-hydroxy-2-phenylethynyl-estra-1,3,5 (10) -trien-17-one
• 69) 16β-fluoro-3-hydroxy-2-phenylethynyl-estra-1,3,5 (10) -trien-17-one
• 70) 2-chloro-16α-fluoro-3-hydroxy-18a-homoestra-1,3,5 (10) -trien-17-one
• 71) 2-Chloro-16β-fluoro-3-hydroxy-18a-homoestra-1,3,5 (10) -trien-17-one
• 72) 2-cyano-16α-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one
• 73) 2-cyano-16β-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one
• 74) 2-Cyano-16α-fluoro-3-hydroxy-18a-homoestra-1,3,5 (10) -trien-17-one
• 75) 2-cyano-16β-fluoro-3-hydroxy-18a-homoestra-1,3,5 (10) -trien-17-one
• 76) 2-Chloro-16α-fluoro-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one
• 77) 2-chloro-16β-fluoro-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one
• 78) 2-Cyano-16α-fluoro-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one
• 79) 2-cyano-16β-fluoro-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraene-17-one
• 80) 3-hydroxy-2- (2'-phenylethyl) -14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one
• 81) 16α-fluoro-3-hydroxy-2- (2'-phenylethyl) -14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one
• 82) 16β-fluoro-3-hydroxy-2- (2'-phenylethyl) -14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one
• 83) 2-chloro-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10) -trien-17-one
• 84) 2-chloro-16β-fluoro-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10) -trien-17-one
• 85) 2-cyano-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10) -trien-17-one
• 86) 2-cyano-16β-fluoro-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10) -trien-17-one
• 87) 3-hydroxy-2- (2'-phenyl-ethyl) -14α, 15α-cyclopropa [a] estra-1,3,5 (10) -trien-17-one
• 88) 16β-fluoro-3-hydroxy-2- (2'-phenylethyl) -14α, 15α-cyclopropa [a] estra-1,3,5 (10) -trien-17-one

Pharmacological data

Inhibition of human activity 17β-hydroxysteroid dehydrogenase Type 1

The Test method is well described in the literature [Adamski J, Sierralta WD, Jungblut PW, Acta Endocrinol (Copenh.) 121 (2) (1989), 161-7] and is shown below.

humane 17β-hydroxysteroid (17β-HSDs) are overexpressed in E. coli bacteria as His tag proteins or as GST fusion proteins. The suspensions of bacteria pellets in isotonic saline are for the Determination of enzyme activities 17β-HSD's or to study their Influenced by potential inhibitors (estrogen derivatives) used.

The measurements are carried out in duplicate and, if necessary, at different concentrations of potential inhibitors (eg when determining the IC ₅₀ values). In addition to the target enzyme 17β-HSD1, other steroid-metabolizing enzymes are included in the assay to study cross-reactivity of the estrogen derivatives.

To a defined volume of 100 mM sodium phosphate buffer are ³ H-labeled substrate, bacterial suspension, DMSO (in the control batch, final 1%) or the potential inhibitors (estrone derivatives in DMSO) and suitable cofactor (NADP (H) or NAD (H); 5 mg / ml in H ₂ O). The incubation of the samples is carried out at 37 ° C in a water bath with shaking, so that in the control (without substances to be tested), a conversion of about 30% is achieved.

The Separation of radioactively labeled substrate and product takes place subsequently, after extraction over 1 ml reversed phase (RP-18) cartridges, by HPLC on a RP18 column with Acetonitrile: water 1: 1 (v / v) as the mobile phase. The radioactivity is with Help a flow scintillation counter detected.

The Evaluation of the substrate conversion with and without substances to be tested is performed by integration of the substrate and product peaks. Of the Sales of control is normalized to 100% sales.

Tab. 1 Inhibition of human 17β-hydroxysteroid dehydrogenase

dosage

in the general are satisfactory results in the treatment estrogen-dependent diseases as well as hormone dependent Tumors can be expected if the daily doses range from 5 μg to 50 mg of the compound of the invention per kg of body weight include. For larger mammals, for example, to humans, is a recommended daily dose in the range of 10 μg to 30 mg per kg of body weight.

suitable Dosages for the compounds of the invention amount from 0.005 to 50 mg per day per kg of body weight, depending on the age and constitution of the patient, taking the necessary daily dose through Single or multiple delivery can be applied.

The formulation of the pharmaceutical preparations based on the new compounds is carried out in a conventional manner, by processing the active ingredient with the commonly used in galenics carriers, fillers, Zerfallbeeinflussern, binders, humectants, lubricants, absorbents, diluents, flavoring agents, colorants, etc., and converted into the desired application form. Reference may be made to Remington's Pharmaceutical Science, 15 ^th ed. Mack Publishing Company, East Pennsylvania (1980).

For the oral In particular, tablets, dragees, capsules, pills, Powders, granules, lozenges, suspensions, emulsions or solutions in Question.

For the parenteral Application injection and infusion preparations are possible.

For intra-articular injection can appropriately prepared crystal suspensions are used.

For intramuscular injection can aqueous and oily injection solutions or suspensions and corresponding depot preparations are used.

For the rectal Application can the new compounds in the form of suppositories, capsules, solutions (e.g. in the form of clysters) and ointments both to the systemic as well used for local therapy.

to pulmonary application of the new compounds may be in the form of aerosols and inhalants.

For the topical Application are formulations in gels, ointments, greases, creams, Pastes, powders, milk and tinctures possible. The dosage of the compounds of the general formula I should be 0.01% -20% in these preparations, to achieve a sufficient pharmacological effect.

The The present invention includes the compounds of the general formula I and their use for the manufacture of a medicament, in particular for the treatment of estrogen-dependent Diseases characterized by the inhibition of 17β-hydroxysteroid dehydrogenase positive be influenced.

The Compounds of the invention of general formula I are preferred for the preparation of a Medicament for the treatment of hormone-dependent tumors of the male and female gonads, male and female sexual organs including the mammary glands, in particular used by prostate cancer or breast cancer.

Farther are the compounds of the invention for the manufacture of a medicament for the treatment of endometriosis prefers.

Further the present invention relates to pharmaceutical compositions, the at least one compound of the invention, optionally in the form of a pharmaceutically / pharmacologically acceptable salt, without or together with pharmaceutically acceptable excipients and / or carriers contain.

These Pharmaceutical compositions and pharmaceuticals can be used for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration be provided. They contain in addition to conventional carriers and / or diluents at least one compound of the invention.

The Medicaments of the invention are mixed with the usual solid or liquid carriers or diluents and usually used pharmaceutical adjuvants according to the desired Type of administration with a suitable dosage in a known manner produced. The preferred preparations consist in a dosage form, which is suitable for oral administration. Such dosage forms are for example tablets, film-coated tablets, dragees, capsules, Pills, powders, solutions or Suspensions or depot forms.

The pharmaceutical compositions comprising at least one of the compounds of the invention contained, are preferably administered orally.

It Also come in parenteral preparations such as injection solutions Consideration. Furthermore, as preparations, for example, also Called suppositories and vaginal use agents.

Appropriate Tablets can for example, by mixing the active ingredient with known excipients, for example, inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants like cornstarch or alginic acid, Binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or Means for obtaining a depot effect such as carboxyl polymethylene, Carboxymethylcellulose, cellulose acetate phthalate or polyvinylactate, to be obtained. The tablets can also consist of several layers.

Corresponding can Dragees by coating of cores produced analogously to the tablets with usually used in dragee coatings Agents, for example polyvinylpyrrolidone or shellac, gum arabic, Talc, titanium oxide or sugar. It can also the dragee envelope consist of several layers, the top of the tablets mentioned Excipients can be used.

Solutions or Suspensions of the compounds of the invention of general formula I can additionally taste-improving agents such as saccharin, cyclamate or sugar as well as B. flavorings such as vanillin or orange extract. You can Furthermore Suspension adjuvants such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.

The Examples of compounds containing the general formula I capsules be prepared by the compounds) of the general Formula I with an inert carrier How to mix milk sugar or sorbitol and encapsulate in gelatine capsules.

suitable Suppositories can be, for example, by mixing with designated carriers as neutral fats or polyethylene glycol or their derivatives.

• 1) Antiandrogene wie Cyproteronacetat, Flutamid, Casodex etc.
• 2) Gonadrotropinhormon (GnRH) Agonisten wie Synarel, Lupron, Busrelin
• 3) Aromatasehemmer wie Anastrozol, Formestan, Letrozol, Exemestan
• 4) 5α-Reduktase Hemmer wie Finasterid
• 5) Zytostatika wie Vinblastin, Daunorubicin
• 6) VEGF-Kinase-Inhibitoren
• 7) Antigestagene wie Onapristone, Mifepristone
• 8) Antiestrogene wie Tamoxifen
• 9) Antisense Oligonukleotide
• 10) EGF-Antikörper

The compounds according to the invention can be administered in combination for the prophylaxis and therapy of breast or prostate carcinomas or endometriosis with one or more of the following active ingredients:

• 1) antiandrogens such as cyproterone acetate, flutamide, Casodex etc.
• 2) Gonadrotropin hormone (GnRH) agonists such as Synarel, Lupron, Busrelin
• 3) aromatase inhibitors such as anastrozole, formestan, letrozole, exemestane
• 4) 5α-reductase inhibitors such as finasteride
• 5) cytostatics such as vinblastine, daunorubicin
• 6) VEGF kinase inhibitors
• 7) Antigestagens like Onapristone, Mifepristone
• 8) antiestrogens like tamoxifen
• 9) antisense oligonucleotides
• 10) EGF antibodies

Furthermore can the compounds of the invention of general formula I for the therapy and prophylaxis of others above unnamed disease states be used.

The The following examples serve to explain the subject of the invention in more detail. without limiting it to this to want.

The Functionalization of C-atom 2 of an estea-1,3,5 (10) -trien-17-one derivative is preferably carried out by Friedel-Crafts acylation as in Literature (T. Nambara et al., Chem. Pharm. Bull. 18, 474). After changing the protective group in position 3 is by Baeyer-Villiger oxidation generated a 2-carboxy-estra-1,3,5 (10) -trien-17-one (M.B. Smith, J. March, March's Advanced Organic Chemistry, 5th Edition, Wiley Sons 2001, 1417-1418 and there zit. Lit.). The ester is saponified and with the corresponding Alkyl halide under basic conditions in a 2-alkyl ether. The Cleavage of the protecting group in position 3 takes place as in the literature (Greene T., P. G. M. Wuts, Protective Groups in Organic Synthesis, T.W. Wiley & Sons, 1999, 249-275).

However, the 2-acyl derivatives represented by the Friedel-Crafts acylation can also be replaced by Reduk Reaction with sodium borohydride and subsequent hydrogenation to 2-Alkylestradiolderivaten reacted and converted by Oppenauer oxidation at C-17 (C. Djerassi, Org React 1951, 6, 207) into the corresponding 2-Alkylestronderivate.

For compounds containing additional double bonds in the steroid skeleton and / or a methylene bridge between C-14 and C-15, the 2-hydroxylation is realized by ortho-metallation, wherein as ortho-directing protecting group preferably an ether (HE pairs, SR fragrance . US 6,448,419 ; PS Kiuru, K. Wähälä, Steroids 2003, 68, 373) or carbamate protecting group (V. Snieckus, Chem. Rev. 1990, 90, 879-933). The electrophilic substitution is carried out after 2-lithiation with trialkyl borate and subsequent basic oxidation with hydrogen peroxide. The selectively obtained 2-hydroxy group is then converted in a known manner (Z. Wang, M. Cushman, Synth.Commun., 1998, 28, 4431) to the 2-alkoxy compound and deprotected at the C-3 atom. Subsequent Oppenauer oxidation (C. Djerassi, Org React 1951, 6, 207, S. Schwarz et al Pharmacy 2001, 56, 843-849) provides the 17-keto compounds.

2-halogen compounds are made by orthothallation of 3-acetyl-estrone and subsequent reaction with a copper halide (P.C. Bulman Page, F. Hussain, J.L. Maggs, P.Morgan, B.K. Park, Tetrahedron, 1990, 46, 2059-2068). 2-alkynyl compounds are starting from 3-acetyl-2-iodo-estrone represented by a Sonogashira coupling. By partial or complete catalytic hydrogenation and subsequent deacetylation passes to give the corresponding 2-alkenyl or 2-alkyl compounds.

alternative can short-chain 2-alkyl or 2-alkenyl substituents also via a ortho-lithiation are shown. Starting from Estron need to do this first Protecting groups can be introduced at C-3 and C-17 of the steroid skeleton. The 17-carbonyl group will with ethylene glycol and trimethyl orthoformate in the presence catalytic amounts of p-toluenesulfonic acid in the corresponding ethylene acetal converted (Caserio Jr., F.F., Roberts, J.D., J. Am. Chem. Soc., 80, 1958, 5837). Subsequently becomes the 3-hydroxy group with an ortho-directing protecting group protected. Preferably, under standard conditions with Hünig base and methoxymethyl chloride converted to methoxymethyl ether (G. Stork, T. Takahashi, J. Am. Chem. Soc., 1975, 99, 1275). The subsequent ortho-lithiation takes place with sec-butyllithium optionally in the presence of copper (I) iodide. The intermediary 2-metallate is with alkyl or alkenyl iodides or bromides to corresponding 2-alkyl or 2-alkenyl derivative implemented. After removal the protective groups in an acidic environment can be reached to the desired 2-alkyl and alkenylestrone derivatives.

to Functionalization of the C-6 atom must first provide protecting groups for the 3-hydroxy function as well introduced the 17-keto group become. As described above, the 17-keto group is preferably used as Ethylene acetal and the 3-hydroxy group in the corresponding methoxymethyl ether converted (G. Stork, T. Takahashi, J. Am. Chem. Soc., 1975, 99, 1275). The subsequent oxidation the benzylic 6-methylene group to the ketone is preferably carried out with chromium trioxide and 3,5-dimethylpyrazole (G. Weber, J. Schaumann, C: Carl, S. Schwarz, J. Prakt. Chem. 1989, 331, 223).

The corresponding 6-oxo derivatives can then under Wittig or Wadsworth-Horner conditions (M.B. Smith, J. March, March's Advanced Organic Chemistry, 5th Edition, Wiley Sons 2001, 1231ff and cited therein Citations) to the corresponding 6-alkylidene compounds be implemented. The corresponding 6-alkyl derivatives may preferably be represented by catalytic hydrogenation.

6-alkyl ethers and -ester can after previous reduction of the 6-oxo group with sodium borohydride under Standard conditions are synthesized. (Ohno, K., Nishiyama, H., Nagase, H., Tetrahedron Lett., 1979, 4405 and Weber, H. Khorana, H.G., J. Mol. Biol., 72, 1972, 219)

The starting material for the functionalization of the carbon atom 7 of an estra-1,3,5 (10) -trien-17-one derivative is 7β-hydroxyestrone, which is prepared by microbiological 7β-hydroxylation of 19-nor-androstene-3,17 dion and subsequent aromatization can be prepared (Squibb and Sons Inc., US 3401180, 1968 ). Oppenauer oxidation leads to the corresponding 7-oxo derivative. The further derivatization of the 7-position can be carried out as described analogously to the functionalization of the 6-position.

The Synthesis of 14,15-dehydro or 15,16-dehydro derivatives can be analogous known methods (see, e.g., P.N. Rao et al., Steroids 2002, 67, 1079) become.

16-fluorinated Estrone derivatives can as from A.C. Stalford et al. (Steroids 1997, 62, 750) or also S. Stavber et al. (Synthesis 2002, 2609) become.

The mentioned methods are correspondingly also to 18a homo-Estronderivate Applicable (P.N. Rao, J.W. Cessac, Steroids 2002, 67, 1065 and there cited ref.).

production method

General Synthesis Instructions A:

One-pot hydrolysis of the 3-Methoxymethylethers as well as the 17-Ethylenactals a 3-Methoxmethoxy-estea-1,3,5 (10) -trien-17-one-17-ethylene acetal derivative

To a solution of 100 mg of a 3-methoxymethoxy-estea-1,3,5 (10) -trien-17-one-17-ethylene acetal derivative in 5 mL of dichloromethane / acetone was added 100 mg of p-toluenesulfonic acid. The solution was over Night stirred, then with 5 mL of a sat. Sodium bicarbonate solution added and the organic of the aqueous Phase separated. The watery Phase was washed with dichloromethane (3 x 5 mL). The combined organic Phases were with a ges. NaCl solution, over sodium sulfate dried and concentrated on a rotary evaporator. The cleaning took place by flash chromatography (cyclohexane / ethyl acetate).

General Synthesis Instructions B:

Preparation of 2-alkynyl and 2-alkyl ester derivatives

0.5 mmol (219 mg) of 3-acetoxy-2-iodo-estra-1,3,5 (10) -triene were in 16 mL of triethylamine / THF (3: 1), with 10 mg of palladium (II) acetate, 8 mg of cuprous iodide, 10 mg of triphenylphosphine and 1 mmol of an alkynyl compound and 45 min at room temperature stirred under argon. Subsequently was diluted with ethyl acetate, with 1N hydrochloric acid, ges. sodium bicarbonate and ges. Sodium chloride solution washed and over Dried sodium sulfate. The solvent was then distilled off on a rotary evaporator. The cleaning took place flash chromatographically (cyclohexane / ethyl acetate).

to Preparation of the 2-alkynyl estrone derivatives was 0.2 mmol of the coupling product in 6 mL of MeOH / THF (1: 1) and mixed with 0.5 mL HCl (conc.). The solution was left at room temperature for 12 hours touched. Then it was diluted with 20 mL of ethyl acetate. After separation of the organic Phase from the aqueous was the organic phase with water, sat. Sodium bicarbonate solution and ges. Sodium chloride solution washed and the watery Phase extracted with ethyl acetate. The combined organic phases were over Dried sodium sulfate, concentrated on a rotary evaporator and flash chromatography purified (cyclohexane / ethyl acetate).

to Preparation of 2-Alkylestronderivate were 0.2 mmol of the coupling product dissolved in 20 mL of ethyl acetate, with 100 mg of palladium on activated carbon (10%) and three hours hydrogenated. Subsequently was the catalyst was filtered off and concentrated on a rotary evaporator. The residue in 20 mL methanol, treated with 100 mg sodium methoxide and 12 Hours stirred. Then it was neutralized with Amberlite IR-120 (H +), filtered and concentrated on a rotary evaporator. The purification was carried out by flash chromatography (cyclohexane / ethyl acetate).

General Synthesis Instructions C:

2-alkylation by ortho-lithiation

Under an argon inert gas atmosphere became one at -78 ° C solution of 502 mg (1.4 mmol) of 3-methoxy-methoxy-estra-1,3,5 (10) -trien-17-one-17-ethylene-acetal in 10 mL THF, add 5.4 mL of a 1.3 M solution of sec-butyllithium (7.0 mmol) is added slowly. The reaction solution was then stirred for two hours at -78 ° C and with 9.8 mmol of an alkyl or alkenyl iodide. The resulting Mixture was over Night stirred the temperature rose to room temperature. The workup was done by adding 10 mL of sat. Sodium bicarbonate solution and subsequent Extraction of the aqueous Phase with ethyl acetate (3 × 30 mL). The combined organic phases were washed with a sat. NaCl solution, over sodium sulfate dried and concentrated on a rotary evaporator. The cleaning took place by flash chromatography (cyclohexane / ethyl acetate).

The Hydrolysis of the 3-methoxymethyl ether and the 17-ethylene acetal was carried out according to general synthesis instructions A.

General Synthesis Instructions D:

2-halogenation of Estrone derivatives (P.C. Bulman Page, F. Hussain, J. L. Maggs, P.Morgan, B.K. Park, Tetrahedron, 1990, 46, 2059).

Examples and manufacturing process

The following examples 1-4 were prepared according to the aforementioned Synthesis B.

example 1

3-hydroxy-2-phenylethynyl-estra-1,3,5 (10) -trien-17-one 19

• ¹ H-NMR (CDCl _3): δ = 0.92 (s, 3H, 13-CH _3), 6.71 (s, 1H, 1H), 7:35 (m, 4H, arom.), 7:51 (m, 2H, arom.)
• ¹³ C-NMR (CDCl _3): δ = 220.5 (q, C = O), 154.0, 139.5, 131.9, 131.3 (2C), 128.4 (2C), 128.3, 128.2, 122.4, 114.4, 106.8 (12C, arom. ) 95.4, 83.4 (2C, -C≡C-), 50.3, 47.9, 43.6, 38.1, 35.8, 31.4, 29.5, 26.3, 25.8, 21.5, 13.8

Example 2

2-hexyl-3-hydroxy-estra-1,3,5 (10) -trien-17-one 20

• ¹ H-NMR (CDCl _3): δ = 0.88 (s, 3H; 2-C ₆ H _13), 0.91 (s, 3H, 13-CH _3), 4.69 (br s, 1H, OH.), 6:51, 7.02 (s, 2H, 1-H, 4-H)

Example 3

3-hydroxy-2- (2'-phenyl-ethyl) estra-1,3,5 (10) -trien-17-one 21

• ¹ H-NMR (CDCl _3): δ = 0.91 (s, 3H, 13-CH _3), 4.74 (br. S, 1H, OH), 6.50, 7:01 (s, 2H, 1H, 4-H) , 7.19-7.30 (m, 5H, arom.)

Example 4

3-hydroxy-2- (3'-phenyl-propyl) estra-1,3,5 (10) -trien-17-one 22

• ¹ H-NMR (CDCl ₃ ): δ = 0.91 (s, 3H, 13-CH ₃ ), 2.60 (t, 2H, ³ J = 7.8 Hz, CH ₂ CH ₂ CH ₂ -Ph), 2.69 (t, 2H , ³ J = 7.8 Hz, CH ₂ CH ₂ CH ₂ -Ph), 4.83 (br.s, 1H, OH), 6.50, 7.01 (s, 2H, 1-H, 4-H), 7.15-7.29 (m , 5H, arom.)

The following examples 5-7 were prepared according to the aforementioned Synthesis Code C.

Example 5

3-hydroxy-2-methyl-estra-1,3,5 (10) -trien-17-one 8th

• ¹ H-NMR (CDCl _3): δ = 0.91 (s, 3H, 13-CH _3), 2.21 (s, 3H; _2-CH3), 5:05 (br s, 1H, OH.), 6.52 7:02 ( s, 2H, 1H, 4H)

Example 6

3-hydroxy-2-propyl-estra-1,3,5 (10) -triene-l7-one 9

• ¹ H-NMR (CDCl ₃ ): δ = 0.91 (s, 3H, 13-CH ₃ ), 0.98 (t, 3H, ³ J = 7.2 Hz, 2-Pr), 6.51, 7.02 (s, 2H, 1 H, 4-H)

Example 7

3-hydroxy-2- (prop-2'-enyl) estra-1,3,5 (10) -trien-17-one 10

The preparation was carried out according to general synthesis instructions C. Before addition of the allyl iodide However, the solution of 2-metalate was first under argon in a solution of 8.4 mmol of copper (I) iodide in 5 mL THF and the resulting reaction mixture stirred for a further hour.
¹ H-NMR (CDCl ₃ ): δ = 0.91 (s, 3H, 13-CH ₃ ), 2.21 (s, 3H, 13-CH ₃ ), 3.37 (dd, 2H, ³ J = 6.3 Hz, ⁴ J = 1.2 Hz, CH ₂ CH = CH ₂ ), 4.99 (br.s, 1H, OH), 5.16 (m, 2H, CH ₂ CH = CH ₂ ), 5.99 (m, 1H, CH ₂ CH = CH ₂ ), 6.56, 7.01 (s, 2H, 1-H, 4-H)

Example 8

3-hydroxy-2-pentanoyl-estra-1,3,5 (10) -trien-17-one 2

• (according to T. Nambara et al., Chem. Pharm. Bull. 1979, 18, 474)
• ¹ H-NMR (CDCl ₃ ): δ = 0.93 (s, 3H, 18-CH ₃ ), 0.97 (t, J = 7.2 Hz, 3H, CH ₂ CH ₃ ), 2.90-2.98 (m, 4H, 6- CH ₂ , CH ₂ CO), 6.71, 7.63 (2 s, 2H, 1-H, 4-H), 12.19 (s, 1H, 3-OH).

Example 9

3-hydroxy-2-methoxymethyl-estra-1,3,5 (10) -trien-17-one 7

262 mg (828 μmol) of 2-methoxymethyl-estra-1,3,5 (10) -triene-3,17β-diol were dissolved in acetone, cooled to -70 ° C and mixed in portions with Jones reagent (1.6 mmol) , After 45 minutes, the mixture was quenched with methanol, admixed with water and extracted with ethyl acetate. The combined organic phases were washed with a sat. Washed sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. Flash chromatography (n-hexane / ethyl acetate) provided 97 mg (37%) of the desired product as colorless crystals.
¹ H-NMR (CDCl _3): δ = 0.91 (s, 3H, 18-CH _3), 2.84-2.44 (m, 2H, _6-CH2), 3:42 (s, 3H; OCH _3), 4.57-4.65 (m, 2H, OCH ₂ ), 5.44 (s, 1H, OH), 6.63, 6.92 (2 s, 2H, 1-H, 4-H), 7.24 (s, 1H, 3-OH)
¹³ C-NMR (CDCl _3): δ = 220.63 (C = O).

The following examples 10-12 were prepared according to the aforementioned Synthesis D.

Example 10

2-chloro-3-hydroxy-estra-1,3,5 (10) -trien-17-one 11

• ¹ H-NMR (CDCl _3): δ = 0.91 (s, 3H; _13-CH3), 5:35 (br. S, 1H, OH), 6.74, 7.20 (s, 2H, 1H, 4-H)

Example 11

2-Chloro-3-hydroxy-18a-homoestra-1,3,5 (10) -trien-17-one 1

• ¹ H-NMR (CDCl _3): δ = 0.79 (t, J = 7.4 Hz, 3H; _18-CH3), 2.82-2.84 (m, 2H, 6-CH _2), 6.69, 7.18 (2 s, 2H ; 1-H, 4-H).

Example 12

2-cyano-3-hydroxy-estra-1,3,5 (10) -trien-17-one 12

• ¹ H-NMR (CDCl ₃ ): δ = 0.92 (s, 3H, 13-CH ₃ ), 6.64, 7.35 (s, 2H, 1-H, 4-H)

Example 13

dione -triene-6.17-3-hydroxy-2-methoxy-estra-1,3,5 (10) 14

A cooled at -35 ° C solution of 22.2 g (222 mmol) of chromium (VI) oxide in 230 mL dichloromethane 22.2 g (236 mmol) of 3,5-dimethylpyrolidinone was added. The solution was stirred for 30 minutes at -35 ° C before a solution of 5.74 g (14.79 mmol) of 2-methoxy-3-methoxmethoxy-estra-1,3,5 (10) -trien-17-one-17-ethylene acetal in 10 mL of dichloromethane. After a further two hours, 96 mL of a 5N sodium hydroxide solution was added to the reaction mixture, and the organic was separated from the aqueous phase. The aqueous phase was extracted with dichloromethane (3 x 50 mL). The combined phases were then filtered, washed with water (3 x 50 mL) and a sat. NaCl solution and dried over sodium sulfate. Flash chromatography afforded 1.94 g (33%) of 2-methoxy-3-methoxy-methoxy-estra-1,3,5 (10) -tri en-6,17-dione-17-ethylene-acetal as a colorless solid.

Of these, 100 mg (0.25 mmol) were reacted according to general procedure A to give 62 mg (80%) of the desired product as colorless crystals.
¹ H-NMR (CDCl _3): δ = 0.93 (s, 3H, 13-CH _3), 3.97 (s, 3H, 2-OCH _3), 5.74 (br s, 1H, OH.), 6.84, 7.60 ( s, 2H, 1H, 4H),
¹³ C-NMR (CDCl ₃ ): δ = 219.5 (17-C), 195.8. (6-C), 151.1, 144.2, 140.2, 126.2, 112.6, 106.5 (6C, arom.), 55.9 (OCH ₃ ), 50.2, 47.6, 43.1, 42.9, 39.6, 35.7, 31.2, 25.3, 21.3, 13.7

Example 14

3,7β-dihydroxy-2-iodo-estra-1,3,5 (10) -trien-17-one 15

1.86 g (6.5 mmol) 7β-hydroxy-estrone were dissolved in 25 mL of pyridine and mixed with 7 mL acetic anhydride. The solution is left at room temperature for 12 hours touched. Thereafter, the solvent became concentrated on a rotary evaporator and the oily residue crystallized in ice water. Subsequently The solid was washed with water and then with n-hexane.

It were obtained 2.3 g of a colorless solid which without further Purification to give 3,7β-diacetoxy-2-iodo-estra-1,3,5 (10) -trien-17-one after P.C. Bulman Page, F. Hussain, J.L. Maggs, P. Morgan, B.K. Park, Tetrahedron, 1990, 46, 2059.

To remove both acetyl protective groups, 700 mg (1.4 mmol) of 3,7β-diacetoxy-2-iodo-estra-1,3,5 (10) -trien-17-one dissolved in 20 ml of methanol were mixed with 200 mg of sodium methoxide and the solution stirred overnight. Then 2.5 g Amberlite IR-120 was added, stirred for 30 minutes, filtered and the solution was concentrated on a rotary evaporator. Flash chromatography (cyclohexane / ethyl acetate) provided 396 mg (68%) of colorless crystals.
¹ H-NMR (DMSO-d ₆ ): δ = 0.81 (s, 3H, 13-CH ₃ ), 2.58 (dd, 2H, ² J = 16.0 Hz, ³ J = 7.4 Hz, 6-H), 2.82 ( dd, 2H, ² J = 16.0 Hz, ³ J = 5.9 Hz, 6-H), 3.76 (br. s, 1H, OH), 4:59 (m, 1H, 7-H), 6.60, 7:41 (s, 2H , 1-H, 4-H), 9.95 (br. S, 1H, OH)

Example 15

7β-acetoxy-3-hydroxy-2-iodo-estra-1,3,5 (10) -trien-17-one 16

700 mg (1.4 mmol) of 3,7β-diacetoxy-2-iodo-estra-1,3,5 (10) -trien-17-one were dissolved in 30 ml of methanol, admixed with 1.0 g of sodium bicarbonate and the reaction mixture was stirred overnight , It was then filtered and the solution was concentrated on a rotary evaporator. Flash chromatography (cyclohexane / ethyl acetate) provided 402 mg (63%) of colorless crystals.
¹ H-NMR (DMSO-d ₆ ): δ = 0.82 (s, 3H, 13-CH ₃ ), 2.64 (dd, 2H, ² J = 16.6 Hz, ³ J = 6.2 Hz, 6-H), 2.99 ( dd, 2H, ² J = 16.6 Hz, ³ J = 5.8 Hz, 6-H), 5.01, (m, 1H, 7-H), 6.60, 7:45 (s, 2H, 1H, 4-H), 6.10 (brs s, 1H, OH)

Example 16

dione -triene-7.17-3-hydroxy-2-iodo-estra-1,3,5 (10) 13

A solution of 206 mg (0.5 mmol) of 3,7β-dihydroxy-2-iodo-estra-1,3,5 (10) -trien-17-one 14 in 15 ml of toluene and 4 ml of cyclohexanone was heated to 140 ° C ( Oil bath temperature) and a solution of 400 mg of aluminum isopropylate in 10 mL of toluene was added dropwise. Meanwhile, a part of the reaction mixture was distilled off. After complete addition of the aluminum isopropoxide was heated for a further 5 hours under reflux. Then the reaction solution was cooled and diluted with 80 mL dichloromethane and 30 mL potassium / sodium tartrate solution and the resulting mixture was stirred vigorously for 30 minutes before the organic phase was separated from the aqueous phase. The aqueous phase was finally extracted with dichloromethane (3 x 30 mL) and the combined organic phases washed with a sat. NaCl solution, dried over sodium sulfate and concentrated on a rotary evaporator. Flash chromatography (cyclohexane / ethyl acetate) afforded 129 mg (63%) of colorless crystals.
¹ H-NMR _(CDCl3) δ = 0.90 (s, 3H; _13-CH3), 3:58 (s, 2H, 6-H), 5.62 (br s, 1H, OH.), 6.77, 7:56 (s , 2H, 1H, 4H)
¹³ C-NMR (CDCl _3): δ = 219.5 (17-C), 208.9 (6C), 153.7, 135.4, 133.9, 133.6, 114.2, 83.4 (6C, arom.), 50.1, 47.8, 45.3, 44.9 , 40.7, 35.5, 30.5, 25.1, 23.0, 13.7

Example 17

2-chloro-3-hydroxy-7α-methyl-estra-1,3,5 (10) -trien-17-one 17

• (Preparation analogous to Ali, H., Lier, J.E. van, J. Chem. Soc. Perkin Trans 1, 10, 1991, 2485)
• ¹ H-NMR (CDCl ₃ ): δ = 0.87 (d, 3H, ³ J = 7.1 Hz, 7α-CH ₃ ) 0.91 (s, 3H, 13-CH ₃ ), 3.03 (dd, 1H, ² J = 16.5 Hz, ³ J = 6.2, 6-H), 5.44 (brs s, 1H, OH), 6.73, 7.21 (s, 2H, 1-H, 4-H)

Example 18

3-hydroxy-2-methoxy-estra-1,3,5 (10), 6-tetraene-17-one 18

To a solution of 1060 mg (2.57 mmol) of 2-methoxy-3-methoxymethoxy-estra-1,3,5 (10) -triene-6,17-dione-17-ethylene-acetal in 40 mL of THF / methanol (1: 1) was added 300 mg (7.94 mmol) of sodium borohydride. The The reaction mixture was stirred for 12 hours at room temperature and then mixed with 20 ml of water and 40 ml of ethyl acetate. The organic phase was from the aqueous Phase separated. Subsequently became the watery Phase with ethyl acetate (3 × 15 mL). The combined organic phases were washed with a sat. NaCl solution, over sodium sulfate dried and concentrated on a rotary evaporator.

crude: 1040 mg colorless solid.

700 mg of the crude product were reacted according to Synthesis Procedure A to give 434 mg (84%) of the desired product as colorless crystals.
¹ H-NMR (CDCl ₃ ): δ = 0.92 (s, 3H, 13-CH ₃ ), 3.90 (s, 3H, OCH ₃ ) 5.49 (s, 1H, OH), 5.92 (dd, 1H, ³ J = 9.8 Hz, ³ J = 9.7 Hz, 7-H) 6.44 (dd, 1H, ³ J = 9.8 Hz, ⁴ J = 2.7 Hz, 6-H) 6.70, 6.80 (s, 2H, 1-H, 4-H )
¹³ C-NMR (CDCl ₃ ): δ = 219.9 (17-C), 145.2, 143.5, 130.6, 128.1, 127.8, 127.5, 112.5, 106.7, 56.0 (OCH ₃ ), 48.8, 48.3, 42.2, 37.9, 35.7, 31.0, 23.9, 21.5, 13.6

Example 19

3-hydroxy-2-methoxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraene-17-one 5

(to P.M. Rao et al., Steroids 2002, 67, 1079)

¹ H-NMR (CDCl _3): δ = 0:15 to 0:17 (m, 1H, 14α, 15α CH _2), 0.83-0.87 (m, 1H, 14α, 15α-CH _2), 1.17 (s, 3H; 18 -CH ₃ ), 3.89 (s, 3H, OCH ₃ ), 5.53 (s, 1H, OH), 6.70, 6.75 (2 s, 2H, 1-H, 4-H).

Example 20

2-Chloro-16-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one

A solution of 58 mg (188 μmol) 2-chloro-3-hydroxy-estra-1,3,5 (10) -trien-17-one in 10 mL of methanol with 190 mg of 1-fluoro-4-hydroxy-1,4-diazonia-bicyclo [2,2,2] octane bis (tetrafluoroborate) on aluminum oxide and heated for five hours under reflux. Subsequently was cooled to room temperature, with 1N hydrochloric acid and extracted with dichloromethane. The organic phases were over Dried sodium sulfate and concentrated on a rotary evaporator. cleaning by HPLC (Chiracel OJ-H, n-heptane / 2-propanol) each supplied about 10 mg of the two stereoisomers.

2-chloro-16α-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one 3

• ¹ H-NMR (CDCl _3): δ = 0.96 (s, 3H; _18-CH3), 5:32 (dd, J _HF = 50.8, J _HH = 7.2 Hz, 1H, 16β-H), 5:37 (s, 1H OH), 6.75, 7.19 (2 s, 2H, 1-H, 4-H) - ¹⁹ F-NMR (CDCl _3): δ = - 192 228 - -192.56 (m).

2-Chloro-16β-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one 4

• ¹ H-NMR (CDCl ₃ ): δ = 1.04 (s, 3H, 18-CH ₃ ), 2.84-2.88 (m, 2H, 6-CH ₂ ), 4.76 (ddd, J _HF = 50.0, J _HH = 8.2 , 8.6 Hz, 1H, 16α-H), 5:36 (s, 1H, OH), 6.75, 7.19 (2 s, 2H, 1H, 4-H) - ¹⁹ F-NMR (CDCl _3): δ = - 192.20 (dd, J = 50.1, 21.5 Hz).

Example 21

3-hydroxy-2-methoxy-estra-1,3,5 (10) -triene-17-thione 6

A solution of 1.09 g (3.63 mmol) of 3-hydroxy-2-methoxy-estra-1,3,5 (10) -trien-17-one in 60 ml of toluene (abs.) Was admixed with 3.7 g of Lawesson's reagent and heated under reflux for four hours. After addition of water was extracted with dichloromethane (3x) and the combined organic phases washed with water, dried over sodium sulfate and concentrated on a rotary evaporator. Flash chromatography (n-hexane / ethyl acetate) provided 412 mg (36%) of the desired product as yellow crystals.
¹ H-NMR (CDCl _3): δ = 0.95 (s, 3H, 18-CH _3), 2.70 (ddd, J = 8.6, 8.6, 21.9 Hz, 1H, 16-H), 2.76-2.90 (m, 2H 6-CH ₂ ), 3.02 (ddd, J = 1.2, 8.6, 21.9 Hz, 1H, 16-H '), 3.87 (s, 3H, OCH ₃ ), 5.44 (s, 1H, OH), 6.66, 6.79 (2s, 2H, 1-H, 4-H), 12.19 (s, 1H, 3-OH).

Claims (14)

2-substituted Estra-1,3,5 (10) -triene-17-ones of the general formula I

wherein R ^{2 is} a saturated or unsaturated C ₁ -C ₈ alkyl group, a C ₁ -C ₅ alkyloxy group, an aralkyl or alkylaryl radical, a radical -OC _n F _m H _o , where n = 1, 2, 3, 4 , 5 or 6, m ≥ 1 and m + o = 2n + 1, or a group CH ₂ XY in which X is an oxygen atom and Y is an alkyl radical having 1 to 4 carbon atoms, and a halogen atom or a nitrile group R R ^{13 is} a hydrogen or a methyl group R ^{16 is} a hydrogen or a fluorine atom Z is an oxygen or a sulfur atom R ³ and R ^{5 are} each independently an α- or β-position hydrogen R ⁴ and R ^{6 are} each independently an α- or β hydrogen, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkyloxy, C ₁ -C ₅ acyl or hydroxy, or aralkyl or alkylaryl, R ₃ and R ₄ together Oxygen atom R ₅ and R ₆ together represent an oxygen atom R ⁷ and R ⁸ each represent a hydrogen atom or together a CH ₂ group, wherein the ge dashed lines in the B, C and D ring of the steroid skeleton may additionally be up to two double bonds, as well as their pharmaceutically acceptable salts. 2-substituted estra-1,3,5 (10) -triene-17-ones according to claim 1, characterized in that R ^{2 is} a C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkyl or C ₂ -C ₃ alkenyl or bromine, iodine or chlorine or a nitrile radical. 2-substituted Estra-1,3,5 (10) -triene-l7-ones according to claim 1, characterized in that R ^{2 is} a methoxy or pentanoyl radical, a methyl or a propyl group, an allyl radical, methoxymethyl and a phenyl -, a phenylethyl is a phenylpropyl or phenylethynyl group. 2-substituted estra-1,3,5 (10) -triene-17-ones according to claim 1, characterized in that R ^{13 is} a hydrogen atom. 2-substituted estra-1,3,5 (10) -triene-17-ones according to claim 1, namely 1) 2-chloro-3-hydroxy-18a-homoestra-1,3,5 (10) -triene-17 -one 1 2) 3-hydroxy-2-pentanoyl-estra-1,3,5 (10) -trien-17-one 2 3) 2-chloro-16α-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one 3 4) 2-chloro-16β-fluoro-3-hydroxy-estra-1,3 , 5 (10) -trien-17-one 4 5) 3-hydroxy-2-methoxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one 5 6 3-Hydroxy-2-methoxy-estra-1,3,5 (10) -triene-17-thione 6 7) 3-hydroxy-2-methoxymethyl-estra-1,3,5 (10) -triene-17 -on 7 8) 3-hydroxy-2-methyl-estra-1,3,5 (10) -trien-17-one 8 9) 2-ethyl-3-hydroxy -estra-1,3,5 (10) -trien-17-one 23 10) 3-hydroxy-2-propyl-estra-1,3,5 (10) -trien-17-one 9 11) 3-hydroxy-2- (prop-2'-enyl) -estra-1,3,5 (10) -trien-17-one 10 12) 2-chloro-3-hydroxy-estra-1,3,5 (10) -trien-17-one 11 13) 2-bromo 3-hydroxy-estra-1,3,5 (10) -trien-17-one 14) 2-cyano-3-hydroxy-estra-1,3,5 (10) -trien-17-one 12 15) 3-hydroxy-2-iodo-estra-1,3,5 (10) -triene-7,17-dione 13 16) 3-hydroxy-2-methoxy-estra-1,3,5 (10) -triene 6,17-dione 14 17) 3,7β-dihydroxy-2-iodo-estra-1,3,5 (10) -trien-17-one 15 18) 7β-acetoxy-3-hydroxy-2-iodo-estra -1,3,5 (10) -trien-17-one 16 19) 2-chloro-3-hydroxy-7α-methyl-estra-1,3,5 (10) -trien-17-one 17 20) 3 -Hy droxy-2-methoxy-estra-1,3,5 (10), 6-tetraen-17-one 18 21) 3-hydroxy-2-phenylethynyl-estra-1,3,5 (10) -triene-17- on 19 22) 2-hexyl-3-hydroxy-estra-1,3,5 (10) -trien-17-one 20 23) 3-hydroxy-2- (2'-phenylethyl) estra-1,3 , 5 (10) -trien-17-one 21 24) 3-hydroxy-2- (3'-phenylpropyl) -estra-1,3,5 (10) -trien-17-one 22 25) 3- Hydroxy-2-pentanoyl-estra-1,3,5 (10) -trien-17-one 26) 2-Bromo-3-hydroxy-estra-1,3,5 (10) -triene-6,17-dione 27) 2-chloro-3-hydroxy-estra-1,3,5 (10) -triene-6,17-dione 28) 2-bromo-3-hydroxy-estra-1,3,5 (10) -triene 7,17-dione 29) 2-chloro-3-hydroxy-estra-1,3,5 (10) -triene-7,17-dione 30) 2-cyano-3-hydroxy-estra-1,3, 5 (10) -triene-6,17-dione 31) 2-cyano-3-hydroxy-estra-1,3,5 (10) -triene-7,17-dione 32) 2-bromo-3-hydroxy estra-1,3,5 (10) -triene-17-thione 33) 2-chloro-3-hydroxy-estra-1,3,5 (10) -triene-17-thione 34) 2-cyano-3- hydroxy-estra-1,3,5 (10) -triene-17-thione 35) 3-hydroxy-2-iodo-estra-1,3,5 (10) -triene-17-thione 36) 3-hydroxy 2-iodo-estra-1,3,5 (10) -triene-6,17-dione 24 37) 2-Chloro-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10 ), 8-te traen-17-one 38) 3-hydroxy-2-iodo-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one 39) 2-bromo-3-hydroxy -14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one 40) 2-cyano-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3 , 5 (10), 8-tetraen-17-one 41) 3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one 42) 3-hydroxy 2-propyl-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one 43) 7β-acetoxy-2-chloro-3-hydroxy -estra-1,3 , 5 (10) -trien-17-one 44) 7β-acetoxy-2-cyano-3-hydroxy-estra-1,3,5 (10) -trien-17-one 45) 7β-acetoxy-2-bromo 3-hydroxy-estra-1,3,5 (10) -trien-17-one 46) 3-hydroxy-2-methyl-estra-1,3,5 (10) -triene-6,17-dione 47 ) 3-hydroxy-2-propyl-estra-1,3,5 (10) -triene-6,17-dione 48) 3-hydroxy-2- (prop-2'-enyl) -estra-1,3, 5 (10) -triene-6,17-dione 49) 3-hydroxy-2-methyl-estra-1,3,5 (10) -triene-7,17-dione 50) 3-hydroxy-2-propyl estra-1,3,5 (10) -triene-7,17-dione 51) 3-hydroxy-2- (prop-2'-enyl) -estra-1,3,5 (10) -triene-7, 17-dione 52) 7β-acetoxy-3-hydroxy-2-methyl-estra-1,3,5 (10) -trien-17-one 53) 7β-acetoxy-3- hydroxy-2-propyl-estra-1,3,5 (10) -trien-17-one 54) 7β-acetoxy-3-hydroxy-2- (prop-2'-enyl) -estra-1,3,5 (10) -trien-17-one 55) 2-bromo-3-hydroxy-18a-homoestra-1,3,5 (10) -trien-17-one 56) 3-hydroxy-2-iodo-18a-homoestra -1,3,5 (10) -trien-17-one 57) 2-cyano-3-hydroxy-18a-homoestra-1,3,5 (10) -trien-17-one 58) 2-bromo-3 -hydroxy-7α-methyl-estra-1,3,5 (10) -trien-17-one 59) 2-cyano-3-hydroxy-7α-methyl-estra-1,3,5 (10) -triene 17-one 60) 3-hydroxy-2-iodo-7α-methyl-estra-1,3,5 (10) -trien-17-one 61) 3-hydroxy-2-iodo-estra-1,3,5 (10) -trien-17-one 62) 3-hydroxy-2-methoxy-estra-1,3,5 (10), 14-tetraene-17-one 63) 16α-fluoro-3-hydroxy-2- (2'-phenyl-ethyl) -estra-1,3,5 (10) -trien-17-one 64) 16β-fluoro-3-hydroxy-2 ( 2'-phenyl-ethyl) -estra-1,3,5 (10) -trien-17-one 65) 3-hydroxy-2- (2'-phenylethyl) -18a-homoestra-1,3,5 (10) -trien-17-one 66) 16α-fluoro-3-hydroxy-2- (2'-phenylethyl) -18a-homoestra-1,3,5 (10) -trien-17-one 67) 16β-fluoro-3-hydroxy-2- (2'-phenylethyl) -18a-homoestra-1,3,5 (10) -trien-17-one 68) 16α-fluoro-3-hydroxy-2-phenylethynyl -estra-1,3,5 (10) -trien-17-one 69) 16β-fluoro-3-hydroxy-2-phenylethynyl-estra-1,3,5 (10) -trien-17-one 70) 2 -Chloro-16α-fluoro-3-hydroxy-18a-homoestra-1,3,5 (10) -trien-17-one 71) 2-chloro-16β-fluoro-3-hydroxy-18a-homoestra-1,3 , 5 (10) -trien-17-one 72) 2-cyano-16α-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one 73) 2-cyano-16β-fluoro 3-hydroxy-estra-1,3,5 (10) -trien-17-one 74) 2-cyano-16α-fluoro-3-hydroxy-18a-homoestra-1,3,5 (10) -triene 17-one 75) 2-cyano-16β-fluoro-3-hydroxy-18a-homoestra-1,3,5 (10) -trien-17-one 76) 2-chloro-16α-fluoro-3-hydroxy-14α , 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one 77) 2 -Chloro-16β-fluoro-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one 78) 2-cyano-16α-fluoro-3-hydroxy -14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraene-17-one 79) 2-cyano-16β-fluoro-3-hydroxy-14α, 15α-cyclopropa [a] estra -1,3,5 (10), 8-tetraen-17-one 80) 3-hydroxy-2- (2'-phenylethyl) -14α, 15α-cyclopropa [a] estra-1,3,5 ( 10), 8-tetraen-17-one 81) 16α-fluoro-3-hydroxy-2- (2'-phenylethyl) -14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraen-17-one 82) 16β-fluoro-3-hydroxy-2- (2'-phenylethyl) -14α, 15α-cyclopropa [a] estra-1,3,5 (10), 8-tetraene -17-one 83) 2-chloro-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10) -trien-17-one 84) 2-chloro-16β-fluoro-3- hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10) -trien-17-one 85) 2-cyano-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3, 5 (10) -trien-17-one 86) 2-cyano-16β-fluoro-3-hydroxy-14α, 15α-cyclopropa [a] estra-1,3,5 (10) -trien-17-one 87) 3-hydroxy-2- (2'-phenylethyl) -14α, 15α-cyclopropa [a] estra-1,3,5 (10) -trien-17-one 88) 16β-fluoro-3-hydroxy-2 - (2'-phenyl-ethyl) -14α, 15α- cyclopropa [a] estra-1,3,5 (10) -trien-17-one Use of 2-substituted Estra-1,3,5 (10) -trien-17-ones according to one of the claims 1 to 5 for the manufacture of a medicament. Use of 2-substituted Estra-1,3,5 (10) -trien-17-ones according to claim 6 for the preparation of a medicament for prophylaxis and therapy of estrogen-dependent Diseases characterized by the inhibition of 17β-hydroxysteroid dehydrogenases positively influence. Use of 2-substituted Estra-1,3,5 (10) -trien-17-ones according to claim 6 or 7, wherein at least one further active ingredient in Combination for the preparation of a drug is used. Use of 2-substituted Estra-1,3,5 (10) -trien-17-ones according to claim 8, wherein the further active ingredient is an antiandrogen, antigestagen, Aromatase inhibitor or an antiestrogen is. Use of 2-substituted Estra-1,3,5 (10) -trien-17-ones according to one of the claims 6 to 9 for the preparation of a medicament for prophylaxis and therapy of hormone addicts Tumor diseases of the male and female gonads, male and female sexual organs including the mammary glands. Use of 2-substituted Estra-1,3,5 (10) -trien-17-ones according to claim 10 for the preparation of a medicament for prophylaxis and therapy of breast cancer. Use of 2-substituted Estra-1,3,5 (10) -trien-17-ones according to claim 10 for the preparation of a medicament for prophylaxis and therapy of prostate cancer. Use of 2-substituted Estra-1,3,5 (10) -trien-17-ones according to claim 10 for the preparation of a medicament for the treatment the endometriosis. Pharmaceutical compositions containing at least a compound of general formula I according to one of claims 1 to 5 and optionally at least one further active ingredient together with pharmaceutical acceptable Auxiliaries and / or carriers, wherein the further active ingredient is an antiandrogen, antigestagen, aromatase inhibitor or an anti-estrogen.