Thepresent invention relates to novel compounds, to their pharma- ceutically acceptable salts, and to their use in therapy for inhibiting 17β- hydroxysteroiddehydrogenases.Theinventionfurtherrelatestopha rmaceutical compositionscomprisingthesecompounds. Backgroundoftheinvention

17β-hydroxysteroid dehydrogenases (17β-HSDs), also known as 17- ketosteroid reductases (17-KSR) areNAD(H)- and/orNAPD(H)-dependentalco- holoxidoreductaseenzymeswhichcatalysethelastandkeystepinform ationof all estrogens and androgens. More specifically 17β-HSDs catalyse the dehydro- genation (oxidation) of 17-hydroxysteroids into corresponding 17-ketosteroids orhydrogenation(reduction)of inactive17-ketosteroids intocorrespondingac- tive17-hydroxysteroids.

Asbothestrogensandandrogenshavethehighestaffinityfortheirre- ceptorsinthe17β-hydroxyform,the17β-HSD/KSRsregulatethebiol ogicalactiv- ityofthesexhormones.Atpresent,15humanmembersof 17β-HSDshavebeen described(type1–15).Differenttypesof17β-HSD/KSRsdifferint heirsubstrate andcofactorspecificities.The17KSRactivitiesconvertlow-activi typrecursorsto more potent formswhile 17β-HSD activities decrease the potency of estrogens andandrogensandconsequentlymayprotecttissuesfromexcessivehor moneac- tion.

Eachtypeof17β-HSDhasaselective substrateaffinityandadistinc- tive,althoughinsomecasesoverlapping,tissuedistribution.

Type117β-hydroxysteroiddehydrogenase(17β-HSD1)is mostabun- dantly expressedintheovariangranulosacellsofthedevelopingfolliclesi nova- riesandinhumanplacenta,bothbeingestrogenbiosynthetictissues. Inaddition, 17β-HSD1isexpressedinestrogentargettissues,includingbreast, endometrium andbone.Thehuman17β-HSD1isspecifictoestrogenicsubstratesand invivo ca- talyzesthereductionofestronetoestradiol.

Type 217β-hydroxysteroid dehydrogenase (17β-HSD2)on the other hand converts estradiol, testosterone and 5a-dihydrotestrosterone to their less activeformsestrone,androstenedioneand5a-androstanedione,resp ectively.Due toitswideandabundantexpressioninnumberofvariousestrogenandan drogen targettissues,suchasuterus,placenta,liverandthegastrointesti nalandurinary tracts, ithasbeensuggestedthat type2enzymeprotects tissues fromexcessive steroidactions.

Estradiol(E2)isabout10timesaspotentasestrone(E1)andabout80 timesaspotentasestratriol(E3)initsestrogeniceffect.Incontras ttocertainot- herestrogens,estradiolbindswelltobothestrogenreceptorsERα andERβ,and thusregulatestheexpressionofavarietyofgenes.

Although both 17β-HSD1 and 17β-HSD2 are present in healthy pre- menopausal humans, increased ratio of 17β-HSD1 to 17-HSD2 in the tumors of postmenopausal patients with hormone-dependent breast cancer has been showninseveralstudies.17HSD1geneamplificationandlossofhetero zygosityof 17HSD2allelearepotentialmechanismsinvolvedtoincreasedreducti veestrogen synthesispathway inbreast tumors. Increasedratioof type1enzymetotype2 enzymeresultsinanincreasedlevelofestradiolthatthenpromotesth eprolifera- tionofthecanceroustissueviatheestrogenreceptors(ER).Highleve lsofestro- genthussupportcertaincancerssuchasbreastcancerandcancerofthe uterine liningi.e.endometrialcanceranduterinecancer.

Similarly it has been suggested that 17β-HSD2 is down-regulated in endometriosis while both aromatase and 17β-HSD1 are expressed or up- regulatedincomparisonwithnormalendometrium.Thisagainresultsi nthepre- senceofhighconcentrationofestradiol(E2)whichdrivestheprolife rationofthe tissue.Similarmechanismhasbeenelucidatedinuterineleiomyoma(u terinefib- roids)andendometrialhyperplasia.

Reduction of the endogenous estradiol concentration in affected tis- sueswillresultinreducedorimpairedproliferationof17β-estradi olcellsinsaid tissuesandmay thusbeutilized inpreventionand treatmentofmalignandbe- nignestradioldependentpathologies.Due to theproposed involvementof17β- estradiol in a number of malign and benign pathologies, inhibitors of 17β- hydroxysteroiddehydrogenases,thatcanbeusedtoimpairendogenous produc- tionofestradiolfromestrone,canhavetherapeuticvalueinthepreve ntionorthe treatmentofsuchdisordersordiseasesareingreatdemand.

Somesmall-moleculeinhibitorsof17β-HSD1enzymehavebeeniden- tifiedandreviewedinPoirierD.(2003)CurrMedChem10:453-77andPoi rierD. (2010)ExpertOpin.Ther.Patents20(9): 1123-1145.Further,smallmoleculein- hibitorsof17β-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. WO2004/085457disclosessteroidalcompoundscapableofinhibiting 17β-hydroxysteroiddehydrogenase.WO2006/003012discloses2-sub stitutedD- homo-estrienederivativessuitable for thetreatmentofestrogen-dependentdis- eases that can be influenced by the inhibition of the 17β-hydroxysteroid dehy- drogenase type 1. Similarly WO2006/003013 presents 2-substituted estratri- enones usable for preventing and treating estrogen-dependent diseases influ- encedbyinhibiting17β-hydroxysteroiddehydrogenasetype1.

15-substituted estradiol analogues acting as locally active estrogens are presented inWO2004/085345.WO2006/027347 discloses 15b-substituted estradiolderivativeshavingselectiveestrogenicactivityforthet reatmentorpre- ventionof estrogen receptor-relateddiseases andphysiological conditions.Fur- ther,WO2005/047303discloses3,15substitutedestronederivatives capableof inhibitingthe17β-hydroxysteroiddehydrogenasetype1.

International applicationWO2008/034796 relates to estratrien tria- zolessuitableforuseintreatmentandpreventionofsteroidhormoned ependent diseasesordisordersrequiringthe inhibitionofa17β-hydroxysteroiddehydro- genasessuchas17β-HSDtype1,type2ortype3enzyme.Inhibitorsof17 β-HSD type3enzymehavebeendisclosedinWO99/46279. Briefdescriptionoftheinvention

Anobjectofthepresentinventionistoprovidenovelcompoundsthat have improved therapeutic properties useful in treating disorders and diseases associatedwithincreasedlevelofestradioland/ortreatablebyinhi bitionof17β- HSD1 enzyme. It is further an object of the present invention to provide com- poundsthatshowlittleornoinhibitoryeffecton17β-HSD2enzyme.

Thecompoundsoftheinventionmayactasprodrugs.Byvirtueofthe natureofthemaskingmoieties,whenincludedinthecompounds ofthepresent invention,masked biologicallyactiveentitiescandeliveredtothepatientsinneed thereof.Moreover, the compounds of the inventionwill advantageously exhibit bettersolubilityandresultantlybetterbioavailabilityinvivo thanthecorrespond- ingnakedbiologicallyactiveentity. Thepresent inventionaccordinglyprovidesnovel compounds of for- mula(I)

whereinR1,R2,R3andR4areasdefinedintheclaims.

The inventionalsorelatestopharmaceuticalcompositionscomprising aneffectiveamountofoneormorecompound(s)offormula(I).

Furthertheinventionrelatestoacompound offormula(I) oraphar- maceutically acceptablesaltthereofforuseasamedicament.

Theinventionalsorelatestoacompoundofformula(I)orapharma- ceutically acceptablesaltthereofforuseinthetreatmentof estradioldependent malignorbenigndiseasesanddisorders.

Finally the invention provides amethod for the preparation of com- pounds offormula(I). Detaileddescriptionoftheinvention

Compoundsoftheinventioncontainsteroidalcorestructurehavinga definedstereochemistrythatisthenaturalconfigurationofestroge ns.

CompoundsoftheinventionbearamethylthiazolylsidechainatC15 inβ-configurationwhich,togetherwiththespecificsubstitutionp atternoftheA ring,providestheinventivepropertiesofthecompoundsofthepresen tinvention. Also,theC-17carbonylgroupofthenativeestronecoreismaskedasaC- 17keti- mine. This particular C-17 moiety enhances the metabolic and/or inhibitory propertiesofthecompoundsofthepresentinvention.Andinparticula rtheC-3 OH^ moietyoftheactiveentityismaskedwithanon-toxicprotectinggroup toadvan- tageouslyalterthesolubilityofthecompounds.

We have earlier shown that compounds disclosed in PCT/FI2014/050518,theentirecontentsanddisclosuresofwhichareh erebyin- corporatedbyreference, areusefulintreatingdisordersanddiseasesassociated with increased levelofestradioland/ortreatableby inhibitionof17β-HSD1en- zyme.Thesecompoundsshowlittleornoinhibitoryeffecton17β-HSD2 enzyme. Particular examples of such compound disclosed in PCT/FI2014/050518 are compoundsofformula(VIV)

wherein

R1andR3areeachindependentlyselectedfromthegroupconsisting ofH,halogen,C1-3-haloalkyl,C1-3-perhaloalkyl,CN,NO2, N(R’)2,(CH2)nN(R’)2,OR’, (CH2)nOR’; and

R4isHorC1-3-alkyl.

However,thecompoundsdisclosedinPCT/FI2014/050518areeither poorlysolubleorinsolubleinwaterthuslimitingroutesofadministr ationand/or drug formulation.Forexample fororaladministrationthecompoundsdisclosed inPCT/FI2014/050518wouldhave tobeadministratedwith surfactantswhich may cause serious side effects to somepatients. Thus development of awater- solublecompoundishighlydesiredtoimprovebioavailability.

Theobjectofthepresentinventionistoprovidecompoundsincluding atherapeuticallyactiveentityofformula(VIV).Inanaspectofthepr esentinven- tionthecompoundsoftheinventionarewater-solubleprodrugcompoun ds.The particularwater-soluble compoundsmay be administered orallywithout unde- sirabledissolvingaids.

Compounds of thepresent inventionconvert to thesubstantiallywa- ter-insolubleselective17β-HSD1 inhibitorycompoundsfollowing administration toasubject.Thecompoundsofthepresentinventionare hydrolyzedbyaneste- raseinvivo todelivertheactiveingredient. Thecompoundsmayalsohavebiolo- gicalactivityassuch.Accordinglythecompounds oftheinventionmaybeactive entitiesassuchaswellasdeliverabiologicallyactiveparentmolecu le.Thecom- pounds of the present invention, having the structural formula (I) below, itself mayshowweakorstronginvitroinhibitoryactivityagainst17β-HSD1 ,whilethe maskedactiveentity (VIV)hasastronginhibitoryactivityagainst17β-HSD1 but shows littleornoinhibitoryeffecton17β-HSD2.

The term“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.

Theterm“haloalkyl”asusedhereinandhereafterreferstoanyoft he 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 othergroupsreferstotheGroupVIIaelementsandincludesF,Cl,Brand I.

Theterm“C _3-6 -cycloalkyl”asusedhereinandhereafterreferstocyclo- alkylgroupshaving 3to6 carbonatomsandthusincludescyclopropyl,cyclobu- tyl,cyclopentyl,andcyclohexyl.

Theterm“alkenyl”asusedherein andhereafter isanunsaturatedlin- ear orbranchedhydrocarbongrouphavingatleastoneolefinicdoublebond be- tweenanytwocarbonatoms andhavingtheindicatednumberofcarbonatoms, forexampleC _2-6 -alkenylhas 2 to6 carbonatoms in thealkenylmoiety, suchas ethenyl,propenyl,butenyl,pentenyl,andhexenyl.Examplesofprefe rredalkenyls groups include, but are not limited to, linear alkenyl groups having a terminal doublebondsuchasvinylandallylgroups.

Theterm“optionallysubstituted”asusedhereinandhereafterin con- textofaphenylgroupdenotesphenylthatis eitherun-substitutedor substituted independentlywithoneormore,inparticular 1,2,or3,substituent(s)attachedat anyavailableatomtoproduceastablecompound,e.g.phenylmaybesubs tituted^ oncewith a denoted substituent attached to o-, p- orm-position of the phenyl ring. In general“substituted” refers to a substituent group as defined herein in whichoneormorebondstoahydrogenatomcontainedthereinarereplace dbya bondtoanon-hydrogenatom unlessotherwisedenoted. Thesubstituentgroups areeachindependentlyselectedfromthegroupconsistingofhalogen; C _1-4 -alkyl, inparticularmethyl;OH;C _1-4 -alkoxy,inparticularmethoxy;CN;NO ₂ ;andacetoxy. Preferablysaidphenylisoptionallysubstitutedwithacetoxy.

“Optional" or "optionally" denotes that the subsequently described eventorcircumstancemaybutneednotoccur,andthatthedescriptioni ncludes instanceswheretheeventorcircumstanceoccursandinstancesinwhic hitdoes not.“Comprises” or“comprising” denotes that the subsequently described set maybutneednotincludeotherelements.

Theexpression"pharmaceuticallyacceptable"representsbeingusef ul inthepreparationapharmaceuticalcompositionthatis generallysafe,non-toxic, andneitherbiologicallynorotherwiseundesirable,andincludesbei ngusefulfor bothveterinaryuseaswellashumanpharmaceuticaluse.

Theterm“pharmaceuticallyacceptablesalts”refersto saltswhichare knowntobenon-toxicandarecommonlyused inthepharmaceutical literature. Typicallytheseare acidadditionsaltsorbaseadditionsaltsofthereferredcom- pounds.

Theexpression“acidadditionsalt”includesanynon-toxicorgan icand inorganicacidadditionsaltsthat compoundsofformula(I)canform.Illustrative inorganicacids,whichformsuitablesalts, include,butarenotlimitedto,hydro- genchloride,hydrogenbromide,sulphuricandphosphoricacids. 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”asusedhereinalsocomprisessolvateswhichthecomp oundsand saltsthereofareabletoform,suchas,forexample,hydrates,alcohol ates,andthe like.Thesesaltsalsoincludesaltsusefulforthechiralresolutiono fracemates.

Theexpression“baseadditionsalt”includesanynon-toxicbasea dditi- on salts that the compoundof formula (I) can form.Suitablebase salts include, butarenotlimitedto,thosederivedfrominorganicbasessuchasalumi num,am- monium, calcium, copper, iron, lithium,magnesium,manganese, potassium, so- dium,andzincsalts,inparticularsodiumandammoniumsalts.Further examples^ oforganicbaseadditionsaltincludesaltsoftrialkylamines,suchas triethylamine andtrimethylamine,andcholinesalts.

The objects of the invention may be achieved by novel compounds havingformula(I)

wherein

R1andR3areeachindependentlyselectedfromthegroupconsisting ofH,halogen,C1-3-haloalkyl,C1-3-perhaloalkyl,CN,NO2, N(R’)2,(CH2)nN(R’)2,OR’, (CH2)nOR’;

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’’’;

R4isHorC1-3-alkyl;

whereby

R’isHorC1-6-alkyl,C1-3-haloalkyl,orC1-3-perhaloalkyl,orwhe npartof anyN(R’)2 bothR’stogetherwiththenitrogentheyareattachedtomayforma5 to6memberedaliphaticoraromaticheterocyclicringcomprising1or2 heteroa- 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- beredaliphaticoraromaticheterocyclicringcomprising1or2hetero atomseach independently selected fromN and O, optionally substituted at any N atom by C(O)R’whereinR’isasdefinedabove;oranoptionallysubstitute dphenyl;

mis0or1;and

nis1or2

provided that when R1 is H, R2 is not C(O)Me, C(O)CH2NMe2, S(O)2NH2,S(O)2NMe2,orS(O)2Me.^ In furtheraspectof the inventionR4 ismethylorethyl, inparticular methyl.Compoundsofformula(I)whereinR4ismethylorethyl,inparti cularme- thyl,exhibitshowlittleornoinhibitoryeffecton17β-HSD2enzyme.

Inanotheraspectof the inventionR1andR3areeach independently selectedfromH,halogen,C _1-3 -haloalkyl,C _1-3 -perhaloalkyl,CN,andNO ₂ ,preferably fromH,halogen,NO ₂ ,andCN. Inaparticularaspectof the inventionR1 andR3 areeachindependentlyHorhalogen;inparticularR1andR3arebothare H.

Instill furtheraspectof thepresent invention isprovidedcompound of formula (I) and (Ia), wherein R2 is selected from the group consisting of (CH ₂ O) _m PO(OR’) ₂ ,C(O)(CH ₂ ) _n N(R’) ₂ ,C(O)CH ₂ NR’C(O)R’,andC(O)CH ₂ NR’C(O)OR’’. Preferredare compoundsof formula (I) as claimed inanyoneof claims1 to5, whereinR2isC(O)(CH ₂ ) _n N(R’) _2. Thesecompoundsexhibitaqueoussolubility.

Further preferred are compounds of formula (I), wherein 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.Thesecompoundsshowparticularlygoodaqueoussolubili tyas willbedemonstratedbelow.

Inanaspectofthepresentinventionrelatestoacompoundofformula (I)selectedfromthegroupconsistingof:

Compound1 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]phenant hren-3-yl}ester;

Compound2 tert-Butoxycarbonylamino-acetic acid (13S,15R)-13- methyl-17[(E)-methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarb amoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-ylester;

Compound3 Aminoacetic acid (13S,15R)-13-methyl-17[(E)- methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarbamoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-ylester;

Compound4 Tert-Butoxycarbonyl-methylamino-acetic acid (13S,15R)-13-methyl-17[(E)-methoxyimino]-15-[2-(5-methyl-thi azol-2-ylcarba- moyl)-ethyl]-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclope nta[a]phenan- thren-3-ylester;

Compound5 Methylamino-acetic acid (13S,15R)-13-methyl-17[(E)- methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarbamoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-ylester; Compound 6 Morpholin-4-yl-acetic acid (13S,15R)-13-methyl-17[(E)- methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarbamoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-yl ester;

Compound 7 1-(tert-butyl)2-(13S,15R,E)-17-(methoxyimino)-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]phenant hren-3-yl)- pyrrolidine-1,2-dicarboxylate;

Compound 8 (13S,15R,E)-17-(methoxyimino)-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-ylprolinate;

Compound 9 di-tert-butyl((((13S,15R,E)-17-(methoxyimino)-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]phenant hren-3-yl)oxy)- methyl) phosphate;

Compound 10(((13S,15R,E)-17-(methoxyimino)-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)oxy)methyl dihydrogen phosphate;

Compound 11(13S,15R)-2,4-dibromo-13-methyl-15-(3-((5-methyl- thiazol-2-yl)amino)-3-oxopropyl)-17-oxo-7,8,9,11,12,13,14,15 ,16,17-decahydro- 6H-cyclopenta[a]phenanthren-3-ylacetate;

Compound 12(13S,15R,E)-2,4-dibromo-17-(hydroxyimino)-13-meth- yl-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-ylacetate;

Compound 13(13S,15R,E)-2,4-dibromo-17-(methoxyimino)-13-meth- yl-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-ylacetate;

Compound 14(13S,15R,E)-2,4-dibromo-17-(methoxyimino)-13-meth- yl-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 dihydrogen phosphate;

Compound 15(13S,15R,Z)-2,4-dibromo-17-(methoxyimino)-13-meth- yl-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;

Compound 16 (13S,15R,E)-2-iodo-17-(methoxyimino)-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; Compound 17(13S,15R,E)-2-iodo-17-(methoxyimino)-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 dihydrogen phosphate;

Compound 18(13S,15R,E)-17-(methoxyimino)-13-methyl-15-(3-((5- methylthiazol-2-yl)amino)-3-oxopropyl)-4-nitro-7,8,9,11,12,1 3,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yl dihydrogen phosphate;

Compound 19(13S,15R,E)-17-(hydroxyimino)-13-methyl-15-(3-((5- methylthiazol-2-yl)amino)-3-oxopropyl)-4-nitro-7,8,9,11,12,1 3,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yl dihydrogen phosphate;

Compound 20 (13S,15R,E)-4-bromo-17-(hydroxyimino)-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 dihydrogen phosphate;

Compound 21 (13S,15R,E)-2,4-diiodo-17-(methoxyimino)-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;

Compound 22 (13S,15R,E)-2,4-dibromo-17-(hydroxyimino)-13-meth- yl-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 dihydrogen phosphate;

Compound 23 (13S,15R,E)-2,4-diiodo-17-(methoxyimino)-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 dihydrogen phosphate;

and pharmaceutically acceptable saltsthereof.

In a preferred aspect of the present invention relatesto a compoundof formula (I) selected from the group consistingof:

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]phenant hren-3-yl} ester;

Compound 2 tert-Butoxycarbonylamino-acetic acid (13S,15R)-13- methyl-17[(E)-methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarb amoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-yl ester;

Compound 3 Aminoacetic acid (13S,15R)-13-methyl-17[(E)-meth- oxyimino]-15-[2-(5-methyl-thiazol-2-ylcarbamoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-yl ester;

Compound 4 Tert-Butoxycarbonyl-methylamino-acetic acid (13S,15R)-13-methyl-17[(E)-methoxyimino]-15-[2-(5-methyl-thi azol-2-ylcarba- moyl)-ethyl]-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclope nta[a]phenan- thren-3-ylester;

Compound 5 Methylamino-acetic acid (13S,15R)-13-methyl-17[(E)- methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarbamoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-ylester;

Compound 6 Morpholin-4-yl-acetic acid (13S,15R)-13-methyl-17[(E)- methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarbamoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-yl ester;

Compound 7 1-(tert-butyl)2-(13S,15R,E)-17-(methoxyimino)-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]phenant hren-3-yl)pyrrol- idine-1,2-dicarboxylate;

Compound 8 (13S,15R,E)-17-(methoxyimino)-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-ylprolinate;

Compound 9 di-tert-butyl((((13S,15R,E)-17-(methoxyimino)-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]phenant hren-3-yl)oxy)- methyl) phosphate;

Compound 10(((13S,15R,E)-17-(methoxyimino)-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)oxy)methyl dihydrogen phosphate;

Compound11(13S,15R,E)-2,4-dibromo-17-(hydroxyimino)-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]phenant hren-3-ylacetate;

Compound 12(13S,15R,E)-2,4-dibromo-17-(methoxyimino)-13-meth- yl-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 dihydrogen phosphate;

Compound 13(13S,15R,Z)-2,4-dibromo-17-(methoxyimino)-13-meth- yl-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;

Compound 14(13S,15R,E)-2-iodo-17-(methoxyimino)-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; Compound 15(13S,15R,E)-2-iodo-17-(methoxyimino)-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;

Compound 16(13S,15R,E)-2-iodo-17-(methoxyimino)-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 dihydrogen phosphate;

Compound 17(13S,15R,E)-17-(methoxyimino)-13-methyl-15-(3-((5- methylthiazol-2-yl)amino)-3-oxopropyl)-4-nitro-7,8,9,11,12,1 3,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yl dihydrogen phosphate;

Compound 18(13S,15R,E)-17-(hydroxyimino)-13-methyl-15-(3-((5- methylthiazol-2-yl)amino)-3-oxopropyl)-4-nitro-7,8,9,11,12,1 3,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yl dihydrogen phosphate;

Compound 19(13S,15R,E)-4-bromo-17-(hydroxyimino)-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 dihydrogen phosphate;

Compound 20 (13S,15R,E)-2,4-diiodo-17-(methoxyimino)-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;

Compound 21(13S,15R,E)-2,4-dibromo-17-(hydroxyimino)-13-meth- yl-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 dihydrogen phosphate;

Compound 22(13S,15R,E)-2,4-diiodo-17-(methoxyimino)-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 dihydrogen phosphate;

and pharmaceutically acceptable saltsthereof.

In another aspect of the present invention relates to a compound of formula (I) selected from the group consisting of:

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]phenant hren-3-yl} ester;

Compound 1a Phosphoric acid mono-{(13S,15R)-17-[(E)- methoxyimino]-13-methyl-15-[2-(5-methylthiazol-2-ylcarbamoyl )ethyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-yl} ester disodium salt Compound 2 tert-Butoxycarbonylamino-acetic acid (13S,15R)-13- methyl-17[(E)-methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarb amoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-yl ester;

Compound 3a Aminoacetic acid (13S,15R)-13-methyl-17[(E)- methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarbamoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-yl ester trifluoroacetate;

Compound 3bAminoacetic acid (13S,15R)-13-methyl-17[(E)- methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarbamoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-yl ester hydrochloride;

Compound 4 Tert-Butoxycarbonyl-methylamino-acetic acid (13S,15R)-13-methyl-17[(E)-methoxyimino]-15-[2-(5-methyl-thi azol-2-ylcarba- moyl)-ethyl]-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclope nta[a]phenan- thren-3-ylester;

Compound 5aMethylamino-acetic acid (13S,15R)-13-methyl-17[(E)- methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarbamoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-yl ester hydrochloride;

Compound 6 Morpholin-4-yl-acetic acid (13S,15R)-13-methyl-17[(E)- methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarbamoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-yl ester;

Compound 7 1-(tert-butyl)2-(13S,15R,E)-17-(methoxyimino)-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]phenant hren-3-yl) pyrrolidine-1,2-dicarboxylate;

Compound 8a (13S,15R,E)-17-(methoxyimino)-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-ylprolinate trifluoroacetate;

Compound 8b(13S,15R,E)-17-(methoxyimino)-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-ylprolinate hydrochloride;

Compound 9 di-tert-butyl((((13S,15R,E)-17-(methoxyimino)-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]phenant hren-3-yl)oxy)- methyl) phosphate; Compound 10(((13S,15R,E)-17-(methoxyimino)-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)oxy)methyl dihydrogen phosphate;

Compound 10a (((13S,15R,E)-17-(methoxyimino)-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]phenant hren-3-yl)oxy)- methyldihydrogen phosphate disodium salt;

Compound 11(13S,15R,E)-2,4-dibromo-17-(hydroxyimino)-13-meth- yl-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-ylacetate;

Compound 12(13S,15R,E)-2,4-dibromo-17-(methoxyimino)-13-meth- yl-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-ylacetate;

Compound 13 (13S,15R,E)-2,4-dibromo-17-(methoxy- imino)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopr opyl)- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-yl dihydrogen phosphate;

Compound 14 (13S,15R,Z)-2,4-dibromo-17-(methoxyimino)-13-meth- yl-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;

Compound 14a (13S,15R,Z)-2,4-dibromo-17-(methoxy- imino)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopr opyl)- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-yl dimethylglycinate hydrochloride;

Compound 15(13S,15R,E)-2-iodo-17-(methoxyimino)-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;

Compound 16(13S,15R,E)-2-iodo-17-(methoxyimino)-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 dihydrogen phosphate;

Compound 16a (13S,15R,E)-2-iodo-17-(methoxyimino)- 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]phenant hren-3-yl dihydrogenphosphate disodium salt; Compound 17(13S,15R,E)-17-(methoxyimino)-13-methyl-15-(3-((5- methylthiazol-2-yl)amino)-3-oxopropyl)-4-nitro-7,8,9,11,12,1 3,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yl dihydrogen phosphate;

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]phenant hren-3-yl dihydrogenphosphate;

Compound 18(13S,15R,E)-17-(hydroxyimino)-13-methyl-15-(3-((5- methylthiazol-2-yl)amino)-3-oxopropyl)-4-nitro-7,8,9,11,12,1 3,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yl dihydrogen phosphate;

Compound 19(13S,15R,E)-4-bromo-17-(hydroxyimino)-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 dihydrogen phosphate;

Compound 19a Sodium (13S,15R,E)-4-bromo-17-(hydroxy- imino)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-oxopr opyl)- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-yl phosphate;

Compound 20(13S,15R,E)-2,4-diiodo-17-(methoxyimino)-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; and

Compound 21(13S,15R,E)-2,4-dibromo-17-(hydroxyimino)-13-meth- yl-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 dihydrogen phosphate;

Compound 22(13S,15R,E)-2,4-diiodo-17-(methoxyimino)-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 dihydrogen phosphate.

Examplesofthetherapeuticallyactiveentitiesofformula(VII)

Representative examples of the active species liberated by the com- poundsofformula(I)areshowninTable1. Table1:

Examplesoftheinvention

Representative examples of compounds of formula (I) are shown in Table2. Table2

Generalpreparationmethods

Compounds of the present invention may be prepared by methods knownintheart. Thefollowingexamplesillustratethepreparationofcompounds offormula(I). Generalinformation

Commercial grade reagents and solvents were used without further purification.Thin-layer chromatography (TLC)was performed onMerck-plates; pre-coatedaluminiumsheets.Visualizationofplateswasdonethefol lowingtech- niques:1)ultravioletillumination(254nm),2)dippingtheplateint oanisaldehy- deorvanillinesolutionfollowedbyheating.1H-NMRspectraweremeas ured with aBrukerDPX(200MHz)spectrometerwiththesolventasindicated.

Compoundsoftheinventionmaybepreparedfromthecorresponding C-17carbonylderivativeswhereinR2isH,followedbyrequiredderiva tizationof theC3–OH rou .

Preparation ofsynthesisstartingmaterialsandprecursors CompoundVII

CompoundVII maybesynthesizedasdisclosedinMessingeretal.Mol Cell Endocrinol.2009 (301) 216-224. The detailed synthesis of compound VII startingfromestronehasbeendescribedintheSolvayPharmaceutical s’ PCTap- plicationsWO2005/047303andWO2006/125800.

Benzyl-C15-C16-dehydroestrone II was prepared in five steps from estroneaccordingtopreviouslydescribedmethods. ThecompoundIIwastreated 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 affordingtheβ -thiazoleVII.

Thesynthesisofthekeyprecursori.e.thephenolicthiazoleVII-1 from estroneisshownbelow.

PreparationofC-17carbonylcompounds NitrationofthecompoundVII

ThereactionvesselwaschargedwiththecompoundVII (1.32g,3mmol) andethanol (45ml) under nitrogenatmosphere.Tetrahydrofuran(THF)(30ml) andferricnitrate (600mg,1.5mmol)wereadded.Afterstirringthereactionmix- ture for 4h at 60°C, the solventswere evaporated.HPLC of the crude reaction mixtureshowed45%of2-nitro-isomerVIII-1 and35%of4-nitroisomerVIII-2. Purificationbyflashchromatographygave358mgofVIII-1 and284mgof VIII-2. Inaddition,theproductmixturecontainedca.5% of2,4-dinitroderivativeVIII-3. CompoundVIII-1

3-((13S,15R)-3-hydroxy-13-methyl-2-nitro-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

1H-NMR (CDCl3): 1.07 (s, 3H), 1.30-2.75 (m, 19H), 2.9-3.05 (m, 2H), 6.89(s,1H),7.05(s,1H),7.98(s,1H).MSm/z (TOFES ⁺ ):506(M + Na). CompoundVIII-2

3-((13S,15R)-3-hydroxy-13-methyl-4-nitro-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

1H-NMR (CDCl ₃ ):1.08 (s,3H),1.3-3.4 (m,21H), 6.96 (d,1H),7.05 (s, 1H),7.45(d,1H).MSm/z (TOFES ⁺ ):506(M+Na) CompoundVIII-3

3-((13S,15R)-3-hydroxy-13-methyl-2,4-dinitro-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

1H-NMR(CDCl3):1.08(s,3H),1.35-3.10(m,21H),7.03(s,1H),8.14(s, 1H).MSm/z (TOFES ⁺ ):529(M+H) 2- and4aminoderivatives CompoundVIII-4

3-((13S,15R)-2-amino-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

Hydrogenation ofthecompoundVIII-1 wascarriedoutatatmospheric pressureatrt inethanol/THF1:1using10%Pd/Cascatalyst.Catalystwasfilte- redoff,solventswereevaporatedandproductpurifiedbyflashchroma tography.

1H-NMR(CDCl ₃ +MeOH-d ₄ ):1.06(s,3H),1.30-2.65(m,19H),2.80-2.95 (m,2H),6.50(s,1H),6.69(s,1H),7.03 (s,1H).MSm/z (TOFES ⁺ ):454(M+H) Compound VIII-5

3-((13S,15R)-4-amino-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

PreparedaccordingtomethodusedforthecompoundVIII-4 usingthe compoundVIII-2 asastartingmaterial.

1H-NMR(CDCl ₃ +MeOH-d ₄ ): 1.03 (s, 3H), 1.35-2.65 (m, 19 H), 2.75- 3.00(m,2H),6.63(s,2H),7.03(s,1H).MSm/z (TOFES ⁺ ):476(M+Na). Halogenationofthearomaticring Compound VIII-6

3-((13S,15R)-3-hydroxy-2,4-diiodo-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

ThecompoundVII (44mg,0.1mmol)wasdissolvedintoDCMandthe mixturewasstirredinicebath.45mg(0.2mmol)ofN-iodosuccinimide( NIS)was addedandreactionmixturewasstirredfor10minat0°Candthenreacti onwas allowed towarm to rt.Waterwasaddedafter20min, theprecipitatedproduct was filtered,washed firstwithwaterand finallywithheptane.Triturationwith DCMgave40%ofpuredi-iododerivativeVIII-6.

MSm/z(TOFES ⁺ ):691(M+1),713(M+Na). Compound VIII-7

3-((13S,15R)-3-hydroxy-4-iodo-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

ThecompoundVIII-5 (23mg,0.05mmol)wasdissolved intoamix- tureof0.5mlofTHFand0.5mlof2NHClandthesolutionchilledto0°C.A nice- coldsolutionofNaNO ₂ (5mg)wasaddedandstirringcontinued15min.Then 30 mgofKIin50ulofwaterwasaddedandthereactionmixturewasstirredat 80°Cfor1h.Waterwasaddedintocooledreactionmixtureandproductw asex- tractedwithethylacetate,organicphaseswerewashedwithwaterandd ried.Af- terevaporationtheproductwaspurifiedbypreparativeTLCgiving7mg ofpure VIII-7.

1H-NMR(CDCl ₃ ): 1.04(s,3H),1.30-2.95(m,21H),6.84(d,1H),7.06(s, 1H),7.19(d,1H).MSm/z (TOFES ⁺ ):565(M+H) Compound VIII-8

3-((13S,15R)-3-hydroxy-2-iodo-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

PreparedusingthesamemethodasforthecompoundVIII-7 using the compoundVIII-4 asastartingmaterial

1H-NMR(CDCl3): 1.05(s,3H),1.28-2.75(m,19H),2,75-2.90(m,2H), 6.74(s,1H),7.05(s,1H),7.51(s,1H).MSm/z (TOFES ⁺ ):587(M+Na) Compounds VIII-9 toVIII-11

ThereactionvesselwaschargedwithVII (2.97g)inDCM(140ml)and methanol (20ml).This solutionwasaddeddropwise to the solutionof tetrabu- tylammonium tribromide inDCM/MeOH(v/v1:1,10ml)during30minutesby stirring at 0-5°C. After 60minutes the HPLC analysis showed the formation of threeproductswithtracesofunreactedstartingmaterial;41%themon obromide VIII-9,38%monobromideVIII-10 and16%dibromideVIII-11. CompoundVIII-9

3-((13S,15R)-2-bromo-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

1H-NMR (DMSO-d6): 0.96 (s, 3H, -Me), 1.35-2.40 (m, 21H), 2.75 (m, 2H),6.67 (s,1H),7.11 (s,1H),7.27(s,1H),9.89 (s,1H),11.92(s,1H). Compound VIII-10

3-((13S,15R)-4-bromo-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

1H-NMR (DMSO-d6): 0.95 (s, 3H, -Me), 1.35-2.40 (m, 21H), 2.83 (m, 2H),6.78 (d,1H),7.11 (m,2H),7.27(s,1H),9.89 (s,1H),11.92(s,1H). Compound VIII-11

3-((13S,15R)-2,4-dibromo-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

Thecompound VII (1.0g,2.3mmol)wasdissolvedinDCM(13ml),the mixturewascooledto8°CandN-bromosuccinimide(NBS)(1.0g,5.6mmo l)was added.Reactionmixturewaswarmed to rt andstirringwascontinuedfor2.5h. Waterwasaddedandprecipitatedproductwasfiltered,yielding1.2go fcrystalli- nedibromideVIII-11. ¹ H-NMR (DMSO-d ₆ ): 0.95 (s, 3H), 1.22-2.32 (m, 19H), 2.79 (m, 2H), 7.12 (s, 1H), 7.40 (s, 1H), 9.55 (s, 1H), 11.92 (s, 1H). MS m/z (TOF ES ⁺ ): 617/619/621(M+Na). CompoundVIII-12

3-((13S,15R)-4-chloro-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

0.5mmoloftheaminecompoundVIII-5 in3ml2NHCland1mlTHF waschilledstirringat0°C.Solutionof50mgofNaNO2 in0.5mlofwaterwasadd- ed dropwise andmixturewas stirred for 15min at this temperature. Then ice bathwas removedandpreheated solutionof250mgofCuCl in5mlof2NHCl wasaddedat80°Candreactionmixturewaskept2hat this temperature.After coolingwaterwasadded,pHwasadjustedtopH 3andextractedwithethylaceta- te,washedwithwaterandbrine,driedwithNa2SO4^andevaporated.Aft er flash chromatography85mg(36%)ofthe4-chlorocompoundVIII-12wasobtain ed.

1H-NMR(CDCl3): 1.05(s,3H),1.30-3.10(m,21H),6.86(d,1H),7.05(s, 1H),7.13(d,1H).MSm/z (TOFES ⁺ ):473/475(M+H). Compound VIII-13

3-((13S,15R)-2-chloro-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

Prepared from the compoundVIII-4 by the samemethod as for the compoundVIII-12 in0.4mmolscalegivingthedesiredproductin28%yield. ¹ H-NMR (CDCl ₃ +MeOH-d ₄ ): 1.06 (s, 3H), 1.20-2.65 (m, 19H), 2,75- 3.05(m,2H),6.70(s,1H),7.03(s,1H),7.18(s,1H).MS m/z (TOFES+):495/497 (M+Na). Compound VIII-14

3-((13S,15R)-2,4-dichloro-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

ThereactionvesselwaschargedwiththecompoundVII(4g)anddry DCM(150ml)at0°Cunderargonatmosphere.Diethylamine(1.4ml,150m ol-%) wasaddeddropwise,followedbysulfurylchloride(1.1ml,150mol-%). After30 minutesat0°Cwaterwasaddedtothereactionmixture.Theorganicpha sewas separated, dried overNa2SO4 and the solventwas evaporated. The residuewas purifiedbycolumnchromatographyusingDCM/acetone98:2asaneluent .

1H-NMR (DMSO-d6): 0.96 (s, 3H), 1.35-2.40 (m, 21H), 2.80 (m, 2H), 7.12 (s,1H),7.23(s,1H),9.75 (s,1H),11.92(s,1H). Fluorides

Fluorides were prepared from the corresponding amines via ther- molysisoftheirdiazoniumfluoboratesaltsin0.05-0.3mmolscale. Compound VIII-15

3-((13S,15R)-4-fluoro-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

Amixtureof thecompoundVIII-5 (91mg,0.2mmol),ethanol(2ml) and48%tetrafluoroboricacid(0.5ml)inwaterwaschilledto0°Cstir ringinice bath.AsolutionofNaNO ₂ (20mg)in0.2mlofwaterwasaddedandstirringcon- tinuedfor1hat0°C.Fluoroboratesaltwasprecipitatedbyaddingdie thylether until therewas nomore salt coming out the solution. Etherwas decanted and precipitatedmaterialwaswashedtwicewithdiethyletherand driedinvacuum. Thedriedfluoroboratesaltwasheatedinaflaskat120-130°Cinagood hoodfor acoupleofhours.TheremainingmaterialwastreatedwithDCMandfilte red. The solventwas evaporated and the productwas purified by flash chromatography affording22mgofthe4-fluorideVIII-15.

1H-NMR(CDCl ₃ ):1.04(s,3H),1.30-3.05(m,21H),6.75-6.98(m,2H), 7.05(brs,1H).MSm/z (TOFES+):479(M+Na). Compound VIII-16

3-((13S,15R)-2-fluoro-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

Prepared from the compoundVIII-4 using the method used for the compound VIII-15.The catecholVIII-17wasisolatedasaby-product.

1H-NMR(CDCl ₃ ):1.05 (s,3H),1.30-2.70 (m,19H),2,75-2.90 (m,2H), 6.73(d,J=10Hz,1H),6.97(d,J=14Hz,1H),7.05(brs,1H).MS m/z (TOFES ⁺ ): 479(M+Na). CompoundVIII-17

3-((13S,15R)-2,3-dihydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

1H-NMR(CDCl ₃ +MeOH-d ₄ ):1.07(s,3H),1.20-2.70(m,21H),7.07(s, 1H),7.16(s,1H),7.31(s,1H).MSm/z (TOFES ⁺ ):477(M+Na). CompoundVIII-18

3-{(13S,15R)-2-Bromo-4-fuoro-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Thestartingmaterial,thecompoundVIII-15 wasbrominatedbyusing NBS(120mol-%)inDCMat0°C.

1H-NMR(CDCl ₃ ):1.05(s,3H),1.26-2.99(m,21H),7.05(s,1H),7.12(s, 1H).MSm/z (TOFES+):557/559(M+Na). Compound VIII-19

3-{(13S,15R)-4-Bromo-2-fluoro-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-- (5-methylthiazol-2-yl)propanamide

Thestartingmaterial,thecompoundVIII-16 wasbrominatedbyusing NBS(120mol-%)inDCMat0°C.

1H-NMR(CDCl ₃ ):1.04 (s,3H),1.36-2.97 (m,21H), 6.99 (d,1H),7.05(br s,1H).MSm/z (TOFES ⁺ ):535/537 (M+H). Furtheraromaticmodificationsoffluorides Compound VIII-20

3-((13S,15R)-4-fluoro-3-hydroxy-13-methyl-2-nitro-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

150mgof the compoundVIII-15 was added into a suspension of 55 mgofsilicaand55μlwater inasolutionof1.4mlTHFand 1.4mlDCM and stirred atrt.340mgofSilica-sulfuricacid (preparedbyaddingdropwise8.0gof sulphuricacidto10gofsilicagel,andstirredfor30minutesatrt) wasadded, fol- lowedby32mgofsodiumnitrite.Stirringwascontinuedatrt andreactionwas monitoredbyTLCandHPLC.Afterthereactionwascompletedsilicawasf iltered off,washedwithDCM andfinallywithDCM-methanol.Solventswereevaporated and theproductwaspurifiedbyflashchromatographygiving40mgofthecom - poundVIII-20.

1H-NMR(CDCl ₃ ): 1.07(s,3H),1.30-3.20(m,21H),7.05(s,1H),7.82(s, 1H).MSm/z (TOFES+):502(M+H). CompoundVIII-21

3-((13S,15R)-2-amino-4-fluoro-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-- (5-methylthiazol-2-yl)propanamide

Preparedbyhydrogenationof the compoundVIII-20 inethanol con- taining20%ofTHFwithPd/Cat25-30°C. ¹ H-NMR(CDCl ₃ ): 1.06 (s,3H),1.30-2.50 (m,21H),6.48 (s,1H), 6.58 (s, 1H).MSm/z (TOFES+):494 (M+Na). Compound VIII-22

3-((13S,15R)-4-chloro-3-hydroxy-13-methyl-2-nitro-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

PreparedfromthecompoundVIII-12 asdescribedforthecompound VIII-20 above.

1H-NMR(CDCl ₃ ): 1.07(s,3H),1.35-3.20(m,21H),7.05(s,1H),7.99(s, 1H).MSm/z (TOFES+):518/520(M+H). CompoundVIII-23

3-((13S,15R)-2-amino-4-chloro-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

Preparedbyhydrogenationof the compoundVIII-22 inethanol con- taining20%ofTHFwithPd/Ccatalystat25-30°C.

1H-NMR(CDCl ₃ +MeOH-d ₄ ): 1.05(s,3H),1.35-3.00(m,21H),6.64(s, 1H),7.04(s,1H).MSm/z (TOFES+):510/512(M+Na). Compound VIII-24

3-((13S,15R)-2-cyano-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

The C-2 bromide VIII-9 (50 mg, 100 mol-%) and copper(I)cyanide (230mol-%)weredissolved indryDMF(5ml)andrefluxed undernitrogenfor sixhours.ThereactionmixturewascooledandFeCl3 (5000mol-%)inconc.HCl (500μl)wasadded,andstirredat55-60°Cfor30minutes.Thereactio nmixture wascooled,dilutedwithwater.TheproductwasextractedwithEtOAc,w ashed with water, sat. NaHCO3-solution until pH was 8, and finally with brine. Purificationbychromatography.

1H-NMR(CDCl3+MeOH-d4):1.05(s,3H),1.40-2.65 (m,19H),2.89 (m, 2H),6.70 (s,1H),7.06(s,1H),7.36 (s,1H). CompoundVIII-25

3-((13S,15R)-4-cyano-3-hydroxy-13-methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamide

Prepared according tomethodused for the compoundVIII-24 using theC-4bromideVIII-10 asastartingmaterial.

1H-NMR(CDCl3+MeOH-d ₄ ):1.03(s,3H),1.22-2.56(m,19H),3.05(m, 2H), 6.76(d,1H),7.06(s,1H),7.31(s,1H).MSm/z (TOFES ⁺ ):464(M+1). CompoundVIII-26

(13S,15R)-2,4-dibromo-13-methyl-15-(3-((5-methylthiazol-2-yl )- amino)-3-oxopropyl)-17-oxo-7,8,9,11,12,13,14,15,16,17-decahy dro-6H- cyclopenta[a]phenanthren-3-yldihydrogenphosphate

VIII-11 (150mg,0.25 mmol,100mol-%)wasdissolvedindryTHF(3 ml) and pyridine (1.5 ml), DMAP (31mg, 0.25 mmol, 100mol-%) was added. Phosphorusoxychloride(70µl,0.76 mmol,300mol-%)wasaddeddropwiseun- dernitrogen.Themixturewasstirredatrtfor5.5h.Themixturewascoo ledwith anicebath,water(2ml)wasaddedandthemixturewasstirredatrtfor1h and left standingovernight.The solventswere evaporated,water (3ml)wasadded andthemixturewaslefttoprecipitateovernight.Theprecipitatewas filteredand washedwithwater, 2NHCl andwater. The precipitatewas then co-evaporated withtolueneandethanolaffording115mgoftheproduct.

1H-NMR(DMSO-d6):0.96(s,3H),1.10-2.90(m,23H),7.11(s,1H),7.51 (s, 1H), 11.91 (br s, 1H). ³¹ P-NMR (DMSO-d6): -7.38. MS m/z (TOF ES ⁺ ): 677 (M+1). CompoundVIII-27

(13S,15R)-13-methyl-15-(3-((5-methylthiazol-2-yl)amino)-3-ox o- propyl)-4-nitro-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro- 6H-cyclopenta[a]- phenanthren-3-yldihydrogenphosphate

VIII-4 (150mg,0.342mmol,100mol-%)wasdissolvedindryTHF (2 ml)andpyridine(1ml),DMAP(42mg,0.342 mmol,100mol-%)wasadded. Phosphorus oxychloride (96 µl, 1.026 mmol, 300mol-%) was added dropwise undernitrogenandthe mixturewasstirredinrtfor3.5h.Themixturewascooled withan icebath, coldwater (2ml)wasadded, stirred for1hand the solvents wereevaporated.Water(3ml)wasaddedandthemixturewastrituratedf orfew minutes.Theprecipitatewasfilteredandwashedwithwater,2NHCland water. Amountoftheproduct119mg,yield62%. ¹ H-NMR(DMSO-d ₆ ):0.97(s,3H),1.10-3.00(m,21H),7.1(s,1H),7.40- 7.47(m,2H),11.90(brs,1H). ³¹ P-NMR(DMSO-d6):-6.70. CompoundVIII-28

(13S,15R)-4-bromo-13-methyl-15-(3-((5-methylthiazol-2-yl)ami no)- 3-oxopropyl)-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H- cyclopenta[a]- phenanthren-3-yldihydrogenphosphate

VIII-10 (120mg, 0.23mmol,100mol-%)wasdissolvedindryTHF (2 ml) and pyridine (1ml), DMAP (28mg, 0.23 mmol, 100mol-%)was added. Phosphorusoxychloride(65µl,0.70 mmol,300mol-%)wasaddeddropwiseun- dernitrogenandthemixturewasstirredinrtfor2.5h.Themixturewasc ooled withan icebath, coldwater (2ml)wasadded, stirred for1hand the solvents wereevaporated.Water(3ml)wasaddedandthemixturewaslefttopreci pitate overnight.Theprecipitatewasfilteredandwashedwithwater,2NHCla ndwater. Theprecipitatewasco-evaporatedwithtolueneandethanol,affordin g109mgof thecrudeproduct. Yield79%.

1H-NMR (DMSO-d6): 0.97 (s, 3H), 1.10-3.00 (m, 21H), 6.90-7.50 (m, 3H),11.90(brs,1H). ³¹ P-NMR(DMSO-d6):-6.72. CompoundVIII-29

(13S,15R)-2,4-dibromo-13-methyl-15-(3-((5-methylthiazol-2-yl )- amino)-3-oxopropyl)-17-oxo-7,8,9,11,12,13,14,15,16,17-decahy dro-6H-cyclo- penta[a]phenanthren-3-ylacetate

VIII-11 (100mg,0.17mmol,100mol-%)andDMAP(6mg,0.050 mmol, 30mol-%)weresuspendedindryDCM(3ml).Pyridine(165µl,2.01mmol, 1200 mol-%)andaceticanhydride(79µl,0.84mmol,500mol-%)wereaddedun der nitrogen and themixturewas stirred overnight at rt. Themixturewas diluted withDCM(3ml) andwashedwithwater,2NHCl,waterandbrine.Dryingwith Na ₂ SO ₄ andevaporating the solventafforded88mgof the crudeproduct. Yield 82%.

1H-NMR(DMSO-d ₆ ):0.96(s,3H),1.10-2.90(m,21H),2.37(s,3H),7.11 (s,1H),7.61(s,1H),11.91(brs,1H). SynthesisofC-17methyloximes

GeneralmethodforthepreparationofC-17methyloximes: Ketone (0.3mmol)wasdissolved inamixtureof ethanol (3ml) and THF(2ml)undernitrogenatmosphere.Pyridine(1.5mmol)andmethoxyl amine hydrochloride(0.9mmol)wereaddedtothissolution.Thereactionmix turewas refluxedfor1-2h.Solventswereevaporated.Waterwasaddedandthepr oduct waseitherfilteredorextractedwithethylacetate,washedwithdilut e hydrochlo- ric acid and finally with water. Oximes were purified further by flash- chromatographyifrequired. CompoundVIV-1

3-{(13S,15R)-3-Hydroxy-17-[(E)-methoxyimino]-13-methyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

ToasuspensionofVII (700mg,100mol-%)andEtOH(abs.)(30ml) wasaddedmethoxylaminehydrochloride(670mg,500mol-%)followedby py- ridine(1.52g,1200mol-%).Theresultingsolutionwasrefluxed3hour s and the solventwasevaporated.Waterwasaddedtotheresidue.Theaqueouslay erwas extractedwithEtOAc.Thecombinedorganiclayerswerewashedwithwat erand brine,driedoverNa ₂ SO ₄ ,filteredandevaporated.Thecrudeproductwastritura- tedwithheptane.Theyieldoftheproduct73was700 mg(94%). ¹ H-NMR(CDCl ₃ ):1.09 (s,3H),1.15-2.90 (m,21H),3.84 (s,3H),6.57- 6.66(m,2H),7.00-7.15(m,2H).MSm/z (TOFES ⁺ ):490(M+Na). CompoundVIV-2

3-{(13S,15R)-3-Hydroxy-17-[(E)-methoxyimino]-13-methyl-2-nit ro- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1 using thecompoundVIII-1 asa startingmaterial.

1H-NMR(CDCl3):1.11(s,3H),1.40-3.05(m,21H),3.85(s,3H),6.87(s, 1H),7.07(s,1H),7.98(s,1H)10.57 (brs,1H),11.91(brs,1H).MSm/z (TOFES ⁺ ): 513(M+H). CompoundVIV-3

3-{(13S,15R)-2-Amino-3-hydroxy-17-[(E)-methoxyimino]-13-meth yl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1 using thecompoundVIII-4 asa startingmaterial.

1H-NMR(CDCl3):1.04(s,3H),1.25-2.90(m, 21H),3.84(s,3H),6.47(s, 1H),6.68(s,1H),7.05(s,1H).MSm/z (TOFES ⁺ ):505(M+Na). CompoundVIV-4

3-{(13S,15R)-3-Hydroxy-17-[(E)-methoxyimino]-13-methyl-4-nit ro- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1 using thecompoundVIII-2 asa startingmaterial.

1H-NMR(CDCl3): 1.12(s,3H),1.20-3.35(m,21H),6.96(d,1H),7.07(s, 1H),7.48(d,1H).MSm/z (TOFES ⁺ ):535(M+Na). CompoundVIV-5

3-{(13S,15R)-4-Amino-3-hydroxy-17-[(E)-methoxyimino]-13-meth yl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1using thecompoundVIII-5 asa startingmaterial.

1H-NMR (CDCl ₃ ): 1.04 (s, 3H), 1.20-2.95 (m, 21H), 3.84 (s, 3H), 6.58 (AB,2H),7.08(s,1H).MSm/z (TOFES ⁺ ):505(M+Na). CompoundVIV-6

3-{(13S,15R)-3-Hydroxy-2-iodo-17-[(E)-methoxyimino]-13-methy l- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1 using thecompoundVIII-18 asastartingmaterial.

1H-NMR(CDCl3): 1.09(s,3H),1.20-2.90(m,21H),3.84(s,3H),6.72(s, 1H),7.07(s,1H),7.51(s,1H).MSm/z (TOFES ⁺ ):616(M+Na). CompoundVIV-7

3-{(13S,15R)-3-Hydroxy-4-iodo-17-[(E)-methoxyimino]-13-methy l- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1using thecompoundVIII-7 asastartingmaterial.

1H-NMR(CDCl3): 1.09(s,3H),1.30-2.95(m,21H),3.85(s,3H),6.83(d, 1H),7.08(s,1H),7.19(d,1H).MSm/z (TOFES ⁺ ):616(M+Na). CompoundVIV-8

3-{(13S,15R)-3-Hydroxy-2,4-diiodo-17-[(E)-methoxyimino]-13-m eth- yl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phen anthren-15-yl}-N- (5-methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1using thecompoundVIII-6 asastartingmaterialin45%yield.

1H-NMR(CDCl ₃ ): 1.09 (s,3H),1.23-2.96(m,21H),3.85(s,3H),7.61(s, 1H),7.08(s,1H).MSm/z (TOFES ⁺ ):720(M+1). Compound VIV-9

3-{(13S,15R)-2-Bromo-3-hydroxy-17-[(E)-methoxyimino]-13-meth yl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)-propanamide

Preparedby themethod asdescribed for the compoundVIV-1 using theC-2 monobromideVIII-9 asastartingmaterial.

1H-NMR (DMSO-d6):1.03 (s,3H),1.2-3.0(m,18H),2.33 (s,3H), 3.73 (s,3H),6.65 (s,1H),7.11 (s,1H),7.27(d,1H),9.86(s,1H),11.91(s,1H).MS m/z (TOFES ⁺ ):546/548. CompoundVIV-10

3-{(13S,15R)-4-Bromo-3-hydroxy-17-[(E)-methoxyimino]-13-meth yl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1 using theC-4 monobromideVIII-10 asastartingmaterial.

1H-NMR (DMSO-d6):1.02 (s,3H),1.2-2.9(m,18H),2.33 (s,3H), 3.73 (s,3H),6.76 (m,1H),7.12 (m,2H),9.89(s,1H),11.92(s,1H).MS m/z (TOFES ⁺ ): 568/570(M+Na). Compound VIV-11

3-{(13S,15R)-2,4-Dibromo-3-hydroxy-17-[(E)-methoxyimino]-13- methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] phenanthren-15- yl}-N-(5-methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1 using theC-2,4-dibromideVIII-11 asastartingmaterial.

1H-NMR(DMSO-d ₆ ):1.01(s,3H),1.10-2.90(m,21H),3.72(s,3H),7.11 (s,1H),7.40(s,1H),9.54(s,1H),11.91(s,1H).MSm/z (TOFES ⁺ ):648(M+Na). CompoundVIV-12

3-{(13S,15R)-2-Chloro-3-hydroxy-17-[(E)-methoxyimino]-13-met hyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1 using thecompoundVIII-13 asastartingmaterial.

1H-NMR(CDCl ₃ ):1.09(s,3H),1.25-2.92(m,21H),3.84(s,3H),6.73(s, 1H),7.07(s,1H),7.19(s,1H).MSm/z (TOFES ⁺ ):524/526(M+Na). CompoundVIV-13

3-{(13S,15R)-4-Chloro-3-hydroxy-17-[(E)-methoxyimino]-13-met hyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1 using thecompoundVIII-12 asastartingmaterial.

1H-NMR(CDCl3): 1.09(s,3H),1.25-3.05(m,21H),3.84(s,3H)6.84(d, 1H),7.07(s,1H),7.12(d,1H).MSm/z (TOFES ⁺ ):524/526(M+Na). CompoundVIV-14

3-{(13S,15R)-2,4-Dichloro-3-hydroxy-17-[(E)-methoxyimino]-13 - methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] phenanthren-15- yl}-N-(5-methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1 using theC-2,4 dichlorideVIII-14 asastartingmaterial.

1H-NMR (CDCl3): 1.10 (s, 3H), 1.4-3.0 (m, 18H), 2.42 (s, 3H), 3.85 (s, 3H),7.07 (s,1H),7.21(s,1H).MSm/z (TOFES ⁺ ):558/560(M+Na). CompoundVIV-15

3-{(13S,15R)-2-Fluoro-3-hydroxy-17-[(E)-methoxyimino]-13-met hyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1 using thecompoundVIII-16 asastartingmaterial.

1H-NMR (CDCl ₃ +MeOH-d ₄ ): 1.10 (s, 3H), 1.25-3.0 (m, 21H), 3.84 (s, 3H),6.66(d,J=10Hz,1H),6.94(d,J=12Hz,1H),7.03(brs,1H).MS m/z (TOF ES ⁺ ):508(M+Na). CompoundVIV-16

3-{(13S,15R)-4-Fluoro-3-hydroxy-17-[(E)-methoxyimino]-13-met hyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Prepared by themethod as described for the compoundVIV-1 using thecompoundVII-18 asastartingmaterial.

1H-NMR(CDCl3): 1.09(s,3H),1.30-2.95(m,21H),3.84(s,3H),6.79(t, J=4Hz,1H),6.94(d,J=4Hz,1H),7.07(brs,1H).MS m/z (TOFES ⁺ ):508(M+ Na). CompoundVIV-17

3-{(13S,15R)-2-Bromo-4-fuoro-3-hydroxy-17-[(E)-methoxyimino] -13- methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] phenanthren-15- yl}-N-(5-methylthiazol-2-yl)propanamide

Prepared by themethod as described for the compoundVIV-1 using thecompoundVII-21 asastartingmaterial.

1H-NMR(CDCl3):1.10(s,3H),1.53-2.90 (m,21H),3.84(s,3H),7.06 (d, 1H),7.17 (d,1H).MSm/z (TOFES ⁺ ):564/566(M ⁺ ). CompoundVIV-18

3-{(13S,15R)-4-Bromo-2-fluoro-3-hydroxy-17-[(E)-methoxyimino ]- 13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta [a]phenanthren- 15-yl}-N-(5-methylthiazol-2-yl)propanamide

Prepared by themethod as described for the compoundVIV-1 using thecompoundVII-22 asastartingmaterial.

1H-NMR(CDCl3): 1.09 (s,3H),1.25-2.91 (m,21H),3.85 (s,3H),7.01 (d, 1H),7.07(d,1H).MSm/z (TOFES ⁺ ):564/566(M ⁺ ). CompoundVIV-19

3-{(13S,15R)-3-hydroxy-17-[(E)-methoxyimino]-13-methyl-2-nit rile- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Prepared by themethod as described for the compoundVIV-1 using thecompoundVII-27 asastartingmaterialinquantitativeyield.

1H-NMR(CDCl3): 1.09(s,3H),1.2-2.43(m,19H),2.87(m,2H),3.85(s, 3H),6.70(s,1H),7.37(s,1H). MSm/z (TOFES ⁺ ):493(M+1). CompoundVIV-20

3-{(13S,15R)-3-hydroxy-17-[(E)-methoxyimino]-13-methyl-4-nit rile- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Prepared by themethod as described for the compoundVIV-1 using thecompoundVII-28 asastartingmaterial.

1H-NMR(CDCl3): 1.09(s,3H),1.4-2.6(m,19H),3.03(m,2H),3.84(s, 3H),6.79(d,1H),7.38(d,1H). MSm/z (TOFES ⁺ ):493(M+1). CompoundVIV-21

3-{(13S,15R)-17-[(E)-Ethoxyimino]-3-hydroxy-13-methyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedby themethod asdescribed for the compoundVIV-1 using thecompoundVII asastartingmaterialandethylhydroxylaminehydrochloride asareagent,yield82%.

1H-NMR (DMSO-d6):1.03 (s,3H),1.17(t,3H),1.2-2.9(m,18H),2.33 (s, 3H), 3.98(q,2H),6.50 (m,2H),7.04 (d,1H),7.11(s,1H),9.04(s,1H),11.91(s, 1H).MSm/z (TOFES ⁺ ):504(M+Na),482(M+1). SynthesisofC-17oximes

C-17-Oximeswere synthesized from C-17 ketones using themethod describedbelow:

Ketone (0.3mmol)wasdissolved inamixtureof ethanol (3ml) and THF(2ml)undernitrogenatmosphere.Pyridine(1.5mmol)andhydroxyl amine hydrochloride(0.9mmol)wereaddedtothissolution.Thereactionmix turewas refluxedfor1-2h.Solventswereevaporated.Waterwasaddedandthepr oduct waseitherfilteredorextractedwithethylacetate,washedwithdilut e hydrochlo- ric acid and finally with water. Oximes were purified further by flash-chrom- atographyifrequired. CompoundVIV-22

3-{(13S,15R)-3-Hydroxy-17-[(E)-hydroxyimino]-13-methyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedusingthegeneralmethod above using thecompound VII asa startingmaterial.

1H-NMR(DMSO-d6):1.02 (s,3H),1.2-2.9 (m,21H),6.46 (s,1H),6.50 (d,3H),7.04(d,1H),7.12 (s,1H),9.02(s,1H),10.18(s,1H),11.92(s,1H).MSm/z (TOFES ⁺ ):476(M+Na). CompoundVIV-23

3-{(13S,15R)-3-Hydroxy-2-nitro-17-[(E)-hydroxyimino]-13-meth yl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedusingthegeneralmethod above using thecompound5 asa startingmaterial.

1H-NMR(CDCl3): 1.15 (s,3H),1.30-2.75 (m,18H),2.85-3.05 (m,3H), 6.87(s,1H),7.06(s,1H) , 7.97(s,1H)8.50(br s,1H),10.55(brs, 1H).MS m/z (TOFES ⁺ ):499(M+H). CompoundVIV-24

3-{(13S,15R)-3-Hydroxy-4-nitro-17-[(E)-hydroxyimino]-13-meth yl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

Preparedusingthegeneralmethod above using thecompound6 asa startingmaterial.

1H-NMR(CDCl ₃ +MeOH-d ₄ ): 1.13(s,3H),1.30-3.30(m,21H),6.91(d, 1H),7.04(s,1H),7.39(d,1H).MSm/z (TOFES ⁺ ):521(M+Na). CompoundVIV-25

3-{(13S,15R)-2-Bromo-3-hydroxy-17-[(E)-hydroxyimino]-13-meth yl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

PreparedusingthegeneralmethodaboveusingtheC-2monobromide 19asastartingmaterial.

1H-NMR (CDCl3 +MeOH-d4): 1.11 (s, 3H), 1.2-3.0 (m, 18H), 2.40 (s, 3H),6.69 (s,1H),7.04 (s,1H),7.32(d,1H).MS m/z (TOFES ⁺ ):532/534. CompoundVIV-26

3-{(13S,15R)-4-Bromo-3-hydroxy-17-[(E)-hydroxyimino]-13-meth yl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

PreparedusingthegeneralmethodaboveusingtheC-4 monobromide 20asastartingmaterial.

1H-NMR (CDCl3 +MeOH-d4): 1.11 (s, 3H), 1.2-3.0 (m, 18H), 2.41 (s, 3H),6.82 (d,1H),7.06 (s,1H),7.14(d,1H).MSm/z (TOFES ⁺ ):532/534. CompoundVIV-27

3-{(13S,15R)-2,4-Dibromo-3-hydroxy-17-[(E)-hydroxyimino]-13- methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] phenanthren-15- yl}-N-(5-methylthiazol-2-yl)propanamide

Preparedusingthegeneralmethodaboveusing thedibromide21 as a startingmaterial.

1H-NMR (DMSO-d6):1.00(s,3H),1.25-2.95 (m,21H), 7.11(s,1H)7.40 (s,1H),9.54(s,1H),10.20(s,1H),11.93(s,1H).MS m/z (TOFES ⁺ ):632/634/636 (M+Na). CompoundVIV-28

3-{(13S,15R)-2-Chloro-3-hydroxy-17-[(E)-hydroxyimino]-13-met hyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

PreparedusingthegeneralmethodaboveusingtheC-2chloride23as astartingmaterial.

1H-NMR(CDCl ₃ ):1.10 (s,3H),1.30-3.0 (m,21H),6.69 (s,1H),7.04 (s, 1H),7.17(s,1H).MSm/z (TOFES ⁺ ):510/512(M+Na). CompoundVIV-29

3-{(13S,15R)-4-Chloro-3-hydroxy-17-[(E)-hydroxyimino]-13-met hyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

PreparedusingthegeneralmethodusingtheC-4chloride22asastar- tingmaterial.

1H-NMR(CDCl3): 1.10(s,3H),1.30-3.05(m,21H),6.80(d,1H),7.05(s, 1H),7.08(d,1H).MSm/z (TOFES ⁺ ):510/512(M+Na). CompoundVIV-30

3-{(13S,15R)-2,4-Dichloro-3-hydroxy-17-[(E)-hydroxyimino]-13 - methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] phenanthren-15- yl}-N-(5-methylthiazol-2-yl)propanamide

Preparedusingthegeneralmethod above usingC-2,4 dichloride24as astartingmaterial.

1H-NMR (CDCl3 +MeOH-d4): 1.11 (s, 3H), 1.4-3.0 (m, 18H), 2.39 (s, 3H),7.03 (s,1H),7.19(s,1H).MSm/z (TOFES ⁺ ):522/524. CompoundVIV-31

3-{(13S,15R)-2-Fluoro-3-hydroxy-17-[(E)-hydroxyimino]-13-met hyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl}-N-(5- methylthiazol-2-yl)propanamide

PreparedusingthegeneralmethodaboveusingtheC-2fluoride26as astartingmaterial.

1H-NMR(CDCl ₃ +MeOH-d ₄ ): 1.10(s,3H),1.25-3.0(m,21H),6.66(d,J= 10Hz,1H),6.92(d,J=12Hz,1H),7.04(brs,1H).MSm/z (TOFES ⁺ ):472(M+H). CompoundVIV-1a

Potassium (13S,15R,E)-17-(methoxyimino)-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-olate

VIV-1 (200mg,0.43mmol)wasdissolvedinethanol(1.5ml)andKOH (36mg, 0.64mmol, 150mol-%)was added inmethanol (300 µl).The reaction mixturewasstirredatrtfor60minutes,thensolventswereevaporated .Thepre- cipitate was triturated with diethylether-ethanol (v/v 2:1) mixture, finally washedwithetheranddriedcarefullyyielding192mgoftheproduct.

1H-NMR (DMSO-d6): 1.03 (s, 3H), 1.30-2.90 (m, 22H), 3.72 (s, 3H), 6.36-6.43 (m,2H),6.71(s,1H),6.92(d,1H). CompoundVIV-1b

3-((13S,15R,E)-3-hydroxy-17-(methoxyimino)-13-methyl- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-15-yl)-N-(5- methylthiazol-2-yl)propanamidehydrochloride

VIV-1 (200mg,0.43mmol)wasdissolvedinEtOAc(1ml)and2NHCl inEtOAc(0.5ml)wasadded.Thereactionmixturewasstirredatrtfor30 minu- tes,whentheproductstartedtoprecipitate.Thesolventwasevaporat edandthe crudeproductwas trituratedwithEtOAc.Theproductwas filteredandwashed severaltimeswithEtOAcanddriedyielding154mgoftheproduct.

1H-NMR (DMSO-d ₆ ): 1.03 (s, 3H), 1.25-2.90 (m, 23H), 3.78 (s, 3H), 6.47-6.53 (m,2H),7.02(s,1H),7.13(d,1H),12.01(brs,1H). C3derivatives Compound1

Phosphoric acid mono-{(13S,15R)-17[(E)-methoxyimino]-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

VIV-1 (3.0 g, 6.42mmol, 100mol-%)was dissolved in dryTHF (40 ml).Pyridine(2.1ml,400mol-%)andphosphorousoxychloride(2.4ml, 400mol- %)wereadded,andthesolutionwasstirredatrtforfourhoursundernit rogen. The solution cooled and 60ml ofwaterwas carefully added. Stirringwas con- tinuedovernight.THFwasevaporated.Theprecipitatesolutionwasma debasic with2NNaOH-solution.AfterwashingwithEtOAc (3x30ml), thewaterphase wasacidifiedwithconc.HCl.Theproductprecipitatedandthenfilter ed.Thesolid materialwaswashedseveraltimeswithwater(5x60ml).Thecrudeprodu ct(3.6 g)wasco-evaporatedwithtolueneandethanol.^ ¹ H-NMR (DMSO-d ₆ ): 1.04 (s, 3H), 1.36-2.90 (m, 23H), 3.73 (s, 3H), 6.88-6.92(m,2H),7.11(s,1H),7.23(d,1H),11.93(brs,1H). Compound1a

Phosphoric acidmono-{(13S,15R)-17-[(E)-methoxyimino]-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}esterdisodiumsalt

Phosphoric acid crude product (3.6 g)was dissolved in abs. ethanol (35ml)andthenNaOH(1.1g)dissolvedinabs.ethanolwasadded.Afters tirring fortwohours,solventswere evaporated.Theprecipitatewaswashedseveralti- meswithEt2OandEt2O:EtOH(3:1).Theyieldof the phosphatedisodiumsaltwas 3.7g.

1H-NMR (MeOH-d4^+D2O): 1.11 (s, 3H), 1.30-1.63 (m, 6H), 1.98-2.46 (14H), 2.73-2.90 (m, 2H), 3.80 (s, 3H), 7.03-7.15 (m, 4H). ³¹ P-NMR (MeOH-d4^+ D2O):0.56.MSm/z(TOFES+):592(M+1),570(-PO3H2 +Na). Compound2

tert-Butoxycarbonylamino-acetic acid (13S,15R)-13-methyl-17[(E)- methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarbamoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-ylester

VIV-1 (500mg,1.1mmol,100mol-%)wasdissolvedinDCM(10ml) and pyridine (173 µl, 200mol-%), BOC-glycine (225mg, 120mol-%) and DCC (330mg,150mol-%)wereaddedtothereactionmixture.Additionalamou ntsof reagents(30%oftheoriginalamounts)wereadded aftersixhours and then stir- ringwascontinuedatrtovernight.TheprecipitatedDHUwasfilteredo ff,andthe filtratewaswashedwithwaterandseveraltimeswithdiluteHCl-solut ion,follo- wedbywashingwithwaterandfinallywithbrine.Thecrudeproductwasp uri- fiedbychromatographyusingDCM-MeOH(v/v99:1)asaneluent.Theamou ntof theproductwas599mg.

1H-NMR (DMSO-d ₆ ): 1.04 (s, 3H), 1.39 (s, 9H), 1.45-2.20 (m, 14H), 2.07-2.95(m,7H),3.65(d,2H),3.73(s,3H),3.92(d,2H),6.82-6.86(m ,2H),7.11 (s,1H),11.90(brs,1H). Compound3a

Aminoacetic acid (13S,15R)-13-methyl-17[(E)-methoxyimino]-15-[2- (5-methyl-thiazol-2-ylcarbamoyl)-ethyl]-7,8,9,11,12,13,14,15 ,16,17-decahydro- 6H-cyclopenta[a]phenanthren-3-ylestertrifluoroacetate

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)affordi ngthe TFA-salt360mg.

1H-NMR(DMSO-d6):1.05(s,3H),1.41-2.25 (m,13H),2.33-2.40 (s +m, 4H),2.60-2.92 (m,3H),3.73(s,3H),3.82(s,2H),4.11(s,2H),6.89-6.94(m,2H), 7.11(s,1H),7.36(d, 2H),11.92(s,1H).MSm/z(TOFES+):547(-TFA;M+Na), 525(-TFA;M+H). Compound3b

Aminoacetic acid (13S,15R)-13-methyl-17[(E)-methoxyimino]-15-[2- (5-methyl-thiazol-2-ylcarbamoyl)-ethyl]-7,8,9,11,12,13,14,15 ,16,17-decahydro- 6H-cyclopenta[a]phenanthren-3-ylesterhydrochloride

Boc-protectedglycinederivative2 (340mg,0.5mmol)wasdissolved inEtOAc(3ml)and2NHCl-solutionwasadded.Thereactionmixturewass tirred at rt for an hour, then the solventwas evaporated, followed by co-evaporation withtoluene.FinallyEtOAc(2ml)wasadded,andthesolidmaterial formed was filteredandwashedseveraltimeswithEtOAcaffordingtheHCl-salt(2 60mg).

1H-NMR (MeOH-d4): 1.13 (s, 3H), 1.31-1.80 (m, 7H), 2.15-3.10 (m, 17H), 3.80 (s, 3H), 4.12 (s, 2H), 6.92 (m, 2H), 7.28-7.37 (m, 2H).MSm/z (TOF ES+):547(-HCl;M+Na),525(-HCl;M+H). Compound4

Tert-Butoxycarbonyl-methylamino-acetic acid (13S,15R)-13-methyl- 17[(E)-methoxyimino]-15-[2-(5-methyl-thiazol-2-ylcarbamoyl)- ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-ylester

VIV-1 (500mg,1.1mmol,100mol-%)wasdissolvedinDCM(12ml). Boc-Sar-OH(326mg,200mol-%),N-methylmorpholine(350µl,300mol- %)and 1-hydroxy-1-H-benzotriazole (289 mg, 200 mol-%) were added. The reaction mixturewasstirredfor5minutesandthenwascooledwithice-bath.EDC I(451 mg,220mmol-%)wasadded,afterstirringfor30minutesatcold,thenov ernight atrt.Tothereactionmixturewasadded1NHCl-solution(10ml), thenthepro- duct was extracted with DCM. The crude product was purified by chromato- graphyusingDCM-MeOH98:2asaneluentaffordingtheproduct(520mg;7 6%).

1H-NMR(DMSO-d6):1.05(s,3H),1.34-2.91(m,33H),3.73(s,3H),4.20 (s, 2H), 6.83-6.88 (m, 2H), 7.10 (s, 1H), 7.31-7.35 (m,1H), 11.90 (br s, 1H).MS m/z(TOFES+)661(M+Na). Compound5a

Methylamino-aceticacid(13S,15R)-13-methyl-17[(E)-methoxyimin o]- 15-[2-(5-methyl-thiazol-2-ylcarbamoyl)-ethyl]-7,8,9,11,12,13 ,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-ylesterhydrochloride

TheBoc-protectedsarcosine4 (500mg,0.8mmol) inEtOAcwasun- protectedbyadditionof2NHCl-EtOAc–solution.Thereactionmixtu rewasstir- redforanhour,followedbyevaporationofthesolvent.Theprecipitat ewastritu- rated several timeswith Et2O, heptane and finallywith EtOAc. The yield of the productwas453mg;quant.

1H-NMR(DMSO-d6):1.05(s,3H),1.40-2.64(m,22H),2.89(brs,2H), 3.74(s,3H),4.23(s,2H),6.91-6.97(m,2H),7.12 (s,1H),7.36(d,1H),9.52(brs, 2H),11.99(brs,1H).MSm/z(TOFES+)561(M+Na),539(M+1). CompoundVV

Chloroacetic acid (13S,15R)-13-methyl-17[(E)-methoxyimino]-15-[2- (5-methyl-thiazol-2-ylcarbamoyl)-ethyl]-7,8,9,11,12,13,14,15 ,16,17-decahydro- 6H-cyclopenta[a]phenanthren-3-ylester

VIV-1 (500mg,1.1mmol, 100mol-%)was dissolved inDCM (5ml) under nitrogen atmosphere and pyridinewas added (215 µl, 2.7 mmol, 250 mol-%).Reactionwas cooledwith icebathandchloroacetyl chloride (215µl, 2.7 mmol,250mol-%)dissolvedinDCM(2ml) wasadded.Reactionwasstirred at0°Cfor1.5hoursandatrtfor40min.Water(10ml)wasaddedandlayer ssep- arated.WaterlayerwasextractedwithDCM(3x5ml).Combinedorganicl ayers wereextractedwith1NHCl(1x10ml),1NNaOH (1x10ml),water (3x30ml), brine (3x15 ml)anddriedwithNa ₂ SO ₄ .Theamountof thecrudeproductwas 517mg.

1H-NMR(DMSO-d ₆ ):1.04(s,3H),1.40-2.74(m,19H),2.87(brs,2H), 3.73(s,3H),4.66(s,2H),6.88-6.92(m,2H),7.11(s,1H),7.33(d,1H), 11.90(brs, 1H). Compound6

Morpholin-4-yl-acetic acid (13S,15R)-13-methyl-17[(E)-methoxy- imino]-15-[2-(5-methyl-thiazol-2-ylcarbamoyl)-ethyl]- 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenant hren-3-ylester

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 µl, 0.55 mmol,150mol-%)dissolvedindryTHF (1ml)wasaddedslowly. Stirringat0°C wascontinuedfor1.5hour,thenatrt for3hours.Morpholine(24 µl)wasadded and stirring continued until completed. EtOAc (10ml)was added and reaction mixturewaspouredintoice-cold0.1NHCl(10ml).Layerswereseparate dand waterlayerwasextractedwithEtOAc(3x5ml).Combinedorganiclayers were extractedwithwater (3 x 10ml) and brine (3 x 10ml) and driedwithMgSO ₄ . Amountofthecrudeproductwas190mg;87%.

1H-NMR(DMSO-d ₆ ):1.05(s,3H),1.40-2.39(m,18H),2.58(m,4H),2.86 (brs,2H),3.49(s,2H),3.60(m,4H),3.73(s,3H),4.23(s,2H),6.84-6. 88(m,2H), 7.11(s,1H),7.30(d,1H),11.90(brs,1H).MSm/z(TOFES+)617(M+Na),5 95 (M+1). Compound7

1-(tert-butyl) 2-(13S,15R,E)-17-(methoxyimino)-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)pyrrolidine-1,2-dicarboxyla te

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-%.

1H-NMR(CDCl ₃ ):1.11 (s,3H),1.48 (s,9H),1.20-3.10 (m,25H),3.38- 3.69(m,2H),3.85(s,3H),4.41-4.55(m,1H),6.80-6.87(m,2H),7.06(s ,1H),7.24- 7.31(m,1H),12.14(brs,1H).MSm/z(TOFES+):687(M+Na). Compound8a

(13S,15R,E)-17-(methoxyimino)-13-methyl-15-(3-((5-methylthia zol- 2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,17-decahydr o-6H-cyclo- penta[a]phenanthren-3-ylprolinatetrifluoroacetate

TheBoc-protectedprolinederivative7 (540 mg,0.81mmol) inDCM wasunprotectedbyadditionof trifluoroaceticacid(TFA)(1.6ml).Thereaction mixturewas stirred first in ice-bath for3hoursand thenat rt foranhour, fol- lowedbyevaporationofthesolvent.Theprecipitatewastrituratedse veraltimes withEt ₂ Oyielding350mgoftheproduct,theyield69%.

1H-NMR(CDCl ₃ ):1.09 (s,3H),1.27-2.91 (m,25H),3.45-3.52 (m,2H), 3.84(s,3H),4.60-4.67(m,1H),6.79-6.85(m,2H),7.09(s,1H),7.24-7 .29(m,1H). Compound8b

(13S,15R,E)-17-(methoxyimino)-13-methyl-15-(3-((5-methylthia zol- 2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,17-decahydr o-6H-cyclopenta- [a]phenanthren-3-ylprolinatehydrochloride

HClsaltoftheproduct 8 waspreparedbydissolvingTFAsaltFP-5683 AII(380mg)inEtOAc(3ml)andadding4MHCl(300µl).Reactionwasstir red foranhour. TriturationseveraltimeswithEt ₂ OendEtOAcyielding222mgofthe product.

1H-NMR (DMSO-d ₆ ): 1.05 (s, 3H), 1.27-3.05 (m, 27H), 3.10-3.45 (m, 3H),3.73(s,3H),4.63(m,1H),6.97-7.01(m,2H),7.12(s,1H),7.36(m, 1H),9.32 (brs,1H),10.36(brs,1H),11.97(brs,1H). Compound9

di-tert-butyl((((13S,15R,E)-17-(methoxyimino)-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)oxy)methyl)phosphate

Starting material VIV-1 (770 mg, 1.65 mmol, 100 mol-%) was dis- solvedindryDMF(10ml).Di-tert-butyl chloromethylphosphate [85%](600mg, 1.97 mmol, 120 mol-%) and tetrabutylammoniumiodide (Bu4NI) (123 mg, 0.33 mmol, 20mol-%) were added. Reaction was cooled to 0°C. NaH [60%] (145 mg,3.62mmol,220mol-%) wascarefullyadded.Reactionwasstirredfirst at0°Cfor30minandthenatrtfor5hours.NaH(35mg)wasaddedandreact ion stirred overnight. Reactionwas 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)anddriedw ith Na2SO4. The crude product was triturated with heptane:EtOAc (8:2) yielding 1.03 g(91%)oftheproduct.^ ¹ H-NMR (DMSO-d ₆ ): 1.03 (s, 3H), 1.10-2.90 (m, 21H), 1.39 (s, 18H), 3.73(s,3H),5.51-5.57(d,2H),6.79-6.84(m,2H),7.11(s,1H),7.20-7 .24(m,1H), 11.90(brs,1H) Compound10 (((13S,15R,E)-17-(methoxyimino)-13-methyl-15-(3-((5-methylth iazol- 2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,17-decahydr o-6H-cyclopenta- [a]phenanthren-3-yl)oxy)methyldihydrogenphosphate

9 (1.0g,1.45mmol,100mol-%)wasdissolvedindryDCM(7ml).Re- actionwascooledto0°C.Trifluoroaceticacid(222µl,2.90 mmol,200mol-%)was dissolved indryDCM(1ml)andadded inreaction.Reactionwasstirredfirstat 0°C for fewhoursandthenatrtovernight.TFA(111µl,100mol-%)wasadded andstirringcontinued.Totalreactiontimewasthreedaysandadditio nalamount (111µl,100mol-%)ofTFAwasadded.SolventwasevaporatedandEtOAcw as added(100ml).SolidmaterialwasfilteredandwashedwithEtOAc(5x3m l)and Et2O(2x3ml)toyield320mgoftheproduct.

1H-NMR (DMSO-d6): 1.04 (s, 3H), 1.10-2.90 (m, 23H), 3.73 (s, 3H), 5.47-5.53(d,2H),6.79-6.84(m,2H),7.11(s,1H),7.19-7.23(m,1H), 11.89(brs, 1H). Compound10a

(((13S,15R,E)-17-(methoxyimino)-13-methyl-15-(3-((5-methylth iazol- 2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,17-decahydr o-6H- cyclopenta[a]phenanthren-3-yl)oxy)methyldihydrogenphosphate disodiumsalt

Startingmaterial10 (310mg,0.54 mmol,100mol-%)wasdissolvedin EtOH (10-15ml).NaOH-EtOH-solution(NaOH86mg,2.15 mmol,400mol-%and EtOH2ml)wasaddedandreactionstirredfor3.5hours.Precipitatewas filtered andwashedwithEtOH:Et ₂ O(0.5:3)(3x3ml)andEt ₂ O(2x3ml)yielding140 mg oftheproduct.^ ¹ H-NMR(D ₂ O):1.01(s,3H),1.10-2.90(m,21H),3.76(s,3H),5.40-5.44 (d,2H),6.83-6.88(m,2H),7.06(s,1H),7.20-7.31(m,1H). ³¹ P-NMR(D ₂ O):0.86. MSm/z(TOFES+):622(M+1). Compound11

(13S,15R,E)-2,4-dibromo-17-(hydroxyimino)-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-lacetate

VIII-29 (48mg,0.08mmol,100mol-%)was suspended inethanol (5ml). Hydroxyaminehydrochloride (26mg,0.38 mmol,500mol-%)andpyri- dine(73µl,0.90mmol,1200mol-%)wereaddedandthemixturewasstirr edat rtundernitrogenfor3h.ThesolventwasevaporatedandEtOAc(5ml)and water (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%).

1H-NMR(DMSO-d ₆ ):1.02(s,3H),1.10-2.90(m,21H),2.38(s,3H),7.11 (s,1H),7.61(s,1H),10.19(s,1H),11.91(brs,1H).

VIV-32: C-3hydrolsedimpurit (31%ofthecrudeproduct):

1H-NMR (DMSO-d6):1.00(s,3H),1.25-2.95 (m,21H), 7.11(s,1H)7.40 (s,1H),9.54(s,1H),10.20(s,1H),11.93(s,1H).MS m/z (TOFES ⁺ ):632/634/636 (M+Na). Compound12

(13S,15R,E)-2,4-dibromo-17-(methoxyimino)-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-lacetate

VIV-11 (100mg,0.16mmol,100mol-%)andDMAP(6mg,0.05 mmol, 30mol-%)weresuspendedindryDCM(3ml).Pyridine(155µl,1.92mmol, 1200 mol-%)andaceticanhydride(75µl,0.80mmol,500mol-%)wereaddedun der nitrogen and themixturewas stirred at rt overnight. Themixturewas diluted withDCM(3ml) andwashedwithwater,2NHCl,waterandbrine.Dryingwith Na ₂ SO ₄ andevaporatingthesolventafforded86mgoftheproduct. Yield80%.

1H-NMR(DMSO-d ₆ ):1.03(s,3H),1.10-2.90(m,21H),2.37(s,3H),3.73 (s,3H),7.11(s,1H),7.61(s,1H),11.90(brs,1H).MSm/z(TOFES ⁺ ):668(M+1). Compound13

(13S,15R,E)-2,4-dibromo-17-(methoxyimino)-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-ldihdroenphosphate

VIV-11 (150mg,0.24mmol,100mol-%)wasdissolvedindryTHF (3 ml)andpyridine(1.5ml).DMAP(29mg,0.24 mmol,100mol-%)wasadded. Phosphorusoxychloride(67µl,0.72 mmol,300mol-%)wasaddeddropwiseun- dernitrogenandthemixturewasstirredovernightatrt.Themixturewa scooled withanicebath,coldwater(2ml)wasaddedandthemixturewasstirreda trtfor 1.5 h. The solventswere evaporated andwater (3ml)was added. Themixture waslefttoprecipitateovertheweekend.Theprecipitatewasfiltered andwashed withwater,2NHClandwateranddried inavacuumoven in50°Cfor3.5h,af- fording125mgoftheproduct.

1H-NMR(DMSO-d ₆ ):1.02(s,3H),1.10-2.90(m,21H),3.73(s,3H),7.11 (s,1H),7.51 (s,1H),11.89 (br s,1H). ³¹ P-NMR(DMSO-d6): -7.43.MSm/z (TOF ES ⁺ ):706(M+1). Compound14

(13S,15R,Z)-2,4-dibromo-17-(methoxyimino)-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-yldimethylglycinate

VIV-11 (100mg,0.16mmol,100mol-%)wassuspended indryDCM (2ml).Pyridine(85µl,1.0mmol,650mol-%),DMAP(6mg,0.05mmol,30m ol- %),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 ,DCMwas addedtotheresidueandthemixturewasagainfilteredthroughCelitet wice.The precipitatewaswashedwithDCMandEtOAc.Thesolventswereevaporate d,DCM (5 ml) andwater (5ml)were added and stirred vigorously. The aqueous layer waswashedwithDCM,theorganiclayerswerecombinedandwashedwith0. 1N HCl,waterandbrine.DryingwithNa2SO4andevaporatingthesolventaf forded 73 mgoftheproduct.

1H-NMR(DMSO-d6):1.03(s,3H),1.10-2.90(m,21H),2.35(s,6H),3.57 (brs,2H),3.73(s,3H),7.10(s,1H),7.61(s,1H),11.90(brs,1H).MSm/ z(TOF ES ⁺ ): 711(M+1). Compound14a

(13S,15R,Z)-2,4-dibromo-17-(methoxyimino)-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-yldimethylglycinatehydrochlori de

14 (56mg,0.08 mmol,100mol-%)wasdissolvedindryEtOAc(1ml). Themixturewasfiltered.Conc.HCl(24µl)inEtOAc(0.2ml)wasaddedd ropwise undernitrogenandthemixturewasstirred inrt for20min.Thesolventswere evaporated and the residuewas co-evaporated twicewith toluene. The residue was triturated several timeswithEtOAc, filteredandwashedagainwithEtOAc. Theresiduewasdriedinavacuumovenin50°Cfor2.5h,affording30mgo fthe crude product. HPLC (280 nm) 54%. The product did not purify with HCl salt preparation.

1H-NMR(DMSO-d ₆ ):1.03(s,3H),1.10-2.90(m,20H),2.94(s,6H),3.73 (s,3H),4.80(brs,2H),7.11(s,1H),7.61(s,1H),10.89(brs,1H),11.9 0(brs,1H). Compound15

(13S,15R,E)-2-iodo-17-(methoxyimino)-13-methyl-15-(3-((5-met hyl- thiazol-2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,17- decahydro-6H- cyclopenta[a]phenanthren-3-yldimethylglycinate

VIV-6 (100mg,0.19 mmol,100mol-%)wasdissolvedinDCM(2 ml) under nitrogen atmosphere. Pyridine (97 µl, 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. Reactionwasstirredat40°Cfor 3hours.Oxalicacid(67mg,0.74 mmol,400mol- %)dissolvedinMeOH(0.5ml)wasaddedandstirringcontinuedfor1h40m in. TheprecipitatedDHUwasfilteredoff.Organiclayerswerewashedseve raltimes withdilute0.1NHCl-solution, followedbywashingwithwaterand finallywith brine.Theamountofthecrudeproductwas110mg. ¹ H-NMR(DMSO-d ₆ ):1.04(s,3H),1.10-2.90(m,21H),2.34(s,6H),3.49 (s,2H),3.73(s,3H),6.93(s,1H),7.10(s,1H),7.67(s,1H),11.87(brs ,1H).MS m/z(TOFES ⁺ ):679(M+1). Compound16

(13S,15R,E)-2-iodo-17-(methoxyimino)-13-methyl-15-(3-((5-met hyl- thiazol-2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,17- decahydro-6H- cyclopenta[a]phenanthren-3-yldihydrogenphosphate

VIV-6 (50mg,0.08 mmol,100mol-%)wasdissolvedindryTHF(1ml) under nitrogen atmosphere. Pyridine (0.5 ml), DMAP (10mg, 0.08 mmol, 100 mol-%)andphosphorousoxychloride(24µl,0.25 mmol,300mol-%)wereadded. Reactionwasstirredatrtforfourhours.Thesolutionwascooledand1m lofwa- terwascarefullyadded.Stirringwascontinuedforonehour.THFwasev aporated andwater(2ml)wasadded.Precipitatedproductwasfilteredandwashe dwith water(2x2ml),2NHCl(3x2ml)andwater(3x2ml). Amount oftheproduct was38mg.

1H-NMR(DMSO-d6):1.03(s,3H),1.10-2.90(m,21H),3.73(s,3H),7.11 (s,2H),7.61 (s,1H),11.90 (br s,1H). ³¹ P-NMR(DMSO-d6): -6.75.MSm/z (TOF ES ⁺ ):674(M+1). Compound16a (13S,15R,E)-2-iodo-17-(methoxyimino)-13-methyl-15-(3-((5-met hyl- thiazol-2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,17- decahydro-6H- cyclopenta[a]phenanthren-3-yldihydrogenphosphatedisodiumsalt

16 (22mg, 0.03mmol, 100mol-%)was dissolved in abs. ethanol (0.2 ml)andthenNaOH(4.2mg,350mol-%)dissolved inabs.ethanol(0.1ml) wasadded.After stirring foronehour, solventwas evaporated.Theprecipitate waswashedwithEt ₂ O(2x0.5ml)andEt ₂ O:EtOH(1:1)(2x0.5ml).Theamount ofthephosphatedisodiumsaltwas17mg.

1H-NMR (MeOH-d ₄ + D ₂ O): 1.12 (s, 3H), 1.10-2.90 (m, 21H), 3.79 (s, 3H),6.97(s,1H),7.50-7.53(m,2H). ³¹ P-NMR(MeOH-d ₄ +D ₂ O):0.25. Compound17

(13S,15R,E)-17-(methoxyimino)-13-methyl-15-(3-((5-methylthia zol- 2-yl)amino)-3-oxopropyl)-4-nitro-7,8,9,11,12,13,14,15,16,17- decahydro-6H- cyclopenta[a]phenanthren-3-yldihydrogenphosphate

Thecompound17 waspreparedbythesamemethodasusedfor16. Yield67%.

1H-NMR(DMSO-d ₆ ):1.04(s,3H),1.10-2.90(m,21H),3.73(s,3H),7.10 (s,1H),7.40-7.47(m,2H), 11.89(brs,1H). ³¹ P-NMR(DMSO-d6): -6.72.MSm/z (TOFES ⁺ ):593 (M+1). Compound17a Disodium (13S,15R,E)-17-(methoxyimino)-13-methyl-15-(3-((5- methylthiazol-2-yl)amino)-3-oxopropyl)-4-nitro-7,8,9,11,12,1 3,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-3-yldihydrogenphosphat e

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). ³¹ P-NMR(DMSO-d6):0.35. Compound18

(13S,15R,E)-17-(hydroxyimino)-13-methyl-15-(3-((5-methylthia zol-2- yl)amino)-3-oxopropyl)-4-nitro-7,8,9,11,12,13,14,15,16,17-de cahydro-6H-cyclo- penta[a]phenanthren-3-yldihydrogenphosphate

VIV-24 (90mg,0.160 mmol,100mol-%)wassuspendedinabs.etha- nol(5ml).Hydroxylaminehydrochloride(56mg,0.798 mmol,500 mol-%)was added. Pyridine (155 µl, 1.916 mmol, 1200mol-%)was added under nitrogen. The mixturewasstirredatrtfor3 h andat50-60°Cfor2h.Solventswereevapo- ratedandcrudeproducttrituratedwithEtOAc:0.25HCl(10ml:10ml).P roduct wasfilteredandwashedwith0.25MHClandwater.Yield84mg,92%.

1H-NMR (DMSO-d ₆ ): 1.02 (s, 3H), 1.10-2.90 (m, 21H), 7.10 (s, 1H), 7.39-7.49(m,2H),10.18(brs,1H),11.91(brs,1H). ³¹ P-NMR(DMSO-d6):-6.87. MSm/z(TOFES ⁺ ):579 (M+1). Compound19

(13S,15R,E)-4-bromo-17-(hydroxyimino)-13-methyl-15-(3-((5-me th- ylthiazol-2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14,15,16,1 7-decahydro-6H- cyclopenta[a]phenanthren-3-yldihydrogenphosphate

Thecompound19 waspreparedbythesamemethodasusedfor21 usingVIII-28 asstartingmaterial.Reactiontimewas3handwork-upwasmodi- fied.Water and 2NHClwere added and precipitated productwas filtered and washedwithwaterandEtOAc.Yield66mg,64%.

1H-NMR (DMSO-d6): 1.01 (s, 3H), 1.10-2.90 (m, 21H), 7.11 (s, 1H), 7.25-7.29(m,2H),10.17(brs,1H),11.92(brs,1H). ³¹ P-NMR(DMSO-d6):-6.77. Compound19a

Sodium (13S,15R,E)-4-bromo-17-(hydroxyimino)-13-methyl-15-(3- ((5-methylthiazol-2-yl)amino)-3-oxopropyl)-7,8,9,11,12,13,14 ,15,16,17-deca- hydro-6H-cyclopenta[a]phenanthren-3-ylphosphate

The compound 19a was prepared by the same method as used for 16a.Thereactiontimewas2h.

1H-NMR (MeOH-d ₄ ): 1.10 (s, 3H), 1.10-3.10 (m, 21H), 7.08 (s, 1H), 7.15-7.20 (d, 1H), 7.56-7.60 (d, 1H). ³¹ P-NMR (DMSO-d6): 0.06. MS m/z (TOF ES ⁺ ):656/658. Compound20

(13S,15R,E)-2,4-diiodo-17-(methoxyimino)-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-yldimethylglycinate

VIV-8 (100mg,0.139mmol,100mol-%)wasdissolvedindryDCM (2 ml) under nitrogen atmosphere. Pyridine (73 µl, 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°Cfor2handlefttostandover nightatrt. Oxalicacid(50mg,0.556 mmol,400mol-%)dissolvedinMeOH(0.2 ml)wasadd- ed and stirring continued for 1.5 h. Solventswere evaporated and residue dis- solvedinDCM.Theprecipitateddicyclohexylurea(DCU) wasfilteredoff.Organic layerswerewashedwith0.1NHCl(3x5ml),water(3x10ml)andbrine(2x 10 ml).Theamountofthe crudeproductwas120mg. ¹ H-NMR(DMSO-d ₆ ):1.03(s,3H),1.10-2.90(m,21H),2.38(s,6H),3.55 (s,2H),3.73(s,3H),7.11(s,1H),7.75(s,1H),11.90(brs,1H).MSm/z( TOFES ⁺ ): 805 (M+1). Compound21

(13S,15R,E)-2,4-dibromo-17-(hydroxyimino)-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-yldihydrogenphosphate

VIII-26 (90mg,0.13mmol,100mol-%)was suspended inethanol (5ml).Hydroxylaminehydrochloride(46mg,0.67 mmol,500mol-%)wasadded. Pyridine(130µl,1.60 mmol,1200mol-%)wasaddedundernitrogen.Themix- turewasstirredatrtfor5h.Additionalamountsofreagents(50%ofthe original amounts)wereaddedandthestirringwascontinuedatrtovernight.The mixture washeatedto40°Candstirredfor3.5h,thenheatedto60°Candstirre dfor1.5h andlefttostandovertheweekend at rt.ThesolventwasevaporatedandEtOAc (10ml)andwater(15ml)wereadded.Theprecipitatewasfiltered,wash edwith waterandEtOAc.Afterdryingandcombiningtheprecipitatewiththead ditional amountof theproductreceivedfromEtOAc-phase, theyieldof theproductwas 38mg.

1H-NMR(DMSO-d6):1.01(s,3H),1.10-2.90(m,24H),7.11(s,1H),7.50 (s, 1H), 10.20 (br s, 1H), 11.92 (br s, 1H). ³¹ P-NMR (DMSO-d6): -7.35.MSm/z (TOFES ⁺ ):692(M+1). Compound22

(13S,15R,E)-2,4-diiodo-17-(methoxyimino)-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-yldihydrogenphosphate

Thecompound22waspreparedbythesamemethodasusedfor18 in 4hoursreactiontime.Yield78mg,70%.

1H-NMR(DMSO-d ₆ ):1.01(s,3H),1.10-3.00(m,21H),3.72(s,3H),7.11 (s,1H),7.68 (s,1H),11.91 (br s,1H). ³¹ P-NMR(DMSO-d6): -7.55. MSm/z (TOF ES ⁺ ):800(M+1). PHARMACOLOGICALTESTS

Thefollowingtestsareprovidedtodemonstratethepresentinvention inillustrativewayandshouldnotbeconsideredaslimitinginthescop eofinven- tion.Further, the concentrationsof the compounds in theassaysare exemplary andshouldnotbetakenaslimiting.Apersonskilledintheartmaydefin ephar- maceuticallyrelevantconcentrationswithmethodknownintheart. Inhibitionof17β-hydroxysteroiddehydrogenasetype1enzyme

17β-HSD1productionand isolation: Recombinantbaculoviruswas generatedbythe“BactoBacExpressionSystem”(Invitrogen).Rec ombinantbac- midwastransfectedtoSd9 insect cellsusing“CellfectinReagent”(Invitrogen). 60 hlatercellswereharvested;themicrosomalfractionwasisolatedasd escribed byPuranen,T.J.,Poutanen,M.H.,Peltoketo,H.E.,Vihko,P.T.andVih ko,R.K.(1994) Site-directed mutagenesis of the putative active site of human 17 β-hydroxy- steroid dehydrogenase type 1. Biochem. J.304: 289-293. Aliquots were stored frozenuntildeterminationofenzymaticactivity.

Assay– Inhibitionof recombinant human17β-HSD1: Protein ho- mogenate(0,1 μg/ml)was incubated in20mMKH2PO4pH7.4with30nMes- trone(including800000cpm/mlof ³ H-estrone)and1mMNADPHfor30minat RT, in thepresenceof thepotential inhibitorat concentrations1 μMor0.1 μM. Inhibitor stock solutionswere prepared inDMSO. Final concentration ofDMSO wasadjustedto1%inallsamples.Theenzymereactionwasstoppedbyadd ition of10% trichloroaceticacid (final concentration). Sampleswere centrifuged ina microtiter plate at 4000 rpm for 10min. Supernatantswere applied to reverse phaseHPLConaWatersSymmetryC18column,equippedwithaWatersSentr y Guard column. Isocratic HPLC runs were performed at RT at a flow rate of1 ml/min in acetonitrile:water 48:52 as running solvent. Radioactivitywasmoni- tored in the eluate by a Packard Flow ScintillationAnalyzer. Total radioactivity forestroneandestradiolweredeterminedineachsampleandpercentco nversion ofestronetoestradiolwascalculatedaccordingtothefollowingform ula: %conversion=100x

{(cpmestradiolinsamplewithinhibitor) /

[(cpmestroneinsamplewithinhibitor)+(cpmestradiolinsamplewith inhibitor)]}

[(cpmestradiolinsamplewithoutinhibitor)/

[(cpmestroneinsamplewithoutinhibitor)+(cpmestradiolinsamplew ithoutinhibitor)]}. Percent inhibition was calculated flowingly:% inhibition = 100 - % conversion

The values% inhibitionwere determined for the parent compounds andtheresultsaresummarizedinTable3. Inhibition ofthe17β-hydroxysteroiddehydrogenasetype2enzyme

17β-HSD2productionandisolation: Similarlyto17β-HSD1the Re- combinant baculovirus was generated by the“Bac to Bac Expression System” (Invitrogen).RecombinantbacmidwastransfectedtoSd9insectcells using“Cell- fectin Reagent” (Invitrogen).60 h later cells were harvested and supernatant werefractionatedbythefollowingprotocol:

- cellsweredissolvedinto40mlofA-buffer(40mMTRIS,pH8.0,20% glycerol,20 μMNAD,0.4mMPMSF,150mMNaCl,0.5%dodecyl-β -maltoside+ proteaseinhibitorcocktail)

- cellsweresonicated

- lysatewasincubatedonicefor15min

- lysatewascentrifuged5000rpm15min,+4°C

- centrifugationofthesupernatant180000g30min,+4°C - pelletwasdissolvedinto8mlofA-buffer

- notresuspendedmaterialwasremovedbycentrifugation5000rpm 15min,+4°C

- theclearsupernatantwasdividedinto100 μlaliquotsandweresto- redfrozenuntildeterminationofenzymaticactivity. Theamountof17β-HSD2wasanalysed by immunoblottingand total proteinconcentrationofeachextractbatchwasdetermined.

Assay– Inhibitionof recombinant human17β-HSD2: Protein ho- mogenate(4 μg/ml)wasincubatedin20mMKH2PO4pH8.5with50nMestradi- ol(including800000cpm/mlof ³ H-estradiol)and1mMNADHfor30minatRT, inthepresenceofthepotentialinhibitoratconcentrations1 μMor0.1 μM.Inhibi- torstocksolutionswerepreparedinDMSO.FinalconcentrationofDMSO wasad- justedto1%inallsamples.Theenzymereactionwas stoppedbyadditionof10% trichloroacetic acid (final concentration). Sampleswere centrifuged in amicro- titerplateat4000rpmfor10min.Supernatantswereappliedtoreverse phase HPLConaWatersSymmetryC18column,equippedwithaWatersSentryGuar d column. IsocraticHPLCrunswereperformedatRTata flowrateof1ml/min in acetonitrile:water48:52as running solvent.Radioactivitywasmonitored in the eluate by a Packard Flow Scintillation Analyzer. Total radioactivity for estrone andestradiol weredeterminedineachsampleandpercentconversionofestradi- oltoestronewascalculatedaccordingtothefollowingformula: %conversion=100x

{(cpmestroneinsamplewithinhibitor)/

[(cpmestradiolinsamplewithinhibitor)+(cpmestroneinsamplewith inhibitor)]}

[(cpmestroneinsamplewithoutinhibitor)/

[(cpmestradiolinsamplewithoutinhibitor)+(cpmestroneinsamplew ithoutinhibitor)]}. Percent inhibition was calculated flowingly:% inhibition = 100 - % conversion

The values% inhibitionwere determined for the active entities and theresultsaresummarizedinTable3. EstrogenReceptorBindingAssay

Thebindingaffinityoftheparentcompoundstotheestrogenreceptor a(ER μ)maybedeterminedaccordingtotheinvitroERbindingassaydescrib ed byKoffmannetalREF.Alternatively,anestrogenreceptorbindingass aymaybe performedaccordingtointernationalpatentapplicationWO2000/079 96. EstrogenReceptorTransactivationAssays

Theparentcompoundsshowingbindingaffinitytowardstheestrogen receptormaybefurthertestedwithregardtotheirindividualestroge nicoranti- estrogenic potential (Agonistic or antagonistic binding to the ERα or ERβ). The determination of the estrogen receptor antagonistic activitymay be performed accordingtoaninvitroassaysystemusingtheMMTV-ERE-LUCreporters ystem forexampledescribedinUSpatentapplicationUS2003/0170292. MetabolicStabilityAssay

The in vitrometabolic stability of the parent compoundswas deter- minedforexemplifiedcompoundsusinghumanlivermicrosomeandhomog enate incubations.Theincubationtimepointsusedwithorwithoutappropri atecofac- torswere0minand60min.Sampleswerecollectedatbothtimepointsand sub- stratesweredetectedusingLC/PDA/TOF-MS.Invitrometabolicstabil ity(%re- maining after 60 min in human liver homogenate or microsomes) of the com- poundswerecalculatedandtheresultsaresummarizedinTable4. Table4:Metabolicstability

Enzymatichydrolysisofcompoundsofinvention

HydrolysisofthecompoundsaccordingtoExamples1a,3b,5a,and 7 totheirparentcompound VIV wastested.Theunitamountsofalkalinephospha- tasetypeVIISfrombovineintestinalmucosawereusedasdefinedbyasu pplier (SigmaAldrich). An appropriate amount of the compound (final concentration typically50μM)wasdissolvedinpreheatedbuffersolution(pH7.4)a ndthesolu- tionswereplacedinathermostaticallycontrolledwaterbathat37°C .Theenzy- maticreactionwasstartedbyaddingenzymetothesolution.Inblankso lutions, enzymewas replacedwith the samevolumeofwater toensure that thehydro- lysiswasclearlyenzymatic.Atpredeterminedtimeintervals,200μl sampleswere removedand200μlicecoldacetonitrilewasaddedtoeachsampletosto ptheen- zymatic hydrolysis. The samples were kept on ice, centrifuged for 10 min at 14000 rpm, and the supernatantwas analyzed by theHPLC. Pseudo-first order halflives(t1/2)forthehydrolysisofthecompounds werecalculatedfromtheslo- peofthelinearportionoftheplottedlogarithmoftheremainingcompo und ver- sustime.

Alltestedcompoundshydrolyzedtotheircorrespondingparentmole- culeswithinabout3to8min. Aqueoussolubility test

The aqueous solubility of the parent compoundVIV-1 and the com- poundofExamples1aand 3 was determinedatrtinanappropriatebuffersoluti- on(0.16Mphosphatebufferor0.05mMTris-HClbufferatpH7.4,0.05Mac etate bufferatpH5.0,50mM(ionicstrength0.15)HClbufferatpH1.0).ThepH ofthe mixtureswasheldconstantduringthestudy.Excessamountsoraknowna mount ofeachcomponentareaddedto1or0.5mlofbuffersolutionandthemixtu res werestirredatrtfor48hoursorless,filtered(0.45μmMillipore)an danalyzed byHPLC.TheresultsarepresentedinTable5. Table5.Solubilitydata

ItwillbeseenfromTable5 thatExamples1aand3 exhibitedimpro- vedaqueoussolubility. Determinationofbioavailability

Thisstudywasperformedinordertodeterminebioavailabilityofthe presentcompoundsinvivo.Allanimalexperimentsareperformedinacc ordance with standardsof ethical conductand appropriate institutional animal careand usepolicies.

Thepharmacokineticstudiesofthecompoundsoftheinventionwere assessed in Cynomolgus monkeys. The study compounds were administrated orally at a dose level corresponding to 10mg/kg of parent drug. The common aqueousformulation,0.5%Carboxymethylcelluloseinwater,wasused asavehi- cle.Thebloodsampleswereobtainedbydirectvenipunctureatpre-dos e,andten sequentialtimepointsafteroraladministration.

Thequantitativebioanalysisofplasmasampleswereperformedinac- cordancewiththeguidanceBioanalyticalMethodValidation (FDA,2001) andthe Guideline on Bioanalytical Method Validation (European Medicines Agency, 2011).Analyticalmethodwasoptimizedforsuitablechromatographic (peaksha- pe,retention)andmassspectrometric(ionizationefficiency)prope rties.

Anon-compartmentalpharmacokineticanalysiswascarriedoutwith individualplasmaconcentration-timecurvesusingWinNonlin ^® ProfessionalVer- sion6.3(PharsightCorporation):

C _max (maximum observed concentration) and tmax (time taken to reachmaximumobservedconcentration)values

Theareaundertheconcentration-timecurvefrom0tothelastmeas- urableconcentration(AUC _t )wascalculatedusingthe linear-logtrapezoidalrule.

TheobtainedC _max andAUC _t valuesofstudycompoundsareshownin theTable6. Table6

ItcanbeseenfromTable6that thatall testedcompoundsof the in- ventionprovidegoodbioavailability. Utilityoftheinvention

Compounds of the inventionwhenmetabolized to their parent com- poundsand/oras such showselective inhibitorypotentialof the17β-HSD1en- zyme and little or no inhibitory activity to the 17β-HSD2 enzyme and therefor, andmaybeuseful for the treatmentof a steroidhormonedependentmalignor benigndiseaseordisorder,inparticularfortreatmentandpreventio nofseveral estrogen dependent diseases and disorders. Further, compoundsof the present inventionmay be useful for the treatment ofdiseases and disorders associated with increased levelsof estradiol andwhichmaybeprevented, treated, and/or amelioratedbyaninhibitorof 17β-HSD1enzyme.

Examplesofinflammatorydiseasesandconditionsinclude,butarenot limitedto, breastcancer,prostatecarcinoma,ovariancancer,uterinecancer,e n- dometrialcancer,endometrialhyperplasia,endometriosis,uterine fibroids,uteri- ne leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, prostadynia,benignprostatichyperplasia,urinarydysfunction,po lycysticovarian syndrome,lowerurinarytractsyndrome,multiplesclerosis,obesity ,rheumatoid arthritis,coloncancer,tissuewounds,skinwrinklesandcataracts.

"Treatment or prevention" as used herein includes prophylaxis, or preventionof,aswellasloweringtheindividual'sriskoffallingill withthenamed disorderorcondition,oralleviation,amelioration,elimination,o rcureofthesaid disorderonceithasbeenestablished.

Thusthecompounds ofthepresentinventionmaybeusefulasactive ingredientsinpharmaceuticalcompositionfortreatmentorpreventi onofadise- aseordisorderrequiringtheinhibitionof17β-HSDenzyme.

Compoundsofthepresentinventionmaybeadministeredinaneffec- tiveamountwithinthedosagerangeofabout0.1 µg/kgtoabout 300mg/kg,prefer- ablybetween1.0 µg/kgto10mg/kgbodyweight.Compoundsofthepresentinven- tionmaybeadministeredinasingledailydose,orthetotaldailydosag emaybe administeredindivideddosesoftwo,threeorfourtimesdaily.

"Aneffectiveamount"referstoanamountofacompoundthatconfers atherapeuticeffectonthetreatedsubject.Thetherapeutic effectmaybeobjective (i.e.measurablebysometestormarker)orsubjective(i.e.subjectgi vesanindica- tionoforfeelsaneffect).Suchtreatmentneednotnecessarilycomple telyamelio- ratetheconditionofdisease.Further,suchtreatmentorpreventionc anbeused 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.

Compounds may be formulated into a suitable composition; suitable administration forms include, for example, solutions, dispersions, suspensions, powders, capsules, tablet, pills, controlled release capsules, controlled release tablets and controlled release pills. In addition to the pharmacologically active compounds, the pharmaceutical 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.

Furthermore, 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.

It will be obvious to a person skilled in the art that, as the technology advances, the inventive concept can be implemented in various ways. The invention and its embodiments are not limited to the examples described above but may vary within the scope of the claims.