Estra-1,3,5(10),16-tetraene-3-carboxamides for inhibition of 17.beta.-hydroxysteroid dehydrogenase (AKR1C3)

Abstract

The invention relates to AKR1C3 inhibitors of formula (I) and to processes for preparation thereof, to the use thereof for treatment and/or prophylaxis of diseases and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of bleeding disorders and endometriosis. ##STR00001##

Claims

1. A compound of the general formula (I) ##STR00084## where X is independently carbon or nitrogen, where the carbon is optionally substituted by R.sup.1, Y is carbon or nitrogen, where the carbon is optionally substituted by R.sup.2, R.sup.1 and R.sup.2 are each independently hydrogen, halogen, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-haloalkoxy, nitrile, nitro, SO.sub.2CH.sub.3, SO.sub.2CH.sub.2CH.sub.3, (CO)CH.sub.3, carboxyl, hydroxyl, NH.sub.2, CH.sub.2NH.sub.2, CH.sub.2OH, CH(OH)CH.sub.3, C(CH.sub.3).sub.2OH, (CO)NH.sub.2, (CO)NHCH.sub.3, (CO)NHCH.sub.2CH.sub.3, (CO)N(CH.sub.3).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, SO.sub.2N(CH.sub.3).sub.2, R.sup.3 is hydrogen or halogen, R.sup.4 is hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl or C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.6-alkyl, which are optionally substituted by up to 6 halogen atoms and are optionally mono- or disubstituted by hydroxyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, R.sup.5 is hydrogen, C.sub.1-C.sub.6-alkyl or C.sub.3-C.sub.6-cycloalkyl, where C.sub.1-C.sub.6-alkyl and C.sub.3-C.sub.6-cycloalkyl are optionally substituted by up to 6 halogen atoms and are optionally mono- or disubstituted by hydroxyl, hydroxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, hydroxy-C.sub.2-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.3-C.sub.6-cycloalkyl, aryl, heteroaryl, 3-10-membered heterocycloalkyl, aryl-C.sub.1-C.sub.6-alkyl, heteroaryl-C.sub.1-C.sub.6-alkyl, C(O)R, C(O)NH.sub.2, C(O)N(H)R, C(O)N(R)R, NH.sub.2, NHRN(R)R, N(H)C(O)R, N(R)C(O)R, N(H)C(O)OR, N(R)C(O)OR, NO.sub.2, N(H)S(O)R, N(R)S(O)R, N(H)S(O).sub.2R, N(R)S(O).sub.2R, NS(O)(R)R, S(O)R, S(O).sub.2R, S(O).sub.2NH.sub.2, S(O).sub.2NHR, S(O).sub.2N(R)R, S(O)(NR)R, where aryl, heteroaryl, aryl-C.sub.1-C.sub.6-alkyl and heteroaryl-C.sub.1-C.sub.6-alkyl are optionally each independently mono- or polysubstituted by R.sup.6, and 3-10-membered heterocycloalkyl is optionally independently mono- or polysubstituted by R, or R.sup.4 and R.sup.5 together with the directly joining nitrogen atom are a 4-7-membered ring which is optionally substituted by one or two substituents from the group consisting of: halogen, nitrile, hydroxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.10-cycloalkyl, aryl, heteroaryl, C(O)NH.sub.2, C(O)N(H)R, C(O)N(R)R, C(O)OH, C(O)OR, NH.sub.2, NHR, N(R)R, N(H)C(O)R, N(R)C(O)R, N(H)S(O)R, N(R)S(O)R, N(H)S(O).sub.2R, N(R)S(O).sub.2R, NS(O)(R)R, OH, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, OC(O)R, OC(O)NH.sub.2, OC(O)NHR, OC(O)N(R)R, SH, C.sub.1-C.sub.6-alkyl-S, S(O)R, S(O).sub.2R, S(O).sub.2NH.sub.2, S(O).sub.2NHR, S(O).sub.2N(R)R, where aryl and heteroaryl are optionally each independently mono- or polysubstituted by R.sup.6, and in which 5-, 6- or 7-membered ring one or more methylene groups are optionally replaced by NH, NR, O or S, R.sup.6 is halogen, nitrile, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.10-cycloalkyl, 3-10-membered heterocycloalkyl, aryl, heteroaryl, C(O)R, C(O)NH.sub.2, C(O)N(H)R, C(O)N(R)R, C(O)OR, NH.sub.2, NHR, N(R)R, N(H)C(O)R, N(R)C(O)R, N(H)C(O)NH.sub.2, N(H)C(O)NHR, N(H)C(O)N(R)R, N(R)C(O)NH.sub.2, N(R)C(O)NHR, N(R)C(O)N(R)R, N(H)C(O)OR, N(R)C(O)OR, NO.sub.2, N(H)S(O)R, N(R)S(O)R, N(H)S(O).sub.2R, N(R)S(O).sub.2R, NS(O)(R)R, OH, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, OC(O)R, OC(O)NH.sub.2, OC(O)NHR, OC(O)N(R)R, SH, C.sub.1-C.sub.6-alkyl-S, S(O)R, S(O).sub.2R, S(O).sub.2NH.sub.2, S(O).sub.2NHR, S(O).sub.2N(R)R, S(O)(NR)R, R and R are each independently C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl or C.sub.1-C.sub.6-haloalkyl, or the stereoisomers, tautomers, N-oxides, or salts thereof.

2. The compound of claim 1, wherein X is carbon substituted by hydrogen, Y is carbon or nitrogen, where the carbon is optionally substituted by R.sup.2, R.sup.2 is hydrogen, fluorine, chlorine, nitrile, methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, trifluoromethyl, (CO)CH.sub.3, R.sup.3 is hydrogen or fluorine, R.sup.4 is hydrogen, methyl, ethyl, isopropyl, propyl, butyl, cyclopropyl or 2,2,2-trifluoroethyl, R.sup.5 is hydrogen, methyl, ethyl, propyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2-fluoroethyl, 2-sulphamoylethyl, 3-sulphamoylpropyl, (1S,2R)-2-hydroxycyclopentyl, 3-hydroxy-2,2-dimethylpropyl, (1S,2S)-2-hydroxycyclopentyl, (3R)-4-hydroxy-3-methylbutyl, 1-(hydroxymethyl)cyclopentyl, (2S)-1-hydroxybutan-2-yl, (2R)-1-hydroxy-3-methylbutan-2-yl, 3-hydroxybutan-2-yl, 2-hydroxyethyl, 3,3,3-trifluoro-2-hydroxypropyl, 2-(1H-tetrazol-5-yl)ethyl, 1H-tetrazol-5-ylmethyl, 2-(methylsulphamoyl)ethyl, 3-amino-3-oxopropyl, 3-(methylamino)-3-oxopropyl, 2-methyl-2-[(methylsulphonyl)amino]propyl, (2S)-2,3-dihydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, (2RS)-2,3-dihydroxypropyl, (2R)-2,3-dihydroxypropyl, 2,3-dihydroxybutyl, 2-(methylsulphinyl)ethyl, 3-(methylsulphinyl)propyl, 2-(methyl sulphonyl)ethyl, 3-(methylsulphonyl)propyl, 2-(S-methylsulphonimidoyl)ethyl, (2R)-2-hydroxypropyl, (2S)-1-hydroxypropan-2-yl, 2-methoxyethyl, 3-methoxypropyl, 2-(isopropylsulphonyl)ethyl, (3-methyloxetan-3-yl)methyl, (2S)-2-hydroxypropyl, 2-(2-hydroxyethoxy)ethyl, or R.sup.4 and R.sup.5 together with the directly joining nitrogen atom are piperidinyl, pyrrolidinyl, morpholinyl, N-methylpiperazinyl, 1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholin-4-yl, 4-hydroxypiperidinyl, 4-(trifluoromethyl)piperidin-4-yl, (3R)-3-hydroxypiperidinyl, (2S)-2-(1H-tetrazol-5-yl)pyrrolidinyl, N-methyl-L-prolinamidyl and L-prolinamidyl, or the stereoisomers, tautomers, N-oxides, or salts thereof.

3. The compound of claim 1, wherein X is carbon substituted by hydrogen, Y is carbon or nitrogen, where the carbon is optionally substituted by R.sup.2, R.sup.2 is hydrogen, fluorine, chlorine, methyl, nitrile, methoxy, trifluoromethyl, R.sup.3 is hydrogen or fluorine, R.sup.4 is hydrogen, methyl, ethyl, isopropyl, propyl or cyclopropyl, R.sup.5 is hydrogen, methyl, ethyl, 2-sulphamoylethyl, 3-sulphamoylpropyl, (1S,2R)-2-hydroxycyclopentyl, 3-hydroxy-2,2-dimethylpropyl, (1S,2S)-2-hydroxycyclopentyl, (3R)-4-hydroxy-3-methylbutyl, 1-(hydroxymethyl)cyclopentyl, (2S)-1-hydroxybutan-2-yl, (2R)-1-hydroxy-3-methylbutan-2-yl, 3-hydroxybutan-2-yl, 2-hydroxyethyl, 3,3,3-trifluoro-2-hydroxypropyl, 2-(1H-tetrazol-5-yl)ethyl, 1H-tetrazol-5-ylmethyl, 2-(methylsulphamoyl)ethyl, 3-amino-3-oxopropyl, 3-(methylamino)-3-oxopropyl, 2-methyl-2-[(methylsulphonyl)amino]propyl, (2S)-2,3-dihydroxypropyl, 3-hydroxypropyl, (2RS)-2,3-dihydroxypropyl, (2R)-2,3-dihydroxypropyl, 2-(methylsulphinyl)ethyl, (2R)-2-hydroxypropyl, (2S)-1-hydroxypropan-2-yl, 2-methoxyethyl, 2-(isopropylsulphonyl)ethyl, (3-methyloxetan-3-yl)methyl, (2S)-2-hydroxypropyl or 2-(2-hydroxyethoxy)ethyl or R.sup.4 and R.sup.5 together with the directly joining nitrogen atom are piperidinyl, pyrrolidinyl, morpholinyl, 4-hydroxypiperidinyl, (3R)-3-hydroxypiperidinyl, (2S)-2-(1H-tetrazol-5-yl)pyrrolidinyl, N-methyl-L-prolinamidyl or L-prolinamidyl or the stereoisomers, tautomers, N-oxides, or salts thereof.

4. The compound of claim 1, wherein X is carbon substituted by hydrogen, Y is carbon or nitrogen, where the carbon is optionally substituted by R.sup.2, R.sup.2 is hydrogen, fluorine, nitrile, methoxy or trifluoromethyl, R.sup.3 is hydrogen or fluorine, R.sup.4 is hydrogen, methyl, ethyl or isopropyl, R.sup.5 is hydrogen, ethyl, 2-sulphamoylethyl, (1S,2R)-2-hydroxycyclopentyl, 3-hydroxy-2,2-dimethylpropyl, (1S,2S)-2-hydroxycyclopentyl, (3R)-4-hydroxy-3-methylbutyl, 1-(hydroxymethyl)cyclopentyl, (2S)-1-hydroxybutan-2-yl, (2R)-1-hydroxy-3-methylbutan-2-yl, 3-hydroxybutan-2-yl, 2-hydroxyethyl, 3,3,3-trifluoro-2-hydroxypropyl, 2-(1H-tetrazol-5-yl)ethyl, 1H-tetrazol-5-ylmethyl, 2-(methylsulphamoyl)ethyl, 3-amino-3-oxopropyl, 3-(methylamino)-3-oxopropyl, 2-methyl-2-[(methylsulphonyl)amino]propyl, (2S)-2,3-dihydroxypropyl, 3-hydroxypropyl, (2RS)-2,3-dihydroxypropyl, (2R)-2,3-dihydroxypropyl, 2-(methylsulphinyl)ethyl, (2R)-2-hydroxypropyl, (2S)-1-hydroxypropan-2-yl, 2-methoxyethyl, 2-(isopropylsulphonyl)ethyl, (3-methyloxetan-3-yl)methyl, (2S)-2-hydroxypropyl or 2-(2-hydroxyethoxy)ethyl, or R.sup.4 and R.sup.5 together with the directly joining nitrogen atom are 4-hydroxypiperidinyl, (3R)-3-hydroxypiperidinyl, (2S)-2-(1H-tetrazol-5-yl)pyrrolidinyl, N-methyl-L-prolinamidyl or L-prolinamidyl or the stereoisomers, tautomers, N-oxides, or salts thereof.

5. A compound of claim 1, selected from the group consisting of: 17-(3-pyridyl)oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-methoxypyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-[5-(trifluoromethyl)pyridin-3-yl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(pyrimidin-5-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-cyanopyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide; 11-fluoro-17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide; 11-fluoro-17-(5-fluoropyridin-3-yl)-N-(2-sulphamoylethyl)oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-[(1S,2R)-2-hydroxycyclopentyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-[2-(hydroxymethyl)-2-methylpropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-[(1S,2S)-2-hydroxycyclopentyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N[(R)-3-(hydroxymethyl)butyl]oestra-1,3,5(10),16-tetraene-3-carboxamide, 17-(5-fluoropyridin-3-yl)-N-[1-(hydroxymethyl)cyclopentyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraen-3-yl 4-hydroxypiperidin-1-yl ketone; 17-(5-fluoropyridin-3-yl)-N[(S)-1-(hydroxymethyl)propyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N[(R)-1-(hydroxymethyl)-2-methylpropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraen-3-yl (R)-3-hydroxypiperidin-1-yl ketone; rel-17-(5-fluoropyridin-3-yl)-N-[(1R,2R)-2-hydroxy-1-methylpropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-(2-hydroxy ethyl)-N-isopropyloestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N[(RS)-3,3,3-trifluoro-2-hydroxypropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-[2-(1H-tetrazol-5-yl)ethyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-(1H-tetrazol-5-ylmethyl)oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(3-pyridyl)-N-(2-sulphamoylethyl)oestra-1,3,5(10),16-tetraene-3-carboxamide; N-(2-sulphamoylethyl)-17-[5-(trifluoromethyl)pyridin-3-yl]oestra-1,3,5(10),16-tetraene-3-carboxamide; N-[2-(N-methylsulphamoyl)ethyl]-17-[5-(trifluoromethyl)pyridin-3-yl]oestra-1,3,5(10),16-tetraene-3-carboxamide; N-(3-amino-3-oxopropyl)-17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-[3-(methylamino)-3-oxopropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraen-3-yl (S)-2-(1H-tetrazol-5-yl)pyrrolidin-1-yl ketone; 1-{[17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraen-3-yl]carbonyl}-N-methyl-L-prolinamide; 1-{[17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraen-3-yl]carbonyl}-L-prolinamide; 17-(5-fluoropyridin-3-yl)-N-{2-methyl-2-[(methyl sulphonyl)amino]propyl}oestra-1,3,5(10),16-tetraene-3-carboxamide; N-ethyl-17-(5-fluoropyridin-3-yl)-N-(2-hydroxy ethyl)oestra-1,3,5(10),16-tetraene-3-carboxamide; N[(S)-2,3-dihydroxypropyl]-17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-(3-hydroxypropyl)-N-methyloestra-1,3,5(10),16-tetraene-3-carboxamide; N[(RS)-2,3-dihydroxypropyl]-17-(5-fluoropyridin-3-yl)-N-methyloestra-1,3,5(10),16-tetraene-3-carboxamide; N[(R)-2,3-dihydroxypropyl]-17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-[2-(methylsulphinyl)ethyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N[(R)-2-hydroxypropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; N-ethyl-17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide; 1-(5-fluoropyridin-3-yl)-N[(S)-1-(hydroxymethyl)ethyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-(2-methoxyethyl)oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-[2-(isopropylsulphonyl)ethyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-[(3-methyloxetan-3-yl)methyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-(2-hydroxy ethyl)-N-methyloestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N[(S)-2-hydroxypropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; 17-(5-fluoropyridin-3-yl)-N-[2-(2-hydroxy ethoxy)ethyl]oestra-1,3,5(10),16-tetraene-3-carboxamide; and 17-(pyrimidin-5-yl)-N-(2-sulphamoylethyl)oestra-1,3,5(10),16-tetraene-3-carboxamide; or the stereoisomers, tautomers, N-oxides, or salts thereof.

6. A medicament comprising a compound of claim 1 and an inert, nontoxic, pharmaceutically suitable excipient.

7. A medicament comprising a compound as defined in claim 1 and at least one active ingredient selected from the group consisting of a selective oestrogen receptor modulator (SERM), an oestrogen receptor (ER) antagonist, an aromatase inhibitor, a 17-HSD1 inhibitor, a steroid sulphatase (STS) inhibitor, a GnRH agonist and antagonist, a kisspeptin receptor (KISSR) antagonist, a selective androgen receptor modulator (SARM), an androgen, a 5-reductase inhibitor, a selective progesterone receptor modulator (SPRM), a gestagen, an antigestagen, an oral contraceptive, an inhibitors of mitogen-activated protein (MAP) kinase and inhibitors of the MAP kinases (Mkk3/6, Mek1/2, Erk1/2), an inhibitors of the protein kinase B (PKB//; Akt1/2/3), an inhibitor of the phosphoinositide 3-kinase (PI3K), an inhibitor of cyclin-dependent kinase (CDK1/2), an inhibitors of the hypoxia-induced signalling pathway (HIF1alpha inhibitor, an activator of prolylhydroxylase), a histone deacetylase (HDAC) inhibitor, a prostaglandin F receptor (FP) (PTGFR) antagonist, and a non-steroidal inflammation inhibitor (NSAID).

8. The medicament of claim 7, wherein the medicament is in the form of a pharmaceutical formulation for enteral, parenteral, vaginal, intrauterine and oral administration.

9. A method of alleviating endometriosis, leiomyoma, dysmenorrhoea, prostate carcinoma, prostate hyperplasia, acne, seborrhoea, hair loss, premature sexual maturity, polycystic ovary syndrome, breast cancer, lung cancer, endometrial carcinoma, renal cell carcinoma, bladder carcinoma, non-Hodgkins lymphoma, chronic obstructive pulmonary disease (COPD), or obesity, comprising administering to a human or animal an effective amount of a compound of claim 1.

10. A method of alleviating endometriosis, uterine leiomyoma, dysmenorrhoea, prostate carcinoma, prostate hyperplasia, acne, seborrhoea, hair loss, premature sexual maturity, polycystic ovary syndrome, breast cancer, lung cancer, endometrial carcinoma, renal cell carcinoma, bladder carcinoma, non-Hodgkins lymphoma, chronic obstructive pulmonary disease (COPD), or obesity, comprising administering the medicament of claim 7 to a human or animal in need thereof.

Description

EXAMPLE 1

17-(pyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(1) ##STR00037##

(2) A mixture of 150 mg (0.37 mmol) of 17-iodooestra-1,3,5(10),16-tetraene-3-carboxamide, 63 mg (0.52 mmol) of pyridine-3-boronic acid, 31 mg of lithium chloride, 1.5 ml of toluene, 493 microliters of 2M sodium carbonate solution and 1 ml of ethanol was admixed with 13 mg of bis(triphenylphosphine)palladium(II) chloride and heated in a microwave at 120 C./100 watts for 90 min. Thereafter, the mixture was filtered, the phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium hydrogencarbonate solution and sodium chloride solution, dried over sodium sulphate and concentrated. After the residue had been purified by preparative HPLC (acetonitrile/water/formic acid), 9 mg of a solid were obtained. UPLC analysis (Method 1) Rt=0.94 min, mass found ESI(+) 358.20.

(3) 1H NMR (300 MHz, DMSO-d6, selected signals): [ppm]=0.99 (s, 3H), 1.38-1.78 (m, 6H), 1.91 (d, 1H), 2.02-2.20 (m, 2H), 2.87 (d, 2H), 6.12 (s., 1H), 7.19 (s., 1H), 7.25-7.38 (m, 2H), 7.50-7.64 (m, 2H), 7.70-7.97 (m, 2H), 8.42 (d, 1H), 8.59 (s, 1H).

EXAMPLE 2

17-(5-methoxypyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(4) ##STR00038##

(5) Analogously, 100 mg (0.24 mmol) of 17-iodooestra-1,3,5(10),16-tetraene-3-carboxamide and 53 mg (1.4 equiv.) of 5-methoxypyridine-3-boronic acid were converted using 14 mg of tetrakis(triphenylphosphine)palladium(0) as a catalyst to 7 mg of the title compound. UPLC analysis (Method 1) Rt=1.24 min, mass found ESI(+) 388.22.

(6) 1H NMR (400 MHz, DMSO-d6): [ppm]=0.99 (s, 3H), 1.37-1.67 (m, 4H), 1.74 (td, 1H), 1.85-1.97 (m, 1H), 2.04-2.18 (m, 2H), 2.20-2.37 (m, 2H), 2.79-2.97 (m, 2H), 3.82 (s, 3H), 6.16 (s., 1H), 7.16 (br. s., 1H), 7.20-7.33 (m), 7.52-7.62 (m, 2H), 7.80 (br. s., 1H), 8.16 (d, 1H), 8.20 (d, 1H).

EXAMPLE 3

17-[5-(trifluoromethyl)pyridin-3-yl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(7) ##STR00039##

(8) Analogously, 150 mg (0.37 mmol) of 17-iodooestra-1,3,5(10),16-tetraene-3-carboxamide and 141 mg (1.4 equiv.) of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine were converted using 21 mg of tetrakis(triphenylphosphine)palladium(0) as a catalyst to 31 mg (20% of theory) of the title compound. UPLC analysis (Method 1) Rt=1.42 min, mass found ESI(+) 426.19.

(9) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=1.01 (s, 3H), 1.38-1.68 (m), 1.75 (td, 1H), 1.84-1.96 (m, 1H), 2.07-2.20 (m, 2H), 2.22-2.44 (m), 2.79-3.01 (m, 2H), 6.36 (br. s., 1H), 7.19 (br. s., 1H), 7.27-7.34 (m, 1H), 7.52-7.66 (m, 2H), 7.82 (br. s., 1H), 8.04 (s, 1H), 8.83 (s, 1H), 8.87-8.95 (m, 1H).

EXAMPLE 4

17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(10) Preparation Method A

(11) ##STR00040##

(12) 700 mg (1.85 mmol) of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were initially charged in 15 ml of 2-methyltetrahydrofuran and 2 ml of NMP, 1,1-carbonyldiimidazole and imidazole hydrochloride were added thereto, and the mixture was stirred at room temp. for 18 h. Then 4.4 ml of 25% aqueous ammonia solution were added and the mixture was stirred at room temp. for 72 h. Thereafter, 1M hydrochloric acid, water and ethyl acetate were added and the mixture was stirred for 10 min. The solids were filtered off with suction and dried. Yield: 406 mg (58% of theory) of the title compound.

(13) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.99 (s, 3H), 1.38-1.78 (m, 5H), 1.85-1.96 (m, 1H), 2.04-2.20 (m, 2H), 2.20-2.44 (m, 3H), 2.81-2.93 (m, 2H), 6.23-6.30 (m, 1H), 7.18 (br. s., 1H), 7.30 (d, 1H), 7.54-7.72 (m, 3H), 7.82 (br. s., 1H), 8.41-8.52 (m, 2H).

(14) Preparation Method B

(15) A mixture of 50 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carbonitrile in 3 ml of ethanol and 2 ml of water was admixed with 86 mg (4 equiv.) of sodium perborate tetrahydrate and the mixture was heated at 130 C. at 300 watts in a microwave for 30 min. 21 mg of sodium perborate tetrahydrate were added and the mixture was stirred at 130 C. at 300 watts for 15 min.

(16) A further 98 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carbonitrile were heated in 5 ml of ethanol and 3 ml of water with 210 mg (5 equiv.) of sodium perborate tetrahydrate at 130 C. in a microwave for 30 min. The reaction mixtures were combined and extracted three times with tert-butyl methyl ether, washed with sodium chloride solution, dried over sodium sulphate and concentrated, and the residue was purified by preparative HPLC. Yield: 75 mg of the title compound.

EXAMPLE 5

17-(pyrimidin-5-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(17) ##STR00041##

(18) Analogously to the preparation of Example 6 (Preparation Method B), 88 mg of 17-(pyrimidin-5-yl)oestra-1,3,5(10),16-tetraene-3-carbonitrile were reacted with sodium perborate at 140 C. and 300 watts in a microwave. After preparative HPLC, 11 mg of the title compound were obtained. C.sub.23H.sub.25N.sub.3O UPLC analysis (Method 1) Rt=1.14 min, mass found ESI(+) 359.20

(19) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.99 (s, 3H), 1.35-1.80 (m, 5H), 1.85-1.96 (m, 1H), 2.07-2.20 (m, 2H), 2.26-2.44 (m, 3H), 2.82-2.93 (m, 2H), 6.28-6.33 (m, 1H), 7.18 (br. s., 1H), 7.30 (d, 1H), 7.55-7.62 (m, 2H), 7.82 (br. s., 1H), 8.83 (s, 2H), 9.04 (s, 1H).

EXAMPLE 6

17-(5-cyanopyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(20) ##STR00042##

(21) 17 mg (0.044 mmol) of 17-(5-cyanopyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were initially charged in 0.4 ml of 2-methyltetrahydrofuran. Then 11 mg of 1,1-carbonyldiimidazole and 2 mg of 1H-imidazole hydrochloride were added thereto and the mixture was stirred at room temp. for 18 h. Then 79 l of 33% ammonia solution were added and the mixture was stirred at room temp. for 72 h, admixed with 10 ml of 1M hydrochloric acid solution, extracted with ethyl acetate and concentrated, and the crude product was purified by preparative HPLC (acetonitrile/water/formic acid). Yield: 9 mg of the title compound.

(22) .sup.1H NMR (400 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.35-1.50 (m, 1H), 1.50-1.68 (m, 3H), 1.73 (td, 1H), 1.85-1.98 (m, 1H), 2.07-2.23 (m, 2H), 2.25-2.36 (m, 2H), 2.36-2.44 (m, partly concealed by DMSO signal), 2.83-2.95 (m, 2H), 6.33-6.36 (m, 1H), 7.19 (br. s., 1H), 7.31 (d, 1H), 7.55-7.61 (m, 2H), 7.82 (br. s., 1H), 8.28 (t, 1H), 8.87 (dd, 2H).

EXAMPLE 7

11-fluoro-17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(23) ##STR00043##

(24) 100 mg of (11beta)-11-fluoro-17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were initially charged in 3 ml of 2-methyltetrahydrofuran, then 62 mg (1.5 equiv.) of 1,1-carbonyldiimidazole and 13 mg of imidazole hydrochloride were added and the mixture was stirred at room temp. for 18 h. Then 597 l of 25% aqueous ammonia solution were added and the mixture was stirred at room temp. for 3 hours, admixed with 10 ml of 1M hydrochloric acid solution, extracted three times with ethyl acetate, concentrated and purified by preparative HPLC. Yield: 51 mg of the title compound. C.sub.24H.sub.24F.sub.2N.sub.2O UPLC analysis (Method 1) Rt=1.22 mass found ESI(+) 394.19.

(25) 1H NMR (400 MHz, DMSO-d6): [ppm]=1.14 (s, 3H), 1.40-1.55 (m, 1H), 1.73-2.03 (m, 4H), 2.13-2.25 (m, 1H), 2.27-2.38 (m, 1H), 2.50-2.60 (m, 1H), 2.67 (dd, 1H), 2.80-2.97 (m, 2H), 5.60-5.81 (1H), 6.30 (br. s., 1H), 7.22 (br. s., 1H), 7.40 (d, 1H), 7.55-7.63 (m, 2H), 7.71 (dt, 1H), 7.85 (s, 1H), 8.45 (d, 1H), 8.48-8.55 (m, 1H).

EXAMPLE 8

11-fluoro-17-(5-fluoropyridin-3-yl)-N-(2-sulphamoylethyl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(26) ##STR00044##

(27) To a mixture of 100 mg of 11-fluoro-17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid and 81 mg (2 equiv.) of 2-aminoethane-1-sulphonamide hydrochloride in 0.5 ml of DMF and 3 ml of THF were added 39 mg of 1-hydroxy-1H-benzotriazole hydrate, 97 mg (2 equiv.) of N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (EDC) [CAS 25952-53-8] and 0.11 ml of triethylamine, and the mixture was stirred at room temp. for 18 h. After addition of water, the mixture was extracted three times with ethyl acetate, and the combined organic phases were concentrated and purified by preparative HPLC. Yield: 24 mg of the title compound. C.sub.26H.sub.29F.sub.2N.sub.3O.sub.3S UPLC analysis (Method 1) Rt=1.19 min, mass found ESI(+) 501.19.

(28) .sup.1H NMR (400 MHz, DMSO-d.sub.6): [ppm]=1.14 (s, 3H), 1.48 (qd, 1H), 1.75-2.01 (m, 4H), 2.14-2.24 (m, 1H), 2.28-2.37 (m, 1H), 2.48-2.66 (m, 2H), 2.71-2.77 (m, 0.5H), 2.82-2.97 (m, 2H), 3.19 (dd, 2H), 3.56-3.63 (m, 2H), 5.64 (br. s, 0.5H), 5.76 (br. s., 0.5H), 6.28-6.32 (m, 1H), 6.91 (s, 2H), 7.43 (d, 1H), 7.53-7.59 (m, 2H), 7.69-7.74 (m, 1H), 8.43-8.53 (m, 3H).

EXAMPLE 9

17-(5-fluoropyridin-3-yl)-N-[(1S,2R)-2-hydroxycyclopentyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(29) ##STR00045##

(30) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 73 mg of (1R,2S)-2-aminocyclopentan-1-ol hydrochloride (1:1) to give 75 mg of the title compound.

(31) UPLC analysis (Method 1) Rt=1.40 min, mass found ESI(+) 460.25.

(32) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.42-1.97 (m, 12H), 2.03-2.21 (m, 2H), 2.21-2.44 (m, 3H), 2.84-2.94 (m, 2H), 3.94-4.05 (m, 2H), 4.68 (d, 1H), 6.24-6.29 (m, 1H), 7.31 (d, 1H), 7.54-7.71 (m, 4H), 8.41-8.51 (m, 2H).

EXAMPLE 10

17-(5-fluoropyridin-3-yl)-N-[2-(hydroxymethyl)-2-methylpropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(33) ##STR00046##

(34) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 55 mg of 3-amino-2,2-dimethylpropan-1-ol to give 53 mg of the title compound. After preparative purification by HPLC, the crude product was admixed with 1 ml of DMSO, and the remaining solids were filtered off with suction and rinsed three times with 0.5 ml each time of DMSO. The filtrate was admixed with water and saturated sodium hydrogencarbonate solution, and subsequently extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. Yield: 54 mg of the title compound.

(35) .sup.1H NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.79 (s, 6H), 1.00 (s, 3H), 1.37-1.66 (m, 4H), 1.74 (td, 1H), 1.87-1.96 (m, 1H), 2.07-2.20 (m, 2H), 2.24-2.44 (m, 3H), 2.84-2.96 (m, 2H), 3.09 (dd, 4H), 4.59 (t, 1H), 6.27 (br. s., 1H), 7.32 (d, 1H), 7.52-7.59 (m, 2H), 7.68 (dt, 1H), 8.25 (t, 1H), 8.43 (d, 1H), 8.49 (s, 1H).

EXAMPLE 11

17-(5-fluoropyridin-3-yl)-N-[(1S,2S)-2-hydroxycyclopentyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(36) ##STR00047##

(37) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 72 mg of (1S,2S)-2-aminocyclopentan-1-ol hydrochloride (1:1) to give 79 mg of the title compound. C.sub.29H.sub.33FN.sub.2O.sub.2 UPLC analysis (Method 1) Rt=1.39 min, mass found ESI(+) 460.25.

(38) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.99 (s, 3H), 1.32-2.02 (m, 13H), 2.05-2.20 (m, 2H), 2.24-2.43 (m, 3H), 2.50 (br. s., 1H), 2.83-2.93 (m, 2H), 3.25 (s, 1H), 3.89-3.99 (m, 2H), 4.70 (d, 1H), 6.24-6.29 (m, 1H), 7.30 (d, 1H), 7.51-7.60 (m, 2H), 7.67 (dt, 1H), 8.05 (d, 1H), 8.41-8.52 (m, 2H).

EXAMPLE 12

17-(5-fluoropyridin-3-yl)-N[(R)-3-(hydroxymethyl)butyl]estra-1,3,5(10),16-tetraene-3-carboxamide

(39) ##STR00048##

(40) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 55 mg of (2R)-4-amino-2-methylbutan-1-ol to give 70 mg of the title compound.

(41) C.sub.29H.sub.35FN.sub.2O.sub.2 UPLC analysis (Method 1) Rt=1.38 min, mass found ESI(+) 462.27.

(42) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.84 (d, 3H), 0.99 (s, 3H), 1.16-1.29 (m, 1H), 1.35-1.79 (m, 7H), 1.91 (d, 1H), 2.04-2.21 (m, 2H), 2.25-2.44 (m, 3H), 2.82-2.93 (m, 2H), 3.14-3.25 (m, 4H), 4.39 (t, 1H), 6.26 (br. s., 1H), 7.30 (d, 1H), 7.50-7.59 (m, 2H), 7.64-7.71 (dd, 1H), 8.24 (t, 1H), 8.41-8.52 (m, 2H).

EXAMPLE 13

17-(5-fluoropyridin-3-yl)-N-[1-(hydroxymethyl)cyclopentyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(43) ##STR00049##

(44) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 61 mg of (1-aminocyclopentyl)methanol to give 34 mg of the title compound.

(45) C.sub.30H.sub.35FN.sub.2O.sub.2 UPLC analysis (Method 1) Rt=1.50 min, mass found ESI(+) 474.27.

(46) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.99 (s, 3H), 1.37-1.78 (m, 11H), 1.86-2.02 (m, 3H), 2.05-2.20 (m, 2H), 2.25-2.41 (m, 3H), 2.83-2.92 (m, 2H), 3.52 (d, 2H), 4.80 (t, 1H), 6.26 (br. s., 1H), 7.28 (d, 1H), 7.48-7.57 (d, 3H), 7.64-7.71 (m, 1H), 8.41-8.51 (m, 2H).

EXAMPLE 14

17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraen-3-yl 4-hydroxypiperidin-1-yl ketone

(47) ##STR00050##

(48) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 54 mg of piperidin-4-ol to give 74 mg of the title compound.

(49) UPLC analysis (Method 1) Rt=1.33 min, mass found ESI(+) 460.25.

(50) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.18-1.97 (m, 10H), 2.03-2.43 (m, 5H), 2.79-2.92 (m, 2H), 3.03-3.19 (m, 2H), 3.53 (br. s., 1H), 3.62-3.75 (m, 1H), 3.94 (br. s., 1H), 4.72 (d, 1H), 6.26 (s, 1H), 6.99-7.13 (m, 2H), 7.29 (d, 1H), 7.63-7.71 (m, 1H), 8.39-8.53 (m, 2H).

EXAMPLE 15

17-(5-fluoropyridin-3-yl)-N[(S)-1-(hydroxymethyl)propyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(51) ##STR00051##

(52) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 47 mg of (2S)-2-aminobutan-1-ol to give 74 mg of the title compound.

(53) C.sub.28H.sub.33FN.sub.2O.sub.2 UPLC analysis (Method 1) Rt=1.38 min, mass found ESI(+) 448.25.

(54) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.82 (t, 3H), 0.99 (s, 3H), 1.31-1.80 (m, 7H), 1.85-1.97 (m, 1H), 2.05-2.43 (m, 5H), 2.82-2.94 (m, 2H), 3.31-3.46 (m, 1H), 3.74-3.89 (m, 1H), 4.59 (t, 1H), 6.27 (s, 1H), 7.30 (d, 1H), 7.53-7.61 (m, 2H), 7.64-7.71 (m, 1H), 7.81 (d, 1H), 8.39-8.53 (m, 2H).

EXAMPLE 16

17-(5-fluoropyridin-3-yl)-N[(R)-1-(hydroxymethyl)-2-methylpropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(55) ##STR00052##

(56) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 55 mg of (2R)-2-amino-3-methylbutan-1-ol to give 78 mg of the title compound.

(57) C.sub.29H.sub.35FN.sub.2O.sub.2 UPLC analysis (Method 1) Rt=1.43 min, mass found ESI(+) 462.27.

(58) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.83 (d, 3H), 0.86 (d, 3H), 0.99 (s, 3H), 1.39-1.67 (m, 4H), 1.68-1.79 (m, 1H), 1.81-1.96 (m, 2H), 2.03-2.22 (m, 2H), 2.22-2.41 (m, 3H), 2.82-2.95 (m, 2H), 3.47 (t, 2H), 3.70-3.82 (m, 1H), 4.49 (t, 1H), 6.27 (br. s., 1H), 7.30 (d, 1H), 7.53-7.61 (m, 2H), 7.63-7.72 (m, 1H), 7.76 (d, 1H), 8.43 (d, 1H), 8.49 (s, 1H).

EXAMPLE 17

17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraen-3-yl (R)-3-hydroxypiperidin-1-yl ketone

(59) ##STR00053##

(60) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 73 mg of (3R)-piperidin-3-ol to give 75 mg of the title compound.

(61) C.sub.29H.sub.33FN.sub.2O.sub.2 UPLC analysis (Method 1) Rt=1.37 min, mass found ESI(+) 460.25.

(62) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.22-1.99 (m, 11H), 2.03-2.43 (m, 5H), 2.72-3.14 (4H, includes broad singlet at 3.02 ppm), 3.44 (broad singlet, 2H), 3.83 (broad singlet, 0.6H), 4.13 (broad singlet, 0.4H), 4.70-4.96 (broad signal, 0.9H), 6.26 (s., 1H), 7.01-7.13 (m, 2H), 7.29 (d, 1H), 7.63-7.72 (m, 1H), 8.39-8.53 (m, 2H).

EXAMPLE 18

rel-17-(5-fluoropyridin-3-yl)-N-[(1R,2R)-2-hydroxy-1-methylpropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(63) ##STR00054##

(64) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 67 mg of rel-(2S,3S)-2-amino-1-methylpropan-1-ol hydrochloride (1:1) to give 80 mg of the title compound.

(65) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.91-1.03 (m, 6H), 1.06 (d, 3H), 1.35-1.80 (m, 5H), 1.85-1.97 (m, 1H), 2.03-2.42 (m, 5H), 2.81-2.94 (m, 2H), 3.59-3.69 (m, 1H), 3.85-3.99 (m, 1H), 4.56 (d, 1H), 6.27 (br. s., 1H), 7.30 (d, 1H), 7.50-7.61 (m, 2H), 7.64-7.80 (m, 2H), 8.39-8.53 (m, 2H).

EXAMPLE 19

17-(5-fluoropyridin-3-yl)-N-(2-hydroxyethyl)-N-isopropyloestra-1,3,5(10),16-tetraene-3-carboxamide

(66) ##STR00055##

(67) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 55 mg of 2-(isopropylamino)ethan-1-ol to give 27 mg of the title compound.

(68) .sup.1H NMR (500 MHz, DMSO-d6): [ppm]=1.01-1.14 (m, 12H), 1.41-1.52 (m, 1H), 1.54-1.71 (m, 4H), 1.77 (td, 1H), 1.90-1.98 (m, 1H), 2.10-2.24 (m, 2H), 2.30-2.39 (m, 2H), 2.40-2.46 (m, 1H), 2.83-2.95 (m, 2H), 3.54 (br. s., 2H), 3.87 (br. s., 1H), 4.72 (br. s., 1H), 6.30 (dd, 1H), 7.03 (s, 1H), 7.07 (d, 1H), 7.32 (d, 1H), 7.70 (dt, 1H), 8.46 (d, 1H), 8.52 (t, 1H).

EXAMPLE 20

17-(5-fluoropyridin-3-yl)-N[(RS)-3,3,3-trifluoro-2-hydroxypropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(69) ##STR00056##

(70) Analogously to Example 8, 250 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 171 mg of 2-amino-1-(trifluoromethyl)ethan-1-ol to give 161 mg of the title compound.

(71) C.sub.27H.sub.28F.sub.4N.sub.2O.sub.2 UPLC analysis (Method 1) Rt=1.45 min, mass found ESI(+) 488.21.

(72) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.99 (s, 3H), 1.35-1.80 (m, 5H), 1.85-1.97 (m, 1H), 2.05-2.21 (m, 2H), 2.25-2.43 (m, 3H), 2.81-2.95 (m, 2H), 3.18-3.26 (m, 1H), 3.49-3.62 (m, 1H), 4.07-4.22 (m, 1H), 6.40-6.30 (m, 1H), 6.45 (d, 1H), 7.33 (d, 1H), 7.52-7.62 (m, 2H), 7.64-7.73 (m, 1H), 8.43 (d, 1H), 8.47-8.51 (m, 1H), 8.55 (t, 1H).

EXAMPLE 21

17-(5-fluoropyridin-3-yl)-N-[2-(1H-tetrazol-5-yl)ethyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(73) ##STR00057##

(74) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 60 mg of 2-(1H-tetrazol-5-yl)ethan-1-amine to give 4 mg of the title compound.

(75) UPLC analysis (Method 1) Rt=1.27 min, mass found ESI(+) 472.24.

(76) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.99 (m, 3H), 1.34-1.79 (m, 5H), 1.84-1.98 (m, 1H), 2.04-2.21 (m, 2H), 2.25-2.40 (m, 3H), 2.50 (s, 3H), 2.81-2.93 (m, 2H), 3.09 (t, 2H), 3.51-3.64 (m, 2H), 6.27 (s., 1H), 7.31 (d, 1H), 7.47-7.56 (m, 2H), 7.68 (dt, 1H), 8.39-8.54 (m, 3H).

EXAMPLE 22

17-(5-fluoropyridin-3-yl)-N-(1H-tetrazol-5-ylmethyl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(77) ##STR00058##

(78) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 53 mg of 1-(1H-tetrazol-5-yl)methylamine to give 14 mg of the title compound.

(79) C.sub.26H.sub.27FN.sub.6O UPLC analysis (Method 1) Rt=1.27 min, mass found ESI(+) 458.22.

(80) .sup.1H NMR (400 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.38-1.68 (m, 4H), 1.74 (td, 1H), 1.86-1.97 (m, 1H), 2.07-2.21 (m, 2H), 2.24-2.43 (m, 3H), 2.83-2.95 (m, 2H), 4.69 (d, 2H), 6.24-6.30 (m, 1H), 7.35 (d, 1H), 7.58-7.65 (m, 2H), 7.68 (dt, 1H), 8.43 (d, 1H), 8.49 (t, 1H), 9.05 (t, 1H).

EXAMPLE 23

17-(3-pyridyl)-N-(2-sulphamoylethyl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(81) ##STR00059##

(82) Analogously to Example 8, 100 mg of 17-(3-pyridyl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 89 mg of 2-aminoethane-1-sulphonamide hydrochloride (1:1) to give 84 mg of the title compound.

(83) UPLC analysis (Method 1) Rt=0.93 min, mass found ESI(+) 465.21.

(84) .sup.1H NMR (400 MHz, DMSO-d.sub.6): [ppm]=0.99 (s, 3H), 1.37-1.67 (m, 4H), 1.73 (td, 1H), 1.86-1.96 (m, 1H), 2.05-2.17 (m, 2H), 2.24-2.44 (m, 3H), 2.82-2.96 (m, 2H), 3.14-3.23 (m, 2H), 3.54-3.66 (m, 2H), 6.12 (s, 1H), 6.91 (s, 2H), 7.29-7.36 (m, 2H), 7.51-7.59 (m, 2H), 7.77 (d, 1H), 8.39-8.45 (m, 1H), 8.48 (t, 1H), 8.58-8.61 (m, 1H).

EXAMPLE 24

N-(2-sulphamoylethyl)-17-[5-(trifluoromethyl)pyridin-3-yl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(85) ##STR00060##

(86) Analogously to Example 8, 70 mg of 17-[5-(trifluoromethyl)pyridin-3-yl]oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 53 mg of 2-aminoethane-1-sulphonamide hydrochloride (1:1) to give 58 mg of the title compound.

(87) C.sub.27H.sub.30F.sub.3N.sub.3O.sub.3S UPLC analysis (Method 1) Rt=1.39 min, mass found ESI(+) 533.20.

(88) .sup.1H NMR (400 MHz, DMSO-d.sub.6): [ppm]=1.01 (s, 3H), 1.38-1.67 (m, 4H), 1.76 (td, 1H), 1.86-1.97 (m, 1H), 2.07-2.20 (m, 2H), 2.27-2.43 (m, 3H), 2.82-2.95 (m, 2H), 3.19 (dd, 2H), 3.53-3.65 (m, 2H), 6.35-6.38 (m, 1H), 6.91 (s, 2H), 7.33 (d, 1H), 7.51-7.57 (m, 2H), 8.04 (s, 1H), 8.48 (t, 1H), 8.82-8.85 (m, 1H), 8.90 (d, 1H).

EXAMPLE 25

N-[2-(N-methylsulphamoyl)ethyl]-17-[5-(trifluoromethyl)pyridin-3-yl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(89) ##STR00061##

(90) Analogously to Example 8, 70 mg of 17-[5-(trifluoromethyl)pyridin-3-yl]oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 57 mg of 2-amino-N-methylethane-1-sulphonamide hydrochloride (1:1) to give 30 mg of the title compound.

(91) C.sub.28H.sub.32F.sub.3N.sub.3O.sub.3S UPLC analysis (Method 1) Rt=1.45 min, mass found ESI(+) 547.21.

(92) .sup.1H NMR (400 MHz, DMSO-d.sub.6): [ppm]=1.01 (s, 3H), 1.38-1.68 (m, 4H), 1.76 (td, 1H), 1.88-1.96 (m, 1H), 2.08-2.20 (m, 2H), 2.27-2.39 (m, 2H), 2.39-2.44 (m), 2.55 (s, 3H), 2.84-2.96 (m, 2H), 3.21 (dd, 2H), 3.51-3.58 (m, 2H), 6.34-6.38 (m, 1H), 6.97 (s, 1H), 7.33 (d, 1H), 7.51-7.58 (m, 2H), 8.02-8.05 (m, 1H), 8.46 (t, 1H), 8.82-8.85 (m, 1H), 8.90 (d, 1H).

EXAMPLE 26

N-(3-amino-3-oxopropyl)-17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(93) ##STR00062##

(94) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 66 mg of -alaninamide to give 87 mg of the title compound.

(95) C.sub.27H.sub.30FN.sub.3O.sub.2 UPLC analysis (Method 1) Rt=1.22 min, mass found ESI(+) 447.23.

(96) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.99 (s, 3H), 1.34-1.80 (m, 5H), 1.84-1.96 (m, 1H), 2.06-2.44 (8H, includes triplet at 2.30 ppm), 2.82-2.93 (m, 2H), 3.32-3.43 (m, 2H), 6.27 (s, 1H), 6.79 (br. s., 1H), 7.25-7.37 (m, 2H), 7.50-7.58 (m, 2H), 7.65-7.72 (m, 1H), 8.34 (t, 1H), 8.43 (d, 1H), 8.47-8.50 (m, 1H).

EXAMPLE 27

17-(5-fluoropyridin-3-yl)-N-[3-(methylamino)-3-oxopropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(97) ##STR00063##

(98) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 73 mg of N-methyl-fl-alaninamide hydrochloride (1:1) to give 45 mg of the title compound.

(99) C.sub.28H.sub.32FN.sub.3O.sub.2 UPLC analysis (Method 1) Rt=1.26 min, mass found ESI(+) 461.25.

(100) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.99 (s, 3H), 1.34-1.80 (m, 5H), 1.85-1.96 (m, 1H), 2.05-2.43 (m, 7H), 2.53 (d, 3H), 2.80-2.96 (m, 2H), 3.33-3.45 (m, 2H), 6.27 (s, 1H), 7.31 (d, 1H), 7.49-7.59 (m, 2H), 7.68 (dt, 1H), 7.73-7.83 (m, 1H), 8.36 (t, 1H), 8.43 (d, 1H), 8.46-8.52 (m, 1H).

EXAMPLE 28

17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraen-3-yl (S)-2-(1H-tetrazol-5-yl)pyrrolidin-1-yl ketone

(101) ##STR00064##

(102) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 74 mg of 5-[(2S)-pyrrolidin-2-yl]-1H-tetrazole to give 83 mg of the title compound.

(103) UPLC analysis (Method 1) Rt=1.35 min, mass found ESI(+) 498.25.

(104) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.35-2.42 (m), 2.78-2.96 (m, 2H), 3.44-3.59 (m, 1H), 3.62-3.75 (m, 1H), 5.19 (br. s., 0.1H), 5.32-5.49 (m, 0.9H), 6.27 (br. s., 1H), 6.68-6.92 (br. s., 0.2H), 7.01-7.20 (br. s., 0.2H), 7.20-7.43 (m, 2.6H), 7.63-7.75 (m, 1H), 8.40-8.55 (m, 2H).

EXAMPLE 29

1-{[17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraen-3-yl]carbonyl}-N-methyl-L-prolinamide

(105) ##STR00065##

(106) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 68 mg of N-methyl-L-prolinamide to give 85 mg of the title compound.

(107) UPLC analysis (Method 1) Rt=1.32 min, mass found ESI(+) 487.26.

(108) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.32-2.42 (m, 15H), 2.58 (d, 3H), 2.75-2.95 (m, 2H), 3.32-3.62 (m), 4.00-4.08 (m), 4.29-4.39 (m), 6.23-6.32 (m, 1H), 6.96-7.06 (m, 0.5H), 7.21-7.36 (m, 2.5H), 7.64-7.82 (m, 2H), 8.43 (d, 1H), 8.47-8.51 (m, 1H).

EXAMPLE 30

1-{[17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraen-3-yl]carbonyl}-L-prolinamide

(109) ##STR00066##

(110) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 60 mg of L-prolinamide to give 92 mg of the title compound.

(111) UPLC analysis (Method 1) Rt=1.29 min, mass found ESI(+) 473.25.

(112) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.33-1.96 (m, 9H), 2.00-2.42 (m), 2.77-2.94 (m, 2H), 3.31-3.42 (m), 3.43-3.62 (m), 4.07-4.16 (m, 0.3H), 4.26-4.36 (m, 0.7H), 6.27 (br. s., 1H), 6.85-7.00 (m, 1H), 7.02-7.12 (m, 0.5H), 7.20-7.40 (m, 3.5H), 7.68 (d, 1H), 8.43 (d, 1H), 8.49 (s, 1H).

EXAMPLE 31

17-(5-fluoropyridin-3-yl)-N-{2-methyl-2-[(methylsulphonyl)amino]propyl}oestra-1,3,5(10),16-tetraene-3-carboxamide

(113) ##STR00067##

(114) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 107 mg of N-[1-(aminomethyl)-1-methylethyl]methanesulphonamide to give 95 mg of the title compound.

(115) C.sub.29H.sub.36FN.sub.3O.sub.3S UPLC analysis (Method 1) Rt=1.40 min, mass found ESI(+) 525.25.

(116) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.23 (s, 6H), 1.39-1.79 (m, 5H), 1.85-1.97 (m, 1H), 2.05-2.41 (m, 5H), 2.84-2.99 (5H, includes singlet at 2.93 ppm), 3.34 (d, 2H), 6.27 (s, 1H), 6.93 (s, 1H), 7.34 (d, 1H), 7.53-7.61 (m, 2H), 7.68 (dt, 1H), 8.25 (t, 1H), 8.43 (d, 1H), 8.48-8.52 (m, 1H).

EXAMPLE 32

N-ethyl-17-(5-fluoropyridin-3-yl)-N-(2-hydroxyethyl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(117) ##STR00068##

(118) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 47 mg of 2-(ethylamino)ethan-1-ol to give 75 mg of the title compound.

(119) UPLC analysis (Method 1) Rt=1.38 min, mass found ESI(+) 448.25.

(120) .sup.1H NMR (400 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.07 (br. s., 3H), 1.37-1.67 (m, 4H), 1.74 (td, 1H), 1.86-1.94 (m, 1H), 2.07-2.20 (m, 2H), 2.25-2.45 (m, 3H), 2.81-2.90 (m, 2H), 3.23 (br. s.), 3.42 (br. s.), 3.54 (br. s.), 4.71 (t, 1H), 6.24-6.29 (m, 1H), 7.00-7.11 (m, 2H), 7.28 (d, 1H), 7.65-7.71 (m, 1H), 8.43 (d, 1H), 8.49 (t, 1H).

EXAMPLE 33

N[(S)-2,3-dihydroxypropyl]-17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(121) ##STR00069##

(122) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 58 mg of (2S)-3-aminopropane-1,2-diol to give 80 mg of the title compound.

(123) UPLC analysis (Method 1) Rt=1.22 min, mass found ESI(+) 450.23.

(124) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.99 (s, 3H), 1.34-1.79 (m, 5H), 1.85-1.96 (m, 1H), 2.05-2.44 (m, 5H), 2.82-2.97 (m, 2H), 3.09-3.23 (m, 1H), 3.23-3.40 (m, obscured by water signal), 3.53-3.63 (m, 1H), 4.53 (t, 1H), 4.76 (d, 1H), 6.27 (br. s., 1H), 7.31 (d, 1H), 7.53-7.62 (m, 2H), 7.68 (dt, 1H), 8.24 (t, 1H), 8.42-8.52 (m, 2H).

EXAMPLE 34

17-(5-fluoropyridin-3-yl)-N-(3-hydroxypropyl)-N-methyloestra-1,3,5(10),16-tetraene-3-carboxamide

(125) ##STR00070##

(126) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 47 mg of 3-(methylamino)propan-1-ol to give 83 mg of the title compound.

(127) UPLC analysis (Method 1) Rt=1.34 min, mass found ESI(+) 448.25.

(128) .sup.1H NMR (400 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.37-1.51 (m, 1H), 1.52-1.78 (m, 6H), 1.86-1.94 (m, 1H), 2.07-2.20 (m, 2H), 2.25-2.45 (m, 3H), 2.80-2.93 (m, 5H), 3.42 (br. s.), 4.42 (br. s., 1H), 6.27 (dd, 1H), 7.01-7.12 (m, 2H), 7.28 (d, 1H), 7.65-7.70 (m, 1H), 8.43 (d, 1H), 8.49 (t, 1H).

EXAMPLE 35

N[(RS)-2,3-dihydroxypropyl]-17-(5-fluoropyridin-3-yl)-N-methyloestra-1,3,5(10),16-tetraene-3-carboxamide

(129) ##STR00071##

(130) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 56 mg of 3-(methylamino)propane-1,2-diol to give 68 mg of the title compound.

(131) UPLC analysis (Method 1) Rt=1.25 min, mass found ESI(+) 464.25.

(132) .sup.1H NMR (400 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.37-1.67 (m, 4H), 1.74 (td, 1H), 1.86-1.94 (m, 1H), 2.07-2.20 (m, 2H), 2.25-2.45 (m, 3H), 2.85 (br. s., 2H), 2.94 (s, 3H), 3.12 (br. s.), 3.23 (br. s.), 3.32 (br. s.), 3.51 (br. s.), 3.66 (br. s.), 3.75 (br. s.), 4.52 (br. s., 1H), 4.80 (br. s.), 4.86 (br. s.), 6.27 (br. s., 1H), 7.06-7.17 (m, 2H), 7.28 (br. s., 1H), 7.68 (dt, 1H), 8.43 (d, 1H), 8.47-8.51 (m, 1H).

EXAMPLE 36

N[(R)-2,3-dihydroxypropyl]-17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(133) ##STR00072##

(134) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 48 mg of (2R)-3-aminopropane-1,2-diol to give 65 mg of the title compound.

(135) UPLC analysis (Method 1) Rt=1.22 min, mass found ESI(+) 450.23.

(136) .sup.1H NMR (400 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.38-1.66 (m, 4H), 1.74 (td, 1H), 1.87-1.95 (m, 1H), 2.08-2.19 (m, 2H), 2.26-2.45 (m, 3H), 2.84-2.93 (m, 2H), 3.12-3.20 (m, 1H), 3.25-3.37 (m, 3H), 3.55-3.62 (m, 1H), 4.51 (t, 1H), 4.75 (d, 1H), 6.27 (dd, 1H), 7.32 (d, 1H), 7.53-7.59 (m, 2H), 7.65-7.70 (m, 1H), 8.22 (t, 1H), 8.43 (d, 1H), 8.49 (t, 1H).

EXAMPLE 37

17-(5-fluoropyridin-3-yl)-N-[2-(methylsulphinyl)ethyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(137) ##STR00073##

(138) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 57 mg of 2-(methylsulphinyl)ethan-1-amine to give 85 mg of the title compound.

(139) UPLC analysis (Method 1) Rt=1.24 min, mass found ESI(+) 466.21.

(140) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.35-1.80 (m, 5H), 1.86-1.96 (m, 1H), 2.06-2.41 (m, 6H), 2.55 (s, 3H), 2.78-2.92 (m, 3H), 2.92-3.06 (m, 1H), 3.47-3.67 (m, 2H), 6.24-6.30 (m, 1H), 7.33 (d, 1H), 7.52-7.59 (m, 2H), 7.64-7.71 (m, 1H), 8.41-8.51 (m, 2H), 8.59 (t, 1H).

EXAMPLE 38

17-(5-fluoropyridin-3-yl)-N[(R)-2-hydroxypropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(141) ##STR00074##

(142) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 40 mg of (2R)-1-aminopropan-2-ol to give 75 mg of the title compound.

(143) UPLC analysis (Method 1) Rt=1.32 min, mass found ESI(+) 434.24.

(144) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.95-1.07 (m, 6H), 1.35-1.81 (m, 5H), 1.86-1.96 (m, 1H), 2.06-2.44 (m, 5H), 2.50 (br. s., 1H), 2.83-2.93 (m, 2H), 3.15 (t, 2H), 3.68-3.79 (m, 1H), 4.67 (d, 1H), 6.23-6.29 (m, 1H), 7.31 (d, 1H), 7.52-7.60 (m, 2H), 7.67 (dt, 1H), 8.21 (t, 1H), 8.41-8.51 (m, 2H).

EXAMPLE 39

N-ethyl-17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(145) ##STR00075##

(146) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 43 mg of ethan-1-amine hydrochloride (1:1) to give 75 mg of the title compound.

(147) UPLC analysis (Method 1) Rt=1.44 min, mass found ESI(+) 404.23.

(148) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.99 (s, 3H), 1.07 (t, 3H), 1.35-1.79 (m, 5H), 1.86-1.96 (m, 1H), 2.06-2.44 (m, 5H), 2.82-2.93 (m, 2H), 3.17-3.26 (m), 6.23-6.29 (m, 1H), 7.30 (d, 1H), 7.50-7.58 (m, 2H), 7.64-7.71 (m, 1H), 8.28 (t, 1H), 8.41-8.51 (m, 2H).

EXAMPLE 40

17-(5-fluoropyridin-3-yl)-N[(S)-1-(hydroxymethyl)ethyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(149) ##STR00076##

(150) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 40 mg of (2S)-2-aminopropan-1-ol to give 79 mg of the title compound.

(151) UPLC analysis (Method 1) Rt=1.32 min, mass found ESI(+) 434.24.

(152) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.08 (d, 3H), 1.35-1.67 (m, 4H), 1.74 (td, 1H), 1.86-1.96 (m, 1H), 2.06-2.20 (m, 2H), 2.25-2.44 (m, 3H), 2.83-2.93 (m, 2H), 3.23-3.33 (m, partly concealed by water signal), 3.37-3.46 (m, 1H), 3.88-4.04 (m, 1H), 4.64 (t, 1H), 6.22-6.30 (m, 1H), 7.30 (d, 1H), 7.51-7.60 (m, 2H), 7.67 (dt, 1H), 7.90 (d, 1H), 8.40-8.51 (m, 2H).

EXAMPLE 41

17-(5-fluoropyridin-3-yl)-N-(2-methoxyethyl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(153) ##STR00077##

(154) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 40 mg of 2-methoxyethan-1-amine to give 77 mg of the title compound.

(155) UPLC analysis (Method 1) Rt=1.41 min, mass found ESI(+) 434.24.

(156) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.99 (s, 3H), 1.35-1.79 (m, 5H), 1.86-1.96 (m, 1H), 2.06-2.44 (m, 5H), 2.83-2.93 (m, 2H), 3.23 (s, 3H), 3.32-3.46 (m, 4H), 6.23-6.29 (m, 1H), 7.31 (d, 1H), 7.52-7.60 (m, 2H), 7.64-7.71 (m, 1H), 8.29-8.37 (m, 1H), 8.40-8.51 (m, 2H).

EXAMPLE 42

17-(5-fluoropyridin-3-yl)-N-[2-(isopropylsulphonyl)ethyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(157) ##STR00078##

(158) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 80 mg of 2-(isopropylsulphonyl)ethan-1-amine to give 71 mg of the title compound.

(159) C.sub.29H.sub.35FN.sub.2O.sub.3S UPLC analysis (Method 1) Rt=1.40 min, mass found ESI(+) 510.24.

(160) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.21 (d, 6H), 1.36-1.79 (m, 5H), 1.86-1.96 (m, 1H), 2.06-2.44 (m, 5H), 2.83-2.93 (m, 2H), 3.21-3.35 (m, partly concealed by water signal), 3.61 (q, 2H), 6.22-6.30 (m, 1H), 7.33 (d, 1H), 7.51-7.58 (m, 2H), 7.67 (dt, 1H), 8.39-8.51 (m, 2H), 8.55 (t, 1H).

EXAMPLE 43

17-(5-fluoropyridin-3-yl)-N-[(3-methyloxetan-3-yl)methyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(161) ##STR00079##

(162) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 54 mg of 1-(3-methyloxetan-3-yl)methylamine to give 69 mg of the title compound.

(163) UPLC analysis (Method 1) Rt=1.40 min, mass found ESI(+) 460.25.

(164) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.21 (s, 3H), 1.35-1.80 (m, 5H), 1.85-1.97 (m, 1H), 2.06-2.41 (m, 5H), 2.83-2.95 (m, 2H), 3.40 (d, 2H), 4.15 (d, 2H), 4.44 (d, 2H), 6.27 (br. s., 1H), 7.33 (d, 1H), 7.52-7.71 (m, 3H), 8.40-8.52 (m, 3H).

EXAMPLE 44

17-(5-fluoropyridin-3-yl)-N-(2-hydroxyethyl)-N-methyloestra-1,3,5(10),16-tetraene-3-carboxamide

(165) ##STR00080##

(166) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 40 mg of 2-(methylamino)ethan-1-ol to give 55 mg of the title compound.

(167) UPLC analysis (Method 1) Rt=1.31 min, mass found ESI(+) 434.24.

(168) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.34-1.80 (m, 5H), 1.84-1.95 (m, 1H), 2.05-2.42 (m, 5H), 2.79-2.97 (5H, includes s at 2.92 ppm), 3.45 (br. s.), 3.55 (br. s.), 4.71 (t, 1H), 6.21-6.31 (m, 1H), 7.03-7.15 (m, 2H), 7.28 (d, 1H), 7.68 (dt, 1H), 8.40-8.51 (m, 2H).

EXAMPLE 45

17-(5-fluoropyridin-3-yl)-N[(S)-2-hydroxypropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(169) ##STR00081##

(170) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 40 mg of (S)-1-(aminomethyl)ethan-1-ol to give 92 mg of the title compound.

(171) C.sub.27H.sub.31FN.sub.2O.sub.2 UPLC analysis (Method 1) Rt=1.32 min, mass found ESI(+) 434.24.

(172) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.95-1.07 (m, 6H), 1.35-1.79 (m, 5H), 1.86-1.96 (m, 1H), 2.06-2.41 (m, 5H), 2.83-2.93 (m, 2H), 3.15 (t, 2H), 3.67-3.79 (m, 1H), 4.67 (d, 1H), 6.23-6.29 (m, 1H), 7.31 (d, 1H), 7.52-7.60 (m, 2H), 7.64-7.71 (m, 1H), 8.21 (t, 1H), 8.43 (d, 1H), 8.46-8.51 (m, 1H).

EXAMPLE 46

17-(5-fluoropyridin-3-yl)-N[(S)-2-hydroxypropyl]oestra-1,3,5(10),16-tetraene-3-carboxamide

(173) ##STR00082##

(174) Analogously to Example 8, 100 mg of 17-(5-fluoropyridin-3-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 56 mg of 2-(2-aminoethoxy)ethan-1-ol to give 64 mg of the title compound. C.sub.28H.sub.33FN.sub.2O.sub.3 UPLC analysis (Method 1) Rt=1.28 min, mass found ESI(+) 464.25.

(175) .sup.1H NMR (400 MHz, DMSO-d.sub.6): [ppm]=1.00 (s, 3H), 1.37-1.66 (m, 4H), 1.74 (td, 1H), 1.87-1.95 (m, 1H), 2.08-2.19 (m, 2H), 2.26-2.45 (m, 3H), 2.84-2.92 (m, 2H), 3.29-3.52 (m, 8H), 4.54 (t, 1H), 6.25-6.28 (m, 1H), 7.31 (d, 1H), 7.52-7.59 (m, 2H), 7.65-7.70 (m, 1H), 8.32 (t, 1H), 8.43 (d, 1H), 8.49 (t, 1H).

EXAMPLE 47

17-(pyrimidin-5-yl)-N-(2-sulphamoylethyl)oestra-1,3,5(10),16-tetraene-3-carboxamide

(176) ##STR00083##

(177) Analogously to Example 8, 100 mg of 17-(pyrimidin-5-yl)oestra-1,3,5(10),16-tetraene-3-carboxylic acid were reacted with 89 mg of 2-aminoethane-1-sulphonamide hydrochloride (1:1) to give 47 mg of the title compound. The title compound was purified by preparative HPLC.

(178) TABLE-US-00004 System: Waters autopurification system: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100 Column: XBridge C18 5 m 100 30 mm Solvent: A = H2O + 0.2% by vol. of NH3 (32%) B = ACN Gradient: 0-8 min 15-60% B Flow rate: 50 ml/min Temperature: room temp. Solution: 126 mg/2.5 ml of DMSO Injection: 5 0.5 ml Detection: DAD scan range 210-400 nm MS ESI+, ESI, scan range 160-1000 m/z ELSD Rt in min Amount in mg Fractions 7.1-7.3 47 Workup: The fractions were concentrated by evaporation, admixed with tBuOH, frozen at 65 C. and then freeze-dried.

(179) .sup.1H NMR (300 MHz, DMSO-d.sub.6): [ppm]=0.99 (s, 3H), 1.34-1.80 (m, 5H), 1.85-1.97 (m, 1H), 2.05-2.41 (m, 6H), 2.83-2.93 (m, 2H), 3.14-3.23 (m, 2H), 3.54-3.64 (m, 2H), 6.31 (s, 1H), 6.90 (s, 2H), 7.33 (d, 1H), 7.50-7.60 (m, 2H), 8.47 (t, 1H), 8.83 (s, 2H), 9.04 (s, 1H).

(180) Pharmacological Study of the Inventive Compounds In Vitro

EXAMPLE 48

AKR1C3-Inhibitory Action

(181) The AKR1C3-inhibitory action of the substances of this invention was measured in the AKR1C3 assay described in the paragraphs which follow.

(182) Essentially, the enzyme activity is measured by quantifying the coumberol formed from coumberone (Halim, M., Yee, D. J., and Sames, D., J. AM. CHEM. SOC. 130, 14123-14128 (2008) and Yee, D. J., Balsanek, V., Bauman, D. R., Penning, T. M., and Sames, D., Proc. Natl. Acad. Sci. USA 103, 13304-13309 (2006)). In this assay, the increase in the highly fluorescent coumberol can be determined by NADPH (nicotinamide adenine dinucleotide phosphate)-dependent reduction of the nonfluorescent coumberone by AKR1C3.

(183) The enzyme used was recombinant human AKR1C3 (aldo-keto reductase family 1 member C3) (GenBank Accession No. NM_003739). This was expressed as the GST (glutathione S-transferase) fusion protein in E. coli and purified by means of glutathione-Sepharose affinity chromatography. The GST was removed by thrombin digestion with subsequent size exclusion chromatography (Dufort, I., Rheault, P., Huang, X F., Soucy, P., and Luu-The, V., Endocrinology 140, 568-574 (1999)).

(184) For the assay, 50 nl of a 100-fold concentrated solution of the test substance in DMSO were pipetted into a black low-volume 384-well microtitre plate (Greiner Bio-One, Frickenhausen, Germany), 2.0 l of a solution of AKR1C3 in assay buffer [50 mM potassium phosphate buffer pH 7, 1 mM DTT, 0.0022% (w/v) Pluronic F-127, 0.01% BSA (w/v) and protease inhibitor cocktail (complete, EDTA-free Protease Inhibitor Cocktail from Roche)] were added and the mixture was incubated for 15 min, in order to enable preliminary binding of the substances to the enzyme prior to the enzyme reaction. Then the enzyme reaction was started by adding 3 l of a solution of NADPH (16.7 M.fwdarw.final concentration in assay volume 5 l is 10 M) and coumberone (0.5 M.fwdarw.final concentration in assay volume 5 l is 0.3 M) in assay buffer and the resulting mixture was incubated at 22 C. for the reaction time of 90 min. The concentration of the AKR1C3 was matched to the respective activity of the enzyme preparation and set such that the assay worked within the linear range. Typical concentrations were in the region of 1 nM. The reaction was stopped by adding 5 l of a stop solution consisting of the inhibitor EM-1404 [F. Labrie et al. U.S. Pat. No. 6,541,463, 2003](2 M.fwdarw.final concentration in assay volume 5 l is 1 M). Subsequently, the fluorescence of coumberol was measured at 520 nm (excitation at 380 nm) with a suitable measuring instrument (Pherastar from BMG Labtechnologies). The intensity of the fluorescence was used as a measure for the amount of coumberol formed and hence for the enzyme activity of AKR1C3. The data were normalized (enzyme reaction without inhibitor=0% inhibition; all other assay components but no enzyme=100% inhibition). Typically, the test substances were tested on the same microtitre plate at 11 different concentrations in the range from 20 M to 96.8 M (20 M, 5.9 M, 1.7 M, 0.5 M, 0.15 M, 44 nM, 12.9 nM, 3.8 nM, 1.1 nM, 0.3 nM and 96.8 M; the dilution series were prepared before the assay at the level of the 100-fold concentrated solution by serial 1:3 dilutions with 100% DMSO) in twin values for each concentration, and IC.sub.50 values were calculated by a 4-parameter fit.

(185) As described, the pharmacological substances claimed were tested for their inhibitory effect on the AKR1C3 enzyme (see Table 1). The compounds claimed show strong inhibition of AKR1C3 in vitro (IC.sub.50 values <500 nM) and predominantly even IC.sub.50 values <100 nM.

(186) TABLE-US-00005 TABLE 1 Inhibition of AKR1C3 by the inventive compounds (for some of the compounds, the values for two experimental determinations are reported) AKR1C3 enzyme Example inhibition IC.sub.50 compound [nmol/l] 1 6 1 5 2 189 2 100 3 46 3 25 4 4 4 4 5 313 5 199 5 143 6 346 7 27 7 27 8 73 9 61 9 81 10 97 10 46 11 34 11 20 12 21 12 20 13 108 13 79 14 54 14 37 15 25 15 25 16 15 16 42 17 29 17 20 18 45 18 35 19 60 19 48 20 12 20 8 20 20 20 16 21 5 22 5 23 9 24 17 25 48 26 5 27 5 28 9 29 10 30 12 31 19 32 11 33 4 33 5 34 6 35 17 36 6 37 5 38 4 39 5 41 8 42 11 43 7 44 12 45 6 46 6 47 119

EXAMPLE 49

Test of AKR1C3 Inhibition in a Cell-Based System

(187) The inhibition of AKR1C3 by the substances described in this invention was measured in a cell-based assay using coumberol as the substrate for the AKR1C3 (Halim, M., Yee, D. J., and Sames, D., J. AM. CHEM. SOC. 130, 14123-14128 (2008) and Yee, D. J., Balsanek, V., Bauman, D. R., Penning, T. M., and Sames, D., Proc. Natl. Acad. Sci. USA 103, 13304-13309 (2006)) (cf. Example 48).

(188) The cell system used was HEK293 cells (ATCC, USA) (cell culture medium: DMEM, 1.5 g of glucose, 10% FCS, PSG). The cells were transfected with an AKR1C3 expression plasmid (pCMV6-AC-AKR1C3, GenBank Accession No. NM_003739.4) overnight (X-tremeGENE HP, Roche). The next morning, the cells were sown into black 96-well culture plates with a cell density of 40 000 cells/well (Greiner Bio-One, Frickenhausen, Germany). 7 h later, the cells were incubated with the test substances (dissolved in 100 concentration in DMSO, final concentration between 10.sup.11M and 10.sup.5M) and coumberol (dissolved in cell culture medium, final concentration 510.sup.6M) overnight. The following morning, the fluorescence of coumberol was measured at 535 nm (excitation at 355 nm) with a suitable measuring instrument (Mithras, from Berthold). The intensity of the fluorescence was used as a measure for the amount of coumberol formed and hence for the enzyme activity of AKR1C3. The data were normalized (transfected cells without inhibitor, only DMSO=0% inhibition; transfected cells, 10 M EM-1404 inhibitor [F. Labrie et al. U.S. Pat. No. 6,541,463, 2003]=100% inhibition) and IC.sub.50 values were calculated by a 4-parameter fit.

(189) The pharmacological substances claimed were tested for their inhibitory action on the AKR1C3 enzyme by means of the cell-based assay described above (see Table 2). The compounds exhibited strong inhibition of cellular AKR1C3 in vitro (IC.sub.50 values <100 nM).

(190) TABLE-US-00006 TABLE 2 Inhibition of AKR1C3 of the inventive compounds in a cellular assay (the values reported are for at least two experimental determinations) Cellular AKR1C3 Example inhibition IC50 compound [nmol/l] 1 13 1 27 1 28 1 66 7 83 7 150 12 68 12 96 12 43 12 23 16 97 16 74 17 34 17 28 20 32 20 42

EXAMPLE 50

Inhibition of Cyp17A1

(191) CYP17A1 (synonym: 17-hydroxylase/17,20 lyase) is an enzyme which adds a hydroxyl group on at position 17 in the steroidal D ring of pregnenolone and of progesterone, which forms 17-hydroxyprogesterone and 17-hydroxypregnenolone. Subsequently, dehydroepiandrosterone and androstenedione are formed. The known CYP17A1 inhibitor abiraterone is used, for example, for the treatment of metastasized, castration-refractory prostate carcinoma after failure of docetaxel-based chemotherapy (Urologe 2010, 49, 64-68). Abiraterone blocks androgen synthesis and oestrogen synthesis in the whole body and accordingly lowers hormone production in a non-tissue-specific manner, which leads to undesirable side effects (cf. press release from FDA, U.S. Food and Drug Admistration dated 28 Apr. 2011).

(192) It has been found that, surprisingly, the inventive compounds, even though they exhibit an aromatic nitrogen-containing heterocycle at position 17 of the steroidal skeleton, inhibit CYP17A1 only very weakly, if at all.

(193) Assay Description:

(194) The inhibition of CYP17A1 by the test compounds was evaluated by means of recombinant enzyme. Human CYP17A1 was expressed in E. coli (Ehmer, P. B. et al.; J. Steroid Biochem. Mol. Biol., 75, 57-63 (2000)). The microsomal fraction and 140 L phosphate buffer (50 mM Na phosphate, 1 mM MgCl.sub.2, 0.1 mM EDTA, 0.1 mM dithiothreitol, pH 7.4) together with a mixture of progesterone (24.95 M) and .sup.3H-progesterone (0.05 M, 101.3 Ci/mmol), 50 M of an NADPH regeneration system (in phosphate buffer with 10 mM NADP+, 100 mM glucose 6-phosphate and 2.5 U glucose 6-phosphate dehydrogenase) and the corresponding test substances (in 5 l of DMSO) were preincubated individually at 37 C. for 5 minutes. The reaction was started by adding the enzyme and, after incubation at 37 C. for 30 minutes, stopped by adding 50 l of 1 N hydrochloric acid.

(195) The steroids were extracted with ethyl acetate. After evaporating the organic phase, the steroids were taken up in acetonitrile. 16-Hydroxyprogesterone, 17-hydroxyprogesterone and progesterone were separated with acetonitrile/water (45:55) as mobile phase on a C18 reverse phase chromatography column (Nucleodur C18 Gravity, 3 m, Macherey-Nagel, Dren) in an HPLC System (Agilent 1100 Series, Agilent Technologies, Waldbronn). Detection and quantification of the steroids were conducted by means of a Radioflow detector (Berthold Technologies, Bad Wildbad). The inhibition was calculated by the following formula:

(196) $\%\mathrm{Inhibition}=\frac{\%\left(17-\mathrm{hydroxyprogesterone}+16-\mathrm{hydroxyprogesterone}\right)}{\begin{array}{c}\%\left(17-\mathrm{hydroxyprogesterone}+16-\mathrm{hydroxyprogesterone}\right)+\\ \mathrm{progesterone}\end{array}}.Math.100$

(197) Each value was calculated from at least three independent experiments. The final IC.sub.50 value was calculated as the mean from 3 or 4 independent IC.sub.50 values.

(198) The inventive compounds do not show any inhibition of Cyp17A1 (Table 3); in contrast, the known Cyp17A1 Inhibitor abiraterone (used as the free base) is active in the assay used.

(199) TABLE-US-00007 TABLE 3 Inhibition of human CYP17 IC.sub.50 SD (M) Example compound CYP17 Abiraterone 0.029 0.004 4 IC.sub.50 > 20 M 20 IC.sub.50 > 20 M

EXAMPLE 51

AKR1C1,2,4-Inhibitory Action

(200) The AKR1C1/AKR1C2/AKR1C4-inhibitory action of the inventive substances, for determination of the selectivity of this invention, was measured in the assay described in the paragraphs which follow.

(201) Essentially, the enzyme activity is measured by the quantification of NADPH (nicotinamide adenine dinucleotide phosphate) consumption in the conversion of phenanthrenequinone (PQ) by the AKR1C enzymes.

(202) The enzymes used were recombinant human AKR1C1, AKR1C2 and AKR1C4 (aldo-keto reductase family 1 members C1, 2 and 4) (GenBank Accession No. NM_001353.5, NM_001354, NM_001818). This was expressed as the GST (glutathione S-transferase) fusion protein in E. coli and purified by means of glutathione-Sepharose affinity chromatography. The GST was removed by thrombin digestion with subsequent size exclusion chromatography (Dufort, I., Rheault, P., Huang, X F., Soucy, P., and Luu-The, V., Endocrinology 140, 568-574 (1999)).

(203) For the assay, 50 nl of a 100-fold concentrated solution of the test substance in DMSO and 90 l of assay buffer [50 mM potassium phosphate buffer pH 7, 0.0022% (w/v) Pluronic F-127, 0.02% BSA (w/v), 170 M NADPH, 100 nM PQ] were pipetted into a black 96-well microtitre plate (Greiner Bio-One, Frickenhausen, Germany). To start the reaction 10 l of enzyme [20 nM] were added and the fluorescence at time 0 was determined at 460 nm (excitation at 355 nm) with a suitable measuring instrument. The mixture was incubated at 37 C. for 3 h, and the fluorescence was determined at the end of the reaction.

(204) The difference in the fluorescence intensities was used as a measure for the consumption of NADPH and hence for the enzyme activity of AKRIC1, -2 and -4. The data were normalized (enzyme reaction without inhibitor=0% inhibition; all other assay components but no enzyme=100% inhibition). Typically, the test substances were tested on the same microtitre plate in 10 different concentrations in the range from 10 M to 1 pM (10 M, 1 M, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM, 1 pM). As described, the pharmacological substances claimed were tested for their inhibitory effect on AKR1C enzymes 1, 2 and 4 (see Table 4).

(205) TABLE-US-00008 TABLE 4 Inhibition of AKR1C1, -2 and -4 by the inventive compounds (the values reported are for two experimental determinations) AKR1C4 AKR1C1 enzyme AKR1C2 enzyme enzyme Example inhibition IC.sub.50 inhibition IC.sub.50 inhibition IC.sub.50 compound [nmol/l] [nmol/l] [nmol/l] 1 no effect no effect no effect 1 no effect no effect no effect phenolphthalein 46 554 21 phenolphthalein 60 438 17

EXAMPLE 52

Kinetic Solubility

(206) The kinetic solubilities of the inventive substances were determined by laser nephelometry.

(207) The data were recorded using the following instruments:

(208) Liquid handling system: Hamilton Star

(209) Nephelometer: Nepheloskan Ascent

(210) The following chemicals and materials were used:

(211) DMSO

(212) disodium hydrogenphosphate dihydrate

(213) potassium dihydrogenphosphate

(214) gum arabic

(215) Preparation of phosphate buffer pH 7.4:

(216) Solution 1: 9.71 g of disodium hydrogenphosphate dihydrate and 1.65 g of potassium dihydrogenphosphate dissolved in 1 liter of water Solution 2: 10 mg of gum arabic dissolved in 1 liter of water

(217) 150 ml of solution 1 and 100 ml of solution 2 were diluted with 750 ml of water.

(218) Experimental Protocol:

(219) 150 l of a 10 mM DMSO stock solution were pipetted into a plate (deep-well plate, Abgene, PP, 1.2 ml). The stock solution was diluted with DMSO, which led to a new multi-titre plate (MTP, Greiner bio-one, PS, V-Form) with eight concentrations: 10/5/2.5/1.25/0.625/0.313/0.156 and 0.078 mM. 261 l of phosphate buffer were transferred into a further plate (96 cliniplate, UB Thermo Electron Corporation) and admixed with 9 l of the DMSO stock solutions.

(220) The concentration of the DMSO cosolvent was kept constant at 3%.

(221) The plates obtained (cliniplates) were analysed in the nephelometer.

(222) The following nephelometric solubilities were determined:

(223) TABLE-US-00009 Nephelometric solubility [mg/l] Example at pH = 7.4 21 158 22 153 28 166 29 24 33 80 35 22 38 145 40 145 43 154 EM-1404 18

EXAMPLE 53

Determination of Antiandrogenic Action

(224) The antiandrogenic action of the substance was measured in adult monkeys (Macaca fascicularis), as a surrogate for the antiproliferative effects in prostate cancer and metastases thereof. The monkeys (4 per group) were treated by the oral route by means of a gavage with 1, 3 or 10 mg/kg substance or with vehicle over 4 weeks. The size of the prostate and of the seminal vesicle was determined by ultrasound at the start of the experiment and after one, two, three and four weeks. The decrease in the weight of these organs was taken as evidence for the antiandrogenicity of the substances. In addition, the blood concentrations (in the serum or in the plasma) of various steroids (DHEA, testosterone, androstenedione, hydroxyprogesterone) and prostaglandins (PGD2, PGJ2, PGF2alpha) were determined at the start of the experiment and after one, two, three or four weeks. Since AKR1C3 is involved both in the steroid synthesis route and in the prostaglandin synthesis route, changes in the blood concentrations of these steroids and prostaglandins are taken as an indication of the in vivo effect of the substances.