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  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
• • A—HUMAN NECESSITIES
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  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
  • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
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• • A—HUMAN NECESSITIES
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Definitions

• Thepresent invention relates to novel compounds, to their pharma- ceutically acceptable salts, and to their use in therapy for inhibiting 17 ⁇ - hydroxysteroiddehydrogenases.
• Theinvention furtherrelatestopharmaceutical compositionscomprisingthesecompounds. Backgroundoftheinvention
• 17 ⁇ -hydroxysteroid dehydrogenases (17 ⁇ -HSDs), also known as 17- ketosteroid reductases (17-KSR) areNAD(H)- and/orNAPD(H)-dependentalco- holoxidoreductaseenzymeswhichcatalysethelastandkeystepinformationof all estrogens and androgens. More specifically 17 ⁇ -HSDs catalyse the dehydro- genation (oxidation) of 17-hydroxysteroids into corresponding 17-ketosteroids orhydrogenation(reduction)of inactive17-ketosteroids intocorrespondingac- tive17-hydroxysteroids.
• Eachtypeof17 ⁇ -HSD hasaselective substrateaffinityandadistinc- tive,althoughinsomecasesoverlapping,tissuedistribution.
• Type117 ⁇ -hydroxysteroiddehydrogenase (17 ⁇ -HSD1)is mostabun- dantly expressedintheovariangranulosacellsofthedevelopingfolliclesinova- riesandinhumanplacenta,bothbeingestrogenbiosynthetictissues.
• 17 ⁇ -HSD1 isexpressedinestrogentargettissues,includingbreast,endometrium andbone.
• Thehuman17 ⁇ -HSD1 isspecifictoestrogenicsubstratesandinvivo ca- talyzesthereductionofestronetoestradiol.
• Type 217 ⁇ -hydroxysteroid dehydrogenase (17 ⁇ -HSD2)on the other hand converts estradiol, testosterone and 5a-dihydrotestrosterone to their less activeformsestrone,androstenedioneand5a-androstanedione,respectively.
• Due toitswideandabundantexpressioninnumberofvariousestrogenandandrogen targettissues,suchasuterus,placenta,liverandthegastrointestinalandurinary tracts ithasbeensuggestedthat type2enzymeprotects tissues fromexcessive steroidactions.
• Estradiol(E2) isabout10timesaspotentasestrone(E1)andabout80 timesaspotentasestratriol(E3)initsestrogeniceffect.
• 17 ⁇ -HSD1 and 17 ⁇ -HSD2 are present in healthy pre- menopausal humans
• increased ratio of 17 ⁇ -HSD1 to 17-HSD2 in the tumors of postmenopausal patients with hormone-dependent breast cancer has been showninseveralstudies.17HSD1geneamplificationandlossofheterozygosityof 17HSD2allelearepotentialmechanismsinvolvedtoincreasedreductiveestrogen synthesispathway inbreast tumors.
• Increasedratioof type1enzymetotype2 enzyme resultsinanincreasedlevelofestradiolthatthenpromotestheprolifera- tionofthecanceroustissueviatheestrogenreceptors(ER).
• Highlevelsofestro- genthussupportcertaincancers suchasbreastcancerandcanceroftheuterine liningi.e.endometrialcanceranduterinecancer.
• 17 ⁇ -HSD2 is down-regulated in endometriosis while both aromatase and 17 ⁇ -HSD1 are expressed or up- regulatedincomparisonwithnormalendometrium.
• Similarmechanism hasbeenelucidatedinuterineleiomyoma(uterinefib- roids)andendometrialhyperplasia.
• Somesmall-moleculeinhibitorsof17 ⁇ -HSD1enzyme havebeeniden- tifiedandreviewedinPoirierD.(2003)CurrMedChem10:453-77andPoirierD. (2010)ExpertOpin.Ther.Patents20(9): 1123-1145.Further,smallmoleculein- hibitorsof17 ⁇ -HSD’shavebeendisclosedinWO 2001/42181,WO 2003/022835, WO 2003/033487, WO 2004/046111, WO 2004/060488, WO 2004/110459, WO 2005/032527,andWO 2005/084295.
• WO2004/085457 disclosessteroidalcompoundscapableofinhibiting 17 ⁇ -hydroxysteroiddehydrogenase.
• WO2006/003012 discloses2-substitutedD- homo-estrienederivativessuitable for thetreatmentofestrogen-dependentdis- eases that can be influenced by the inhibition of the 17 ⁇ -hydroxysteroid dehy- drogenase type 1.
• WO2006/003013 presents 2-substituted estratri- enones usable for preventing and treating estrogen-dependent diseases influ- encedbyinhibiting17 ⁇ -hydroxysteroiddehydrogenasetype1.
• Anobjectofthepresentinventionistoprovidenovelcompounds that have improved therapeutic properties useful in treating disorders and diseases associatedwithincreasedlevelofestradioland/ortreatablebyinhibitionof17 ⁇ - HSD1 enzyme. It is further an object of the present invention to provide com- poundsthatshowlittleornoinhibitoryeffecton17 ⁇ -HSD2enzyme.
• Thecompoundsoftheinvention mayactasprodrugs.Byvirtueofthe natureofthemaskingmoieties,whenincludedinthecompounds ofthepresent invention,masked biologicallyactiveentitiescandeliveredtothepatientsinneed thereof. Furthermore, the compounds of the inventionwill advantageously exhibit bettersolubilityandresultantlybetterbioavailabilityinvivo thanthecorrespond- ingnakedbiologicallyactiveentity.
• Thepresent invention accordinglyprovidesnovel compounds of for- mula(I)
• the invention alsorelatestopharmaceuticalcompositionscomprising aneffectiveamountofoneormorecompound(s)offormula(I).
• Theinvention alsorelatestoacompoundofformula(I)orapharma- ceutically acceptablesaltthereofforuseinthetreatmentof estradioldependent malignorbenigndiseasesanddisorders.
• CompoundsoftheinventionbearamethylthiazolylsidechainatC15 in ⁇ -configuration which,togetherwiththespecificsubstitutionpatternoftheA ring,providestheinventivepropertiesofthecompoundsofthepresentinvention.
• theC-17carbonylgroupofthenativeestronecore ismaskedasaC-17keti- mine. This particular C-17 moiety enhances the metabolic and/or inhibitory propertiesofthecompoundsofthepresentinvention.AndinparticulartheC-3 OH ⁇ moietyoftheactiveentityismaskedwithanon-toxicprotectinggrouptoadvan- tageouslyalterthesolubilityofthecompounds.
• Theobjectofthepresentinventionisto providecompoundsincluding atherapeuticallyactiveentityofformula(VIV).Inanaspectofthepresentinven- tionthecompoundsoftheinventionarewater-solubleprodrugcompounds.
• the particularwater-soluble compounds may be administered orallywithout unde- sirabledissolvingaids.
• Compounds of thepresent invention convert to thesubstantiallywa- ter-insolubleselective17 ⁇ -HSD1 inhibitorycompoundsfollowing administration toasubject.
• Thecompoundsofthepresentinvention are hydrolyzedbyaneste- raseinvivo todelivertheactiveingredient.
• Thecompounds may alsohavebiolo- gicalactivityassuch.Accordinglythecompounds oftheinventionmaybeactive entitiesassuchaswellasdeliverabiologicallyactiveparentmolecule.
• Thecom- pounds of the present invention having the structural formula (I) below, itself mayshowweakorstronginvitroinhibitoryactivityagainst17 ⁇ -HSD1,whilethe maskedactiveentity (VIV)hasastronginhibitoryactivityagainst17 ⁇ -HSD1 but shows littleornoinhibitoryeffecton17 ⁇ -HSD2.
• alkyl as used herein and hereafter as such or as part of haloalkyl, perhaloalkylor alkoxygroup isanaliphatic linear, branched orcyclic, especiallylinearorbranched, hydrocarbongrouphavingtheindicatednumberof carbonatoms,forexampleC 1-6 -alkylhas 1to6carbonatomsinthealkylmoiety and thus, forexample,C 1-3 -alkyl includes methyl, ethyl,n-propyl, isopropyl, and C 1-6 -alkyl additionally includes branchedandstraightchainn-butyl,sec-butyl, iso- butyl,tert-butyl, pentylandhexyl.
• haloalkyl asusedhereinandhereafterreferstoanyofthe above alkyl groups where one or more hydrogen atoms are replaced by halo- gen(s): inparticular I,Br,ForCl.
• Examplesofhaloalkylgroups include without limitation chloromethyl, fluoromethyl and -CH 2 CF 3 .
• the term“perhaloalkyl” is understood to refer to an alkyl group, inwhich all the hydrogen atoms are re- placedbyhalogenatoms.Preferredexamplesinclude trifluoromethyl (-CF 3 ) and trichloromethyl (-CCl 3 ).
• Theterm“halogen” as usedhereinandhereafterbyitselforaspartof othergroups referstotheGroupVIIaelementsandincludesF,Cl,Brand I.
• C 3-6 -cycloalkyl asusedhereinandhereafterreferstocyclo- alkylgroupshaving 3to6 carbonatomsandthusincludescyclopropyl,cyclobu- tyl,cyclopentyl,andcyclohexyl.
• alkenyl asusedherein andhereafter isanunsaturatedlin- ear orbranchedhydrocarbongrouphavingatleastoneolefinicdoublebondbe- tweenanytwocarbonatoms andhavingtheindicatednumberofcarbonatoms, forexampleC 2-6 -alkenylhas 2 to6 carbonatoms in thealkenylmoiety, suchas ethenyl,propenyl,butenyl,pentenyl,andhexenyl.
• Examplesofpreferredalkenyls groups include, but are not limited to, linear alkenyl groups having a terminal doublebondsuchasvinylandallylgroups.
• Theterm“optionallysubstituted”asusedhereinandhereafterincon- textofaphenylgroupde notesphenylthatis eitherun-substitutedor substituted independentlywithoneormore,inparticular 1,2,or3,substituent(s)attachedat anyavailableatomtoproduceastablecompound,e.g.phenylmaybesubstituted ⁇ oncewith a denoted substituent attached to o-, p- orm-position of the phenyl ring.
• “substituted” refers to a substituent group as defined herein in whichoneormorebondstoahydrogenatomcontainedthereinarereplacedbya bondtoanon-hydrogenatom unlessotherwisedenoted.
• Thesubstituentgroups areeachindependentlyselectedfromthegroupconsistingofhalogen;C 1-4 -alkyl, inparticularmethyl;OH;C 1-4 -alkoxy,inparticularmethoxy;CN;NO 2 ;andacetoxy.
• Preferablysaidphenyl isoptionallysubstitutedwithacetoxy.
• Theterm“pharmaceuticallyacceptablesalts” refersto saltswhichare knowntobenon-toxicandarecommonlyused inthepharmaceutical literature. Typicallytheseare acidadditionsaltsorbaseadditionsaltsofthereferredcom- pounds.
• Illustrativeor- ganicacids,whichformsuitablesalts include,butarenotlimitedto,aceticacid, lacticacid,malonicacid,succinicacid,glutaricacid,fumaricacid,malicacid,tar- taric acid, citric acid, ascorbic acid,maleic acid, benzoic acid, phenylacetic acid, cinnamicacid,methane sulfonicacid, salicylic acid, and the like.
• the term“acid additionsalt”asusedherein alsocomprisessolvateswhichthecompoundsand saltsthereofareabletoform,suchas,forexample,hydrates,alcoholates,andthe like.Thesesaltsalsoincludesaltsusefulforthechiralresolutionofracemates.
• baseadditionsalt includesanynon-toxicbaseadditi- on salts that the compoundof formula (I) can form.
• suitablebase salts include, butarenotlimitedto,thosederivedfrominorganicbasessuchasaluminum,am- monium, calcium, copper, iron, lithium,magnesium,manganese, potassium, so- dium,andzincsalts,inparticularsodiumandammoniumsalts.Furtherexamples ⁇ oforganicbaseadditionsaltincludesaltsoftrialkylamines,suchastriethylamine andtrimethylamine,andcholinesalts.
• R2 is selected from thegroupconsistingof SO2OH,SO2R’’, SO2N(R’)2, (CH2O)mPO(OR’)2, COOR’’’, C(O)N(R’)2, C(O)(CH2)nN(R’)2, C(O)CH2NR’C(O)R’, C(O)CH2NR’C(O)OR’’andC(O)R’’’;
• R’ isHorC1-6-alkyl,C1-3-haloalkyl,orC1-3-perhaloalkyl,orwhenpartof anyN(R’)2 bothR’stogetherwiththenitrogentheyareattachedtomayforma5 to6memberedaliphaticoraromaticheterocyclicringcomprising1or2heteroa- toms each independently selected from N and O or a charged N(R’)3 + group whereinR’isasdefinedabove;
• R’’ is C1-6-alkyl,C1-3-haloalkyl,C1-3-perhaloalkyl, oranoptionally sub- stitutedphenyl;
• R’’ is C1-6-alkyl; C2-6-alkenyl; -(CH2)n-C3-6-cycloalkyl; a 5 to 6 mem- beredaliphaticoraromaticheterocyclicringcomprising1or2heteroatomseach independently selected fromN and O, optionally substituted at any N atom by C(O)R’whereinR’isasdefinedabove;oranoptionallysubstitutedphenyl;
• R4 ismethylorethyl, inparticular methyl.
• Inaparticularaspectof the inventionR1 andR3 areeachindependentlyHorhalogen;inparticularR1andR3arebothareH.
• R2 is (CH 2 O) m PO(OR’) 2 ,whereinR’ is H, C 1-6 -alkyl, C 1-3 -haloalkyl, or C 1-3 -perhaloalkyl, andmis0or1.
• Compound 1 Phosphoric acid mono- ⁇ (13S,15R)-17-[(E)-methoxy- imino]-13-methyl-15-[2-(5-methylthiazol-2-ylcarbamoyl)ethyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl ⁇ ester;
• Compound 1 Phosphoric acid mono- ⁇ (13S,15R)-17[(E)-methoxy- imino]-13-methyl-15-[2-(5-methylthiazol-2-ylcarbamoyl)ethyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl ⁇ ester;
• Compound 14a (13S,15R,Z)-2,4-dibromo-17-(methoxy- imino)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl dimethylglycinate hydrochloride;
• Compound 17a Disodium (13S,15R,E)-17-(methoxyimino)- 13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopropyl)-4-nitro- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl dihydrogenphosphate;
• CompoundVII maybesynthesizedasdisclosedinMessingeretal.Mol Cell Endocrinol.2009 (301) 216-224.
• Benzyl-C15-C16-dehydroestrone II was prepared in five steps from estroneaccordingtopreviouslydescribedmethods.
• ThecompoundII wastreated with an allylic Grignard reagent in the presence of cuprous iodide and lithium chloride in temperature-78°C.Hydroborationbyboranetetrahydrofurancomp- lexatroomtemperaturetocompoundIII andfollowinghydrogenperoxideoxida- tioninalkalineconditionsproduceddiolIV inover90%yields.Jonesoxidationin acetone-water afforded acid V, which was debenzylated by hydrogenation to compoundVI byusingPd/Casacatalyst.Thefinalstepwastheamideformation affordingthe ⁇ -thiazoleVII.
• Thestartingmaterial,thecompoundVIII-15 wasbrominatedbyusing NBS(120mol-%)inDCMat0°C.
• Thestartingmaterial,thecompoundVIII-16 wasbrominatedbyusing NBS(120mol-%)inDCMat0°C.
• Ketone (0.3mmol) wasdissolved inamixtureof ethanol (3ml) and THF(2ml)undernitrogenatmosphere.Pyridine(1.5mmol)andhydroxylamine hydrochloride(0.9mmol)wereaddedtothissolution.Thereactionmixture was refluxedfor1-2h.Solventswereevaporated.Waterwasaddedandtheproduct waseitherfilteredorextractedwithethylacetate,washedwithdilute hydrochlo- ric acid and finally with water. Oximes were purified further by flash-chrom- atographyifrequired. CompoundVIV-22
• VIV-1 (200mg,0.43mmol) wasdissolvedinethanol(1.5ml)andKOH (36mg, 0.64mmol, 150mol-%)was added inmethanol (300 ⁇ l).
• the reaction mixture wasstirredatrtfor60minutes,thensolventswereevaporated.
• Thepre- cipitate was triturated with diethylether-ethanol (v/v 2:1) mixture, finally washedwithetheranddriedcarefullyyielding192mgoftheproduct.
• VIV-1 (200mg,0.43mmol)wasdissolvedinEtOAc(1ml)and2NHCl inEtOAc(0.5ml)wasadded.Thereactionmixturewasstirredatrtfor30minu- tes,whentheproductstartedtoprecipitate.Thesolventwasevaporatedandthe crudeproduct was trituratedwithEtOAc.Theproductwas filteredandwashed severaltimeswithEtOAcanddriedyielding154mgoftheproduct.
• VIV-1 (3.0 g, 6.42mmol, 100mol-%) was dissolved in dryTHF (40 ml).Pyridine(2.1ml,400mol-%)andphosphorousoxychloride(2.4ml,400mol- %)wereadded,andthesolutionwasstirredatrtforfourhoursundernitrogen. The solution cooled and 60ml ofwaterwas carefully added.
• VIV-1 (500mg,1.1mmol,100mol-%)wasdissolvedinDCM(10ml) and pyridine (173 ⁇ l, 200mol-%), BOC-glycine (225mg, 120mol-%) and DCC (330mg,150mol-%)wereaddedtothereactionmixture. Additionalamountsof reagents(30%oftheoriginalamounts)wereadded aftersixhours and then stir- ringwascontinuedatrtovernight. TheprecipitatedDHUwasfilteredoff,andthe filtratewaswashedwithwaterandseveraltimeswithdiluteHCl-solution,follo- wedbywashingwithwaterandfinallywithbrine.Thecrudeproductwaspuri- fiedbychromatographyusingDCM-MeOH(v/v99:1)asaneluent.Theamountof theproductwas599mg.
• Boc-protectedglycinederivative 2 (310mg,0.5mmol) wasdissolved inDCM (5ml) and cooledwith ice bath. Trifluoroacetic acid (1ml)was added dropwise,andthenthereactionmixturewasstirredat rtfortwohours.Solvents were evaporated.TheprecipitatewastrituratedwithEt2O(5x2ml)affordingthe TFA-salt360mg.
• Boc-protectedglycinederivative2 (340mg,0.5mmol)wasdissolved inEtOAc(3ml)and2NHCl-solutionwasadded.Thereactionmixturewasstirred at rt for an hour, then the solventwas evaporated, followed by co-evaporation withtoluene.FinallyEtOAc(2ml)wasadded,andthesolidmaterial formed was filteredandwashedseveraltimeswithEtOAcaffordingtheHCl-salt(260mg).
• VIV-1 (500mg,1.1mmol,100mol-%)wasdissolvedinDCM(12ml).
• the reaction mixture wasstirredfor5minutesandthenwascooledwithice-bath.EDCI(451 mg,220mmol-%)wasadded,afterstirringfor30minutesatcold,thenovernight atrt.Tothereactionmixturewasadded1NHCl-solution(10ml), thenthepro- duct was extracted with DCM.
• the crude product was purified by chromato- graphyusingDCM-MeOH98:2asaneluentaffordingtheproduct(520mg;76%).
• VIV-1 (500mg,1.1mmol, 100mol-%)was dissolved inDCM (5ml) under nitrogen atmosphere and pyridinewas added (215 ⁇ l, 2.7 mmol, 250 mol-%).Reactionwas cooledwith icebathandchloroacetyl chloride (215 ⁇ l, 2.7 mmol,250mol-%)dissolvedinDCM(2ml) wasadded.Reactionwasstirred at0°Cfor1.5hoursandatrtfor40min.Water(10ml)wasaddedandlayerssep- arated.WaterlayerwasextractedwithDCM(3x5ml).Combinedorganiclayers wereextractedwith1NHCl(1x10ml),1NNaOH (1x10ml),water (3x30ml), brine (3x15 ml)anddriedwithNa 2 SO 4 .Theamountof thecrudeproduct was 517mg.
• VV (200mg,0.37mmol,100mol-%)wasdissolvedindryTHF (4ml) and NaI(165mg,1.1mmol,300mol-%) wasadded.Reactionwasstirredatrt for 1 hour. Reactionwas cooledwith ice-bath to 0 ° C andmorpholine (48 ⁇ l, 0.55 mmol,150mol-%)dissolvedindryTHF (1ml)wasaddedslowly. Stirringat0°C wascontinuedfor1.5hour,thenatrt for3hours.Morpholine(24 ⁇ l)wasadded and stirring continued until completed.
• EtOAc (10ml) was added and reaction mixture waspouredintoice-cold0.1NHCl(10ml).Layerswereseparatedand waterlayerwasextractedwithEtOAc(3x5ml).Combinedorganiclayerswere extractedwithwater (3 x 10ml) and brine (3 x 10ml) and driedwithMgSO 4 . Amountofthecrudeproduct was190mg;87%.
• Thecompound7 waspreparedbyusing the samemethodas for the compound4 usingVIV-1 asstartingmaterialandBoc-Pro-OHasreagentin83% yield. Reaction needed higher amount of the reagents to be completed; N- methylmorpholine 380 mol-%, 1-hydroxy-1-H-benzotriazole 220 mol-% and EDCI290mol-%.
• TheBoc-protectedprolinederivative7 (540 mg,0.81mmol) inDCM wasunprotectedbyadditionof trifluoroaceticacid(TFA)(1.6ml).Thereaction mixture was stirred first in ice-bath for3hoursand thenat rt foranhour, fol- lowedbyevaporationofthesolvent.Theprecipitatewastrituratedseveraltimes withEt 2 Oyielding350mgoftheproduct,theyield69%.
• HClsaltoftheproduct 8 waspreparedbydissolvingTFAsaltFP-5683 AII(380mg)inEtOAc(3ml)andadding4MHCl(300 ⁇ l).Reactionwasstirred foranhour. TriturationseveraltimeswithEt 2 OendEtOAcyielding222mgofthe product.
• Reaction was quenchedwith 10% citric acid (20ml) and ex-tracted with EtOAc (3 x 20ml). Combined organic layers were extracted with 10%citricacid(1x20ml),water(2x30ml)andbrine(2x30ml)anddriedwith Na2SO4.
• VIII-29 (48mg,0.08mmol,100mol-%)was suspended inethanol (5ml). Hydroxyaminehydrochloride (26mg,0.38 mmol,500mol-%)andpyri- dine(73 ⁇ l,0.90mmol,1200mol-%)wereaddedandthemixturewasstirredat rtundernitrogenfor3h. ThesolventwasevaporatedandEtOAc(5ml)andwater (5ml)wereadded intotheresidue.Themixturewasstirredvigorouslyandthe organic layerwaswashedwith 0.25MHCl,water and brine. The organic layer wasdriedwithNa 2 SO 4 andevaporatedtoafford57mgofthecrudeproduct,con- tainingtheacetate(67%)withofC-3hydrolysedC-17oxime VIV-32 (31%).
• VIV-32 C-3hydrolsedimpurit (31%ofthecrudeproduct):
• VIV-11 (100mg,0.16mmol,100mol-%)andDMAP(6mg,0.05 mmol, 30mol-%)weresuspendedindryDCM(3ml).Pyridine(155 ⁇ l,1.92mmol,1200 mol-%)andaceticanhydride(75 ⁇ l,0.80mmol,500mol-%)wereaddedunder nitrogen and themixturewas stirred at rt overnight. Themixture was diluted withDCM(3ml) andwashedwithwater,2NHCl,waterandbrine.Dryingwith Na 2 SO 4 andevaporatingthesolventafforded86mgoftheproduct. Yield80%.
• VIV-11 (150mg,0.24mmol,100mol-%)wasdissolvedindryTHF (3 ml)andpyridine(1.5ml).DMAP(29mg,0.24 mmol,100mol-%)wasadded.
• Phosphorusoxychloride (67 ⁇ l,0.72 mmol,300mol-%)wasaddeddropwiseun- dernitrogenandthemixturewasstirredovernightatrt.
• Themixture wascooled withanicebath,coldwater(2ml)wasaddedandthemixturewasstirredatrtfor 1.5 h.
• the solvents were evaporated andwater (3ml)was added.
• VIV-11 (100mg,0.16mmol,100mol-%)wassuspended indryDCM (2ml).Pyridine(85 ⁇ l,1.0mmol,650mol-%),DMAP(6mg,0.05mmol,30mol-%),N,N-dimethyl glycine (33 mg, 0.32 mmol, 200mol-%) and DCC (132mg, 0.64 mmol,400mol-%)wereaddedandthemixturewasstirredundernitrogen at 40°C for 6 h and then left standing in rt overnight.
• Oxalic acid (58mg, 0.64 mmol,400mol-%)dissolved inmethanol (1ml)wasadded to themixtureand stirredfor2h.
• ThemixturewasfilteredthroughCeliteandevaporated,DCM was addedtotheresidueandthemixturewasagainfilteredthroughCelitetwice.
• Thesolvents wereevaporated,DCM (5 ml) andwater (5ml)were added and stirred vigorously.
• VIV-6 (100mg,0.19 mmol,100mol-%)wasdissolvedinDCM(2 ml) under nitrogen atmosphere.
• Pyridine (97 ⁇ l, 1.20mmol, 650mol-%),DMAP (7 mg,0.06 mmol,30mol-%),N,N-dimethylglycine(38mg,0.37mmol,200mol-%) andDCC (153mg,0.74mmol,400mol-%)wereadded to the reactionmixture.
• VIV-6 (50mg,0.08 mmol,100mol-%)wasdissolvedindryTHF(1ml) under nitrogen atmosphere.
• Pyridine 0.5 ml
• DMAP 10mg, 0.08 mmol, 100 mol-%)andphosphorousoxychloride(24 ⁇ l,0.25 mmol,300mol-%)wereadded.
• Reactionwasstirredatrtforfourhours Thesolutionwascooledand1mlofwa- terwascarefullyadded.Stirringwascontinuedforonehour.THFwasevaporated andwater(2ml)wasadded.Precipitatedproductwasfilteredandwashedwith water(2x2ml),2NHCl(3x2ml)andwater(3x2ml). Amount oftheproduct was38mg.
• Thecompound17 waspreparedbythesamemethodasusedfor16. Yield67%.
• the compound 17a was prepared by the same method as used for 16a.
• 1 H-NMR(MeOH-d4) 1.12 (s,3H),1.10-2.90 (m,21H),3.79 (s,3H),6.97 (s, 1H),7.50-7.53(m,2H).
• VIV-24 (90mg,0.160 mmol,100mol-%)wassuspendedinabs.etha- nol(5ml).Hydroxylaminehydrochloride(56mg,0.798 mmol,500 mol-%)was added. Pyridine (155 ⁇ l, 1.916 mmol, 1200mol-%)was added under nitrogen. The mixturewasstirredatrtfor3 h andat50-60°Cfor2h.Solventswereevapo- ratedandcrudeproducttrituratedwithEtOAc:0.25HCl(10ml:10ml).Product wasfilteredandwashedwith0.25MHClandwater.Yield84mg,92%.
• the compound 19a was prepared by the same method as used for 16a.Thereactiontimewas2h.
• VIV-8 (100mg,0.139mmol,100mol-%)wasdissolvedindryDCM (2 ml) under nitrogen atmosphere.
• Pyridine (73 ⁇ l, 0.904 mmol, 650mol-%), DMAP(5mg,0.058 mmol,30mol-%),N,N-dimethylglycine(29mg,0.278mmol, 200mol-%)andDCC(114mg,0.556 mmol,400mol-%)wereaddedtothereac- tionmixture.Reactionwasstirredat40°Cfor2handlefttostandovernightatrt.
• 17 ⁇ -HSD2productionandisolation Similarlyto17 ⁇ -HSD1the Re- combinant baculovirus was generated by the“Bac to Bac Expression System” (Invitrogen).RecombinantbacmidwastransfectedtoSd9insectcellsusing“Cell- fectin Reagent” (Invitrogen).60 h later cells were harvested and supernatant werefractionatedbythefollowingprotocol:
• the determination of the estrogen receptor antagonistic activity may be performed accordingtoaninvitroassaysystemusingtheMMTV-ERE-LUCreportersystem forexampledescribedinUSpatentapplicationUS2003/0170292.
• the aqueous solubility of the parent compoundVIV-1 and the com- poundofExamples1aand 3 was determinedatrtinanappropriatebuffersoluti- on(0.16Mphosphatebufferor0.05mMTris-HClbufferatpH7.4,0.05Macetate bufferatpH5.0,50mM(ionicstrength0.15)HClbufferatpH1.0).
• Thepharmacokineticstudiesofthecompoundsoftheinvention were assessed in Cynomolgus monkeys.
• the study compounds were administrated orally at a dose level corresponding to 10mg/kg of parent drug.
• Thebloodsamples wereobtainedbydirectvenipunctureatpre-dose,andten sequentialtimepointsafteroraladministration.
• Thequantitativebioanalysisofplasmasamples wereperformedinac- cordancewiththeguidanceBioanalyticalMethodValidation (FDA,2001) andthe Guideline on Bioanalytical Method Validation (European Medicines Agency, 2011).Analyticalmethodwasoptimizedforsuitablechromatographic(peaksha- pe,retention)andmassspectrometric(ionizationefficiency)properties.
• compounds of the invention whenmetabolized to their parent com- poundsand/oras such showselective inhibitorypotentialof the17 ⁇ -HSD1en- zyme and little or no inhibitory activity to the 17 ⁇ -HSD2 enzyme and therefor, andmaybeuseful for the treatmentof a steroidhormonedependentmalignor benigndiseaseordisorder,inparticularfortreatmentandpreventionofseveral estrogen dependent diseases and disorders.
• compoundsof the present invention may be useful for the treatment ofdiseases and disorders associated with increased levelsof estradiol andwhichmaybeprevented, treated, and/or amelioratedbyaninhibitorof 17 ⁇ -HSD1enzyme.
• Examplesofinflammatorydiseasesandconditionsin include,butarenot limitedto, breastcancer,prostatecarcinoma,ovariancancer,uterinecancer,en- dometrialcancer,endometrialhyperplasia,endometriosis,uterinefibroids,uteri- ne leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, prostadynia,benignprostatichyperplasia,urinarydysfunction,polycysticovarian syndrome,lowerurinarytractsyndrome,multiplesclerosis,obesity,rheumatoid arthritis,coloncancer,tissuewounds,skinwrinklesandcataracts.
• Treatment or prevention includes prophylaxis, or preventionof,aswellasloweringtheindividual'sriskoffallingillwiththenamed disorderorcondition,oralleviation,amelioration,elimination,orcureofthesaid disorderonceithasbeenestablished.
• Compoundsofthepresentinvention maybeadministeredinaneffec- tiveamountwithinthedosagerangeofabout0.1 ⁇ g/kgtoabout 300mg/kg,prefer- ablybetween1.0 ⁇ g/kgto10mg/kgbodyweight.
• Compoundsofthepresentinven- tion maybeadministeredinasingledailydose,orthetotaldailydosagemaybe administeredindivideddosesoftwo,threeorfourtimesdaily.
• “Aneffectiveamount” referstoanamountofacompoundthatconfers atherapeuticeffectonthetreatedsubject.
• Thetherapeutic effectmaybeobjective i.e.measurablebysometestormarker
• thetherapeutic effectorprevention i.e.subjectgivesanindica- tionoforfeelsaneffect.
• Sudther suchtreatmentorpreventioncanbeused in conjunction with other traditional treatments for reducing the condition knowntothoseskilledintheart.
• Compounds of the invention are most preferably used alone or in other active ingredients.
• Compounds of the invention may be administered by various routes, for example, parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, and by intradermal injections, and via transdermal, rectal, buccal, oromucosal, nasal, ocular routes and via inhalation and via implant.
• the pharmaceutical compositions including the compound of the present invention as active ingredients may further include pharmaceutically acceptable additives.
• compositions of the compounds can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
• compounds of formula (I) can be used as synthesis intermediates for the preparation of other compounds, in particular of other pharmaceutically active ingredients, which are obtainable from compounds of formula (I), for example by introduction of substituents or modification of functional groups.

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