Patent Application: US-44120006-A

Abstract:
the present invention relates to novel substituted steroid derivatives which represent selective inhibitors of the 17β - hydroxysteroid dehydrogenase type i and , in addition , which may represent inhibitors of the steroid sulphatase , as well as to their salts , to pharmaceutical preparations containing these compounds and to processes for the preparation of these compounds . furthermore , the invention concerns the therapeutic use of said novel substituted steroid derivatives , particularly their use in the treatment , inhibition , prophylaxis or prevention of steroid hormone dependent diseases or disorders , such as steroid hormone dependent diseases or disorders requiring the inhibition of 17β - hydroxysteroid dehydrogenase type i and / or steroid sulphatase enzymes and / or requiring the lowering of the endogenous 17β - estradiol concentration .

Description:
the following terms are used to describe the present invention and in particular , to describe various constituents of the chemical composition useful in this invention . the terms are defined as follows : as used herein , the terms “ comprising ” and “ including ” are used herein in their open , non - limiting sense . the word “ compound ” shall here be understood to cover any and all isomers ( e . g ., enantiomers , stereoisomers , diastereomers , rotomers , tautomers ) or any mixture of isomers , prodrugs , and any pharmaceutically acceptable salt of said compound , unless the formula depicting the compound explicitly shows a particular stereochemistry . where the plural form is used for compounds , salts , and the like , this is taken to mean also a single compound , salt , or the like . the term “ 17β - hydroxysteroid dehydrogenase type i ” or “ 17β - hsd1 ” for short is used for the enzyme ec 1 . 1 . 1 . 62 and reduces estrone ( e1 ) to the biologically active estrogen , estradiol ( e2 ). the term “ steroid sulphatase ” or “ sts ” for short is used for the enzyme ec 3 . 1 . 6 . 2 and hydrolyses several sulphate steroids , such as estrone sulphate , dehydroepiandrosterone sulphate and cholesterol sulphate . the terms “ inhibit ” and “ inhibition ” include the meaning of to reduce and / or eliminate and / or mask and / or prevent a certain enzyme action . the term “ 17β - hsd1 inhibitor ” as used herein with respect to the compound of the present invention means a compound that can inhibit 17β - hsd1 activity , such as to reduce and / or eliminate and / or mask and / or prevent the action of 17β - hsd1 . the 17β - hsd1 inhibitor may act as an reversible or irreversible inhibitor of 17β - hsd1 . the ability of compounds to inhibit 17β - hsd1 activity can be assessed using cell lines recombinantly expressing the human 17β - hsd1 enzyme . details on a suitable assay protocol are presented in the examples section . it is to be noted that the compound of the present invention may have other beneficial properties in addition to or in the alternative to its ability to inhibit 17β - hsd1 activity ; in particular a 17β - hsd1 inhibitor may have antagonistic activity towards the nuclear estrogen receptor . the term “ sts inhibitor ” as used herein with respect to the compound of the present invention means a compound that can inhibit sts activity , such as to reduce and / or eliminate and / or mask and / or prevent the action of sts . the sts inhibitor may act as an antagonist . the ability of compounds to inhibit estrone sulphate activity can be assessed using either intact mcf - 7 breast cancer cells or placenta microsomes . in addition , an animal model may be used . details on suitable assay protocols are presented in following sections . it is to be noted that other assays could be used to determine sts activity and thus sts inhibition . for example , reference may also be made to the teachings of international patent application wo 99 / 50453 . preferably , for some applications , a “ sts inhibitor ” is further characterized by the feature that if the sulphamate group were to be substituted by a sulphate group to form a sulphate derivative , then the sulphate derivative would be hydrolysable by an enzyme having steroid sulphatase ( ec 3 . 1 . 6 . 2 ) activity , i . e . when incubated with steroid sulphatase ec 3 . 1 . 6 . 2 at ph 7 . 4 and 37 ° c . in one preferred embodiment , if the sulphamate group of the compound were to be replaced with a sulphate group to form a sulphate compound then that sulphate compound would be hydrolysable by an enzyme having steroid sutphatase ( ec 3 . 1 . 6 . 2 ) activity and would yield a km value of less than 200 mm , preferably less than 150 mm , preferably less than 100 mm , preferably less than 75 mm , preferably less than 50 mm , when incubated with steroid sulphatase ec 3 . 1 . 6 . 2 at ph 7 . 4 and 37 ° c . in one preferred embodiment , if the sulphamate group of the compound were to be replaced with a sulphate group to form a sulphate compound then that sulphate compound would be hydrolysable by an enzyme having steroid sutphatase ( ec 3 . 1 . 6 . 2 ) activity and would yield a km value of less than 200 μm , preferably less than 150 μm , preferably less than 100 μm , preferably less than 75 μm , preferably less than 50 μm , when incubated with steroid sulphatase ec 3 . 1 . 6 . 2 at ph 7 . 4 and 37 ° c . in a preferred embodiment , the compound of the present invention is not hydrolysable by an enzyme having steroid sulphatase ( ec 3 . 1 . 6 . 2 ) activity . it is to be noted that the compound of the present invention may have other beneficial properties in addition to or in the alternative to its ability to inhibit sts activity . the terms “ selective ” and “ selectivity ” as used herein with respect to the compounds of the present invention means a compound that can inhibit 17β - hsd1 and / or sts activity , and shows a higher inhibition value for these particular targets than with regard to other enzyme targets , in particular with regard to the 17β - hsd1 enzyme , and that has weak or no affinity for nuclear receptors , in particular that has weak or no affinity for the er . preferably a compound of the present invention has at least about a 100 fold selectivity to a desired target ( e . g . 17β - hsd1 or sts ), preferably at least about a 150 fold selectivity to the desired target , preferably at least about a 200 fold selectivity to the desired target , preferably at least about a 250 fold selectivity to the desired target , preferably at least about a 300 fold selectivity to the desired target , preferably at least about a 350 fold selectivity to the desired target . the term “ substituted ” means that the specified group or moiety bears one or more substituents . where any group may carry multiple substituents and a variety of possible substituents is provided , the substituents are independently selected and need not be the same . the term “ unsubstituted ” means that the specified group bears no substituents . the term “ optionally substituted ” means that the specified group is unsubstituted or substituted by one or more substituents . any asymmetric carbon atoms may be present in the ( r )-, ( s )- or ( r , s )- configuration preferably in the ( r )- or ( s )- configuration , whichever is most active , unless the stereochemistry is explicitly depicted in the corresponding compound formula . substituents at a double bond or a ring may be present in cis - (.= z -) or trans (= e -) form , unless the stereochemistry is explicitly depicted in the corresponding compound formula . the compounds of formula ( i ) have a defined stereochemistry within the steroidal core structure according to the natural configuration for estrogenic steroids such as estradiol : the stereochemistry within the steroidal core structure is always shown in the corresponding compound formula and should not vary within the scope of the present invention , whereas the stereochemistry at the carbon atoms in the steroidal core carrying additional side chains and the stereochemistry of any asymmetric carbon atom within the side chains themselves is not fixed . therefore , the term “ compounds of formula ( i )” or “ compounds of formula ( ii )” etc also comprises the stereoisomers of the depicted compounds , unless a particular stereochemistry is explicitly shown within the formula . the stereochemistry shown in the respective formula prevails over the general term “ stereoisomers ”. the compounds of the formula i contain at least one additional chiral carbon atom , namely the carbon atom carrying the side chain in the 15 - position of the steroid structure . the compounds can thus be present at least in two optically active stereoisomeric forms or as a racemate . the present invention includes both the racemic mixtures and the isomerically pure compounds of the formula i . the position of the substituents within the c15 position is characterized by α or β . a c15α derivative according to the present invention is represented by a compound of the following formula ( ii ) whereas a c15β derivative according to the present invention is represented by a compound of the following formula ( iii ) the compounds of the present invention may contain further asymmetric centers on the molecule , depending upon the nature of the various substituents . in certain instances , asymmetry may also be present due to restricted rotation about the central bond adjoining the two aromatic rings of the specified compounds . it is intended that all isomers ( including enantiomers and diastereomers ), either by nature of asymmetric centers or by restricted rotation as described above , as separated , pure or partially purified isomers or racemic mixtures thereof , be included within the ambit of the instant invention , unless a particular stereochemistry is explicitly depicted in the formula representing a respective compound . the term “ halogen ” refers to fluorine ( f , fluoro -), bromine ( br , bromo -), chlorine ( cl , chloro ), and iodine ( j , iodo -) atoms . the terms “ dihalogen ”, “ trihalogen ” and “ perhalogen ” refer to two , three and four substituents , respectively , each individually selected from the group consisting of fluorine , bromine , chlorine , and iodine atoms . the term “ sulfoxy ” or “ sulfonyl ” refers to the group — so 2 — for the purpose of the present invention , the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety , i . e ., the prefix c i - c j defines the number of carbon atoms present from the integer “ i ” to the integer “ j ” inclusive . thus c 1 - c 4 - alkyl refers to alkyl of 1 - 4 carbon atoms , inclusive , or methyl , ethyl , propyl , butyl and isomeric forms thereof . the term “ alkyl ” stands for a hydrocarbon radical which may be linear , cyclic or branched , with single or multiple branching , whereby the alkyl group comprises 1 to 12 carbon atoms . in one embodiment , the term “ alkyl ” stands for a linear or branched ( with single or multiple branching ) alkyl chain of 1 to 8 carbon atoms , exemplified by the term ( c 1 - c 8 ) alkyl , more preferably of 1 to 6 carbon atoms exemplified by the term ( c 1 - c 6 ) alkyl . the term ( c 1 - c 8 ) alkyl is further exemplified by such groups as methyl ; ethyl ; n - propyl ; isopropyl ; n - butyl ; sec - butyl ; isobutyl ; tert - butyl ; n - pentyl ; isopentyl ; neopentyl ; tert - pentyl ; 2 - or 3 - methylpentyl ; n - hexyl ; isohexyl , heptyl , octyl and the like . the alkyl or ( c 1 - c 8 ) alkyl group may be partially unsaturated , forming such groups as , for example , vinyl , propenyl ( allyl ), butenyl , pentenyl , pentinyl , hexenyl , octadienyl , and the like . the term “ alkyl ” further comprises cycloalkyl groups , preferably cyclo ( c 3 - c 8 ) alkyl which refers to cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , cycloheptyl , cyclooctyl and isomeric forms thereof such as methylcyclopropyl ; 2 - or 3 - methylcyclobutyl ; 2 -, or 3 - methylcyclopentyl , and the like . the cycloalkyl group may also be partly unsaturated , forming such groups as , for example , cyclohexenyl , cyclopentenyl , cyclooctadienyl , and the like . furthermore , the term “ alkyl ” comprises a cycloalkyl - alkyl group comprising 4 to 12 carbon atoms , preferably “—( c 1 - c 4 ) alkyl - cyclo ( c 3 - c 8 ) alkyl ” which refers to a alkyl group of 1 to 4 carbon atoms as described above substituted with a cyclo ( c 3 - c 8 ) alkyl group as described above , forming such groups as for example cyclopropylmethyl , cyclohexylmethyl , cyclopentylethyl or cyclohexenylethyl . the term “ alkyl ” further comprises bicyclic ring systems of 6 to 10 carbon atoms , preferably bicyclo [ 2 . 1 . 1 ] hexyl , bicyclo [ 2 . 2 . 1 ] heptyl , bicyclo [ 3 . 2 . 1 ] octyl , bicyclo [ 2 . 2 . 2 ] octyl , bicyclo [ 3 . 2 . 2 ] nonanyl , bicyclo [ 3 . 3 . 1 ] nonanyl , bicyclo [ 3 . 3 . 2 ] decanyl ; and the like , preferably bicyclo [ 2 . 2 . 1 ] heptyl , and fused ring systems of up to 10 carbon atoms such as adamantyl and the like . the alkyl group may optionally be substituted by up to five , more preferably by up to three substituents independently selected from the group consisting of halogen , hydroxyl , optionally substituted aryl , optionally substituted heteroaryl , optionally substituted cycloheteroalkyl , thiol , nitro , nitrile , alkoxy , aryloxy , arylalkyloxy , amino , amido , alkylthio , arylthio , arylalkylthio , sulfamoyl , sulfonamide , acyl , carboxyl , and acylamino , as defined herein . these groups may be attached to any carbon atom of the alkyl moiety . the alkyl group substituted with up to three independently selected aryl preferably refers to “ aryl -( c 1 - c 4 )- alkyl ” or “ diaryl -( c 1 - c 4 )- alkyl ”, wherein the aryl is phenyl , naphthyl , indanyl , indenyl , or 1 , 2 , 3 , 4 - tetrahydro - naphthalen - 1 - yl , preferably aryl is phenyl or naphthyl , forming such groups as for example benzyl , diphenylmethyl , phenethyl , phenylpropyl , diphenylpropyl , phenylbutyl , naphthylmethyl or naphthylethyl . the alkyl chain may be further substituted as defined above ; for example the alkyl chain may carry an additional hydroxyl group . furthermore , the alkyl chain may be partially unsaturated , such as a vinyl group . the aryl moiety may optionally be substituted as defined herein . the alkyl group substituted with up to three independently selected heteroaryl group preferably refers to “ heteroaryl -( c 1 - c 4 )- alkyl ”, wherein the heteroaryl is pyrrolyl , thienyl , furyl , imidazolyl , thiazolyl , isothiazolyl , oxazolyl , isoxazolyl , pyrazolyl , pyridinyl , pyrimidinyl , pyrazinyl , indolyl , quinolinyl , isoquinolinyl , benzoimidazolyl , benzofuran , benzo [ b ] thiophene , preferably heteroaryl is furyl , indolyl , benzoimidazolyl , pyridinyl , thienyl or imidazolyl , forming such groups as for example benzoimidazolylmethyl , pyridinylmethyl , thienylmethyl , furylmethyl , indolylethyl , thienylethyl , pyridinylethyl , or imidazolylpropyl . the heteroaryl moiety may optionally be substituted as defined herein . the alkyl group substituted with up to three independently selected cycloheteroalkyl groups preferably refers to “ cycloheteroalkyl -( c 1 - c 4 )- alkyl ”, wherein the cycloheteroalkyl is pyrrolidinyl , tetrahydrofuryl , tetrahydrothiophenyl , piperidinyl , morpholinyl , thiomorpholinyl , piperazinyl , azepanyl , diazepanyl , oxazepanyl or thiazepanyl , preferably cycloheteroalkyl is piperidinyl , pyrrolidinyl , or morpholinyl , forming such groups as for example morpholinylethyl , morpholinylpropyl , piperidinylethyl or pyrrolidinylethyl . the cycloheteroalkyl moiety may optionally be substituted as defined herein . the term “ alkoxy ” refers to a group — or , where r may be alkyl ( wherein the alkyl chain may be optionally further substituted as defined herein ). preferably , the term “ alkoxy ” refers to — o —( c 1 - c 6 ) alkyl ( or ( c 1 - c 6 ) alkoxy ), with the ( c 1 - c 6 ) alkyl group as defined above and optionally substituted with up to three hydroxyl groups . the term “ aryloxy ” refers to a group — oar , where ar represents aryl as defined herein , which is optionally substituted in the aryl group with up to five independently selected substituents as defined herein , in particular hydroxyl , halogen , ( c 1 - c 4 )- alkyl , ( c 1 - c 4 )- alkoxy , halogenated ( c 1 - c 4 )- alkyl , or halogenated ( c 1 - c 4 )- alkoxy ; the number of said substituents being up to five for halogen , and up to three for any combination of said other substituents . preferably , aryloxy refers to phenoxy , optionally substituted as defined above . the term “ arylalkyloxy ” refers to a group — o —( c 1 - c 4 ) alkyl - ar , where ar represents aryl , which is optionally substituted in the aryl group with up to five independently selected substituents as defined herein , in particular hydroxyl , halogen , ( c 1 - c 4 )- alkyl , ( c 1 - c 4 )- alkoxy , halogenated ( c 1 - c 4 )- alkyl , or halogenated ( c 1 - c 4 )- alkoxy ; the number of said substituents being up to five for halogen , and up to three for any combination of said other substituents . preferably , arylalkyloxy refers to benzyloxy , optionally substituted as defined above . the term “ acyl ” refers to a group —( c ═ o )— r , where r may be hydrogen , optionally substituted alkyl , optionally substituted aryl or aryl -( c 1 - c 4 )- alkyl , optionally substituted heteroaryl or heteroaryl -( c 1 - c 4 )- alkyl , as defined herein . preferably , the term “ acyl ” refers to a group —( c ═ o )— r ′, where r ′ represents hydrogen , ( c 1 - c 4 ) alkyl , phenyl , or phenyl -( c 1 - c 4 ) alkyl , preferably benzyl , or heteroaryl -( c 1 - c 4 ) alkyl , preferably indolyl - methyl ; whereby the phenyl moiety may be optionally substituted with independently selected substituents , especially hydroxyl , halogen , ( c 1 - c 4 ) alkoxy , ( c 1 - c 4 )- alkyl or halogenated ( c 1 - c 4 ) alkyl , the number of said substituents being up to five for halogen , and up to three for any combination of said other substituents . the term “ carbonyl ” represents a preferred selection of the term “ acyl ” and refers to the group — cho . the term “ alkylacyl ” represents a preferred selection of the term “ acyl ” and refers to a group —( c ═ o )- alkyl , preferably —( c ═ o )—( c 1 - c 4 ) alkyl . the term “ carboxyl ” refers to a group —( c ═ o )— or , wherein r may be hydrogen , optionally substituted alkyl ( preferably substituted with hydroxyl , halogen or ( c 1 - c 4 )- alkoxy ), optionally substituted aryl or aryl -( c 1 - c 4 )- alkyl , or optionally substituted heteroaryl or heteroaryl -( c 1 - c 4 )- alkyl , each as defined herein . preferably , the term “ carboxyl ” refers to a group —( c ═ o )— or ′, where r ′ represents hydrogen , ( c 1 - c 4 ) alkyl , phenyl , or phenyl -( c 1 - c 4 ) alkyl , preferably benzyl ; whereby the phenyl moiety may be optionally substituted with substituents independently selected from the group consisting of hydroxyl , halogen , ( c 1 - c 4 ) alkoxy , ( c 1 - c 4 )- alkyl , halogenated ( c 1 - c 4 ) alkyl and halogenated ( c 1 - c 4 ) alkoxy , the number of said substituents being up to five for halogen , and up to three for any combination of said other substituents . the terms “ carboxyl -( c 1 - c 6 ) alkyl ” and “ carboxyl -( c 1 - c a ) alkyl ” refer to groups —( c 1 - c 6 ) alkyl -( c ═ o )— or and —( c 1 - c 4 ) alkyl -( c ═ o )— or , respectively , which refer to an alkyl group of 1 to 6 and 1 to 4 carbon atoms , respectively , as described above , substituted with a —( c ═ o )— or group as described above . preferably the carboxyl group refers to —( c ═ o )— or ′, wherein r ′ represents hydrogen , ( c 1 - c 4 ) alkyl , phenyl , or ( c 1 - c 4 ) alkyl - phenyl , preferably benzyl . preferred examples of such carboxyl -( c 1 - c 6 ) alkyl groups include acetic acid methyl ester , acetic acid ethyl ester , propionic acid benzyl ester , propionic acid ethyl ester , butyric acid methyl ester , and 3 - methyl - butyric acid methyl ester . the term “ amino ” refers to the group — nrr ′, where r and r ′ may independently be hydrogen , optionally substituted alkyl ( preferred substituents comprise hydroxyl , halogen or ( c 1 - c 4 )- alkoxy ), optionally substituted aryl or aryl -( c 1 - c 4 )- alkyl , or optionally substituted heteroaryl or heteroaryl -( c 1 - c 4 )- alkyl , each as defined herein . the term “ alkylamino ” represents a preferred selection of the term “ amino ” and refers to the group — nrr ′, where r and r ′ may independently be hydrogen or ( c 1 - c 4 ) alkyl . the term “ alkylthio ” or “ alkylsulfanyl ” refers to a group — sr , where r represents optionally substituted alkyl ( preferred substituents comprise hydroxyl , ( c 1 - c 4 )- alkoxy or halogen ), as defined herein ; preferably r represents ( c 1 - c 6 ) alkyl , in particular ( c 1 - c 4 ) alkyl . the term “ arylthio ” or “ arylsulfanyl ” refers to a group — s — ar , where ar represents optionally substituted aryl ( preferred substituents comprise hydroxyl , halogen , ( c 1 - c 4 )- alkyl , ( c 1 - c 4 )- alkoxy , halogenated ( c 1 - c 4 )- alkyl , or halogenated ( c 1 - c 4 )- alkoxy ), as defined herein . preferably , arylthio refers to optionally substituted phenylsulfanyl . the term “ arylalkylthio ” or “ arylalkylsulfanyl ” refers to a group — s —( c 1 - c 4 ) alkyl - ar , where ar represents optionally substituted aryl ( preferred substituents comprise hydroxyl , halogen , ( c 1 - c 4 )- alkyl , ( c 1 - c 4 )- alkoxy , halogenated ( c 1 - c 4 )- alkyl , or halogenated ( c 1 - c 4 )- alkoxy ), as defined herein . preferably , arylalkylthio refers to optionally substituted benzylsulfanyl . the term “ alkylsulfonyl ” refers to a group — so 2 — r , where r represents optionally substituted alkyl ( preferred substituents comprise hydroxyl , ( c 1 - c 4 )- alkoxy or halogen ), as defined herein ; preferably r represents ( c 1 - c 6 ) alkyl , in particular ( c 1 - c 4 ) alkyl . the term “ arylsulfonyl ” refers to a group — so 2 — ar , where ar represents optionally substituted aryl ( preferred substituents comprise hydroxyl , halogen , ( c 1 - c 4 )- alkyl , ( c 1 - c 4 )- alkoxy , halogenated ( c 1 - c 4 )- alkyl , or halogenated ( c 1 - c 4 )- alkoxy ), as defined herein . preferably , arylsulfonyl refers to optionally substituted benzenesulfonyl . the term “ arylalkylsulfonyl ” refers to a group — so 2 —( c 1 - c 4 ) alkyl - ar , where ar represents optionally substituted aryl ( preferred substituents comprise hydroxyl , halogen , ( c 1 - c 4 )- alkyl , ( c 1 - c 4 )- alkoxy , halogenated ( c 1 - c 4 )- alkyl , or halogenated ( c 1 - c 4 )- alkoxy ), as defined herein . preferably , arylalkyl - sulfonyl refers to optionally substituted benzylsulfonyl . the term “ amido ” refers to the group —( c ═ o )— nrr ′, where r and r ′ may independently be hydrogen , optionally substituted alkyl ( preferred substituents comprise hydroxyl , halogen or ( c 1 - c 4 )- alkoxy ), optionally substituted aryl or aryl -( c 1 - c 4 )- alkyl (( preferred substituents comprise hydroxyl , halogen , ( c 1 - c 4 )- alkyl , ( c 1 - c 4 )- alkoxy , halogenated ( c 1 - c 4 )- alkyl , or halogenated ( c 1 - c 4 )- alkoxy ), or optionally substituted heteroaryl or heteroaryl -( c 1 - c 4 )- alkyl , as defined herein . the term “ alkylamido ” represents a preferred selection of the term “ amido ” and refers to the group —( c ═ o )— nrr ′, where r and r ′ may be independently selected from hydrogen or ( c 1 - c 4 ) alkyl . the term “ acylamino ” refers to the group — nr — co — r ′, where r and r ′ may independently be hydrogen , optionally substituted alkyl ( preferred substituents comprise hydroxyl , halogen or ( c 1 - c 4 )- alkoxy ), optionally substituted aryl or aryl -( c 1 - c 4 )- alkyl ( preferred substituents comprise hydroxyl , halogen , ( c 1 - c 4 )- alkyl , ( c 1 - c 4 )- alkoxy , halogenated ( c 1 - c 4 )- alkyl , or halogenated ( c 1 - c 4 )- alkoxy ), optionally substituted heteroaryl or heteroaryl -( c 1 - c 4 )- alkyl , as defined herein . preferably , acylamino refers to — nh — co —( c 1 - c 4 )- alkyl . the term “ carbonylamino ” represents a preferred selection of the term “ acylamino ” and refers to the group — nr — co — ch 2 — r ′, where r and r ′ may be independently selected from hydrogen or ( c 1 - c 4 ) alkyl . the term “ sulfonamide ” refers to the group — so 2 — nrr ′, wherein r and r ′ may independently be selected from hydrogen or ( c 1 - c 4 ) alkyl . halogenated alkyl , halogenated alkoxy and halogenated alkylthio are substituents in which the alkyl moieties ( preferably ( c 1 - c 6 ) alkyl , more preferred ( c 1 - c 4 ) alkyl , and most preferred methyl ) are substituted either partially or in full with halogens , generally with chlorine and / or fluorine . preferred examples of such substituents are trifluoromethyl , trifluoromethoxy , trifluoromethylthio , dichloromethyl , pentafluoroethyl , dichloropropyl , fluoromethyl and difluoromethyl . the term “ cycloheteroalkyl ” refers to a four - to eight - membered heterocyclic ring containing at least one heteroatom , such as n , o or s , the number of n atoms being 0 - 3 and the number of o and s atoms each being 0 - 1 , which system may be saturated , partly unsaturated or hydroaromatic , and which ring can be part of a multiple condensed ring - system in which some rings may be aromatic . examples of such cycloheteroalkyls include pyrrolidinyl , tetrahydrofuryl , tetrahydrothiophenyl , tetrahydropyridinyl , azetidinyl , thiazolidinyl , oxazolidinyl , piperidinyl , morpholinyl , thiomorpholinyl , piperazinyl , azepanyl , diazepanyl , oxazepanyl , thiazepanyl , dihydro - 1h - pyrrolyl , 3 , 6 - dihydro - 2h - pyridinyl , 1 , 3 - dihydro - benzoimidazolyl and the like . preferred examples of such cycloheteroalkyl groups are pyrrolidinyl , morpholinyl , tetrahydrofuryl , piperidinyl or azepanyl . the cycloheteroalkyl group may optionally be substituted by up to three substituents , independently selected from the group consisting of oxo , alkyl , optionally substituted aryl or aryl -( c 1 - c 4 )- alkyl , hydroxyl , ( c 1 - c 6 ) alkoxy , halogenated ( c 1 - c 6 ) alkyl , halogenated ( c 1 - c 6 ) alkoxy , carboxyl -( c 1 - c 6 ) alkyl , thiol , nitrile , sulfamoyl , sulfonamide , carboxyl , aryloxy or arylalkyloxy , ( c 1 - c 6 ) alkylthio , arylthio or arylalkylthio , amino , amido , acyl , and acylamino , as defined herein . the substituents of the cycloheteroalkyl groups may be attached to any carbon atom of the cycloheteroalkyl moiety . substituted cycloheteroalkyl is preferably substituted with oxo , ( c 1 - c 4 ) alkyl , preferably methyl , phenyl and / or phenyl -( c 1 - c 4 ) alkyl , in particular benzyl . the terms “ aryl ” or “ ar ” refer to an aromatic carbocyclic group comprising 6 to 14 , more preferably 6 to 10 , carbon atoms and having at least one aromatic ring or multiple condensed rings in which at least one ring is aromatic . preferably , aryl is phenyl , naphthyl , indanyl , indenyl , or 1 , 2 , 3 , 4 - tetrahydro - naphthalen - 1 - yl . the term “ heteroaryl ” refers to an aromatic carbocyclic group of having a single 4 to 8 membered ring or multiple condensed rings comprising 6 to 14 , more preferably 6 to 10 , ring atoms and containing at least one heteroatom , such as n , o or s , within at least one ring , the number of n atoms being 0 - 3 and the number of o and s atoms each being 0 - 1 ; in which group at least one heterocyclic ring is aromatic . examples of such groups include pyrrolyl , thienyl , furyl , imidazolyl , thiazolyl , isothiazolyl , oxazolyl , isoxazolyl , pyrazolyl , pyridinyl , pyrimidinyl , pyrazinyl , pyridazinyl , indolyl , quinolinyl , isoquinolinyl , benzothiazolyl , benzoimidazolyl , 1 , 3 - dihydro - benzoimidazolyl , benzofuran , benzo [ b ] thiophene and the like . preferably , heteroaryl is quinolinyl , furyl , benzoimidazolyl , pyridinyl , thienyl , indolyl , benzo [ b ] thiophene , pyridinyl , imidazolyl , pyrazolyl or thiazolyl . the aryl and the heteroaryl group may optionally be substituted by substituents independently selected from the group consisting of halogen , hydroxyl , ( c 1 - c 6 ) alkoxy , ( c 1 - c 6 ) alkyl , halogenated ( c 1 - c 6 ) alkyl , halogenated ( c 1 - c 6 ) alkoxy , carboxyl -( c 1 - c 6 ) alkyl , oxo , thiol , nitro , nitrile , sulfamoyl , sulfonamide , carboxyl , aryloxy or arylalkyloxy , ( c 1 - c 6 ) alkylthio , arylthio or arylalkylthio , alkylsulfonyl , arylsulfonyl , amino , amido , acyl , and acylamino , as defined herein , the number of said substituents being up to five for halogen , and up to three for any combination of said other substituents ; whereby the aryloxy , arylalkyloxy , arylthio or arylalkylthio group may be further optionally substituted in the aryl moiety with independently selected substituents as defined herein . the heteroaryl group may further be optionally substituted with an aryl group , which may be optionally substituted in the aryl moiety with independently selected substituents as defined herein . the aryl group may further be optionally substituted with a heteroaryl group or a second aryl group . the aryl may be further substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5 , 6 , 7 , or 8 membered ring system , optionally containing up to three heteroatoms , such as n , o or s , the number of n atoms being 0 - 3 and the number of o and s atoms each being 0 - 2 . preferably , the two groups which are attached to adjacent carbon atoms , are combined into a saturated cyclic 5 or 6 membered ring system , optionally containing up to three heteroatoms , such as n or o , the number of n atoms being 0 - 3 and the number of o atoms each being 0 - 2 . this cyclic ring system may optionally be further substituted by an oxo group . preferred examples of such a substituted aryl groups are benzo [ 1 , 3 ] dioxol and 1 , 3 - dihydro - benzoimidazol - 2 - one . the statement is made that when two side chains are found on a single n , they can be combined , including the n to which they are attached , into a heterocyclic ring of 4 -, 5 -, 6 -, 7 - or 8 atoms , which can be saturated , partly unsaturated or aromatic , which can optionally contain up to three additional heteroatoms selected from n , o or s , the number of n atoms being 0 - 3 and the number of o and s atoms each being 0 - 2 ; and which ring can be part of a multiple condensed ring - system , in which some rings may be aromatic . preferred examples of such heterocyclic ring systems , including the n , to which the respective side chains are attached , are : the aforementioned heterocyclic ring system can be optionally substituted by up to three substituents , which can be attached to any carbon or nitrogen atom of the heterocyclic ring system . preferred examples of substituted heterocyclic ring systems are : the optional up to three independently selected substituents for the heterocyclic ring system may be chosen among optionally substituted alkyl , halogen , hydroxyl , oxo , thiol , nitro , nitrile , ( c 1 - c 6 )- alkoxy , aryl , heteroaryl , optionally substituted cycloheteroalkyl , aryloxy , arylalkyloxy , amino , amido , alkylthio , arylthio , arylalkylthio , sulfamoyl , sulfonamide , acyl , carboxyl , and acylamino , as defined herein , whereby all aryl or heteroaryl moieties may be optionally substituted with up to five , preferably up to three independently selected substituents as defined herein . furthermore , the aforementioned heterocyclic ring system may be substituted by two groups which are attached to the same carbon atom and are combined into a saturated or partly unsaturated cyclic 4 , 5 , 6 , 7 , or 8 membered ring system , optionally containing up to three heteroatoms , such as n , o or s , the number of n atoms being 0 - 3 and the number of o and s atoms each being 0 - 2 . this cyclic ring system may optionally be further substituted by up to three substitutents independently selected from oxo , ( c 1 - c 6 )- alkyl , aryl , preferably phenyl , and aryl -( c 1 - c 4 )- alkyl , preferably benzyl . preferred examples of such substituted heterocyclic ring systems are 1 , 4 - dioxa - 8 - aza - spiro [ 4 . 5 ] decane , 1 , 3 , 8 - triaza - spiro [ 4 . 5 ] decane , 1 , 3 , 8 - triaza - spiro [ 4 . 5 ] decan - 4 - one , 1 - phenyl - 1 , 3 , 8 - triaza - spiro [ 4 . 5 ] decane , and 1 - phenyl - 1 , 3 , 8 - triaza - spiro [ 4 . 5 ] decan - 4 - one . the term “ sulphamate group ” as used herein , refers to a group — o — so 2 — nr 3 r 3 ′, and includes a steroidal ester of sulphamic acid or a steroidal ester of an n - substituted derivative of sulphamic acid , or a salt thereof . if — o — r 1 is a sulphamate group then the compound of the present invention is referred to as a sulphamate compound . the term “ carbamate group ” as used herein , refers to a group — o — co — nr 3 r 3 ′, and includes a steroidal ester of carbamic acid or a steroidal ester of an n - substituted derivative of carbamic acid , or a salt thereof . if — o — r 1 is a carbamate group then the compound of the present invention is referred to as a carbamate compound . the term “ phosphonate group ” as used herein , refers to a group — o — po ( or 16 )— r 3 , and includes a steroidal ester of phosphonic acid or a steroidal ester of an o - substituted derivative of phosphonic acid , or a salt thereof . if — o — r 1 is a phosphonate group then the compound of the present invention is referred to as a phosphonate compound . the term “ thiophosphonate group ” as used herein , refers to a group — o — ps ( or 16 )— r 3 , and includes a steroidal ester of thiophosphonic acid or a steroidal ester of an o - substituted derivative of thiophosphonic acid , or a salt thereof . if — o — r 1 is a thiophosphonate group then the compound of the present invention is referred to as a thiophosphonate compound . the term “ phosphate group ” as used herein , refers to a group — o — po ( or 16 )— or 3 , and includes a steroidal ester of phosphoric acid or a steroidal ester of an o - substituted derivative of phosphoric acid , or a salt thereof . if — o — r 1 is a phosphate group then the compound of the present invention is referred to as a phosphate compound . the term “ sulphonate group ” as used herein , refers to a group — o — so 2 — r 3 , and includes a steroidal ester of sulphonic acid , or a salt thereof . if — o — r 1 is a sulphonate group then the compound of the present invention is referred to as a sulphonate compound . the term “ sulphate group ” as used herein , refers to a group — o — so 2 — or 3 , and includes a steroidal ester of sulphuric acid , or a salt thereof . if — o — r 1 is a sulphate group then the compound of the present invention is referred to as a sulphate compound . for all above - mentioned sulphamate -, carbamate -, phosphonate -, thiophosphonate -, phosphate -, sulphonate -, and sulphate - groups , the substituents r 3 and r 3 ′, if present , are independently selected from h , alkyl , aryl and arylalkyl , as defined herein , or form together with the nitrogen atom , to which r 3 and r 3 ′ are attached , a heterocyclic 4 -, 5 -, 6 -, 7 - or 8 - membered ring , which is optionally saturated , partly unsaturated , or aromatic ; which optionally contains up to three additional heteroatoms selected from n , o or s , the number of additional n atoms being 0 , 1 , 2 or 3 and the number of o and s atoms each being 0 , 1 or 2 . preferably , at least one of r 9 and r 10 is h , and even more preferred , each of r 9 and r 10 is h . if the substituent r 16 is present in one of the aforementioned groups , then represents — h , alkyl , or arylalky , as defined herein above . preferably , r 16 represents — h . the term “ prodrug ” as used herein , represents derivatives of the compounds of the invention that are drug precursors which , following administration to a patient , release the drug in vivo via a chemical or physiological process . in particular , pro - drugs are derivatives of the compounds of the invention in which functional groups carry additional substituents which may be cleaved under physiological conditions in vivo and thereby releasing the active principle of the compound ( e . g ., a pro - drug on being brought to a physiological ph or through an enzyme action is converted to the desired drug form ). the term “ pharmaceutically acceptable salts ” refers to salt forms that are pharmacologically acceptable and substantially non - toxic to the subject being administered the compounds of the invention . pharmaceutically acceptable salts of compounds of formula i include conventional and stoichiometrical acid - addition salts or base - addition salts formed from suitable non - toxic organic or inorganic acids or inorganic bases . acid addition salts , for example , from compounds of formula i with a basic nitrogen atom are formed preferably with organic or inorganic acids . suitable inorganic acids are , for example , halogenic acids such as hydrochloric acid , sulfuric acid , or phosphoric acid . suitable organic acids are , for example , carboxylic , phosphonic , or sulfonic acids , for example acetic acid , propionic acid , glycolic acid , lactic acid , hydroxybutyric acid , malic acid , malenic acid , malonic acid , salicylic acid , fumaric acid , succinic acid , adipic acid , tartaric acid , citric acid , glutaric acid , 2 - or 3 - glycerophosphoric acid and other mineral and carboxylic acids well known to those skilled in the art . the salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner . compounds containing acidic substituents may also form salts with inorganic or organic bases . examples of suitable bases for salt formation include , but are not limited to , inorganic bases such as alkali or alkaline earth - metal ( e . g ., sodium , potassium , lithium , calcium , or magnesium ) hydroxides , and those derived from ammonium hydroxides ( e . g ., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide ). also contemplated are salts formed with pharmaceutical acceptable amines such as ammonia , alkyl amines , hydroxyalkylamines , n - methylglucamine , benzylamines , piperidines , and pyrrolidines and the like . certain compounds will be acidic in nature , e . g . those compounds which possess a carboxyl or phenolic hydroxyl group . salts of phenols can be made by heating acidic compounds with any of the above mentioned bases according to procedures well known to those skilled in the art . as used herein , the term “ composition ” is intended to encompass a product comprising the specified ingredients in the specified amounts , as well as any product which results , directly or indirectly , from combination of the specified ingredients in the specified amounts . the phrase “ effective amount ” as used herein , means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and / or conditions to be treated ( e . g ., provide a positive clinical response ). the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated , the severity of the condition , the duration of the treatment , the nature of concurrent therapy , the particular active ingredient ( s ) being employed , the particular pharmaceutically acceptable excipient ( s )/ carrier ( s ) utilized , and like factors within the knowledge and expertise of the attending physician . the method of the invention is primarily intended for treatment in a mammal , preferably in humans and other primates , of steroid hormone dependent diseases or disorders , in particular estradiol dependent diseases or disorders , wherein the steroid hormone dependent disease or disorder preferably requires the inhibition of a 17β - hsd enzyme , preferably the 17β - hsd1 enzyme . the compounds may be administered orally , dermally , parenterally , by injection , by pulmonal or nasal delivery , or sublingually , rectally or vaginally in dosage unit formulations . the term “ administered by injection ” includes intravenous , intraarticular , intramuscular ( e . g . by depot injection where the active compounds are released slowly into the blood from the depot and carried from there to the target organs ), intraperitoneal , intradermal , subcutaneous , and intrathecal injections , as well as use of infusion techniques . dermal administration may include topical application or transdermal administration . one or more compounds may be present in association with one or more non - toxic pharmaceutically acceptable auxiliaries such as excipients , adjuvants ( e . g . buffers ), carriers , inert solid diluents , suspensing agents , preservatives , fillers , stabilizers , anti - oxidants , food additives , bioavailability enhancers , coating materials , granulating and disintegrating agents , binding agents etc ., and , if desired , other active ingredients . the pharmaceutical composition may be formulated for example as immediate release , sustained release , pulsatile release , two or more step release , depot or other kind of release formulations . the manufacture of the pharmaceutical compositions according to the invention may be performed according to methods known in the art and will be explained in further detail below . commonly known and used pharmaceutically acceptable auxiliaries as well as further suitable diluents , flavorings , sweetening agents , coloring agents etc . may be used , depending on the intended mode of administration as well as particular characteristics of the active compound to be used , such as solubility , bioavailability etc . suitable auxiliaries and further ingredients may be such as recommended for pharmacy , cosmetics and related fields and which preferably are listed in the european pharmacopoeia , fda approved or cited in the “ gras ” list ( fda list of food additives that are ‘ generally recognized as safe ’ ( gras )). one mode of application of the compounds of general formula ( i ) or of pharmaceutical compositions comprising one or more of said compounds is oral application , e . g ., by tablets , pills , dragees , hard and soft gel capsules , granules , pellets , aqueous , lipid , oily or other solutions , emulsions such as oil - in - water emulsions , liposomes , aqueous or oily suspensions , syrups , elixiers , solid emulsions , solid dispersions or dispersible powders . for the preparation of pharmaceutical compositions for oral administration , the compounds suitable for the purposes of the present invention as defined above can be admixed with commonly known and used adjuvants and excipients such as for example , gum arabic , talcum , starch , sugars ( such as , e . g ., mannitose , methyl cellulose , lactose ), gelatine , surface - active agents , magnesium stearate , aqueous or non - aqueous solvents , paraffin derivatives , cross - linking agents , dispersants , emulsifiers , lubricants , conserving agents , flavoring agents ( e . g ., ethereal oils ), solubility enhancers ( e . g ., benzyl benzoate or benzyl alcohol ) or bioavailability enhancers ( e . g . geluciretm ). in the pharmaceutical composition , the active ingredients may also be dispersed in a microparticle , e . g . a nanoparticulate , composition . for parenteral administration , the active agents can be dissolved or suspended in a physiologically acceptable diluent , such as , e . g ., water , buffer , oils with or without solubilizers , surface - active agents , dispersants or emulsifiers . as oils for example and without limitation , olive oil , peanut oil , cottonseed oil , soybean oil , castor oil and sesame oil may be used . more generally spoken , for parenteral administration the active agent can be in the form of an aqueous , lipid , oily or other kind of solution or suspension or even administered in the form of liposomes or nano - suspensions . transdermal application can be accomplished by suitable patches , as generally known in the art , specifically designed for the transdermal delivery of active agents , optionally in the presence of specific permeability enhancers . furthermore , also emulsions , ointments , pastes , creams or gels may be used for transdermal delivery . another suitable mode of administration is via intravaginal devices ( e . g . vaginal rings ) or intrauterine systems ( ius ) containing reservoirs for controlled release of active agents over extended periods of time . for rectal or vaginal administration of the drug the compounds may also be administered in the form of suppositories . these compositions can be prepared by mixing the drug with a suitable non - irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug . another mode of application is by implantation of a depot implant comprising an inert carrier material , such as biologically degradable polymers or synthetic silicones such as e . g . silicone rubber . such implants are designed to release the active agent in a controlled manner over an extended period of time ( e . g ., 3 to 5 years ). it will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors , all of which are considered routinely when administering therapeutics . it will also be understood , however , that the actual dosages of the agents of this invention for any given patient will depend upon a variety of factors , including , but not limited to the activity of the specific compound employed , the particular composition formulated , the mode of administration , time of administration , route of administration and the particular site , host , and disease being treated , and furthermore the age of the patient , the body weight of the patient , the general health of the patient , the gender of the patient , the diet of the patient , rate of excretion , drug combinations , and the severity of the condition undergoing therapy . it will be further appreciated by one skilled in the art that the optimal course of treatment , i . e ., the mode of treatment and the daily number of doses of a compound of formula i or a pharmaceutically acceptable salt thereof given for a defined number of days , can be ascertained by those skilled in the art using conventional treatment tests . optimal dosages for a given set of conditions may be ascertained by those skilled in the art using conventional dosage - determination tests in view of the experimental data for a given compound . for oral administration , an exemplary daily dose generally employed will be from about 0 . 01 μg / kg to about 100 mg / kg of total body weight , whereby courses of treatment may be repeated at appropriate time intervals . administration of pro - drugs may be dosed at weight levels that are chemically equivalent to the weight levels of the fully active compounds . the daily dosage for parenteral administration will generally be from about 0 . 01 μg / kg to about 100 mg / kg of total body weight . a daily rectal dosage regimen will generally be from about 0 . 01 μg / kg to about 200 mg / kg of total body weight . a daily vaginal dosage regimen will generally be from about 0 . 01 μg / kg to about 100 mg / kg of total body weight . the daily topical dosage regimen will generally be from about 0 . 1 μg to about 100 mg administered between one to four times daily . the transdermal concentration will generally be that required to maintain a daily dose of from 0 . 01 μg / kg to 100 mg / kg of total body weight . the general structure formulas are typically designated with a number in roman format , followed by a or p indicating the stereochemistry at the c15 atom of the estron core if necessary . if the number of methylen groups attached at the c15 position is specified ( i . e . the value of “ n ”), the roman number is followed by a hyphen and a number indicating the amount of methylen groups . finally , a letter a , b or c is attached after the number “ n ”, indicating the nature of the substituent r 1 at the o - atom in c3 position of the estron core ( a = hydrogen , b = methyl , and c = benzyl ). the prefix c in front of the number indicates that the compound may be substituted in c2 by a residue r 14 . the prefix d in front of the number that the compound may be substituted in c2 by a residue r 14 and may be additionally modified within the c16 - c17 position . therefore , a compound ivβ - 3a would represent a derivative of iv with β stereochemistry at c15 , three methylen groups and a hydroxy group in c3 position , i . e . : if particular structures of synthesized examples falling under a general formula are presented , then the designation of the general formula is followed by the particular number of this example , i . e . example no . 652 of formula ( xxxiiiα - 1a )- 652 this example 652 is a particular compound of the general formula xxxiiiα - 1a , wherein r 2 is a 4 - fluoro - phenyl residue . the compounds of the present invention may be prepared by use of known chemical reactions and procedures . nevertheless , the following general preparative methods are presented to aid the reader in synthesizing the 17β - hsd1 and / or sts inhibitors , with specific details provided below in the experimental section to illustrate working examples . all variable groups of these methods are as described in the generic description if they are not specifically defined below . it is recognized that compounds of the invention with each claimed optional functional group may not be prepared by each of the below - listed methods . within the scope of each method , optional substituents may appear on reagents or intermediates which may act as protecting or otherwise non - participating groups . utilizing methods well known to those skilled in the art , these groups are introduced and / or removed during the course of the synthetic schemes which provide the compounds of the present invention . the synthesis of 3 , 15 substituted estrone derivatives bearing a side chain of the amide , ester , carbonyl , hydrazone , alcohol , ether , urea , carbamate , “ retro ”- amide , sulfonyl urea , sulfamide , sulfamate , “ retro ”- sulfonamide , “ retro ”- carbamate , “ retro ”- ester or sulfonylcarbamate type in position c15 is extensively described within the international application wo 2005 / 047303 , which is hereby incorporated by reference in its entity . the additional modifications of the steroidal core at positions c2 , c3 , c16 and or c17 , which are disclosed in the present invention , may be introduced in the following order of general chemical modifications ( general synthesis scheme ). the introduction of the r 14 substituent in c2 position — if present in the final compound — has to take place first , starting from the 17β - estradiol using methods well known in the art ( steps a ). in parallel , the c17 - oh function is oxidized to the corresponding keto function . depending on the desired nature of r 1 , a suitable group also functioning as protecting group may be introduced at this point . then , the estron derivative of formula ( v ) is converted into the central intermediate , the 15 , 16 - unsaturated estrone of formula x ( steps b ), which is further derivated in the c15 position by introduction of the basic side chain (“ so called building blocks ”). these building blocks are reacted with the appropriate compounds carrying the r 2 / r 4 substitutents to lead to the desired c15 substituted compound ( steps c ). the obtained educt may be further modified within the c16 and c17 position by introducing appropriate substituents r 10 , r 12 and r 13 or by introducing a heterocyclic ring structure ( steps d ). finally , if necessary , the protection group in c1 position may be separated to deliver the c3 - oh derivative or may be further substituted with an alternative r 1 side chain or may be derivated to the corresponding sulphamate , phosphonate , carbamate , thiophosphonate , sulphonate , sulphate or phosphate compounds ( steps e ). step a — introduction of a r 14 side chain in c2 position of 17β - estradiol or estron the introduction of various side chains in the estron core is known from the literature , e . g . rao et al ( 2002 ) describe the synthesis of 2 - methoxyestradiol , and the synthesis of 2 - ethoxy - estradiol was disclosed by verdier - pinard et al ( 2000 ). 2 - ethyl - estron may be prepared from estrone by friedel - crafts acetylation of estrone - 3 - o - methyl ether and catalytic hydrogenation , followed by demethylation , which produced the desired product . alternatively , the introduction of substituents on the 2 - position may be obtained by using a fries - rearrangement starting with estradiol and the reagent ( rco ) 2 o with r = lower alkyl , as described by rao et al . ( 2002 ): after acylation , the compounds should be converted into the r — co - substituted derivatives in c2 position . reduction of the acyl function may be achieved by reduction with pd / c and h 2 [ gonzalez et al ( 1982 )]. alternatively , the acetoxy - group in c2 - position could be oxidized with phi ( cf 3 co 2 ) 2 according to [ yoshikawa et al . ( 2002 )]. the newly introduced hydroxy group may be further alkylated , followed by reduction of the ketone , resulting in an alkoxy - alkyl substituted estradiol derivative . an alternative strategy to introduce an alkoxy - alkyl group is exemplified for the methoxy - ethyl group : after mom - protection of the 17β - estradiol , the mom - protected estradiol is iodinated [ mohanakrishnan & amp ; cushman ( 1999 )]. then , the mom - group is replaced with a tbdms group . negishi coupling with allylbromide gives the 2 - allyl substituted estrone derivative , which can be oxidised and methylated ( including some protective group manipulations ). further synthetic ways to 2 - alkyl - substituted estron or estradiol derivatives have been displayed previously [ see e . g . mohanakrishnan & amp ; cushman ( 1999 ); day et al . ( 2003 ); cushman et al ( 1995 ), and lunn & amp ; farkas ( 1968 )] the synthesis of further estron derivatives with various substituents in 2 - position was disclosed by cushman et al ( 2002 ). during the introduction of the c2 side chain , the 3 - hydroxy function of the steroidal core is typically protected with a methyl or benzyl group ( exemplified by pg ). for example , the methyl derivative can be prepared using mej and acetone , whereas the corresponding benzyl - derivative may be prepared using benzylbromid , dipea and acetone . enone intermediates with other substituents in r 1 (= pg ), in particular optionally substituted c 1 - c 4 - alkyl , can be prepared accordingly by using the appropriate optionally substituted c 1 - c 4 - alkyl - bromide or c 1 - c 4 - alkyl - iodide . step b — synthesis of the 15 , 16 - unsaturated estrone of formula x ( intermediate i ) the ketal of the formula ( ix ) can be prepared according to nambara from the corresponding 2 - substituted estron of formula v [ nambara et al . ( 1976 )] as depicted within the following scheme 1 . if not yet protected , the introduction of pg groups in c3 position can be achieved according to a procedure described by labaree ( 2003 ). the c17 keto function of the c2 substituted and protected estron derivative of formula ( v ) is protected as acetal , followed by bromination . the elimination of the bromide yielded the desired 15 , 16 - unsaturated estron . finally , the ketal derivative is hydrolysed to give the appropriate enonederivative x . alternatively , the enone intermediate of formula x can be prepared from the corresponding estrone derivative according to a procedure described by poirier et al . ( 1991 ). the “ step c ” modification — the introduction of the side chain in c15 position — is carried out in two major steps : in a first step the 15 , 16 - unsaturated estrone of formula x is converted into a so - called building block carrying an alkyl side chain in c15 position with a terminal amino , carboxy , or alcohol function . the synthesis of some exemplary building blocks is depicted in the experimental section “ intermediates ”, and was fully disclosed in international patent application wo 2005 / 047303 . the second step of the “ step c ” modification — the conversion of the building blocks into the desired derivatives carrying the complete side chain in c15 position — is exemplified below by using one of the following synthetic schemes as shown in flow diagrams i to xv . certain formula i compounds , in which x represents a bond , a represents co , y represents nh or nr 4 and n represents an integer from 0 to 5 , may be prepared by a reaction as shown in flow diagram ia . the free acid ( iv ) may be converted to the reactive acyl halide , in particular the acid chloride , by reaction with socl , cocl 2 , pcl5 or pbr 3 or the like . the amide derivatives c -( vi ) may be prepared by a base catalyzed addition - elimination reaction , where the halogen residue is substituted with the appropriate amine r 2 nh 2 or r 2 nhr 4 in the presence of a base , for example dipea . alternatively , especially suited for derivatives with n & gt ; 2 , the amide derivatives may be prepared directly from the free acids by nucleophilic substitution with the appropriate amine . alternatively , the amide derivatives may be prepared directly from the free acids by nucleophilic substitution with the appropriate amine as shown in flow diagram ib : certain formula i compounds , in which x represents a bond , a represents co , y represents o , and n represents an integer from 0 to 5 , may be prepared by a reaction as shown in flow diagram ii : the ester derivatives c -( vii ) may be prepared from the free acid ( iv ) by esterification with the appropriate alcohol r 2 — oh . certain formula i compounds , in which x represents a bond , a represents co , y represents a bond , and n represents an integer from 0 to 5 , may be prepared by a reaction as shown in flow diagram iii : the alcohol mom may be converted to the corresponding aldehyde ( xxxiii ) via dess - martin oxidation . subsequently the aldehyde may be converted by a nucleophilic addition - elimiation reaction with a grignard or other organometallic reagent , substituted with the appropriate r 2 residue to the corresponding secondary alcohol ( xxi ), which thereafter can be oxidized again to the desired ketone c -( viii ). certain formula i compounds , in which x represents a bond , a represents co , y represents nh — nr 4 or nh — nh , and n represents an integer from 0 to 5 , may be prepared by a reaction as shown in flow diagram iva . the free acid ( iv ) may be converted to the reactive acyl halide , in particular the acid chloride , by reaction with socl , cocl 2 , pcl 5 or pbr 3 or the like . the hydrazide derivatives c -( xli ) may be prepared by a base catalysed addition - elimination reaction , where the halogen residue is substituted with the appropriate hydrazine h 2 n — nhr 2 or h 2 n — nr 2 r 4 in the presence of a base , for example dipea . alternatively , especially suited for derivatives with n & gt ; 2 , the hydrazide derivatives may be prepared directly from the free acids by nucleophilic substitution with the appropriate hydrazine using e . g . polymer bound carbodiimid , hobt and dcm , as shown in flow diagram ivb : certain formula i compounds , in which x represents a nh , a represents co , y represents nh , and n represents an integer from 1 to 6 , may be prepared by a reaction as shown in flow diagram va : the urea derivatives of the general formula c -( xvii ) may be prepared by the reaction of the amine building block ( xv ) with an appropriately substituted isocyanate ( r 2 — n ═ c ═ o ). after the addition , the ketal function is converted into the keto function . alternatively , the amine may be first reacted with carbodiimidazol or triphosghen to form a reactive carbamoyl compound , which than can react further with a suitable amine r 2 r 4 — nh . a further synthesis variant may use the unprotected amine ( xxix ) as starting material for the reaction with an appropriately substituted isocyanate ( r 2 — n ═ c ═ o ) as shown in flow diagram vb certain formula i compounds , in which x represents a — nh —, a represents so 2 , y represents nh , and n represents an integer from 1 to 6 , may be prepared by a reaction as shown in flow diagram vi in a first step , the amine building block ( xv ) may be converted into a protected , for example boc - protected , sulfamide compound by a reaction with the appropriately protected chlorosulfonyl isocyanate . in a second step , the protected sulfamide compound is allowed to react with the appropriate bromo - reagent ( r 2 — br ) to provide the still protected , substituted sulfamide derivative of the formula ( xviii ). after deprotection , the desired n - substituted sulfamide derivative of formula c -( xix ) is obtained . certain formula i compounds , in which x represents a nh , a represents co , y represents o , and n represents an integer from 1 to 6 , may be prepared by a reaction as shown in flow diagram vii : the carbamate derivatives of the general formula c -( xx ) may be prepared by the reaction of the amine building block ( xv ) with an appropriate chloroformic acid ester ( r 2 — o — co — cl ). after the addition - elimination reaction , in a second step the ketal function is converted into the keto function . certain formula i compounds , in which x represents a nh , a represents so 2 , y represents o , and n represents an integer from 1 to 6 , may be prepared by a reaction as shown in flow diagram viii : the sulfamate derivatives of the general formula c -( xxii ) may be prepared by the reaction of the amine building block ( xv ) with an appropriate chlorosulfonic acid ester ( r 2 — o — so 2 — cl ). after the addition - elimination reaction , in a second step the ketal function is converted into the keto function . certain formula i compounds , in which x represents a nh , a represents co , y represents a bond , and n represents an integer from 1 to 6 , may be prepared by a reaction as shown in flow diagram ixa : the “ retro ”- amide derivatives of the general formula c -( xxiii ) may be prepared by the reaction of the amine building block ( xv ) with an appropriate acid halide , e . g . an acid chloride ( r 2 — co — cl ). after the addition - elimination reaction , in a second step the ketal function is converted into the keto function . alternatively , the reaction with an appropriate acid halide , e . g . an acid chloride ( r 2 — co — cl ), can be performed using the amino - hydrochloride salt of the estrone ( xxix ) as starting material as shown in the following flow diagram ab : certain formula i compounds , in which x represents a nh , a represents so 2 , y represents a bond , and n represents an integer from 1 to 6 , may be prepared by a reaction as shown in flow diagram xa : the sulfonamide derivatives of the general formula c -( xxiv ) may be prepared by the reaction of the amine building block ( xv ) with an appropriate sulfonic acid halide , e . g . a sulfonic acid chloride ( r 2 — so 2 — cl ). after the addition - elimination reaction , in a second step the ketal function is converted into the keto function . alternatively , the reaction with an appropriate sulfonic acid halide , e . g . sulfonic acid chloride ( r 2 — so 2 — cl ), can be performed using the amino - hydrochloride salt of the estrone ( xxix ) as starting material as shown in the following flow diagram xb : certain formula i compounds , in which x represents a nh , a represents co , y represents nh — so 2 , and n represents an integer from 1 to 6 , may be prepared by a reaction as shown in flow diagram xi : the sulfonyl urea derivatives of the general formula c -( xxv ) may be prepared by the reaction of the amine building block ( xv ) with an appropriately substituted sulfonyl isocyanate ( r 2 — so 2 — n ═ c ═ o ). after the addition , the ketal function is converted into the keto function . certain formula i compounds , in which x represents an o , a represents co , y represents nr 4 , and n represents an integer from 1 to 6 , may be prepared by a reaction as shown in flow diagram xii : the “ retro ”- carbamate derivatives of the general formula c -( xxvi ) may be prepared by the reaction of the estrone alcohol building block map with an appropriately substituted isocyanate ( r 2 — n ═ c ═ o ) and subsequent purification . certain formula i compounds , in which x represents a o , a represents co , y represents a bond , and n represents an integer from 1 to 6 , may be prepared by a reaction as shown in flow diagram xiii : the “ retro ”- ester derivatives of the general formula c -( xxvii ) may be prepared by the esterification of the estrone alcohol building block ( xxxi ) with the appropriate carboxylic acid r 2 — cooh and subsequent purification . certain formula i compounds , in which x represents a o , a represents co , y represents nh — so 2 — nr 4 , and n represents an integer from 1 to 6 , may be prepared by a reaction as shown in flow diagram xiv : the sulfonylcarbamate derivatives of the general formula c -( xxviii ) may be prepared by a two - step synthesis : in a first step , the estrone alcohol building block ( xxxi ) is converted to the chlorosulfonylcarbamate intermediate by reaction with chlorosulfonyl isocyanate . subsequently , the intermediate is allowed to react with the appropriate primary or secondary amine hnr 2 r 4 in in order to give the desired sulfonylcarbamate derivative . certain formula i compounds , in which x - a - y represents , and r 2 is different from h may be prepared by a reaction as shown in flow diagram xv : the ether derivatives of the general formula c -( xxx ) may be prepared the reaction of an appropriate grignard reagent brmg —( ch 2 ) n — o — r 2 ( for n = 3 - 6 ) with the 15 , 16 - unsaturated estrone derivative of formula x . alternatively , ether derivatives may be prepared by derivatisation of the corresponding alcohol of the general formula ( xxxi ). the synthesis of certain formula i compounds , in which x - a - y represents o , r 2 represents h , and n represents an integer from 1 to 6 , according to general formula c -( xxxi ) is described within the section “ intermediates ”. step d — modification of the c17 - keto function or introduction of a heterocyclic ring system in c16 - c17 since the c15 - side chain as well as the c2 side chain were already introduced , it is clear for the skilled artisan , that , where necessary , functional groups in the alcohol d ( i )- oh may be protected in known manner and the protecting group or groups removed at the end of the reaction . step d - 1 , for compounds when the substituents r 10 , r 11 , r 12 and r 13 together with the carbon atoms , to which they are attached , form a structure — cr 13 r 12 — cr 11 r 10 —, which is selected from the group of wherein r 12 represents — f , — cf 3 , or — cf 2 h ; and wherein r 12 represents — f , — cf 3 , or — cf 2 h . for synthesis of some d -( i ) compounds and in order to enable library synthesis , it might be necessary that some of the reaction steps explained under “ steps c — the introduction of the c15 side chain ” have to be carried out after having introduced the respective fluoro group . a typical scenario might be that after optional introduction of the r 14 residue in c2 position , the 15 , 16 - unsaturated intermediate ( x ) is prepared . this is further derivatized to the appropriate acid , alcohol , amid or alkenyl intermediate (“ building block ”— see section “ intermediates ”). then , the fluoro group is introduced into c17 position of the steroidal core using a synthesis scheme as described in more detail below . the so - obtained intermediate is then used for optional further modification of the c15 side chain and introduction of the r 2 / r 4 substituents . finally any protection groups in c3 position might be cleaved off . d -( i )-( a ): synthesis of compounds , wherein r 10 and r 11 both represent — h and r 12 and r 13 together represent ═ cf 2 the introduction of a ═ cf 2 group in c17 position of the estron core is a reaction well known in the art , see e . g . edwards et al ( 1990 ) using f 2 cp ( o ( ph ) 2 as fluorinating reagent , or by using the horner reaction with f 2 cp ( o )( oet ) 2 as fluorinating reagent schwarz et al ( 2001 ). in addition , the reaction can be carried out according to procedures described within international patent application wo 96 / 28462 . subsequent deprotection of the c3 - hydroxy function may be obtained using standard techniques . d -( i )-( b ): synthesis of compounds , wherein r 10 and r 11 both represent — h and r 12 and r 13 both individually represent — f the difluorination of the c17 atom of the estron core is a reaction well known in the art and was already disclosed in u . s . pat . no . 3 , 413 , 321 and u . s . pat . no . 3 , 347 , 878 . furthermore , the difluorination of the c17 atom of the estron core may be achieved using the dast ( n , n - diethylaminosulfur trifluoride ) reagent [ liu et al ( 1992 )]. d -( i )-( c ): synthesis of compounds , wherein r 10 , r 11 and r 13 all represent — h and r 12 is selected from — f , — cf 3 , and — cf 2 h the mono - fluorination of the c17 atom of the estron core is a reaction well known in the art and may be performed according to the disclosure of u . s . pat . no . 3 , 275 , 623 . the desired compound of the general formula d -( i )-( c )- cf 2 h may be obtained by hydrogenation of the corresponding 17 - difluoromethylene substituted derivative , the synthesis of which is described above . if desired , the protection group is subsequently removed . the introduction of the — cf 3 group in c17 position of the estron core may be performed according to wang & amp ; ruan ( 1994 ). then , the double bond in c16 , c17 position is introduced by acidic elimination to deliver a compound of general formula d -( i )-( d )- cf 3 . the unsaturated derivative may be converted into the corresponding saturated compound by hydrogenation . if desired , the protection group is subsequently removed to deliberate the 3 - hydroxy function . d -( i )-( d ): synthesis of compounds , wherein r 10 represents — h , r 11 together with r 13 forms a bond , and r 12 is selected from — f , — cf 3 , and — cf 2 h the 17 - monofluorinated , 16 , 17 - unsaturated estron derivative may be obtained starting from the corresponding 17 - difluorinated compound , the synthesis of which was explained above , according to the procedure described by liu et al . ( 1992 ). if desired , the protection group can be subsequently removed . the desired compound of the general formula d -( i )-( d )- cf 2 h may be obtained by pd - catalyzed isomerization of the double bond of the corresponding 17 - difluoromethylene substituted derivative , the synthesis of which has been described above . if desired , the protection group can be subsequently removed . the introduction of the — cf 3 group in c17 position of the estron core may be performed according to wang & amp ; ruan ( 1994 ). then , the double bond in c16 , c17 position is introduced by acidic elimination to deliver the 16 , 17 unsaturated estron derivative of general formula d -( i )-( d )- cf3 . if desired , the protection group is subsequently removed to deliberate the 3 - hydroxy function . step d - 2 , for compounds when the substituents r 10 , r 11 , r 12 and r 13 together with the carbon atoms , to which r 10 , r 11 , r 12 and r 13 are attached , form a heterocyclic 5 - or 6 - membered ring , which is partly unsaturated or aromatic , which contains one , two or three heteroatoms independently selected from n , o and s , the number of n atoms being 0 , 1 , 2 or 3 and the number of o and s atoms each being 0 , 1 or 2 , wherein one heteroatom is directly attached to the c17 c - atom of the steroidal core ; and which ring is optionally substituted with an alkyl group . the synthesis of estron derivatives carrying an additional heterocyclic ring in c16 - c17 position of the steroidal core has already been disclosed within international patent application wo 2004 / 085457 ; the synthesis schemes depicted there can also be applied to the intermediates of the present invention in order to receive the compounds of the present invention . some reactions are exemplified in more detail below . preferably , the substituents r 10 , r 11 , r 12 and r 13 together with the carbon atoms , to which r 10 , r 11 , r 12 and r 13 are attached , form a heterocyclic 5 - or 6 - membered ring to provide a compound of one of the following formulas wherein r 15 represents — h or —( c 1 - c 4 ) alkyl . for synthesis of the d -( ii ) compounds it might be necessary that some of the reaction steps explained under “ steps c — the introduction of the c15 side chain ” have to be carried out after having introduced the heterocyclic ring system . a typical scenario might be , that after optional introduction of the r 14 residue in c2 position , the 15 , 16 - unsaturated intermediate ( x ) is prepared . this is further derivatized to the appropriate acid , alcohol , amid or alkenyl intermediate (“ building block ”). then , the heterocyclic ring system is introduced including the c16 - c17 carbon atoms attached to the d - ring using a synthesis scheme according to wo 2004 / 085457 or as described below . the so - obtained intermediate is then used for further modification of the c15 side chain and introduction of the r 2 / r 4 substituents . finally any protection groups in c3 position might be cleaved off . the pyrazole - unit is known in steroid - chemistry and is constructed in 3 steps as depicted in the following scheme for d -( ii )-( a ): the r * residue may represent the completely introduced c15 side chain —( ch 2 ) n — x - a - y — r 2 , or may represent an intermediate side chain such as — ch 2 — ch ═ ch 2 , or — ch 2 — ch 2 — ch 2 — ch ═ ch 2 ( see also schemes 7b and 7c for introduction and further modification of this alkenyl side chain ). first a α - hydroxymethylene moiety is introduced with naome ( or nah ) and ethylformate [ wölfling et al ( 2003 ), oda et al ( 1989 ), schneider et al ( 1983 )]. after methylation with k 2 co 3 and mei ( wo 2004 / 85457 ) or meoh and cec13 [ akanni & amp ; marples ( 1993 )], the ring is closed with the appropriate hydrazine or alkylhydrazine , e . g . methylhydrazine [ xenos & amp ; catsoulacos ( 1985 )]. alternatively , the methylpyrazine is constructed from the methoxymethylene compound with hydrazine , followed by alkylation with mei . the introduction of the isooxazole group as attached heterocycle to the d - ring of the steroidal core may be achieved according to the synthesis of the corresponding pyrazole derivative and is constructed in 3 steps as depicted in the following scheme for d -( ii )-( c / d ): the r * residue may represent the completely introduced c15 side chain —( ch 2 ) n — x - a - y — r 2 , or may represent an intermediate side chain such as — ch 2 — ch ═ ch 2 , or — ch 2 — ch 2 — ch 2 — ch ═ ch 2 ( see also schemes 7b and 7c for introduction and further modification of this alkenyl side chain ). first a α - hydroxymethylene moiety is introduced with naome ( or nah ) and ethylformate [ wölfling et al ( 2003 ), oda et al ( 1989 ), schneider et al ( 1983 )]. after methylation with k 2 co 3 and mei ( wo 2004 / 85457 a2 ) or meoh and cecl 3 [ akanni & amp ; marples ( 1993 )], the ring is closed with the appropriate hydroxylamine . the synthesis of the c15 estrone derivatives with an attached pyridin ring to the d - ring of the steroidal core is fully disclosed in internation patent application wo 2004 / 085457 . in case that r1 represents — h , or optionally substituted —( c1 - c6 ) alkyl , phenyl or —( c1 - c6 ) alkylphenyl , then the substituent may already have been introduced during synthesis of the intermediates as explained for r1 = h , r1 = methyl and r1 = benzyl . in case of further modification of the 3 - oh function to a sulphamate , carbamate , phosphonate , thiophosphonate , sulphonate , phosphate or sulphate group , this may be obtained by one of the following reactions : the sulphamate compounds of the present invention may be prepared by reacting the correspondingly substituted estron derivative of the general formula d -( i ) with a free 3 - oh group with a suitable sulfamoyl chloride of the general formula r 3 r 3 ′ nso 2 cl . typical conditions for carrying out the reaction are as follows : sodium hydride and a sulfamoyl chloride are added to a stirred solution of the alcohol d ( i )- oh in anhydrous dimethyl formamide at 0 ° c . subsequently , the reaction is allowed to warm to rt whereupon stirring is continued for a further 24 h . the reaction mixture is poured onto a cold saturated solution of sodium bicarbonate and the resulting aqueous phase is extracted with dcme . the combined organic extracts are dried over anhydrous mgso 4 . filtration followed by solvent evaporation in vacuo and co - evaporated with toluene affords a crude residue which is further purified by flash chromatography . alternatively , sulfamoyl chloride ( 1 mmol ) was added to a stirred solution of the alcohol d ( i )- oh ( 0 . 5 mmol ) in anhydrous n , n - dimethylacetamide ( 0 . 75 ml ) at 0 ° c . the mixture was stirred at rt for 3 h and then poured into cold brine ( 10 ml ). the resulting mixture was extracted with etoac ( 3 × 10 ml ), the combined organic layers were washed with brine ( 10 ml ), dried ( mgso 4 ), and concentrated under reduced pressure . the product was purified by flash chromatography on silica gel . where necessary , functional groups in the alcohol d ( i )- oh may be protected in known manner and the protecting group or groups removed at the end of the reaction . preferably , the sulphate compounds are prepared according to the teachings of page et al ( 1990 ). the carbamate compounds of the present invention may be prepared by derivatisation of the correspondingly substituted estron derivative of the general formula d -( i ) with a free 3 - oh group . typical conditions for carrying out the reaction are as follows : 1 eq estrone derivative d -( i )- oh , 3 eq n - methyl - morpholine and 1 / 3 eq triphosgen were dissolved in dcm and stirred for 30 min at 0 ° c . then , 1 eq of the desired amine was added and the reaction mixture stirred for 12 h at rt . thereafter the reaction mixture was quenched by adding 1m nahco 3 . the organic layer was separated and extracted with 1m khso 4 and 1m nacl . after drying over na 2 so 4 the solution was evaporated to dryness and purified by column chromatography . where necessary , functional groups in the alcohol d ( i )- oh may be protected in known manner and the protecting group or groups removed at the end of the reaction . the sulphonate compounds of the present invention may be prepared starting from the correspondingly substituted estron derivative and by suitably combining the teachings of page et al ( 1990 ) and published international patent application wo 93 / 05063 . the phosphonate compounds of the present invention may be prepared starting from the correspondingly substituted estron derivative and by suitably combining the teachings of page et al ( 1990 ) and published international patent application wo 93 / 05063 . the thiophosphonate compounds of the present invention may be prepared starting from the correspondingly substituted estron derivative and by suitably combining the teachings of page et al ( 1990 ) and published international patent application wo 93 / 05063 . the sulphate compounds of the present invention may be prepared starting from the correspondingly substituted estron derivative using known sulfating reagents , such as complexes of sulfur trioxide with lewis bases such as trialkylamines ( e . g . so 3 * et 3 n ), dmf , or pyridine . the phosphate compounds of the present invention may be prepared starting from the correspondingly substituted estron derivative by phosphorylation using e . g . phosphoramidite chemistry or treatment with pyrophosphoric tetrachloride . examples of preparations of compounds of the invention are provided in the following detailed synthetic procedures . in the tables of compounds to follow , the synthesis of each compound is referenced back to these exemplary preparative steps . in single compound synthesis as well as in combinatorial synthesis all reactions were stirred magnetically or shaked with an orbital shaker unless otherwise indicated . sensitive liquids and solutions were transferred via syringe or cannula , and introduced into reaction vessels through rubber septa , in these cases the reaction were carried out under a positive pressure of dry argon or dry nitrogen . commercial grade reagents and solvents were used without further purification . unless otherwise stated , the term “ concentration under reduced pressure ” refers to use of a buchi or heidolph rotary evaporator (“ rotavapor ”) or vacuum centrifuges (“ genevac ” or “ christ alpha rvc ”) at approximately 15 mm of hg . all temperatures are reported uncorrected in degrees celsius (° c .). unless otherwise indicated , all parts and percentages are by volume . thin - layer chromatography ( tlc ) was performed on merck ® precoated glass - backed silica gel or aluminium sheets 60a f - 254 250 μm plates . visualization of plates was effected by one or more of the following techniques : ( a ) ultraviolet illumination ( 254 nm or 266 nm ), ( b ) exposure to iodine vapor , ( c ) spraying of the plate with schlittler &# 39 ; s reagent solution followed by heating , ( d ) spraying of the plate with anisaldehyde solution followed by heating , and / or ( e ) spraying of the plate with rauxz reagent solution followed by heating . column chromatography ( flash chromatography ) was performed using 230 - 630 mesh icn , silitech 60a silica gel . melting points ( mp ) were determined using a reichert thermovar melting point apparatus or a mettler dsc822 automated melting point apparatus and are uncorrected . fourier transform infrared spectra were obtained using a perkin elmer spectrophotometer . proton ( 1 h ) nuclear magnetic resonance ( nmr ) spectra were measured with a bruker arx ( 400 mhz ) or bruker advance ( 500 mhz ) spectrometer with either me 4 si ( δ 0 . 00 ) or residual protonated solvent ( chcl 3 δ 7 . 26 ; chd 2 od δ 3 . 30 ; dmso - d 5 δ 2 . 50 ) as standard . carbon ( 13 c ) nmr spectra were measured with a bruker arx ( 100 mhz ) or bruker advance ( 126 mhz ) spectrometer with either me 4 si ( δ 0 . 00 ) or solvent ( cdcl 3 δ 77 . 05 ; cd 3 od δ 49 . 0 ; dmso - ds δ 39 . 45 ) as standard . hplc electrospray mass spectra ( hplc es_ms ) were obtained using the following method and equipment : samples were separated by reversed phase high pressure liquid chromatography ( rp - hplc ) coupled to a quadrupol ms . hplc was performed at a flow of 1000 μl / min using xterrams c18 columns ( i . d . 4 . 6 mm , length 50 mm , particle size 2 . 5 μm ) or phenomenex luna c18 ( 2 ) 30 * 4 . 6 mm columns . for most samples , a gradient from 0 % eluent b to 95 % b was run in 10 min , with eluent a consisting of water , 10 mm ammonium - acetate at ph 5 + 5 % acetonitrile and eluent b consisting of acetonitrile . two different setups were used : 1 . waters alliance 2795 coupled to a waters zq ms , a waters 2996 diode array detector ( dad ) and an evaporative light scattering detector ( elsd , el - els1000 , polymerlabs ). ionization : electrospray positive and negative mode es +/−; or 2 . lc200 pump ( pe ) coupled to an api100 ms ( applied biosystems sciex ), a variable wavelength detector waters 2487 set to 225 nm , and an elsd ( sedex 75 ), es +. in both setup versions spectra were scanned with a scan range of m / z 100 to 800 or 100 to 900 . gas chromatography — mass spectra ( gc - ms ) analyses were performed with an agilent 6890 gas chromatograph equipped with an db - 5ms column ( 0 . 25 i . d ., length 30 m ) and an agilent 5973 msd quadrupol detector ( ionization with electron impact ( e1 ) at 70 ev ; source temperature 230 ° c .). elemental analyses were conducted by a varioel elemental analyzer ( elementar analysensysteme ) for determination of c , h , and n . acetanilide was used for conditioning and calibration . nmr spectra , lrms , elemental analyses and hrms of the compounds were consistent with the assigned structures . estron derivatives substituted in c2 position of the steroidal core of formula ( v ) ( step a ) 3 - benzyloxy - estra - 1 , 3 , 5 ( 10 )- trien - 2 , 17 - diol was prepared starting from estradiol by introduction of the hydroxy side chain in c2 position as described by rao et al . ( 2002 ) in which a fries rearrangement and a baeyer villiger reaction is used . under an n 2 - atmosphere , ac 2 o ( 375 ml , 3 . 993 mol ) was added dropwise during 20 min to a solution of estradiol ( 150 g , 0 . 551 mol ) in pyridine ( 1500 ml ). the clear colourless solution obtained was stirred at rt overnight . the reaction mixture was then cooled to 0 ° c . and meoh ( 375 ml ) was added dropwise during 25 min . the reaction mixture was stirred at 0 ° c . for 2 h , then allowed to warm to rt and concentrated in vacuo . the residue was recrystallized from hot meoh to yield ( c2 - 2 ) ( 176 g , 90 %) as white crystals . under an n 2 - atmosphere , zrcl 4 ( 530 g , 2 . 27 mol ) was added in one portion to a solution of ( c2 - 2 ) ( 176 g , 0 . 493 mol ) in dcm ( 13 l ). the turbid yellow mixture obtained was stirred at rt for 48 h . the reaction mixture was then cooled to 0 ° c ., ice water ( 3 l ) was added and the mixture was allowed to warm to rt for overnight . the mixture was washed with h 2 o , sat nahco 3 ( aq ), brine , dried over na 2 so 4 , filtered , and concentrated in vacuo to yield ( c2 - 3 ) ( 167 g , 95 %) as a yellow powder . under an n 2 - atmosphere , k 2 co 3 ( 97 g , 0 . 702 mol ) was added in one portion to a solution of ( c2 - 3 ) ( 167 g , 0 . 468 mol ), benzyl bromide ( 61 . 6 ml , 0 . 515 mol ) and 18 - crown - 6 ( 4 . 7 g , 0 . 018 mol ) in acetone ( 1 l ). after 108 h at t intern = 56 ° c ., the reaction mixture was allowed to cool to rt , poured into h 2 o , stirred for 1 h after which the turbid mixture was filtered over a glass fritted filter . the residue was washed with h 2 o , and dried in vacuo to yield ( c2 - 4 ) ( 209 g , 100 %) as a brown solid . under an n 2 - atmosphere , nah 2 po 4 ( 354 g , 2 . 496 mol ) was added to a solution of c2 - 4 ( 167 g , 0 . 468 mol ) in dcm ( 7 l ). then m - cpba ( 205 g , 75 % with h 2 o , 0 . 889 mol ) was added portionwise during 10 min . the turbid mixture obtained was stirred at rt for overnight . the reaction mixture was poured into h 2 o ( 9 l ) and the mixture obtained was stirred for 1 h . the organic layer was isolated and the aqueous layer was extracted with dcm . the combined organic layers were washed with h 2 o , 10 % na 2 so 3 ( aq ), half - sat . nahco 3 ( aq ), brine , dried over na 2 so 4 , filtered , and concentrated in vacuo to yield c2 - 5 ( 247 g , quant .) as a clear yellow powder . a solution of koh ( 250 g , 4 . 46 mol ) in h 2 o ( 5 l ) was added in one portion to a solution of ( c2 - 5 ) ( 511 g , 1 . 181 mol ) in thf ( 5 l ) and meoh ( 5 l ). the mixture obtained was stirred at t intern = 65 ° c . for over night , after which it was allowed to cool to rt . the reaction mixture was acidified with conc . hoac to ph 4 and diluted with h 2 o and etoac ( 1 : 3 ). the organic layer was isolated and the aqueous layer was extracted with etoac . the combined organic layers were washed with brine , dried over na 2 so 4 , filtered , and concentrated in vacuo to yield 358 g brown solid . the solid was triturated with tbme ( 2 l ) for 2 h , filtered over a glass fitted filter ( p2 ) and the residue was washed with tbme , then with acetone , and dried in vacuo to yield ( c2 - a ) ( 256 g ) as an offwhite solid . the combined filtrates were concentrated in vacuo to yield 125 g brown resin . the resin was dissolved in dcm , applied to sio 2 and eluted with dcm : nh 3 7n in meoh = 97 . 5 : 2 . 5 to yield 76 g yellow solid ( r f = 0 . 39 ). the solid was triturated with tbme ( 250 ml ), filtered over a glass fritted filter ( p4 ). the residue was washed with dcm and dried in vacuo to yield ( v - c2 - a ) ( 15 . 4 g ) as an off - white solid . total yield : 61 %. 3 - benzyloxy - 2 - methoxy - estra - 1 , 3 , 5 ( 10 )- triene - 17 □ one was prepared starting from ( v - c2 - a ) according to the procedure described by rao et al . ( 2002 ) and within u . s . pat . no . 6 , 043 , 236 . under an n 2 - atmosphere , lioh . h 2 o ( 16 . 2 g , 0 . 386 mol ) was added to a solution of ( v - c2 - a ) ( 118 g , 0 . 312 mol mol ) in thf ( 1 . 5 l ). after adding me 2 so 4 ( 33 . 1 ml , 0 . 350 mol ) the mixture obtained was stirred at 55 ° c . for 3 h . the mixture was allowed to cool to rt overnight , concentrated in vacuo , and the residue was dissolved in dcm ( 1200 ml ). the organic layer was washed with h 2 o , brine , dried over na 2 so 4 , filtered , and concentrated in vacuo to yield ( c2 - 6 ) ( 115 g , 94 %) as an orange resin . to a mixture of ( c2 - 6 ) ( 118 g , 0 . 301 mol ) and tpap ( 5 . 0 g , 0 . 014 mol ) in acetone ( 2 l ) was added portion - wise nmo ( 52 . 5 g , 0 . 448 mol ) at such rate as to keep t intern ≦ 31 ° c . the mixture obtained was stirred at rt overnight . the reaction mixture was concentrated in vacuo to yield 128 g black solid . the solid was applied and eluted from sio 2 with dcm to yield ( v - c2 - b ) ( 97 g , 83 %) as a pale yellow solid ( r f = 0 . 78 ). 3 - benzyloxy - 2 - ethyl - estra - 1 , 3 , 5 ( 10 )- triene - 17 □ one was prepared starting from ( c2 - 4 ) by performing a wolff - kishner reduction to obtain the ethyl side chain . the oxidation of the c17 hydroxyl function was achieved by tpap oxidation using the procedures of ley et al ( 1994 ). alternatively , 3 - benzyloxy - 2 - ethyl - estra - 1 , 3 , 5 ( 10 )- triene - 17 - one was prepared starting from ( c2 - 3 ) by reduction of the acyl function which was achieved by reaction with pd / c and h 2 [ gonzalez et al ( 1982 )], subsequent benzylation of the 3 - hydroxy function , deprotection of the c17 hydroxy function and tpap oxidation . to benzyl protected acyl ketone ( c2 - 4 ) ( 765 g , 1 . 71 mol ) was added diethylene glycol ( 1900 ml ), koh ( 288 g , 5 . 14 mol ) and h 2 nnh 2 * h 2 o . the mixture was heated to 120 - 140 ° c . overnight . a dean - stark trap was placed and water and h 2 nnh 2 * h 2 o were removed by distillation by heating the reaction mixture to 190 ° c . after nmr analysis revealed complete conversion , the mixture was cooled to 50 ° c . and water ( 3 l ) was added . the mixture became very thick and unstirrable . the dissolved part was poured in a mixture of water ( 15 l ) and etoac ( 5 l ) and the sticky oil was first dissolved in etoac ( 5 l ) and then added to the mixture . the layers were separated and the organic layer was washed with water and concentrated to give ( c2 - 7 ) ( 543 g , 81 %) as an orange / yellow oil which solidified upon standing . alcohol ( c2 - 7 ) ( 433 g , 1 . 39 mol ) and powdered 4a molsives ( 695 g , 500 mg / mmol ) in dcm ( 2 . 7 l ) were cooled with an ice bath and tpap ( 19 . 5 g , 55 . 6 mmol , 4 mol %) was added . nmo ( 282 g , 2 . 09 mol ) was added under ice / water cooling . after 3 h the reaction mixture was filtered over sio 2 ( 10 l , dcm ) and all fraction before the black fraction ( tpap ) were collected . the dcm was concentrated to give ketone ( v - c2 - c ) ( 465 g , 86 %) as a yellow solid . in the first step , the 2 - hydroxy function of 3 - benzyloxy - estra - 1 , 3 , 5 ( 10 )- triene - 2 , 17β - diol ( c2 - a ) was alkylated using ethylsulfate and lioh or methoxyethanol under mitsunobu conditions . subsequently , the alcohol was oxidated with tpap and nmo to the corresponding estron derivative . intermediate ( v - c2 - a ) ( 15 . 0 g , 39 . 68 mmol ) was dissolved in thf ( 250 ml ), under nitrogen atmosphere . lioh ( 2 . 0 g , 47 . 62 mmol ) and et 2 so 4 ( 5 . 7 ml , 43 . 65 mmol ) were added . the mixture was heated at 55 ° c . for 5 h , then cooled to rt and stirred for 48 h . the mixture was concentrated in vacuo . dcm ( 400 ml ) was added and the organic layer was washed with water ( 2 × 250 ml ) and brine ( 1 × 250 ml ), dried over na 2 so 4 and concentrated in vacuo yielding 21 . 7 g of a greenish semi - solid . the mixture was dissolved in thf ( 250 ml ) under nitrogen atmosphere . lioh ( 0 . 8 g ) and et 2 so 4 ( 2 . 0 ml ) were added . the mixture was heated to reflux and refluxed over the weekend . the mixture was concentrated in vacuo . dcm ( 400 ml ) was added and the organic layer was washed with water and brine , dried over na 2 so 4 and concentrated in vacuo to afford 16 . 7 g ( 41 . 07 mmol , quant .) of brown oil . pentane was added and the formed solid was filtered yielding 13 . 5 g ( c2 - 8 ) ( 84 %) as a white solid . intermediate ( v - c2 - a ) ( 15 . 0 g , 39 . 68 mmol ), pph 3 ( 20 . 79 g , 79 . 37 mmol ) and methoxyethanol ( 6 . 3 ml , 79 . 37 mmol ) were suspended in dcm ( 500 ml ) and cooled in an ice / water bath , under n2 atmosphere . diad ( 15 . 6 ml , 79 . 37 mmol ) was added drop wise in 1 h at below 5 ° c . after addition a clear solution was formed which was warmed to rt overnight . the solution was concentrated in vacuo yielding 58 . 8 g thick brown oil . purification via column chromatography ( sio 2 , eluens dcm to 1 % meoh in dcm ) yielded 34 g of thick oil . a second purification via column chromatography was done ( sio 2 , eluens 10 % etoac to 50 % etoac in heptan ). two fractions were collected , 7 . 61 g ( 44 %) of pure product and 5 . 3 g which was purified via column chromatography yielding 3 . 1 g ( 18 %). both fractions were mixed yielding 10 . 8 g ( c2 - 9 ) ( 62 %) as white powder . alcohol ( c2 - 8 ) ( 13 . 5 g , 33 . 25 mmol ) was dissolved in aceton ( 350 ml ), under nitrogen atmosphere . tpap ( 0 . 6 g , 1 . 663 mmol ) was added . nmo ( 5 . 8 g , 49 . 88 mmol ) was added portion wise . the mixture was stirred at rt overnight . the mixture was concentrated in vacuo yielding 16 . 3 g of a black tar . the mixture was filtered over silica with dcm . filtrate was concentrated in vacuo yielding 11 . 8 g ( v - c2 - d ) ( 29 . 6 mmol , 89 %) as yellow solid . alcohol ( c2 - 9 ) ( 10 . 8 g , 24 . 54 mmol ) was dissolved in aceton ( 300 ml ), under nitrogen atmosphere . tpap ( 0 . 43 g , 1 . 23 mmol ) was added . nmo ( 4 . 31 g , 36 . 81 mmol ) was added portion wise . the mixture was stirred at rt overnight . the mixture was concentrated in vacuo yielding 12 . 5 g of a black tar . the mixture was filtered over silica with 1 % meoh in dcm . filtrate was concentrated in vacuo yielding 11 . 6 g ( v - c2 - e ) ( 26 . 8 mmol , & gt ; 100 %) as white solid . building block v - c2 - f was prepared starting from intermediate 2 - acetyl - 3 - benzyloxy - estra - 1 , 3 , 5 ( 10 )- triene - 17β - ol 17 - acetate ( c2 - 4 ). compound ( c2 - 4 ) ( 119 g , 266 mmol ) was dissolved in a mixture of thf ( 500 ml ) and meoh ( 500 ml ) under a n2 atmosphere . a solution of koh ( 60 . 0 g , 1 . 06 mol ) in water ( 1 l ) was added forming a suspension . the reaction mixture was stirred at 75 ° c . ( external ) for 16 h . after cooling to rt the ph of the mixture was adjusted to 4 using acetic acid . after dilution with water ( 1 l ) the aqueous layer was separated . the organic layer was washed with brine , dried over na 2 so 4 , concentrated in vacuo , stripped with toluene and again dried in vacuo yielding compound ( c2 - 10 ) ( 70 . 0 g , 173 . 0 mmol , 65 %) as a yellow syrup , which was used without further purification . compound c2 - 10 ( 70 g , 173 mmol ) was suspended in diethyl ether ( 2 l ) and bromine ( 18 . 67 ml , 58 . 1 g , 363 mmol ) slowly dropwise added at 0 ° c . under n2 atmosphere . the reaction mixture was stirred at ambient temperature for 14 h . the solvent was removed in vacuo and the residue suspended in methanol ( 2 l ). sodium methoxide ( 94 g , 173 mmol ) was added and the reaction mixture stirred at rt for 72 h . this was poured into water ( 1 l ), acidified with conc . aq . hcl and the water layer extracted with dcm . the organic layer was washed with brine , dried over na 2 so 4 and concentrated in vacuo . via column chromatography ( sio 2 , heptane / etoac 2 / 1 to 0 / 100 stepwise ) compound c2 - 11 ( 14 . 3 g , 32 . 9 mmol , 19 %) was isolated . palladium on charcoal ( 10 %, 15 g ) was suspended in water ( 175 ml ) under a nitrogen atmosphere and added to a solution of compound c2 - 11 ( 14 . 3 g , 32 . 9 mmol ) in thf ( 175 ml ) and t - butanol ( 175 ml ). h 2 at ambient pressure was applied and the reaction mixture was stirred at ambient temperature for 80 h . the reaction mixture was filtered over celite and the filter cake was washed with ethanol . the filtrate was concentrated in vacuo yielding crude compound c2 - 12 ( 8 . 3 g , 25 . 1 mmol , 77 %). after purification by column chromatography ( sio 2 , heptane / etoac = 3 / 1 to 1 / 2 stepwise ) pure c2 - 12 ( 3 . 6 g , 10 . 89 mmol , 33 %) was isolated . compound c2 - 12 ( 3 . 6 g , 10 . 89 mmol ) was dissolved in acetone ( 30 ml ) under n2 atmosphere . subsequently , benzylbromide ( 2 . 61 ml , 3 . 73 g , 21 . 78 mol ), anhydrous k 2 co 3 ( 3 . 01 g , 21 . 78 mmol ) and 18 - crown - 6 ( 290 mg , 1 . 09 mmol ) were added . the reaction mixture was refluxed for 24 h ( 65 ° c . external ) and allowed to cool to rt . the mixture was poured into water ( 150 ml ) and stirred for 1 h . the water layer was separated and extracted with toluene . the combined organic layers were washed with brine , dried over na 2 so 4 and evaporated in vacuo leaving compound c2 - 13 ( 4 . 92 g , max . 10 . 89 mmol , quant .) as a yellowish solid . compound c2 - 13 ( 4 . 92 g , max . 10 . 89 mmol ) was suspended in acetone ( 75 ml ) under n2 atmosphere . subsequently , tetrapropylammonium perruthenate ( tpap ) ( 191 mg , 0 . 54 mmol ) and n - methylmorpholine n - oxide ( nmo ) ( 1 . 91 g , 16 . 34 mmol ) were added . after the reaction mixture had been stirred for 80 h at ambient temperature , it was filtered over celite . the filtrate was concentrate in vacuo yielding compound v - c2 - f ( 3 . 43 g , 8 . 19 mmol , 70 %) as a pale solid after column chromatography ( sio 2 , dcm / methanol = 100 / 0 to 95 / 5 stepwise ). 3 - benzyloxy - 2 - propyl - estra - 1 , 3 , 5 ( 10 )- triene - 17one was prepared starting from estradiol by introduction of the propionate side chain in c2 position as described by rao et al . ( 2002 ) using a fries rearrangement . then the keto function is reduced to obtain the propyl side chain by reaction with pd / c and h 2 [ gonzalez et al ( 1982 )]. the subsequent oxidation of the c17 hydroxyl function was achieved by tpap oxidation using the procedures of ley et al . ( 1994 ). estradiol ( 200 g , 0 . 734 mol ) was dissolved in pyridine ( 2 l ) under n2 atmosphere . propionic anhydride ( 344 g , 2 . 64 mol ) was added . the reaction mixture was stirred at ambient temperature until the reaction was completed . the reaction mixture was cooled on an ice - water bath , quenched with meoh ( 250 ml ) and stirred at ambient temperature for 1½ h . the mixture was concentrated in vacuo and the residue was dissolved in toluene . the organic layer was separated , washed with water , 10 % aqueous citric acid , sat . aq . nahco 3 and dried over na 2 so 4 . the organic layer was concentrated in vacuo and the residue was stripped with toluene , yielding compound c2 - 14 ( 272 g , 0 . 708 mol , 96 %) as a white solid . compound c2 - 14 ( 272 g , 0 . 708 mol ) was dissolved in dcm ( 10 l ) under n2 atmosphere . zirconium chloride ( 758 g , 3 . 25 mol ) was added , which resulted in a yellow suspension . the mixture was stirred at ambient temperature until the conversion was completed . the reaction mixture was cooled to 3 ° c . before 200 g ice was added in batches . water ( 2 l ) was added and the mixture was stirred at 4 ° c . for 1 hr . then an additional amount of water ( 5 l ) was added . the aqueous layer was separated and extracted with dcm . the combined organic layers were filtered over na 2 so 4 and concentrated in vacuo . the residue was stripped with toluene leaving a green residue . the residue was dissolved in dcm and filtered over sio 2 leaving compound c2 - 15 ( 255 g , 0 . 663 mol , 94 %) as an orange solid . pd ( 10 %) on charcoal ( 120 g ) was suspended in water ( 800 ml ) under n2 atmosphere . t - butanol ( 800 ml ) and a solution of compound c2 - 15 ( 115 g , 0 . 299 mol ) in thf ( 800 ml ) were added . the mixture was applied to h 2 ( ambient pressure ) and stirred at ambient temperature until the reaction was completed . the mixture was filtered over celite ( 2 ×) and the filter cake was washed with thf . the filtrate was concentrated in vacuo yielding compound c2 - 16 ( 107 g , 0 . 289 mol , 97 %) as gray solid . compound c2 - 16 ( 238 g , 0 . 642 mol ) was dissolved in acetone ( 1 . 5 l ) under n2 atmosphere . subsequently , benzylbromide ( 83 ml , 0 . 700 mol ), anhydrous k 2 co 3 ( 100 g , 0 . 723 mol ) and 18 - crown - 6 ( 10 g , 0 . 038 mol ) were added . the reaction mixture was refluxed overnight . additional amounts of k 2 co 3 ( 25 g , 0 . 181 mol + 50 g , 0 . 362 mol ) and benzylbromide ( 10 ml , 14 g , 0 . 084 mol ) were added . after refluxing the mixture for additional 64 h , the mixture was allowed to cool to 30 ° c . and poured into water ( 4 . 5 l ). the mixture was extracted with toluene , the organic layers were combined and concentrated in vacuo . the residue was stripped with toluene leaving compound c2 - 17 ( 335 g , max . 0 . 642 mol ) as a wax like solid . compound c2 - 17 ( 69 . 9 g , max . 134 mmol ) was dissolved in a mixture of thf ( 600 ml ) and meoh ( 600 ml ) under n2 atmosphere . a solution of koh ( 34 . 4 g , 613 mmol ) in water ( 600 ml ) was added . the reaction mixture was stirred at 55 ° c . for 3 h . meoh was removed in vacuo from the mixture . dcm ( 400 ml ) was added and the ph of the mixture was adjusted to 1 using 3 m hcl . the aqueous layer was separated and extracted with dcm ( 2 × 200 ml ). the organic layers were combined , washed with sat aq nahco 3 ( 200 ml ) and dried over na 2 so 4 . the organic layer was concentrated in vacuo yielding compound c2 - 18 ( 61 . 6 g , 152 mmol , 88 %) as a yellow syrup after column chromatography ( sio 2 , dcm / heptane = 85 / 15 ). compound c2 - 18 ( 61 . 6 g , 152 mmol ) was dissolved in acetone ( 1250 ml ) under n 2 atmosphere . subsequently , tpap ( 5 . 1 g , 14 . 5 mmol ) and nmo ( 48 . 6 g , 415 mmol ) were added . after the reaction mixture was stirred for 4½ h at ambient temperature , it was filtered over celite . the filtrate was concentrated in vacuo yielding compound v - c2 - g ( 57 . 6 g , 143 mmol , 94 %) as a pale solid after column chromatography ( sio 2 , dcm ). compound v - c2 - g ( 1 . 10 g , 2 . 73 mmol ) was dissolved in thf ( 15 ml ) under a nitrogen atmosphere . a suspension of palladium on charcoal ( 10 %, 130 mg ) in thf ( 10 ml ) was added . h 2 was applied at ambient pressure and the reaction mixture was stirred at rt for 3 d . the reaction mixture was filtered over celite and the filter cake was washed with thf ( 20 ml ). the filtrate was concentrated in vacuo yielding compound ( v - c2 - g - a ) ( 240 mg , 0 . 768 mmol , 28 %) after column chromatography ( sio 2 , dcm ). ii . 15 , 16 - unsaturated and c2 substituted estrone derivatives of formula ( x ) ( step b ) the estrone of general formula v was converted into the corresponding 15 , 16 unsaturated derivative by the 4 - step reaction as depicted in scheme 1 according to nambara 1976 : after protection of the c17 keto function as acetal ( ethylene glycol , teof and p - tosoh in toluene , work - up with water and tea ), the acetal was brominated ( with pyridinium perbromate and ethylene glycol in dme , work - up with na 2 s 2 o 3 ). subsequently , hbr was eliminated by reaction with k — o - tert - butyl in dmso . finally , the deprotection of the acetal was achieved with p - tosoh in dme and water . 3 - benzyloxy - 2 - methoxy - estra - 1 , 3 , 5 ( 10 ), 15 - tetraene - 17 - one ( x - c2 - b ) 3 - benzyloxy - 2 - ethyl - estra - 1 , 3 , 5 ( 10 ), 15 - tetraene - 17 - one ( x - c2 - c ) 3 - benzyloxy - 2 - ethoxy - estra - 1 , 3 , 5 ( 10 ), 15 - tetraene - 17 - one ( x - c2 - d ) 3 - benzyloxy - 2 - methoxy - ethoxy - estra - 1 , 3 , 5 ( 10 ), 15 - tetraene - 17 - one ( x - c2 - e ) 3 - benzyloxy - 2 - methoxy - ethyl - estra - 1 , 3 , 5 ( 10 ), 15 - tetraene - 17 - one ( x - c2 - f ) 3 - benzyloxy - 2 - propyl - ethoxy - estra - 1 , 3 , 5 ( 10 ), 15 - tetraene - 17 - one ( x - c2 - g ) the detailed synthesis of the following intermediates , wherein r 14 represents h , is fully disclosed within international patent application wo 2005 / 47303 , which is incorporated by reference herein . for intermediates with r 14 is different from h , detailed synthesis is given for exemplary compounds . iiia . the optionally 2 - substituted ketal derivative of the estron - 15α - yl - carbaldehyde of formula xiii - 0 the protected aldehyde intermediate of formula xiii - 0 with pg = ch 3 ( xiiib ) or pg = benzyl ( xiiic ) can be prepared according to a procedure depicted within the following scheme 2 : the optionally 2 - substituted 15 , 16 - unsaturated estrone of formula ( x ) was converted into the corresponding cyano - estrone ( xi ) by a cyanide michael addition at the d - ring . the nitrile was introduced in the beta configuration as was proven by 2d - nmr . epimerization of this stereocenter had been accomplished in a following step . first the ketone functionality was protected as the acetal ( xii ), followed by conversion of the nitrile to the corresponding aldehyde ( xiii - 0 ) by the addition of dibah to the nitrile and the consecutive hydrolysis of the imine product . at this stage the epimerization took place for about 90 % ( 2d - nmr ). consecutive washing of the mixture with aqueous bicarbonate gave the α - isomer with a d . e ≦ 98 %. iiib . optionally 2 - substituted compounds of formula iv : estron - 15 - yl - c 0 - c 5 - alkyl - carboxylic acid the individual steps in the synthesis of acid building block of the formula iv - 0b are depicted in the following scheme 3 . the ketal derivative of the optionally 2 - substituted 17 - oxo - estra - 1 , 3 , 5 ( 10 )- trien - 15α - yl - carbaldehyde of formula xiii - 0 is oxidized to the corresponding carboxylic acid and converted into the unprotected 15α - substituted estrone derivative of formula iv - 0 . the acid building block iv - 1 may be synthesized via two different routes . the individual steps of the first synthesis route of acid building block iv - 1 are depicted in the following scheme 4 . the same kind of procedure can be applied for n = 2 and for other side chains within the pg position . the ketal derivative of the 17 - oxo - estra - 1 , 3 , 5 ( 10 )- trien - 15α - yl - carbaldehyde of formula xiii - 0 is converted into the methyl enol ether of the formula xxxiv via a wittig reaction with meoch 2 lip ( ph ) 3 . hydrolysis with hcl ( aq ) delivered the unprotected acetaldehyde derivative xxxiii - 1 . the acetaldehyde derivative is then further oxidized to the corresponding carboxylic acid iv - 1 . alternative synthesis route for the acid building block iv - 1 : ( n = 1 ): iv - 1b : ( n = 1 and pg = ch 3 ): 3 - methoxy - 17 - oxo - estra - 1 , 3 , 5 ( 10 )- trien - 15α - yl - acetic acid alternatively , compound iv - 1b can be prepared directly from the enone derivative of formula x according to the following synthesis scheme 5 : a michael addition of the dimethylmalonate - anion to the enone derivative delivered the diester xxxvib , which was converted into the acid building block of formula iv - b by alkaline ester hydrolysis and decarboxylation in refluxing acetic acid . optionally 2 - substituted acid building blocks ivβ - 2 , ivβ - 3 , ivβ - 4 , 1vβ - 5 , ivβ - 6 ( n = 2 , 3 , 4 , 5 , 6 ): ivβ - 3b ( n = 3 and pg = ch 3 ): 4 -( 3 - methoxy - 17 - oxo - estra - 1 , 3 , 5 ( 10 )- trien - 15β -) 7d - butyric acid the individual steps in the synthesis of acid building block of the formula ivβ - 3b are depicted in the following scheme 6 . the same kind of procedure can be applied for n = 4 , 5 , or 6 and for other alkyl side chains within the r 1 position using the appropriate brmg — c 5 - c7 - alkoxy - thp as grignard reagent . furthermore , this reaction scheme also delivers the estrone - alcohol building block in form of the intermediate of formula xxxiβ - 4b . 4 - bromo - butanol - thp ether was prepared by adding hbr solution to refluxing thf . the resulting bromide was dissolved in dcm , p - tosoh and dhp were added at 0 ° c . to give the protected alcohol . this was filtered over sio 2 and further purified by column chromatography , yielding 9 . 3 % over 2 steps . the protected alcohol was dissolved in thf and added to activated magnesium , and the resulting grignard reagent added to cui 2 in hmpa . the 15 , 16 - unsaturated estrone derivative of formula xb , dissolved in dry thf and tmscl , was added at − 40 ± 5 ° c . subsequently , after hydrolysis of the silyl ether , the resulting compound xxx - 4b - thp was deprotected with p - tosoh / meoh to give the alcohol derivative xxxi - 4b , which was converted , without purification , into the free acid iv - 3b by a jones oxidation . the oil was purified by column chromatography , yielding the free acid of formula iv - 3b in 30 % yield over three steps . acid building blocks ivβ - 2 ( n = 2 and pg = h , ch 3 or benzyl ): optionally 2 - substituted 3 -( 3 - benzyloxy / methoxy / hydroxy - 17 - oxo - estra - 1 , 3 , 5 ( 10 )- trien - 15β - yl )- propanoic acid the optionally 2 - substituted carboxylic acid ivβ - 2 can be prepared by oxidation of the alcohol derivative of formula xxxiβ - 3b or xxxiβ - 3c according to the preparation of the carboxylic acid ivβ - 3b ( see section for the preparation of the alcohol derivatives below for synthesis of xxxiβ - 3b and xxxiβ - 3c ) and optionally subsequent debenzylation of the c3 hydroxy function . the individual steps in the synthesis of acid building block of the formula ivβ - 3c are performed according to any of the procedures depicted in the following schemes 7a , 7b and 7c . furthermore , reaction scheme 7a also delivers the estrone - alcohol building block in form of the intermediate of formula xxxiβ - 4c . the same kind of procedure can be applied for n = 4 , 5 , or 6 and for other alkylaryl substitutents within the r 1 position using the appropriate brmg — c 5 - c 7 - alkoxy - thp as grignard reagent . 4 - bromo - butanol - thp ether was prepared by adding hbr solution to refluxing thf . the resulting bromide was dissolved in dcm , p - tosoh and dhp were added at 0 ° c . to give the protected alcohol . this was filtered over sio 2 and further purified by column chromatography , yielding 9 . 3 % over 2 steps . the protected alcohol was dissolved in thf and added to the activated magnesium , and the resulting grignard reagent added to cui2 in hmpa . the 15 , 16 - unsaturated estrone derivative of formula xc ( preferably with r 14 = h ), dissolved in dry thf and tmscl , was added at − 40 ± 5 ° c . subsequently , the resulting compound xxx - 4c - thp was deprotected with p - tosoh / meoh to give xxxiβ - 4c in 47 % over 2 steps , which was converted , without purification , into the free acid ivβ - 3c by a jones oxidation in a yield of 96 %. the 15 , 16 - unsaturated estrone derivative of formula xc ( preferably with r 14 = ethyl , n - propyl or methoxyethyl ) was subjected to a 1 , 4 addition using a freshly prepared gringard reagent . subsequently , the resulting compound xxx - 4c was oxidized to the free acid ivβ - 3c ( see also the reaction scheme 12 ). the 15 , 16 - unsaturated estrone derivative of formula xc ( preferably with r 14 = methoxy ) was subjected to a 1 , 4 addition using a freshly prepared gringard reagent . subsequently , the resulting compound xxx - 2c was reacted with acrylic acid methyl ester using a grubb ii catalyst , known as olefin metathesis . after removal of the methyl group , the free acid ( ivb - 3a ) is obtained by hydrogenation and deprotection . alternatively , the last two steps may be performed in reversed order . compound ( ivβ -( c2 - b )- 3a ) was prepared according to general procedure depicted in scheme 7c starting from compound ( x - c2 - b ). under n 2 - atmosphere , in flame - dried glassware , licl ( 247 mmol ) and cui ( 247 mmol ) were dissolved in thf ( 500 ml ). the solution obtained was cooled to t intern =− 78 ° c ., and allyl magnesiumbromide ( 1 m in et 2 o , 246 mmol ) was added dropwise during 1 . 5 h while keeping t intern ≦− 75 ° c . after stirring for 0 . 5 h , tmscl ( 171 mmol ) was added and the reaction mixture was further stirred at t intern =− 78 ° c . for 0 . 5 h . then , a solution of ( x - c2 - b ) ( 26 . 5 g , 68 . 2 mmol ) in thf ( 250 ml ) was added dropwise during 1 . 5 h , while keeping t intern ≦− 75 ° c . the reaction mixture was stirred at t intern =− 78 ° c . for 1 . 5 h , after which it was allowed to warm to rt , quenched with sat . nh 4 cl ( aq ) ( 600 ml ), and stirred at rt overnight . the reaction mixture was filtered over celite and the residue was washed with etoac ( 200 ml ). the organic layer was isolated from the combined filtrates , and the aqueous layer was extracted with etoac ( 100 ml ). the combined organic layers were washed with 1n hcl ( aq ) ( 250 ml ), 1n nh 4 oh ( aq ) ( 3 × 250 ml ), brine ( 250 ml ), dried over na 2 so 4 , filtered , and concentrated in vacuo to yield ( xxx -( c2 - b )- 2c ) ( 34 . 8 g , 98 %). under n 2 - atmosphere , in oven - dried glassware , grubbs ii catalyst ( 2 . 36 mmol ) was added to a solution of ( xxx -( c2 - b )- 2c ) ( 60 . 4 mmol ) and methyl acrylate ( 150 mmol ) in dcm ( 500 ml ). the mixture obtained was stirred at rt overnight , heated at t intern = 39 ° c . for 8 h , after which it was allowed to cool to rt . the reaction mixture was evaporated to dryness to furnish 30 . 8 g resin , which was applied to sio 2 ( 1500 ml ) with dcm and eluted with a dcm : etoac gradient ( 99 : 1 to 90 : 10 ) to yield the desired compound ( 18 . 5 g , 63 %) ( r f = 0 . 1 ( dcm )). this was dissolved in thf ( 250 ml ) and heated at reflux with activated charcoal ( 1 g ) for 20 min . the mixture obtained was allowed to cool to rt , filtered and the filtrate was concentrated in vacuo . a solution of 4 -( 3 - benzyloxy - 2 - methoxy - 17 - oxo - estra - 1 , 3 , 5 ( 10 )- trien - 15β - yl )- but - 2 - enoic acid methyl ester ( 17 . 3 g , 2 . 36 mmol ) in thf ( 440 ml ) and meoh ( 440 ml ) was purged with h 2 ( balloon ). then pd ( 10 % on carbon , 50 % h 2 o ) ( 1 . 80 g ) was added , and the mixture obtained was stirred under h 2 pressure for over night . the reaction mixture was filtered over two filter papers and concentrated in vacuo to yield the desired compound ( viiβ -( c2 - b )- 3a - 1 ) ( 13 . 8 g , 97 %), which represents a compound falling under the scope of the present invention . a solution of lioh . h 2 o ( 197 mmol ) in h 2 o ( 450 ml ) was added to a solution of ( viiβ -( c2 - b )- 3a - 1 ) ( 34 . 5 mmol ) in thf ( 450 ml ) and the mixture obtained was stirred at rt overnight . the reaction mixture was concentrated in vacuo to remove thf and diluted with h 2 o ( 1300 ml ). the mixture was washed with dcm ( 3 × 300 ml ), acidified with 1n hcl to ph ≈ 1 and extracted with dcm ( 3 × 400 ml ). the combined extracts were washed with brine ( 400 ml ), dried over na 2 so 4 , filtered and concentrated in vacuo to yield ( ivβ -( c2 - b )- 3a ) ( 11 . 7 g , 88 %). compound ( ivβ -( c2 - f )- 3a ) was prepared according to general procedure depicted in scheme 7c starting from compound ( x - c2 - f ). a flame dried flask was charged with cui ( 1 . 38 mmol ) and licl ( 1 . 38 mmol ) under n2 atmosphere . thf ( 5 ml ) was added and stirred at ambient temperature until a clear green solution was obtained . after cooling the solution to − 78 ° c ., allylmagnesium bromide in eto 2 ( 1 . 38 mmol ) was added dropwise and stirred at − 78 ° c . for 1 h . then tmscl ( 1 . 38 mmol ) was added in a single batch . a solution of compound x - c2 - f ( 192 mg , 0 . 46 mmol ) in thf ( 5 ml ) was added dropwise at − 78 ° c . the reaction mixture was stirred at − 78 ° c . for 2 h and the mixture was allowed to reach rt overnight . the mixture was quenched with sat aq nh 4 cl ( 50 ml ). the organic layer was separated and washed with aq . 1m hcl ( 25 ml ), aq . 1m nh 4 oh ( 25 ml ) and brine ( 25 ml ). the combined organic layers were dried over naso 4 and concentrated in vacuo yielding compound ( xxxβ -( c2 - f )- 2c ) ( 220 mg , max . 0 . 46 mmol ). purification via sio 2 ( dmc / methanol = 100 / 0 to 98 / 2 ) delivered pure ( xxxβ -( c2 - f )- 2c ) ( 56 mg , 0 . 122 mmol , 22 %). compound ( xxxβ -( c2 - f )- 2c ) ( 46 mg , 0 . 10 mmol ) was dissolved in dcm ( 5 ml ) under n2 atmosphere . ethyl acrylate ( 0 . 135 mmol ) and grubbs ii catalyst ( 0 . 01 mmol ) were added . the reaction mixture was stirred at ambient temperature for 18 h . the reaction mixture was filtered over celite and concentrated in vacuo yielding the title compound ( 46 mg , 0 . 086 mmol , 85 %) after purification over sio 2 ( dcm / meoh = 100 / 0 to 98 / 2 ). palladium on charcoal ( 10 %, 15 mg ) was suspended in methanol ( 5 ml ) under n2 atmosphere . a solution of the previous compound ( 45 g , 0 . 085 mmol ) in thf ( 5 ml ) was added carefully . h 2 at ambient pressure was applied and the reaction mixture was stirred at ambient temperature over the weekend . the reaction mixture was filtered over celite and the filter cake was washed with thf ( 10 ml ). the filtrate was concentrated in vacuo yielding compound ( viiβ -( c2 - f )- 3a - 1 ) ( 40 mg , max . 0 . 085 mmol ), which also represents a compound falling under the scope of the present invention . the previous compound ( 40 mg , max . 0 . 085 mmol ) was dissolved in a mixture of thf ( 2 ml ), water ( 2 ml ) and lioh . h 2 o ( 0 . 45 mmol ). the mixture was stirred at ambient temperature for 5 h . thf was removed in vacuo and the residue diluted with water ( 5 ml ). the alkaline layer was washed with dcm ( 1 × 10 ml ) and the organic layer discarded . the water layer was acidified till ph 3 using aq . 1m hcl and extracted with dcm ( 4 × 25 ml ). the combined organic layers were washed with brine ( 25 ml ), dried over na 2 so 4 and concentrated in vacuo yielding compound ( ivβ -( c2 - f )- 3a ) ( 26 mg , 0 . 063 mmol , 74 %) as pale solid . the following further building blocks were prepared according to this procedure : optionally 2 - substituted acid building block with a stereochemistry at c15 : ivα - 3a ( n = 3 and pg = h ): 4 -( 3 - hydroxy - 17 - oxo - estra - 1 , 3 , 5 ( 10 )- trien - 15α - yl )- butyric acid the individual steps in the synthesis of the optionally 2 - substituted acid building block of the formula ivα - 3a are performed according to any of the procedures depicted in schemes 8a and 8b . furthermore , reaction scheme 8a also delivers the still ketal - protected estrone - alcohol building block in form of the intermediate of formula xlivα - 1c . debenzylation and deprotection delivers the estrone - alcohol xxxiα - 1a . reduction of the aldehyde xiii - 0c with nabh 4 ( etoh , 2 h , rt ) gave the alcohol xlivα - 1c , which was further treated with iodine , triphenylphosphine and imidazole to give the iodide xlv . subsequently , ethylacrylate was coupled to iodine xlv and gave compound xlvi after purification by column chromatography . reduction of compound xlvi was performed under h 2 atmosphere to give compound xlvii , which was transformed into the protected carboxylic acid building block xlviiiα - 3a by saponification . the carboxylic acid ivα - 3a was obtained by deprotection . the allyl group was introduced into the optionally c2 substituted , 15 , 16 - unsaturated estrone derivative of formula xc by reaction with allylmagnesium chloride or bromide , followed by an oxy - cope rearrangement catalysed by kh and 18 - crown - 6 . subsequently , the resulting compound xxx - 2c was reacted with acrylic acid methyl ester using a grubb ii catalyst , known as olefin metathesis . the free acid ( ivα - 3a ) is obtained by hydrogenation , deprotection , and , in the last step , hydrolysation of the methyl ester with lioh . allylmagnesiumchloride ( 1 . 7 m in thf , 48 . 39 mmol ) was added dropwise to a solution of ketone x - c2 - d ( 6 . 5 g , 16 . 1 mmol ) in thf ( 200 ml ) under n 2 atmosphere at 0 ° c . after stirring for 4 h at 0 - 5 ° c ., the solution was poured into sat aq nh 4 cl ( 200 ml ). the water layer was extracted with dcm ( 3 × 100 ml ). the combined organic layers were washed with sat nahco 3 ( 1 × 300 ml ), dried over na 2 so 4 and concentrated in vacuo yielding 7 . 8 g (& gt ; 100 %) as thick yellow oil . kh 30 % in oil ( 89 . 98 mmol ) was suspended in thf ( 50 ml ), under n2 atmosphere . 17 - allyl - 3 -( benzyloxy )- 2 - ethoxy - estra - 1 , 3 , 5 ( 10 )- trien - 17 - ol ( 7 . 7 g , 17 . 30 mmol ) and 18 - crown - 6 ( 88 . 25 mmol ) were dissolved in thf ( 200 ml ) and added dropwise in 40 min . the mixture was stirred for 3 h at rt . the mixture was carefully poured into ipa via canula . the mixture was poured into aq . sat . nh 4 cl ( 1 l ). the water layer was extracted with etoac ( 3 × 250 ml ). the combined organic layers were washed with brine ( 1 × 500 ml ), dried over na 2 so 4 and concentrated in vacuo . purification via filtration over silica ( eluens heptan to 40 % dcm in heptan ) provided 4 . 2 g ( 9 . 51 mmol , 55 %) of ( xxx -( c2 - d )- 2c ). substrate ( xxx -( c2 - d )- 2c ) ( 4 . 2 g , 9 . 51 mmol ) was dissolved in dcm ( 100 ml ) under n2 atmosphere . methylacrylate ( 23 . 76 mmol ) and grubbs ( ii ) catalyst ( 0 . 380 mmol ) were added . the mixture was heated to reflux and refluxed overnight . the mixture was concentrated in vacuo to afford 4 . 7 g of a dark brown solid . purification via column chromatography ( ca . 150 ml silica ) yielded 3 . 17 g ( 66 %) of a brown semi - solid . 4 -( 3 - benzyloxy - 2 - ethoxy - 17 - oxo - estra - 1 , 3 , 5 ( 10 )- trien - 15α - yl ) but - 2 - enoic acid methyl ester ( 3 . 17 g , 6 . 30 mmol ) was dissolved in thf ( 80 ml ) and meoh ( 80 ml ). pd / c 10 % ( 50 % in water , 0 . 3 g ) was added . the mixture was stirred at 1 atm h 2 ( balloon ) at rt for 48 h . the mixture was filtered over celite . the filter cake was rinsed with meoh ( 200 ml ) and the filtrate was concentrated in vacuo to provide 2 . 8 g ( 6 . 72 mmol , & gt ; 100 %) of a greenish solid . methylester ( viia -( c2 - d )- 3a ) ( 2 . 8 g , 6 . 72 mmol ) was dissolved in thf ( 80 ml ). lioh ( 39 . 86 mmol ) was dissolved in water ( 80 ml ) and added in one portion . the solution was stirred at rt overnight . the solution was concentrated in vacuo and water ( 350 ml ) was added . the water layer was washed with dcm ( 3 × 200 ml ) and acidified to ph = 1 with 2n hcl and extracted dcm ( 3 × 200 ml ). the combined organic layers were washed with brine ( 1 × 300 ml ), dried over na 2 so 4 and concentrated in vacuo to afford 1 . 84 g ( 68 %) of a white foam , lc - ms purity of 97 - 100 %. 1 h - nmr ( cdcl 3 , 300 mhz ): δ 0 . 95 ( s , 3h ), 1 . 25 ( m , 2h ), 1 . 4 ( t , 3h ), 1 . 5 ( m , 3h ), 1 . 60 - 2 . 1 ( m , 6h ), 2 . 1 - 2 . 45 ( m , 6h ), 2 . 80 ( m , 3h ), 4 . 1 ( q , 2h ), 6 . 65 ( s , 1h ), 6 . 80 ( s , 1h ) these two intermediates were synthesized accordingly from ketones x - c2 - b and x - c2 - e , respectively . 1 h - nmr ( cdcl 3 , 300 mhz ): δ 0 . 95 ( s , 3h ), 1 . 3 ( t , 2h ), 1 . 5 ( m , 3h ), 1 . 6 - 2 . 1 ( m , 6h ), 2 . 1 - 2 . 4 ( m , 6h ), 2 . 8 ( m , 3h ), 3 . 4 ( s , 3h ), 3 . 7 ( t , 2h ), 4 . 1 ( m , 2h ), 6 . 62 ( s , 1h ), 6 . 9 ( s , 1h ) 1 h - nmr ( shifts in ppm ): 0 . 96 - 1 . 04 ( s , 3h ), 1 . 20 - 2 . 48 ( m , 16h ), 2 . 70 - 2 . 94 ( m , 3h ), 3 . 80 - 3 . 92 ( s , 3h ), 6 . 60 - 6 . 68 ( s , 1h ), 6 . 76 - 6 . 80 ( s , 1h ). iiic . compounds of formula xxxi ( alcohol derivatives ): optionally 2 - substituted 15 - hydroxy - c 1 - c 6 - alkyl - estron the synthesis of the alcohol derivatives xxxiα - 1a ( pg = r 1 = h ), xxxiα - 1b ( pg = r 1 = ch 3 ), and xxxiα - 1c ( pg = r 1 = benzyl ) is depicted in the following scheme 9 : reduction of the aldehydes xiii - 0b or xiii - 0c using nabh 4 followed by ketal hydrolysis gave the corresponding alcohols xxxiα - 1b and xxxiα - 1c . the alcohol xxxiα - 1c was debenzylated to give xxxiα - 1a using pd / c and a 5 bar hydrogen atmosphere . alcohol building blocks xxxi - 3c and xxxi - 3a ( n = 3 ) and xxxi - 5c and xxxi - 5a ( n = 5 ) with pg = r 1 = benzyl or pg = r 1 = h ): the synthesis of the optionally 2 - substituted alcohol building blocks of formula xxxi - 3 and xxxi - 5 is depicted in the following scheme 10 . the 15 , 16 - unsaturated estrone derivative of formula xc ( preferably with r 14 = h , ethyl , n - propyl or methoxyethyl ) was subjected to a 1 , 4 addition using a freshly prepared gringard reagent ( allylmagnesiumchloride or pentenylmagnesiumchloride ) delivering compound xxxv . after protection of the ketone functionality in c17 as ketal , the alkenyl side chain was hydroborated and subsequently oxidized to provide compound xxxii . after deprotection of the c17 keto function by treatment with ptosoh , the benzyl function is optionally cleaved off to deliver the alcohol building blocks xxxi - 3 and xxxi - 5 , respectively . alcohol building blocks xxxi - 4b , xxxi - 5b , xxxi - 6b ( n = 4 , 5 , 6 ): 15β -( 4 - hydroxy - c 4 - c 6 - alkyl )- 3 - methoxy - estra - 1 , 3 , 5 ( 10 )- trien - 17 - one the general synthesis of the alcohol building block of formula xxxi - 4 / 5 / 6b is depicted in the following scheme 11 . magnesium ( 3 - 10 eq ) is added in a dry three - neck flask under n2 atmosphere and activated by iodine . the bromo compound ( 2 - 6 . 5 eq ) dissolved in dry thf is added dropwise to the magnesium . the reaction mixture is allowed to react for 1 - 2 h at rt or reflux . the solution is transferred to dry three - neck flask containing cui ( 0 . 06 - 0 . 7 eq ) and dmpu or hmpa ( 2 - 7 eq ) in dry thf cooled to − 40 ° c . the resulting mixture is stirred for 30 min at − 40 ° c . after which a mixture of 15 , 16 - unsaturated estron derivative of formula x ( 1 eq ) and tmscl ( 2 - 2 . 5 eq ) dissolved in thf is added dropwise . after complete addition the mixture is allowed to reach rt . then nh 4 cl - solution is added , the layers are separated and the aqueous phase is extracted with etoac ( 3 ×). the combined organic phases are dried over na 2 so 4 and the solvent is evaporated . the crude product is dissolved in methanol and k 2 co 3 ( 1 eq ) is added to hydrolyse the silyl ether . after complete hydrolysis water is added and most of the methanol is evaporated . the mixture is diluted with etoac , the layers are separated and the water layer is extracted with etoac . the combined organic layers are dried over na 2 so 4 and the solvent is evaporated . the resulting product of general formula xxx is then further worked - up to give the alcohol of general formula xxxi . the detailed synthesis of these compounds is already displayed within the section for the synthesis of acid building block of the formula iv - 3c above . the 3 - hydroxy - derivative can be obtained by debenzylation of the xxxi - 4c compound . the detailed synthesis of these compounds is performed according to the general procedure displayed in scheme 11 starting with the 15 , 16 unsaturated estron derivative xc as educt . the 3 - hydroxy - derivative can be obtained by hydrolysis of the xxxi - 6c compound . iiid . optionally 2 - substituted compounds of formula iv with a fluoro atom containing substitution of the c17 keto function the individual steps in the synthesis of the acid building block of the formula ivβ - 2a - d1f2 are depicted in the following scheme 12 . 3 -( 3 - benzyloxy - 17 - oxo - estra - 1 , 3 , 5 ( 10 )- trien - 15β - yl )- propanoic acid of formula ivβ - 2c is transformed in the corresponding methyl ester by an esterification reaction as depicted in general flow diagram ii using an edci coupling . fluorination of the obtained methyl ester with deoxofluor gave compound vim - 2c - d1f2 . subsequent debenzylation , followed by saponification with lioh afforded the desired building block ivβ - 2a - d1f2 . a mixture of compound ivb - 2c ( 38 mmol ), et 3 n ( 117 mmol ), meoh ( 44 mmol ), hobt ( 44 mmol ) and edci ( 49 mmol ) in dcm ( 650 ml ) was stirred overnight . the reaction mixture was washed with 1n hcl ( 2 × 250 ml ) and h 2 o ( 250 ml ). the organic layer was dried over na 2 so 4 and concentrated in vacuo to yield viiβ - 2c ( 38 mmol , 99 %) as orange oil . deoxofluor ( 50 % in toluene , 247 ml , 670 mmol ) was added to a solution of viiβ - 2c ( 27 . 2 g , 60 . 9 mmol ) in toluene ( 130 ml ). the mixture was stirred for 5 d , during which two times 10 drops of etoh were added . dcm ( 200 ml ) was added and the mixture was cooled on ice . saturated nahco 3 ( 300 ml ) was added . the layers were separated and the aqueous layer was extracted with dcm ( 3 × 300 ml ). the combined organic layers were washed with brine ( 500 ml ), dried over na 2 so 4 and concentrated in vacuo to give crude viiβ - 2c - d1f2 ( 26 . 5 g ). purification by column chromatography ( sio 2 , dcm - heptan 2 : 1 to dcm ) gave viiβ - 2c - d1f2 ( 2 . 94 g , 6 . 3 mmol , 10 %) as yellow oil . a mixture of viiβ - 2c - d1f2 ( 2 . 94 g , 6 . 3 mmol ), pd / c ( 10 %, 440 mg ), meoh ( 75 ml ) and etoac ( 32 ml ) was stirred for 2 d under 1 bar h 2 . after 1 day another portion of pd / c ( 484 mg ) was added . the mixture was filtered over celite and the filter cake was washed with meoh and etoac . the filtrate was concentrated in vacuo to give 2 . 1 g of crude viiβ - 2a - d1f2 . purification by column chromatography ( sio 2 , dcm ) gave viiβ - 2a - d1f2 ( 1 . 46 g , 3 . 9 mmol , 61 %) as yellow oil . a solution of lioh * h 2 o ( 934 mg , 22 mmol ) in water ( 60 ml ) was added to a solution of viiβ - 2a - d1f2 ( 1 . 46 g , 3 . 9 mmol ) in thf ( 60 ml ). the mixture was stirred overnight and concentrated in vacuo . water ( 250 ml ) was added and the mixture was washed with dcm ( 2 × 200 ml ) and the ph was adjusted to 1 . the aq . layer was extracted with dcm ( 3 × 200 ml ). the combined organic layers were dried over na 2 so 4 and concentrated in vacuo to yield ivβ - 2a - d1f2 ( 1 . 2 g , 3 . 3 mmol , 85 %) as yellow foam . 1 h - nmr - listing : 1 . 027 - 1 . 34 ( s , 3h ), 1 . 408 - 2 . 421 ( m , 15h ), 2 . 837 - 2 . 960 ( m , 2h ), 6 . 573 - 6 . 651 ( m , 2h ), 7 . 121 - 7 . 257 ( d , 1h ). the acid building block of formula ivα - 3a - d1f2 was synthesized starting from intermediate compound xc and using the reaction steps as depicted in scheme 8b : the allyl group was introduced into the 15 , 16 - unsaturated estrone derivative of formula xc by reaction with allylmagnesium chloride , followed by an oxy - cope rearrangement catalysed by kh and 18 - crown - 6 . subsequently , the resulting compound xxx - 2c was reacted with acrylic acid methyl ester using a grubb ii catalyst , known as olefin metathesis . then , deviating from scheme 8b , the 17 - keto function of the resulting 4 -( 3 - benzyloxy - 17 - oxo - estra - 1 , 3 , 5 ( 10 )- trien - 15α - yl ) but - 2 - enoic acid methyl ester was converted to a bisfluoro group using deoxofluor as described for viiβ - 2c - d1f2 . subsequently , the well known hydrogenation step was performed to obtain the butanoic acid ester side chain , and finally the ester was hydrolysed with lioh to give the target compound . 1 h - nmr - listing : 0 . 94 ( s , 3h ), 1 . 10 - 2 . 06 ( m , 4h ), 2 . 18 - 2 . 55 ( m , 14h ), 2 . 74 - 2 . 92 ( m , 2h ), 6 . 52 ( d , 1h ), 6 . 64 ( dd , 1h ), 7 . 15 ( d , 1h ) synthesis of xxxiiβ - 4c - d -( i )-( a )= cf 2 was achieved in a 3 - step reaction starting from intermediate compound xxxiiβ - 4c using the horner reaction as described for general synthesis step d -( i )-( a ). subsequently , the fluorinated alcohol derivative xxxi - 4c - d -( i )-( a )= cf 2 was converted into the free acid by a jones oxidation , followed by a debenzylation step using bbr 3 to deliver the desired intermediate vβ - 3a - d -( i )-( a )= cf 2 . to a solution of intermediate xxxiβ - 4c ( 108 mg ; 0 . 25 mmol ) and imidazole ( 41 . 0 mg ; 0 . 60 mmol ) in dmf ( 1 ml ) tert - butyldimethylsilylchloride ( 0 . 30 ml ; 0 . 30 mmol ; 1m in thf ) was added dropwise . after stirring for 16 h at rt , the reaction mixture was poured into h 2 o and extracted with dcm . the organic phases were dried over mgso 4 . after removal of the solvent , the oily residue was purified by column chromatography ( sio 2 , dcm ) to yield 3 - benzyloxy - 15 -[ 4 -( tert - butyldimethylsilanyloxy )- butyl ]- estra - 1 , 3 , 5 ( 10 )- trien - 17 - one ( 126 mg , 92 %) as colourless oil . lithium diisopropylamide ( 0 . 60 ml ; 1 . 08 mmol ; 1 . 8 m in thf / heptane / ethylbenzene ) is added dropwise to a solution of difluoromethylphosphonic acid diethylester ( 204 mg ; 1 . 08 mmol ) in thf ( 3 ml ) at − 78 ° c . and stirred for 30 min . subsequently , a solution of the ketone obtained in the previous reaction step ( 148 mg ; 0 . 27 mmol ) in thf ( 4 ml ) is added and the mixture is stirred for 30 min and further until the mixture was warmed to rt . the mixture is heated for 5 h under reflux and allowed to cool to rt . after addition of water , the solution is extracted with dcm . the combined organic phases are dried over mgso 4 . after removal of the solvent , the residue is purified by column chromatography ( sio 2 , dcm / hexane 1 : 2 ) to yield [ 4 -( 3 - benzyloxy - 17 - difluoromethylene - estra - 1 , 3 , 5 ( 10 )- trien - 15 - yl )- butoxy ]- tert - butyldimethylsilane ( 107 mg , 68 %) as colorless oil . a solution of the obtained tbdms - ether ( 97 . 0 mg ; 167 μmol ) in tbaf ( 1 ml ; 1 mmol ; 1 m in thf ) was stirred for 4 h at rt . the reaction mixture is poured into h 2 o and extracted with dcm . the combined organic phases are dried over mgso 4 . after removal of the solvent , the residue is purified by column chromatography ( sio 2 , dcm ) to yield xxxiβ - 4c - d -( i )-( a )= cf 2 ( 76 . 0 mg , 98 %) as yellow solid . after dissolving the alcohol xxxiiβ - 4c - d -( i )-( a )= cf 2 in 10 ml acetone , jones reagent ( 1 g cro 3 , 7 ml h 2 o , 3 ml 100 % h 2 so 4 ) was added at 0 ° c . up to the point the solution remained reddish . after stirring for 10 min , any excess of jones reagent was destroyed by adding isopropanol . after filtration over silicagel , the filtrate was evaporated to dryness . the residue was diluted with dcm and washed several times with water , dried over na 2 so 4 and again evaporated to dryness . the crude product was used further without any purification . the crude benzylated estrone acid derivative ivβ - 3c - d -( i )-( a )= cf 2 was dissolved in 10 ml dry dcm and few drops bbr 3 were added at ambient temperature . the reaction mixture was stirred for 1 h and directly used in further reaction steps without any work - up . synthesis of xxxiβ - 4c - d -( i )-( d )- cf 3 was achieved in a 4 - step reaction starting from intermediate compound xxxiiβ - 4c as described for general synthesis step d -( i )-( d ). subsequently , the fluorinated alcohol derivative xxxi - 4c - d -( i )-( d )= cf 3 was converted into the free acid by a jones oxidation , followed by a debenzylation step using bbr 3 to deliver the desired intermediate vβ - 3a - d -( i )-( d )- cf 3 . ( trifluoromethyl ) trimethylsilan ( 7 . 60 ml ; 15 . 0 mmol ; 2m in thf ) was added to a solution of intermediate xxxiβ - 4c ( 1 . 08 g ; 2 . 50 mmol ) in thf pre - cooled to 0 ° c . after addition of tbaf ( 60 . 0 mg ; 0 . 63 mmol ), the reaction mixture was stirred for 0 . 5 h at 0 ° c . and for 16 h at rt . water was added and the resulting the solution was extracted with ether . the combined organic phases were dried over mgso 4 . after removal of the solvent , the residue was dissolved in tbaf solution ( 10 . 0 ml ; 10 . 0 mmol ; 1 m in thf ) and the resulting mixture was stirred for 4 h at rt . water was added and the resulting the solution was extracted with ether . the combined organic phases were dried over mgso 4 . the remaining oil was purified by column chromatography ( sio 2 ; ether / dcm 1 : 1 ) yielding the title compound ( 942 mg , 75 %) as colourless oil . pivaloylchloride ( 0 . 50 ml ; 4 . 10 mmol ) was added dropwise to a solution of 3 - benzyloxy - 15 -( 4 - hydroxybutyl )- 17 - trifluoromethyl - estra - 1 , 3 , 5 ( 10 )- trien - 17 - ol ( 1 . 65 g ; 3 . 28 mmol ) in pyridine ( 15 ml ) at 0 ° c . after stirring for 2 h , the reaction mixture was poured into ice water and stirred for another h . after extraction with dcm , the combined organic phases were dried over mgso 4 . after evaporation of the solvent , the residue was purified by column chromatography ( sio 2 , dcm ) yielding the title compound ( 1 . 85 g , 96 %) as colourless oil . phosphorylchloride ( 0 . 25 ml ; 200 μmol ) was added to a solution of 2 , 2 - dimethylpropionic acid 4 -( 3 - benzyloxy - 17 - hydroxy - 17 - trifluoromethyl - estra - 1 , 3 , 5 ( 10 )- trien - 15 - yl )- butylester ( 80 . 0 mg ; 136 μmol ) in pyridine ( 2 . 50 ml ) and the resulting mixture is heated under reflux for 24 h . then , the mixture was allowed to cool to rt , diluted with ice water and extracted with ether . the combined organic phases were dried over mgso 4 and the solvent was evaporated . the residue was purified by column chromatography ( sio 2 , dcm ) yielding the title compound ( 60 . 0 mg , 78 %) as colourless oil . dibah ( 1 . 00 ml ; 1 . 00 mmol ; 1m in thf ) was added dorpwise to a solution of the pivaloate ( 60 . 0 mg ; 106 μmol ) in dcm ( 5 ml ) at − 78 ° c . after stirring for 6 h , 1 n hcl ( 20 ml ) was added and the reaction mixture was extracted with dcm . the combined organic phases were dried over mgso 4 and the solvent was evaporated . the residue was purified by column chromatography ( sio 2 , dcm ) yielding xxxiβ - 4c - d -( i )- d - cf 3 ( 46 . 0 mg , 90 ) as colourless oil . after dissolving 180 mg of the alcohol xxxiβ - 4c - d -( i )-( d )- cf 3 in 10 ml acetone , jones reagent ( 1 g cro 3 , 7 ml h 2 o , 3 ml 100 % h 2 so 4 ) was added at 0 ° c . up to the point the solution remained reddish . after stirring for 10 min , any excess of jones reagent was destroyed by adding isopropanol . after filtration over silicagel , the filtrate was evaporated to dryness . the residue was diluted with dcm and washed several times with water , dried over na 2 so 4 and again evaporated to dryness . the crude product was used further without any purification . the crude benzylated estrone acid derivative ivβ - 3c - d -( i )-( d )- cf 3 was dissolved in 10 ml dry dcm and few drops bbr3 were added at ambient temperature . the reaction mixture was stirred for 1 h and directly used in further reaction steps without any work - up . iiie . optionally 2 - substituted compounds of formula xv ( protected amine building block ) ( n = 1 − 6 ) the individual steps in the synthesis of amine building block of the formula xv - 1 are depicted in the following scheme 13 . dissolving aldehydes xiii - 0b ( pg = ch 3 ) or xiii - 0c ( pg = benzyl ) in benzylamine and reduction of the residual imine in thf gave benzylamine xiv - 1b ( pg = ch 3 ) and xiv - 1c ( pg = benzyl ), which were debenzylated to xv - 1b ( pg = ch 3 ) and xv - 1a ( pg = h ), using pd / c and h 2 at 5 bar , and dissolved in dilute hcl to give the respective ammonium chlorides xxix - 1b ( pg = ch 3 ) and xxix - 1a ( pg = h ). standard purification methods failed due to what seems to be instability of these ammonium salts . for these amines it was known that these should be treated as hcl salts since the free amine is not stable ( eneamines ), but even the salts seem to be at least heat - sensitive . the crude reaction mixture has a purity of ˜ 90 % ( hplc - ms ). the individual steps in the synthesis of amine building block of the formula xvα - 3 are depicted in the following scheme 16 . the protected aldehyde derivative of formula ( xiiiα - 0 ) is converted into the corresponding aminopropenyl by a wittig reaction ( see also scheme 4 ). the aminopropenyl ( xxxvii - 3 ) is subsequently reduced to the 15 - aminopropyl derivative of formula xvα - 3 . the protecting ketal group is converted into the 17 - oxo group via acid hydrolysis . the same kind of procedure can be applied using different wittig reagents of the general formula hal ( ph ) 3 p —( ch 2 ) n = 3 - 5 — r * in order to obtain amine building blocks with longer side chains ( i . e . n = 4 , 5 , or 6 ), wherein r * for example represents — n ═ p ( ph ) 3 , — n3 , or — nh — co — o — ch 3 . furthermore , the amine building block xvα - 4b was synthesized corresponding to scheme 16 using halph 3 p — ch 2 — ch 2 — ch 2 — n3 as wittig reagent . ( lc - ms ( es +): rt 4 . 57 min , m / z ( rel . intens ) 386 [( m + h ) + , 100 %]) the individual steps in the synthesis of amine building block of the formula xvβ - 4 with β configuration at the c15 atom of the steroidal core are depicted in the following scheme 17 . in a first step , the 17 oxo function of the butanol derivative of the formula xxxiβ - 4 ( for synthesis of xxxiβ - 4 see above ) is converted into the ketal group ( compound of formula xxxiiiβ - 4 ). then , the alcohol function is selectively reduced to the aldehyde giving compound of the formula xiiiβ - 3 . the protected aldehyde derivative of the formula xiiiβ - 3 is converted into a secondary amine by addition of benzylamine and subsequent reduction ( reductive amination ). further reduction of the secondary amine delivers the desired , still protected amine building block of the formula xvβ - 4 . the protecting ketal group can be converted into the 17 - oxo group via acid hydrolysis . the same kind of procedure can be applied for n = 5 or 6 and for other substituents within the r 1 position . alternatively , the synthesis of the amine building blocks of general formula xxix can also be performed starting with an activated alcohol function and a subsequence substitution reaction , and does not need any protection of the estron - c17 keto function according to the following general scheme 18 . step c — synthesis of intermediates of general formula c -( i ) with r 14 ═ h the synthesis of the intermediates falling under the general formula c -( i ), wherein r 14 represents h , is fully disclosed in international patent application wo 2005 / 047303 , and was performed according to the reaction schemes depicted in general flow diagrams i to xv herewithin . the following table gives an overview of exemplary intermediates prepared . the number given in the first column corresponds to the compound number as disclosed in international patent application wo 2005 / 047303 . in order to more fully illustrate the nature of the invention and the manner of practicing the same , the following examples are presented , but they should not be taken as limiting . compounds carrying an additional substituent in c2 position of the steroidal core example 1 was obtained from intermediate compound ( ivb -( c2 - c )- 3a ) by amid coupling according to flow diagram ib : compound ( ivb -( c2 - c )- 3a ) ( 100 mg , 0 . 26 mmol ) was dissolved in a mixture of etoac ( 35 ml ), benzyl amine ( 0 . 26 mmol ), tea ( 0 . 52 mmol ) and propylphosphonic acid anhydride in etoac ( t3p ) ( 50 w / w %, 0 . 52 mmol ) under n2 atmosphere at 0 ° c . after stirring for 2 h at ambient temperature , the reaction mixture was poured into water ( 50 ml ) and diluted with etoac ( 25 ml ). the aqueous layer was neutralized to ph 8 with aq . nahco 3 , separated and extracted with etoac ( 2 × 25 ml ). the combined organic layers were washed with water ( 25 ml ) and dried over na 2 so 4 . the organic layer was concentrated in vacuo yielding compound no . 1 ( 56 mg , 0 . 12 mmol , 46 %) after column chromatography ( sio 2 , dcm / meoh = 100 / 0 to 95 / 5 ). 1 h - nmr ( 300 mhz , cdcl 3 ): δ 0 . 99 ( s , 3h , steroid - chs ), 1 . 22 ( t , j = 7 . 4 hz , 3h , ethyl ), 1 . 3 - 1 . 8 ( m , 11h , steroid ), 2 . 2 - 2 . 42 ( m , 8h , steroid ), 2 . 60 ( q , j = 7 . 4 hz , 2h , ethyl ), 2 . 8 - 2 . 88 ( m , 2h , steroid ), 4 . 44 ( d , j = 5 . 8 hz , 2h , ch 2 - ph ), 4 . 64 ( bs , 1h , oh ), 5 . 67 ( bs , 1h , nh ), 6 . 53 ( s , 1h , steroid - ar — h ), 7 . 03 ( s , 1h , steroid - ar — h ), 7 . 23 - 7 . 34 ( m , 5h , bn ) ppm . example 2 was obtained from intermediate compound ( ivb -( c2 - g )- 3a ) by amid coupling according to flow diagram ib : compound ( ivb -( c2 - g )- 3a ) ( 500 mg , 1 . 25 mmol ) was dissolved in a mixture of etoac ( 25 ml ), benzyl amine ( 2 . 50 mmol ), tea ( 3 . 75 mmol ) and propylphosphonic acid anhydride in etoac ( t3p ) ( 50 w / w %, 1 . 50 mmol ) under n2 atmosphere . after the reaction mixture had been stirred at ambient temperature for 1 h , it was stirred at 45 ° c . for 16 h . the reaction mixture was allowed to reach ambient temperature , poured into water ( 50 ml ) and diluted with etoac ( 25 ml ). the aqueous layer was separated and extracted with etoac ( 2 × 25 ml ). the combined organic layers were , washed with aq . 1m hcl ( 25 ml ), washed with brine ( 25 ml ) and dried over na 2 so 4 . the organic layer was concentrated in vacuo yielding compound no . 2 ( 370 mg , 0 . 756 mmol , 60 %) after column chromatography ( sio 2 , dcm / meoh = 97 . 5 / 2 . 5 ). 1 h - nmr ( 300 mhz , cdcl 3 ): δ 0 . 96 ( t , 3h ), 0 . 98 ( s , 3h ), 1 . 3 - 1 . 6 ( m , 4h ), 1 . 6 - 1 . 8 ( m , 7h ), 1 . 90 ( d , 1h ), 2 . 00 ( d , 1h , broad ), 2 . 2 - 2 . 5 ( m , 7h ), 2 . 58 ( t , 2h ), 2 . 7 - 2 . 9 ( m , 2h ), 4 . 23 ( d , 2h ), 4 . 97 ( s , 1h , broad ), 5 . 72 ( t , 1h , broad ), 6 . 50 ( s , 1h ), 7 . 00 ( s , 1h ), 7 . 2 - 7 . 3 ( m , 5h ) ppm . example 3 was obtained from intermediate compound ( ivb -( c2 - f )- 3a ) by amid coupling according to flow diagram ib using the procedure as described for example 1 . 1 h - nmr ( 300 mhz , cdcl 3 ): δ 0 . 99 ( s , 3h , steroid - chs ), 1 . 2 - 2 . 0 ( m , 11h , steroid ), 2 . 2 - 2 . 42 ( m , 7h , steroid ), 2 . 84 ( m , 4h , steroid ), 3 . 41 ( s , 3h , ome ), 3 . 67 ( m , 2h , och 2 ), 4 . 44 ( d , j = 5 . 5 hz , 2h , ch 2 - ph ), 5 . 71 ( bm , 1h , oh or nh ), 6 . 67 ( s , 1h , steroid - ar — h ), 6 . 94 ( s , 1h , steroid - ar — h ), 7 . 25 - 7 . 34 ( m , 5h , bn ), 7 . 96 ( s , 1h , oh or nh ) ppm . example 4 was obtained starting from intermediate compound ( ivb -( c2 - b )- 3a ) by amide coupling according to flow diagram ib . a solution of the 0 . 07 mmol ( ivb -( c2 - b )- 3a ), 0 . 077 mmol hobt , 0 . 231 mmol nmm and 0 . 154 mmol edci in 5 ml dcm were added to 0 . 07 mmol of benzyl amine . the reaction mixture was stirred for 24 h at ambient temperature . the solvent was removed in vacuo at 40 ° c . than 4 ml etoac and 4 ml water were added . after vigorous stirring for 2 min , the organic phase was separated , dried with na 2 so 4 and evaporated in vacuo at 40 ° c . the crude product was treated with 2 ml thf , 10 mg lioh and 0 . 5 ml water . after evaporation and further extraction ( etoac and 0 . 1 m khso 4 ), 50 mg trisaminoeethlyamine polymer bound were added . after filtration and evaporating to dryness the compound no . 4 was obtained ( hplc rt = 3 . 79 ). example 5 was prepared starting from intermediate compound ( ivb -( c2 - c )- 3a ), which was converted into the desired amid by amid coupling with morpholine according to flow diagram ib and as described above for example 2 ( compound ( ivb -( c2 - c )- 3a ) ( 110 mg , 0 . 28 mmol ), etoac ( 30 ml ), morpholine ( 0 . 28 mmol ), tea ( 0 . 57 mmol ), t3p ( 0 . 34 mmol ). compound no . 5 ( 68 mg , 0 . 15 mmol , 54 %) obtained after column chromatography ( sio 2 , dcm / meoh = 100 / 0 to 95 / 5 ). 1 h - nmr ( 300 mhz , cdcl 3 ): δ 1 . 01 ( s , 3h , steroid - chs ), 1 . 22 ( t , j = 7 . 5 hz , 3h , ethyl ), 1 . 3 - 2 . 0 ( m , 11h , steroid ), 2 . 2 - 2 . 42 ( m , 7h , steroid / morpholine ), 2 . 60 ( q , j = 7 . 7 hz , 2h , ethyl ), 2 . 82 - 2 . 90 ( m , 2h , steroid ), 3 . 44 - 3 . 50 ( m , 2h ), 3 . 6 - 3 . 70 ( m , 6h , morpholine ), 4 . 61 ( s , 1h , oh ), 6 . 53 ( s , 1h , steroid - ar — h ), 7 . 04 ( s , 1h , steroid - ar — h ) ppm . example 6 was prepared as described above for example 2 starting from intermediate compound ( ivb -( c2 - g )- 3a ), which was converted into the desired amid by amid coupling with morpholine according to flow diagram ib ( compound ( ivb -( c2 - g )- 3a ) ( 500 mg , 1 . 25 mmol ), etoac ( 25 ml ), morpholine ( 2 . 5 mmol ), tea ( 3 . 75 mmol ), t3p ( 1 . 5 mmol ). compound no . 6 ( 225 mg , 0 . 481 mmol , 38 %) was obtained after column chromatography ( sio 2 , dcm / meoh = 97 . 5 / 2 . 5 ). 1 h - nmr ( 300 mhz , cdcl 3 ): δ 0 . 98 ( t , 3h ), 1 . 01 ( s , 3h ), 1 . 3 - 1 . 8 ( m , 11h ), 1 . 90 ( d , 1h ), 2 . 00 ( d , 1h , broad ), 2 . 2 - 2 . 5 ( m , 7h ), 2 . 35 ( t , 2h ), 2 . 8 - 3 . 0 ( m , 2h ), 3 . 45 ( t , 2h ), 3 . 6 - 3 . 70 ( m , 6h ), 5 . 30 ( s , 1h ), 6 . 54 ( s , 1h ), 7 . 00 ( s , 1h ) ppm . example 7 was prepared from intermediate compound ( ivb -( c2 - f )- 3a ) by amid coupling according to flow diagram ib : compound ( ivb -( c2 - f )- 3a ) ( 85 mg , 0 . 221 mmol ) was dissolved in a mixture of etoac ( 40 ml ), morpholine ( 0 . 24 mmol ), tea ( 0 . 44 mmol ) and t3p in in etoac ( 50 w / w %, 0 . 26 mmol ) under n 2 atmosphere at 0 ° c . after stirring at ambient temperature for 16 h , the reaction mixture was poured into water ( 100 ml ) and diluted with etoac ( 50 ml ). the aqueous layer was neutralized to ph 8 with aq . nahco 3 , separated and extracted with etoac ( 3 × 50 ml ). the combined organic layers were washed with water ( 50 ml ) and dried over na 2 so 4 . the organic layer was concentrated in vacuo yielding compound no . 7 ( 43 mg , 0 . 088 mmol , 40 %) after column chromatography ( sio 2 , dcm / meoh = 99 / 1 to 94 / 6 ). 1 h - nmr ( 300 mhz , cdcl 3 ): δ 1 . 00 ( s , 3h , steroid - chs ), 1 . 2 - 2 . 05 ( m , 9h , steroid ), 2 . 2 - 2 . 44 ( m , 8h , steroid + morpholine ), 2 . 81 ( m , 41 - 1 , steroid ), 3 . 40 ( s , 3h , ome ), 3 . 45 ( t , j = 4 . 7 hz , 2h , och 2 ), 3 . 57 - 3 . 72 ( m , 81 - 1 , morpholine ), 6 . 67 ( s , 1h , steroid - ar — h ), 6 . 94 ( s , 1h , steroid - ar — h ), 7 . 97 ( s , 1h , oh or nh ) ppm . example 8 was prepared starting from intermediate compound ( ivb -( c2 - b )- 3a ), which was converted into the desired amid by amid coupling with morpholine according to flow diagram ib and as described above for example 4 using 0 . 07 mmol of ( ivb -( c2 - b )- 3a ) and 0 . 07 mmol morpholine , yielding compound no . 4 . 13 c nmr ( 126 mhz , chloroform - d ): 0 ppm 17 . 7 ( q , 1 c ) 25 . 1 ( t , 1 c ) 25 . 8 ( t , 1 c ) 26 . 8 ( t , 1 c ) 28 . 7 ( t , 1 c ) 30 . 9 ( t , 1 c ) 32 . 8 ( t , 1 c ) 33 . 9 ( t , 1 c ) 34 . 4 ( d , 1 c ) 36 . 0 ( d , 1 c ) 41 . 9 ( t , 1 c ) 42 . 7 ( t , 1 c ) 44 . 8 ( d , 1 c ) 45 . 9 ( t , 1 c ) 47 . 1 ( s , 1 c ) 52 . 8 ( d , 1 c ) 56 . 1 ( d , 1 c ) 66 . 6 ( t , 1 c ) 66 . 9 ( t , 1 c ) 107 . 8 ( d , 1 c ) 114 . 6 ( d , 1 c ) 129 . 2 ( s , 1 c ) 131 . 4 ( s , 1 c ) 143 . 7 ( s , 1 c ) 144 . 7 ( s , 1 c ) 171 . 2 ( s , 1 c ) 220 . 9 ( s , 1 c ) 1 h nmr ( 501 mhz , chloroform - d ): □ ppm 1 . 02 ( s , 3h ) 1 . 32 - 1 . 85 ( m , 7h ) 1 . 87 - 1 . 95 ( m , 1h ) 1 . 98 - 2 . 06 ( m , 1h ) 2 . 25 - 2 . 51 ( m , 5h ) 2 . 75 - 2 . 92 ( m , 2h ) 3 . 42 - 3 . 51 ( m , 2h ) 3 . 57 - 3 . 72 ( m , 6h ) 3 . 86 ( s , 3h ) 5 . 52 ( s , 1h ) 6 . 67 ( s , 1h ) 6 . 78 ( s , 1h ) example 9 was prepared as described above for example 2 starting from intermediate compound ( ivb -( c2 - c )- 3a ), which was converted into the desired amid by amid coupling with 2 - amino - 5 - methylthiazole according to flow diagram ib : ( compound ( ivb -( c2 - c )- 3a ) ( 730 mg , 1 . 89 mmol ), etoac ( 150 ml ), 2 - amino - 5 - methylthiazole ( 216 mg , 1 . 89 mmol ), tea ( 3 . 79 mmol ), t3p ( 2 . 27 mmol ). compound no . 9 ( 280 mg , 0 . 58 mmol , 31 %) was obtained after recrystallization from dcm . 1 h - nmr ( 300 mhz , d - dmso ): δ 0 . 90 ( s , 3h , steroid - chs ), 1 . 05 ( t , j = 7 . 4 hz , 3h , ethyl ), 1 . 2 - 1 . 4 ( m , 4h , steroid ), 1 . 44 - 1 . 74 ( m , 6h , steroid ), 1 . 82 - 1 . 93 ( m , 1h , steroid ), 2 . 1 - 2 . 7 ( m , 14h , steroid ), 6 . 43 ( s , 1h , steroid - ar — h ), 6 . 89 ( s , 1h , steroid - ar — h ), 7 . 08 ( d , j = 1 . 0 hz , 1h , thiazol - h ), 8 . 82 ( bs , 1h , nh or oh ), 11 . 82 ( bs , 1h , nh or oh ) ppm . example 10 was prepared starting from intermediate compound ( ivb -( c2 - b )- 3a ), which was converted into the desired amid by amide coupling according to flow diagram ib and as described above for example 4 using 0 . 07 mmol of ( ivb -( c2 - b )- 3a ) and 0 . 07 mmol 2 - amino - 5 - methylthiazole , yielding compound no . 10 ( 33 . 7 mg , ms 484 , rt 3 . 86 ). a variety of compounds numbered 11 to 28 and falling under the scope of general formula ( i ), in which x - a - y represents — co — nr 4 , r 1 represents h , r 14 represents — o — ch 3 , c15 is substituted in the β position and n is 3 , were prepared by parallel chemistry using a reaction according to general flow diagram ib and as described in example 4 . a variety of compounds numbered 29 to 89 and falling under the scope of general formula ( i ), in which x - a - y represents — co — nr 4 , r 1 represents h , and n is 3 , were prepared by parallel chemistry using a reaction according to general flow diagram ib . synthesis protocol : 0 . 07 mmol of the individual amine was weight out into a reaction flask . a solution of 0 . 07 mmol of the respective steroidal building block ( ivb -( c2 - g )- 3a ), ( iva -( c2 - d )- 3a ), and ( iva -( c2 - b )- 3a ) in 5 ml dcm were added . then , 0 . 077 mmol polymer bound hobt , 0 . 231 mmol polymer bound nmm and 0 . 154 mmol polymer bound edci were added . the reaction mixture was stirred for 24 h at ambient temperature . afterwards , the reaction mixture was filtrated , washed twice with 1 ml dcm and evaporated to dryness . the crude product was treated with 2 ml thf , 10 mg lioh and 0 . 5 ml water . after evaporation and further extraction ( etoac and 0 . 1 m khso 4 ) approx . 50 mg trisaminoeethlyamine polymer bound were added yielding the desired product after filtration and evaporating to dryness . example 90 was prepared from the intermediate no . 1 ( 3 - hydroxy - 15β -( 4 - morpholin - 4 - yl - 4 - oxo - butyl )- estra - 1 , 3 , 5 ( 10 )- trien - 17 - one ) according to the reaction depicted in section d -( i )-( b ): to a solution of the estron derivative ( 106 mg ; 250 μmol ) in deoxofluor ( 0 . 96 ml ; 5 . 00 mmol ) a drop of ethanol was added ; the solution was stirred at rt for 5 d . subsequently , dcm ( 10 ml ) was added and the product was hydrolyzed by addition of saturated nahco 3 solution under ice cooling . for work up , the organic phase was separated off , and the remaining water phase was extracted with dcm ( 2 × 10 ml ). the combined dcm fractions were dried over mgso 4 . after evaporation and subsequent purification using column chromatography ( dcm / ether 1 : 1 ), 81 mg of a colourless solid were obtained ( mw 489 . 64 ). 13 c nmr ( 126 mhz , chloroform - d ): □ ppm 17 . 0 ( q , j ( c , f ) , 1 c ) 24 . 5 ( t , 1 c ) 25 . 0 ( t , 1 c ) 27 . 4 ( t , 1 c ) 29 . 3 ( t , j ( c , f ) , 1 c ) 30 . 7 ( t , 1 c ) 31 . 7 ( t , 1 c ) 32 . 9 ( d , j ( c , f ) , 1 c ) 34 . 4 ( t , 1 c ) 35 . 9 ( d , 1 c ) 39 . 7 - 40 . 5 ( t , j ( c , f ) , 1 c ) 42 . 0 ( t , 1 c ) 44 . 1 ( d , 1 c ) 45 . 2 ( t , 1 c ) 46 . 1 ( s , j ( c , f ) , 1 c ) 50 . 3 ( d , j ( c , f ) , 1 c ) 66 . 7 ( t , 1 c ) 67 . 0 ( t , 1 c ) 112 . 7 ( d , 1 c ) 115 . 3 ( d , 1 c ) 126 . 0 ( d , 1 c ) 132 . 3 ( s , 1 c ) 138 . 0 ( s , 1 c ) 153 . 9 ( s , 1 c ) 171 . 5 ( s , 1 c ) 1 h nmr ( 501 mhz , chloroform - d ): □ ppm 0 . 99 ( s , 3h ) 1 . 23 - 2 . 5 ( m , 18h ) 2 . 82 ( m , 2h ) 3 . 43 - 3 . 52 ( m , 2h ) 3 . 59 - 3 . 73 ( m , 6h ) 5 . 66 ( br . s ., 1h ) 6 . 57 ( d , j = 2 . 55 hz , 1h ) 6 . 63 ( dd , j = 8 . 5 , 2 . 5 hz , 1h ) 7 . 10 ( d , j = 8 . 5 hz , 1 h ) example 91 was prepared from the intermediate no . 40 named 3 - hydroxy - 15α -( 4 - morpholin - 4 - yl - 4 - oxo - butyl )- estra - 1 , 3 , 5 ( 10 )- trien - 17 - one as described for example 90 . 13 c nmr ( 126 mhz , chloroform - d ): □ ppm 14 . 9 ( q , j ( c , f ) = 3 . 89 hz , 1 c ) 23 . 8 ( t , 1 c ) 26 . 2 ( t , 1 c ) 27 . 6 ( t , 1 c ) 28 . 6 ( t , j ( c , f ) = 4 . 67 hz , 1 c ) 29 . 7 ( t , 1 c ) 33 . 2 ( t , 1 c ) 35 . 9 ( d , j ( c , f ) = 6 . 75 hz , 1 c ) 36 . 8 ( t , 1 c ) 39 . 4 ( d , 1 c ) 39 . 5 - 40 . 0 ( t , j ( c , f ) , 1 c ) 42 . 1 ( t , 1 c ) 43 . 8 ( d , 1 c ) 46 . 1 ( t , 1 c ) 46 . 8 ( s , j ( c , f ) = 19 . 98 hz , 1 c ) 53 . 1 ( d , j ( c , f ) = 4 . 15 hz , 1 c ) 66 . 6 ( t , 1 c ) 66 . 9 ( t , 1 c ) 113 . 1 ( d , 1 c ) 115 . 1 ( d , 1 c ) 126 . 8 ( d , 1 c ) 128 . 9 - 133 . 4 ( s , j ( c , f ) , 1 c ) 131 . 5 ( s , 1 c ) 137 . 5 ( s , 1 c ) 154 . 0 ( s , 1 c ) 171 . 8 ( s , 1 c ) 1 h nmr ( 501 mhz , chloroform - d ): □ ppm 0 . 92 ( s , 3h ) 1 . 19 - 1 . 36 ( m , 3h ) 1 . 38 - 1 . 50 ( m , 1h ) 1 . 51 - 1 . 83 ( m , 7h ) 1 . 86 - 1 . 99 ( m , 2h ) 2 . 13 - 2 . 23 ( m , 1h ) 2 . 28 - 2 . 53 ( m , 4h ) 2 . 70 - 2 . 83 ( m , 2h ) 3 . 43 - 3 . 52 ( m , 2h ) 3 . 59 - 3 . 73 ( m , 6h ) 6 . 06 ( br . s ., 1h ) 6 . 55 ( d , j = 2 . 75 hz , 1h ) 6 . 64 ( dd , j = 8 . 54 , 2 . 75 hz , 1h ) 7 . 12 ( d , j = 8 . 24 hz , 1h ) example 92 was isolated as by - product during the synthesis of example no . 91 . 1 h nmr ( 501 mhz , chloroform - d ): □ ppm 0 . 99 ( s , 3h ) 1 . 23 - 1 . 85 ( m , 9h ) 1 . 93 - 2 . 00 ( m , 1h ) 2 . 12 - 2 . 20 ( m , 1h ) 2 . 25 - 2 . 48 ( m , 5h ) 2 . 68 - 2 . 84 ( m , 2h ) 3 . 44 - 3 . 53 ( m , 2h ) 3 . 63 - 3 . 70 ( m , 6h ) 4 . 83 - 4 . 87 ( m , 1h ) 6 . 55 ( d , j = 2 . 4 hz , 1h ) 6 . 63 ( dd , j = 8 . 5 , 2 . 7 hz , 1h ) 7 . 08 ( d , j = 8 . 5 hz , 1h ) 13 c nmr ( 126 mhz , chloroform - d ): □ ppm 17 . 1 ( q , j c , f = 4 . 2 hz , 1 c ) 23 . 3 ( t , 1 c ) 26 . 4 ( t , 1 c ) 27 . 8 ( t , 1 c ) 29 . 7 ( t , 1 c ) 32 . 9 ( t , 1 c ) 33 . 3 ( t , 1 c ) 34 . 2 ( t , 1 c ) 37 . 8 ( d , 1 c ) 40 . 4 ( d , j c , f = 5 . 7 hz , 1 c ) 42 . 1 ( t , 1 c ) 44 . 3 ( s , j c , f = 20 . 5 hz , 1 c ) 44 . 4 ( d , 1 c ) 46 . 1 ( t , 1 c ) 57 . 9 ( d , j c , f = 5 . 2 hz , 1 c ) 66 . 6 ( t , 1 c ) 66 . 9 ( t , 1 c ) 104 . 2 ( d , j c , f = 8 . 0 hz , 1 c ) 112 . 9 ( d , 1 c ) 115 . 1 ( d , 1 c ) 126 . 3 ( d , 1 c ) 131 . 8 ( s , 1 c ) 137 . 4 ( s , 1 c ) 154 . 1 ( s , 1 c ) 170 . 7 ( s , j c , f = 289 . 9 hz , 1 c ) 172 . 0 ( s , 1 c ) example 93 was prepared from the intermediate ivβ - 2a - d1f2 using amide coupling with 2 - amino - 5 - methylthiazole according to general flow diagram ib and as described for synthesis of example 4 . 1 h nmr ( 501 mhz , dmso - d 6 ): □ ppm 1 . 01 ( s , 3h ) 1 . 28 - 1 . 37 ( m , 2 h ) 1 . 47 - 1 . 74 ( m , 5h ) 1 . 86 - 1 . 96 ( m , 1h ) 1 . 97 - 2 . 04 ( m , 1h ) 2 . 06 - 2 . 22 ( m , 3 h ) 2 . 24 - 2 . 39 ( m , 6h ) 2 . 40 - 2 . 48 ( m , 1h ) 2 . 68 - 2 . 84 ( m , 2h ) 6 . 47 ( d , j = 2 . 4 hz , 1h ) 6 . 52 ( dd , j = 8 . 4 , 2 . 6 hz , 1h ) 7 . 01 - 7 . 05 ( m , 1h ) 7 . 09 - 7 . 11 ( m , 1h ) 8 . 96 - 9 . 03 ( m , 1h ) 11 . 86 ( s , 1h ) 13 c nmr ( 126 mhz , dmso - d 6 ): □ ppm 11 . 0 ( q , 1 c ) 16 . 6 - 16 . 7 ( q , j c , f , 1 c ) 24 . 5 ( t , 1 c ) 26 . 8 ( t , 1 c ) 26 . 8 ( t , 1 c ) 28 . 8 ( t , 1 c ) 30 . 4 ( t , j c , f = 4 . 9 hz , 1 c ) 33 . 4 ( d , j c , f = 6 . 7 hz , 1 c ) 34 . 2 ( t , 1 c ) 35 . 5 ( d , 1 c ) 38 . 5 - 38 . 8 ( t , j c , f , 1 c ) 43 . 7 ( d , 1 c ) 44 . 5 - 45 . 0 ( s , j c , f , 1 c ) 49 . 7 ( d , j c , f = 4 . 9 hz , 1 c ) 112 . 6 ( d , 1 c ) 114 . 9 ( d , 1 c ) 125 . 6 ( d , 1 c ) 125 . 9 ( s , 1 c ) 130 . 1 ( s , 1 c ) 130 . 6 - 134 . 7 ( s , j c , f , 1 c ) 134 . 6 ( d , 1 c ) 137 . 1 ( s , 1 c ) 155 . 0 ( s , 1 c ) 156 . 1 ( s , 1 c ) 170 . 7 ( s , 1 c ) example 94 was prepared from intermediate vβ - 3a - d -( i )-( d )- cf 3 by amide coupling according to general flow diagram ia : to the solution of vβ - 3a - d -( i )-( d )- cf 3 in dcm , a large excess of the hünig base n ( ipr ) 2 et and morpholine was added . the solution was stirred over night at ambient temperature . after dilution with further dcm and washing twice with 1 m khso 4 , the organic layer was dried over na 2 so 4 and evaporated to dryness . the crude material was purified by flash chromatography with dcm / etoac and by preparative hplc yielding 15 mg of compound no . 95 as white solid . 13 c nmr ( 126 mhz , chloroform - d ): □ ppm 22 . 2 ( q , 1 c ) 24 . 7 ( t , 1 c ) 25 . 6 ( t , 1 c ) 27 . 3 ( t , 1 c ) 29 . 1 ( t , 1 c ) 29 . 3 ( t , 1 c ) 33 . 1 ( t , 1 c ) 35 . 1 ( d , 1 c ) 36 . 1 ( t , 1 c ) 42 . 1 ( t , 1 c ) 44 . 2 ( d , 1 c ) 44 . 6 ( d , 1 c ) 46 . 1 ( t , 1 c ) 46 . 3 ( s , 1 c ) 57 . 6 ( d , 1 c ) 66 . 7 ( t , 1 c ) 67 . 0 ( t , 1 c ) 112 . 7 ( d , 1 c ) 115 . 3 ( d , 1 c ) 122 . 4 - 124 . 8 ( s , 1 c ) 125 . 8 ( d , 1 c ) 132 . 5 ( s , 1 c ) 137 . 9 ( s , 1 c ) 138 . 5 ( d , j = 5 . 7 hz , 1 c ) 143 . 3 - 144 . 3 ( s , 1 c ) 153 . 9 ( s , 1 c ) 171 . 5 ( s , 1 c ) 1 h nmr ( 501 mhz , chloroform - d ): □ ppm 1 . 14 ( s , 3h ) 1 . 32 - 1 . 78 ( m , 8h ) 1 . 84 ( dd , j = 11 . 9 , 7 . 3 hz , 1h ) 1 . 95 - 2 . 04 ( m , 2h ) 2 . 27 - 2 . 36 ( m , 4 h ) 2 . 57 - 2 . 64 ( m , 1h ) 2 . 80 - 2 . 88 ( m , 2h ) 3 . 44 - 3 . 51 ( m , 2h ) 3 . 62 - 3 . 71 ( m , 6 h ) 5 . 40 - 5 . 73 ( m , 1h ) 6 . 45 - 6 . 48 ( m , 1h ) 6 . 58 ( d , j = 2 . 7 hz , 1h ) 6 . 63 ( dd , j = 8 . 2 , 2 . 7 hz , 1h ) 7 . 09 ( d , j = 8 . 2 hz , 1h ) example 95 was prepared from intermediate vβ - 3α - d -( i )-( a )= cf 2 by amide coupling according to general flow diagram ia : to the solution of vβ - 3a - d -( i )-( a )= cf 2 in dcm , a large excess of the hünig base n ( ipr ) 2 et and morpholine was added . the solution was stirred over night at ambient temperature . after dilution with further dcm and washing twice with 1 m khso 4 , the organic layer was dried over na 2 so 4 and evaporated to dryness . the crude material was purified by flash chromatography with dcm / etoac and by preparative hplc yielding 15 mg of compound no . 95 as white solid . 1 h nmr ( 501 mhz , chloroform - d ): □ ppm 1 . 05 ( s , 3h ) 1 . 18 - 1 . 30 ( m , 1h ) 1 . 32 - 1 . 81 ( m , 7h ) 1 . 87 - 1 . 97 ( m , 1h ) 2 . 03 - 2 . 15 ( m , 2h ) 2 . 18 - 2 . 36 ( m , 4h ) 2 . 53 - 2 . 68 ( m , 1h ) 2 . 77 - 2 . 91 ( m , 2h ) 3 . 43 - 3 . 53 ( m , 2h ) 3 . 59 - 3 . 72 ( m , 6h ) 5 . 53 ( br . s ., 1h ) 6 . 57 ( d , j = 2 . 44 hz , 1h ) 6 . 63 ( dd , j = 8 . 39 , 2 . 59 hz , 1h ) 7 . 11 ( d , j = 8 . 24 hz , 1h ) 13 c nmr ( 126 mhz , chloroform - d ): 0 ppm 20 . 9 ( q , j ( c , f ) = 2 . 60 hz , 1 c ) 25 . 3 ( t , 1 c ) 26 . 2 ( t , 1 c ) 27 . 5 ( t , 1 c ) 29 . 5 ( t , 1 c ) 31 . 0 ( t , 1 c ) 31 . 3 ( t , 1 c ) 33 . 1 ( t , 1 c ) 35 . 8 ( d , 1 c ) 37 . 7 ( d , 1 c ) 38 . 0 ( t , j ( c , f ) = 4 . 15 hz , 1 c ) 42 . 1 ( t , 1 c ) 42 . 3 ( s , j ( c , f ) = 2 . 98 hz , 1 c ) 44 . 3 ( d , 1 c ) 46 . 1 ( t , 1 c ) 57 . 7 ( d , 1 c ) 66 . 7 ( t , 1 c ) 67 . 0 ( t , 1 c ) 99 . 2 ( s , j ( c , f ) = 17 . 26 hz , 1 c ) 112 . 7 ( d , 1 c ) 115 . 3 ( d , 1 c ) 126 . 0 ( d , 1 c ) 132 . 5 ( s , 1 c ) 138 . 0 ( s , 1 c ) 148 . 3 - 153 . 0 ( s , j ( c , f ) , 1 c ) 153 . 8 ( s , 1 c ) 171 . 7 ( s , 1 c ) example 96 can be prepared from the intermediate no . 40 named 3 - hydroxy - 15α -( 4 - morpholin - 4 - yl - 4 - oxo - butyl )- estra - 1 , 3 , 5 ( 10 )- trien - 17 - one of formula ( viα - 3a )- 40 according to the reaction depicted in section d -( i )-( a )/ 1 . example 97 can be prepared from the intermediate no . 40 named 3 - hydroxy - 15α -( 4 - morpholin - 4 - yl - 4 - oxo - butyl )- estra - 1 , 3 , 5 ( 10 )- trien - 17 - one of formula ( viα - 3a )- 40 according to the reaction depicted in section d -( i )-( d )/ 3 . example 98 can be prepared from example 16 according to the last reaction step depicted in section d -( i )-( c )/ 3 . example 99 can be prepared starting from example 9 ( 4 -( 2 - ethyl - 3 - hydroxy - 17 - oxo - estra - 1 , 3 , 5 ( 10 )- trien - 15β - yl )- n -( 5 - methyl - thiazol - 2 - yl )- butyramide ) as educt , according to the reaction depicted in section d -( i )-( c )/ 2 . example 100 can be prepared starting from example 95 ( 4417 - difluoromethylene - 3 - hydroxy - estra - 1 , 3 , 5 ( 10 )- trien - 15β - yl )- 1 - morpholin - 4 - yl - butan - 1 - one ) according to the reaction scheme depicted in section d -( i )-( d )/ 2 . a variety of compounds numbered 101 to 138 and falling under the scope of general formula ( i ), in which x - a - y represents — co — nr 4 , r 1 represents — h , r 14 represents — h , and the c17 keto function is replaced by a difluoro group , was prepared by parallel chemistry using a reaction according to general flow diagram ib starting from the already fluorinated intermediates ivα - 3a - d1f2 and ivβ - 2a - d1f2 , respectively . synthesis protocol : 0 . 07 mmol of the individual amine was weight out into a reaction flask . a solution of 0 . 07 mmol of the respective steroidal building block ( ivα - 3a - d1f2 and ivβ - 2a - d1f2 ), 0 . 077 mmol hobt , 0 . 231 mmol nmm and 0 . 154 mmol polymer bound edci in 5 ml dcm were added . the reaction mixture was stirred for 24 h at ambient temperature . the solvent was removed in a vacuum centrifuge at 40 ° c . than 4 ml etoac and 4 ml h 2 o were added . the two phases were stirred vigorously for 2 min , than the organic phase was dried with na 2 so 4 and evaporated in a vacuum centrifuge at 40 ° c . after treatment of the crude product with 2 ml thf , 10 mg lioh and 0 . 5 ml water , the solvent was evaporated and the residue further extracted ( etoac and 0 . 1 m khso 4 ). then , 50 mg polymer bound trisaminoeethlyamine was added yielding after filtration and evaporating to dryness the desired product . if still necessary , products were further purified by flash chromatography ( 4 g silica gel , eluent etoac / cyclohexane ). examples 151 to 165 were prepared from the corresponding intermediates ( e . g . no . 1 , 3a , 39 , 1 , 40 etc .) using the reaction scheme as depicted in section d -( ii ). alternatively , depending on the nature of the c15 side chain , some of the reaction steps had to be carried out after having introduced the heterocyclic ring system , i . e . the 15 , 16 - unsaturated intermediate ( x ) was derivatized to the appropriate acid or alkenyl intermediate ( see e . g . schemes 7b , 7c , 8a and 8b ). then , the heterocyclic ring system was introduced including the c16 - c17 carbon atoms attached to the d - ring . the so - obtained intermediates were then used for further modification and amidation of the c15 side chain ( introduction of the r2 / r4 substituents ). finally the protection group in c3 position was cleaved off . starting from intermediate compound xc , an allyl side chain was introduced into c15 position using 1 , 4 - addition of allylbromide according to step 1 of scheme 7c , followed by construction of the pyrazol - ring according to d -( ii )-( a ). ringclosure with methyl hydrazine gave a mixture of the corresponding isomers . conversion of the allyl into the n - benzyl - butyramide side chain was performed according to steps 2 - 4 of scheme 7c and to the reaction as depicted in general flow diagram ib by reaction with benzylamine . finally the obtained isomers were separated by preparative hplc . example 151 : 1 h - nmr ( 300 mhz , cdcl 3 ): δ 1 . 10 - 1 . 20 ( s , 3h ), 1 . 20 - 2 . 32 ( m , 17h ), 2 . 68 - 2 . 88 ( m , 3h ), 3 . 72 - 3 . 80 ( s , 3h ), 4 . 24 - 4 . 40 ( dd , 2h ), 6 . 48 - 6 . 52 ( s , 1h ), 6 . 52 - 6 . 60 ( d , 1h ), 6 . 96 - 7 . 08 ( d , 1h ), 7 . 08 - 7 . 28 ( m , 6h ). example 152 : 1 h - nmr ( 300 mhz , cdcl 3 ): δ 1 . 08 - 1 . 16 ( s , 3h ), 1 . 16 - 2 . 40 ( m , 17h ), 2 . 68 - 2 . 88 ( m , 3h ), 3 . 72 - 3 . 84 ( s , 3h ), 4 . 24 - 4 . 44 ( dd , 2h ), 6 . 44 - 6 . 54 ( s , 1h ), 6 . 54 - 6 . 60 ( d , 1h ), 7 . 00 - 7 . 12 ( d , 1h ), 7 . 12 - 7 . 32 ( m , 6h ). examples 153 and 154 were prepared according to the procedure described for examples 151 and 152 using morpholine as amine for the amide coupling step . example 153 : 1 h - nmr ( 300 mhz , cdcl 3 ): δ 1 . 04 - 1 . 20 ( s , 3h ), 1 . 24 - 1 . 84 ( m , 9h ), 2 . 00 - 2 . 52 ( m , 8h ), 2 . 88 - 2 . 96 ( m , 3h ), 3 . 40 - 3 . 70 ( m , 8h ), 3 . 70 - 3 . 92 ( s , 3h ), 6 . 22 - 6 . 44 ( m , 2h ), 6 . 96 - 7 . 12 ( d , 1h ), 7 . 20 - 7 . 28 ( s , 1h ). example 154 : 1 h - nmr ( 300 mhz , cdcl 3 ): δ 1 . 16 - 1 . 22 ( s , 3h ), 1 . 22 - 1 . 88 ( m , 9h ), 2 . 04 - 2 . 56 ( m , 8h ), 2 . 76 - 2 . 96 ( m , 3h ), 3 . 48 - 3 . 70 ( m , 8h ), 3 . 72 - 3 . 84 ( s , 3h ), 6 . 48 - 6 . 60 ( m , 2h ), 7 . 00 - 7 . 12 ( d , 1h ), 7 . 16 - 7 . 24 ( s , 1h ). starting from intermediate compound xc , an allyl side chain was introduced into c15 position using 1 , 2 - addition of allylbromide and subsequent rearrangement with potassium hydride according to steps 1 and 2 of scheme 8b , followed by construction of the pyrazol - ring according to d -( ii )-( a ). ringclosure with methyl hydrazine gave a mixture of the corresponding isomers . conversion of the allyl into the n - benzyl - butyramide side chain was performed according to steps 3 - 5 of scheme 8b and to the reaction as depicted in general flow diagram ib by reaction with benzylamine . finally the obtained isomers were separated by preparative hplc . example 155 : 1 h - nmr ( 300 mhz , cdcl 3 ): δ 0 . 94 - 1 . 04 ( s , 3h ), 1 . 20 - 2 . 50 ( m , 17h ), 2 . 60 - 2 . 88 ( m , 3h ), 3 . 72 - 3 . 84 ( s , 3h ), 4 . 28 - 440 ( s , 2h ), 6 . 40 - 6 . 50 ( s , 1h ), 6 . 52 - 6 . 60 ( d , 1h ), 7 . 04 - 7 . 12 ( d , 1h ), 7 . 14 - 7 . 36 ( m , 5h ). example 156 : 1 h - nmr ( 300 mhz , cdcl 3 ): δ 0 . 96 - 1 . 08 ( s , 3h ), 1 . 24 - 2 . 48 ( m , 17h ), 2 . 64 - 2 . 88 ( m , 3h ), 3 . 72 - 3 . 84 ( s , 3h ), 4 . 28 - 4 . 44 ( s , 2h ), 6 . 40 - 6 . 50 ( s , 1h ), 6 . 50 - 6 . 60 ( d , 1h ), 7 . 00 - 7 . 12 ( d , 1h ), 7 . 12 - 7 . 36 ( m , 5h ). examples 157 and 158 were prepared according to the procedure described for examples 155 and 156 using morpholine as amine for the amide coupling step . example 157 : 1 h - nmr ( 300 mhz , cdcl 3 ): δ 0 . 96 - 1 . 08 ( s , 3h ), 1 . 12 - 2 . 36 ( m , 17h ), 2 . 72 - 2 . 96 ( m , 3h ), 3 . 50 - 3 . 72 ( m , 8h ), 3 . 76 - 3 . 86 ( s , 3h ), 6 . 44 - 6 . 50 ( s , 1h ), 6 . 52 - 6 . 60 ( d , 1h ), 7 . 04 - 7 . 12 ( d , 1h ), 7 . 24 - 7 . 30 ( s , 1h ). example 158 : 1 h - nmr ( 300 mhz , cdcl 3 ): δ 0 . 92 - 1 . 08 ( s , 3h ), 1 . 24 - 2 . 56 ( m , 17h ), 2 . 68 - 2 . 92 ( m , 3h ), 3 . 22 - 3 . 70 ( m , 8h ), 370 - 3 . 88 ( s , 3h ), 6 . 40 - 6 . 48 ( s , 1h ), 6 . 48 - 6 . 60 ( d , 1h ), 7 . 00 - 7 . 10 ( d , 1h ), 7 . 12 - 7 . 22 ( s , 1h ). examples 159 and 160 were prepared according to the procedure described for examples 155 and 156 using 2 - amino - 5 - methylthiazole for the amide coupling step . example 159 : 1 h - nmr ( 300 mhz , cdcl 3 ): δ 0 . 80 - 0 . 90 ( s , 3h ), 0 . 90 - 2 . 48 ( m , 20h ), 2 . 56 - 2 . 80 ( m , 3h ), 3 . 60 - 3 . 68 ( s , 3h ), 6 . 36 - 6 . 42 ( s , 1h ), 6 . 44 - 6 . 52 ( d , 1h ), 6 . 84 - 6 . 92 ( s , 1h ), 6 . 96 - 7 . 04 ( m , 2h ). example 160 : 1 h - nmr ( 300 mhz , cdcl 3 ): δ 0 . 84 - 0 . 96 ( s , 3h ), 0 . 96 - 2 . 48 ( m , 20h ), 2 . 58 - 2 . 80 ( m , 3h ), 3 . 60 - 3 . 72 ( s , 3h ), 6 . 36 - 6 . 44 ( s , 1h ), 6 . 44 - 6 . 56 ( d , 1h ), 6 . 84 - 6 . 92 ( s , 1h ), 6 . 96 - 7 . 04 ( d , 1h ), 7 . 04 - 7 . 08 ( s , 1h ). starting from intermediate compound xc , an allyl side chain was introduced into c15 position using 1 , 4 - addition of allylbromide according to step 1 of scheme 7c , followed by construction of the oxazole - ring according to d -( ii )-( c ) using hydroxylamine for the ringclosure . conversion of the allyl into the 4 - morpholin - 4 - yl - 4 - oxo - butyl side chain can be performed according to steps 2 - 4 of scheme 7c and to the reaction as depicted in general flow diagram ib by amide coupling with morpholine . starting from intermediate compound xc , an allyl side chain was introduced into c15 position using 1 , 4 - addition of allylbromide according to step 1 of scheme 7c , followed by construction of the pyrazol - ring according to d -( ii )-( a ) using benzylhydrazine for the ringclosure to give a protected pyrazol . conversion of the allyl into the 4 - morpholin - 4 - yl - 4 - oxo - butyl side chain was performed according to steps 2 ( metathesis ) and 3 ( saponification ) of scheme 7c , followed by amide coupling with morpholine according to general flow diagram ib . finally , reduction of the double bond and debenzylation gave the desired end product no . 162 . 1 h - nmr ( 300 mhz , cdcl 3 ): δ 1 . 08 - 1 . 20 ( s , 3h ), 1 . 22 - 2 . 48 ( m , 17h ), 2 . 72 - 3 . 00 ( m , 3h ), 3 . 40 - 3 . 76 ( m , 8h ), 6 . 52 - 6 . 56 ( s , 1h ), 6 . 56 - 6 . 60 ( d , 1h ), 7 . 00 - 7 . 12 ( d , 1h ), 7 . 22 - 7 . 28 ( s , 1h ). iv . compounds carrying a sulphamate , carbamate , phosphonate , thiophosphonate , sulphonate , phosphate or sulphate group in r1 example 163 was prepared from the intermediate no . 1 named 3 - hydroxy - 15β -( 4 - morpholin - 4 - yl - 4 - oxo - butyl )- estra - 1 , 3 , 5 ( 10 )- trien - 17 - one of formula ( viβ - 3a )- 1 using sulfamoyl chloride as sulfamoylating agent . example 164 was prepared from the intermediate no . 1 named 3 - hydroxy - 15β -( 4 - morpholin - 4 - yl - 4 - oxo - butyl )- estra - 1 , 3 , 5 ( 10 )- trien - 17 - one of formula ( viβ - 3a )- 1 using sulfur trioxide - triethylamine complex : the estron derivative ( viβ - 3a )- 1 ( 0 . 25 mmol ) and sulfur trioxide - triethylamine complex ( 54 . 4 mg , 0 . 30 mmol , “ fluka ”) were stirred in anhydrous dmf ( 1 ml ) at rt overnight . ca . 0 . 3 g silica gel ( for column chromatography ) was added , and the solvent was removed in high vacuum at 35 ° c . the remaining powder was loaded on the column prepacked with ca . 6 g silica gel . flash chromatography with afforded the desired triethylammonium phenol sulfate . 17β - hsd1 purification : recombinant baculovirus was generated by the “ bac to bac expression system ” ( invitrogen ). recombinant bacmid was transfected to sf9 insect cells using “ cellfectin reagent ” ( invitrogen ). 60 h later cells were harvested ; the microsomal fraction was isolated as described by puranen et al . ( 1994 ). aliquots were stored frozen until determination of enzymatic activity . assay — inhibition of recombinant human 17β - hydroxysteroid dehydrogenase type 1 : recombinant protein ( 0 . 1 μg / ml ) was incubated in 20 mm kh 2 po 4 ph 7 . 4 with 30 nm 3h - estrone and 1 mm nadph for 30 min at rt , in the presence of potential inhibitors at concentrations of 1 μm or 0 . 1 μm . inhibitor stock solutions were prepared in dmso . final concentration of dmso was adjusted to 1 % in all samples . the enzyme reaction was stopped by addition of 10 % trichloroacetic acid ( final concentration ). samples were centrifuged in a microtiter plate at 4000 rpm for 10 min . supernatants were applied to reverse phase hplc on a waters symmetry c18 column , equipped with a waters sentry guard column . isocratic hplc runs were performed at rt at a flow rate of 1 ml / min of acetonitrile : water 48 : 52 as running solvent . radioactivity was monitored in the eluate by a packard flow scintillation analyzer . total radioactivity for estrone and estradiol were determined in each sample and percent conversion of estrone to estradiol was calculated according to the following formula : the values “% inhibition ” were determined for exemplified compounds , and the results are summarized in table 19 . the binding affinity of the compounds of the invention to the estrogen receptor α and to the estrogen receptor β may be determined according to the in vitro er binding assays described by koffman et al ( 1991 ). alternatively , an estrogen receptor binding assay may be performed according to international patent application wo 00 / 07996 . compounds of the invention showing binding affinity towards the estrogen receptor may be further tested with regard to their individual estrogenic or anti - estrogenic potential ( agonistic binding or antagonistic binding to the erα or erβ ). the determination of the estrogen receptor agonist activity may be performed according to an in vitro assay system using the mmtv - ere - luc reporter system which is for example described within published us patent application us 2003 / 0170292 : to assay estrogen receptor agonist activity , hela cells are grown in 24 - well microtiter plates and then transiently co - transfected with two plasmids using lipofectamine . the first plasmid comprises dna encoding human estrogen receptor ( either er - alpha or er - beta ), and the second plasmid comprises an estrogen - driven reporter system comprising : a luciferase reporter gene ( luc ) whose transcription is under the control of upstream regulatory elements comprising 4 copies of the vitellogenin estrogen response element ( ere ) cloned into the mouse mammary tumor virus ( mmtv ) promoter ( the full name for the reporter system being “ mmtv - ere - luc ”). cells are exposed to the compounds of the invention in rpmi 1640 medium , supplemented with 10 % charcoal - treated fetal calf serum , 2 mm l - glutamine , 0 . 1 mm non - essential amino acids and 1 mm sodium pyruvate for 42 - 48 h at 37 ° c . in a 5 % carbon dioxide incubator . concurrently , cells exposed to estradiol ( 1 nm ) serve as positive controls . replicate wells exposed to the solvent in which the compounds of the invention are dissolved ( i . e . ethanol or methanol ) are used as negative controls . after the 42 - 48 h incubation period , cells are rinsed with phosphate buffered saline ( pbs ), lysis buffer ( promega corp ) is added , and cell lysates are collected for measurement of luciferase activity with a luminometer . estrogenic activity of the compounds of the invention is expressed as fold - increase in luciferase activity as compared to that observed in negative control cells . alternatively , the determination of the estrogen receptor transactivation activity ( estrogenicity assay or agonist assay ) and of the inhibitory potency of transactivation activity ( anti - estrogenicity assay or antagonist assay ) may be performed according to international patent application wo 00 / 07996 . steroid sulphate activity is measured in vitro using intact mcf - 7 human breast cancer cells . this hormone dependent cell line is widely used to study the control of human breast cancer cell growth . it possesses significant steroid sulphate activity and is available in the u . s . a . form the american type culture collection ( atcc ) and in the u . k . ( e . g . from the imperial cancer research fund ). cells are maintained in minimal essential medium ( mem ) ( flow laboratories , irvine , scotland ) containing 20 mm hepes , 5 % foetal bovine serum , 2 mm glutamin , non - essential amino acids and 0 . 075 % sodium bicarbonate . up to 30 replicate 25 cm 2 tissue culture flasks are seeded with approximately 1 × 10 5 cells / flask using the above medium . cells are grown to 80 % confluency and the medium is changed every third day . intact monolayers &# 39 ; of mcf - 7 cells in triplicate 25 cm 2 tissue culture flasks are washed with earle &# 39 ; s balanced salt solution ( ebss from icn flow , high wycombe , u . k .) and incubated for 3 - 4 h at 37 ° c . with 5 pmol ( 7 × 10 5 dpm ) [ 6 , 7 - 3 h ] oestrone - 3 - sulphate ( specific activity 60 ci / mmol from new england nuclear , boston , mass ., u . s . a .) in serum - free mem ( 2 . 5 ml ) together with oestrone - 3 - sulphamate ( 11 concentrations : 0 ; 1fm ; 0 . 01 pm ; 0 . 1 pm ; 1 pm ; 0 . 01 nm ; 0 . 1 nm ; 1 nm ; 0 . 01 mm ; 0 . 1 mm ; 1 mm ). after incubation each flask is cooled and the medium ( 1 ml ) is pipette into separate tubes containing [ 14 c ] oestrone ( 7 × 10 3 dpm ) ( specific activity 97 ci / mmol from amersham international radiochemical centre , amersham , u . k .). the mixture is shaken thoroughly for 30 seconds with toluene ( 5 ml ). experiments have shown that & gt ; 90 % [ 14 c ] oestrone and & lt ; 0 . 1 % [ 3 h ] oestrone - 3 - sulphate is removed from the aqueous phase by this treatment . a portion ( 2 ml ) of the organic phase is removed , evaporated and the 3 h and 14 c content of the residue determined by scintillation spectrometry . the mass of oestrone - 3 - sulphate hydrolyse was calculated from the 3 h counts obtained ( corrected for the volumes of the medium and organic phase used , and for recovery of [ 14 c ] oestrone added ) and the specific activity of the substrate . each batch of experiments includes incubations of microsomes prepared from a sulphatase - positive human placenta ( positive control ) and flasks without cells ( to assess apparent non - enzymatic hydrolysis of the substrate ). the number of cell nuclei per flask is determined using a coulter counter after treating the cell monolayers with zaponin . one flask in each batch is used to assess cell membrane status and viability using the trypan blue exclusion method . results for steroid sulphate activity are expressed as the mean ± 1 s . d . of the total product ( oestrone + oestradiol ) formed during the incubation period ( 20 h ) calculated for 106 cells and , for values showing statistical significance , as a percentage reduction ( inhibition ) over incubations containing no oestrone - 3 - sulphamate . unpaired student &# 39 ; s t - test was used to test the statistical significance of results . cho cells stably transfected with human steroid sulfatase ( cho / sts ) are seeded into microtiter plates . after reaching approximately 90 % confluency , they are incubated overnight with graded concentrations of test substances ( e . g . compounds of the present invention or compounds for use in the present invention ). they are then fixed with 4 % paraformaldehyde for 10 min at rt and washed 4 times with pbs , before incubation with 100 μl / well 0 . 5 mm 4 - methylumbelliferyl sulfate ( mus ), dissolved in 0 . 1 m tris - hcl , ph 7 . 5 . the enzyme reaction is carried out at 37 ° c . for 30 min . then 50 μl / well stop solution ( 1m tris - hcl , ph 10 . 4 ) are added . the enzyme reaction solutions are transferred to white plates ( microfluor , dynex , chantilly , va .) and read in a fluoroskan ii or tecan fluorescence microtiter plate reader . reagent blanks are subtracted from all values . optionally , for drug testing , the fluorescence units ( fu ) are divided by the optical density readings after staining cellular protein with sulforhodamine b ( od 550 ), in order to correct for variations in cell number . ic 5o values are determined by linear interpolation between two bracketing points . in each assay with inhibitors , estrone 3 - o - sulfamate is run as a reference compound , and the ic50 values are normalized to estrone 3 - o - sulfamate ( relative ic 5o = ic 5o compound / ic 50 estrone 3 - o - sulfamate ). sulphatase - positive human placenta from normal term pregnancies are thoroughly minced with scissors and washed once with cold phosphate buffer ( ph 7 . 4 , 50 mm ) then re - suspended in cold phosphate buffer ( 5 ml / g tissue ). homogenisation is accomplished with an ultra - turrax homogeniser , using three 10 second bursts separated by 2 min cooling periods in ice . nuclei and cell debris are removed by centrifuging ( 4 ° c .) at 2000 g for 30 min and portions ( 2 ml ) of the supernatant are stored at 20 ° c . the protein concentration of the supernatants is determined by the method of bradford [ anal . biochem . 72 : 248 - 254 ( 1976 )]. incubations ( 1 ml ) are carried out using a protein concentration of 100 mg / ml , substrate concentration of 20 mm [ 6 , 7 - 3 h ] oestrone - 3 - sulphate ( specific activity 60 ci / mmol from new england nuclear , boston , mass ., u . s . a .) and an incubation time of 20 min at 37 ° c . if necessary eight concentrations of compounds are employed : 0 ( i . e . control ); 0 . 05 mm ; 0 . 1 mm ; 0 . 2 mm ; 0 . 4 mm ; 0 . 6 mm ; 0 . 8 mm ; and 1 . 0 mm . after incubation each sample is cooled and the medium ( 1 ml ) was pipetted into separate tubes containing [ 14 c ] oestrone ( 7 × 10 3 dpm ) ( specific activity 97 ci / mmol from amersham international radiochemical centre , amersham , u . k .). the mixture is shaken thoroughly for 30 seconds with toluene ( 5 ml ). experiments have shown that & gt ; 90 % [ 14 c ] oestrone and & lt ; 0 . 1 % [ 3h ] oestrone - 3 - sulphate is removed from the aqueous phase by this treatment . a portion ( 2 ml ) of the organic phase was removed , evaporated and the 3 h and 14 c content of the residue determined by scintillation spectrometry . the mass of estrone - 3 - sulphate hydrolyse is calculated from the 3 h counts obtained ( corrected for the volumes of the medium and organic phase used , and for recovery of [ 14 c ] oestrone added ) and the specific activity of the substrate . the inhibition of sts activity in vivo may be determined by using the compounds of the present invention in an animal model , in particular in ovariectomised rats . in this model compounds which are estrogenic stimulate uterine growth . the compound ( 10 mg / kg / day for five days ) was administered orally to rats with another group of animals receiving vehicle only ( propylene glycol ). a further group received the compound emate subcutaneously in an amount of 10 μg / day for five days . at the end of the study samples of liver tissue were obtained and oestrone sulphate activity assayed using 3h oestrone sulphate as the substrate as previously described ( see international application wo 96 / 15257 ). the foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting . since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to person skilled in the art , the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof . akanni & amp ; 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