NO315655B1 - 7 <alfa> - (<Epsilon> -aminoalkyl) -ostratrienes, pharmaceutical preparations containing them, and their use in the manufacture of pharmaceuticals - Google Patents

7 <alfa> - (<Epsilon> -aminoalkyl) -ostratrienes, pharmaceutical preparations containing them, and their use in the manufacture of pharmaceuticals Download PDF

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NO315655B1
NO315655B1 NO19990793A NO990793A NO315655B1 NO 315655 B1 NO315655 B1 NO 315655B1 NO 19990793 A NO19990793 A NO 19990793A NO 990793 A NO990793 A NO 990793A NO 315655 B1 NO315655 B1 NO 315655B1
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Prior art keywords
estra
methyl
fluoro
pentyl
diol
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NO19990793A
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Norwegian (no)
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NO990793L (en
NO990793D0 (en
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Rolf Bohlmann
Dieter Bittler
Josef Heindl
Nikolaus Heinrich
Helmut Hofmeister
Hermann Kuenzer
Gerhard Sauer
Christa Hegele-Hartung
Rosemarie Lichtner
Yukishige Nishino
Karsten Parczyk
Martin Schneider
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Schering Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • C07J53/004—3 membered carbocyclic rings
    • C07J53/008—3 membered carbocyclic rings in position 15/16
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/006—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused

Description

Foreliggende oppfinnelse angår substituerte 7a-(£-aminoalkyl)-østratriener, som er kjennetegnet ved at de har den generelle formel I The present invention relates to substituted 7a-(£-aminoalkyl)-estratrienes, which are characterized in that they have the general formula I

hvori in which

sidekjeden SK betegner en rest med delformel the side chain SK denotes a residue with partial formula

hvori in which

m er 4, 5 eller 6, m is 4, 5 or 6,

n er 0, 1 eller 2, n is 0, 1 or 2,

x er 0, 1 eller 2, x is 0, 1 or 2,

A betegner et hydrogenatom eller en Ci_5-alkylgruppe, A denotes a hydrogen atom or a Ci_5 alkyl group,

B og D betegner et hydrogenatom eller B and D denote a hydrogen atom or

A og B betegner sammen en alkylengruppe (CH2)P der p = 2, 3, 4 eller S og D er et hydrogenatom, eller A and B together denote an alkylene group (CH2)P where p = 2, 3, 4 or S and D is a hydrogen atom, or

A og D betegner sammen en alkylengruppe (CH2)q der q = 2, 3 eller 4 og B er et(hydrogenatom, og A and D together denote an alkylene group (CH2)q where q = 2, 3 or 4 and B is a (hydrogen atom, and

E betegner en usubstituert eller en én- til fem-fluorert etylrest eller den terminale substituent (CH2)3-E i sidekjeden er erstattet med en eventuelt med CF3 substituert fenylgruppe, eller en furyl- eller tienylgruppe som via en mono-, E denotes an unsubstituted or a one- to five-fluorinated ethyl residue or the terminal substituent (CH2)3-E in the side chain is replaced by a phenyl group optionally substituted with CF3, or a furyl or thienyl group which via a mono-,

di- eller trimetylengruppe er bundet til svovelatomet( di- or trimethylene group is attached to the sulfur atom (

R<3> betegner et hydrogenatom eller en rest med delformel R<3>'-C(0), hvori R<3>' er en hydrokarbonrest med inntil 8 karbonatomer, R<3> denotes a hydrogen atom or a residue with partial formula R<3>'-C(0), in which R<3>' is a hydrocarbon residue with up to 8 carbon atoms,

R<11> betegner et hydrogenatom, et halogenatom eller en nitrooksygruppe 0-N02, R<11> denotes a hydrogen atom, a halogen atom or a nitrooxy group 0-NO2,

R14, R15°, R15p, R16a og R1<6p> betegner et hydrogenatom, eller R14, R15°, R15p, R16a and R1<6p> denote a hydrogen atom, or

R14 og R15a betegner en ytterligere binding, eller R14 and R15a denote a further bond, or

R<lsp> betegner en metylgrup<p>e og R<15>° betegner et hydrogenatom, eller R<lsp> denotes a methyl group and R<15>° denotes a hydrogen atom, or

R<1>5<p> og R1<6p> betegner sammen en metylenbro, eller R1Sa eller R<16p> betegner et halogenatom, R<1>5<p> and R1<6p> together denote a methylene bridge, or R1Sa or R<16p> denote a halogen atom,

R<17>' i a- eller p-posisjon, betegner et hydrogenatom, en Ci-S-alkyl-, Ci-6-alkanoyloksy-, C2.5-alkenyl- eller C2.5-alkynylgruppe eller en trifluormetylgruppe, R<17>' in a- or p-position, denotes a hydrogen atom, a C1-S alkyl, C1-6 alkanoyloxy, C2.5-alkenyl or C2.5-alkynyl group or a trifluoromethyl group,

og and

R<17>" betegner et hydrogenatom eller en rest med delformel R<17>"'-C(0), hvori R1<7>"' betegner et hydrogenatom eller en hydrokarbonrest med inntil 8 karbonatomer eller, når R<17>' befinner seg i a-posisjon, så betegner R<17>' sammen med R14 en etanolbro, R<17>" denotes a hydrogen atom or a residue of partial formula R<17>"'-C(0), in which R1<7>"' denotes a hydrogen atom or a hydrocarbon residue with up to 8 carbon atoms or, when R<17>' is in the a-position, then R<17>' together with R14 denotes an ethanol bridge,

med det forbehold at, når A og B sammen ikke betegner (CH2)P eller A og D sammen betegner (CH2)q, så er minst en av substituentene R11, R14, R15Q, R<15p>, R16a og R<16p> ikke et hydrogen-atom, with the proviso that, when A and B together do not denote (CH2)P or A and D together denote (CH2)q, then at least one of the substituents R11, R14, R15Q, R<15p>, R16a and R<16p> not a hydrogen atom,

så vel som deres fysiologisk forenlige addisjonssalter med organiske og uorganiske syrer. as well as their physiologically compatible addition salts with organic and inorganic acids.

Foreliggende oppfinnelse angår dessuten farmasøytiske preparater inneholdende disse forbindelser med generell formel I, samt deres fysiologisk forenlige addisjonssalter med organiske og uorganiske syrer, så vel som deres anvendelse for fremstilling av legemidler. The present invention also relates to pharmaceutical preparations containing these compounds of general formula I, as well as their physiologically compatible addition salts with organic and inorganic acids, as well as their use for the production of pharmaceuticals.

I forbindelsene med generell formel I er fortrinnsvis nitrogenatomet i sidekjeden atskilt fra karbonatom 7 i stereoidskjelettet med 5 metylengrupper. In the compounds of general formula I, the nitrogen atom in the side chain is preferably separated from carbon atom 7 in the steroid skeleton by 5 methylene groups.

Dersom A betegner en alkylgruppe med inntil 5 karbonatomer, er den en metyl-, etyl-, propyl-, isopropyl-, butyl-, isobutyl-, tert.-butyl-, pentyl-, isopentyl- eller neopentylgruppe; fortrinnsvis er A en metylgruppe. If A denotes an alkyl group with up to 5 carbon atoms, it is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or neopentyl group; preferably A is a methyl group.

Indeksen n kan ha verdien 0, 1 eller 2, idet når A er et hydrogenatom eller en alkylgruppe med inntil 5 karbonatomer, er verdien 1 foretrukket for n, slik at nitrogenatomet og svovelatomet er atskilt med 3 metylengrupper. The index n can have the value 0, 1 or 2, since when A is a hydrogen atom or an alkyl group with up to 5 carbon atoms, the value 1 is preferred for n, so that the nitrogen atom and the sulfur atom are separated by 3 methylene groups.

A og B er fortrinnsvis en trimetylengruppe, dvs. at de sammen med nitrogenatomet og nabokarbonatornet danner en pyrrolidinring som er substituert i 2-stilling. A and B are preferably a trimethylene group, i.e. together with the nitrogen atom and the neighboring carbon atom they form a pyrrolidine ring which is substituted in the 2-position.

I det sist nevnte tilfellet er verdien 0 for n og 0 for x foretrukket. In the latter case, the value 0 for n and 0 for x is preferred.

Svovelatomet i sidekjeden kan foreligge som en enkel svovelbro (sulfid) som sulfon eller sulfoksid. Sulfid er foretrukket. The sulfur atom in the side chain can exist as a simple sulfur bridge (sulfide) such as sulfone or sulfoxide. Sulfide is preferred.

Som rest E kommer en usubstituert eller en en- til fem-fluorert etylrest på tale; perfluorresten er foretrukket for E. As residue E, an unsubstituted or a one- to five-fluorinated ethyl residue is mentioned; The perfluorine residue is preferred for E.

Ved substituenten R<3> på 3-oksygenatomet handler det først og fremst om et hydrogenatom, eller det kan være forestret med en acylrest R<3>'-C(0), hvori R<3>' er en hydrokarbonrest med inntil 8 karbonatomer. The substituent R<3> on the 3-oxygen atom is primarily a hydrogen atom, or it can be esterified with an acyl residue R<3>'-C(0), in which R<3>' is a hydrocarbon residue with up to 8 carbon atoms.

Substituenten R11 kan være et hydrogenatom, et halogenatom (F, Cl, Br, I) eller en nitrooksygruppe; et fluoratom er foretrukket. The substituent R 11 can be a hydrogen atom, a halogen atom (F, Cl, Br, I) or a nitrooxy group; a fluorine atom is preferred.

R<17>' kan foreligge i a- eller p-stilling. R<17>' can be in the a- or p-position.

I tilfelle med en Ci.5-alkylgruppe er denne metyl-, etyl-, propyl-, isopropyl-, butyl-, isobutyl-, tert.-butyl-, pentyl-, isopentyl- eller neopentylgruppe. Som C2.s-alkylengruppe kan f.eks. nevnes en vinyl- eller allylrest. Eksempler på en C2.5-alkynylgruppe er en etynyl- og 1-propynylrest. In the case of a C 1-5 alkyl group, this is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or neopentyl group. As a C2.s-alkylene group, e.g. a vinyl or allyl residue is mentioned. Examples of a C2.5-alkynyl group are an ethynyl and 1-propynyl residue.

Dersom R<17>' befinner seg i a-stilling er denne spesielt et hydrogenatom, en metyl- eller trifluormetylgruppe eller danner sammen med R<14> en etanolbro. If R<17>' is in the a-position, this is in particular a hydrogen atom, a methyl or trifluoromethyl group or forms together with R<14> an ethanol bridge.

R<17>' i p-stilling er først og fremst et hydrogenatom og en metylgruppe. R<17>' in the p-position is primarily a hydrogen atom and a methyl group.

Forbindelser med generell formel I er spesielt foretrukne der sidekjeden SK enten er en rest med delformel (CH2)5_N(CH3)_(CH2)3_SOx_(CH2)3_C2F5, der x = 0, 1 eller 2. Compounds of general formula I are particularly preferred where the side chain SK is either a residue of partial formula (CH2)5_N(CH3)_(CH2)3_SOx_(CH2)3_C2F5, where x = 0, 1 or 2.

Egnede for dannelse av syreaddisjonssalter er uorganiske og organiske syrer som er kjent for fagfolk for dannelse av fysiologisk forenlige salter. Som addisjonssalter med syrer skal spesielt nevnes hydroklorider og metansulfonat. Suitable for forming acid addition salts are inorganic and organic acids known to those skilled in the art for forming physiologically compatible salts. As addition salts with acids, particular mention should be made of hydrochlorides and methanesulfonate.

De etterfølgende forbindelser er spesielt foretrukne ved foreliggende oppfinnelse: llp-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentaf luor-pentyltio) propylamino] pentyl } østra-1 , 3 , 5(10)-trien-3,17|3-diol, The following compounds are particularly preferred in the present invention: llp-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio) propylamino] pentyl } estra- 1 , 3 , 5(10)-triene-3,17|3-diol,

llp-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfinyl)propylamino]pentyl}østra-1,3,5(10)-trien-3,17£-diol, llp-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}oestra-1,3,5(10)-triene-3, 17£-diol,

HJ3-fluor-7a-{5- [N-metyl-N-3 - (4,4,5,5,5-pentafluorpentansulfonyl)propylamino]pentylJøstra-1,3,5(10)-trien-3,170-diol, HJ3-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)propylamino]pentylJöstra-1,3,5(10)-triene-3,170-diol,

16a-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}østra-l,3,5(10)-trien-3,17£-diol, 16a-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}oestra-1,3,5(10)-trien-3, 17£-diol,

16a-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentylJøstra-1,3,5(10)-trien-3,17a-diol, 16a-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentylJöstra-1,3,5(10)-trien-3,17a- diol,

16a-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfinyl)propylamino]pentyl}østra-1,3,5(10)-trien-3,17p-diol, 16a-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}oestra-1,3,5(10)-triene-3, 17p-diol,

16a-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulf onyl) propylamino] pentyl Jøstra-1, 3,5(10) -trien-3,17|3-diol, 16a-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)propylamino]pentyl Jøstra-1, 3,5(10)-trien- 3,17|3-diol,

7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)-pyrrolidin-l-yl] -pentyl}-østra-1,3,5 (10) -trien-3,17]3-diol, 7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-3 ,17]3-diol,

7a-{5-[(2R)-2-(4,4,5,5,5-pentafluorpentyltiometyl)-pyrrolidin-l-yl]-pentyl}-østra-1,3,5(10)-trien-3,17p-diol, 7a-{5-[(2R)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-3 ,17p-diol,

17a-metyl-7a-{5-[2-(4,4,5,5,5-pentafluorpentyltiometyl)pyrrolidin-l-yl]pentyl}-østra-l, 3, 5 (10) -trien-3,17{3-diol, 17α-methyl-7α-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}-estral-1, 3,5(10)-trien-3,17 {3-diol,

llp-fluor-7a-{5-[2-(4,4,5,5,5-pentafluorpentyltiometyl) pyrrolidin-l-yl] pentyl J -østra-1,3, 5 (10) -trien-3,17{S-diol, 11p-fluoro-7a-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl J -estra-1,3,5(10)-trien-3,17 {S-diol,

lip-fluor-17a-metyl-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)pyrrolidin-l-yl]pentyl}-østra-1,3,5(10)-trien-3,17p-diol, lip-fluoro-17α-methyl-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}-estra-1,3,5( 10)-triene-3,17p-diol,

lip-fluor-17a-metyl-7a-{5-[(2S)-2-(4,4,5,5,5-penta-fluorpentansulfinylmetyl)pyrrolidin-1-yl]pentyl}-østra-1,3,5(10)-trien-3,17p-diol, lip-fluoro-17a-methyl-7a-{5-[(2S)-2-(4,4,5,5,5-penta-fluoropentanesulfinylmethyl)pyrrolidin-1-yl]pentyl}-estra-1,3, 5(10)-triene-3,17p-diol,

llp-fluor-17a-metyl-7a-{5-[(2S)-2-(4,4,5,5,5-penta-fluorpentansulfonylmetyl)pyrrolidin-l-yl]pentyl}-østra-1,3,5(10)-trien-3,17p-diol, 11p-fluoro-17a-methyl-7a-{5-[(2S)-2-(4,4,5,5,5-penta-fluoropentanesulfonylmethyl)pyrrolidin-1-yl]pentyl}-estra-1,3, 5(10)-triene-3,17p-diol,

7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentansulfinyl-raet<y>l)p<y>rrolidin-l-<y>l]<p>ent<y>l}-østra-l,3,5(10)-trien-3,17£-diol, 7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentanesulfinyl-raet<y>l)p<y>rrolidin-l-<y>l]<p>ent<y >1}-estra-1,3,5(10)-triene-3,17£-diol,

7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentansulfonyl-metyl) pyrrolidin-l-yl] pentyl-østra-1 , 3 , 5 (10) -trien-3,17{J-diol, 7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentanesulfonyl-methyl)pyrrolidin-1-yl]pentyl-estra-1,3,5(10)-trien-3, 17{J-diol,

lip-fluor-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]-pentyl}-østra-1,3,5(10)-trien-3,170-diol, lip-fluoro-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]-pentyl}-estra-1,3,5(10 )-triene-3,170-diol,

lip-fluor-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfinyl)propylamino]pentyl}-østra-1,3,5(10)-trien-3,17p-diol, lip-fluoro-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}-estra-1,3,5(10) -triene-3,17p-diol,

lip-fluor-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulfonyl)propylamino]pentyl}-østra-1,3,5(10)-trien-3,17p-diol, lip-fluoro-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfonyl)propylamino]pentyl}-estra-1,3,5( 10)-triene-3,17p-diol,

llp-fluor-7a-{5-[N-metyl-N-2-(4,4,5,5,5-pentafluor-pentansulf onyl) etylamino] pentyl}-østra-1,3,5(10)-trien-3,17p-diol, llp-fluoro-7a-{5-[N-methyl-N-2-(4,4,5,5,5-pentafluoro-pentanesulfonyl)ethylamino]pentyl}-estra-1,3,5(10)- triene-3,17p-diol,

llp-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio) propylamino]pentyl}-3-hydroksy-østra-l,3,5(10)-trien-17-on, 11p-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-3-hydroxy-estra-1,3,5(10) -trien-17-one,

lip-fluor-7a-{6-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio) <p>rop<y>lamino]heks<y>l}-østra-1,3,5(10)-trien-3,17p<->diol, lip-fluoro-7a-{6-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)<p>rop<y>lamino]hex<y>l}-estra-1 ,3,5(10)-triene-3,17p<->diol,

llp-fluor-7a-{6-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulf inyl) propylamino] heksyl}-østra-1,3,5(10)-trien-3,17p-diol, llp-fluoro-7a-{6-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfinyl)propylamino]hexyl}-estra-1,3,5(10)- triene-3,17p-diol,

lip-fluor-7a-(5-{[N-3-(furan-2-ylmetyltio)propyl]-N-metylaminojpentyl)-østra-1,3,5(10)-trien-3,17p-diol, lip-fluoro-7a-(5-{[N-3-(furan-2-ylmethylthio)propyl]-N-methylaminojpentyl)-estra-1,3,5(10)-triene-3,17p-diol,

llp-fluor-7a-(5-{N-metyl-[N-3-(tiofen-2-ylmetyltio)-propyl]aminojpentyl)-østra-1,3,5(10)-trien-3,17p-diol, 11p-fluoro-7a-(5-{N-methyl-[N-3-(thiophen-2-ylmethylthio)-propyl]aminojpentyl)-estra-1,3,5(10)-triene-3,17p-diol ,

lip-fluor-7a-{5-[(2S)-2-(4-trifluormetylfenyltiometyl) pyrrolidin-l-yl] pentyl}østra-l, 3 ,5(10)-trien-3,17p-diol, lip-fluoro-7a-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)pyrrolidin-1-yl]pentyl}oestra-1, 3,5(10)-triene-3,17p-diol,

lip-fluor-17a-metyl-7a-{5-[(2S)-2-(4,4,5,5,5-penta-fluorpentansulfinylmetyl)pyrrolidin-l-yl]pentyl}-østra-1,3,5(10)-trien-3,17p-diol, lip-fluoro-17α-methyl-7α-{5-[(2S)-2-(4,4,5,5,5-penta-fluoropentanesulfinylmethyl)pyrrolidin-1-yl]pentyl}-estra-1,3, 5(10)-triene-3,17p-diol,

lip-fluor-17a-metyl-7a-{5-[(2R)-2-(4,4,5,5,S-penta-fi luorpentyltiometyl) pyrrolidin-l-yl] pentyl } -østra-1 , 3 , 5 (10) - trien-3,17p-diol, lip-fluoro-17α-methyl-7α-{5-[(2R)-2-(4,4,5,5,S-penta-fluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}-estra-1 , 3 , 5 (10)-triene-3,17p-diol,

llp-fluor-7a-{5- [ (2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl) pyrrolidin-l-yl] pentyl}-østra-1,3,5(10)-trien-3,17p-diol, 11p-fluoro-7a-{5-[ (2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}-estra-1,3,5(10)-triene -3,17p-diol,

llp-fluor-17a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentan-sulf inylmetyl) pyrrolidin-l-yl] pentyl} -østra-1, 3, 5 (10)-trien-3,17p-diol, 11p-fluoro-17a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentane-sulfinylmethyl)pyrrolidin-1-yl]pentyl}-estra-1, 3, 5 (10 )-triene-3,17p-diol,

lip-fluor-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentan-sulfonylmetyl)pyrrolidin-l-yl]pentyl}-østra-1,3,5(10)-trien-3,17p-diol. lip-fluoro-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentane-sulfonylmethyl)pyrrolidin-1-yl]pentyl}-estra-1,3,5(10) -triene-3,17p-diol.

Forbindelsene med generell formel I representerer forbindelser med meget sterk antiøstrogenaktivitet. The compounds of general formula I represent compounds with very strong antiestrogen activity.

Forbindelsene ifølge oppfinnelsen er på den ene side rene antiøstrogener, eller på den andre side såkalte partiellantagonister, dvs. antiøstrogener med østrogen partiellvirkning, slik som tamoksifen eller raloksifen. Den agonistiske, østrogene virkning er imidlertid for forbindelsene ifølge oppfinnelsen i alle tilfeller betydelig svakere ut-preget enn for tamoksifen. I motsetning til tamoksifen opptrer for partiel1antagonistene med generell formel I, deres agonistiske, østrogene virkning vevsselektivt. Den agonistiske virkning opptrer spesielt på skjelettet, i hjerte-krets-løpssystemet og i SNS (sentralnervesystemet). Ingen agonistisk virkning opptrer spesielt på uterus. The compounds according to the invention are on the one hand pure antiestrogens, or on the other hand so-called partial antagonists, i.e. antiestrogens with partial estrogenic action, such as tamoxifen or raloxifene. However, the agonistic, estrogenic effect for the compounds according to the invention is in all cases significantly weaker than for tamoxifen. In contrast to tamoxifen, for the partial 1 antagonists of general formula I, their agonistic, estrogenic action is tissue-selective. The agonistic effect occurs especially on the skeleton, in the cardiovascular system and in the SNS (central nervous system). No agonistic effect occurs especially on the uterus.

Forbindelser med antiøstrogene egenskaper, dvs. stoffer med inhiberende virkninger overfor østrogener, er allerede tallrikt beskrevet. Compounds with antiestrogenic properties, i.e. substances with inhibitory effects on oestrogens, have already been described in large numbers.

Forbindelsene som er strukturelt nærmest beslektede med forbindelsene ifølge foreliggende oppfinnelse med generell formel I, er steroidderivatene beskrevet i EP-A 0 138 504, og av disse spesielt 7a-[9-(4,4,5,5,5-pentafluorpentylsulfinyl)-n-nonyl]-østra-1,3,5(10)-trien-3,17p-diol (EP-A 0 138 504, s. 58, nest siste forbindelse). Denne forbindelse er i dag under klinisk utprøvning mot hormonavhengige tumorer (brystkreft) og representerer i dag den best kjente forbindelse, dvs. forbindelsen med den sterkeste antiøstrogene aktivitet, av disse steroidderivater. The compounds that are structurally most closely related to the compounds according to the present invention with general formula I are the steroid derivatives described in EP-A 0 138 504, and of these in particular 7a-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)- n-nonyl]-estra-1,3,5(10)-triene-3,17p-diol (EP-A 0 138 504, p. 58, penultimate compound). This compound is currently undergoing clinical trials against hormone-dependent tumors (breast cancer) and today represents the best known compound, i.e. the compound with the strongest antiestrogenic activity, of these steroid derivatives.

Farmasøytiske sammensetninger inneholdende seksual-steroidinhibitorer med et steroid grunnskjeilett som inneholder en 7a-sidekjede, med samtidig tilstedeværelse av minst en ytterligere substituent i posisjon 14, 15 eller 16, er gjenstand for EP-A 0 376 576 og må likeledes tas i betraktning som nærliggende teknikkens stand. Mange forskjellige forbindelser - blant annet slike opprinnelige, steroide forbindelser og også forbindelser med 2-fenylindolgrunnskjel-lett - som har antiøstrogen virkning og/eller undertrykker østrogenbiosyntese, er beskrevet i WO 93/10 741. Pharmaceutical compositions containing sex-steroid inhibitors with a steroid skeleton containing a 7a side chain, with the simultaneous presence of at least one additional substituent in position 14, 15 or 16, are the subject of EP-A 0 376 576 and must likewise be taken into account as close state of the art. Many different compounds - including such original, steroidal compounds and also compounds with a 2-phenylindole backbone - which have an antiestrogenic effect and/or suppress estrogen biosynthesis, are described in WO 93/10 741.

Ytterligere steroide antiøstrogener som inneholder en lip-fenylrest er beskrevet i EP-AS 0 384 842 og 0 629 635. Further steroidal antiestrogens containing a lip-phenyl residue are described in EP-AS 0 384 842 and 0 629 635.

Ved forbindelsene ifølge foreliggende oppfinnelse handler det om antiøstrogener med sterkere antiøstrogen virkning enn den allerede nevnte 7a-[9-(4,4,5,5,5-pentafluor-pentylsulfinyl)-n-nonyl]-østra-1,3,5(10)-trien-3,17£-diol. The compounds according to the present invention are antiestrogens with stronger antiestrogenic effects than the already mentioned 7a-[9-(4,4,5,5,5-pentafluoro-pentylsulfinyl)-n-nonyl]-estra-1,3,5 (10)-triene-3,17£-diol.

Forbindelsene med generell formel I ifølge foreliggende patentsøknad utmerker seg, sammenlignet med de allerede kjente steroidderivater ifølge EP-A 0 138 504 og EP-A 0 367 576 ved nye sidekjeder på karbonatom 7 i steroidskjellett-et. Denne strukturmodifikasjon fører til forbindelser med spesiell høy antiøstrogen virkning, slik som er blitt påvist i transaktiveringstester. The compounds of general formula I according to the present patent application are distinguished, compared to the already known steroid derivatives according to EP-A 0 138 504 and EP-A 0 367 576, by new side chains on carbon atom 7 in the steroid skeleton. This structural modification leads to compounds with particularly high antiestrogenic activity, as has been demonstrated in transactivation tests.

Forbindelsene ifølge EP-A 0 138 504 skiller seg dessuten fra forbindelsene med formel I med hensyn til sub-stitusjon på karbonatom 11 og/eller D-ringen [foruten når A og B til sammen betegner (CH2)P, eller A og D til sammen betegner (CH2)q] . Sammenlignet med forbindelsene ifølge EP-A 0 367 576 kan forbindelsene med generell formel I også inneholde andre substituenter på karbonatom 11 og/eller i selve D-ringen. The compounds according to EP-A 0 138 504 also differ from the compounds of formula I with regard to substitution on carbon atom 11 and/or the D ring [except when A and B together denote (CH 2 )P, or A and D to together denote (CH2)q] . Compared to the compounds according to EP-A 0 367 576, the compounds of general formula I may also contain other substituents on carbon atom 11 and/or in the D ring itself.

Gjennom "disclaimeren" i definisjonen av den generelle formel I er forbindelsene beskrevet i den ikke-offen-tliggjorte DE P 196 22 457 utelukket fra denne definisjonen. Through the "disclaimer" in the definition of the general formula I, the compounds described in the unpublished DE P 196 22 457 are excluded from this definition.

Den antiøstrogene virkning av forbindelsene ifølge foreliggende oppfinnelse ble bestemt ved hjelp av transaktiveringsanalyser [Demirpence E., Duchesne M. J., Badia E., Gagne D. og Pons M.: MVLN Cells: A Bioluminescent MCF-7-Derived Cell Line to study the Modulation of Estrogenic Activity; J. Steroid. Molec. Biol. Vol. 46, nr. 3, 355-364 The antiestrogenic effect of the compounds according to the present invention was determined by means of transactivation assays [Demirpence E., Duchesne M.J., Badia E., Gagne D. and Pons M.: MVLN Cells: A Bioluminescent MCF-7-Derived Cell Line to study the Modulation of Estrogenic Activity; J. Steroid. Molec. Biol. Vol. 46, No. 3, 355-364

(1993), samt Berry M., Metzger D. Chambon P.: Role of the two activating domains of the estrogen receptor in the cell-type and promoter-context dependent agonistic activity of the anti-estrogen 4-hydroxytamoxifen; The EMBO Journal Vol. 9, 2811-2818 (1990)]. (1993), as well as Berry M., Metzger D. Chambon P.: Role of the two activating domains of the estrogen receptor in the cell-type and promoter-context dependent agonistic activity of the anti-estrogen 4-hydroxytamoxifen; The EMBO Journal Vol. 9, 2811-2818 (1990)].

Hela-cellene er transient transfektert med human østrogenreseptor-ekspresjonsvektor (HEGO) og Vit-TK-CAT-rap-portørgen og MVLN-cellene er stabilt transfektert med rapport-ørgenet Vit-TK-LUC. Den østrogene aktivitet ble bestemt i nærvær av 0,1 nM østradiol. The Hela cells are transiently transfected with human estrogen receptor expression vector (HEGO) and the Vit-TK-CAT rap reporter gene and the MVLN cells are stably transfected with the Vit-TK-LUC reporter gene. The estrogenic activity was determined in the presence of 0.1 nM estradiol.

IC50-verdiene for de nye forbindelser ligger i det nanomolare området. I Hela-cellelinjen og MVLN-cellelinjen ga forbindelsene ifølge eksempel 12, 15, 18, 25, 29, 31 og 36, samt forbindelsen 7a-[9-(4,4,5,5,5-pentafluorpentylsulfinyl)-n-nonyl]-østra-1,3,5(10)-trien-3,17£-diol de følgende IC50-verdier (testutførelse ifølge de ovenfor angitte litte-raturreferanser) : The IC50 values for the new compounds are in the nanomolar range. In the Hela cell line and the MVLN cell line, the compounds of Example 12, 15, 18, 25, 29, 31 and 36, as well as the compound 7a-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-n-nonyl ]-estra-1,3,5(10)-triene-3,17£-diol the following IC50 values (test execution according to the littrate references indicated above) :

Tester in vivo viser likeledes overlegenheten av forbindelsene ifølge foreliggende oppfinnelse ifølge 7a-[9- Tests in vivo likewise show the superiority of the compounds according to the present invention according to 7a-[9-

(4,4,5,5,5-pentafluorpentansulfinyl)-nonyl]-østra-1,3,5(10)-trien-3,17p-diol. De etterfølgende beskrevne tester ble ut-ført : 1. Uterusveksttest på rotteunger, p.o. (test på anti-østrogen virkning) 2. Tumortester: antitumorvirkning på den hormonavhengige mammaka rs i nora (4,4,5,5,5-pentafluoropentanesulfinyl)-nonyl]-estra-1,3,5(10)-triene-3,17p-diol. The subsequently described tests were carried out: 1. Uterine growth test on rat pups, p.o. (test for anti-oestrogen effect) 2. Tumor tests: anti-tumor effect on the hormone-dependent breast cancer in nora

DMBA<*->indusert mammakarsinom hos rotte DMBA<*->induced mammary carcinoma in the rat

= dimetylbenzantrazen = the dimethylbenzanthracene

1. Uterusveksttest på rotteunger ( antiøstrogen virkning) 1. Uterus growth test on rat pups (antiestrogenic effect)

Prinsipp for metoden Principle of the method

Hos gnagere reagerer uterus på administrering av østrogener med en vektøkning (både proliferasjon og lagring av vann). Denne vekst hemmes doseavhengig ved samtidig tilførsel av forbindelser med antiøstrogenvirkning. In rodents, the uterus responds to the administration of estrogens with an increase in weight (both proliferation and water retention). This growth is dose-dependently inhibited by the simultaneous administration of compounds with antiestrogen action.

Forsøksut førelse Experimental execution

Dyr: Animals:

Hunnrotteunger med vekt 35-45 g ved forsøks-begynnelsen, pr. dose 5-6 dyr. Female rat pups weighing 35-45 g at the start of the experiment, per dose 5-6 animals.

Formulering og administrering av stoffene: Formulation and administration of the drugs:

For administrering p.o. oppløses stoffene i en del etanol (E) og påfylles med 9 deler jordnøttolje (EØ). For administration p.o. dissolve the substances in one part ethanol (E) and top up with 9 parts peanut oil (EØ).

Forsøksoppst i11ing Trial setup i11ing

De unge rotter som nettopp var fjernet fra mødrene b le levert til innveiing en dag før start av behandlingen og straks foret - også i dyreburet. Behandlingen ble deretter ut-ført daglig, én gang pr. dag i 3 dager, i kombinasjon med 0,5 ug østradiolbenzoat (EB). EB administreres alltid subkutant (s.c), mens teststoffet administreres pr. oralt (p.o.). 24 t etter den siste administrering blir dyrene veid, avlivet og deres uterus fjernet. Våtvektene (uten innhold) beregnes fra de preparerte uteri. The young rats that had just been removed from their mothers were delivered for weighing one day before the start of the treatment and immediately fed - also in the animal cage. The treatment was then carried out daily, once per day for 3 days, in combination with 0.5 ug estradiol benzoate (EB). EB is always administered subcutaneously (s.c), while the test substance is administered per orally (p.o.). 24 h after the last administration, the animals are weighed, euthanized and their uterus removed. The wet weights (without contents) are calculated from the prepared uteri.

Kontroller Check

Negativ kontroll: vehikkel (E/EØ), 0,2 ml/dyr/dag Positiv kontroll: 0,5 ug EB/0,1 ml/dyr/dag Negative control: vehicle (E/EØ), 0.2 ml/animal/day Positive control: 0.5 ug EB/0.1 ml/animal/day

Evaluering Evaluation

Fra de relative organvekter {mg/100 g kroppsvekt) blir det for hver gruppe beregnet middelverdien med stand-ardavvik (X+SD), og signifikansen av forskjellen med kontrol-lgruppen (EB) i Dunnett-test (p<0,05). Beregningen av inhiber-ingen (i %) overfor EB-kontrollen utføres med et program. De relative aktiviteter av teststoffene bestemmes ved hjelp av en kovarians- og regresjonsanalyse. From the relative organ weights {mg/100 g body weight) the mean value with standard deviation (X+SD) is calculated for each group, and the significance of the difference with the control group (EB) in the Dunnett test (p<0.05) . The calculation of the inhibition (in %) compared to the EB control is carried out with a program. The relative activities of the test substances are determined using a covariance and regression analysis.

Antiuterotrof virkning på rotte Antiuterotrophic effect on the rat

Disse resultater demonstrerer den langt høyere anti-østrogene aktivitet av forbindelsene med generell formel I, sammenlignet med forbindelsen 7a-[9-(4,4,5,5,5-pentafluor-pentylsulf inyl) -n-nonyl] -østra-1,3, 5 (10) -trien-3,17f3-diol etter oral administrering. These results demonstrate the far higher anti-estrogenic activity of the compounds of general formula I compared to the compound 7a-[9-(4,4,5,5,5-pentafluoro-pentylsulfinyl)-n-nonyl]-estra-1 ,3,5(10)-triene-3,17f3-diol after oral administration.

Forbindelsene ifølge foreliggende oppfinnelse utmerker seg ved en bedre biologisk forenlighet etter oral administre-ring. The compounds according to the present invention are distinguished by a better biological compatibility after oral administration.

2. Tumortest 2. Tumor test

Innvirkning på tumorveksten i DMBA*- modellen hos rotte ( DMBA- tumormodell) Effect on tumor growth in the DMBA* model in rats (DMBA tumor model)

<*>9,10-dimetyl-l,2-benzantracen. <*>9,10-dimethyl-1,2-benzanthracene.

Biologisk grunnlag Biological basis

Veksten av den DMBA-induserte mammatumor hos rotte er hovedsakelig avhengig av østrogener og prolaktin. Aktive antiøstrogener, antigestagener og aromatasehemmere fører til hemming av tumorveksten. Stoffer med antigonadotrope og andro-gene egenskaper har likeledes tumorhemmende virkning. The growth of the DMBA-induced mammary tumor in the rat is mainly dependent on estrogens and prolactin. Active antiestrogens, antigestagens and aromatase inhibitors lead to inhibition of tumor growth. Substances with antigonadotropic and androgenic properties also have a tumor-inhibiting effect.

Dyremateriale Animal material

45-47 dager gamle hunnrotter {Sprague-Dawley, Zuchter ZIH eller Mollegard), pr. gruppe 8-10 dyr. 45-47 day old female rats (Sprague-Dawley, Zuchter ZIH or Mollegard), per group 8-10 animals.

Forsøksoppstilling Experimental set-up

Dyrene gis 10 mg DMBA oralt én gang. Dyrene blir deretter undersøkt for hånden én gang pr. uke med henblikk på tumorutvikling. 6 til 10 uker etter DMBA-behandlingen utvikles ca. 1 til 10 tumorer pr. dyr. Tumorstørrelsen bestemmes én gang pr. uke ved hjelp av et skyvelær. Dersom minst én tumor har nådd en definert størrelse (150 mm<2> tumoroverflate), utføres ovariektomi av dyrene eller behandlingen av dyrene med testforbindelse startes. Behandlingen utføres for det meste daglig i ca. 28 dager (detaljer for avvikling,- se for-søksplan) . Tumorstørrelsen måles videre én gang pr. uke. The animals are given 10 mg of DMBA orally once. The animals are then examined by hand once per week with a view to tumor development. 6 to 10 weeks after the DMBA treatment, approx. 1 to 10 tumors per animals. The tumor size is determined once per week using a caliper. If at least one tumor has reached a defined size (150 mm<2> tumor surface), the animals are ovariectomized or the treatment of the animals with test compound is started. The treatment is mostly carried out daily for approx. 28 days (details for liquidation, - see application plan) . The tumor size is further measured once per week.

Evaluering Evaluation

Den samlede tumorstørrelse pr. dyr bestemmes før start av behandlingen (forhåndsverdi). For hver gruppe beregnes deretter middelverdien for de prosentvise forandringer av tumorstørrelse, i forhold til de opprinnelige verdier. Det blir dessuten bestemt det prosentvise antall dyr pr. gruppe, hvis tumorer (1) har gått totalt tilbake (total regresjon), delvis tilbake (partiell regresjon), (3) er uendrede (ingen forandring) eller (4) er ytterligere forstørret (forstørr-else) . The total tumor size per animal is determined before the start of the treatment (preliminary value). For each group, the mean value for the percentage changes in tumor size, in relation to the original values, is then calculated. The percentage number of animals per group, whose tumors (1) have completely regressed (total regression), partially regressed (partial regression), (3) are unchanged (no change), or (4) have further enlarged (enlargement).

De bestemte verdier er testet i Dunnett-test på signifikans og er fremstilt grafisk. The determined values are tested in the Dunnett test for significance and are presented graphically.

Testresultat Test result

Ved en oral dose på 3 mg/kg/dag inhiberer llp-fluor-7a-{5-[2-(4,4,5,5,5-pentafluorpentyltiometyl)pyrrolidin-1-yl] pentyl} -østra-1, 3, 5 (10) -trien-3,17{3-diol (forbindelse ifølge eksempel 29) tumorveksten sterkere enn oral dose på 10 mg/kg/dag 7a-[9-(4,4,5,5,5-pentafluorpentansulfinyl)-nonyl]-østra-1, 3, 5 (10) -trien-3,17fJ-diol, som ved denne dose kun utøver en liten virkning sammenlignet med intakt kontroll. Ovariektomi fører til en total remisjon av tumorene (fig. 1). At an oral dose of 3 mg/kg/day, llp-fluoro-7a-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl] pentyl}-estra-1 inhibits 3, 5 (10)-triene-3,17{3-diol (compound according to Example 29) the tumor growth stronger than oral dose of 10 mg/kg/day 7a-[9-(4,4,5,5,5- pentafluoropentanesulfinyl)-nonyl]-estra-1, 3, 5 (10)-triene-3,17fJ-diol, which at this dose exerts only a small effect compared to the intact control. Ovariectomy leads to a total remission of the tumors (Fig. 1).

Forbindelsene virker inhiberende på veksten av hormonavhengige tumorceller, spesielt inhiberer de veksten av østrogenavhengige menneskelige mammatumorceller (MCF-7). The compounds have an inhibitory effect on the growth of hormone-dependent tumor cells, in particular they inhibit the growth of estrogen-dependent human mammary tumor cells (MCF-7).

Den antiproliferative aktivitet av de nye forbindelser i mammakarsinomcellelinjer er høyere enn aktiviteten av 7a-[9-(4,4,5,5,5-pentafluorpentylsulfinyl)-n-nonyl]-østra-1, 3, 5 (10) - trien-3,17j3-diol. The antiproliferative activity of the new compounds in mammary carcinoma cell lines is higher than the activity of 7a-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-n-nonyl]-estra-1, 3, 5 (10)-triene -3,17j3-diol.

Forbindelser med generell formel I skal ved foreliggende oppfinnelse, anses som rent antiøstrogene når de i den etterfølgende in vitro-test på østrogen virkning ikke viser noen, eller kun ubetydelig, agonistisk virkning (inntil ca. 10 % av virkningen av østradiol). Compounds of general formula I shall, in the present invention, be considered purely antiestrogenic when, in the subsequent in vitro test for estrogenic action, they show no, or only negligible, agonistic action (up to about 10% of the action of estradiol).

Den østrogene partiellvirkning bestemmes likeledes ved transaktiveringsanalyser. HeLa-celler ble transfektert med human østrogenreseptor-ekspresjonsvektor (HEGO) og et rap-portørgen rPR-TK-CAT. Dette rapportørgen inneholder det "øst-rogenresponderende element" fra kanin-progesteronreseptorgenet (+698/+729-området) før et TK-CAT-gen [Savouret J. F., Bailly A., Misrahi M., Rauch C, Redeuilh G., Chauchereau A., Milgrom E., Characterization of the hormone responsive element in-volved in the regulation of the progesterone receptor gene. EMBO J. 10, 1875-1883 (1991)]. The estrogenic partial action is likewise determined by transactivation assays. HeLa cells were transfected with human estrogen receptor expression vector (HEGO) and a reporter gene rPR-TK-CAT. This reporter gene contains the "oestrogen-responsive element" from the rabbit progesterone receptor gene (+698/+729 region) before a TK-CAT gene [Savouret J. F., Bailly A., Misrahi M., Rauch C, Redeuilh G., Chauchereau A., Milgrom E., Characterization of the hormone responsive element involved in the regulation of the progesterone receptor gene. EMBO J. 10, 1875-1883 (1991)].

Den østrogene aktivitet ble bestemt ved en konsen-trasjon på 1 uM. The estrogenic activity was determined at a concentration of 1 µM.

Forbindelsene ifølge foreliggende oppfinnelse, spesielt når de er rent antiøstrogene, er egnede for terapi av østrogenavhengige sykdommer, f.eks. mammakarsinom ("second-line" terapi av den tamoksifenresistente mammakarsinom; for assisterende behandling av mammakarsinom isteden for tamoksifen) , endometriumkarsinom, prostatahyperplasi, anovulatorisk infertilitet og melanom. De rene antiøstrogener med generell formel I, kan dessuten anvendes som komponenter i produktene beskrevet i EP 346 014 Bl, som inneholder et østrogen og et rent antiøstrogen, dvs. for samtidig, sekvensiell eller atskilt anvendelse for selektiv østrogenterapi av peri- eller postmenopausale kvinner. Forbindelsene med generell formel I, spesielt når det handler om rene antiøstrogener, kan anvendes sammen med antigestagener (kompetitive progesteronan-tagonister) for behandling av hormonavhengige tumorer (EP 310 542 A) . The compounds according to the present invention, especially when they are purely antiestrogenic, are suitable for the therapy of estrogen-dependent diseases, e.g. mammary carcinoma ("second-line" therapy of tamoxifen-resistant mammary carcinoma; for adjuvant treatment of mammary carcinoma instead of tamoxifen), endometrial carcinoma, prostatic hyperplasia, anovulatory infertility and melanoma. The pure antiestrogens of general formula I can also be used as components in the products described in EP 346 014 B1, which contain an estrogen and a pure antiestrogen, i.e. for simultaneous, sequential or separate use for selective estrogen therapy of peri- or postmenopausal women. The compounds of general formula I, especially when it comes to pure antiestrogens, can be used together with antigestagens (competitive progesterone antagonists) for the treatment of hormone-dependent tumors (EP 310 542 A).

Ytterligere indikasjoner for anvendelse av forbindelsene med generell formel I er håravfall hos menn, diffus alopeci, alopeci fremkalt av kjemoterapi, samt hirsutisme [Hye-Sun Oh und Robert C. Smart, Proe. Nati. Acad. Sei. USA, 93 (1996), 12525-12530]. Further indications for the use of the compounds of general formula I are male pattern baldness, diffuse alopecia, alopecia induced by chemotherapy, as well as hirsutism [Hye-Sun Oh und Robert C. Smart, Proe. Nati. Acad. Pollock. USA, 93 (1996), 12525-12530].

Forbindelsene med generell formel I kan dessuten anvendes for fremstilling av medikamenter for behandling av endometriose og endometrialkarsinomer. The compounds of general formula I can also be used for the production of drugs for the treatment of endometriosis and endometrial carcinomas.

Forbindelsene med generell formel I kan dessuten anvendes for fremstilling av farmasøytiske preparater for fertilitetskontroll av menn og kvinner (fertilitetskontroll av menn: DE-A 195 10 862.0). The compounds of general formula I can also be used for the production of pharmaceutical preparations for fertility control of men and women (fertility control of men: DE-A 195 10 862.0).

Forbindelser med generell formel I med vevsselektiv, østrogen partialvirkning, kan først og fremst anvendes for profylakse og terapi av osteoporose og for fremstilling av preparater for substitusjonsterapi i pre-, peri- og post-menopausen (HRT) [Black, L. J., Sato, M., Rowley, E. R., Magee, D. E., Bekele, A., Williams, D. C, Cullinan, G. J., Bendele, R., Kauffman, R. F., Bensch, W. R., Frolik, C. A., Termine, J. D. og Bryant, H. U.: Raloxifene (LY 139481 HCl) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats; J. Clin. Invest. 93: 63-69, 1994]. Den østrogene partialvirkning opptrer utelukkende i det ønskede målorgan. Compounds of general formula I with tissue-selective, estrogenic partial action can be used primarily for the prophylaxis and therapy of osteoporosis and for the preparation of preparations for replacement therapy in pre-, peri- and post-menopause (HRT) [Black, L. J., Sato, M ., Rowley, E. R., Magee, D. E., Bekele, A., Williams, D. C, Cullinan, G. J., Bendele, R., Kauffman, R. F., Bensch, W. R., Frolik, C. A., Termine, J. D. and Bryant, H. U.: Raloxifene (LY 139481 HCl) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats; J. Clin. Invest. 93: 63-69, 1994]. The estrogenic partial action occurs exclusively in the desired target organ.

Foreliggende oppfinnelse angår også farmasøytiske preparater som inneholder minst én forbindelse med generell formel I (eller fysiologisk forenlige addisjonssalter med organiske og uorganiske syrer) og anvendelse av disse forbindelser for fremstilling av legemidler, spesielt for behandling av østrogenavhengige sykdommer og tumorer, og legemidler for hormonsubstitusjonsterapi (HRT). The present invention also relates to pharmaceutical preparations containing at least one compound of general formula I (or physiologically compatible addition salts with organic and inorganic acids) and the use of these compounds for the production of pharmaceuticals, especially for the treatment of estrogen-dependent diseases and tumors, and pharmaceuticals for hormone replacement therapy ( HRT).

Forbindelsene ifølge oppfinnelsen og deres syreaddisjonssalter er egnede for fremstilling av farmasøytiske sammensetninger og preparater. De farmasøytiske preparater, hhv. legemidler, inneholder som aktivt stoff, én eller flere av forbindelsene ifølge oppfinnelsen eller deres syreaddisjonssalter, eventuelt i blanding med andre farmakologisk, hhv. farmasøytisk, aktive stoffer. Legemiddelfremstillingen utføres på kjent måte, idet det kan anvendes kjente og vanlige farmasøytiske hjelpestoffer, samt vanlige bærer- og fortyn-ningsmidler. The compounds according to the invention and their acid addition salts are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical preparations, respectively pharmaceuticals, contain as active substance, one or more of the compounds according to the invention or their acid addition salts, possibly in a mixture with other pharmacological, or pharmaceutical, active substances. The preparation of the medicine is carried out in a known manner, as known and common pharmaceutical excipients can be used, as well as common carriers and diluents.

Som bærer- og hjelpestoffer kan det f.eks. anvendes slike som er anbefalt, hhv. angitt, i: Ullmans Encyklopådie der technischen Chemie, bind 4 (1953), s. 1-39; Journal of Pharmaceutical Sciences, bind 52 (1963), s. 918 u. ff.; H.v. Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie und angrenzende Gebiete; Pharm. Ind. Heft 2, 1961, s. 72 u. ff.; Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete Cantor KG. Aulendorf i Wiirttemberg 1971. As carriers and auxiliary substances, it can e.g. those recommended are used, respectively stated, in: Ullman's Encyklopådie der technischen Chemie, volume 4 (1953), pp. 1-39; Journal of Pharmaceutical Sciences, Volume 52 (1963), pp. 918 et seq.; h.v. Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie und angrenzende Gebiete; Pharm. Ind. Volume 2, 1961, pp. 72 et seq.; Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete Cantor KG. Aulendorf in Wiirttemberg 1971.

Forbindelsene kan administreres oralt eller parente-ralt, f.eks. intraperitonealt, intramuskulært, subkutant eller perkutant. Forbindelsene kan også implanteres i vev. Mengden av forbindelsene som skal administreres, varierer innenfor et bredt område og kan avdekke enhver aktiv mengde. Avhengig av tilstanden som skal behandles og type administrering, kan mengden av den administrerte forbindelse oppgå til 0,1-25 mg/kg kroppsvekt, fortrinnsvis 0,5-5 mg/kg kroppsvekt, pr. dag. For mennesker tilsvarer dette en daglig dose på 5 til 1 250 mg. Den foretrukne daglige dosering for mennesker er 50 til 200 mg. Dette gjelder spesielt tumorterapi. The compounds can be administered orally or parenterally, e.g. intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted in tissue. The amount of the compounds to be administered varies within a wide range and may reveal any active amount. Depending on the condition to be treated and the type of administration, the amount of the administered compound can amount to 0.1-25 mg/kg body weight, preferably 0.5-5 mg/kg body weight, per day. For humans, this corresponds to a daily dose of 5 to 1,250 mg. The preferred daily dosage for humans is 50 to 200 mg. This particularly applies to tumor therapy.

For oral administrering kan det anvendes kapsler, piller, tabletter, dragéer osv. Doseringsenhetene kan, foruten det aktive stoff, inneholde en farmasøytisk forenlig bærer, slik som f.eks. stivelse, sukker, sorbitol, gelatin, glidemid-del, kiselsyre, talkum osv. De enkelte doseringsenheter for oral administrering, kan f.eks. inneholde 5 til 500 mg av det aktive stoff. For oral administration, capsules, pills, tablets, dragées etc. can be used. The dosage units can, in addition to the active substance, contain a pharmaceutically compatible carrier, such as e.g. starch, sugar, sorbitol, gelatin, gliding agent, silicic acid, talc etc. The individual dosage units for oral administration, can e.g. contain 5 to 500 mg of the active substance.

For å oppnå en bedre biologisk forenlighet av det aktive stoff, kan forbindelsene også formuleres som syklodek-strinklatrater. For dette omsettes forbindelsene med a-, £S-eller ysyklodekstrin eller derivater av disse (PCT/EP95/- 02656). For parenteral administrering kan de aktive stoffer være oppløst eller suspendert i et fysiologisk forenlig fortynningsmiddel. Som fortynningsmiddel anvendes meget ofte oljer med eller uten tilsetning av et løsningsmiddel, et over-flateaktivt middel, suspenderings- eller emulgeringsmiddel. Eksempler på anvendte oljer er olivenolje, jordnøttolje, bomullsfrøolje, soyabønneolje, rizinusolje og sesamolje. In order to achieve a better biological compatibility of the active substance, the compounds can also be formulated as cyclodextrin lactrates. For this, the compounds are reacted with a-, £S- or ycyclodextrin or derivatives thereof (PCT/EP95/- 02656). For parenteral administration, the active substances may be dissolved or suspended in a physiologically compatible diluent. As a diluent, oils are very often used with or without the addition of a solvent, a surface-active agent, suspending or emulsifying agent. Examples of oils used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

Forbindelsene kan også anvendes i form av en depot-injeksjon eller et implantatpreparat som kan være formulert slik at det muliggjør en forsinket frigivelse av aktivt stoff. The compounds can also be used in the form of a depot injection or an implant preparation which can be formulated so that it enables a delayed release of active substance.

Implantater kan som inerte materialer, f.eks. inneholde biologisk nedbrytbare polymerer eller syntetiske sili-koner, slik som f.eks. silikonkautschuk. De aktive stoffer kan dessuten f.eks. innarbeides i et plaster for perkutan app-lisering. Implants can, as inert materials, e.g. contain biodegradable polymers or synthetic silicones, such as e.g. silicone rubber. The active substances can also e.g. incorporated into a patch for percutaneous application.

Forbindelsene ifølge foreliggende oppfinnelse kan fremstilles som beskrevet i det etterfølgende. De etterfølg-ende eksempler tjener til nærmere belysning av oppfinnelsen. Ved analoge fremgangsmåter under anvendelse av analoge rea-genser som de angitte i eksemplene, kan det fremstilles alle forbindelser med generell formel I. Forsåpningen av ester-grupper, så vel som forestring og foretring av frie hydroksygrupper, utføres etter etablerte fremgangsmåter i den organiske kjemi. Ved å ta hensyn til den forskjellige reaktivitet av de forestrede og frie 3- og 17-hydroksygrupper, kan 3,17-diesteren spaltes selektivt i 3-posisjon og 3-hydroksy-17-acyloksyforbindelsen kan deretter målrettet videre funksjo-naliseres i 3-posisjonen; det er likeledes også mulig å for-estre eller foretre 3,17-dihydroksyforbindelsen selektivt i kun 3-posisjonen og deretter målrettet innføre i 17-posisjonen en andre rest som allerede befinner seg i 3-stilling. The compounds according to the present invention can be prepared as described below. The following examples serve to further elucidate the invention. By analogous methods using analogous reagents as those indicated in the examples, all compounds of general formula I can be prepared. The saponification of ester groups, as well as the esterification and etherification of free hydroxy groups, is carried out according to established methods in organic chemistry . By taking into account the different reactivity of the esterified and free 3- and 17-hydroxy groups, the 3,17-diester can be selectively cleaved in the 3-position and the 3-hydroxy-17-acyloxy compound can then be further functionalized in a targeted manner in the 3- the position; it is likewise also possible to esterify or etherify the 3,17-dihydroxy compound selectively in the 3-position only and then purposefully introduce in the 17-position a second residue which is already in the 3-position.

Syreaddisjonssaltene av forbindelsene med generell formel I, kan likeledes fremstilles fra forbindelsene med generell formel I ved vanlige fremgangsmåter. The acid addition salts of the compounds of general formula I can likewise be prepared from the compounds of general formula I by usual methods.

De etterfølgende eksempler tjener til nærmere belysning av oppfinnelsen: Eksempel 1 The following examples serve to further elucidate the invention: Example 1

14, 17- etan- 7a- f5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl} østra- l, 3, 5( 10) - trien- 3, 17j3- diol 14, 17- ethane- 7a- f5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl} estral- l, 3, 5( 10)- trien- 3 , 17j3- diol

a) 7 a-( 5- tert.- butyldimetylsilyloksypentyl) østr- 4- en-3, 17- dion a) 7 a-(5-tert.-butyldimethylsilyloxypentyl)estr-4-ene-3,17-dione

I 70 ml absolutt tetrahydrofuran omsettes 15,1 g magnesiumspon med 175,6 g l-brom-5-tert.-butyl-dimetylsilyl-oksypentan [Tetrahedron Letters 23, 1982, 40, 4147-4150] opp-løst i 600 ml absolutt tetrahydrofuran som et Grignard-reagens. Til denne løsning, avkjølt til -20 °C, tilsettes under en nitrogenstrøm, 59 g kobber-(I)-jodid og tildryppes deretter i løpet av 1 t 50 g østra-4,6-dien-3,17-dion [Steroids Vol. l, 1963, 233-249] oppløst i 300 ml absolutt THF. For opparbeidelse tildryppes 37,5 ml eddiksyre, reaksjonsblandingen fortynnes med eddikester, vaskes med mettet ammoniumklorid-løsning, vann og natriumhydrogenkarbonatløsning og tørkes. Den oppnådde rest etter inndamping kromatograferes på kiselgel. In 70 ml of absolute tetrahydrofuran, 15.1 g of magnesium shavings are reacted with 175.6 g of 1-bromo-5-tert-butyl-dimethylsilyl-oxypentane [Tetrahedron Letters 23, 1982, 40, 4147-4150] dissolved in 600 ml of absolute tetrahydrofuran as a Grignard reagent. To this solution, cooled to -20 °C, 59 g of copper (I)-iodide are added under a stream of nitrogen and then 50 g of estra-4,6-diene-3,17-dione are added dropwise over the course of 1 h [Steroids Vol. 1, 1963, 233-249] dissolved in 300 ml of absolute THF. For work-up, 37.5 ml of acetic acid is added dropwise, the reaction mixture is diluted with ethyl acetate, washed with saturated ammonium chloride solution, water and sodium bicarbonate solution and dried. The residue obtained after evaporation is chromatographed on silica gel.

Det oppnås 35,4 g 7a-(5-tert.-butyldimetylsilyloksypentyl)-østr-4-en-3,17-dion. [a]D<22> = +52 , 8 <0> (c = 0,535 % 35.4 g of 7α-(5-tert-butyldimethylsilyloxypentyl)-estr-4-ene-3,17-dione are obtained. [a]D<22> = +52 , 8 <0> (c = 0.535%

i kloroform). in chloroform).

b) 7 a-( 5- hydroksypentyl)-østr-4-en-3, 17- dion b) 7 a-(5- hydroxypentyl)-estr-4-ene-3, 17-dione

En løsning av 125,4 g 7a-(5-tert.-butyldimetylsilyloksypentyl) -østr-4-en-3,17-dion i 625 ml metanol og 347 ml vann omrøres med 694 ml iseddik i 2,5 t ved 50 °C. Etter inndamping ved 60 °C i vakuum oppnås 94,1 g urenset 7a-(5-hydroksypentyl)-østr-4-en-3,17-dion som en olje. A solution of 125.4 g of 7a-(5-tert-butyldimethylsilyloxypentyl)-estr-4-ene-3,17-dione in 625 ml of methanol and 347 ml of water is stirred with 694 ml of glacial acetic acid for 2.5 h at 50 ° C. After evaporation at 60 °C in vacuum, 94.1 g of impure 7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione are obtained as an oil.

c) 7 a-( 5- acetoksypentyl)- østr- 4- en- 3, 17- dion c) 7a-(5-acetoxypentyl)-estr-4-ene-3,17-dione

En løsning av 94 g urenset 7a-(5-hydroksypentyl)-østr-4-en-3,17-dion i 620 ml pyridin tilsettes langsomt 310 ml acetanhydrid og omrøres i 2 t ved 25 °C. Blandingen tilsettes deretter langsomt under isavkjøling 116 ml vann, fortynnes med 3 1 dietyleter, den organiske fase vaskes deretter med natriumhydrogenkarbonatløsning, tørkes og inndampes. Bunnfallet kromatograferes på kiselgel og det oppnås 84,4 g 7a-(5-acetoksypentyl)-østr-4-en-3,17-dion som en olje. A solution of 94 g of impure 7a-(5-hydroxypentyl)-estr-4-ene-3,17-dione in 620 ml of pyridine is slowly added to 310 ml of acetic anhydride and stirred for 2 h at 25 °C. The mixture is then added slowly under ice-cooling to 116 ml of water, diluted with 3 1 of diethyl ether, the organic phase is then washed with sodium bicarbonate solution, dried and evaporated. The precipitate is chromatographed on silica gel and 84.4 g of 7a-(5-acetoxypentyl)-estr-4-ene-3,17-dione is obtained as an oil.

d) 7 a-( 5- acetoksypentyl)- 3- hydroksy- østra- l, 3, 5( 10)-trien- 17- on d) 7 a-(5-acetoxypentyl)-3-hydroxy-estral-1,3,5(10)-trien-17-one

Til en løsning av 82,3 g 7a-(5-acetoksypentyl)-østr-4-en-3,17-dion i 936 ml acetonitril tilsettes ved 80 °C badtemperatur 17,8 g litiumbromid og 92,83 g kopper-II-bromid. Etter 10 min ved 80 °C badtemperatur avkjøles reaksjonsløsnin-gen, ekstraheres 3 ganger med eddikester, vaskes med vann og natriumhydrogenkarbonatløsning og tørkes. Resten oppnådd etter inndamping, kromatograferes på kiselgel og det oppnås 60,4 g 7a-(5-acetoksypentyl)-3-hydroksy-østra-l,3,5(10)-trien-17-on som en olje. To a solution of 82.3 g of 7a-(5-acetoxypentyl)-estr-4-ene-3,17-dione in 936 ml of acetonitrile, 17.8 g of lithium bromide and 92.83 g of copper-II are added at 80 °C bath temperature - bromide. After 10 min at 80 °C bath temperature, the reaction solution is cooled, extracted 3 times with acetic acid, washed with water and sodium bicarbonate solution and dried. The residue obtained after evaporation is chromatographed on silica gel and 60.4 g of 7a-(5-acetoxypentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained as an oil.

e) 3- acetoksy- 7a-( 5- acetoksypentyl)- østra- 1, 3, 5( 10)-trien- 17- on e) 3- acetoxy- 7a-( 5- acetoxypentyl)- estra- 1, 3, 5( 10)-trien- 17- one

En løsning av 60,4 g 7a-(5-acetoksypentyl)-3-hydroksy-østra-1,3,5(10)-trien-17-on i 300 ml pyridin omrøres ved romtemperatur ilt med 150 ml acetanhydrid. Blandingen tilsettes deretter en is/vann/koksalt/saltsyreblanding, det utfelte materialet oppløses i eddikester, vaskes nøytralt med natriumhydrogenkarbonat og koksaltløsning og tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 63,9 g 3-acetoksy-7a-(5-acetoksypentyl)-østra-1,3,5(10)-trien-17-on som en olje. A solution of 60.4 g of 7a-(5-acetoxypentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one in 300 ml of pyridine is stirred at room temperature in oxygen with 150 ml of acetic anhydride. The mixture is then added to an ice/water/common salt/hydrochloric acid mixture, the precipitated material is dissolved in vinegar, washed neutrally with sodium bicarbonate and common salt solution and dried over sodium sulfate and evaporated in vacuum. 63.9 g of 3-acetoxy-7a-(5-acetoxypentyl)-estra-1,3,5(10)-trien-17-one are obtained as an oil.

f) 3- acetoksy- 7a-( 5- acetoksypentyl)- 17, 17- etylendioksy-østra- 1, 3, 5( 10)- trien f) 3- acetoxy- 7a-( 5- acetoxypentyl)- 17, 17- ethylenedioxy-estra- 1, 3, 5( 10)- triene

En løsning av 63,9 g 3-acetoksy-7a-(5-acetoksypentyl) -østra-1 , 3 , 5 (10) -trien-17-on i 460 ml diklormetan omrøres med 460 ml etylenglykol, 155 ml trimetylortoformiat og 1,2 g para-toluensulfonsyre i 3 t ved 50 °C badtemperatur. Blandingen fortynnes deretter med diklormetan, vaskes med natriumhydrogenkarbonat- og koksaltløsning og tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med heksan/eddikester. Det oppnås 63,2 g 3-acetoksy-7a-(5-acetoksypentyl)-17,17-etylendioksy-østra-l,3,5(10)-trien som en olje. A solution of 63.9 g of 3-acetoxy-7a-(5-acetoxypentyl)-estra-1,3,5(10)-trien-17-one in 460 ml of dichloromethane is stirred with 460 ml of ethylene glycol, 155 ml of trimethyl orthoformate and 1 .2 g para-toluenesulfonic acid for 3 h at 50 °C bath temperature. The mixture is then diluted with dichloromethane, washed with sodium bicarbonate and sodium chloride solution and dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with hexane/acetic acid. 63.2 g of 3-acetoxy-7α-(5-acetoxypentyl)-17,17-ethylenedioxy-estra-1,3,5(10)-triene are obtained as an oil.

g) 3- acetoksy- 7g-( 5- acetoksypentyl)- 16a- brom- 17, 17-etylendioksy- østra- l , 3, 5( 10)- trien g) 3-acetoxy-7g-(5-acetoxypentyl)-16a-bromo-17, 17-ethylenedioxy-estral, 3,5(10)-triene

En løsning av 63,2 g 3-acetoksy-7a-(5-acetoksypentyl)-17,17-etylendioksy-østra-l, 3 , 5 (10) -trien i 630 ml tetrahydrofuran tilsettes porsjonsvis ved 0 °C 61,7 g pyridinhydrobromidper-bromid og omrøres i 2 t ved 0 °C. Blandingen tilsettes deretter en løsning av 15 g natriumsulfid i 70 ml vann, fortynnes med eddikester, vaskes med natriumhydrogenkarbonat- og kok-saltløsning og tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 74,1 g 3-acetoksy-7a-(5-acetoksypentyl)-16a-brom-17,17-etylendioksy -østra-1,3,5(10)-trien som en ol^e. A solution of 63.2 g of 3-acetoxy-7a-(5-acetoxypentyl)-17,17-ethylenedioxy-estra-1,3,5(10)-triene in 630 ml of tetrahydrofuran is added portionwise at 0 °C 61.7 g pyridine hydrobromide per-bromide and stirred for 2 h at 0 °C. A solution of 15 g of sodium sulphide in 70 ml of water is then added to the mixture, diluted with acetic acid, washed with sodium bicarbonate and common salt solution and dried over sodium sulphate and evaporated in vacuo. 74.1 g of 3-acetoxy-7α-(5-acetoxypentyl)-16α-bromo-17,17-ethylenedioxy-estra-1,3,5(10)-triene are obtained as an oil.

h) 17, 17- etylendioksy- 7a-( 5- hydroksypentyl)- østra-1, 3, 5( 10), 15- tetraen- 3- ol h) 17, 17- ethylenedioxy- 7a-(5- hydroxypentyl)- estra-1, 3, 5( 10), 15- tetraen- 3-ol

En løsning av 74,1 g 3-acetoksy-7a-(5-acetoksypentyl) -16a-brom-17, 17-etylendioksy-østra-l, 3, 5 (10) -trien i 740 ml dimetylsulfoksid og 74 ml metanol omrøres med 74 g kalium-hydroksid i 7,5 t ved 85 °C badtemperatur. Blandingen tilsettes deretter is/vann/koksalt, det utfelte materialet oppløses i eddikester, vaskes nøytralt, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med heksan/eddikester. Det oppnås 36,12 g ren 17,17-etylendioksy-7a-(5-hydroksypentyl)-østra-1,3,5(10),15-tetraen-3-ol som et skum. A solution of 74.1 g of 3-acetoxy-7α-(5-acetoxypentyl)-16α-bromo-17, 17-ethylenedioxy-estra-1,3,5(10)-triene in 740 ml of dimethylsulfoxide and 74 ml of methanol is stirred with 74 g of potassium hydroxide for 7.5 h at 85 °C bath temperature. The mixture is then added to ice/water/common salt, the precipitated material is dissolved in ethyl acetate, washed neutrally, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with hexane/ethyl acetate. 36.12 g of pure 17,17-ethylenedioxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol are obtained as a foam.

i) 3- hydroksy- 7g-( 5- hydroksypentyl)- østra- 1, 3, 5( 10), 15-tetraen- 17- on i) 3- hydroxy- 7g-( 5- hydroxypentyl)- estra- 1, 3, 5( 10), 15-tetraen- 17- one

En løsning av 36,12 g 17,17-etylendioksy-7a-(5-hydroksypentyl)-østra-1,3,5(10),15-tetraen-3-ol i 958 ml aceton og 111 ml vann omrøres i 2 t ved romtemperatur med 2,76 g para-toluensulfonsyre. Blandingen inndampes deretter i vakuum til 1/3 av volumet, oppløses i eddikester, vaskes nøy-tralt, tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 31,7 g 3-hydroksy-7a-(5-hydroksypentyl)-østra-l,3,5(10),15-tetraen-17-on som krystaller med smp. 194-196 °C. A solution of 36.12 g of 17,17-ethylenedioxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol in 958 ml of acetone and 111 ml of water is stirred for 2 t at room temperature with 2.76 g of para-toluenesulfonic acid. The mixture is then evaporated in vacuo to 1/3 of the volume, dissolved in acetic acid, washed neutrally, dried over sodium sulphate and evaporated in vacuo. 31.7 g of 3-hydroxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one are obtained as crystals with m.p. 194-196 °C.

j) 3, 17- diacetoksy- 7g-( 5- acetoksypentyl)- østra-I, 3, 5( 10), 14, 16- pentaen j) 3, 17- diacetoxy- 7g-( 5- acetoxypentyl)- estra-I, 3, 5( 10), 14, 16- pentaene

En løsning av 15,7 g 3-hydroksy-7a-(5-hydroksypentyl) -østra-1 , 3 , 5 (10) , 15-tetraen-l7-on i 330 ml eddiksyrean-hydrid omrøres med 4,6 g para-toluensulfonsyre i 4 t ved romtemperatur. Blandingen tilsettes deretter pyridin/vann/- koksalt, det utfelte materialet oppløses i eddikester, vaskes med natriumhydrogenkarbonat- og koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med heksan/eddikester. Det oppnås 11,1 g ren 3,17-diacetoksy-7a-(5-acetoksypentyl)-østra-1,3,5(10),14,16-pentaen som en olje. A solution of 15.7 g of 3-hydroxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one in 330 ml of acetic anhydride is stirred with 4.6 g of para -toluenesulfonic acid for 4 h at room temperature. The mixture is then added to pyridine/water/sodium bicarbonate, the precipitated material is dissolved in ethyl acetate, washed with sodium bicarbonate and sodium bicarbonate solution, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with hexane/acetic acid. 11.1 g of pure 3,17-diacetoxy-7a-(5-acetoxypentyl)-estra-1,3,5(10),14,16-pentaene are obtained as an oil.

k) 3, 17j3- diacetoksy- 7g- ( 5- acetoksypentyl) - 14a, 17a- eteno-østra- 1, 3, 5( 10)- trien k) 3, 17j3- diacetoxy- 7g-( 5- acetoxypentyl)- 14a, 17a- etheno- estra- 1, 3, 5( 10)- triene

II, 0 g 3,17-diacetoksy-7o-(5-acetoksypentyl)-østra-1,3,5(10),14,16-pentaen i 120 ml benzen behandles ved 300 bar og 175 °C i 6,5 dager med etan. Blandingen oppløses deretter i eddikester, vaskes med natriumhydrogenkarbonat- og koksalt-løsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med heksan/eddikester. Det oppnås 8,4 g 3,17£-diacetoksy-7a-(5-acetoksypentyl)-14a,17a-eteno-østra-1,3,5(10)-trien som et skum. II, 0 g of 3,17-diacetoxy-7o-(5-acetoxypentyl)-estra-1,3,5(10),14,16-pentaene in 120 ml of benzene is treated at 300 bar and 175 °C for 6.5 days with ethane. The mixture is then dissolved in ethyl acetate, washed with sodium bicarbonate and sodium chloride solution, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with hexane/acetic acid. 8.4 g of 3,17α-diacetoxy-7α-(5-acetoxypentyl)-14α,17α-etheno-estra-1,3,5(10)-triene are obtained as a foam.

1) 3, 17J3- diacetoksy- 7a- ( 5- acetoksypentyl) - 14g, 17a- etan-østra- 1, 3, 5( 10)- trien 1) 3, 17J3- diacetoxy- 7a- ( 5- acetoxypentyl)- 14g, 17a- ethane- estra- 1, 3, 5( 10)- triene

En løsning av 8,4 g 3,17{3-diacetoksy-7a- (5-acetoksypentyl) -14a,17a-eteno-østra-l,3,5(10)-trien i 200 ral eddikester omrøres med 1,5 g palladium (10%) på karbon i én time ved romtemperatur under hydrogen. Blandingen filtreres deretter gjennom celitt som vaskes med eddikester, blandingen inndampes i vakuum og kromatograferes på kiselgel med heksan/eddikester. Det oppnås 6,0 g 3,17£-diacetoksy-7a-(5-acetoksypentyl)-14a,17a-etan-østra-l,3,5(10)-trien som et skum. A solution of 8.4 g of 3,17{3-diacetoxy-7a-(5-acetoxypentyl)-14a,17a-etheno-estra-1,3,5(10)-triene in 200 ral of acetic acid is stirred with 1.5 g of palladium (10%) on carbon for one hour at room temperature under hydrogen. The mixture is then filtered through celite which is washed with ethyl acetate, the mixture is evaporated in vacuo and chromatographed on silica gel with hexane/ethyl acetate. 6.0 g of 3,17α-diacetoxy-7α-(5-acetoxypentyl)-14α,17α-ethane-estra-1,3,5(10)-triene are obtained as a foam.

m) 14 a, 17a- etan- 7a-( 5- hydroksypentyl)- østra- 1, 3, 5( 10)-trien- 3, 17fi- diol m) 14 a, 17a- ethane- 7a-(5- hydroxypentyl)- estra- 1, 3, 5( 10)-trien- 3, 17fi- diol

En løsning av 6,0 g 3,17£-diacetoksy-7a-(5-acetoksypentyl) -14a,17a-etan-østra-l,3,5(10)-trien i 100 ml av en 1-molar kaliumhydroksidløsning hensettes i 7,5 t ved romtemperatur. Blandingen tilsettes deretter 1-molar saltsyre, ekstraheres 3 ganger med eddikester, vaskes med natriumhydrogenkarbonat- og koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og omkrystalliseres fra aceton/heksan. Det oppnås 4,57 g 14a,17a-etan-7a-(5-hydroksypentyl)-østra-1,3,5(10)-trien-3,170-diol som fargeløse krystaller med smp. 63-65 °C. A solution of 6.0 g of 3,17α-diacetoxy-7α-(5-acetoxypentyl)-14α,17α-ethane-estra-1,3,5(10)-triene in 100 ml of a 1-molar potassium hydroxide solution is prepared for 7.5 h at room temperature. The mixture is then added to 1-molar hydrochloric acid, extracted 3 times with acetic acid, washed with sodium bicarbonate and sodium bicarbonate solution, dried over sodium sulfate, evaporated in vacuo and recrystallized from acetone/hexane. 4.57 g of 14α,17α-ethane-7α-(5-hydroxypentyl)-estra-1,3,5(10)-triene-3,170-diol are obtained as colorless crystals with m.p. 63-65 °C.

n) 3- benzyloksy- 14a, 17a- etan- 7a-( 5- hydroksypentyl)-østra- 1, 3, 5( 10)- trien- 17p- ol n) 3- benzyloxy- 14a, 17a- ethane- 7a-( 5- hydroxypentyl)- estra- 1, 3, 5( 10)- trien- 17p-ol

En løsning av 4,5 g 14a,17a-etan-7a-(5-hydroksypentyl) -østra-1, 3, 5 (10)'-trien-3,17^-diol i 90 ml acetonitril omrøres med 1,91 g kaliumkarbonat og 1,53 ml benzylbromid i 6,5 t ved 80 °C badtemperatur. Blandingen inndampes deretter i vakuum til 1/3 av volumet, helles over på vann, ekstraheres 3 ganger med eddikester, vaskes nøytral, tørkes over natrium-sulf at, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/aceton. Det oppnås 4,8 g 3-benzyloksy-14a,17a-etan-7a-(5-hydroksypentyl)-østra-1,3,5(10)-trien-17£-ol som et skum. A solution of 4.5 g of 14α,17α-ethane-7α-(5-hydroxypentyl)-estra-1,3,5(10)'-triene-3,17α-diol in 90 ml of acetonitrile is stirred with 1.91 g of potassium carbonate and 1.53 ml of benzyl bromide for 6.5 h at 80 °C bath temperature. The mixture is then evaporated under vacuum to 1/3 of the volume, poured onto water, extracted 3 times with ethyl acetate, washed neutral, dried over sodium sulfate, evaporated under vacuum and chromatographed on silica gel with dichloromethane/acetone. 4.8 g of 3-benzyloxy-14α,17α-ethan-7α-(5-hydroxypentyl)-estra-1,3,5(10)-trien-17α-ol are obtained as a foam.

o) 3- benzyloksy- 14g, 17g- etan- 7g-( 5- tosyloksypentyl)-østra- 1, 3, 5( 10)- trien- 17|3- ol o) 3- benzyloxy- 14g, 17g- ethan- 7g-(5- tosyloxypentyl)-estra- 1, 3, 5( 10)- trien- 17|3-ol

En løsning av 4,8 g 3-benzyloksy-14a,17a-etan-7g<->(5-hydroksypentyl)-østra-1,3,5(10)-trien-17£-ol i 50 ml pyridin omrøres ved 0 °C med 3,63 g toluensulfonsyreanhydrid i 4 t. Blandingen fortynnes deretter med eddikester, ekstraheres med 2-molar saltsyre, vaskes nøytral, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med heksan/eddikester. Det oppnås 4,75 g 3-benzyloksy-14a,17o-etan-7a- (5-tosyloksypentyl) -østra-1, 3, 5 (10) -trien-17{5-ol som et skum. A solution of 4.8 g of 3-benzyloxy-14a,17a-ethan-7g<->(5-hydroxypentyl)-estra-1,3,5(10)-trien-17£-ol in 50 ml of pyridine is stirred at 0 °C with 3.63 g of toluenesulfonic anhydride for 4 h. The mixture is then diluted with ethyl acetate, extracted with 2-molar hydrochloric acid, washed neutral, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with hexane/ethyl acetate. 4.75 g of 3-benzyloxy-14a,17o-ethan-7a-(5-tosyloxypentyl)-estra-1,3,5(10)-trien-17{5-ol are obtained as a foam.

p) 3- benzyloksy- 14g, 17g- etan- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl}-østra- 1, 3, 5( 10)- trien- 17g- ol p) 3- benzyloxy- 14g, 17g- ethane- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl}- estra- 1, 3, 5(10)-triene- 17g- ol

En løsning av 4,7 g 3-benzyloksy-14a,17a-etan-7a-(5-tosyloksypentyl) -østra-1,3,5 (10)-trien- 17J3-ol i 100 ml dimetylformamid omrøres med 2,7 g metyl-[3-(4,4,5,5,5-pentafluorpentyltio)propyl]amin i 4 t ved 80 °C badtemperatur. Blandingen helles deretter over i vann, ekstraheres 3 ganger med eddikester, vaskes med koksaltløsning, tørkes over natri-umsulf at, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 3,8 g 3-benzyloksy-14a,17a-etan-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-1,3,5(10)-trien-17£-ol som en ol je. A solution of 4.7 g of 3-benzyloxy-14a,17a-ethan-7a-(5-tosyloxypentyl)-estra-1,3,5 (10)-trien-17J3-ol in 100 ml of dimethylformamide is stirred with 2.7 g methyl-[3-(4,4,5,5,5-pentafluoropentylthio)propyl]amine for 4 h at 80 °C bath temperature. The mixture is then poured into water, extracted 3 times with acetic acid, washed with sodium chloride solution, dried over sodium sulphate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 3.8 g of 3-benzyloxy-14a,17a-ethane-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra- 1,3,5(10)-trien-17£-ol as an ol je.

3) 14 a, 17a- etan- 7a-{ 5- [ N- metyl- N- 3- ( 4, 4, 5, 5, 5-pentafluorpentyltio) propylamino] pentyl}- østra-1, 3, 5( 10)- trien- 3, 17p- diol 3) 14 a, 17a- ethane-7a-{ 5- [ N- methyl- N- 3-( 4, 4, 5, 5, 5-pentafluoropentylthio) propylamino] pentyl}- estra-1, 3, 5( 10 )-triene-3, 17p-diol

En løsning av 3,7 g 3-benzyloksy-14a,17a-etan-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfinyl)propylamino]-pentyl}-østra-1,3,5(10)-trien-17p-ol i 65 ml diklormetan, omrøres ved 0 °C med 2,1 ml N,N-dimetylanilin i 5 min, tilsettes 2,75 g vannfritt aluminiumklorid og omrøres i 3,5 t ved 0 °C. Blandingen tilsettes deretter mettet, vandig kaliumnatrium-tartratløsning, helles over i vann, ekstraheres 3 ganger med diklormetan, vaskes nøytral, tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 6,3 g råprodukt som kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 2,85 g ren 14a,17a-etan-7a-{5-[N-metyl-N-3-{4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-1,3,5(10)-trien-3,17£-diol som krystaller med smp. 63-67 °C, [a]D<22> = +19,4 ° (c = 0,505 % i kloroform). A solution of 3.7 g of 3-benzyloxy-14a,17a-ethane-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]-pentyl}- estra-1,3,5(10)-trien-17p-ol in 65 ml of dichloromethane, stir at 0 °C with 2.1 ml of N,N-dimethylaniline for 5 min, add 2.75 g of anhydrous aluminum chloride and stir in 3.5 h at 0 °C. The mixture is then added to saturated aqueous potassium sodium tartrate solution, poured into water, extracted 3 times with dichloromethane, washed neutral, dried over sodium sulfate and evaporated in vacuo. 6.3 g of crude product is obtained which is chromatographed on silica gel with dichloromethane/methanol. 2.85 g of pure 14a,17a-ethane-7a-{5-[N-methyl-N-3-{4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra-1,3 are obtained ,5(10)-triene-3,17£-diol as crystals with m.p. 63-67 °C, [a]D<22> = +19.4 ° (c = 0.505% in chloroform).

Eksempel 2 Example 2

14, 17- etan- 7g-{ 5- [ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentan-sulf inyl) - propylamino] pentyl} - østra- 1, 3, 5( 10) - trien- 3, 17j3- diol 14, 17- ethane- 7g-{ 5- [ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentane-sulfinyl) - propylamino] pentyl} - estra- 1, 3, 5( 10) - triene-3, 17j3-diol

En løsning av 1,0 g 14a,17a-etan-7a-{5-[N-metyl-N-3-{4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-1, 3,5 (10)-trien-3,17p"-diol i 37,5 ml metanol og 1,78 ml vann, omrøres med 381 mg natriumperjodat i 5 t ved romtemperatur. Blandingen helles deretter over i vann, ekstraheres 3 ganger med diklormetan, vaskes nøytral, tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 985 mg råprodukt som kromatograf eres på kiselgel med diklormetan/metanol. Det oppnås 514,3 mg ren 14,17-etan-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulf inyl)-propylamino]pentyl}-østra-1,3,5(10)-trien-3,17p"-diol som krystaller med smp. 84-86 °C; [a]D<22> = +13 , 0 <0> (c = 0,5 % i kloroform). A solution of 1.0 g of 14a,17a-ethane-7a-{5-[N-methyl-N-3-{4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra-1, 3 ,5(10)-triene-3,17p"-diol in 37.5 ml of methanol and 1.78 ml of water, stirred with 381 mg of sodium periodate for 5 h at room temperature. The mixture is then poured into water, extracted 3 times with dichloromethane , washed neutral, dried over sodium sulfate and evaporated in vacuo. 985 mg of crude product is obtained which is chromatographed on silica gel with dichloromethane/methanol. 514.3 mg of pure 14,17-ethane-7a-{5-[N-methyl- N-3-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-propylamino]pentyl}-estra-1,3,5(10)-triene-3,17p"-diol as crystals with m.p. 84-86 °C; [a]D<22> = +13 , 0 <0> (c = 0.5% in chloroform).

Eksempel 3 Example 3

3, 17p- diacetoksy- 14a, 17a- etan- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5-pentafluorpentyltio) propylamino] pentyl}- østra- 1, 3, 5( 10)- trien 3, 17p- diacetoxy- 14a, 17a- ethane- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5-pentafluoropentylthio) propylamino] pentyl}- estra- 1, 3, 5( 10)- the trien

En løsning av 600 mg 14a,17a-etan-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-1,3,5(10)-trien-3,17p-diol i 2 ml pyridin og 1 ml acetanhydrid omrøres med 5 mg dimetylaminopyridin i 4,5 t ved romtemperatur. Blandingen fortynnes deretter med eddikester, vaskes med vann og koksaltløsning, tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 680 mg 3,17p-diacetoksy-14a,17a-etan-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio) propylamino]pentyl}-østra-1,3,5(10)-trien som en olje. A solution of 600 mg of 14a,17a-ethane-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra-1,3,5 (10)-triene-3,17p-diol in 2 ml of pyridine and 1 ml of acetic anhydride is stirred with 5 mg of dimethylaminopyridine for 4.5 h at room temperature. The mixture is then diluted with ethyl acetate, washed with water and sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. 680 mg of 3,17p-diacetoxy-14a,17a-ethane-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra- 1,3,5(10)-triene as an oil.

Eksempel 4 Example 4

14, 17- etan- 7g-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentan-sul fonyl) propylamino] pentyl}- østra- 1, 3, 5( 10)- trien- 3, 17p- diol 14, 17- ethane- 7g-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentane-sulfonyl) propylamino] pentyl}- estra- 1, 3, 5( 10 )-triene-3, 17p-diol

En løsning av 650 mg 3,17£-diacetoksy-14a,17a-etan-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino] pentyl } -østra-1, 3 , 5 (10) -trien i 15 ml iseddik omrøres med 1,5 g natriumperborattetrahydrat i 3 t ved romtemperatur. Blandingen helles deretter over i vann, ekstraheres 3 ganger med diklormetan, vaskes nøytral, tørkes over natriumsulfat, inndampes i vakuum, oppløses i 10 ml 0,2 molar metanolisk kaliumhydroksidløsning omrøres i 24 t ved romtemperatur, helles over i vann, ekstraheres 3 ganger med diklormetan, vaskes nøytral, tørkes over natriumsulfat, inndampes i vakuum, suspenderes i 20 ml eddikester, tilsettes 10 ml tinn(II)kloridløsning, omrøres i 4 t ved romtemperatur, fortynnes med eddikester, vaskes med koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med heksan/eddikester. Det oppnås 300 mg ren 14,17-etan-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulfonyl)-propylamino]pentyl}-østra-1,3,5(10)-trien-3,17p-diol som krystaller med smp. 55-58 °C; [<x]D<22> = +19 , 4 <0> (c = 0,51 % i kloroform). A solution of 650 mg of 3,17£-diacetoxy-14a,17a-ethane-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino] pentyl } - estra-1, 3, 5 (10)-triene in 15 ml of glacial acetic acid is stirred with 1.5 g of sodium perborate tetrahydrate for 3 h at room temperature. The mixture is then poured into water, extracted 3 times with dichloromethane, washed neutral, dried over sodium sulfate, evaporated in vacuo, dissolved in 10 ml of 0.2 molar methanolic potassium hydroxide solution, stirred for 24 h at room temperature, poured into water, extracted 3 times with dichloromethane, washed neutral, dried over sodium sulfate, evaporated in vacuo, suspended in 20 ml of ethyl acetate, added 10 ml of stannous chloride solution, stirred for 4 h at room temperature, diluted with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate, evaporated in vacuum and chromatographed on silica gel with hexane/acetic acid. 300 mg of pure 14,17-ethane-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-propylamino]pentyl}-estra-1 are obtained, 3,5(10)-triene-3,17p-diol as crystals with m.p. 55-58 °C; [<x]D<22> = +19 , 4 <0> (c = 0.51% in chloroform).

Eksempel 5 Example 5

17a- trifluormetyl- 7a- f5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl} - østra- 1, 3, 5( 10)- trien- 3, 17g- diol 17a- trifluoromethyl- 7a- f5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl} - estra- 1, 3, 5( 10)- trien- 3, 17g- diol

a) 17p- acetoksy- 7a-( 5- tert.- butyldimetylsilyloksypentyl)- østr- 4- en- 3- on a) 17p-acetoxy-7a-(5-tert.-butyldimethylsilyloxypentyl)-estrone-4-en-3-one

I 200 ml absolutt THF omsettes 22,9 g magnesiumspon med 261 g l-brom-5-tert.-butyl-dimetylsilyloksypentan [Tetrahedron Letters 23, 1982, 40, 4147-4150] oppløst i 250 ml absolutt THF, til et Grignard-reagens. Til denne løsning avkjølt til -20 °C, tilsettes under en nitrogenstrøm, 92,9 g kopper(I)jodid og i løpet av 1 t tildryppes deretter 73,5 g 17fJ-acetoksyøstra-4,6-dien-3-on [J. Am. Chem. Soc. 80, 1958, 2596-2597] i 3 00 ml absolutt THF. For opparbeidelse tildryppes 61,2 ml eddiksyre, reaksjonsblandingen fortynnes med eddikester, vaskes med mettet ammoniumkloridløsning, vann og natriumhydrogenkarbonat løsning og tørkes. Resten etter inndamping, kromatograferes på kiselgel. Det oppnås 48 g 17p-acetoksy-7a-(5-tert.-butyldimetylsilyloksypentyl)-østr-4-en-3-on. In 200 ml of absolute THF, 22.9 g of magnesium shavings are reacted with 261 g of l-bromo-5-tert.-butyl-dimethylsilyloxypentane [Tetrahedron Letters 23, 1982, 40, 4147-4150] dissolved in 250 ml of absolute THF, to a Grignard reagent. To this solution cooled to -20 °C, 92.9 g of copper(I) iodide are added under a stream of nitrogen and, over the course of 1 h, 73.5 g of 17fJ-acetoxyestran-4,6-dien-3-one are then added dropwise [ J. Am. Chem. Soc. 80, 1958, 2596-2597] in 300 ml of absolute THF. For work-up, 61.2 ml of acetic acid is added dropwise, the reaction mixture is diluted with ethyl acetate, washed with saturated ammonium chloride solution, water and sodium bicarbonate solution and dried. The residue after evaporation is chromatographed on silica gel. 48 g of 17β-acetoxy-7α-(5-tert-butyldimethylsilyloxypentyl)-estr-4-en-3-one are obtained.

b) 17fS- acetoksy- 7a-( 5- hydroksypentyl)-østr-4-en-3-on b) 17fS-acetoxy-7a-(5-hydroxypentyl)-estr-4-en-3-one

En løsning av 48 g 17p-acetoksy-7a-(5-tert.-butyldimetylsilyloksypentyl)-østr-4-en-3-on i 350 ml metanol hensettes med 35 ml av en 8 vol% svovelsyre i 30 min ved romtemperatur. Løsningen fortynnes med dietyleter, vaskes nøytral med vann og tørkes. Etter inndamping oppnås 37,7 g 17£-acetoksy-7a-(5-hydroksypentyl)-østr-4-en-3-on som en olje. A solution of 48 g of 17p-acetoxy-7a-(5-tert.-butyldimethylsilyloxypentyl)-estr-4-en-3-one in 350 ml of methanol is prepared with 35 ml of an 8 vol% sulfuric acid for 30 min at room temperature. The solution is diluted with diethyl ether, washed neutral with water and dried. After evaporation, 37.7 g of 17β-acetoxy-7α-(5-hydroxypentyl)-estr-4-en-3-one are obtained as an oil.

c) 17p- acetoksy- 7a-( 5- acetoksypentyl)- østr- 4- en- 3- on c) 17p-acetoxy-7a-(5-acetoxypentyl)-estrone-4-en-3-one

En løsning av 37,7 g 17pS-acetoksy-7a-(5-hydroksypentyl) -østr-4-en-3-on i 160 ml pyridin tilsettes langsomt 80 ml acetanhydrid og omrøres i 16 t ved 25 °C. Blandingen fortynnes deretter med eddikester, den organiske fase tørkes og inndampes etter vask med natriumhydrogenkarbonatløsning. Bunnfallet kromatograferes på kiselgel og det oppnås 26,6 g 17p-acetoksy-7a-(5-acetoksypentyl)-østr-4-en-3-on som en olje. [a]D<2z> 1= +20,0 ° (c = 0,51 % i kloroform). A solution of 37.7 g of 17pS-acetoxy-7a-(5-hydroxypentyl)-estr-4-en-3-one in 160 ml of pyridine is slowly added to 80 ml of acetic anhydride and stirred for 16 h at 25 °C. The mixture is then diluted with ethyl acetate, the organic phase is dried and evaporated after washing with sodium bicarbonate solution. The precipitate is chromatographed on silica gel and 26.6 g of 17β-acetoxy-7a-(5-acetoxypentyl)-estr-4-en-3-one is obtained as an oil. [a]D<2z> 1= +20.0 ° (c = 0.51% in chloroform).

d) 17p- acetoksy- 7a-( 5- acetoksypentyl)- østra- 1, 3, 5( 10)-trien- 3- ol d) 17p-acetoxy-7a-(5- acetoxypentyl)- estra- 1, 3, 5( 10)-trien- 3-ol

Til en løsning oppvarmet til 80 °C av 26,6 g 17p-acetoksy-7a-(5-acetoksypentyl)-østr-4-en-3-on i 260 ml acetonitril tildryppes enn løsning av 5,18 g litiumbromid og 26,73 g kopper(II)bromid i 260 ml acetonitril i løpet av 30 min under omrøring. Etter endt tilsetning avkjøles reaksjonsblandingen, fortynnes med dietyleter, vaskes med vann og natriumhydrogenkarbonatløsning og tørkes. Bunnfallet etter inndamping kromatograferes på kiselgel og det oppnås 21,3 g 17p-acetoksy-7a-(5-acetoksypentyl)-1,3,5(10)-østratrien-3-ol som en olje. [a]D<22> = +28.9 <0> (c = 0,535 % i kloroform) . To a solution heated to 80 °C of 26.6 g of 17p-acetoxy-7a-(5-acetoxypentyl)-estr-4-en-3-one in 260 ml of acetonitrile is added dropwise a solution of 5.18 g of lithium bromide and 26, 73 g of copper (II) bromide in 260 ml of acetonitrile during 30 min with stirring. After the addition is complete, the reaction mixture is cooled, diluted with diethyl ether, washed with water and sodium bicarbonate solution and dried. The precipitate after evaporation is chromatographed on silica gel and 21.3 g of 17β-acetoxy-7a-(5-acetoxypentyl)-1,3,5(10)-estratrien-3-ol are obtained as an oil. [a]D<22> = +28.9 <0> (c = 0.535% in chloroform) .

e) 17p- acetoksy- 7a-( 5- acetoksypentyl)- 3-( tetrahydropyran- 2- yloksy)- østra- 1, 3, 5( 10)- trien e) 17p-acetoxy-7a-(5-acetoxypentyl)-3-(tetrahydropyran-2-yloxy)- estra- 1,3,5(10)-triene

En løsning av 21,3 g 17p-acetoksy-7a-(5-acetoksypentyl) -østra-1, 3, 5 (10) -trien-3-ol i 213 ml tetrahydrofuran hensettes med 21,3 ml 3,4-dihydro-2H-pyran og 1,065 g p-toluensulfonsyre i 8 t ved romtemperatur. Reaksjonsløsningen tilsettes 3 ml pyridin og fortynnes deretter med dietyleter, vaskes med vann og tørkes. Resten etter inndamping, kromatograferes på kiselgel og det oppnås 24,3 g 17p-acetoksy-7a-(5-acetoksypentyl)-3-(tetrahydropyran-2-yloksy)østra-1,3,5(10)-trien som en olje. [a]D<22> 2= 31,5 0 (c = 0,535 % i kloroform). A solution of 21.3 g of 17β-acetoxy-7α-(5-acetoxypentyl)-estra-1,3,5(10)-trien-3-ol in 213 ml of tetrahydrofuran is prepared with 21.3 ml of 3,4-dihydro -2H-pyran and 1.065 g of p-toluenesulfonic acid for 8 h at room temperature. 3 ml of pyridine is added to the reaction solution and then diluted with diethyl ether, washed with water and dried. The residue after evaporation is chromatographed on silica gel and 24.3 g of 17β-acetoxy-7a-(5-acetoxypentyl)-3-(tetrahydropyran-2-yloxy)oestra-1,3,5(10)-triene is obtained as an oil . [a]D<22> 2= 31.5 0 (c = 0.535% in chloroform).

f) 17p- acetoksy- 7g-( 5- hydroksypentyl)- 3-( tetrahydropyran- 2- yloksy)- østra- 1, 3, 5( 10)- trien f) 17p-acetoxy-7g-(5-hydroxypentyl)-3-(tetrahydropyran-2-yloxy)- estra- 1,3,5(10)-triene

En løsning av 10,2 g 17p-acetoksy-7a-(5-acetoksypentyl) -3-(tetrahydropyran-2-yloksy)østra-l,3,5(10)-trien i 205 ml metanol omrøres med 33,7 ml natronlut i 45 min ved 15 °C. Blandingen fortynnes deretter med dietyleter, vaskes med vann, tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 5,6 g 17p-acetoksy-7a-(5-hydroksypentyl)-3-(tetrahydropyran-2-yloksy)-østra-1,3,5 (10)-trien. [or]D<22> 3= +32,2 ° (c = 0,505 % i kloroform). A solution of 10.2 g of 17β-acetoxy-7α-(5-acetoxypentyl)-3-(tetrahydropyran-2-yloxy)oestra-1,3,5(10)-triene in 205 ml of methanol is stirred with 33.7 ml caustic soda for 45 min at 15 °C. The mixture is then diluted with diethyl ether, washed with water, dried over sodium sulfate and evaporated in vacuo. 5.6 g of 17β-acetoxy-7α-(5-hydroxypentyl)-3-(tetrahydropyran-2-yloxy)-oestra-1,3,5 (10)-triene are obtained. [or]D<22> 3= +32.2 ° (c = 0.505% in chloroform).

g) 17J3- acetoksy- 3- ( tetrahydropyran- 2- yloksy) - 7a- ( 5- p-toluensulfonyloksypentyl) østra- 1, 3, 5( 10)- trien g) 17J3-acetoxy-3-(tetrahydropyran-2-yloxy)-7a-(5-p-toluenesulfonyloxypentyl) estra-1,3,5(10)-triene

En løsning av 5,5 g 17p-acetoksy-7a-(5-hydroksypentyl) -3-(tetrahydropyran-2-yloksy)-østra-1,3,5(10)-trien i 47 ml pyridin hensettes med 5,5 g p-toluensulfonsyreanhydrid i 45 min ved romtemperatur. Reaksjonsblandingen avkjøles deretter på et isbad, tilsettes 4 ml vann og omrøres i 45 min. Blandingen fortynnes deretter med eddikester, vaskes med vann, tørkes og inndampes. Det oppnås 8,2 g 17p-acetoksy-3-(tetrahydropyran-2-yloksy)-7a-(5-p-toluensulfonyloksypentyl)-østra-1,3,5(10)-trien som en olje. A solution of 5.5 g of 17β-acetoxy-7α-(5-hydroxypentyl)-3-(tetrahydropyran-2-yloxy)-oestra-1,3,5(10)-triene in 47 ml of pyridine is prepared with 5.5 g of p-toluenesulfonic anhydride for 45 min at room temperature. The reaction mixture is then cooled in an ice bath, 4 ml of water is added and stirred for 45 min. The mixture is then diluted with vinegar, washed with water, dried and evaporated. 8.2 g of 17β-acetoxy-3-(tetrahydropyran-2-yloxy)-7α-(5-p-toluenesulfonyloxypentyl)-estra-1,3,5(10)-triene are obtained as an oil.

h) 17J3- acetoksy- 7a- ( 5- metylaminopentyl) - 3- ( tetrahydropyran- 2- yloksy)- østra- 1, 3, 5( 10)- trien h) 17J3-acetoxy-7a-(5-methylaminopentyl)-3-(tetrahydropyran-2-yloxy)- estra- 1,3,5(10)-triene

I en løsning av 8,2 g 17p-acetoksy-3-(tetrahydropyran-2-yloksy)-7a-(5-p-toluensulfonyloksypentyl)østra-1,3,5(10)-trien i 80 ml tetrahydrofuran blir det i et trykkrør inkondensert 6,3 g metylamin under isavkjøling. Det lukkede trykkrør oppvarmes deretter i 6 t ved 60 °C. Etter avkjøling inndampes blandingen i vakuum til tørrhet og resten kromatograferes på kiselgel. Det oppnås 5,1 g 17£-acetoksy-7a-(5-metylaminopentyl)-3-(tetrahydropyran-2-yloksy)-østra-1,3,5 (10)-trien som en olje. [0£]D<22> = +29, 7 ° (c = 0,535 % i kloroform). In a solution of 8.2 g of 17p-acetoxy-3-(tetrahydropyran-2-yloxy)-7a-(5-p-toluenesulfonyloxypentyl)estra-1,3,5(10)-triene in 80 ml of tetrahydrofuran, a pressure tube incondensed 6.3 g of methylamine under ice-cooling. The closed pressure tube is then heated for 6 h at 60 °C. After cooling, the mixture is evaporated in vacuo to dryness and the residue is chromatographed on silica gel. 5.1 g of 17β-acetoxy-7α-(5-methylaminopentyl)-3-(tetrahydropyran-2-yloxy)-oestra-1,3,5 (10)-triene are obtained as an oil. [0£]D<22> = +29.7 ° (c = 0.535% in chloroform).

i) 17J3- acetoksy- 7a-{ 5- [ N- metyl- N- 3- ( 4, 4, 5, 5, 5- pentafluorpentyltio)- propylamino] pentyl)- 3-( tetrahydropyran- 2- yloksy)- østra- 1, 3, 5( 10)- trien i) 17J3- acetoxy- 7a-{ 5- [ N- methyl- N- 3- ( 4, 4, 5, 5, 5- pentafluoropentylthio)- propylamino] pentyl)- 3-( tetrahydropyran- 2- yloxy)- estra - 1, 3, 5( 10)- the three

En løsning av 1,64 g 17£-acetoks<y->7a- (5-metylaminopentyl) -3-(tetrahydropyran-2-yloksy)-østra-1,3,5(10)-trien i 25 ml absolutt DMP omrøres med 159 mg 80 % natriumhydrid under nitrogen i 2 t ved romtemperatur. Blandingen tildryppes deretter 1,43 g 3-klorpropyl-4,4,5,5,5-pentafluorpentylsulfid i 7 ml absolutt DMF og omrøres deretter i 22 t ved 80 °C. Reak-sjonsløsningen fortynnes deretter med eddikester, vaskes med vann, tørkes, inndampes og resten kromatograferes på kiselgel. Det oppnås 820 mg 17]3-acetoksy-7a- {5-[N-metyl-N-3-(4,4, 5, 5, 5-pentafluorpentyltio)-propylamino]pentyl}-3-(tetrahydropyran-2-yloksy)-østra-1,3,5 (10)-trien som en olje. [a]D<22> = +21,5 ° (c = 0,51 % i kloroform). A solution of 1.64 g of 17β-acetoxy<y>7α-(5-methylaminopentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene in 25 ml of absolute DMP stirred with 159 mg of 80% sodium hydride under nitrogen for 2 h at room temperature. The mixture is then added dropwise to 1.43 g of 3-chloropropyl-4,4,5,5,5-pentafluoropentyl sulfide in 7 ml of absolute DMF and is then stirred for 22 h at 80 °C. The reaction solution is then diluted with vinegar, washed with water, dried, evaporated and the residue chromatographed on silica gel. 820 mg of 17]3-acetoxy-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]pentyl}-3-(tetrahydropyran-2- yloxy)-estra-1,3,5(10)-triene as an oil. [a]D<22> = +21.5 ° (c = 0.51% in chloroform).

j) 7a-{5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluor- pentyltio)-propylamino] pentyl}- 3-( tetrahydropyran- 2- yloksy)-østra- 1, 3, 5( 10)- trien- 17fi- ol j) 7a-{5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5-pentafluoro- pentylthio)-propylamino] pentyl}- 3-( tetrahydropyran- 2- yloxy)- estra- 1 , 3, 5( 10)- trien- 17fi- ol

En løsning av 790 mg 17£-acetoksy-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)-propylamino]pentyl}-3-(tetrahydropyran-2-yloksy)-østra-1,3,5(10)-trien i 8 ml metanol og 3 ml THF omrøres med 430 mg kaliumkarbonat i 18 t ved romtemperatur. Reaksjonsløsningen fortynnes med dietyleter, vaskes med vann, tørkes og inndampes. Det oppnås 750 mg urenset 7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentyltio)-propylamino]pentyl}-3-(tetrahydropyran-2-yloksy)-østra-1,3,5(10)-trien-17£-ol. A solution of 790 mg of 17£-acetoxy-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]pentyl}-3-(tetrahydropyran-2- yloxy)-estra-1,3,5(10)-triene in 8 ml of methanol and 3 ml of THF is stirred with 430 mg of potassium carbonate for 18 h at room temperature. The reaction solution is diluted with diethyl ether, washed with water, dried and evaporated. 750 mg of impure 7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)-propylamino]pentyl}-3-(tetrahydropyran-2-yloxy)- estra-1,3,5(10)-trien-17£-ol.

k) 7 a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluor- pentyltio) - k) 7 a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) -

propylamino] pentyl}- østra- 1, 3, 5 ( 10) - trien- 3, 17fS- diol propylamino]pentyl}-estradi- 1,3,5(10)-triene-3,17fS-diol

En løsning av 750 mg 7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentyltio)propylamino]pentyl}-3-(tetrahydropyran-2-yloksy)-østra-1,3,5(10)-trien-17£-ol i 28 ml metanol og 2,8 ml vann omrøres med 350 mg oksalsyre i 17 t ved romtemperatur. Blandingen fortynnes deretter med eddikester, vaskes med natriumhydrogenkarbonatløsning og vann, tørkes og inndampes. Resten kromatograferes på kiselgel og det oppnås 640 mg 7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentyltio)-propylamino]pentyl}-østra-1,3,5(10)-trien-3,17p-diol som en olje. [a]D<22> = +24 , 0 ° (c = 0,515 % i kloroform). A solution of 750 mg of 7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]pentyl}-3-(tetrahydropyran-2-yloxy)-estra -1,3,5(10)-trien-17£-ol in 28 ml of methanol and 2.8 ml of water is stirred with 350 mg of oxalic acid for 17 h at room temperature. The mixture is then diluted with ethyl acetate, washed with sodium bicarbonate solution and water, dried and evaporated. The residue is chromatographed on silica gel and 640 mg of 7a-{5-[N-methyl-N-3-(4,4,5,5-pentafluoro-pentylthio)-propylamino]pentyl}-estra-1,3 is obtained, 5(10)-triene-3,17p-diol as an oil. [a]D<22> = +24 , 0 ° (c = 0.515% in chloroform).

1) 7 a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluor- pentyltio)-propylamino] pentyl}- 3-( tetrahydropyran- 2- yloksy)-østra- 1, 3, 5( 10)- trien- 17- on 1) 7 a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoro- pentylthio)-propylamino] pentyl}- 3-( tetrahydropyran- 2- yloxy)- estra- 1, 3, 5( 10)- trien- 17- on

En løsning av 900 mg 7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentyltio)propylamino]pentyl}-3-(tetrahydropyran-2-yloksy)østra-1,3,5(10)-trien-17p-ol i 30 ml toluen og 9,6 ml sykloheksanon, tilsettes en løsning av 900 mg aluminium-isopropylat i 16 ml toluen og oppvarmes i 30 min under langsom avdestillering. Reaksjonsløsningen fortynnes deretter med eddikester, vaskes med 20 % kaliumnatriumtartratløsning, tørkes og inndampes. Resten kromatograferes på kiselgel med heksan/eddikester. Det oppnås 715 mg 7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentyltio)propylamino]pentyl}-3-(tetrahydropyran-2-yloksy)østra-l,3,5(10)-trien-17-on som en olje. A solution of 900 mg of 7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]pentyl}-3-(tetrahydropyran-2-yloxy)estra- 1,3,5(10)-trien-17p-ol in 30 ml of toluene and 9.6 ml of cyclohexanone, a solution of 900 mg of aluminum isopropylate in 16 ml of toluene is added and heated for 30 min under slow distillation. The reaction solution is then diluted with acetic acid, washed with 20% potassium sodium tartrate solution, dried and evaporated. The residue is chromatographed on silica gel with hexane/acetic acid. 715 mg of 7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]pentyl}-3-(tetrahydropyran-2-yloxy)oestra-1 are obtained ,3,5(10)-trien-17-one as an oil.

m) 7 a- trifluormetyl- 3-( tetrahydropyran- 2- yloksy)- 7a-( 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio)-propylamino] pentyl}- østra- 1, 3, 5( 10)- trien- 17- ol m) 7a- trifluoromethyl- 3-( tetrahydropyran-2-yloxy)- 7a-( 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio)-propylamino] pentyl}- estra- 1, 3, 5( 10)- trien- 17- ol

En løsning av 500 mg 7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-3-(tetrahydropyran-2-yloksy)østra-1,3,5(10)-trien-17-on (s. Ausw.-Pat. Eks. 2a) i 5 ml absolutt tetrahydrofuran tilsettes ved 0 °C badtemperatur 0,27 ml (trifluormetyl)-trimetylsilan. 0,2 ml av en 1,1 molar tetrabutylammoniumfluoridløsning tildryppes deretter langsomt og blandingen omrøres i 45 min, tilsettes på nytt 1 ml av den 1,1 molare tetrabutylammoniumfluoridløsning og omrøres i ytterligere 30 min. Blandingen fortynnes deretter med eddikester, vaskes med vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol . Det oppnås 285 mg 7a-trifluormetyl-3-(tetrahydropyran-2-yloksy)-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio) propylamino] pentyl} -østra- 1,3, 5(10)-trien-17£-ol som en olje. A solution of 500 mg of 7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-3-(tetrahydropyran-2-yloxy)estra-1, 3,5(10)-trien-17-one (s. Ausw.-Pat. Ex. 2a) in 5 ml absolute tetrahydrofuran is added at 0 °C bath temperature 0.27 ml (trifluoromethyl)-trimethylsilane. 0.2 ml of a 1.1 molar tetrabutylammonium fluoride solution is then slowly added dropwise and the mixture is stirred for 45 min, 1 ml of the 1.1 molar tetrabutylammonium fluoride solution is again added and stirred for a further 30 min. The mixture is then diluted with ethyl acetate, washed with water, dried over sodium sulphate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 285 mg of 7α-trifluoromethyl-3-(tetrahydropyran-2-yloxy)-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}- estra- 1,3, 5(10)-trien-17£-ol as an oil.

n) 17 g- trifluormetyl- 7g- f 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5-pentafluorpentyltio) propylamino] pentyl}- østra-1, 3, 5 ( 10) - trien- 3, 17j3- diol n) 17 g- trifluoromethyl- 7g- f 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5-pentafluoropentylthio) propylamino] pentyl}- estra-1, 3, 5 ( 10) - triene-3, 17j3-diol

En løsning av 280 mg 17a-trifluormetyl-3-(tetrahydropyran-2-yloksy)-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio) propylamino] pentyl} -østra- 1,3, 5 (10)-trien-17p-ol i 5,6 ml metanol og 0,56 ml vann, omrøres med 140 mg oksalsyre i 18 t ved romtemperatur. Blandingen fortynnes deretter med eddikester, vaskes med natriumhydrogenkarbonat og vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 215 mg 17a-trifluormetyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio) propylamino]pentyl}-østra-1,3,5(10)-trien-3,17p-diol som en olje. A solution of 280 mg of 17α-trifluoromethyl-3-(tetrahydropyran-2-yloxy)-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl} -estra-1,3,5 (10)-trien-17p-ol in 5.6 ml of methanol and 0.56 ml of water, stirred with 140 mg of oxalic acid for 18 h at room temperature. The mixture is then diluted with ethyl acetate, washed with sodium bicarbonate and water, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 215 mg of 17α-trifluoromethyl-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra-1,3,5(10) are obtained -triene-3,17p-diol as an oil.

Eksempel 6 Example 6

15P, 16| 3- metano- 17a- metyl- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentaf luorpentyltio) propylamino] pentyl}- østra- 1, 3, 5( 10)- trien-3, 17fi- diol 15P, 16| 3- methano- 17a- methyl- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl}- estra- 1, 3, 5( 10 )-trien-3, 17fi- diol

a) 3- benzyloksy- 17, 17- etylendioksy- 7a-( 5- hydroksypentyl) - østra- 1, 3, 5( 10), 15- tetraen a) 3- benzyloxy- 17, 17- ethylenedioxy- 7a-( 5- hydroxypentyl) - estra- 1, 3, 5( 10), 15- tetraene

En løsning av 32,7 g 17,17-etylendioksy-7a-(5-hydroksypentyl)-østra-1,3,5(10),15-tetraen-3-ol (s. eks. lh) i 327 ml dimetylformamid tilsettes ved romtemperatur 5,73 g litiumhydroksid og omrøres med 15,1 ml benzylbromid i 2 t ved 60 °C. Blandingen fortynnes deretter med eddikester, vaskes med vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 32,8 g 3-benzyloksy-17,17-etylendioksy-7a-(5-hydroksypentyl) -østra-1,3,5(10),15-tetraen. A solution of 32.7 g of 17,17-ethylenedioxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol (see ex. lh) in 327 ml of dimethylformamide 5.73 g of lithium hydroxide are added at room temperature and stirred with 15.1 ml of benzyl bromide for 2 h at 60 °C. The mixture is then diluted with ethyl acetate, washed with water, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 32.8 g of 3-benzyloxy-17,17-ethylenedioxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraene are obtained.

b) 3- benzyloksy- 7a-( 5- hydroksypentyl)- østra-1, 3, 5 ( 10), 15- tetraen- 17- on b) 3- benzyloxy- 7a-( 5- hydroxypentyl)- estra-1, 3, 5 ( 10), 15- tetraen- 17- one

En løsning av 32,8 g 3-benzyloksy-17,17-etylendioksy-7a-(5-hydroksypentyl)-østra-1,3,5(10),15-tetraen i 328 ml aceton og 32,8 ml vann omrøres ved romtemperatur med 1,033 g para-toluensulfonsyre i 2 t. Blandingen fortynnes deretter med dietyleter, vaskes med natriumhydrogenkarbonat og vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/aceton. Det oppnås 25,4 g 3-benzyloksy-7a-(5-hydroksypentyl)-østra-1,3,5(10),15-tetraen-17-on. A solution of 32.8 g of 3-benzyloxy-17,17-ethylenedioxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraene in 328 ml of acetone and 32.8 ml of water is stirred at room temperature with 1.033 g para-toluenesulfonic acid for 2 h. The mixture is then diluted with diethyl ether, washed with sodium bicarbonate and water, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/acetone. 25.4 g of 3-benzyloxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one are obtained.

c) 3- benzyloksy- 7a- ( 5- hydroksypentyl) - 15J3, 16p- metano-østra- 1, 3, 5( 10), 15- tetraen- 17- on c) 3- benzyloxy- 7a-( 5- hydroxypentyl)- 15J3, 16p- methano-estra- 1, 3, 5( 10), 15- tetraen- 17- one

2,861 g trimetylsulfoksoniumjodid omsettes i 65 ml dimetylsulfoksid med 345 mg 80 % natriumhydrid i 2 t ved romtemperatur. Til denne løsning tilsettes 4,44 g 3-benzyloksy-7a-(5-hydroksypentyl)-østra-1,3,5(10),15-tetraen-17-on og den omrøres i 45 min ved romtemperatur. Det utfelte bunnfall avfiltreres og vaskes med vann. Bunnfallet oppløses i eddikester, vaskes med vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med heksan/aceton. Det oppnås 2,8 g 3-benzyloksy-7a- (5-hydroksypentyl)-150,16J3-metano-østra-1,3, 5 (10) , 15-tetraen-17-on..4 = +13,1 (c = 0,525 % i kloroform). 2.861 g of trimethylsulfoxonium iodide is reacted in 65 ml of dimethylsulfoxide with 345 mg of 80% sodium hydride for 2 h at room temperature. 4.44 g of 3-benzyloxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one are added to this solution and it is stirred for 45 minutes at room temperature. The precipitate is filtered off and washed with water. The precipitate is dissolved in acetic acid, washed with water, dried over sodium sulphate, evaporated in vacuo and chromatographed on silica gel with hexane/acetone. 2.8 g of 3-benzyloxy-7a-(5-hydroxypentyl)-150,16J3-methano-estra-1,3,5 (10) ,15-tetraen-17-one..4 = +13.1 are obtained (c = 0.525% in chloroform).

d) 3- benzyloksy- 15£, 16j3- metano-7 a- ( 5- tosyloksypentyl) - østra- 1, 3, 5( 10), 15- tetraen- 17- on d) 3- benzyloxy- 15£, 16j3- methano-7a-( 5- tosyloxypentyl) - estra- 1, 3, 5( 10), 15- tetraen- 17- one

En løsning av 2,5 g 3-benzyloksy-7a-(5-hydroksypentyl) -150,160-metano-østra-l,3,5(10),15-tetraen-17-on i 25 ml pyridin tilsettes ved romtemperatur 2,5 g para-toluensulfonsyreanhydrid og hensettes i 30 min, tilsettes under is-avkjøling 1 ml vann og hensettes i ytterligere 45 min. Blandingen fortynnes deretter med dietyleter, vaskes med vann, tør-kes over natriumsulfat og inndampes i vakuum. Det oppnås 3,4 g urenset 3-benzyloksy-150,160-metano-7a-(5-tosyloksypentyl)-østra-1,3,5(10),15-tetraen-17-on. A solution of 2.5 g of 3-benzyloxy-7a-(5-hydroxypentyl)-150,160-methano-estra-1,3,5(10),15-tetraen-17-one in 25 ml of pyridine is added at room temperature 2, 5 g of para-toluenesulfonic anhydride and leave for 30 min, add under ice-cooling 1 ml of water and leave for a further 45 min. The mixture is then diluted with diethyl ether, washed with water, dried over sodium sulfate and evaporated in vacuo. 3.4 g of impure 3-benzyloxy-150,160-methano-7a-(5-tosyloxypentyl)-estra-1,3,5(10),15-tetraen-17-one are obtained.

e) 3- benzyloksy- 150, 160- metano-7 a-{ 5- [ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl}-østra- 1, 3, 5( 10), 15- tetraen- 17- on e) 3- benzyloxy- 150, 160- methano-7 a-{ 5- [ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl}- estra- 1, 3 , 5( 10), 15- tetraen- 17- one

Til en løsning av 3,4 g urenset 3-benzyloksy-150,160-metano-7a-(5-tosyloksypentyl)-østra-1,3,5(10),15-tetraen-17-on i 34 ml dimetylformamid og omrøres i 3,5 t ved 100 °C. Blandingen fortynnes deretter med eddikester, vaskes med vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 2,6 g 3-benzyloksy-150,160-metano-7a-{5-[N-metyl-N-3- To a solution of 3.4 g of crude 3-benzyloxy-150,160-methano-7a-(5-tosyloxypentyl)-estra-1,3,5(10),15-tetraen-17-one in 34 ml of dimethylformamide and stirred in 3.5 h at 100 °C. The mixture is then diluted with ethyl acetate, washed with water, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 2.6 g of 3-benzyloxy-150,160-methano-7a-{5-[N-methyl-N-3-

(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-1,3,5(10),15-tetraen-17-on som en olje. (4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra-1,3,5(10),15-tetraen-17-one as an oil.

f) 150, 160- metano-7g- f5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl}- 3- hydroksy-østra-1, 3, 5( 10), 15- tetraen- 17- on f) 150, 160- methano-7g- f5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl}- 3- hydroxy-estra-1, 3, 5 ( 10), 15- tetraen- 17- one

En løsning av 2,3 g 3-benzyloksy-150,160-metano-7o-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]-pentyl}-østra-1,3,5(10),15-tetraen-17-on i 53 ml diklormetan omrøres ved 0 °C badtemperatur med 1,12 ml N,N-dimetylanilin og 1,64 g aluminiumklorid (vannfritt) i 4,5 t. Blandingen fortynnes deretter med eddikester, vaskes med 30 % kaliumnatrium-tartratløsning og vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 1,52 g 150,160-metano-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-3-hydroksy-østra-l, 3 , 5 (10) , 15-tetraen-17-on som en olje. 5 = -2,5 ° (c = 0,505 % i kloroform). A solution of 2.3 g of 3-benzyloxy-150,160-methano-7o-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]-pentyl}-estra- 1,3,5(10),15-tetraen-17-one in 53 ml dichloromethane is stirred at 0 °C bath temperature with 1.12 ml N,N-dimethylaniline and 1.64 g aluminum chloride (anhydrous) for 4.5 h The mixture is then diluted with ethyl acetate, washed with 30% potassium sodium tartrate solution and water, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 1.52 g of 150,160-methano-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-3-hydroxy-estra-1 are obtained, 3,5(10),15-tetraen-17-one as an oil. δ = -2.5° (c = 0.505% in chloroform).

g) 150, 160- metano- 17g- metyl- 7a- f5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl}-østra- 1, 3, 5( 10)- trien- 3, 170- diol g) 150, 160- methano- 17g- methyl- 7a- f5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl}- estra- 1, 3, 5 ( 10)- triene- 3, 170- diol

Til en løsning av 515 mg 150,160-metano-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-3-hydroksy-østra-l,3,5(10),15-tetraen-17-on i 10 ml tetrahydrofuran tildryppes ved 0 °C badtemperatur 1,8 ml av en 3 molar metylmagnesiumbromidløsning og omrøres i 2 t ved romtemperatur, blandingen fortynnes deretter med eddikester, vaskes med mettet ammoniumkloridløsning og vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 395 mg 150,160-metano-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)-propylamino]pentyl}-østra-1,3,5(10)-trien-3,170-diol som en olje. 6 -5,1 ° (c = 0,52 % i kloroform). To a solution of 515 mg of 150,160-methano-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-3-hydroxy-estra-1, 3,5(10),15-tetraen-17-one in 10 ml tetrahydrofuran is added dropwise at 0 °C bath temperature 1.8 ml of a 3 molar methylmagnesium bromide solution and stirred for 2 h at room temperature, the mixture is then diluted with acetic acid, washed with saturated ammonium chloride solution and water, dried over sodium sulphate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 395 mg of 150,160-methano-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]pentyl}-estra-1,3 are obtained ,5(10)-triene-3,170-diol as an oil. 6 -5.1 ° (c = 0.52% in chloroform).

Eksempel 7 Example 7

150, 160- metano- 17a- metyl- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentansulfinyl) propylamino] pentyl}- østra- 1, 3, 5( 10)- trien-3, 170- diol 150, 160- methano- 17a- methyl- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentanesulfinyl) propylamino] pentyl}- estra- 1, 3, 5( 10)-triene-3, 170-diol

En løsning av 115 mg 150,160-metano-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]-pentyl}-østra-1,3,5(10)-trien-3,170-diol (s. eks. 6) i 5 ml metanol omrøres med 80 mg natriumperjodat i 3 t ved romtemperatur. Blandingen fortynnes deretter med eddikester, vaskes med vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 65 mg 150,160-metano-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfinyl)propylamino]pentyl}-østra-1,3,5 (10)-trien-3,170-diol som en olje. [0£]D22 = -13,3 ° (c = 0,27 % i kloroform). A solution of 115 mg of 150,160-methano-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]-pentyl}-estra-1, 3,5(10)-triene-3,170-diol (see ex. 6) in 5 ml of methanol is stirred with 80 mg of sodium periodate for 3 h at room temperature. The mixture is then diluted with ethyl acetate, washed with water, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 65 mg of 150,160-methano-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}-estra-1,3 are obtained, 5 (10)-triene-3,170-diol as an oil. [0£]D22 = -13.3° (c = 0.27% in chloroform).

Eksempel 8 Example 8

150, 160- metano- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl } - østra- 1 , 3, 5 ( 10)- trien- 3, 170- diol 150, 160- methano-7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl } - estra- 1, 3, 5 ( 10)- triene - 3, 170- diol

En løsning av 500 mg 150,160-metano-7a-{5-[N-metyl-N-3 -(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-3-hydroksy-østra-1,3,5(10),15-tetraen-17-on (s. eks. 6f) i 10 ml metanol og 1 ml vann omrøres med 100 mg natriumborhydrid i 3 t ved romtemperatur. Blandingen fortynnes deretter med eddikester, vaskes med vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 340 mg 150,160-metano-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-1,3,5 (10)-trien-3,170-diol som en olje. [a]D<22> = +11,9 <0 >(c = 0,52 % i kloroform). A solution of 500 mg of 150,160-methano-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-3-hydroxy-estra-1,3 ,5(10),15-tetraen-17-one (see ex. 6f) in 10 ml of methanol and 1 ml of water is stirred with 100 mg of sodium borohydride for 3 h at room temperature. The mixture is then diluted with ethyl acetate, washed with water, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 340 mg of 150,160-methano-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra-1,3,5 (10) are obtained -triene-3,170-diol as an oil. [a]D<22> = +11.9 <0 >(c = 0.52% in chloroform).

Eksempel 9 Example 9

150, 160- metano- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentan-sulf inyl) propylamino] pentyl} - østra- 1, 3, 5( 10)- trien- 3, 170- diol 10 )- trien- 3, 170- diol

En løsning av 100 mg 150,160-metano-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-l,3,5(10)-trien-3,170-diol (s. eks. 8) i 5 ml metanol omrøres med 80 mg natriumperjodat i 3 t ved romtemperatur. Blandingen fortynnes deretter med eddikester, vaskes med vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 70 mg 150,160-metano-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansul-finyl)-propylamino]pentyl}-østra-1,3,5(10)-trien-3,170-diol som en olje. [a]D<22> = +12,2 ° (c = 0,515 % i kloroform). A solution of 100 mg of 150,160-methano-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra-1,3,5(10 )-triene-3,170-diol (see ex. 8) in 5 ml of methanol is stirred with 80 mg of sodium periodate for 3 h at room temperature. The mixture is then diluted with ethyl acetate, washed with water, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 70 mg of 150,160-methano-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-propylamino]pentyl}-estra-1,3 are obtained ,5(10)-triene-3,170-diol as an oil. [a]D<22> = +12.2 ° (c = 0.515% in chloroform).

Eksempel 10 Example 10

150- metyl- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluor- pentyltio)-propylamino] pentyl}- østra- 1, 3, 5( 10)- trien- 3, 170- diol 150- methyl- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoro- pentylthio)-propylamino] pentyl}- estra- 1, 3, 5( 10)- triene-3, 170-diol

a) 3- benzyloksy- 7a-( 5- hydroksypentyl)- 150- metyl- østra-1, 3, 5( 10)- trien- 17- on a) 3- benzyloxy- 7a-( 5- hydroxypentyl)- 150- methyl- estra-1, 3, 5( 10)- trien- 17- one

Til en isavkjølt løsning av 11,9 ml av en 3 molar metylmagnesiumbromidløsning i 68 ml tetrahydrofuran, tilsettes under en nitrogenstrøm, 5,35 g kopper(I)jodid. Deretter tildryppes en løsning av 4,26 g 3-benzyloksy-7a-(5-hydroksypentyl) -østra-1,3,5(10),15-tetraen-17-on (s. eks. 6b) i 50 ml tetrahydrofuran og blandingen omrøres i 30 min ved 0 °C badtemperatur. Det overflødige reagens dekomponeres deretter med mettet ammoniumkloridløsning, blandingen fortynnes med eddikester, vaskes med ammoniumkloridløsning og vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med heksan/aceton. Det oppnås 3,6 g 3-benzyloksy-7a-(5-hydroksypentyl)-150-metyl-østra-1,3,5(10)-trien-17-on som en olje. [a]D<22> = +66 , 4 ° (c = 0,515 % i kloroform). To an ice-cooled solution of 11.9 ml of a 3 molar methylmagnesium bromide solution in 68 ml of tetrahydrofuran, under a stream of nitrogen, 5.35 g of cupric (I) iodide are added. A solution of 4.26 g of 3-benzyloxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one (see ex. 6b) in 50 ml of tetrahydrofuran is then added dropwise and the mixture is stirred for 30 min at 0 °C bath temperature. The excess reagent is then decomposed with saturated ammonium chloride solution, the mixture is diluted with ethyl acetate, washed with ammonium chloride solution and water, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with hexane/acetone. 3.6 g of 3-benzyloxy-7a-(5-hydroxypentyl)-150-methyl-estra-1,3,5(10)-trien-17-one are obtained as an oil. [a]D<22> = +66 , 4 ° (c = 0.515% in chloroform).

b) 3- benzyloksy- 150- metyl- 7a-( 5- tosyloksypentyl)- østra-1, 3, 5( 10)- trien- 17- on b) 3- benzyloxy- 150- methyl- 7a-( 5- tosyloxypentyl)- estra-1, 3, 5( 10)- trien- 17- one

En løsning av 3,6 g 3-benzyloksy-7a-(5-hydroksypentyl) -15<0->metyl-østra-l,3,5(10)-trien-17-on tosyleres som beskrevet i eksempel 6d. Det oppnås 4,9 g urenset 3-benzyloksy- 150-metyl -7a- (5-tosyloksypentyl)-østra-1,3,5(10)-trien-17-on. A solution of 3.6 g of 3-benzyloxy-7a-(5-hydroxypentyl)-15<0->methyl-estra-1,3,5(10)-trien-17-one is tosylated as described in example 6d. 4.9 g of impure 3-benzyloxy-150-methyl-7a-(5-tosyloxypentyl)-estra-1,3,5(10)-trien-17-one are obtained.

c) 3- benzyloksy- 150- metyl- 7a-( 5- N- metylaminopentyl)-østra- 1, 3, 5( 10)- trien- 17- on c) 3- benzyloxy- 150- methyl- 7a-( 5- N- methylaminopentyl)- estra- 1, 3, 5( 10)- trien- 17- one

I en løsning av 4,9 g 3-benzyloksy-150-metyl-7a-(5-tosyloksypentyl)-østra-1,3,5(10)-trien-17-on i 30 ml tetrahydrofuran i en trykkreaktor, kondenseres under avkjøling 3,8 g metylamin, den lukkede reaktor oppvarmes i 5,5 t ved 80 °C, avkjøles og åpnes. Blandingen fortynnes deretter med eddikester, vaskes med vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol/l % trietylamin. Det oppnås 3,15 g 3-benzyloksy-150-metyl-7a-(5-N-metylaminopentyl)-østra-1,3,5(10)-trien-17-on som en olje. In a solution of 4.9 g of 3-benzyloxy-150-methyl-7a-(5-tosyloxypentyl)-estra-1,3,5(10)-trien-17-one in 30 ml of tetrahydrofuran in a pressure reactor, condense under cooling 3.8 g methylamine, the closed reactor is heated for 5.5 h at 80 °C, cooled and opened. The mixture is then diluted with ethyl acetate, washed with water, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol/1% triethylamine. 3.15 g of 3-benzyloxy-150-methyl-7a-(5-N-methylaminopentyl)-estra-1,3,5(10)-trien-17-one are obtained as an oil.

d) 3- benzyloksy- 150- metyl- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5-pentafluor- pentyltio) propylamino] pentyl}- østra-1, 3, 5( 10)- trien- 17- on d) 3- benzyloxy- 150- methyl- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5-pentafluoro-pentylthio) propylamino] pentyl}- estra-1, 3, 5( 10)- trien- 17- on

En løsning av 3,15 g 3-benzyloksy-150-metyl-7a- (5-N-metylaminopentyl) -østra-1,3,5(10)-trien-17-on i 31,5 ml absolutt dimetylformamid tilsettes 228 mg 80 % natriumhydrid og omrøres i 5 t ved romtemperatur, tilsettes 2,6 g 3-klorpropyl-4,4,5,5,5-pentafluorpentylsulfid i 2 ml absolutt dimetylformamid og omrøres i 24 t ved 80 °C. Blandingen fortynnes deretter med eddikester, vaskes med natriumhydrogenkarbonat og vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 3,1 g 3-benzyloksy-150-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentyltio)propylamino]pentyl}-østra-1,3,5(10),15-trien-17-on som en olje. A solution of 3.15 g of 3-benzyloxy-150-methyl-7a-(5-N-methylaminopentyl)-estra-1,3,5(10)-trien-17-one in 31.5 ml of absolute dimethylformamide is added 228 mg of 80% sodium hydride and stirred for 5 h at room temperature, 2.6 g of 3-chloropropyl-4,4,5,5,5-pentafluoropentyl sulphide are added in 2 ml of absolute dimethylformamide and stirred for 24 h at 80 °C. The mixture is then diluted with ethyl acetate, washed with sodium bicarbonate and water, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 3.1 g of 3-benzyloxy-150-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]pentyl}-estra- 1,3,5(10),15-trien-17-one as an oil.

e) 3- hydroksy- 150- metyl- 7a-( 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5-pentafluor- pentyltio) propylamino] pentyl}- østra-1, 3, 5( 10)- trien- 17- on e) 3- hydroxy- 150- methyl- 7a-( 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5-pentafluoro-pentylthio) propylamino] pentyl}- estra-1, 3, 5( 10)- trien- 17- on

En løsning av 3,1 g 3-benzyloksy-150-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentyltio)propylamino]pentyl}-østra-1,3,5(10)-trien-17-on debenzyleres som beskrevet i eksempel 6f. Det oppnås 830 mg 3-hydroksy-150-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentyltio)propylamino]pentyl}-østra-1,3,5(10)-trien-17-on som en olje. A solution of 3.1 g of 3-benzyloxy-150-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]pentyl}-estra -1,3,5(10)-trien-17-one is debenzylated as described in example 6f. 830 mg of 3-hydroxy-150-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]pentyl}-estra-1 are obtained, 3,5(10)-trien-17-one as an oil.

f) 150- metyl- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl}- østra- 1, 3, 5( 10)- trien-3, 170- diol f) 150- methyl- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl}- estra- 1, 3, 5( 10)- triene -3, 170- diol

En løsning av 460 mg 3-hydroksy-150-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentyltio)propylamino]pentyl}-østra-1,3,5(10)-trien-17-on reduseres som beskrevet i eksempel 8. Det oppnås 200 mg 150-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentyltio)propylamino]pentyl}-østra-1,3,5(10)-trien-3,170-diol som en olje. [ a] D22 = +4,5 <0> (c = 0,51 % i kloroform). A solution of 460 mg of 3-hydroxy-150-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]pentyl}-estra-1 ,3,5(10)-trien-17-one is reduced as described in example 8. 200 mg of 150-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5 ,5-pentafluoro-pentylthio)propylamino]pentyl}-estra-1,3,5(10)-triene-3,170-diol as an oil. [a] D22 = +4.5 <0> (c = 0.51% in chloroform).

Eksempel 11 Example 11

150, 17g- dimetyl- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl } - østra- 1 , 3, 5( 10)- trien- 3, 170- diol 150, 17g- dimethyl- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl } - estra- 1, 3, 5( 10)- triene - 3, 170- diol

I 15 ml tetrahydrofuran omrøres 1,44 g tørket Cer(III)klorid i 2 t ved romtemperatur, tilsettes under is-avkjøling 3,75 ml av en 3-molar metylmagnesiumbromidløsning, omrøres i 15 min under avkjøling og i 30 min ved romtemperatur, tildryppes en løsning av 650 mg 3-hydroksy-150-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentyltio)propylamino]-pentyl}-østra-1,3,5(10)-trien-17-on (s. eks. 10e) i 7 ml tetrahydrofuran, omrøres i 2 t ved romtemperatur og overflødig reagens dekomponeres med mettet ammoniumkloridløsning. Blandingen fortynnes deretter med eddikester, vaskes med mettet ammoniumkloridløsning og vann, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol . Det oppnås 145 mg 150,17a-dimetyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentyltio)propylamino]pentyl}-østra-1, 3, 5 (10)-trien-3,170-diol som en olje. [a]D<22> = -7,3 ° (c = 0,505 % i kloroform). In 15 ml of tetrahydrofuran, 1.44 g of dried Cer(III) chloride is stirred for 2 h at room temperature, 3.75 ml of a 3-molar methylmagnesium bromide solution is added under ice-cooling, stirred for 15 min while cooling and for 30 min at room temperature, a solution of 650 mg of 3-hydroxy-150-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]-pentyl}-estra is added dropwise -1,3,5(10)-trien-17-one (see e.g. 10e) in 7 ml tetrahydrofuran, stirred for 2 h at room temperature and excess reagent decomposed with saturated ammonium chloride solution. The mixture is then diluted with ethyl acetate, washed with saturated ammonium chloride solution and water, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 145 mg of 150,17a-dimethyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]pentyl}-estra-1, 3, 5 (10)-triene-3,170-diol as an oil. [a]D<22> = -7.3 ° (c = 0.505% in chloroform).

Eksempel 12 Example 12

110- fluor- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio)-propylamino] pentyl}- østra- 1, 3, 5( 10)- trien- 3, 170- diol 110- fluoro- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio)-propylamino] pentyl}- estra- 1, 3, 5( 10)- trien- 3, 170- diol

a) 110- fluor- østr- 4- en- 3, 17- dion a) 110-fluoro-estr-4-ene-3,17-dione

Til 5,0 g lla-hydroksy-østr-4-en-3,17-dion i 100 ml To 5.0 g of lla-hydroxy-estr-4-ene-3,17-dione in 100 ml

toluen og 7,3 ml 1,8-diazabisyklo[5.4.0]undec-7-en tildryppes ved 0 °C 4,6 ml perfluorbutan-l-sulfonsyrefluorid. Etter 30 min fortynnes løsningen med eddikester, vaskes med mettet natriumkloridløsning, tørkes og inndampes i. vakuum. Etter kromatograf ering av råproduktet på kiselgel med en heksan-eddikester-gradient oppnås 3,8 g 110-fluor-østr-4-en-3,17-dion med smp. 173-174 °C. toluene and 7.3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene are added dropwise at 0 °C to 4.6 ml of perfluorobutane-1-sulfonic acid fluoride. After 30 min, the solution is diluted with vinegar, washed with saturated sodium chloride solution, dried and evaporated in vacuo. After chromatography of the crude product on silica gel with a hexane-acetic ester gradient, 3.8 g of 110-fluoro-estr-4-ene-3,17-dione are obtained with m.p. 173-174 °C.

b) 110- fluor- 3- metoksy- østra- 3, 5- dien- 17- on b) 110- fluoro- 3- methoxy-estrane- 3, 5- diene- 17- one

7,8 g 110-fluor-østr-4-en-3,17-dion omrøres i 40 ml Stir 7.8 g of 110-fluoro-estr-4-ene-3,17-dione in 40 ml

2,2-dimetoksypropan med 780 mg pyridin-toluen-4-sulfonat i 5 t 2,2-dimethoxypropane with 780 mg of pyridine-toluene-4-sulfonate for 5 h

ved 80 °C. Blandingen tilsettes deretter 1,5 ml trietylamin, fortynnes med eddikester og vaskes med mettet natrium-kloridløsning. Etter krystallisering fra metanol oppnås 5,3 g 110-fluor-3-metoksy-østra-3,5-dien-17-on med smp. 173 °C. at 80 °C. The mixture is then added with 1.5 ml of triethylamine, diluted with ethyl acetate and washed with saturated sodium chloride solution. After crystallization from methanol, 5.3 g of 110-fluoro-3-methoxy-estra-3,5-dien-17-one with m.p. 173 °C.

c) 110- fluor- østra- 4, 6- dien- 3, 17- dion c) 110-fluoro-oestradiol-4,6-diene-3,17-dione

Til 5,0 g 110-fluor-3-metoksy-østra-3,5-dien-17-on i 50 ml DMF tilsettes ved 0 °C i rekkefølge 5 ml av en 10 % natriumacetatløsning og porsjonsvis 2,5 g 1,3-dibrom-5,5-di-metylhydantoin. Etter 30 min tilsettes 2,3 g natriumsulfitt og deretter 2,5 g litiumbromid og 2,0 g litiumkarbonat, og blandingen omrøres i 2 t ved 100 °C. Reaksjonsblåndingen omrøres i is-vann. Det utfelte produkt avsuges, løses i eddikester, vaskes med vann, tørkes og inndampes i vakuum. Etter omkrys-tallisering fra eddikester oppnås 3,6 g 110-fluor-østra-4,6-dien-3,17-dion med smp. 198 °C. To 5.0 g of 110-fluoro-3-methoxy-estra-3,5-dien-17-one in 50 ml of DMF, at 0 °C, 5 ml of a 10% sodium acetate solution and portionwise 2.5 g of 1, 3-dibromo-5,5-dimethylhydantoin. After 30 min, 2.3 g of sodium sulphite and then 2.5 g of lithium bromide and 2.0 g of lithium carbonate are added, and the mixture is stirred for 2 h at 100 °C. The reaction mixture is stirred in ice-water. The precipitated product is filtered off, dissolved in vinegar, washed with water, dried and evaporated in a vacuum. After recrystallization from ethyl acetate, 3.6 g of 110-fluoro-estra-4,6-diene-3,17-dione are obtained with m.p. 198 °C.

d) 110- fluor- 7a-( 5- tert.- butyldimetylsilyloksypentyl)-østr- 4- en- 3, 17- dion d) 110-fluoro-7a-(5-tert.-butyldimethylsilyloxypentyl)-estr-4-ene-3,17-dione

7,9 g magnesium i 40 ml THF omsettes under nitrogen med en løsning av 95,3 g t-brom-5-tert.-butyl-dimetylsilyl-oksypentan [Tetrahedron Letters 1982, 4147-4150] i 260 ml THF, til et Grignard-reagens. Ved -30 °C tilsettes 32 g kopper-(I)jodid og deretter dråpevis 29 g 110-fluor-østra-4,6-dien-3,17-dion i 290 ml THF. Etter endt reaksjon tilsettes 20,4 ml iseddik og reaksjonsblandingen omrøres i is-vann. Det utfelte produkt avsuges, oppløses i eddikester, vaskes nøytralt med vann og tørkes. Etter kromatografering av råproduktet på kiselgel med en heksan-eddikestergradient oppnås 23,9 g 110-fluor-7a-(5-tert.-butyldimetylsilyloksypentyl)-østr-4-en-3,17-dion som et skum. 7.9 g of magnesium in 40 ml of THF are reacted under nitrogen with a solution of 95.3 g of t-bromo-5-tert.-butyl-dimethylsilyl-oxypentane [Tetrahedron Letters 1982, 4147-4150] in 260 ml of THF, to a Grignard reagent. At -30 °C, 32 g of copper (I) iodide and then 29 g of 110-fluoro-estra-4,6-diene-3,17-dione in 290 ml of THF are added dropwise. After the reaction is complete, 20.4 ml of glacial acetic acid are added and the reaction mixture is stirred in ice water. The precipitated product is filtered off, dissolved in vinegar, washed neutrally with water and dried. After chromatography of the crude product on silica gel with a hexane-acetic ester gradient, 23.9 g of 110-fluoro-7a-(5-tert-butyldimethylsilyloxypentyl)-estr-4-ene-3,17-dione are obtained as a foam.

e) 110- fluor- 7g-( 5- hydroksypentyl)- østr- 4- en- 3, 17- dion e) 110-fluoro-7g-(5-hydroxypentyl)-estr-4-ene-3,17-dione

En løsning av 23,1 g 110-fluor-7a-(5-tert.-butyldimetylsilyloksypentyl) -østr-4 -en-3 , 17-dion i 115 ml THF og 64 ml vann omrøres med 128 ml iseddik i 2,5 t ved 50 °C. Reaksjonsblandingen inndampes i vakuum, oppløses i eddikester, vaskes med vann og tørkes. Det oppnås 20,4 g 110-fluor-7a-(5-hydroksypentyl)-østr-4-en-3,17-dion som et skum. A solution of 23.1 g of 110-fluoro-7a-(5-tert-butyldimethylsilyloxypentyl)-estr-4-ene-3,17-dione in 115 ml of THF and 64 ml of water is stirred with 128 ml of glacial acetic acid for 2.5 h at 50 °C. The reaction mixture is evaporated in vacuo, dissolved in vinegar, washed with water and dried. 20.4 g of 110-fluoro-7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione are obtained as a foam.

f) 7 g-( 5- acetoksypentyl)- 110- fluor- østr- 4- en- 3, 17- dion 20 g 110-fluor-7a-(5-hydroksypentyl)-østr-4-en-3,17-dion i 100 ml pyridin omsettes i 2 t med 50 ml acetanhydrid ved 25 °C. Ved 0 °C tilsettes deretter 5 ml vann og blandingen omrøres i 45 min. Blandingen ekstraheres med dietyleter, vaskes pyridinfri med 2 N svovelsyre og løsningen nøytraliseres i rekkefølge med mettet natriumhydrogenkarbonat-løsning og vann. Etter tørking og inndamping i vakuum kromatograferes råproduktet på kiselgel med en heksan-eddikestergradient. Det oppnås 17 g 7a-(5-acetoksypentyl)-110-fluor-østr-4-en-3,17-dion med smp. 78,4 °C. f) 7 g-(5-acetoxypentyl)-110-fluoro-estr-4-ene-3,17-dione 20 g 110-fluoro-7a-(5-hydroxypentyl)-estr-4-ene-3,17- dione in 100 ml of pyridine is reacted for 2 h with 50 ml of acetic anhydride at 25 °C. At 0 °C, 5 ml of water is then added and the mixture is stirred for 45 min. The mixture is extracted with diethyl ether, washed free of pyridine with 2 N sulfuric acid and the solution is neutralized in sequence with saturated sodium bicarbonate solution and water. After drying and evaporation in vacuum, the crude product is chromatographed on silica gel with a hexane-acetic ester gradient. 17 g of 7α-(5-acetoxypentyl)-110-fluoro-estr-4-ene-3,17-dione are obtained with m.p. 78.4 °C.

g) 7 a-( 5- acetoksypentyl)- 110- fluor- 3- hydroksy- østra-1, 3, 5( 10)- trien- 17- on g) 7a-(5-acetoxypentyl)-110-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one

Til 16,5 g 7a-(5-acetoksypentyl)-110-fluor-østr-4-en-3,17-dion i 190 ml acetonitril tilsettes ved 80 °C 18,6 g kopper(II)bromid og 3,6 g litiumbromid. Etter 15 min innrøres reaksjonsblandingen i natriumhydrogenkarbonatholdig is-vann. Det utfelte produkt avsuges, oppløses i eddikester, vaskes med vann, tørkes og inndampes i vakuum. Etter kromatografi av råproduktet på kiselgel med en heksan-eddikestergradient oppnås 8,5 g 7a-(5-acetoksypentyl)-110-fluor-3-hydroksy-østra-1,3,5(10)-trien-17-on som et skum. To 16.5 g of 7a-(5-acetoxypentyl)-110-fluoro-estr-4-ene-3,17-dione in 190 ml of acetonitrile are added at 80 °C 18.6 g of copper(II) bromide and 3.6 g lithium bromide. After 15 minutes, the reaction mixture is stirred into ice-water containing sodium bicarbonate. The precipitated product is filtered off, dissolved in vinegar, washed with water, dried and evaporated in a vacuum. After chromatography of the crude product on silica gel with a hexane-acetic ester gradient, 8.5 g of 7a-(5-acetoxypentyl)-110-fluoro-3-hydroxy-estran-1,3,5(10)-trien-17-one are obtained as a foam.

h) 7 g-( 5- acetoksypentyl)- 110- fluor- 3-( tetrahydropyran- 2-yloksy)- østra- 1, 3, 5( 10)- trien- 17- on h) 7 g-(5-acetoxypentyl)-110-fluoro-3-(tetrahydropyran-2-yloxy)- estra- 1,3,5(10)-trien-17-one

8,2 g 7o-(5-acetoksypentyl)-110-fluor-3-hydroksy-østra-l, 3,5(10)-trien-17-on i 86 ml THF omrøres med 8,6 ml 3,4-dihydro-2H-pyran og 820 mg p-toluensulfonsyrehydrat i 2,5 t ved romtemperatur. Blandingen tilsettes deretter 0,5 ml trietylamin, fortynnes med eddikester, vaskes med mettet natriumkloridløsning, tørkes og inndampes i vakuum. Etter kromatografering av råproduktet på kiselgel med en heksan-eddikestergradient, oppnås 7,8 g 7a-(5-acetoksypentyl)-110-fluor-3-(tetrahydropyran-2-yloksy)-østra-1,3,5(10)-trien-17-on som et skum. 8.2 g of 7o-(5-acetoxypentyl)-110-fluoro-3-hydroxy-estra-1, 3,5(10)-trien-17-one in 86 ml of THF are stirred with 8.6 ml of 3,4- dihydro-2H-pyran and 820 mg of p-toluenesulfonic acid hydrate for 2.5 h at room temperature. 0.5 ml of triethylamine is then added to the mixture, diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated in vacuo. After chromatography of the crude product on silica gel with a hexane-acetic ester gradient, 7.8 g of 7a-(5-acetoxypentyl)-110-fluoro-3-(tetrahydropyran-2-yloxy)-oestra-1,3,5(10)- trien-17-one as a foam.

i) 110- fluor- 7a-( 5- hydroksypentyl)- 3-( tetrahydropyran- 2-yloksy)- østra- 1, 3, 5( 10)- trien- 17- on i) 110-fluoro-7a-(5-hydroxypentyl)-3-(tetrahydropyran-2-yloxy)- estra- 1, 3, 5( 10)- trien- 17- one

7,4 g 7a-(5-acetoksypentyl)-lip-fluor-3-(tetrahydropyran-2-yloksy)-østra-1,3,5(10)-trien-17-on i 370 ml metanol og 37 ml vann omrøres ved romtemperatur med 1,8 g kaliumkarbonat. Etter 3 t tilsettes reaksjonsblandingen til is-vann. Det utfelte produkt avsuges, oppløses i eddikester, vaskes nøytralt med vann, tørkes og inndampes i vakuum. Det oppnås 7,0 g llp-fluor-7a-(5-hydroksypentyl)-3-(tetrahydropyran-2-yloksy)-østra-1,3,5(10)-trien-17-on som et skum. 7.4 g of 7a-(5-acetoxypentyl)-lip-fluoro-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-17-one in 370 ml of methanol and 37 ml of water stirred at room temperature with 1.8 g of potassium carbonate. After 3 h, the reaction mixture is added to ice-water. The precipitated product is filtered off, dissolved in vinegar, washed neutrally with water, dried and evaporated in a vacuum. 7.0 g of 11p-fluoro-7a-(5-hydroxypentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-17-one are obtained as a foam.

j) lip- fluor- 3-( tetrahydropyran- 2- yloksy)- 7a-( 5- p- tolu-ensulfonyloksypentyl)- østra- 1, 3, 5( 10)- trien- 17- on j) lip- fluoro- 3-( tetrahydropyran-2- yloxy)- 7a-( 5- p-toluenesulfonyloxypentyl)- estra- 1, 3, 5( 10)- trien- 17- one

6,7 g llp-fluor-7a-(5-hydroksypentyl)-3-(tetrahydropyran-2-yloksy)-østra-1,3,5(10)-trien-17-on i 70 ml pyridin omrøres ved romtemperatur med 6,0 g p-toluensulfonsyreanhydrid i 3 t. Løsningen fortynnes med eddikester, vaskes med mettet natriumkloridløsning, tørkes og inndampes i vakuum. Råproduktet kromatograferes på kiselgel med heksan-eddikestergradient. Det oppnås 5,7 g lip-fluor-3-(tetrahydropyran-2-yloksy)-7a-(5-p-toluensulfonyloksypentyl)-østra-1,3,5(10)-trien-17-on som et skum. 6.7 g of llp-fluoro-7a-(5-hydroxypentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-17-one in 70 ml of pyridine are stirred at room temperature with 6.0 g of p-toluenesulfonic anhydride for 3 h. The solution is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated in vacuo. The crude product is chromatographed on silica gel with a hexane-acetic ester gradient. 5.7 g of lip-fluoro-3-(tetrahydropyran-2-yloxy)-7a-(5-p-toluenesulfonyloxypentyl)-estra-1,3,5(10)-trien-17-one are obtained as a foam.

k) lip- fluor- 7a- f5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl)- 3-( tetrahydrapyran- 2-yloksy) østra- 1, 3, 5( 10)- trien- 17- on k) lip- fluoro- 7a-f5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl)- 3-( tetrahydrapyran-2-yloxy) estra- 1, 3, 5( 10)- trien- 17- on

2,0 g lip-fluor-3-(tetrahydropyran-2-yloksy)-7a-(5-p-toluensulfonyloksypentyl)-østra-1,3,5(10)-trien-17-on i 44 ml DMF omrøres ved 80 °C med 1,2 g metyl-[3-(4,4,5,5,5-pentafluorpentyltio)propyl]amin. Etter 6,5 t tilsettes reaksjonsblandingen vann. Blandingen ekstraheres med eddikester, vaskes med mettet natriumkloridløsning og inndampes i vakuum. Etter kromatografering av råproduktet på kiselgel med en metylenklorid-metanolgradient, oppnås 1,3 g lip-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]-pentyl}-3-(tetrahydrapyran-2-yloksy)østra-1,3,5(10)-trien-17-on som en olje. 2.0 g of lip-fluoro-3-(tetrahydropyran-2-yloxy)-7a-(5-p-toluenesulfonyloxypentyl)-estra-1,3,5(10)-trien-17-one in 44 ml of DMF are stirred at 80 °C with 1.2 g of methyl-[3-(4,4,5,5,5-pentafluoropentylthio)propyl]amine. After 6.5 h, water is added to the reaction mixture. The mixture is extracted with ethyl acetate, washed with saturated sodium chloride solution and evaporated in vacuo. After chromatography of the crude product on silica gel with a methylene chloride-methanol gradient, 1.3 g of lip-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino] is obtained -pentyl}-3-(tetrahydrapyran-2-yloxy)estra-1,3,5(10)-trien-17-one as an oil.

llp- fluor- 7a- f5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl)- 3 -( tetrahydrapyran- 2-yloksy) østra- 1, 3, 5( 10)- trien- 17p- ol llp- fluoro- 7a- f5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl)- 3 - ( tetrahydrapyran- 2-yloxy) estra- 1, 3, 5( 10)- triene- 17p- ol

Til 2,0 g lip-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-3-(tetrahydrapyran-2-yloksy)østra-1,3,5(10)-trien-17-on i 17 ml THF, 10 ml etanol og 4,2 ml vann, tilsettes ved 0 °C porsjonsvis 350 mg natriumborhydrid. Etter 3 0 min omrøres reaksjonsblandingen i isvann, ekstraheres med eddikester, vaskes med mettet natri-umkloridløsning og inndampes i vakuum. Det oppnås 1,7 g urenset lip-f luor-7a-{5 - [N-metyl-N-3 - (4,4,5, 5, 5-pentaf luor-pentyltio) propylamino] pentyl}-3- (tetrahydrapyran-2-yloksy)-østra-1,3,5(10)-trien-17p-ol som et skum. To 2.0 g lip-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-3-(tetrahydrapyran-2-yloxy) estra-1,3,5(10)-trien-17-one in 17 ml of THF, 10 ml of ethanol and 4.2 ml of water, 350 mg of sodium borohydride are added in portions at 0 °C. After 30 minutes, the reaction mixture is stirred in ice water, extracted with ethyl acetate, washed with saturated sodium chloride solution and evaporated in vacuo. 1.7 g of impure lip-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]pentyl}-3- ( tetrahydrapyran-2-yloxy)-estra-1,3,5(10)-trien-17p-ol as a foam.

m) lip- fluor- 7a-( 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl} - østra- 1, 3, 5( 10)- trien-3, 17p- diol m) lip- fluoro- 7a-( 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl}- estra- 1, 3, 5( 10)- triene -3, 17p-diol

En løsning av 1,6 g lip-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-3-(tetra-hydrapyran-2-yloksy)østra-1,3,5(10)-trien-17p-ol i 20 ml metanol og 2 ml vann omrøres ved 1,0 g oksalsyre. Etter 3 t tilsettes reaksjonsblandingen til is-vann. Blandingen ekstraheres med metylenklorid, vaskes med mettet natriumkloridløsning, tørkes og inndampes i vakuum. Etter kromatografering av råproduktet på kiselgel med en metylenklorid-metanolgradient, oppnås 1,1 g lip-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-1,3,5(10)-trien-3,17p-diol med smp. 95 °C. A solution of 1.6 g of lip-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-3-(tetra-hydrapyran- 2-yloxy)estra-1,3,5(10)-trien-17p-ol in 20 ml of methanol and 2 ml of water is stirred with 1.0 g of oxalic acid. After 3 h, the reaction mixture is added to ice-water. The mixture is extracted with methylene chloride, washed with saturated sodium chloride solution, dried and evaporated in vacuo. After chromatography of the crude product on silica gel with a methylene chloride-methanol gradient, 1.1 g of lip-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino] is obtained pentyl}-estra-1,3,5(10)-triene-3,17p-diol with m.p. 95 °C.

Eksempel 13 Example 13

llp- fluor- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentansulfinyl) propylamino] pentyl}- østra- 1, 3, 5( 10)- trien- 3, 17p- diol llp- fluoro- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentanesulfinyl) propylamino] pentyl}- estra- 1, 3, 5( 10)- trien- 3 , 17p-diol

580 mg llp-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-1,3,5(10)-trien-3,17p-diol i 24 ml metanol og 1,1 ml vann omrøres ved romtemperatur med 350 ml natriumperjodat. Etter 1,5 t fortynnes blandingen med metylenklorid, vaskes med mettet natri-umkloridløsning, tørkes og inndampes i vakuum. Råproduktet kromatograferes på kiselgel med en metylenklorid-metanolgradient. Det oppnås 287 mg lip-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfinyl)propylamino]pentyl}-østra-1,3,5(10)-trien-3,17p-diol med smp. 87 °C. 580 mg llp-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra-1,3,5(10)-triene -3,17p-diol in 24 ml of methanol and 1.1 ml of water is stirred at room temperature with 350 ml of sodium periodate. After 1.5 h, the mixture is diluted with methylene chloride, washed with saturated sodium chloride solution, dried and evaporated in vacuo. The crude product is chromatographed on silica gel with a methylene chloride-methanol gradient. 287 mg of lip-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}-estra-1,3,5(10) are obtained -triene-3,17p-diol with m.p. 87 °C.

Eksempel 14 Example 14

llp- fluor- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentansulfonyl) propylamino] pentyl}- østra- 1, 3, 5( 10)- trien- 3, 17ft- diol llp- fluoro- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentanesulfonyl) propylamino] pentyl}- estra- 1, 3, 5( 10)- trien- 3 , 17ft- diol

a) lip- fluor- 7a- f5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluor-pentansulf onyl) propylamino] pentyl}- 3-( tetrahydra-pyran- 2- yloksy)- østra- 1, 3, 5( 10)- trien- 17- on a) lip- fluoro- 7a- f5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoro-pentanesulfonyl) propylamino] pentyl}- 3-( tetrahydra-pyran-2- yloxy )- estra- 1, 3, 5( 10)- trien- 17- one

2,0 g llp-fluor-3-(tetrahydropyran-2-yloksy)-7a-(5-p-toluensulfonyloksypentyl)-østra-1,3,5(10)-trien-17-on i 40 ml DMF omrøres ved 80 °C med 2,1 g metyl-[3 - (4,4, 5,5,5-pentaf luor-pentansulf onyl) propyl] amin. Etter 7 t tilsettes reaksjonsblandingen til is/vann, ekstraheres med eddikester, vaskes med mettet natriumkloridløsning, tørkes og inndampes i vakuum. Etter kromatografering av råproduktet på kiselgel med en metylenklorid-metanolgradient, oppnås 1,1 g llp-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulfonyl)propylamino] pentyl}-3-(tetrahydrapyran-2-yloksy)østra-1,3,5(10)-trien-17-on som en olje. 2.0 g of llp-fluoro-3-(tetrahydropyran-2-yloxy)-7a-(5-p-toluenesulfonyloxypentyl)-estra-1,3,5(10)-trien-17-one in 40 ml of DMF are stirred at 80 °C with 2.1 g of methyl-[3-(4,4,5,5,5-pentafluoropentanesulfonyl)propyl]amine. After 7 h, the reaction mixture is added to ice/water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated in vacuo. After chromatography of the crude product on silica gel with a methylene chloride-methanol gradient, 1.1 g of llp-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfonyl) is obtained propylamino]pentyl}-3-(tetrahydrapyran-2-yloxy)estra-1,3,5(10)-trien-17-one as an oil.

b) lip- fluor- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluor-pentansulf onyl) propylamino] pentyl}- 3-( tetrahydra-pyran- 2- yloksy)- østra- 1, 3, 5( 10)- trien- 17p- ol b) lip- fluoro- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoro-pentanesulfonyl) propylamino] pentyl}- 3-( tetrahydra-pyran- 2- yloxy)- estra- 1, 3, 5( 10)- trien- 17p-ol

1,5 g llp-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulfonyl)propylamino]pentyl}-3-(tetrahydrapyran-2-yloksy)østra-1,3,5(10)-trien-17-on i en blanding av 13 ml THF, 7,5 ml etanol og 3,2 ml vann, tilsettes porsjonsvis ved 0 °C, 270 mg natriumborhydrid. Etter 90 min tilsettes vann, blandingen ekstraheres med eddikester, vaskes med mettet natriumkloridløsning, tørkes og inndampes i vakuum. Det oppnås 1,5 g lip-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulf onyl) propylamino] pentyl}-3 -(tetrahydrapyran-2-yloksy)-østra-1,3,5(10)-trien-17p-ol som råprodukt. 1.5 g llp-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfonyl)propylamino]pentyl}-3-(tetrahydrapyran-2-yloxy )estra-1,3,5(10)-trien-17-one in a mixture of 13 ml of THF, 7.5 ml of ethanol and 3.2 ml of water, is added portionwise at 0 °C, 270 mg of sodium borohydride. After 90 min, water is added, the mixture is extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated in vacuo. 1.5 g of lip-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)propylamino]pentyl}-3-(tetrahydrapyran- 2-yloxy)-estra-1,3,5(10)-trien-17p-ol as crude product.

c) lip- fluor- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluor-pentansulf onyl) propylamino] pentyl} - østra- 1, 3, 5 ( 10) - c) lip- fluoro- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoro-pentanesulfonyl) propylamino] pentyl}- estra- 1, 3, 5 ( 10 ) -

trien- 3, 17p- diol triene-3, 17p-diol

1,4 g llp-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulfonyl)propylamino]pentyl}-3-(tetrahydrapyran-2-yloksy)-østra-1,3,5(10)-trien-l7p-ol omrøres i 18 ml metanol og 1,8 ml vann ved romtemperatur med 900 mg oksalsyre. Etter 4 1.4 g llp-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfonyl)propylamino]pentyl}-3-(tetrahydrapyran-2-yloxy )-estra-1,3,5(10)-trien-17p-ol is stirred in 18 ml of methanol and 1.8 ml of water at room temperature with 900 mg of oxalic acid. After 4

t omrøres reaksjonsblandingen i is-vann. Det utfelte produkt oppløses i metylenklorid, vaskes med vann, tørkes og inndampes i vakuum. Etter kromatografi av råproduktet på kiselgel med en metylenklorid-metanolgradient, oppnås 325 mg llp-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulfonyl)-propylamino]pentyl}-østra-1,3,5(10)-trien-3,17p-diol med smp. 70 °C. t the reaction mixture is stirred in ice-water. The precipitated product is dissolved in methylene chloride, washed with water, dried and evaporated in vacuo. After chromatography of the crude product on silica gel with a methylene chloride-methanol gradient, 325 mg of llp-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-propylamino ]pentyl}-estra-1,3,5(10)-triene-3,17p-diol with m.p. 70 °C.

Eksempel 15 Example 15

16 a- fluor- 17a- metyl- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl) - østra- 1, 3, 5 ( 10)- trien- 3, 17p- diol 16 a- fluoro- 17a- methyl- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl) - estra- 1, 3, 5 ( 10 )-triene-3, 17p-diol

a) 7 a( 5- klorpentyl)- østr- 4- en- 3, 17- dion a) 7a(5-chloropentyl)-estr-4-ene-3,17-dione

I 150 ml vannfritt tetrahydrofuran suspenderes 11,6 g 11.6 g are suspended in 150 ml of anhydrous tetrahydrofuran

magnesiumspon og Grignard-reagenset prepareres med 58,8 ml 1-brom-5-klorpentan i 40 ml vannfritt tetrahydrofuran. Blandingen omrøres i 30 min ved romtemperatur, fortynnes med ytterligere 100 ml vannfritt tetrahydrofuran og avkjøles til - 70 °C. En løsning av 3,04 g kopper-I-bromid-dimetylsulfid-kompleks i 72 ml 1,3-dimetyltetrahydro-2(1H)-pyrimidinon (DMPU) og 150 ml tetrahydrofuran tildryppes deretter ved -65 til -70 °C. En løsning av 50 g østra-4,6-dien-3,17-dion (Steroids Vol. 1, 1963, 223) og 75 ml trimetylklorsilan i 700 ml vannfritt tetrahydrofuran, tilsettes deretter i løpet av 2,5 t. Blandingen hensettes til langsom oppvarming til romtemperatur på et vannbad, surgjøres den neste morgen med 48 ml eddiksyre under isavkjøling og tilsettes eddikester etter 15 min omrøring. Den organiske fase ekstraheres 3 ganger med mettet ammoniumkloridløsning og den vandige fase ekstraheres med eddikester, de sammenslåtte organiske faser vaskes med natriumbikarbonatløsning, tørkes med magnesiumsulfat og inndampes i vakuum. Bunnfallet på 53 g kromatograferes på kiselgel med heksan/diklormetan og eddikester, utbytte 35 g 7a-(5-klorpentyl)-østr-4-en-3,17-dion. magnesium shavings and the Grignard reagent are prepared with 58.8 ml of 1-bromo-5-chloropentane in 40 ml of anhydrous tetrahydrofuran. The mixture is stirred for 30 min at room temperature, diluted with a further 100 ml of anhydrous tetrahydrofuran and cooled to -70 °C. A solution of 3.04 g of copper I-bromide-dimethylsulfide complex in 72 ml of 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU) and 150 ml of tetrahydrofuran is then added dropwise at -65 to -70 °C. A solution of 50 g of estra-4,6-diene-3,17-dione (Steroids Vol. 1, 1963, 223) and 75 ml of trimethylchlorosilane in 700 ml of anhydrous tetrahydrofuran is then added over 2.5 h. The mixture is allowed to stand to slowly warm to room temperature on a water bath, acidify the next morning with 48 ml of acetic acid under ice-cooling and add vinegar after 15 min of stirring. The organic phase is extracted 3 times with saturated ammonium chloride solution and the aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with sodium bicarbonate solution, dried with magnesium sulfate and evaporated in vacuo. The precipitate of 53 g is chromatographed on silica gel with hexane/dichloromethane and ethyl acetate, yield 35 g of 7a-(5-chloropentyl)-estr-4-ene-3,17-dione.

Det samme produkt oppnås fra 8,05 g 7a-(5-hydroksypentyl)-østr-4-en-3,17-dion (eksempel lb) ved omsetning i 3,5 time med 8,66 g trifenylfosfin i 85 ml karbontetraklorid og 30 ml acetonitril ved romtemperatur. Reaksjonsblandingen fortynnes med diklormetan, ristes med mettet bikarbonatløsning og mettet koksaltløsning, tørkes med natriumsulfat og inndampes i vakuum, bunnfallet kromatograferes på kiselgel med diklormetan og eddikester, hvorved det oppnås 4,08 g 7a-(5-klorpentyl)-østr-4-en-3,17-dion, [0£]D2Z = +68 <0> (c = 0,5 % i kloroform). The same product is obtained from 8.05 g of 7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione (Example 1b) by reaction for 3.5 hours with 8.66 g of triphenylphosphine in 85 ml of carbon tetrachloride and 30 ml of acetonitrile at room temperature. The reaction mixture is diluted with dichloromethane, shaken with saturated bicarbonate solution and saturated sodium chloride solution, dried with sodium sulfate and evaporated in vacuo, the precipitate is chromatographed on silica gel with dichloromethane and ethyl acetate, whereby 4.08 g of 7a-(5-chloropentyl)-estr-4-ene is obtained -3,17-dione, [0£]D2Z = +68 <0> (c = 0.5% in chloroform).

b) 7 a-( 5- klorpentyl)- 3- hydroksy- østra- l, 3, 5( 10)- trien-17- on b) 7a-(5-chloropentyl)-3-hydroxy-estral-1, 3,5(10)-trien-17-one

18,96 g 7a-(5-klorpentyl)-østr-4-en-3,17-dion opp-løses i 350 ml vannfri acetonitril og tilsettes under en inert gass ved 80 °C en løsning av 4,36 g litiumbromid og 22,5 g kopper(II)bromid i 390 ml vannfri acetonitril. Blandingen omrøres i 5 min, avkjøles på isbad og tilsettes vann og eddikester. Den organiske fase ekstraheres med mettet natrium-bikarbonatløsning, den vandige fase ekstraheres med eddikester, de sammenslåtte organiske faser ristes med mettet kok-saltløsning, tørkes med natriumsulfat og inndampes i vakuum. Utbyttet av råprodukt på 19,1 g kromatograferes på kiselgel i heksan og eddikester, hvorved det oppnås 10,0 g oljeaktig 7a-(5-klorpentyl)-3-hydroksy-østra-l,3,5(10)-trien-17-on som kan krystalliseres fra heksan/diklormetan. 18.96 g of 7a-(5-chloropentyl)-estr-4-ene-3,17-dione are dissolved in 350 ml of anhydrous acetonitrile and added under an inert gas at 80 °C to a solution of 4.36 g of lithium bromide and 22.5 g of copper(II) bromide in 390 ml of anhydrous acetonitrile. The mixture is stirred for 5 min, cooled in an ice bath and water and vinegar are added. The organic phase is extracted with saturated sodium bicarbonate solution, the aqueous phase is extracted with vinegar, the combined organic phases are shaken with saturated sodium chloride solution, dried with sodium sulfate and evaporated in vacuo. The yield of crude product of 19.1 g is chromatographed on silica gel in hexane and ethyl acetate, whereby 10.0 g of oily 7a-(5-chloropentyl)-3-hydroxy-estra-1,3,5(10)-triene-17 is obtained -one which can be crystallized from hexane/dichloromethane.

Smp. 143,5 °C, [ oi] d22 +112 ° (c = 0,5 % i kloroform). Temp. 143.5 °C, [ oi] d22 +112 ° (c = 0.5% in chloroform).

c) Bis- 3, 17- trimetylsilyloksy- 7a-( 5- klorpentyl)- østra-1, 3, 5( 10), 16- tetraen c) Bis- 3, 17- trimethylsilyloxy- 7a-(5- chloropentyl)- estra-1, 3, 5( 10), 16- tetraene

I 75 ml benzen oppløses 5,65 g 7a-(5-klorpentyl)-østra-1,3,5(10)-trien-3-ol-17-on, 9 ml trietylamin og 9 ml trifluormetansulfonsyretrimetylsilylester og tilbakeløpskokes i 2 t. Etter avkjøling fortynnes blandingen med heksan, den øvre fase ristes med mettet natriumbikarbonatløsning og med mettet koksaltløsning, tørkes med natriumsulfat og inndampes i vakuum for å gi Bis-3,17-trimetylsilyloksy-7a-(5-klorpentyl)-østra-1,3,5(10),16-tetraen som en olje. In 75 ml of benzene, 5.65 g of 7a-(5-chloropentyl)-estra-1,3,5(10)-trien-3-ol-17-one, 9 ml of triethylamine and 9 ml of trifluoromethanesulfonic acid trimethylsilyl ester are dissolved and refluxed for 2 h After cooling, the mixture is diluted with hexane, the upper phase is shaken with saturated sodium bicarbonate solution and with saturated sodium bicarbonate solution, dried with sodium sulfate and evaporated in vacuo to give Bis-3,17-trimethylsilyloxy-7a-(5-chloropentyl)-estra-1, 3,5(10),16-tetraene as an oil.

d) 7 a-( 5- klorpentyl)- 16a- fluor- østra- 1, 3, 5( 10)- trien- 3-ol- 17- on d) 7a-(5- chloropentyl)-16a- fluoro- estra- 1, 3, 5( 10)- trien- 3-ol- 17- one

Produktet fra det foregående forsøk oppløses i 150 ml vannfri diklormetan og tilsettes 14,2 g N-fluorbenzen-sulfonimid. Etter 2 timers omrøring ved romtemperatur tilsettes 50 ml 8 % svovelsyre, blandingen omrøres intensivt i ytterligere 3 t og fasene atskilles. Vannfasen ristes to ganger med diklormetan, den organiske fase ristes i rekkefølge med mettet natriumbikarbonat- og natriumkloridløsning, tørkes med natriumsulfat og inndampes i vakuum. Råproduktet på 15,3 g kromatograferes på kiselgel med diklormetan/diisopropyleter, hvorved det oppnås 2,92 g 7a-(5-klorpentyl)-16a-fluor-østra-1,3,5(10)-trien-3-ol-17-on som en olje. Produktet kan krystalliseres fra diisopropyleter, smp. 176 °C, [QE]D<22> = +114 ° (c = 0,5 % i kloroform). The product from the previous experiment is dissolved in 150 ml of anhydrous dichloromethane and 14.2 g of N-fluorobenzenesulfonimide is added. After stirring for 2 hours at room temperature, 50 ml of 8% sulfuric acid is added, the mixture is stirred intensively for a further 3 hours and the phases are separated. The aqueous phase is shaken twice with dichloromethane, the organic phase is shaken successively with saturated sodium bicarbonate and sodium chloride solution, dried with sodium sulfate and evaporated in vacuo. The crude product of 15.3 g is chromatographed on silica gel with dichloromethane/diisopropyl ether, whereby 2.92 g of 7a-(5-chloropentyl)-16a-fluoro-estra-1,3,5(10)-trien-3-ol- 17-on as an oil. The product can be crystallized from diisopropyl ether, m.p. 176 °C, [QE]D<22> = +114 ° (c = 0.5% in chloroform).

e) 7 g-( 5- klorpentyl)- 16a- fluor-l7 a- metyl- østra-1, 3, 5 ( 10) - trien- 3, 170- diol e) 7 g-(5-chloropentyl)-16a-fluoro-17a-methyl- estra-1,3,5(10)-triene-3,170-diol

3,0 g 7a-(5-klorpentyl)-16a-fluor-østra-1,3,5(10)-trien-3-ol-17-on oppløses i 300 ml vannfri toluen under en inert gass og tilsettes 3 porsjoner å 20 ml av en 1,5 molar løsning av metyllitium og litiumbromid i eter ved romtemperatur, med 15 minutters mellomrom. Etter ytterligere 30 min innrøres reaksjonsblandingen i en halvmettet ammoniumklorid-løsning under isavkjøling, surgjøres med 8 % svovelsyre og ekstraheres med eddikester. De forenede organiske faser ristes med natriumkloridløsning, tørkes med natriumsulfat og inndampes i vakuum. Råproduktet på 3,2 g kromatograferes på kiselgel med heksan og metyl-tert.-butyleter. Den polare fraksjon på 1,21 g er 7a-(5-klorpentyl)-16a-fluor-17a-metyl-østra-1,3,5(10)-trien-3,170-diol som krystalliserer fra diisopropyleter/heksan, smp. 70 °C, [a]D<22> +7 <0> (c = 0,5 % i kloroform). Dissolve 3.0 g of 7a-(5-chloropentyl)-16a-fluoro-estra-1,3,5(10)-trien-3-ol-17-one in 300 ml of anhydrous toluene under an inert gas and add 3 portions to 20 ml of a 1.5 molar solution of methyllithium and lithium bromide in ether at room temperature, at 15 minute intervals. After a further 30 minutes, the reaction mixture is stirred into a half-saturated ammonium chloride solution under ice-cooling, acidified with 8% sulfuric acid and extracted with acetic acid. The combined organic phases are shaken with sodium chloride solution, dried with sodium sulfate and evaporated in vacuo. The crude product of 3.2 g is chromatographed on silica gel with hexane and methyl tert-butyl ether. The polar fraction of 1.21 g is 7α-(5-chloropentyl)-16α-fluoro-17α-methyl-estra-1,3,5(10)-triene-3,170-diol which crystallizes from diisopropyl ether/hexane, m.p. 70 °C, [a]D<22> +7 <0> (c = 0.5% in chloroform).

f) 16 a- fluor- 17a- metyl- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5-pentafluorpentyltio) propylamino] pentyl}- østra-1, 3, 5 ( 10) - trien- 3, 170- diol f) 16 a- fluoro- 17a- methyl- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5-pentafluoropentylthio) propylamino] pentyl}- estra-1, 3, 5 (10)-triene-3,170-diol

40,8 mg 7a-(5-klorpentyl)-16a-fluor-17a-metyl-østra-1,3,5(10)-trien-3,170-diol oppløses i 0,5 ml dimetylformamid og tilsettes en løsning av 58 mg 3-(N-metylamino)-propyl-4,4,5,5,5-pentafluorpentylsulfid og 13 mg litiumjodid og oppvarmes i 17 t ved 100 °C under inert gass. Etter avkjøling tilsettes blandingen eddikester, ristes i rekkefølge med mettet natriumhydrogenkarbonat- og koksaltløsning, tørkes med natriumsulfat og løsningsmidlet avdampes i vakuum. Resten kromatograferes på kiselgel med eddikester/metanol, utbytte 25 40.8 mg of 7a-(5-chloropentyl)-16a-fluoro-17a-methyl-estra-1,3,5(10)-triene-3,170-diol is dissolved in 0.5 ml of dimethylformamide and a solution of 58 mg is added 3-(N-methylamino)-propyl-4,4,5,5,5-pentafluoropentyl sulfide and 13 mg of lithium iodide and heated for 17 h at 100 °C under inert gas. After cooling, acetic acid is added to the mixture, shaken in sequence with saturated sodium bicarbonate and sodium bicarbonate solution, dried with sodium sulfate and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel with ethyl acetate/methanol, yield 25

mg 16a-fluor-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-1,3,5(10)-trien-3,170-diol som en olje. mg 16a-fluoro-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra-1,3,5(10 )-triene-3,170-diol as an oil.

Eksempel 16 Example 16

16 a- fluor- 17p- metyl- 7g-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl}- østra- 1, 3, 5( 10)- trien- 3, 17a- diol 16 a- fluoro- 17p- methyl- 7g-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl}- estra- 1, 3, 5( 10 )-triene-3, 17a-diol

Som et upolart produkt fra kromatografien i eksempel 15e) isoleres 7g<->(5-klorpentyl)-16o-fluor-170-metyl-østra-1,3,5(10)-trien-3,17a-diol i en mengde på 0,48 g. Ved krystallisering fra diisopropyleter/heksan oppnås krystaller med smp. 65 °C og .7 = +5 ° (c = 0,5 % i kloroform) . As a non-polar product from the chromatography in example 15e) 7g<->(5-chloropentyl)-16o-fluoro-170-methyl-estra-1,3,5(10)-triene-3,17a-diol is isolated in a quantity of 0.48 g. By crystallization from diisopropyl ether/hexane, crystals with m.p. 65 °C and .7 = +5 ° (c = 0.5% in chloroform) .

Av dette produkt omsettes 41 mg som beskrevet i eksempel 15f) , hvorved det oppnås 23 mg 16a-fluor-170-metyl-7a-(5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino] pentyl}-østra-1,3,5(10)-trien-3,17a-diol. 41 mg of this product is reacted as described in example 15f), whereby 23 mg of 16a-fluoro-170-methyl-7a-(5-[N-methyl-N-3-(4,4,5,5,5 -pentafluoropentylthio)propylamino]pentyl}-estra-1,3,5(10)-triene-3,17a-diol.

Eksempel 17 Example 17

16a- fluor- 17a- metyl- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluor-pentansulf onyl) propylamino] pentyl } - østra- 1 , 3, 5( 10)- trien-3, 170- diol 16a- fluoro- 17a- methyl- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoro-pentanesulfonyl) propylamino] pentyl } - estra- 1, 3, 5 (10)-triene-3, 170-diol

Som beskrevet i eksempel 15f) omsettes 40,8 mg 7a-(5-klorpentyl)-16a-fluor-17a-metyl-østra-1,3,5(10)-trien-3,170-diol i dimetylformamid med 70 mg 3-(N-metylamino)propyl-4,4,5,5,5-pentafluorpentylsulfon. Etter opparbeidelse oppnås 21 mg 16a-fluor-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentaf luor-pentansulf onyl) propylamino] pentyl}-østra-1,3,5(10)-trien-3,170-diol som en olje. As described in example 15f), 40.8 mg of 7a-(5-chloropentyl)-16a-fluoro-17a-methyl-estra-1,3,5(10)-triene-3,170-diol are reacted in dimethylformamide with 70 mg of 3- (N-methylamino)propyl-4,4,5,5,5-pentafluoropentyl sulfone. After work-up, 21 mg of 16a-fluoro-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfonyl)propylamino]pentyl}-estra are obtained -1,3,5(10)-triene-3,170-diol as an oil.

Eksempel 18 Example 18

7 a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl}- østra- 1, 3, 5( 10), 14- tetraen- 3, 170- diol 7 a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl}- estra- 1, 3, 5( 10), 14- tetraene- 3, 170-diol

a) 7g-( 5- tert.- butyldimetylsilyloksypentyl)-østr-4-en-3, 17- dion a) 7g-(5-tert.-butyldimethylsilyloxypentyl)-estr-4-ene-3, 17-dione

I 34 ml absolutt tetrahydrofuran omsettes 8,9 g magnesiumspon med 103 g l-brom-5-tert.-butyl-dimetylsilyloksy-pentan, oppløst i 110 ml tetrahydrofuran, til et Grignard-reagens. Til denne løsning tilsettes ved -70 °C til -65 °C, 2,5 g kobber(I)bromid-dimetylsulfoksidkompleks og en blanding av 60 ml 1,3-dimetyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon og 70 ml tetrahydrofuran og suspensjonen omrøres i ytterligere 30 min ved -70 °C under en argonatmosfære. In 34 ml of absolute tetrahydrofuran, 8.9 g of magnesium shavings are reacted with 103 g of 1-bromo-5-tert-butyl-dimethylsilyloxy-pentane, dissolved in 110 ml of tetrahydrofuran, to a Grignard reagent. To this solution is added at -70 °C to -65 °C, 2.5 g of copper (I) bromide-dimethylsulfoxide complex and a mixture of 60 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2( 1H)-pyrimidinone and 70 ml of tetrahydrofuran and the suspension is stirred for a further 30 min at -70°C under an argon atmosphere.

Ved -70 °C til -65 °C tildryppes deretter en løsning av 50 g østra-4,6-dien-3,17-dion [Steroids Vol. 1, 1963, 233-249] i 730 ml absolutt tetrahydrofuran og 62,7 ml klortri-metylsilan, og blandingen omrøres over natten ved -70 °C. For opparbeidelse tilsettes reaksjonsblandingen ved -15 °C, 48 ml iseddik og helles etter 15 minutters omrøring ved denne temperatur, over i en blanding av mettet ammoniumkloridløsning og etylacetat. Den organiske fase atskilles og vaskes i rek-kefølge til nøytral pH med mettet ammoniumkloridløsning, mettet natriumhydrogenkarbonatløsning og til sist med mettet koksaltløsning, tørkes over natriumsulfat og inndampes. At -70 °C to -65 °C, a solution of 50 g of estra-4,6-diene-3,17-dione [Steroids Vol. 1, 1963, 233-249] in 730 ml of absolute tetrahydrofuran and 62, 7 ml of chlorotrimethylsilane, and the mixture is stirred overnight at -70 °C. For work-up, 48 ml of glacial acetic acid is added to the reaction mixture at -15 °C and, after stirring for 15 minutes at this temperature, is poured into a mixture of saturated ammonium chloride solution and ethyl acetate. The organic phase is separated and washed in order to neutral pH with saturated ammonium chloride solution, saturated sodium bicarbonate solution and finally with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated.

Bunnfallet kromatograferes på kiselgel med diklormetan/aceton. Det oppnås 47 g 7a-(5-tert.-butyldimetylsilyloksypentyl) -østr-4-en-3,17-dion som en gul olje. [a]D<22> = +62,2<0> (c = 0,545 i kloroform). The precipitate is chromatographed on silica gel with dichloromethane/acetone. 47 g of 7α-(5-tert-butyldimethylsilyloxypentyl)-estr-4-ene-3,17-dione are obtained as a yellow oil. [a]D<22> = +62.2<0> (c = 0.545 in chloroform).

b) 3- hydroksy- 7a-( 5- hydroksypentyl)- østra- 1, 3, 5( 10), 15-tetraen- 17 - on b) 3- hydroxy- 7a-( 5- hydroxypentyl)- estra- 1, 3, 5( 10), 15-tetraen- 17 - one

Etter fremgangsmåten beskrevet i eksempel lb-li omsettes 62,7 g 7a-(5-tert.-butyldimetylsilyloksypentyl)-østr-4-en-3,17-dion med 15,8 g 3-hydroksy-7a-(5-hydroksypentyl)-østra-1,3,5(10),15-tetraen-17-on. Following the procedure described in examples lb-li, 62.7 g of 7a-(5-tert-butyldimethylsilyloxypentyl)-estr-4-ene-3,17-dione are reacted with 15.8 g of 3-hydroxy-7a-(5-hydroxypentyl )-estra-1,3,5(10),15-tetraen-17-one.

c) 3- benzyloksy- 7a-( 5- hydroksypentyl)- østra-1, 3, 5( 10), 15- tetraen- 17- on c) 3- benzyloxy- 7a-( 5- hydroxypentyl)- estra-1, 3, 5( 10), 15- tetraen- 17- one

En løsning av 2,85 g 3-hydroksy-7a-(5-hydroksypentyl) -østra-1 , 3 , 5 (10) , 15-tetraen-17-on i 57 ml aceton tilsettes 3,25 g cesiumkarbonat og 1,14 ml benzylbromid og blandingen tilbakeløpskokes ilt. Reaksjonsblandingen inndampes, bunnfallet tilsettes vann, ristes med etylacetat, den organiske fase tørkes over natriumsulfat og inndampes. Resten kromatograferes på kiselgel med heksan/etylacetat. Det oppnås 3,12 g 3-benzyloksy-7a-(5-hydroksypentyl)-østra-1,3,5(10),15-tetraen- 17-on som et skum. A solution of 2.85 g of 3-hydroxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one in 57 ml of acetone is added to 3.25 g of cesium carbonate and 1, 14 ml of benzyl bromide and the mixture is refluxed in oxygen. The reaction mixture is evaporated, the precipitate is added to water, shaken with ethyl acetate, the organic phase is dried over sodium sulphate and evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate. 3.12 g of 3-benzyloxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one are obtained as a foam.

d) 17- acetoksy- 7g- ( 5- acetoksypentyl) - 3- benzyloksy- østra-1, 3, 5( 10), 14, 16- pentaen d) 17- acetoxy- 7g-( 5- acetoxypentyl)- 3- benzyloxy- estra-1, 3, 5( 10), 14, 16- pentaene

En løsning av 6,12 g 3-benzyloksy-7a-(5-hydroksypentyl) -østra-1, 3 , 5 (10) , 15-tetraen-17-on i 717 ml acetanhydrid omrøres med 920 mg p-toluensulfonsyre ilt ved romtemperatur. Reaksjonsblandingen opparbeides etter fremgangsmåten angitt i eksempel lj og råproduktet kromatograferes på kiselgel med heksan/etylacetat. Det oppnås 4,6 g 17-acetoksy-7a-(5-acetoksypentyl) -3 -benzyloksy-østra- 1,3, 5 (10) , 14, 16-pentaen som en olje. A solution of 6.12 g of 3-benzyloxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one in 717 ml of acetic anhydride is stirred with 920 mg of p-toluenesulfonic acid at room temperature. The reaction mixture is worked up according to the method indicated in example lj and the crude product is chromatographed on silica gel with hexane/ethyl acetate. 4.6 g of 17-acetoxy-7a-(5-acetoxypentyl)-3-benzyloxy-estra-1,3,5(10),14,16-pentaene are obtained as an oil.

e) 7 a-( 5- acetoksypentyl)- 3- benzyloksy- østra-1, 3, 5 ( 10) , 14- tetraen-17J3-ol e) 7a-(5-acetoxypentyl)-3-benzyloxy-estra-1,3,5(10),14-tetraen-17J3-ol

Til en løsning av 4,58 g 17-acetoksy-7a-(5-acetoksypentyl) -3-benzyloksy-østra-1,3,5(10),14,16-pentaen i 26,8 ml tetrahydrofuran og 161 ml etanol, tildryppes ved romtemperatur en løsning av 1,25 g natriumborhydrid i 90 ml etanol og 18 ml vann, og blandingen omrøres ilt. Reaksjonsblandingen tilsettes 4 ml iseddik, inndampes og bunnfallet oppløses i etylacetat. Den organiske fase vaskes med natriumhydrogenkarbonat, tørkes over natriumsulfat og inndampes. Bunnfallet kromatograferes på kiselgel med heksan/etylacetat. Det oppnås 2,16 g 7a-(5-acetoksypentyl)-3-benzyloksy-østra-1, 3, 5 (10) , 14-tetraen-17fJ-ol som et skum. To a solution of 4.58 g of 17-acetoxy-7a-(5-acetoxypentyl)-3-benzyloxy-estra-1,3,5(10),14,16-pentaene in 26.8 ml of tetrahydrofuran and 161 ml of ethanol , a solution of 1.25 g of sodium borohydride in 90 ml of ethanol and 18 ml of water is added dropwise at room temperature, and the mixture is stirred in oxygen. Add 4 ml of glacial acetic acid to the reaction mixture, evaporate and dissolve the precipitate in ethyl acetate. The organic phase is washed with sodium bicarbonate, dried over sodium sulphate and evaporated. The precipitate is chromatographed on silica gel with hexane/ethyl acetate. 2.16 g of 7α-(5-acetoxypentyl)-3-benzyloxy-estra-1,3,5(10),14-tetraen-17β-ol are obtained as a foam.

f) 3- benzyloksy- 7a-( 5- hydroksypentyl)- østra-1, 3, 5( 10), 14- tetraen- 17g- ol f) 3- benzyloxy- 7a-(5- hydroxypentyl)- estra-1, 3, 5( 10), 14- tetraen- 17g-ol

2,16 g 7o-(5-acetoksypentyl)-3-benzyloksy-østra-1,3,5(10),14-tetraen-17p-ol forsåpes med 38 ml 1 N metanolisk kaliumhydroksidløsning over natten ved romtemperatur. Reaksjonsblandingen helles over i iskald, mettet koksaltløsning, bunnfallet avsuges, oppløses i diklormetan, vaskes med mettet koksaltløsning, tørkes over natriumsulfat og inndampes. Det oppnås 1,86 g 3-benzyloksy-7a-(5-hydroksypentyl)-østra-1,3,5 (10) , 14-tetraen-17j3-ol som et skum. 2.16 g of 7o-(5-acetoxypentyl)-3-benzyloxy-estra-1,3,5(10),14-tetraen-17p-ol are saponified with 38 ml of 1 N methanolic potassium hydroxide solution overnight at room temperature. The reaction mixture is poured into ice-cold, saturated sodium chloride solution, the precipitate is filtered off with suction, dissolved in dichloromethane, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. 1.86 g of 3-benzyloxy-7a-(5-hydroxypentyl)-estra-1,3,5 (10), 14-tetraen-17j3-ol are obtained as a foam.

g) 3- benzyloksy- 7g-( 5- tosyloksypentyl)- østra-1, 3, 5 ( 10), 14- tetraen- 17p- ol g) 3- benzyloxy- 7g-(5- tosyloxypentyl)- estra-1, 3, 5 ( 10), 14- tetraen- 17p-ol

Under betingelsene ifølge eksempel lo omsettes 3,03 g 3-benzyloksy-7a-(5-hydroksypentyl)-østra-1,3,5(10),14-tetraen-170-ol med 2,31 g p-toluensulfonsyreanhydrid i 58 1 pyridin, opparbeides og kromatograferes på kiselgel. Det oppnås 3 g 3-benzyloksy-7a-(5-tosyloksypentyl)-østra-1,3,5(10),14-tetraen-170-ol som et skum. Under the conditions according to example 10, 3.03 g of 3-benzyloxy-7a-(5-hydroxypentyl)-estra-1,3,5(10),14-tetraen-170-ol are reacted with 2.31 g of p-toluenesulfonic anhydride in 58 1 pyridine, worked up and chromatographed on silica gel. 3 g of 3-benzyloxy-7a-(5-tosyloxypentyl)-estra-1,3,5(10),14-tetraen-170-ol are obtained as a foam.

h) 3- benzyloksy- 7g-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl}- østra-1, 3, 5( 10), l4- tetraen- 170- ol h) 3- benzyloxy- 7g-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl}- estra-1, 3, 5( 10), l4 - tetraene- 170- ol

En løsning av 2 g 3-benzyloksy-7a-(5-tosyloksypentyl) -østra-1, 3 , 5 (10) , 14-tetraen-170-ol i 28 ml etylmetylketon omrøres med 1,77 g N-metyl-3-(4,4,5,5,5-pentafluorpentyltio)-propylamin i nærvær av 950 mg kaliumkarbonat og 230 mg kalium-jodid i 5 t ved 80 °C badtemperatur. Reaksjonsblandingen helles over i koksaltløsning, ekstraheres med etylacetat, vaskes med koksaltløsning, tørkes over natriumsulfat og inndampes. Bunnfallet kromatograferes på kiselgel med heksan/etylacetat. Det oppnås 1,93 g 3-benzyloksy-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-1,3,5(10),14-tetraen-170-ol i form av en resin..8 = +47,3 ° (c = 0,505 i kloroform). A solution of 2 g of 3-benzyloxy-7a-(5-tosyloxypentyl)-estra-1,3,5(10),14-tetraen-170-ol in 28 ml of ethyl methyl ketone is stirred with 1.77 g of N-methyl-3 -(4,4,5,5,5-pentafluoropentylthio)-propylamine in the presence of 950 mg potassium carbonate and 230 mg potassium iodide for 5 h at 80 °C bath temperature. The reaction mixture is poured into sodium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate and evaporated. The precipitate is chromatographed on silica gel with hexane/ethyl acetate. 1.93 g of 3-benzyloxy-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra-1,3,5( 10),14-tetraen-170-ol in the form of a resin..8 = +47.3 ° (c = 0.505 in chloroform).

i) 7 g-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio)-propylamino] pentyl)- østra- 1, 3, 5( 10), 14- tetraen- 3, 170-diol i) 7 g-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio)-propylamino] pentyl)- estra- 1, 3, 5( 10), 14- tetraene - 3, 170-diol

Til en løsning av 850 mg 3-benzyloksy-7a-{5-[N-metyl-N-3- (4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-1,3,5(10),14-tetraen-170-ol i 10,2 ml toluen tildryppes ved romtemperatur 10,2 ml av enn 1,2 molar løsning av diiso-butylaluminiumhydrid i toluen, og blandingen oppvarmes i 5 t ved 120 °C badtemperatur. Reaksjonsblandingen tildryppes under omrøring og i en argonatmosfære til en blanding av mettet koksaltløsning og 2 N svovelsyre, ekstraheres 3 ganger med etylacetat, den organiske fase vaskes to ganger med 2 N svovelsyre og 3 ganger med mettet koksaltløsning, tørkes over natriumsulfat og inndampes. Resten kromatograferes på kiselgel med heksan/etylacetat/0-30 % metanol. Det oppnås 670 mg 7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino] pentyl } -østra-1 , 3 , 5 (10) , 14-tetraen-3 , 170-diol som et To a solution of 850 mg of 3-benzyloxy-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra-1,3,5( 10),14-tetraen-170-ol in 10.2 ml of toluene is added dropwise at room temperature to 10.2 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene, and the mixture is heated for 5 hours at 120 °C bath temperature. The reaction mixture is added dropwise while stirring and in an argon atmosphere to a mixture of saturated sodium chloride solution and 2 N sulfuric acid, extracted 3 times with ethyl acetate, the organic phase is washed twice with 2 N sulfuric acid and 3 times with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate/0-30% methanol. 670 mg of 7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-ostra-1,3,5(10),14-tetraene are obtained -3, 170-diol as a

skum. [a]D<22> = +43 <0> (c = 0,520 i kloroform/metanol). foam. [a]D<22> = +43 <0> (c = 0.520 in chloroform/methanol).

Eksempel 19 Example 19

7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentansulfinyl) propylamino] pentyl}- østra- 1, 3, 5( 10), 14- tetraen- 3, 170- diol 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentanesulfinyl) propylamino] pentyl}- estra- 1, 3, 5( 10), 14- tetraene- 3, 170 - diol

Under betingelsene ifølge eksempel 2, omsettes 400 mg 7a-{5-[N-metyl-N-3- (4,4,5,5,5-pentafluorpentyltio)propylamino] pentyl}-østra-1,3,5(10),14-tetraen-3,170-diol med 177 mg natriumperjodat, opparbeides og råproduktet kromatograferes på kiselgel med etylacetat/metanol. Det oppnås 287 mg av tittelforbindelsen som et skum. [a]D<22> = +30,7 ° (c = 0,530 i kloroform/metanol). Under the conditions according to example 2, 400 mg of 7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra-1,3,5(10 ),14-tetraene-3,170-diol with 177 mg of sodium periodate, is worked up and the crude product is chromatographed on silica gel with ethyl acetate/methanol. 287 mg of the title compound are obtained as a foam. [a]D<22> = +30.7 ° (c = 0.530 in chloroform/methanol).

Eksempel 20 Example 20

7 a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluor- pentansulfonyl)-propylamino] pentyl)- østra- 1, 3, 5( 10), 14- tetraen- 3, 170- diol 7 a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoro- pentanesulfonyl)-propylamino] pentyl)- estra- 1, 3, 5( 10), 14- tetraene - 3, 170- diol

a) 3- benzyloksy- 7a{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluor-pentansulf onyl) propylamino] pentyl)- østra-1, 3, 5( 10), 14- tetraen- 170- ol a) 3- benzyloxy- 7a{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentanesulfonyl) propylamino] pentyl)- estra-1, 3, 5( 10) , 14- tetraene- 170- ol

Under betingelsene ifølge eksempel 23h omsettes 1 g 3-benzyloksy-7a-(5-tosyloksypentyl)-østra-1,3,5(10),14-tetraen-170-ol med 990 mg N-metyl-3-(4,4,5,5,5-pentafluor-pentan-sulf onyl) propyl amin, opparbeides og råproduktet kromatograf eres på kiselgel med etylacetat/metanol. Det oppnås 960 mg 3-benzyloksy-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentan-sulfonyl)propylamino]pentyl}-østra-l,3,5(10),14-tetraen-170-ol som en olje. [a]D<22> = +48,5 ° (c = 0,535 i kloroform). Under the conditions according to example 23h, 1 g of 3-benzyloxy-7a-(5-tosyloxypentyl)-estra-1,3,5(10),14-tetraen-170-ol is reacted with 990 mg of N-methyl-3-(4, 4,5,5,5-pentafluoro-pentane-sulfonyl) propyl amine, is worked up and the crude product is chromatographed on silica gel with ethyl acetate/methanol. 960 mg of 3-benzyloxy-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentane-sulfonyl)propylamino]pentyl}-estra-1,3 are obtained, 5(10),14-tetraen-170-ol as an oil. [a]D<22> = +48.5 ° (c = 0.535 in chloroform).

b) 7 g-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluor- pentansul-fonyl) propylamino] pentyl)- østra- 1, 3, 5( 10), 14- tetraen-3, 170- diol b) 7 g-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoro-pentanesulfonyl) propylamino] pentyl)- estra- 1, 3, 5( 10), 14- tetraene-3, 170- diol

En løsning av 100 mg 3-benzyloksy-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulfonyl)propylamino]pentyl}-østra-1,3,5(10),14-tetraen-170-ol i 1 ml diklormetan tilsettes under avkjøling på isbad 0,2 ml dimetylanilin og 73 mg aluminiumklorid og omrøres ilt ved denne temperatur. Reaksjonsblandingen helles over på 1 N saltsyre, ristes med etylacetat, vaskes med natriumhydrogenkarbonatløsning og mettet koksaltløsning, tørkes over natriumsulfat og inndampes. Råproduktet kromatograferes på kiselgel med diklormetan/0-10 % metanol. Det oppnås 74 mg av tittelforbindelsen som et skum. A solution of 100 mg of 3-benzyloxy-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfonyl)propylamino]pentyl}-estra-1,3,5 (10),14-tetraen-170-ol in 1 ml of dichloromethane is added while cooling in an ice bath 0.2 ml of dimethylaniline and 73 mg of aluminum chloride and oxygen is stirred at this temperature. The reaction mixture is poured over 1 N hydrochloric acid, shaken with ethyl acetate, washed with sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel with dichloromethane/0-10% methanol. 74 mg of the title compound are obtained as a foam.

[tt]D<22> = +36 <0> (c = 0,525 kloroform/metanol). [tt]D<22> = +36 <0> (c = 0.525 chloroform/methanol).

Eksempel 21 Example 21

7 a-{ 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl)- pyrrolidin-l- yl] pentyl}- østra- l, 3, 5( 10)- trien- 3, 170- diol 7 a-{ 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluoropentylthiomethyl)- pyrrolidin-l- yl] pentyl}- estral- 1, 3, 5( 10)- trien- 3 , 170-diol

a) 7 a-( 5- acetoksypentyl)- 3- benzyloksy- østra- 1, 3, 5( 10)-trien- 17- on a) 7 a-(5- acetoxypentyl)-3- benzyloxy- estra- 1, 3, 5( 10)-trien- 17- one

En løsning av 6,5 g 7a-(5-acetoksypentyl)-3-hydroksy-østra-l, 3,5(10)-trien-17-on (eksempel ld) i 65 ml dimetylformamid tilsettes 3,3 ml benzylklorid, 8,7 g cesiumkarbonat og 400 mg natriumjodid og omrøres over natten ved romtemperatur. Reaksjonsblandingen helles over i vann, ristes med etylacetat, den organiske fase vaskes med mettet koksalt-løsning, tørkes over natriumsulfat og inndampes. Bunnfallet kromatograferes på kiselgel med heksan/etylacetat. Det oppnås 7,26 g 7a-(5-acetoksypentyl)-3-benzyloksy-østra-l,3,5(10)-trien-17-on som en olje. A solution of 6.5 g of 7α-(5-acetoxypentyl)-3-hydroxy-estra-1, 3,5(10)-trien-17-one (Example 1d) in 65 ml of dimethylformamide is added to 3.3 ml of benzyl chloride, 8.7 g of cesium carbonate and 400 mg of sodium iodide and stirred overnight at room temperature. The reaction mixture is poured into water, shaken with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The precipitate is chromatographed on silica gel with hexane/ethyl acetate. 7.26 g of 7α-(5-acetoxypentyl)-3-benzyloxy-estra-1,3,5(10)-trien-17-one are obtained as an oil.

b) 3- benzyloksy- 7g-( 5- hydroksypentyl)- østra- 1, 3, 5( 10)-trien- 17- on b) 3- benzyloxy- 7g-(5- hydroxypentyl)- estra- 1, 3, 5( 10)-trien- 17- one

En løsning av 7,26 g a-(5-acetoksypentyl)-3-benzyloksy-østra-l, 3,5(10)-trien-17-on i 80 ml metanol og 3 ml tetrahydrofuran, forsåpes med 22,2 ml 2 N natronlut over A solution of 7.26 g of α-(5-acetoxypentyl)-3-benzyloxy-estra-1, 3,5(10)-trien-17-one in 80 ml of methanol and 3 ml of tetrahydrofuran is saponified with 22.2 ml 2 N caustic soda over

natten ved romtemperatur. Reaksjonsløsningen helles over i 2 N saltsyre, ristes med etylacetat, den organiske fase vaskes med mettet koksaltløsning, tørkes over natriumsulfat og inndampes. Det oppnås 6,7 g 3-benzyloksy-7a-(5-hydroksypentyl)-østra-1,3,5(10)-trien-17-on som et skum. overnight at room temperature. The reaction solution is poured into 2 N hydrochloric acid, shaken with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. 6.7 g of 3-benzyloxy-7a-(5-hydroxypentyl)-estra-1,3,5(10)-trien-17-one are obtained as a foam.

c) 3- benzyloksy- 7g-( 5- tosyloksypentyl)- østra- 1, 3, 5( 10)-trien- 17- on c) 3- benzyloxy- 7g-(5- tosyloxypentyl)- estra- 1, 3, 5( 10)-trien- 17- one

Under betingelsene ifølge eksempel lo omsettes 6,5 g 3-benzyloksy-7o-(5-hydroksypentyl)-østra-1,3,5(10)-trien med 7,|4 g p-toluensulfonsyreanhydrid, opparbeides og kromatograferes på kiselgel med heksan/etylacetat. Det oppnås 7,45 g 3-benzyloksy-7o-(5-tosyloksypentyl)-østra-1,3,5(10)-trien-17-on som et skum. [0£]D<22> = +80,6 ° (c = 0,620 i kloroform). Under the conditions according to example 10, 6.5 g of 3-benzyloxy-7o-(5-hydroxypentyl)-estra-1,3,5(10)-triene are reacted with 7.|4 g of p-toluenesulfonic anhydride, worked up and chromatographed on silica gel with hexane/ethyl acetate. 7.45 g of 3-benzyloxy-70-(5-tosyloxypentyl)-estra-1,3,5(10)-trien-17-one are obtained as a foam. [0£]D<22> = +80.6° (c = 0.620 in chloroform).

d) 3- benzyloksy- 7a-{ 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluor-pentylt iometyl) pyrrolidin- 1- yl]- pentyl} østra-1, 3, 5( 10)- trien- 17- on d) 3- benzyloxy- 7a-{ 5-[( 2S )- 2-( 4, 4, 5, 5, 5- pentafluoro-pentyl iomethyl) pyrrolidin- 1- yl]-pentyl} estra-1, 3, 5 ( 10)- trien- 17- on

Under betingelsene ifølge eksempel 23h omsettes 4,58 g 3-benzyloksy-7a-(5-tosyloksypentyl)-østra-1,3,5(10)-trien-17-on med 3,17 g (2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl) pyrrol idin, opparbeides og råproduktet kromatograferes på kiselgel med heksan/etylacetat. Det oppnås 3,9 g 3-benzyloksy-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)-pyrrolidin-l-yl]-pentyl}østra-l,3,5(10)-trien-17-on som en olje. [0£]D<22> = +32 , 5 ° (c = 0,117 i kloroform). Under the conditions according to example 23h, 4.58 g of 3-benzyloxy-7a-(5-tosyloxypentyl)-estra-1,3,5(10)-trien-17-one are reacted with 3.17 g of (2S)-2-( 4,4,5,5,5-pentafluoropentylthiomethyl) pyrrolidine, is worked up and the crude product is chromatographed on silica gel with hexane/ethyl acetate. 3.9 g of 3-benzyloxy-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}oestra-1,3 are obtained ,5(10)-trien-17-one as an oil. [0£]D<22> = +32 , 5 ° (c = 0.117 in chloroform).

e) 3- hydroksy- 7a-( 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl) pyrrolidin- l- yl] - pentyl} østra- l, 3, 5( 10)-trien- 17- on e) 3- hydroxy- 7a-( 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluoropentylthiomethyl) pyrrolidin- 1- yl] - pentyl} estral- 1, 3, 5( 10) -trien- 17- Wed

Under betingelsene ifølge eksempel 6f debenzyleres 2,05 g 3-benzyloksy-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl) pyrrolidin-l-yl]-pentyl}østra-l,3,5(10)-trien-17-on. Det oppnås 1,25 g 3-hydroksy-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)pyrrolidin-l-yl]-pentyl}østra-l,3,5(10)-trien-17-on som en olje. [at]D22 = +22, 7 ° (c = 0,475 i kloroform). Under the conditions according to example 6f, 2.05 g of 3-benzyloxy-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]-pentyl}oestra- 1,3,5(10)-trien-17-one. 1.25 g of 3-hydroxy-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]-pentyl}oestra-1,3 are obtained, 5(10)-trien-17-one as an oil. [at]D22 = +22.7° (c = 0.475 in chloroform).

f) 7a-{5- [ ( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl)-pyrrolidin- l- yl] pentyl}- østra- 1, 3, 5( 10)- trien- 3, 170-diol f) 7a-{5- [ ( 2S)- 2-( 4, 4, 5, 5, 5- pentafluoropentylthiomethyl)-pyrrolidin- 1- yl] pentyl}- estra- 1, 3, 5( 10)- trien- 3, 170-diol

Under betingelsene ifølge eksempel 8 reduseres 500 mg 3-hydroksy-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl) pyrrolidin-l-yl]-pentyl}østra-l,3,5(10)-trien-17-on med 100 mg natriumborhydrid. Det oppnås 325 mg av tittelforbindelsen som en olje. [Qé]d22 = -8, 7 <0> (c = 0,510 i metanol). Under the conditions of Example 8, 500 mg of 3-hydroxy-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]-pentyl}oestra-1 is reduced, 3,5(10)-trien-17-one with 100 mg of sodium borohydride. 325 mg of the title compound are obtained as an oil. [Qe]d 22 = -8.7<0> (c = 0.510 in methanol).

Eksempel 22 Example 22

17a- metyl- 7g-{ 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl)-pyrrolidin- l- yl] pentyl}- østra- 1, 3, 5( 10)- trien- 3, 170- diol 17a- methyl- 7g-{ 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluoropentylthiomethyl)-pyrrolidin- 1- yl] pentyl}- estra- 1, 3, 5( 10)- triene-3, 170-diol

a) 7 a-( 5- klorpentyl)- 17a- metyl- østra- 1, 3, 5( 10)- trien-3, 170- diol a) 7a-(5-chloropentyl)-17a- methyl- estra- 1,3,5(10)-triene-3,170-diol

En suspensjon av 5,21 g vannfritt Cer(III)klorid i 53,2 ml tetrahydrofuran omrøres i 2 t ved romtemperatur, tildryppes ved 0 ° 7 ml av en metylmagnesiurnbromidløsning (3 M i dietyleter) og blandingen omrøres i 30 min ved 0 °C og i 15 min ved romtemperatur. En løsning av 1 g 7a-(5-klorpentyl)-3-hydroksy-østra-1,3,5(10)-trien-17-on (eksempel 15b) i 24 ml tetrahydrofuran tilsettes deretter og blandingen omrøres i ytterligere 30 min ved romtemperatur. Reaksjonsblandingen helles over i iskald, mettet ammoniumkloridløsning, ristes med etylacetat, den organiske fase tørkes over natriumsulfat og inndampes. Resten kromatograferes på kiselgel med heksan/etylacetat. Det oppnås 753 mg 7a-(5-klorpentyl)-17a-metyl-østra-1,3, 5 (10)-trien-3,170-diol som et skum. [a]D<22> = +27 , 3 ° (c = 0,515 i kloroform). A suspension of 5.21 g of anhydrous Cer(III) chloride in 53.2 ml of tetrahydrofuran is stirred for 2 h at room temperature, 7 ml of a methylmagnesium bromide solution (3 M in diethyl ether) is added dropwise at 0 ° and the mixture is stirred for 30 min at 0 ° C and for 15 min at room temperature. A solution of 1 g of 7a-(5-chloropentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one (Example 15b) in 24 ml of tetrahydrofuran is then added and the mixture is stirred for a further 30 min at room temperature. The reaction mixture is poured into ice-cold, saturated ammonium chloride solution, shaken with ethyl acetate, the organic phase is dried over sodium sulphate and evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate. 753 mg of 7α-(5-chloropentyl)-17α-methyl-estra-1,3,5(10)-triene-3,170-diol are obtained as a foam. [a]D<22> = +27 , 3 ° (c = 0.515 in chloroform).

b) 7 a-( 5- jodpentyl)- 17a- metyl- østra- l, 3, 5( 10)- trien-3, 170- diol b) 7a-(5-iodopentyl)-17a-methyl-estral-1,3,5(10)-triene-3,170-diol

En løsning av 735 mg 7a-(5-klorpentyl)-17a-metyl-østra-1,3,5(10)-trien-3,170-diol i 4 ml etylmetylketon tilsettes 5,6 g natriumjodid og oppvarmes i 17 t ved 80 °C badtemperatur. Reaksjonsblandingen helles over i vann, ristes med etylacetat, den organiske fase vaskes med mettet koksaltløs-ning, tørkes ver natriumsulfat og inndampes. Det oppnås 834 mg 7a-(5-jodpentyl)-17a-metyl-østra-1,3,5(10)-trien-3,170-diol som et skum. [or]D22 = +20,2 ° (c = 0,500 i kloroform). A solution of 735 mg of 7a-(5-chloropentyl)-17a-methyl-estra-1,3,5(10)-triene-3,170-diol in 4 ml of ethyl methyl ketone is added to 5.6 g of sodium iodide and heated for 17 h at 80 °C bath temperature. The reaction mixture is poured into water, shaken with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. 834 mg of 7α-(5-iodopentyl)-17α-methyl-estra-1,3,5(10)-triene-3,170-diol are obtained as a foam. [or]D22 = +20.2° (c = 0.500 in chloroform).

c) 17 a- metyl- 7a- f5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl) - pyrrolidin- l- yl] pentyl}- østra- 1, 3, 5( 10)-trien- 3, 170- diol c) 17a-methyl-7a-f5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]pentyl}-estra-1,3,5( 10 )-triene-3,170-diol

En løsning av 453 mg 7a-(5-jodpentyl)-17a-metyl-østra-1,3,5(10)-trien-3,170-diol og 390 mg (2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)-pyrrolidin i 8 ml N-metyl-2-pyrro-lidinon oppvarmes i 4 t ved 80 °C badtemperatur. Den avkjølte reaksjonsblanding helles over i mettet natriumhydrogenkarbo-natløsning, ristes med etylacetat, den organiske fase vaskes med mettet koksaltløsning, tørkes over natriumsulfat og inndampes. Bunnfallet kromatograferes på kiselgel med diklormetan/etylacetat. Det oppnås 413 mg av tittelforbindelsen som et skum. [a]D<22> = -25, 8 ° (c = 0,500 i kloroform). A solution of 453 mg of 7α-(5-iodopentyl)-17α-methyl-estra-1,3,5(10)-triene-3,170-diol and 390 mg of (2S)-2-(4,4,5,5 ,5-pentafluoropentylthiomethyl)-pyrrolidine in 8 ml of N-methyl-2-pyrrolidinone is heated for 4 hours at 80 °C bath temperature. The cooled reaction mixture is poured into saturated sodium hydrogen carbonate solution, shaken with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The precipitate is chromatographed on silica gel with dichloromethane/ethyl acetate. 413 mg of the title compound are obtained as a foam. [a]D<22> = -25.8° (c = 0.500 in chloroform).

Eksempel 23 Example 23

110- f luor- 7a- { 5- [ 2-( 4, 4, 5, 5, 5- pentaf luorpentyltiometyl) - pyrrolidin- l- yl] pentyl}- østra- l, 3, 5( 10)- trien- 3, 170- diol 110- f fluoro- 7a- { 5- [ 2-( 4, 4, 5, 5, 5- pentafluoropentylthiomethyl)- pyrrolidin- l- yl] pentyl}- estra- l, 3, 5( 10)- trien- 3, 170- diol

a) 7a-( 5- klorpentyl)- 110- fluor- østr- 4- en- 3, 17- dion a) 7a-(5-chloropentyl)-110-fluoro-estr-4-ene-3,17-dione

En løsning av 78,7 g 110-fluor-7a-(5-hydroksypentyl)-østr-4-en-3,17-dion (eksempel 12e) i 1,4 1 karbontetraklorid og 475 ml acetonitril omrøres med 71 g trifenylfosfin i 8,5 t ved romtemperatur. Blandingen ekstraheres deretter med vann, vandig natriumhydrogenkarbonat- og koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med heksan/eddikester. Det oppnås 48,0 g 7a-(5-klorpentyl)-110-fluor-østr-4-en-3,17-dion som krystaller med smp. 51-53 °C. [a]D<22> = +78,5 <0> (c =0,5 % i kloroform). A solution of 78.7 g of 110-fluoro-7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione (Example 12e) in 1.4 L of carbon tetrachloride and 475 ml of acetonitrile is stirred with 71 g of triphenylphosphine in 8.5 h at room temperature. The mixture is then extracted with water, aqueous sodium bicarbonate and sodium bicarbonate solution, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with hexane/acetic acid. 48.0 g of 7α-(5-chloropentyl)-110-fluoro-estr-4-ene-3,17-dione are obtained as crystals with m.p. 51-53 °C. [a]D<22> = +78.5 <0> (c =0.5% in chloroform).

b) 7 a-( 5- klorpentyl)- 110- fluor- 3- hydroksy- østra-1, 3, 5( 10)- trien- 17- on b) 7 a-(5-chloropentyl)-110-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one

Til en løsning av 47 g 7a-(5-klorpentyl)-110-fluor-østr-4-en-3,17-dion i 470 ml acetonitril tildryppes ved 80 °C badtemperatur, en løsning av 10,34 g litiumbromid og 53,2 g kopper(II)bromid i 280 ml acetonitril. Etter tilsetning i 20 min påventes avfarging av løsningen og resten av løsningen tilsettes i løpet av 12 min og blandingen omrøres i ytterligere 5 min ved 80 °C badtemperatur. Blandingen avkjøles deretter til 0 °C, tilsettes natriumhydrogenkarbonatløsning, helles over i vann, ekstraheres 4 ganger med eddikester, vaskes nøytral, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med heksan/eddikester. Det oppnås 25,3 g 7a-(5-klorpentyl)-110-fluor-3-hydroksy-østra-1,3,5(10)-trien-17-on. [a]D<22> = +115,4 <0> (c = 0,5 % i kloroform). A solution of 10.34 g of lithium bromide and 53 .2 g of copper(II) bromide in 280 ml of acetonitrile. After addition for 20 min, decolorization of the solution is awaited and the rest of the solution is added during 12 min and the mixture is stirred for a further 5 min at 80 °C bath temperature. The mixture is then cooled to 0 °C, sodium bicarbonate solution is added, poured into water, extracted 4 times with ethyl acetate, washed neutral, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with hexane/ethyl acetate. 25.3 g of 7α-(5-chloropentyl)-110-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one are obtained. [a]D<22> = +115.4 <0> (c = 0.5% in chloroform).

c) 110- fluor- 3- hydroksy- 7a-{ 5-[ 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl) - pyrrolidin- 1- yl] pentyl}- østra-1, 3, 5( 10)- trien- 17- on c) 110-fluoro-3-hydroxy-7a-{ 5-[ 2-( 4, 4, 5, 5, 5- pentafluoropentylthiomethyl) - pyrrolidin- 1- yl] pentyl}- estra-1, 3, 5( 10 )- trien- 17- on

En løsning av 785,9 mg 7a-(5-klorpentyl)-110-fluor-3-hydroksy-østra-1,3,5(10)-trien-17-on i 7 ml N-metyl-2-pyrro-lidinon tilsettes 535,5 mg litiumjodid og 520 mg (2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)-pyrrolidin og omrøres i 2,5 t ved 100 °C badtemperatur. Blandingen helles deretter over i vann, ekstraheres 3 ganger med dietyleter, vaskes nøytral, tørkes over natriumsulfat, inndampes i vakuum og kromatograf eres på kiselgel med diklormetan/metanol. Det oppnås 525 mg rent llp-fluor-3-hydroksy-7a-{5-[2-(4,4,5,5,5-pentafluorpentyltiometyl) -pyrrolidin-l-yl]pentyl}-østra-1,3,5(10)-trien-17-on. [ a] D22 = +29, 3 0 (c = 0,5 % i kloroform). A solution of 785.9 mg of 7α-(5-chloropentyl)-110-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one in 7 ml of N-methyl-2-pyrro- lidinone, 535.5 mg of lithium iodide and 520 mg of (2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidine are added and stirred for 2.5 h at 100 °C bath temperature. The mixture is then poured into water, extracted 3 times with diethyl ether, washed neutrally, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 525 mg of pure 11p-fluoro-3-hydroxy-7a-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]pentyl}-estra-1,3 are obtained, 5(10)-trien-17-one. [a] D22 = +29.30 (c = 0.5% in chloroform).

d) lip- fluor- 7g-{ 5-[ 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl) - pyrrolidin- l- yl] pentyl}- østra- 1, 3, 5( 10)- trien-3, 17- diol d) lip- fluoro- 7g-{ 5-[ 2-( 4, 4, 5, 5, 5- pentafluoropentylthiomethyl)- pyrrolidin- 1- yl] pentyl}- estra- 1, 3, 5( 10)- trien- 3, 17-diol

500 mg llp-fluor-3-hydroksy-7a-{5-[2-(4,4,5,5,5-pentafluorpentyltiometyl)-pyrrolidin-1-yl]pentyl}-østra-1,3,5(10)-trien-17-on oppløses i 5 ml tetrahydrofuran, 2,75 ml etanol og 1,1 ml vann og tilsettes ved 0 °C badtemperatur 100 mg natriumborhydrid og omrøres i 0,5 t ved romtemperatur. Blandingen helles deretter over i vann, ekstraheres 3 ganger med eddikester, vaskes nøytral med mettet koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograf eres på kiselgel med diklormetan/metanol. Det oppnås 441,3 mg llp-fluor-7a-{5-[2-(4,4,5,5,5-pentafluorpentyltiometyl) -pyrrolidin-l-yl]pentyl}-østra-1,3,5(10)-trien-3,17p-diol som krystaller med smp. 174-176 °C. [a]D<22> = -14,9 ° (c = 0,5 % i pyridin). 500 mg llp-fluoro-3-hydroxy-7a-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]pentyl}-estra-1,3,5(10 )-trien-17-one is dissolved in 5 ml of tetrahydrofuran, 2.75 ml of ethanol and 1.1 ml of water and 100 mg of sodium borohydride is added at 0 °C bath temperature and stirred for 0.5 h at room temperature. The mixture is then poured into water, extracted 3 times with ethyl acetate, washed neutrally with saturated sodium chloride solution, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 441.3 mg of llp-fluoro-7a-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]pentyl}-estra-1,3,5(10 )-triene-3,17p-diol as crystals with m.p. 174-176 °C. [a]D<22> = -14.9° (c = 0.5% in pyridine).

Eksempel 24 Example 24

llp- fluor-17 g- metyl- 7g- f5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl) - pyrrolidin- l- yl] pentyl}- østra- 1, 3, 5( 10)- trien- 3, 17p-diol llp- fluoro-17g- methyl- 7g- f5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluoropentylthiomethyl) - pyrrolidin- 1- yl] pentyl}- estra- 1, 3, 5 ( 10)-triene-3, 17p-diol

a) 7 a-( 5- klorpentyl)-llp- fluor-17 a- metyl- østra-1, 3, 5( 10)- trien- 3, 17p- diol a) 7 a-(5-chloropentyl)-llp-fluoro-17 a- methyl- estra-1, 3, 5( 10)- trien- 3, 17p- diol

Under betingelsene ifølge eksempel 28a omsettes Under the conditions according to example 28a is converted

750 mg 7a-(5-klorpentyl)-lip-fluor-3-hydroksy-østra-l,3,5(10)-trien-17-on (eksempel 29b) med 4,9 ml metylmagnesiumbromidløs-ning (3 M i dietyleter), opparbeides og kromatograferes. Det oppnås 561 mg 7a-(5-klorpentyl)-lip-fluor-17a-metyl-østra-1,3,5 (10)-trien-3,17p-diol som et skum. [Qé]d22 = +51, 6 <0> (c = 0,515 i kloroform). 750 mg of 7a-(5-chloropentyl)-lip-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one (Example 29b) with 4.9 ml of methylmagnesium bromide solution (3 M in diethyl ether), worked up and chromatographed. 561 mg of 7α-(5-chloropentyl)-lip-fluoro-17α-methyl-estra-1,3,5 (10)-triene-3,17β-diol are obtained as a foam. [Qé]d22 = +51.6<0> (c = 0.515 in chloroform).

b) lip- fluor-17 a- metyl- 7g- f5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl)- pyrrolidin- l- yl] pentyl}- østra-1, 3, 5( 10)- trien- 3, 170- diol b) lip-fluoro-17α-methyl-7g-f5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]pentyl}-oestra-1,3 , 5( 10)- triene- 3, 170- diol

Under betingelsene ifølge eksempel 15f omsettes 408 mg 7a-(5-klorpentyl)-110-fluor-17a-metyl-østra-l,3,5(10)-trien-3,170-diol i 5 ml N-metyl-2-pyrrolidinon i nærvær av 130 mg litiumjodid, med 606 mg (2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl) -pyrrolidin, opparbeides og kromatograferes. Det oppnås 326 mg av tittelforbindelsen som krystaller med smp. 120-121 °c. [a]D<22>= -5, 8 <0> (c = 0,535 % i kloroform). Under the conditions according to example 15f, 408 mg of 7a-(5-chloropentyl)-110-fluoro-17a-methyl-oestra-1,3,5(10)-triene-3,170-diol are reacted in 5 ml of N-methyl-2-pyrrolidinone in the presence of 130 mg of lithium iodide, with 606 mg of (2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidine, is worked up and chromatographed. 326 mg of the title compound are obtained as crystals with m.p. 120-121 °c. [a]D<22>= -5.8 <0> (c = 0.535% in chloroform).

Eksempel 25 Example 25

3, 17ø- diacetoksy-l10- fluor-17a- metyl- 7a- f5-[( 2S)- 2-( 4, 4, 5, 5, 5-pentafluorpentansulfonylmetyl) pyrrolidin- 1- yl] pentyl}- østra-1, 3, 5( 10)- trien 3, 17ø- diacetoxy-110- fluoro-17a- methyl- 7a- f5-[( 2S)- 2-( 4, 4, 5, 5, 5-pentafluoropentanesulfonylmethyl) pyrrolidin- 1- yl] pentyl}- estra-1 , 3, 5( 10)- the trien

Under betingelsene ifølge eksempel 3 acetyleres 65 mg 110-fluor-17a-metyl-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl) -pyrrolidin-l-yl]pentyl}-østra-l,3,5(10)-trien-3,170-diol (eksempel 31b) med acetanhydrid og råproduktet oksideres som beskrevet i eksempel 4 med natriumperborat-tetrahydrat, opparbeides og kromatograferes. Det oppnås 27 mg av tittelforbindelsen som en olje. Under the conditions of Example 3, 65 mg of 110-fluoro-17a-methyl-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]pentyl} is acetylated -estra-1,3,5(10)-triene-3,170-diol (Example 31b) with acetic anhydride and the crude product is oxidized as described in Example 4 with sodium perborate tetrahydrate, worked up and chromatographed. 27 mg of the title compound are obtained as an oil.

Eksempel 26 Example 26

7 a-( 5-[( 2S)-2 -( 4, 4, 5, 5, 5- pentafluorpentansulfinylmetyl)- pyrrolidin- l- yl] pentyl)- østra- 1, 3, 5( 10)- trien- 3, 170- diol 7. , 170-diol

Ved oksidasjon med natriumperjodat oppnås det, som beskrevet i eksempel 2, fra 152 mg 7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)-pyrrolidin-l-yl]pentyl}-østra-1,3,5(10)-trien-3,170-diol (eksempel 26f), 66 mg av tittelforbindelsen som en olje. [<g>j]d<22> = +11/ 8 0 (c = 0,53 % i metanol) . By oxidation with sodium periodate, it is obtained, as described in example 2, from 152 mg of 7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]pentyl} -estra-1,3,5(10)-triene-3,170-diol (Example 26f), 66 mg of the title compound as an oil. [<g>j]d<22> = +11/ 8 0 (c = 0.53% in methanol) .

Eksempel 27 Example 27

7g-{ 5-[( 2S)-2-( 4, 4, 5, 5, 5- pentafluorpentansulfonylmetyl)- pyrrolidin- l- yl] pentyl} - østra- 1, 3, 5 ( 10)- trien- 3, 170- diol 7g-{ 5-[( 2S)-2-( 4, 4, 5, 5, 5- pentafluoropentanesulfonylmethyl)- pyrrolidin- 1- yl] pentyl}- estra- 1, 3, 5 ( 10)- trien- 3, 170-diol

Under betingelsene ifølge eksempel 3 acetyleres 76 mg 7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)-pyrrolidin-1-yl]pentyl}-østra-1,3,5(10)-trien-3,170-diol (eksempel 26f) , med acetanhydrid og råproduktet oksideres som beskrevet i eksempel 4 med natriumperborat-tetrahydrat, opparbeides og kromatograferes. Det oppnås 31 mg av tittelforbindelsen som en olje. [a]D<22> = +3 0,6 ° (c = 0,515 % i metanol) . Under the conditions according to example 3, 76 mg of 7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]pentyl}-estra-1,3,5 (10)-triene-3,170-diol (example 26f), with acetic anhydride and the crude product is oxidized as described in example 4 with sodium perborate tetrahydrate, worked up and chromatographed. 31 mg of the title compound are obtained as an oil. [a]D<22> = +3 0.6° (c = 0.515% in methanol) .

Eksempel 28 Example 28

lip- fluor- 17a- metyl- 7g- f5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propylamino] pentyl } - østra- 1 , 3 , 5 ( 10) - trien- 3, 17j3- diol lip- fluoro- 17a- methyl- 7g- f5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio) propylamino] pentyl } - estra- 1, 3 , 5 ( 10) - triene-3, 17j3-diol

a) lip- fluor- 3- hydroksy- 17a- metyl- 7a-( 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio)- propylamino] pentyl}-østra- 1, 3, 5( 10)- trien- 17- on a) lip- fluoro- 3- hydroxy- 17a- methyl- 7a-( 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio)- propylamino] pentyl}- estra- 1 , 3, 5( 10)- trien- 17- on

En løsning av 2,0 g lip-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentyltio)propylamino]pentyl}-3 -(tetra-hydrapyran-2-yloksy)-østra-1,3,5(10)-trien-17-on i 20 ml metanol og 2 ml vann omrøres ved romtemperatur med 1,2 g oksalsyre. Etter 2,5 t helles blandingen over på isvann, ekstraheres med diklormetan, vaskes med mettet koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograf eres på kiselgel med diklormetan/metanol. Det oppnås 1,2 g lip-fluor-3-hydroksy-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)-propylamino]pentyl}-østra-1,3,5(10)-trien-17-on som et skum. [0£]D22 = +69 ° (c = 0,5 % i kloroform). A solution of 2.0 g of lip-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]pentyl}-3-(tetra- hydrapyran-2-yloxy)-estra-1,3,5(10)-trien-17-one in 20 ml of methanol and 2 ml of water is stirred at room temperature with 1.2 g of oxalic acid. After 2.5 h, the mixture is poured over ice water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 1.2 g of lip-fluoro-3-hydroxy-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]pentyl} are obtained -estra-1,3,5(10)-trien-17-one as a foam. [0£]D22 = +69° (c = 0.5% in chloroform).

b) 1ip- fluor- 17a- metyl- 7g- f 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5-pentafluorpentyltio) propylamino] pentyl}- østra-1, 3, 5( 10)- trien- 3, 17p- diol b) 1ip- fluoro- 17a- methyl- 7g- f 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5-pentafluoropentylthio) propylamino] pentyl}- estra-1, 3, 5( 10)-triene-3, 17p-diol

Til 5 g llp-fluor-3-hydroksy-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)-propylamino]pentyl}-østra-1,3,5(10)-trien-17-on i 150 ml tetrahydrofuran, tildryppes ved romtemperatur, 33 ml av en 1,6 molar eterisk litium-metylatløsning. Etter 2,5 t tilsettes under isavkjøling, mettet ammoniumkloridløsning, blandingen ekstraheres med eddikester, vaskes med mettet koksaltløsning, tørkes over natriumsulfat og inndampes i vakuum. Etter kromatografi på kiselgel, inneholdende 2 % trietylamin, med diklormetan/metanol, oppnås 2,0 g lip-fluor-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-1,3,5(10)-trien-3,17p-diol som krystaller med smp. 83 °C. To 5 g of llp-fluoro-3-hydroxy-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]pentyl}-estra- 1,3,5(10)-trien-17-one in 150 ml of tetrahydrofuran, at room temperature, is added dropwise 33 ml of a 1.6 molar ethereal lithium methylate solution. After 2.5 h, saturated ammonium chloride solution is added under ice cooling, the mixture is extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. After chromatography on silica gel, containing 2% triethylamine, with dichloromethane/methanol, 2.0 g of lip-fluoro-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5 ,5-pentafluoropentylthio)propylamino]pentyl}-estra-1,3,5(10)-triene-3,17p-diol as crystals with m.p. 83 °C.

Eksempel 29 Example 29

110- fluor- 17o- metyl- 7a-{ 5- [ N- metyl- N- 3- ( 4, 4, 5, 5, 5- pentaf luor-pentansulf inyl) propylamino] pentyl}- østra- 1, 3, 5( 10)- trien-3, 170- diol 110- fluoro- 17o- methyl- 7a-{ 5- [ N- methyl- N- 3- ( 4, 4, 5, 5, 5- pentafluoro-pentanesulfinyl) propylamino] pentyl}- estra- 1, 3, 5(10)-triene-3,170-diol

En løsning av 500 mg 110-fluor-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-østra-1,3,5(10)-trien-3,170-diol i 20 ml metanol og 0,9 ml vann, omrøres ved romtemperatur med 355 mg natriumperjodat i 3 t. Blandingen helles deretter over på isvann, ekstraheres med diklormetan, vaskes med mettet koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 216 mg 110-fluor-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentan-sulf inyl) propylamino] pentyl} -østra-1, 3, 5 (10)-trien-3,170-diol som krystaller med smp. 83,4 °C. A solution of 500 mg of 110-fluoro-17α-methyl-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-estra-1,3 ,5(10)-triene-3,170-diol in 20 ml of methanol and 0.9 ml of water, stirred at room temperature with 355 mg of sodium periodate for 3 h. The mixture is then poured onto ice water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over sodium sulphate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 216 mg of 110-fluoro-17α-methyl-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentane-sulfinyl)propylamino]pentyl}-estra-1 are obtained , 3, 5 (10)-triene-3,170-diol as crystals with m.p. 83.4 °C.

Eksempel 30 Example 30

110- fluor- 17a- metyl- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluor-pentansulf onyl) propylamino] pentyl}- østra- 1, 3, 5( 10)- trien-3, 170- diol 110- fluoro- 17a- methyl- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoro-pentanesulfonyl) propylamino] pentyl}- estra- 1, 3, 5 (10)-triene-3, 170-diol

a) 110- fluor- 3- hydroksy- 17a- metyl- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentansulfonyl) propylamino]-pentyl}- østra- 1, 3, 5( 10)- trien- 17- on a) 110- fluoro- 3- hydroxy- 17a- methyl- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentanesulfonyl) propylamino]-pentyl}- estra- 1 , 3, 5( 10)- trien- 17- on

En løsning av 3 g 7a-(5-klorpentyl)-110-fluor-3-hydroksy-østra-1,3,5(10)-trien-17-on i 50 ml dimetylformamid omrøres med 1,6 g litiumjodid og 6,2 g metyl-[3-(4,4,5,5,5-pentafluorpentansulfonyl)propyl]amin i 22 t ved 100 °C. Blandingen ekstraheres deretter med eddikester, vaskes med mettet koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 4,5 g 110-fluor-3-hydroksy-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfonyl)propylamino]pentyl}-østra-1,3,5(10)-trien-17-on som et skum. A solution of 3 g of 7a-(5-chloropentyl)-110-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one in 50 ml of dimethylformamide is stirred with 1.6 g of lithium iodide and 6 .2 g of methyl-[3-(4,4,5,5,5-pentafluoropentanesulfonyl)propyl]amine for 22 h at 100 °C. The mixture is then extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 4.5 g of 110-fluoro-3-hydroxy-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)propylamino]pentyl}- are obtained estra-1,3,5(10)-trien-17-one as a foam.

b) 110- fluor- 17a- metyl- 7g- f5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5-pentafluorpentansulfonyl) propylamino] pentyl}- østra-1, 3, 5( 10)- trien- 3, 170- diol b) 110- fluoro- 17a- methyl- 7g- f5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5-pentafluoropentanesulfonyl) propylamino] pentyl}- estra-1, 3, 5( 10 )- trien- 3, 170- diol

En suspensjon av 11,4 g vannfritt Cer(III)klorid i 120 ml tetrahydrofuran omrøres i 2 t ved romtemperatur under nitrogen, tilsettes ved 0 °C dråpevis 17,5 ml av en 3 molar eterisk metylmagnesiumbromidløsning, omrøres i 30 min, tilsettes en løsning av 3,5 g 110-fluor-3-hydroksy-17o-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfonyl)propylamino] pentyl}-østra-1,3,5(10)-trien-17-on i 24 ml tetrahydrofuran og omrøres i ytterligere 30 min. Blandingen tilsettes deretter mettet ammoniumkloridløsning, fortynnes med eddikester, vaskes med mettet koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 110-fluor-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfonyl)propylamino]-pentyl}-østra-1,3,5(10)-trien-3,170-diol som krystaller med smp. 82,5 °C. A suspension of 11.4 g of anhydrous Cer(III) chloride in 120 ml of tetrahydrofuran is stirred for 2 h at room temperature under nitrogen, 17.5 ml of a 3 molar ethereal methylmagnesium bromide solution is added dropwise at 0 °C, stirred for 30 min, a solution of 3.5 g of 110-fluoro-3-hydroxy-17o-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)propylamino]pentyl}- estra-1,3,5(10)-trien-17-one in 24 ml of tetrahydrofuran and stirred for a further 30 min. The mixture is then added to saturated ammonium chloride solution, diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 110-fluoro-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)propylamino]-pentyl}-estra-1,3,5 (10)-triene-3,170-diol as crystals with m.p. 82.5 °C.

Rksempel 31 Example 31

110- fluor- 7g-{ 5-[ N- metyl- N- 2-( 4, 4, 5, 5, 5- pentafluorpentansulfonyl) etylamino] pentyl}- østra- 1, 3, 5( 10)- trien- 3, 170- diol 110- fluoro- 7g-{ 5-[ N- methyl- N- 2-( 4, 4, 5, 5, 5- pentafluoropentanesulfonyl) ethylamino] pentyl}- estra- 1, 3, 5( 10)- trien- 3 , 170-diol

a) 7 g-( 5- brompentyl)- 110- fluor- østr- 4- en- 3, 17- dion a) 7 g-(5-bromopentyl)-110-fluoro-estr-4-ene-3,17-dione

En løsning av 33 g 110-fluor-7a-(5-hydroksypentyl)-østr-4-en-3,17-dion i 330 ml diklormetan tilsettes ved -5 °C 28,9 g trifenylfosfin og 36,7 g karbontetrabromid og omrøres i 0,5 t. Blandingen tilsettes deretter diklormetan og vaskes med vann, mettet natriumhydrogenkarbonat- og koksaltløsning. A solution of 33 g of 110-fluoro-7a-(5-hydroxypentyl)-estr-4-ene-3,17-dione in 330 ml of dichloromethane is added at -5 °C to 28.9 g of triphenylphosphine and 36.7 g of carbon tetrabromide and stirred for 0.5 h. Dichloromethane is then added to the mixture and washed with water, saturated sodium bicarbonate and sodium bicarbonate solution.

Den organiske fase tørkes over natriumsulfat og inndampes i vakuum. Råproduktet kromatograferes deretter på kiselgel med en heksan-eddikestergradient. Det oppnås 28,5 g 7o-(5-brom-pentyl) -110-f luor-østr-4-en-3 , 17-dion med smp. 75-76 °C. The organic phase is dried over sodium sulfate and evaporated in vacuo. The crude product is then chromatographed on silica gel with a hexane-acetic ester gradient. 28.5 g of 7o-(5-bromo-pentyl)-110-fluoro-estr-4-ene-3,17-dione with m.p. 75-76 °C.

b) 7q-( 5- brompentyl)- 110- fluor- 3- hydroksy- østra-1, 3, 5( 10)- trien- 17- on b) 7q-(5- bromopentyl)- 110- fluoro- 3- hydroxy- estra-1, 3, 5( 10)- trien- 17- one

Til 27,8 g 7a-(5-brompentyl)-llø-fluor-østr-4-en-3,17-dion i 190 ml acetonitril tilsettes ved 80 °C, 17,0 g kopper(II)bromid. Etter 8 t innrøres reaksjonsblandingen i vann, ekstraheres 3 ganger med eddikester, 2 ganger med ammo-niumklorid, vaskes med natriumhydrogenkarbonat og koksalt, tørkes og inndampes i vakuum. Etter kromatografering av råproduktet på kiselgel med en heksan-eddikestergradient, oppnås 20,4 g 7o-(5-brompentyl)-110-fluor-3-hydroksy-østra-1,3,5(10)-trien-17-on som fargeløse krystaller med smp. 178 °C. To 27.8 g of 7a-(5-bromopentyl)-yl-fluoro-estr-4-ene-3,17-dione in 190 ml of acetonitrile is added at 80 °C, 17.0 g of copper (II) bromide. After 8 h, the reaction mixture is stirred in water, extracted 3 times with acetic acid, 2 times with ammonium chloride, washed with sodium bicarbonate and common salt, dried and evaporated in vacuo. After chromatography of the crude product on silica gel with a hexane-acetic ester gradient, 20.4 g of 7o-(5-bromopentyl)-110-fluoro-3-hydroxy-estran-1,3,5(10)-trien-17-one are obtained as colorless crystals with m.p. 178 °C.

c) 7a-( 5- brompentyl)- 110- fluor- østra- 1, 3, 5( 10)- trien-3, 170- diol c) 7a-(5- bromopentyl)- 110- fluoro- estra- 1, 3, 5( 10)- trien-3, 170- diol

En løsning av 16,2 g 7a-(5-brompentyl)-110-fluor-3-hydroksy-østra-1,3,5(10)-trien-17-on i 162 ml tetrahydrofuran, samt 90 ml etanol og 3 6 ml vann, tilsettes porsjonsvis ved 0 °C 4,7 g natriumborhydrid og omrøres i 2 t ved 0 °C. Blandingen helles deretter over i vann, ekstraheres 4 ganger med eddikester, vaskes med vann og koksaltløsning, tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 17,1 g råprodukt. Etter kromatografi å kiselgel med heksan/eddikester, oppnås 15,6 g ren 7a-(5-brompentyl)-110-fluor-østra-1,3,5(10)-trien-3,170-diol. A solution of 16.2 g of 7a-(5-bromopentyl)-110-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one in 162 ml of tetrahydrofuran, as well as 90 ml of ethanol and 3 6 ml of water, 4.7 g of sodium borohydride are added in portions at 0 °C and stirred for 2 h at 0 °C. The mixture is then poured into water, extracted 4 times with vinegar, washed with water and sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. 17.1 g of crude product is obtained. After chromatography on silica gel with hexane/acetic ester, 15.6 g of pure 7α-(5-bromopentyl)-110-fluoro-estra-1,3,5(10)-triene-3,170-diol are obtained.

d) 110- fluor- 7a-[ 5-( metylamino)- pentyl] østra- 1, 3, 5( 10)-trien- 3, 170- diol d) 110-fluoro-7a-[5-(methylamino)-pentyl] estradiol-1,3,5(10)-triene-3,170-diol

En løsning av 2 g 7a-(5-brompentyl)-110-fluor-østra-l,3,5(10)-trien-3,170-diol i 20 ml dimetylformamid omrøres med 8 ml av en 40 % vandig metylaminløsning i 3,5 t ved 80 °C. Blandingen helles deretter over i vann, ekstraheres 3 ganger med eddikester, vaskes med vann og koksaltløsning, tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 1,77 g 110-fluor-7a-[5-(metylamino)-pentyl]østra-1,3,5(10)-trien-3,170-diol . A solution of 2 g of 7α-(5-bromopentyl)-110-fluoro-estra-1,3,5(10)-triene-3,170-diol in 20 ml of dimethylformamide is stirred with 8 ml of a 40% aqueous methylamine solution in 3, 5 h at 80 °C. The mixture is then poured into water, extracted 3 times with vinegar, washed with water and sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. 1.77 g of 110-fluoro-7a-[5-(methylamino)-pentyl]estra-1,3,5(10)-triene-3,170-diol are obtained.

e) 110- fluor- 7g-{ 5-[N-metyl-N-2-( 4, 4, 5, 5, 5- pentafluor-pentansulf onyl) etylamino] pentyl}- østra- 1, 3 , 5( 10) - e) 110-fluoro-7g-{ 5-[N-methyl-N-2-( 4, 4, 5, 5, 5-pentafluoro-pentanesulfonyl) ethylamino] pentyl}- estra- 1, 3 , 5( 10 ) -

trien- 3, 170- diol triene-3, 170-diol

En løsning av 440 mg 110-fluor-7g<->[5-(metylamino)-pentyl]østra-1,3,5(10)-trien-3,170-diol i 15 ml metanol om-røres med 500 mg 4,4,5,5,5-pentafluorpentylvinylsulfon ilt ved 90 °C. Blandingen helles deretter over i vann, ekstraheres 3 ganger med eddikester, vaskes med vann og koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 488 mg 110-fluor-7o-{5-[N-metyl-N-2-(4,4,5,5,5-pentafluorpentansulfonyl)etylamino]pentyl}-østra-1,3,5(10)-trien-3,170-diol som krystaller med smp. 74-76 °C. A solution of 440 mg of 110-fluoro-7g<->[5-(methylamino)-pentyl]estra-1,3,5(10)-triene-3,170-diol in 15 ml of methanol is stirred with 500 mg of 4, 4,5,5,5-pentafluoropentylvinylsulfone oxygen at 90 °C. The mixture is then poured into water, extracted 3 times with acetic acid, washed with water and sodium chloride solution, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 488 mg of 110-fluoro-7o-{5-[N-methyl-N-2-(4,4,5,5,5-pentafluoropentanesulfonyl)ethylamino]pentyl}-estra-1,3,5(10) are obtained -triene-3,170-diol as crystals with m.p. 74-76 °C.

Det avbeskyttede mellomprodukt 12k) har sterk anti-østrogen virkning: Eksempel 32 The deprotected intermediate 12k) has a strong anti-estrogenic effect: Example 32

110- fluor- 7a-{ 5-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio)-propylamino] pentyl}- 3- hydroksy- østra- l, 3, 5( 10)- trien- 17 on 110- fluoro- 7a-{ 5-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio)-propylamino] pentyl}- 3- hydroxy- estra- l, 3, 5( 10 )- trien- 17 on

En løsning av 1,6 g 110-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]pentyl}-3-(tetra-hydrapyran-2-yloksy)-østra-1,3,5(10)-trien-17 on i 20 ml metanol og 2 ml vann omrøres med 1,0 g oksalsyre. Etter 3 t tilsettes reaksjonsblandingen til is-vann. Blandingen ekstraheres med metylenklorid, vaskes med mettet natriumkloridløsning, tørkes og inndampes i vakuum. Etter kromatografering av råproduktet på kiselgel med en metylenklorid-metanolgradient oppnås 1,1 g 110-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)-propylamino]pentyl}-3-hydroksy-østra-1,3,5 (10)-trien-17 on..9 = +69 <0> (c = 0,5 % i kloroform). A solution of 1.6 g of 110-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-3-(tetra-hydrapyran- 2-yloxy)-estra-1,3,5(10)-trien-17-one in 20 ml of methanol and 2 ml of water is stirred with 1.0 g of oxalic acid. After 3 h, the reaction mixture is added to ice-water. The mixture is extracted with methylene chloride, washed with saturated sodium chloride solution, dried and evaporated in vacuo. After chromatography of the crude product on silica gel with a methylene chloride-methanol gradient, 1.1 g of 110-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino] is obtained pentyl}-3-hydroxy-estra-1,3,5 (10)-trien-17 one..9 = +69 <0> (c = 0.5% in chloroform).

Eksempel 33 Example 33

110- fluor- 7a-{ 6-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio)-propylamino] heksyl}- østra- 1, 3, 5( 10)- trien- 3, 170- diol 110- fluoro- 7a-{ 6-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio)-propylamino] hexyl}- estra- 1, 3, 5( 10)- trien- 3, 170- diol

a) 7a-( 6- klorheksyl)- 110- fluor- østr- 4- en- 3, 17- dion a) 7a-(6-chlorohexyl)-110-fluoro-estr-4-ene-3,17-dione

Til en suspensjon av 6,8 g magnesiumspon i 100 ml THF To a suspension of 6.8 g of magnesium shavings in 100 ml of THF

tilsettes under nitrogen, først 30 ml av en løsning av 41 ml l-brom-6-klor-heksan i 270 ml THF. Etter at reaksjonen er startet blir resten av løsningen tildryppet slik at den indre temperatur ikke overskrider 35 °C. I en annen kolbe blir det til en suspensjon av 26,4 g kopper(I)jodid i 120 ml THF ved 0 °C, tilsatt 48,1 g litiumbromid, hvorved den indre temperatur stiger til 40 °C. Uten avkjøling tilsettes nå 46,4 ml 1,3-dimetyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-on og blandingen omrøres i 30 min ved 40 °C. Det oppnås en klar løsning som tildryppes til Grignard-løsningen avkjølt til -40 °C. Blandingen omrøres deretter i 30 min ved -3 0 °C og tilsettes ved -50 °C dråpevis en løsning av 23,5 g 110-fluor-østra-4,6-dien-3,17-dion i 230 ml THF, 24,6 ml 1,3-dimetyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-on og 55 ml trimetylklorsilan, slik at den indre temperatur ikke overskrider -40 °C. Blandingen omrøres ved denne temperatur ilt, tildryppes deretter 32 is added under nitrogen, first 30 ml of a solution of 41 ml of 1-bromo-6-chloro-hexane in 270 ml of THF. After the reaction has started, the rest of the solution is dripped in so that the internal temperature does not exceed 35 °C. In another flask, 48.1 g of lithium bromide is added to a suspension of 26.4 g of copper(I) iodide in 120 ml of THF at 0 °C, whereby the internal temperature rises to 40 °C. Without cooling, 46.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one are now added and the mixture is stirred for 30 minutes at 40 °C. A clear solution is obtained which is added dropwise to the Grignard solution cooled to -40 °C. The mixture is then stirred for 30 min at -30 °C and a solution of 23.5 g of 110-fluoro-estra-4,6-diene-3,17-dione in 230 ml of THF is added dropwise at -50 °C, 24 .6 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 55 ml of trimethylchlorosilane, so that the internal temperature does not exceed -40 °C. The mixture is stirred at this temperature with oxygen, then 32 is added drop by drop

ml iseddik, kuldebadet fjernes og blandingen omrøres ilt ved romtemperatur. For opparbeidelse blir reaksjonsblandingen helt over i 1,5 1 vann, fortynnes med den samme mengde eddikester, bunnfallet separeres over celitt, vaskes med eddikester, den vandige fase ekstraheres 3. ganger med eddikester, vaskes med natriumhydrogenkarbonat- og koksaltløsning, tørkes over magnesiumsulfat og inndampes i vakuum. Etter kromatografering av råproduktet på kiselgel med en heksan-eddikestergradient, oppnås 25,2 g 7a-(6-klorheksyl)-110-fluor-østr-4-en-3,17-dion. ml of glacial acetic acid, the cold bath is removed and the mixture is stirred in oxygen at room temperature. For work-up, the reaction mixture is completely poured into 1.5 1 water, diluted with the same amount of ethyl acetate, the precipitate is separated over celite, washed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuum. After chromatography of the crude product on silica gel with a hexane-acetic ester gradient, 25.2 g of 7α-(6-chlorohexyl)-110-fluoro-estr-4-ene-3,17-dione are obtained.

b) 7 a-( 6- klorheksyl)- 110- fluor- 3- hydroksy- østra-1, 3, 5( 10)- trien- 17- on b) 7 a-(6-chlorohexyl)-110-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one

Til 25,2 g 7a-(6-klorheksyl)-110-fluor-østr-4-en-3,17-dion i 175 ml vannfri acetonitril, tilsettes ved 80 °C 28,1 g kopper(II)bromid og 5,4 g litiumbromid i 105 ml vannfri acetonitril. Etter 15 min avkjøles reaksjonsblandingen til 0 °C og tildryppes 250 ml mettet natriumhydrogenkarbonatløsning. Løsningen innrøres deretter ill vann, bringes til pH = 6 med 2 N saltsyre, ekstraheres 3 ganger med eddikester, vaskes med koksaltløsning, tørkes over magnesiumsulfat og inndampes i vakuum. Kromatografi av råproduktet på kiselgel med en heksan-eddikestergradient, gir 5,7 g 7a-(6-klorheksyl)-110-fluor-3-hydroksy-østra-1,3,5(10)-trien-17-on som et skum. To 25.2 g of 7a-(6-chlorohexyl)-110-fluoro-estr-4-ene-3,17-dione in 175 ml of anhydrous acetonitrile, add at 80 °C 28.1 g of copper(II) bromide and 5 .4 g of lithium bromide in 105 ml of anhydrous acetonitrile. After 15 min, the reaction mixture is cooled to 0 °C and 250 ml of saturated sodium bicarbonate solution are added dropwise. The solution is then stirred into cold water, brought to pH = 6 with 2 N hydrochloric acid, extracted 3 times with acetic acid, washed with sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. Chromatography of the crude product on silica gel with a hexane-acetic ester gradient gives 5.7 g of 7α-(6-chlorohexyl)-110-fluoro-3-hydroxy-estran-1,3,5(10)-trien-17-one as a foam.

c) 110- fluor- 3- hydroksy-7 a-( 6- jodheksyl)-østra-1, 3, 5( 10)- trien- 17- on c) 110-fluoro-3-hydroxy-7a-(6-iodohexyl)-estra-1,3,5(10)-trien-17-one

2,7 g 7a-(6-klorheksyl)-110-fluor-3-hydroksy-østra-1,3,5(10)-trien-17-on oppløses i 40 ml etylmetylketon, tilsettes 3,0 g natriumjodid og omrøres over natten ved 90 °C badtemperatur. For opparbeidelse avkjøles reaksjonsblandingen til romtemperatur, innrøres i vann, ekstraheres 3 ganger med eddikester, vaskes med koksaltløsning, tørkes over magnesiumsulfat og inndampes i vakuum. Det oppnås 3,4 g 110-fluor-3-hydroksy-7a-(6-jodheksyl)-østra-1,3,5(10)-trien-17-on som råprodukt som anvendes i det neste trinn uten ytterligere ren-sing. Dissolve 2.7 g of 7a-(6-chlorohexyl)-110-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one in 40 ml of ethyl methyl ketone, add 3.0 g of sodium iodide and stir overnight at 90 °C bath temperature. For workup, the reaction mixture is cooled to room temperature, stirred in water, extracted 3 times with vinegar, washed with sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. 3.4 g of 110-fluoro-3-hydroxy-7a-(6-iodohexyl)-estra-1,3,5(10)-trien-17-one are obtained as crude product which is used in the next step without further purification sing.

d) 110- fluor- 3- hydroksy-7 a- f6-[ N- metyl- N- 3-( 4, 4, 5, 5, 5-pentafluorpentyltio) propylamino] heksyl}- østra- d) 110- fluoro- 3- hydroxy-7 a- f 6-[ N- methyl- N- 3-( 4, 4, 5, 5, 5-pentafluoropentylthio) propylamino] hexyl}- estra-

1, 3, 5( 10)- trien- 17- on 1, 3, 5( 10)- trien- 17- on

2,5 g 110-fluor-3-hydroksy-7a-(6-jodheksyl)-østra-1,3,5(10)-trien-17-on i 20 ml vannfritt DMF omrøres ved 100 badtemperatur med 2,0 g metyl-[3-(4,4,5,5,5-pentafluorpentyltio) propyl] amin. Etter 2 t helles reaksjonsløsningen over i halvmettet natriumhydrogenkarbonatløsning, ekstraheres 3 ganger med metylenklorid, tørkes over magnesiumsulfat og inndampes i vakuum. Resten kromatograferes på kiselgel med en metylenklorid-metanolgradient. Det oppnås 3,15 g llp-fluor-3-hydroksy-7a-{6-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]heksyl}-østra-1,3,5(10)-trien-17 -on som et skum. 2.5 g of 110-fluoro-3-hydroxy-7a-(6-iodohexyl)-estra-1,3,5(10)-trien-17-one in 20 ml of anhydrous DMF are stirred at 100 bath temperature with 2.0 g methyl-[3-(4,4,5,5,5-pentafluoropentylthio)propyl]amine. After 2 h, the reaction solution is poured into half-saturated sodium bicarbonate solution, extracted 3 times with methylene chloride, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with a methylene chloride-methanol gradient. 3.15 g of llp-fluoro-3-hydroxy-7a-{6-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]hexyl}-estra-1 are obtained, 3,5(10)-trien-17-one as a foam.

e) llp- fluor- 7a- f 6-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) - propylamino] heksyl}- østra- 1, 3, 5( 10)- trien-3, 17p- diol e) llp- fluoro- 7a- f 6-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentylthio)- propylamino] hexyl}- estra- 1, 3, 5( 10)- triene-3, 17p-diol

250 mg llp-fluor-3-hydroksy-7a-{6-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]heksyl}-østra-1,3,5(10)-trien-17-on oppløses i 4,5 ml metanol og tilsettes porsjonsvis ved 0 °C, 60 mg natriumborhydrid. Etter 3 timers omrøring ved romtemperatur avsuges løsningsmidlet i vakuum, bunnfallet tilsettes mettet koksaltløsning, ekstraheres 3 ganger med metylenklorid, tørkes over magnesiumsulfat og inndampes i vakuum. Etter kromatografi på kiselgel med en metylenklorid-metanolgradient oppnås 165 mg llp-fluor-7a-{6-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)-propylamino]-heksyl}-østra-1,3,5(10)-trien-3,17-diol som et skum, [a]D = +37 ° (c = 1,01 i kloroform). 250 mg llp-fluoro-3-hydroxy-7a-{6-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]hexyl}-estra-1,3,5( 10)-trien-17-one is dissolved in 4.5 ml of methanol and 60 mg of sodium borohydride is added portionwise at 0 °C. After stirring for 3 hours at room temperature, the solvent is suctioned off in vacuum, the precipitate is added to saturated sodium chloride solution, extracted 3 times with methylene chloride, dried over magnesium sulfate and evaporated in vacuum. After chromatography on silica gel with a methylene chloride-methanol gradient, 165 mg of llp-fluoro-7a-{6-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]-hexyl}- are obtained estra-1,3,5(10)-triene-3,17-diol as a foam, [α]D = +37 ° (c = 1.01 in chloroform).

Eksempel 34 Example 34

llp- fluor- 7g-{ 6-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluorpentansulfinyl) propylamino] heksyl}- østra- 1, 3, 5( 10)- trien- 3, 17- diol llp- fluoro- 7g-{ 6-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoropentanesulfinyl) propylamino] hexyl}- estra- 1, 3, 5( 10)- trien- 3 , 17-diol

a) 11(3 - fluor - 3- hydroksy- 7a- f 6-[ N- metyl- N- 3-( 4, 4, 5, 5, 5-pentafluorpentansulfinyl) propylamino] heksyl)- østra-1, 3, 5 ( 10)- trien- 17- on a) 11(3 - fluoro - 3- hydroxy- 7a- f 6-[ N- methyl- N- 3-( 4, 4, 5, 5, 5-pentafluoropentanesulfinyl) propylamino] hexyl)- estra-1, 3, 5 ( 10)- trien- 17- on

500 mg lip-fluor-3-hydroksy-7a-{6-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]heksyl}-østra-1,3,5(10)-trien-17-on oppløses i 17 ml metanol og 3,3 ml vann, tilsettes 262 mg natriumperjodat og omrøres i 2 t ved rom- 500 mg lip-fluoro-3-hydroxy-7a-{6-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]hexyl}-estra-1,3,5( 10)-trien-17-one is dissolved in 17 ml of methanol and 3.3 ml of water, 262 mg of sodium periodate is added and stirred for 2 h at room

temperatur. For opparbeidelse tilsettes reaksjonsblandingen halvmettet koksaltløsning, ekstraheres 3 ganger med metylenklorid, tørkes over magnesiumsulfat og inndampes i vakuum. Bunnfallet opprenses på kiselgel med en metylenklorid-metanolgradient. Det isoleres 149 mg lip-fluor-3-hydroksy-Va-ie- [N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfinyl)-propylamino]heksyl}-østra-1,3,5(10)-trien-17-on som et skum. temperature. For work-up, half-saturated sodium chloride solution is added to the reaction mixture, extracted 3 times with methylene chloride, dried over magnesium sulfate and evaporated in vacuo. The precipitate is purified on silica gel with a methylene chloride-methanol gradient. 149 mg of lip-fluoro-3-hydroxy-Va-ie-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)-propylamino]hexyl}-estra-1,3 are isolated, 5(10)-trien-17-one as a foam.

[a]D = +45 <0> (c = 1,015 i kloroform). [a]D = +45 <0> (c = 1.015 in chloroform).

b) lip- fluor- 7g-{ 6-[ N- metyl- N- 3-( 4, 4, 5, 5, 5- pentafluor-pentansulf inyl) propylamino] heksyl}- østra- 1, 3, 5( 10)-trien- 3, 17- diol b) lip- fluoro- 7g-{ 6-[ N- methyl- N- 3-( 4, 4, 5, 5, 5- pentafluoro-pentanesulfinyl) propylamino] hexyl}- estra- 1, 3, 5( 10 )-triene-3, 17-diol

149 mg lip-fluor-3-hydroksy-7a-{6-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfinyl)-propylamino]heksyl}-østra-1,3,5(10)-trien-17-on oppløses i 3 ml metanol og tilsettes porsjonsvis 35 mg natriumborhydrid. Etter 30 min om-røring ved romtemperatur avsuges løsningsmidlet i vakuum, resten tilsettes vann, ekstraheres 3 ganger med metylenklorid, tørkes over magnesiumsulfat og inndampes i vakuum. Preparativ tynnsjiktskromatografi med metylenklorid/metanol = 9/1 som løpemiddel, gir 109 mg llp-fluor-7a-{6-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfinyl)propylamino]heksyl}-østra-1,3,5 (10)-trien-3,17-diol som et skum. [a]D = +24 ° (c = 0,51 i kloroform). 149 mg lip-fluoro-3-hydroxy-7a-{6-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)-propylamino]hexyl}-estra-1,3,5 (10)-trien-17-one is dissolved in 3 ml of methanol and 35 mg of sodium borohydride is added in portions. After stirring for 30 min at room temperature, the solvent is filtered off in vacuo, the residue is added to water, extracted 3 times with methylene chloride, dried over magnesium sulphate and evaporated in vacuo. Preparative thin-layer chromatography with methylene chloride/methanol = 9/1 as eluent gives 109 mg llp-fluoro-7a-{6-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]hexyl }-estra-1,3,5 (10)-triene-3,17-diol as a foam. [a]D = +24 ° (c = 0.51 in chloroform).

Eksempel 35 Example 35

lip- fluor- 7a-( 5-{[ N- 3-( furan- 2- ylmetyltio) propyl]- N- metylamino}- pentyl)- østra- 1, 3, 5( 10)- trien- 3, 17p- diol lip- fluoro- 7a-( 5-{[ N- 3-( furan- 2- ylmethylthio) propyl]- N- methylamino}- pentyl)- estra- 1, 3, 5( 10)- trien- 3, 17p- diol

a) 7 a-( 5- klorpentyl)- llp- fluor- østr- 4- en- 3, 17- dion a) 7 a-(5- chloropentyl)-llp- fluoro-estr- 4- ene- 3, 17-dione

Til en suspensjon av 7,2 g magnesiumspon i 100 ml THF To a suspension of 7.2 g of magnesium shavings in 100 ml of THF

tilsettes under nitrogen, først 20 % av en løsning av 39 ml 1-brom-5-klorpentan i 300 ml THF. Etter at reaksjonen er startet, hvilket kan oppnås ved tilsetning av jod og dibrom-metan, tildryppes resten av løsningen slik at den indre temperatur ikke overskrider 35 °C. I en annen kolbe blir det til en suspensjon av 28,1 g kopper(I)jodid i 13 0 ml THF ved 0 °C, tilsatt 51,2 g litiumbromid, hvorved den indre temperatur stiger til 40 °C. Uten avkjøling tilsettes nå 49,4 ml 1,3-dimetyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-on og blandingen is added under nitrogen, first 20% of a solution of 39 ml of 1-bromo-5-chloropentane in 300 ml of THF. After the reaction has started, which can be achieved by adding iodine and dibromo-methane, the rest of the solution is added drop by drop so that the internal temperature does not exceed 35 °C. In another flask, 51.2 g of lithium bromide is added to a suspension of 28.1 g of copper(I) iodide in 130 ml of THF at 0 °C, whereby the internal temperature rises to 40 °C. Without cooling, 49.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one are now added and the mixture

omrøres i 15 min ved 40 °C. Det oppnås en klar løsning som tildryppes til Grignard-løsningen avkjølt til -50 °C. Blandingen omrøres deretter i 15 min ved -30 °C og tilsettes ved -70 °C dråpevis en løsning av 25 g lip-fluor-østra-4,6-dien-3,17-dion i 260 ml THF, 26 ml 1,3-dimetyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-on og 59 ml trimetylklorsilan, slik at den indre temperatur ikke overskrider -65 °C. Blandingen omrøres i 30 min ved denne temperatur, tildryppes deretter 34,7 ml iseddik, kuldebadet fjernes og blandingen omrøres ilt ved romtemperatur. For opparbeidelse helles reaksjonsblandingen over i 1,5 1 vann, fortynnes med den samme mengde eddikester, bunnfallet separeres over celitt, vaskes med eddikester, den vandige fase ekstraheres 3 ganger med eddikester, vaskes med natriumhydrogenkarbonat- og koksaltløsning, tørkes over magnesiumsulfat og inndampes i vakuum. Etter kromatografering av råproduktet på kiselgel med en heksan-eddikestergradient, oppnås 22,1 g 7a-(5-klorpentyl)-llp-fluor-østr-4-en-3,17-dion. stirred for 15 min at 40 °C. A clear solution is obtained which is added dropwise to the Grignard solution cooled to -50 °C. The mixture is then stirred for 15 min at -30 °C and a solution of 25 g lip-fluoro-estra-4,6-diene-3,17-dione in 260 ml THF, 26 ml 1, 3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 59 ml of trimethylchlorosilane, so that the internal temperature does not exceed -65 °C. The mixture is stirred for 30 min at this temperature, 34.7 ml of glacial acetic acid are then added dropwise, the cold bath is removed and the mixture is stirred in oxygen at room temperature. For work-up, the reaction mixture is poured into 1.5 1 of water, diluted with the same amount of ethyl acetate, the precipitate is separated over celite, washed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuum. After chromatography of the crude product on silica gel with a hexane-acetic ester gradient, 22.1 g of 7a-(5-chloropentyl)-11p-fluoro-estr-4-ene-3,17-dione are obtained.

b) 7a-( 5- klorpentyl)- lip- fluor- 3- hydroksy- østra-1, 3, 5( 10)- trien- 17- on b) 7a-(5- chloropentyl)- lip- fluoro- 3- hydroxy- estra-1, 3, 5( 10)- trien- 17- one

Til 22,1 g 7a-(5-klorpentyl)-lip-fluor-østr-4-en-3,17-dion i 160 ml vannfri acetonitril, tilsettes ved 80 °C 25,4 g kopper(II)bromid og 4,9 g litiumbromid i 95 ml vannfri acetonitril. Etter 20 min avkjøles reaksjonsblandingen til 0 °C og tildryppes 200 ml mettet natriumhydrogenkarbonatløsning. Løsningen innrøres deretter i 750 ml vann, bringes til pH = 6 med 2 N saltsyre, ekstraheres 3 ganger med eddikester, vaskes med koksaltløsning, tørkes over magnesiumsulfat og inndampes i vakuum. Kromatografi av råproduktet på kiselgel med en heksan-eddikestergradient, gir 14,7 g 7a-(5-klorpentyl)-lip-fluor-3-hydroksy-østra-1,3,5(10)-trien-17-on. To 22.1 g of 7a-(5-chloropentyl)-lip-fluoro-estr-4-ene-3,17-dione in 160 ml of anhydrous acetonitrile, add at 80 °C 25.4 g of copper(II) bromide and 4 .9 g lithium bromide in 95 ml anhydrous acetonitrile. After 20 min, the reaction mixture is cooled to 0 °C and 200 ml of saturated sodium bicarbonate solution are added dropwise. The solution is then stirred into 750 ml of water, brought to pH = 6 with 2 N hydrochloric acid, extracted 3 times with vinegar, washed with sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. Chromatography of the crude product on silica gel with a hexane-acetic ester gradient gives 14.7 g of 7α-(5-chloropentyl)-lip-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one.

c) lip- fluor- 3- hydroksy-7 a-( 5- jodpentyl)- østra-1, 3, 5( 10)- trien- 17- on c) lip- fluoro- 3- hydroxy-7 a-( 5- iodopentyl)- estra-1, 3, 5( 10)- trien- 17- one

5,0 g 7a-(5-klorpentyl)-lip-fluor-3-hydroksy-østra-1,3,5(10)-trien-17-on oppløses i 80 ml etylmetylketon, tilsettes 5,7 g natriumjodid og omrøres over natten ved 90 °C badtemperatur. For opparbeidelse avkjøles reaksjonsblandingen til romtemperatur, innrøres i vann, ekstraheres 3 ganger med Dissolve 5.0 g of 7a-(5-chloropentyl)-lip-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one in 80 ml of ethyl methyl ketone, add 5.7 g of sodium iodide and stir overnight at 90 °C bath temperature. For work-up, the reaction mixture is cooled to room temperature, stirred into water, extracted 3 times with

eddikester, vaskes med koksaltløsning, tørkes over magnesiumsulfat og inndampes i vakuum. Det oppnås 6,8 g llp-fluor-3-hydroksy-7a-(5-jodpentyl)-østra-1,3,5(10)-trien-17-on som råprodukt som anvendes i det neste trinn uten ytterligere ren-sing. acetic acid, washed with sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. 6.8 g of llp-fluoro-3-hydroxy-7a-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one are obtained as crude product which is used in the next step without further purification sing.

d) llp- fluor- 3- hydroksy-7 a-[ 5( metylamino) pentyl] østra-1, 3, 5( 10)- trien- 17- on d) llp-fluoro-3-hydroxy-7a-[5(methylamino)pentyl]estra-1,3,5(10)-trien-17-one

I en løsning av 6,8 g lip-fluor-3-hydroksy-7a-(5-jodpentyl)-østra-1,3,5(10)-trien-17-on i 35 ml vannfri tetrahydrofuran, kondenseres ved -78 °C 5,1 g metylamin og blandingen omrøres over natten ved romtemperatur i en trykkreaktor. Etter at trykkreaktoren er blitt åpnet ved -20 °C, hensettes den til oppvarming til romtemperatur for å avdampe overskytende metylamin. Reaksjonsløsningen tilsettes deretter til mettet natriumhydrogenkarbonatløsning, ekstraheres 3 ganger med eddikester, tørkes over magnesiumsulfat og inndampes i vakuum. Det oppnås 6,7 g llp-fluor-3-hydroksy-7a-[5(metylamino)pentyl]østra-1,3,5(10)-trien-17-on som råprodukt . In a solution of 6.8 g of lip-fluoro-3-hydroxy-7a-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one in 35 ml of anhydrous tetrahydrofuran, condense at -78 °C 5.1 g of methylamine and the mixture is stirred overnight at room temperature in a pressure reactor. After the pressure reactor has been opened at -20 °C, it is allowed to warm to room temperature to evaporate excess methylamine. The reaction solution is then added to saturated sodium bicarbonate solution, extracted 3 times with ethyl acetate, dried over magnesium sulfate and evaporated in vacuo. 6.7 g of llp-fluoro-3-hydroxy-7a-[5(methylamino)pentyl]estra-1,3,5(10)-trien-17-one are obtained as crude product.

e) llp- fluor- 7a-( 5-{[ N- 3-( furan- 2- ylmetyltio) propyl]- N-metylamino} pentyl)- 3- hydroksy- østra- l, 3, 5( 10)- trien-17 - on e) 11p-fluoro-7a-(5-{[N-3-(furan-2-ylmethylthio)propyl]-N-methylamino}pentyl)-3-hydroxy-estral-1,3,5(10)-triene -17 - Wed

526 mg lip-fluor-3-hydroksy-7a-[5(metylamino)pentyl]-østra-1,3,5(10)-trien-17-on og 95 mg 2-(3-klor-propyl-tiometyl) f uran oppløses i 5 ml etylmetylketon, tilsettes 112 mg natriumjodid og 104 mg kaliumkarbonat og omrøres i 3 t ved 90 °C badtemperatur. For opparbeidelse tilsettes reaksjonsblandingen til halvmettet natriumhydrogenkarbonatløsning, ekstraheres 3 ganger med metylenklorid, vaskes med koksaltløs-ning, tørkes over magnesiumsulfat og inndampes i vakuum. Kromatografi av råproduktet på kiselgel med en metylenklorid-metanolgradient, gir 229 mg llp-fluor-7a-(5-{[N-3-(furan-2-ylmetyltio)propyl]-N-metyl-amino}pentyl)-3-hydroksy-østra-1,3,5(10)-trien-17-on som et skum. 526 mg lip-fluoro-3-hydroxy-7a-[5(methylamino)pentyl]-estra-1,3,5(10)-trien-17-one and 95 mg 2-(3-chloro-propyl-thiomethyl) f furan is dissolved in 5 ml of ethyl methyl ketone, 112 mg of sodium iodide and 104 mg of potassium carbonate are added and stirred for 3 h at 90 °C bath temperature. For work-up, the reaction mixture is added to half-saturated sodium bicarbonate solution, extracted 3 times with methylene chloride, washed with sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. Chromatography of the crude product on silica gel with a methylene chloride-methanol gradient gives 229 mg of llp-fluoro-7a-(5-{[N-3-(furan-2-ylmethylthio)propyl]-N-methyl-amino}pentyl)-3- hydroxy-estra-1,3,5(10)-trien-17-one as a foam.

f) lip- fluor- 7a-( 5- f[ N- 3-( furan- 2- ylmetyltio) propyl]- N-metylamino} pentyl) østra- 1, 3, 5( 10)- trien- 3, 17p- diol 217 mg llø-fluor-7g<->(5-{[N-3-(furan-2-ylmetyltio)-propyl]-N-metylamino}pentyl)-3-hydroksy-østra-l,3,5(10)-trien-17-on oppløses i 6 ml metanol og tilsettes porsjonsvis 44 mg natriumborhydrid. Etter 1 times omrøring ved romtemperatur avsuges løsningsmidlet i vakuum, resten tilsettes koksaltløs-ning, ekstraheres 3 ganger med metylenklorid, tørkes over magnesiumsulfat og inndampes i vakuum. Preparativ søyle-kromatografi med en metylenklorid/metanolgradient, gir 146 mg 110-fluor-7a-(5-{[N-3-(furan-2-ylmetyltio)propyl]-N-metylamino}-pentyl)-østra-1,3,5(10)-trien-3,170-diol som et skum. f) lip- fluoro- 7a-(5-f[N- 3-(furan-2- ylmethylthio)propyl]-N-methylamino}pentyl) estra- 1, 3, 5( 10)- trien- 3, 17p- diol 217 mg iso-fluoro-7g<->(5-{[N-3-(furan-2-ylmethylthio)-propyl]-N-methylamino}pentyl)-3-hydroxy-estra-1,3,5( 10)-trien-17-one is dissolved in 6 ml of methanol and 44 mg of sodium borohydride is added in portions. After stirring for 1 hour at room temperature, the solvent is sucked off in vacuo, the residue is added to sodium chloride solution, extracted 3 times with methylene chloride, dried over magnesium sulphate and evaporated in vacuo. Preparative column chromatography with a methylene chloride/methanol gradient gives 146 mg of 110-fluoro-7a-(5-{[N-3-(furan-2-ylmethylthio)propyl]-N-methylamino}-pentyl)-estra-1, 3,5(10)-triene-3,170-diol as a foam.

Eksempel 36 Example 36

110- fluor- 7a-( 5-{ N- metyl-[ N- 3-( tiofen- 2- ylmetyltio) propyl]-amino} pentyl) østra- 1, 3, 5( 10)- trien- 3, 170- diol 110- fluoro- 7a-( 5-{ N- methyl-[ N- 3-( thiophen- 2- ylmethylthio) propyl]-amino} pentyl) estra- 1, 3, 5( 10)- trien- 3, 170- diol

a) 110- fluor- 3- hydroksy- 7g-( 5-{ N- metyl-[ N- 3-( tiofen- 2-ylmetyltio) propyl] amino} pentyl) østra- l, 3, 5( 10)- trien-17- on a) 110-fluoro-3-hydroxy-7g-(5-{N-methyl-[N-3-(thiophen-2-ylmethylthio)propyl]amino}pentyl)estral-1,3,5(10)-triene -17- Wed

526 mg 110-fluor-3-hydroksy-7o-[5-(metylamino)-pentyl]østra-1,3,5(10)-trien-17-on og 103 mg 2-(3-klorpropyltiometyl) tiof en oppløses i 5 ml etylmetylketon, tilsettes 112 mg natriumjodid og 104 mg kaliumkarbonat og omrøres i 4,5 t ved 90 °C badtemperatur. For opparbeidelse blir reaksjonsblandingen tilsatt til halvmettet natriumhydrogenkarbonat løsning, ekstraheres 3 ganger med metylenklorid, vaskes med koksaltløsning, tørkes over magnesiumsulfat og inndampes i vakuum. Kromatograf! av råproduktet på kiselgel med en metylenklorid-metanolgradient, gir 191 mg 110-fluor-3-hydroksy-7a-(5-{N-metyl-[N-3-(tiofen-2-ylmetyltio)propyl]aminojpentyl)-østra-1,3,5(10)-trien-17-on som et skum. 526 mg of 110-fluoro-3-hydroxy-7o-[5-(methylamino)-pentyl]estra-1,3,5(10)-trien-17-one and 103 mg of 2-(3-chloropropylthiomethyl)thiophene are dissolved in 5 ml of ethyl methyl ketone, 112 mg of sodium iodide and 104 mg of potassium carbonate are added and stirred for 4.5 h at 90 °C bath temperature. For work-up, the reaction mixture is added to half-saturated sodium bicarbonate solution, extracted 3 times with methylene chloride, washed with sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. Chromatograph! of the crude product on silica gel with a methylene chloride-methanol gradient gives 191 mg of 110-fluoro-3-hydroxy-7a-(5-{N-methyl-[N-3-(thiophen-2-ylmethylthio)propyl]aminojpentyl)-estra- 1,3,5(10)-trien-17-one as a foam.

b) 110- fluor- 7a-( 5-{ N- metyl-[ N- 3-( tiofen- 2- ylmetyltio) propyl]- aminojpentyl) østra- 1, 3, 5( 10)- trien- 3, 170-diol b) 110- fluoro- 7a-( 5-{ N- methyl-[ N- 3-( thiophen- 2- ylmethylthio) propyl]- aminojpentyl) estra- 1, 3, 5( 10)- trien- 3, 170- diol

185 mg 110-fluor-3-hydroksy-7a-(5-{N-metyl-[N-3-(tiofen-2-ylmetyltio)propyl]aminojpentyl)østra-1,3,5(10)-trien-17-on oppløses i 5 ml metanol og tilsettes porsjonsvis 2 8 mg natriumborhydrid. Etter 45 min omrøring ved romtemperatur blir det meste av løsningsmidlet avsugd i vakuum, resten tilsettes til koksaltløsning, ekstraheres 3 ganger med metyl- 185 mg 110-fluoro-3-hydroxy-7a-(5-{N-methyl-[N-3-(thiophen-2-ylmethylthio)propyl]aminojpentyl)oestra-1,3,5(10)-trien-17 -one is dissolved in 5 ml of methanol and 28 mg of sodium borohydride are added in portions. After stirring for 45 min at room temperature, most of the solvent is sucked off under vacuum, the remainder is added to sodium chloride solution, extracted 3 times with methyl

enklorid, tørkes over magnesiumsulfat og inndampes i vakuum. Preparativ søylekromatografi med en metylenklorid/metanolgradient gir 93 mg 110-fluor-7a-(5-{N-metyl-[N-3-(tiofen-2-ylmetyltio)propyl]-aminojpentyl)østra-1,3,5(10)-trien-3,170-diol som et skum. monochloride, dried over magnesium sulphate and evaporated in vacuo. Preparative column chromatography with a methylene chloride/methanol gradient gives 93 mg of 110-fluoro-7a-(5-{N-methyl-[N-3-(thiophen-2-ylmethylthio)propyl]-aminojpentyl)estra-1,3,5(10 )-triene-3,170-diol as a foam.

Eksempel 37 Example 37

110- fluor- 7a-{ 5-[( 2S)- 2-( 4- trifluormetylfenyltiometyl)- pyrrolidin- l- yl] pentylJøstra- 1, 3, 5( 10)- trien- 3, 170- diol 110- fluoro- 7a-{ 5-[( 2S)- 2-( 4- trifluoromethylphenylthiomethyl)- pyrrolidin- 1- yl] pentyl Jöstra- 1, 3, 5( 10)- trien- 3, 170- diol

a) 110- fluor- 3- hydroksy- 7g-{ 5-[( 2S)- 2-( 4- trifluormetylfenyltiometyl) pyrrolidin- 1- yl] pentylJ- østra-1, 3, 5( 10)- trien- 17- on a) 110- fluoro- 3- hydroxy- 7g-{ 5-[( 2S)- 2-( 4- trifluoromethylphenylthiomethyl) pyrrolidin- 1- yl] pentyl J- estra-1, 3, 5( 10)- trien- 17- Wed

En løsning av 0,5 g 7a-(5-klorpentyl)-110-fluor-3-hydroksy-østra-1,3,5(10)-trien-17-on i 4 ml dimetylformamid omrøres med 0,55 g (2S)-2-(4-trifluormetylfenyltiometyl)pyrrolidin og 0,32 g litiumjodid i 2 t ved 100 °C badtemperatur. Blandingen tilsettes deretter til natriumhydrogenkarbonat-løsning, ekstraheres 3 ganger med eddikester, vaskes med koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/aceton. Det oppnås 0,45 g 110-fluor-3-hydroksy-7a-{5-[(2S)-2-(4-trifluor-metylf enyltiometyl) pyrrolidin-l-yl] pentyl}-østra-1,3,5(10)-trien-17-on med [0£]D22 = +32, 7 ° (c = 0,51 % i kloroform). A solution of 0.5 g of 7a-(5-chloropentyl)-110-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one in 4 ml of dimethylformamide is stirred with 0.55 g ( 2S)-2-(4-trifluoromethylphenylthiomethyl)pyrrolidine and 0.32 g lithium iodide for 2 h at 100 °C bath temperature. The mixture is then added to sodium bicarbonate solution, extracted 3 times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/acetone. 0.45 g of 110-fluoro-3-hydroxy-7a-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)pyrrolidin-1-yl]pentyl}-estra-1,3,5 (10)-trien-17-one with [0£]D22 = +32.7° (c = 0.51% in chloroform).

b) llø- fluor- 7g-{ 5-[( 2S)- 2-( 4- trifluormetylfenyltiometyl) - pyrrolidin- l- yl] pentylJøstra- 1, 3, 5( 10)- trien-3, 170- diol b) lleo-fluoro-7g-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidin-1-yl]pentylJöstra-1,3,5(10)-trien-3,170-diol

En løsning av 0,43 g 110-fluor-3-hydroksy-7o-{5-[(2S)-2-(4-trifluormetylfenyltiometyl)pyrrolidin-l-yl]pentyl}-østra-1,3,5(10)-trien-17-on i 4 ml tetrahydrofuran, 2,3 ml etanol og 1 ml vann, tilsettes ved 0 °C porsjonsvis 111 mg natriumborhydrid og omrøres i 2 t. Blandingen tilsettes deretter til isvann, ekstraheres 3 ganger med eddikester, vaskes med koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/aceton. Det oppnås 0,32 g 110-fluor-7a-{5-[(2S)-2-(4-trifluor-metylf enyltiometyl)-pyrrolidin-l-yl]pentylJøstra-1,3,5(10)-trien-3,170-diol med [0£]D22 = +16, 2 <0> (c = 0,51 % i metanol). A solution of 0.43 g of 110-fluoro-3-hydroxy-70-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)pyrrolidin-1-yl]pentyl}-estra-1,3,5(10 )-trien-17-one in 4 ml of tetrahydrofuran, 2.3 ml of ethanol and 1 ml of water, add 111 mg of sodium borohydride in portions at 0 °C and stir for 2 h. The mixture is then added to ice water, extracted 3 times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulphate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/acetone. 0.32 g of 110-fluoro-7a-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidin-1-yl]pentyl Jöstra-1,3,5(10)-trien- 3,170-diol with [0£]D22 = +16, 2 <0> (c = 0.51% in methanol).

Eksempel 38 Example 38

llp- fluor- 17a- metyl- 7o-{ 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentan-sulf inylmetyl) pyrrolidin- l- yl] - pentyl}- østra- 1, 3, 5( 10)- trien-3, 170- diol llp- fluoro- 17a- methyl- 7o-{ 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluoropentane- sulfinylmethyl) pyrrolidin- 1- yl] - pentyl}- estra- 1, 3,5(10)-triene-3,170-diol

En løsning av 0,2 g 110-fluor-17o-metyl-7a-{5-[(2S)-2 -(4,4,5,5,5-pentafluorpentyltiometyl)pyrrolidin-l-yl]-pentyl }-østra-1,3,5(10)-trien-3,170-diol i 5,8 ml metanol og 2,9 ml vann omrøres med 82 mg natriumperjodat i 5 t ved romtemperatur. Blandingen tilsettes deretter til vann, ekstraheres 3 ganger med diklormetan, vaskes nøytral, tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 210 mg råprodukt som kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 105 mg rent 14,17-etan-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfinyl)propylamino]pentyl}-østra-1,3 ,5 (10)-trien-3,17£-diol. IR 1610 og 1190 [cm"<1>]. A solution of 0.2 g of 110-fluoro-17o-methyl-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]-pentyl}- estra-1,3,5(10)-triene-3,170-diol in 5.8 ml of methanol and 2.9 ml of water is stirred with 82 mg of sodium periodate for 5 h at room temperature. The mixture is then added to water, extracted 3 times with dichloromethane, washed neutral, dried over sodium sulfate and evaporated in vacuo. 210 mg of crude product is obtained which is chromatographed on silica gel with dichloromethane/methanol. 105 mg of pure 14,17-ethane-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}-estra-1,3,5 (10)-triene-3,17£-diol. IR 1610 and 1190 [cm"<1>].

Eksempel 3 9 Example 3 9

llp- fluor- 17a- metyl- 7g- f5-[( 2R)- 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl) pyrrolidin- l- yl] - pentyl}- østra- 1, 3, 5( 10)- trien- 3, 170-diol llp- fluoro- 17a- methyl- 7g- f5-[( 2R)- 2-( 4, 4, 5, 5, 5- pentafluoropentylthiomethyl) pyrrolidin- 1- yl] - pentyl}- estra- 1, 3, 5( 10)-triene-3,170-diol

Analogt med eksempel 29 fremstilles 110-fluor-17o-metyl-7a-{5-[(2R)-2-(4,4,5,5,5-pentafluorpentyltiometyl)-pyrrolidin-l-yl]-pentyl}-østra-1,3,5(10)-trien-3,170-diol med [a]D<22> = +68,7 ° (c = 0,74 % i kloroform). Analogously to example 29, 110-fluoro-17o-methyl-7a-{5-[(2R)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra is prepared -1,3,5(10)-triene-3,170-diol with [a]D<22> = +68.7 ° (c = 0.74% in chloroform).

Eksempel 40 Example 40

110- fluor- 17a- metyl- 7g-{ 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentan-sulf onylmetyl) pyrrolidin- l- yl] - pentyl}- østra- 1, 3, 5( 10)- trien-3, 170- diol , 3,5(10)-triene-3,170-diol

En løsning av 100 mg 3,17 p-diacetoksy-lip-fluor-17o-metyl-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentansulfonylmetyl)-pyrrolidin-l-yl]-pentyl}-østra-1,3,5(10)-trien i 1,3 ml 0,2 M metanolisk kaliumhydroksidløsning omrøres i 2 t ved romtemperatur. Blandingen tilsettes deretter til vann, ekstraheres 3 ganger med diklormetan, vaskes med koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/aceton. Det oppnås 63 mg lip-fluor-17o-metyl-7g<->{5-[(2S)-2-(4,4,5,5,5-pentafluorpentan-sul fonylmetyl) pyrrol idin- 1 -yl] -pentyl}-østra-1,3,5(10)-trien-3,170-diol. IR: 1710, 1660, 1610 [cm-<1>]. A solution of 100 mg of 3,17 p-diacetoxy-lip-fluoro-17o-methyl-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentanesulfonylmethyl)-pyrrolidine-1- yl]-pentyl}-estra-1,3,5(10)-triene in 1.3 ml of 0.2 M methanolic potassium hydroxide solution is stirred for 2 h at room temperature. The mixture is then added to water, extracted 3 times with dichloromethane, washed with sodium chloride solution, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/acetone. 63 mg of lip-fluoro-17o-methyl-7g<->{5-[(2S)-2-(4,4,5,5,5-pentafluoropentane-sulfonylmethyl)pyrrolidin-1-yl]- pentyl}-estra-1,3,5(10)-triene-3,170-diol. IR: 1710, 1660, 1610 [cm-<1>].

Eksempel 41 Example 41

110- fluor- 7a-{ 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentansulfinyl-metyl) pyrrolidin- l- yl] - pentyl)- østra- 1, 3, 5( 10)- trien- 3, 170-diol 110- fluoro- 7a-{ 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluoropentanesulfinyl-methyl) pyrrolidin- 1- yl]-pentyl)- estra- 1, 3, 5( 10 )-triene-3,170-diol

En løsning av 300 mg 110-fluor-7o-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)pyrrolidin-l-yl]-pentyl}-østra-1,3,5(10)-trien-3,170-diol i 4,3 ml metanol og 2,1 ml vann omrøres med 131 mg natriumperjodat i 4 t ved romtemperatur. Blandingen tilsettes deretter til vann, ekstraheres 3 ganger med eddikester, vaskes med koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/eddikester. Det oppnås 203 mg 110-fluor-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentansulfinylmetyl)-pyrrolidin-l-yl]-pentyl}-østra-1,3,5(10)-trien-3,170-diol. [a]D<23> = +11,8 ° (c = 0,53 % i metanol). A solution of 300 mg of 110-fluoro-7o-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]-pentyl}-oestra-1,3, 5(10)-triene-3,170-diol in 4.3 ml of methanol and 2.1 ml of water is stirred with 131 mg of sodium periodate for 4 h at room temperature. The mixture is then added to water, extracted 3 times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/ethyl acetate. 203 mg of 110-fluoro-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentanesulfinylmethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3 are obtained, 5(10)-triene-3,170-diol. [a]D<23> = +11.8° (c = 0.53% in methanol).

Eksempel 42 Example 42

110- fluor- 7g-{ 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentansulfonyl-metyl) pyrrolidin- l- yl]- pentyl}- østra- 1, 3, 5( 10)- trien- 3, 170-diol 110- fluoro- 7g-{ 5-[( 2S)- 2-( 4, 4, 5, 5, 5- pentafluoropentanesulfonyl-methyl) pyrrolidin- 1- yl]-pentyl}- estra- 1, 3, 5( 10 )-triene-3,170-diol

Analogt med eksempel 48 fremstilles 110-fluor-7o-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentansulfonylmetyl)pyrrolidin-l-yl] -pentyl} -østra-1, 3, 5 (10) -trien-3, 170-diol. [0f]D22 = +30 , 6 Analogously to example 48, 110-fluoro-7o-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentanesulfonylmethyl)pyrrolidin-1-yl]-pentyl}-oestra-1, 3, 5(10)-triene-3,170-diol. [0f]D22 = +30 , 6

(c = 0,515 % i metanol). (c = 0.515% in methanol).

Fremstilling av utgangsforbindelser Production of output connections

N- metyl-[ 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propyl] amin N-methyl-[3-(4,4,5,5,5-pentafluoropentylthio)propyl]amine

a) 3 - jodpropyl- 4, 4, 5, 5, 5- pentafluorpentylsulfid a) 3 - iodopropyl- 4, 4, 5, 5, 5- pentafluoropentyl sulfide

En løsning av 22,8 g 3-klorpropyl-4,4,5,5,5-pentafluorpentylsulfid i 500 ml etylmetylketon omrøres med 40 g natriumjodid i 5 t ved 100 °C badtemperatur. Blandingen inndampes deretter til tørrhet, oppløses i vann, ekstraheres 3 ganger med eddikester, vaskes nøytral, tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 30,6 g 3-jodpropyl-4,4,5,5,5-pentafluorpentylsulfid. A solution of 22.8 g of 3-chloropropyl-4,4,5,5,5-pentafluoropentyl sulfide in 500 ml of ethyl methyl ketone is stirred with 40 g of sodium iodide for 5 h at 100 °C bath temperature. The mixture is then evaporated to dryness, dissolved in water, extracted 3 times with ethyl acetate, washed neutral, dried over sodium sulfate and evaporated in vacuo. 30.6 g of 3-iodopropyl-4,4,5,5,5-pentafluoropentyl sulphide is obtained.

b) N- metyl-[ 3-( 4, 4, 5, 5, 5- pentafluorpentyltio) propyl] amin b) N-methyl-[3-(4,4,5,5,5-pentafluoropentylthio)propyl]amine

I en løsning av 30,6 g 3-jodpropyl-4,4,5,5,5-pentafluorpentylsulfid i 200 ml absolutt tetrahydrofuran kondenseres 45 g metylamin ved -78 °C badtemperatur og omrøres i 1,5 t ved romtemperatur og i 4 t ved 60 °C i en trykkreaktor. Reaktoren åpnes og hensettes over natten ved romtemperatur og avkjøles deretter til -78 °C. Temperaturen tillates deretter å stige til romtemperatur, overskytende metylamin avdampes, blandingen fortynnes med eddikester, vaskes nøytral, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 15,7 g N-metyl-[3-(4,4,5,5,5-pentafluorpentyltio)propyl]amin som en olje. In a solution of 30.6 g of 3-iodopropyl-4,4,5,5,5-pentafluoropentyl sulfide in 200 ml of absolute tetrahydrofuran, 45 g of methylamine is condensed at -78 °C bath temperature and stirred for 1.5 h at room temperature and for 4 t at 60 °C in a pressure reactor. The reactor is opened and left overnight at room temperature and then cooled to -78 °C. The temperature is then allowed to rise to room temperature, excess methylamine is evaporated, the mixture is diluted with ethyl acetate, washed neutral, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 15.7 g of N-methyl-[3-(4,4,5,5,5-pentafluoropentylthio)propyl]amine are obtained as an oil.

N- metyl-[ 3-( 4, 4, 5, 5, 5- pentafluorpentansulfonyl) propyl] amin N-methyl-[3-(4,4,5,5,5-pentafluoropentanesulfonyl)propyl]amine

a) 3- klorpropyl- 4, 4, 5, 5, 5- pentafluorpentansulfon a) 3- chloropropyl- 4, 4, 5, 5, 5- pentafluoropentanesulfone

En løsning av 23 g 3-klorpropyl-4,4,5,5,5-pentafluorpentylsulfid i 230 ml kloroform tilsettes porsjonsvis ved 0 °C 41,8 g 70 i m-klorperbenzosyre og omrøres i 1,5 t ved romtemperatur. Blandingen fortynnes deretter med diklormetan, vaskes med natriumhydrogensulfitt, natriumhydrogenkarbonat- og koksaltløsning, tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 23,8 g rent 3-klorpropyl-4,4,5,5,5-pentaf luorpentansulfon som krystaller med smeltepunkt 74-76 °C. A solution of 23 g of 3-chloropropyl-4,4,5,5,5-pentafluoropentyl sulphide in 230 ml of chloroform is added in portions at 0 °C 41.8 g of 70 in m-chloroperbenzoic acid and stirred for 1.5 h at room temperature. The mixture is then diluted with dichloromethane, washed with sodium hydrogen sulphite, sodium hydrogen carbonate and sodium bicarbonate solution, dried over sodium sulphate and evaporated in vacuo. 23.8 g of pure 3-chloropropyl-4,4,5,5,5-pentafluoropentane sulfone are obtained as crystals with a melting point of 74-76 °C.

b) 3- jodpropyl- 4, 4, 5, 5, 5- pentafluorpentansulfon b) 3- iodopropyl- 4, 4, 5, 5, 5- pentafluoropentanesulfone

En løsning av 23,5 g 3-klorpropyl-4,4,5,5,5-pentafluorpentansulfon i 500 ml etylmetylketon omrøres med 40 g natriumjodid i 5 t ved 100 °C badtemperatur. Blandingen inndampes deretter i vakuum til tørrhet, oppløses i vann, ekstraheres 3 ganger med eddikester, vaskes nøytral, tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 30,6 g 3-jodpropyl-4 , 4 , 5 , 5 , 5-pentaf luorpentansulf on som krystaller med smeltepunkt 88-89 °C. A solution of 23.5 g of 3-chloropropyl-4,4,5,5,5-pentafluoropentanesulfone in 500 ml of ethyl methyl ketone is stirred with 40 g of sodium iodide for 5 h at 100 °C bath temperature. The mixture is then evaporated in vacuo to dryness, dissolved in water, extracted 3 times with ethyl acetate, washed neutral, dried over sodium sulfate and evaporated in vacuo. 30.6 g of 3-iodopropyl-4,4,5,5,5-pentafluoropentanesulfon are obtained as crystals with a melting point of 88-89 °C.

c) N- metyl-[ 3-( 4, 4, 5, 5, 5- pentafluorpentansulfonyl)-propyl] amin c) N-methyl-[3-(4,4,5,5,5-pentafluoropentanesulfonyl)-propyl]amine

En løsning av 23,5 g 3-jodpropyl-4,4,5,5,5-pentafluorpentansulfon i 2 00 ml absolutt tetrahydrofuran kondenseres ved -78 °C badtemperatur i 44 g metylamin og omrøres i 1,5 t ved romtemperatur og i 4 t ved 60 °C i en trykkreaktor. Reaktoren åpnes og hensettes over natten ved romtemperatur og avkjøles deretter til -78 °C. Temperaturen tillates å stige til romtemperatur, overskytende metylamin avdampes, blandingen fortynnes med eddikester, vaskes nøytral, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med diklormetan/metanol. Det oppnås 14,8 g N-metyl-[3-(4,4,5,5,5-pentafluorpentansulfonyl)propyl]amin som krystaller med smeltepunkt 55-57 °C. A solution of 23.5 g of 3-iodopropyl-4,4,5,5,5-pentafluoropentanesulfone in 200 ml of absolute tetrahydrofuran is condensed at -78 °C bath temperature in 44 g of methylamine and stirred for 1.5 h at room temperature and in 4 h at 60 °C in a pressure reactor. The reactor is opened and left overnight at room temperature and then cooled to -78 °C. The temperature is allowed to rise to room temperature, excess methylamine is evaporated, the mixture is diluted with ethyl acetate, washed neutral, dried over sodium sulfate, evaporated in vacuo and chromatographed on silica gel with dichloromethane/methanol. 14.8 g of N-methyl-[3-(4,4,5,5,5-pentafluoropentanesulfonyl)propyl]amine are obtained as crystals with a melting point of 55-57 °C.

l- brom- 5- tert.- butyldimetylsilyloksypentan l-bromo-5-tert.-butyldimethylsilyloxypentane

a) 5- brom- 1- pentanol a) 5-bromo-1-pentanol

Til en løsning av 50 g 5-brompentylacetat i 1,6 1 To a solution of 50 g of 5-bromopentyl acetate in 1.6 1

metanol tildryppes 50 ml konsentrert svovelsyre og blandingen omrøres i 30 t ved romtemperatur. Metanolen fjernes i vakuum, resten oppløses i dietyleter, vaskes nøytral med mettet kok-saltløsning, tørkes over natriumsulfat og inndampes. Det oppnås 28 g 5-brom-1-pentanol som råprodukt. methanol is added dropwise to 50 ml of concentrated sulfuric acid and the mixture is stirred for 30 h at room temperature. The methanol is removed in vacuo, the residue is dissolved in diethyl ether, washed neutral with saturated sodium chloride solution, dried over sodium sulfate and evaporated. 28 g of 5-bromo-1-pentanol are obtained as crude product.

b) l- brom- 5- tert.- butyldimetylsilyloksypentan b) 1-bromo-5-tert.-butyldimethylsilyloxypentane

En løsning av 28 g av den urensede 5-brom-1-pentanol A solution of 28 g of the crude 5-bromo-1-pentanol

i 144 ml tetrahydrofuran tilsettes 24 g imidazol. En løsning av 30,3 g tert.-butyldimetylklorsilan i 46 ml tetrahydrofuran tildryppes deretter og blandingen omrøres i 4 t ved romtemperatur. Reaksjonsblandingen helles over i vann, ristes med dietyleter, den organiske fase vaskes 4 ganger med vann, tørkes over natriumsulfat og inndampes. Råproduktet kromatograf eres å kiselgel med heksan/dietyleter. Det oppnås 42 g av tittelforbindelsen som en fargeløs væske. 24 g of imidazole are added to 144 ml of tetrahydrofuran. A solution of 30.3 g of tert-butyldimethylchlorosilane in 46 ml of tetrahydrofuran is then added dropwise and the mixture is stirred for 4 h at room temperature. The reaction mixture is poured into water, shaken with diethyl ether, the organic phase is washed 4 times with water, dried over sodium sulphate and evaporated. The crude product is chromatographed on silica gel with hexane/diethyl ether. 42 g of the title compound are obtained as a colorless liquid.

( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl) pyrrolidin ( 2S )- 2-( 4, 4, 5, 5, 5- pentafluoropentylthiomethyl) pyrrolidine

a) N- tert.- butyloksykarbonyl- L- prolinol- p- tosylat a) N-tert.-butyloxycarbonyl-L-prolinol-p-tosylate

Til en løsning av 10 g N-tert.-butyloksykarbonyl-L-prolinol i 170 ml pyridin tilsettes ved 0 °C porsjonsvis 24,2 g p-toluensulfonsyreanhydrid og blandingen omrøres i 5 t ved 0 °C. Reaksjonsblandingen helles over i 2 N saltsyre, ekstraheres med etylacetat, den organiske fase vaskes med mettet koksaltløsning, tørkes over natriumsulfat og inndampes. Det oppnås 17,7 g N-tert.-butyloksykarbonyl-L-prolinol-p-tosylat som et oljeaktig råprodukt. [ a] D" = -28,0 ° {c = 0545 i To a solution of 10 g of N-tert.-butyloxycarbonyl-L-prolinol in 170 ml of pyridine, 24.2 g of p-toluenesulfonic anhydride is added in portions at 0 °C and the mixture is stirred for 5 h at 0 °C. The reaction mixture is poured into 2 N hydrochloric acid, extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. 17.7 g of N-tert-butyloxycarbonyl-L-prolinol-p-tosylate are obtained as an oily crude product. [ a] D" = -28.0° {c = 0545 in

kloroform). chloroform).

b) N- tert.- butyloksykarbonyl-( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl) pyrrolidin b) N-tert.-butyloxycarbonyl-(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidine

En løsning av 3,93 g 4,4,5,5,5-pentafluorpentyltio-acetat i 18 ml metanol tilsettes 2,94 ml av en natriummetano-latløsning (30 % i metanol) og omrøres i 30 min ved romtemperatur. Reaksjonsløsningen tilsettes til en løsning av 3,0 g N-tert.-butyloksykarbonyl-L-prolinol-p-tosylat og blandingen omrøres i 3 t ved romtemperatur og 3 t ved 50 °C. Reaksjonsblandingen helles over i vann, ekstraheres med etylacetat, vaskes med mettet natriumkloridløsning, tørkes over natriumsulfat og inndampes. Resten kromatograferes på kiselgel med heksan/etylacetat. Det oppnås 2,59 g N-tert.-butyloksykarbonyl-(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)pyrrolidin som en olje. [ a] D22 = -41, 3 0 (c = 0,530 i kloroform). A solution of 3.93 g of 4,4,5,5,5-pentafluoropentylthioacetate in 18 ml of methanol is added to 2.94 ml of a sodium methanolate solution (30% in methanol) and stirred for 30 min at room temperature. The reaction solution is added to a solution of 3.0 g of N-tert-butyloxycarbonyl-L-prolinol-p-tosylate and the mixture is stirred for 3 h at room temperature and 3 h at 50 °C. The reaction mixture is poured into water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate. 2.59 g of N-tert-butyloxycarbonyl-(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidine are obtained as an oil. [a] D22 = -41.30 (c = 0.530 in chloroform).

c) ( 2S)- 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl) pyrrolidin c) ( 2S )- 2-( 4, 4, 5, 5, 5- pentafluoropentylthiomethyl) pyrrolidine

Til 5,4 ml trifluoreddiksyre avkjølt til 0 °C tilsettes 2,55 g N-tert.-butyloksykarbonyl-(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)pyrrolidin og blandingen omrøres i 1,5 t ved 0 °C og 16 t ved romtemperatur. Reaksjonsblandingen helles over i 10 % natriumhydrogenkarbonatløsning, ekstraheres med etylacetat, vaskes med mettet koksaltløsning, tørkes over natriumsulfat og inndampes. Det oppnås 1,8 g av tittelforbindelsen som et oljeaktig råprodukt. To 5.4 ml of trifluoroacetic acid cooled to 0 °C, 2.55 g of N-tert-butyloxycarbonyl-(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidine is added and the mixture is stirred for 1.5 h at 0 °C and 16 h at room temperature. The reaction mixture is poured into 10% sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. 1.8 g of the title compound are obtained as an oily crude product.

( 2R)- 2-( 4, 4, 5, 5, 5- pentafluorpentyltiometyl) pyrrolidin ( 2R )- 2-( 4, 4, 5, 5, 5- pentafluoropentylthiomethyl) pyrrolidine

På fullstendig analog måte som beskrevet for frem-stillingen av (2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)-pyrrolidin oppnås det fra 10 g N-tert.-butyloksykarbonyl-D-prolinol 9,69 g av tittelforbindelsen som et oljeaktig råprodukt . In a completely analogous manner to that described for the preparation of (2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidine, 10 g of N-tert-butyloxycarbonyl-D-prolinol is obtained from 9.69 g of the title compound as an oily crude product.

( 4, 4, 5, 5, 5- pentafluorpentyl) vinylsulfon (4, 4, 5, 5, 5- pentafluoropentyl) vinyl sulfone

a) ( 4, 4, 5, 5, 5- pentafluorpentyl) vinylsulfid a) (4, 4, 5, 5, 5- pentafluoropentyl) vinyl sulphide

En løsning av 40 g 4,4,5,5,5-pentafluorpentyl-tio-acetat i 2 00 ml metanol omrøres med 34 ml av en 30 % natrium-metylatløsning ilt ved 25 °C, tilsettes dråpevis 21 ml 1,2-dibroraetan, omrøres i ytterligere 2 t ved romtemperatur, tilsettes dråpevis ytterligere 70 ml 30 % natriummetylat og om-røres i 3 t ved 25 °C. Metanolen fjernes deretter ved inndamping i vakuum, resten tilsettes vann, ekstraheres 3 ganger med eddikester, vaskes med vann og koksaltløsning, tørkes over natriumsulfat og inndampes i vakuum. Det oppnås 34 g (4,4,5,5,5-pentafluorpentyl)vinylsulfid. A solution of 40 g of 4,4,5,5,5-pentafluoropentyl-thio-acetate in 200 ml of methanol is stirred with 34 ml of a 30% sodium methylate solution in oxygen at 25 °C, 21 ml of 1,2- dibroroethane, stirred for a further 2 h at room temperature, a further 70 ml of 30% sodium methylate are added dropwise and stirred for 3 h at 25 °C. The methanol is then removed by evaporation in a vacuum, the residue is added to water, extracted 3 times with vinegar, washed with water and sodium chloride solution, dried over sodium sulfate and evaporated in a vacuum. 34 g of (4,4,5,5,5-pentafluoropentyl)vinyl sulfide is obtained.

b) ( 4, 4, 5, 5, 5- pentafluorpentyl) vinylsulfon b) (4, 4, 5, 5, 5- pentafluoropentyl) vinyl sulfone

En løsning av 34 g (4,4,5,5,5-pentafluorpentyl)vinyl-sulf id i 74 ml iseddik tilsettes dråpevis 59 ml 3 0 % hydrogenperoksid, slik at reaksjonstemperaturen ikke overskrider 70 °C. Blandingen omrøres deretter ilt ved 70 °C badtemperatur. Blandingen helles deretter over i vann, ekstraheres 3 ganger med eddikester, vaskes med natriumtio-sulfatløsning, vann og koksaltløsning, tørkes over natriumsulfat, inndampes i vakuum og kromatograferes på kiselgel med heksan/eddikester. Det oppnås 12,3 g (4,4,5,5,5-pentafluorpentyl) vinyl sul f on som en olje. A solution of 34 g of (4,4,5,5,5-pentafluoropentyl)vinyl sulphide in 74 ml of glacial acetic acid is added dropwise to 59 ml of 30% hydrogen peroxide, so that the reaction temperature does not exceed 70 °C. The mixture is then stirred in oxygen at 70 °C bath temperature. The mixture is then poured into water, extracted 3 times with ethyl acetate, washed with sodium thiosulphate solution, water and sodium chloride solution, dried over sodium sulphate, evaporated in vacuo and chromatographed on silica gel with hexane/ethyl acetate. 12.3 g of (4,4,5,5,5-pentafluoropentyl) vinyl sulfone is obtained as an oil.

2-( 3- klorpropyltiometyl) furan 2-(3-Chloropropylthiomethyl)furan

Til 1,77 ml furan-2-yl-metantiol i 18 ml vannfri acetonitril tildryppes ved 0 °C 3,3 ml av en 30 % natrium-metylatløsning i metanol. Etter 5 min tilsettes dråpevis 2,6 ml l-brom-3-klorpropan. Reaksjonsløsningen omrøres deretter i5t ved romtemperatur. For opparbeidelse fortynnes blandingen med eddikester, vaskes med vann og koksaltløsning, tørkes over magnesiumsulfat og inndampes i vakuum. Kromatograf i av råproduktet på kiselgel med en heksan-eddikestergradient gir 1,1 g 2-(3-klorpropyltiometyl)furan som en olje. To 1.77 ml of furan-2-yl-methanethiol in 18 ml of anhydrous acetonitrile, 3.3 ml of a 30% sodium methylate solution in methanol are added dropwise at 0 °C. After 5 min, 2.6 ml of 1-bromo-3-chloropropane is added dropwise. The reaction solution is then stirred for 15 h at room temperature. For processing, the mixture is diluted with vinegar, washed with water and sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. Chromatography of the crude product on silica gel with a hexane-acetic ester gradient gives 1.1 g of 2-(3-chloropropylthiomethyl)furan as an oil.

2-( 3- klorpropyltiometyl) tiofen 2-(3-Chloropropylthiomethyl)thiophene

Til 1,0 g tiofen-2-yl-metantiol i 8 ml vannfri acetonitril tildryppes ved 0 °C 1,5 ml av en 30 % natrium-metylatløsning i metanol. Etter 5 min tilsette dråpevis 1,1 ml l-brom-3-klorpropan. Reaksjonsløsningen omrøres deretter i 5 t ved romtemperatur. For opparbeidelse fortynnes blandingen med eddikester, vaskes med vann og koksaltløsning, tørkes over magnesiumsulfat og inndampes i vakuum. Kromatografi av råproduktet på kiselgel med en heksan-eddikestergradient, gir 1,3 g 2-(3-klorpropyltiometyl)tiofen som" en olje. To 1.0 g of thiophen-2-yl-methanethiol in 8 ml of anhydrous acetonitrile is added dropwise at 0 °C 1.5 ml of a 30% sodium methylate solution in methanol. After 5 min, add dropwise 1.1 ml of 1-bromo-3-chloropropane. The reaction solution is then stirred for 5 h at room temperature. For processing, the mixture is diluted with vinegar, washed with water and sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. Chromatography of the crude product on silica gel with a hexane-acetic ester gradient gives 1.3 g of 2-(3-chloropropylthiomethyl)thiophene as an oil.

( 2S)- 2-( 4- trifluormetylfenyltiometyl) pyrrolidin (2S)-2-(4-trifluoromethylphenylthiomethyl)pyrrolidine

a) N- tert.- butyloksykarbonyl-( 2S)-2-( 4- trifluormetylfenyltiometyl) pyrrolidin a) N-tert.-butyloxycarbonyl-(2S)-2-(4-trifluoromethylphenylthiomethyl)pyrrolidine

En løsning av 1,65 g 4-trifluormetyltiofenol i 18 ml dimetylformamid tilsettes 3 g cesiumkarbonat og 3 g N-tert.-butyloksykarbonyl-L-prolinol-p-tosylat og omrøres i 8 t ved romtemperatur. Reaksjonsblandingen helles over i vann, ekstraheres med etylacetat, vaskes med mettet natriumklorid-løsning, tørkes over natriumsulfat og inndampes. Resten kromatograf eres på kiselgel med heksan/etylacetat. Det oppnås 2,59 g N-tert.-butyloksykarbonyl-(2S)-2-(4-trifluormetylfenyltiometyl) pyrrol idin som en olje. A solution of 1.65 g of 4-trifluoromethylthiophenol in 18 ml of dimethylformamide is added to 3 g of cesium carbonate and 3 g of N-tert-butyloxycarbonyl-L-prolinol-p-tosylate and stirred for 8 h at room temperature. The reaction mixture is poured into water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate. 2.59 g of N-tert-butyloxycarbonyl-(2S)-2-(4-trifluoromethylphenylthiomethyl)pyrrolidine are obtained as an oil.

b) ( 2S)- 2-( 4- trifluormetylfenyltiometyl) pyrrolidin b) (2S)-2-(4-trifluoromethylphenylthiomethyl)pyrrolidine

En løsning av 2,55 g N-tert.-butyloksykarbonyl-(2S)-2-(4-trifluormetylfenyltiometyl)pyrrolidin i 5,64 ml trifluoreddiksyre omrøres ilt ved 0 °C og deretter i 3,5 t ved romtemperatur. Reaksjonsblandingen helles over i 10 % natriumhydrogenkarbonatløsning, ekstraheres med etylacetat, vaskes 2 ganger med 2 M saltsyre, vannfasen ekstraheres med eter, gjøres basisk med natriumhydrogenkarbonat, ekstraheres 3 ganger med eddikester, vaskes med koksaltløsning, tørkes over natriumsulfat og inndampes. Det oppnås 557 mg (2S)-2-(4-trifluormetylfenyltiometyl)pyrrolidin. A solution of 2.55 g of N-tert.-butyloxycarbonyl-(2S)-2-(4-trifluoromethylphenylthiomethyl)pyrrolidine in 5.64 ml of trifluoroacetic acid is stirred in oxygen at 0 °C and then for 3.5 h at room temperature. The reaction mixture is poured into 10% sodium hydrogen carbonate solution, extracted with ethyl acetate, washed 2 times with 2 M hydrochloric acid, the aqueous phase is extracted with ether, made basic with sodium hydrogen carbonate, extracted 3 times with acetic acid, washed with sodium chloride solution, dried over sodium sulfate and evaporated. 557 mg of (2S)-2-(4-trifluoromethylphenylthiomethyl)pyrrolidine are obtained.

Claims (23)

l. Substituerte 7a-(£-aminoalkyl)-østratriener, karakterisert ved at de har den generelle formel I hvori sidekjeden SK betegner en rest med delformel hvori m er 4, 5 eller 6, n er 0, l eller 2, x er 0, 1 eller 2, A betegner et hydrogenatom eller en Ci-5- alkylgruppe, B og D betegner et hydrogenatom eller A og B betegner sammen en alkylengruppe (CH2)P der p = 2, 3, 4 eller 5 og D er et hydrogenatom, eller A og D betegner sammen en alkylengruppe (CH2}q der q = 2, 3 eller 4 og B er et hydrogenatom, og E betegner en usubstituert eller en én- til fem-fluorert etylrest eller den terminale substituent (CH2)3-E i sidekjeden er erstattet med en eventuelt med CF3 substituert fenylgruppe, eller en furyl- eller tienylgruppe som via en mono-, di- eller trimetylengruppe er bundet til svovelatomet, R<3> betegner et hydrogenatom eller en rest med delformel R<3>'-C(0), hvori R<3>' er en hydrokarbonrest med inntil 8 karbonatomer, R11 betegner et hydrogenatom, et halogenatom eller en nitrooksygruppe 0-N02, R14, R15Q, R<15f>\ R<1Sa> og R1<6p> betegner et hydrogenatom, eller R<14> og R<150> betegner en ytterligere binding, eller Rls<p> betegner en metylgruppe og R<15a> betegner et hydrogenatom, eller R<1>5<p> og R1<6p> betegner sammen en metylenbro, eller R<16a> eller R<16p> betegner et halogenatom, R17' i a- eller 0-posisjon, betegner et hydrogenatom, en Ci-5- alkyl-, Ci-e-alkanoyloksy-, C2-s-alkenyl- eller C2.5-alkynylgruppe eller en trifluormetylgruppe, og R17" betegner et hydrogenatom eller en rest med del formel R<17>'"-C(0), hvori R17"'betegner et hydrogenatom eller en hydrokarbonrest med inntil 8 karbonatomer eller, når R<17>' befinner seg i op-posisjon, så betegner R<17>' sammen med R<14> en etanolbro, med det forbehold at, når A og B sammen ikke betegner (CH2)P eller A og D sammen betegner (CH2)q, så er minst en av substituentene R<1>1, R14, R1S<Q>, R<15p>, R1Sa og R1<6p> ikke et hydrogen-atom, så vel som deres fysiologisk forenlige addisjonssalter med organiske og uorganiske syrer.1. Substituted 7a-(£-aminoalkyl)-oestratrienes, characterized in that they have the general formula I in which the side chain SK denotes a residue with partial formula in which m is 4, 5 or 6, n is 0, l or 2, x is 0, 1 or 2, A denotes a hydrogen atom or a Ci-5- alkyl group, B and D denote a hydrogen atom or A and B together denote an alkylene group (CH2)P there p = 2, 3, 4 or 5 and D is a hydrogen atom, or A and D together denote an alkylene group (CH2}q where q = 2, 3 or 4 and B is a hydrogen atom, and E denotes an unsubstituted or a one-to five-fluorinated ethyl residue or the terminal substituent (CH2)3-E in the side chain is replaced by a phenyl group optionally substituted with CF3, or a furyl or thienyl group which via a mono-, di- or trimethylene group is bound to the sulfur atom, R<3> denotes a hydrogen atom or a residue with partial formula R<3>'-C(0), in which R<3>' is a hydrocarbon residue with up to 8 carbon atoms, R 11 denotes a hydrogen atom, a halogen atom or a nitrooxy group 0-NO2, R14, R15Q, R<15f>\ R<1Sa> and R1<6p> denote a hydrogen atom, or R<14> and R<150> denote an additional bond, or Rls<p> denote a methyl group and R<15a> denotes a hydrogen atom, or R<1>5<p> and R1<6p> together denote a methylene bridge, or R<16a> or R<16p> denote a halogen atom, R17' in a- or 0-position, denotes a hydrogen atom, a Ci-5- alkyl, C1-e-alkanoyloxy, C2-s-alkenyl or C2.5-alkynyl group or a trifluoromethyl group, and R17" denotes a hydrogen atom or a residue with moiety formula R<17>'"-C(0), in which R17"' denotes a hydrogen atom or a hydrocarbon residue with up to 8 carbon atoms or, when R<17>' is in the op position, R<17>' together denote with R<14> an ethanol bridge, with the proviso that, when A and B together do not denote (CH2)P or A and D together denote (CH2)q, then at least one of the substituents R<1>1, R14, R1S<Q>, R<15p> , R1Sa and R1<6p> not a hydrogen atom, as well as their physiologically compatible addition salts with organic and inorganic acids. 2. Østratriener ifølge krav 1, karakterisert ved at m er 5.2. Ostratrians according to claim 1, characterized by m being 5. 3. Østratriener ifølge krav 1, karakterisert ved atnerl.3. Ostratrians according to claim 1, characterized by atnerl. 4. Østratriener ifølge krav 1, karakterisert ved at A er en metylgruppe.4. Ostratrians according to claim 1, characterized in that A is a methyl group. 5. Østratriener ifølge krav 1, karakterisert ved at x er 0.5. Estratriene according to claim 1, characterized by x being 0. 6. Østratriener ifølge krav 1, karakterisert ved at x er 1.6. Ostratrians according to claim 1, characterized by x being 1. 7. Østratriener ifølge krav 4, karakterisert ved atnerl.7. Estratriene according to claim 4, characterized by atnerl. 8. Østratriener ifølge krav 1, karakterisert ved at A og B sammen er (CH2)3.8. Ostratrians according to claim 1, characterized in that A and B together are (CH2)3. 9. Østratriener ifølge krav 8, karakterisert ved atnerO.9. Ostratrians according to claim 8, characterized by atnerO. 10. Østratriener ifølge krav 9, karakterisert ved at x er 0.10. Austratriene according to claim 9, characterized by x being 0. 11. Østratriener ifølge krav 1, karakterisert ved at E er en perfluoretylrest.11. Austratriene according to claim 1, characterized in that E is a perfluoroethyl residue. 12. Østratriener ifølge krav 1, karakterisert ved at R3 er et hydrogenatom.12. Ostratrians according to claim 1, characterized in that R3 is a hydrogen atom. 13. Østratriener ifølge krav 1, karakterisert ved at R<11> er et fluoratom.13. Austratriene according to claim 1, characterized in that R<11> is a fluorine atom. 14. Østratriener ifølge krav 1, karakterisert ved at R<16a> er et halogenatom (F, Cl, Br, I).14. Ostratrians according to claim 1, characterized in that R<16a> is a halogen atom (F, Cl, Br, I). 15. Østratriener ifølge krav 14, karakterisert ved at R<16a> er et fluoratom.15. Austratriene according to claim 14, characterized in that R<16a> is a fluorine atom. 16. Østratriener ifølge krav 1, karakterisert ved at R<17>' befinner seg i a-stilling.16. Austratrien according to claim 1, characterized in that R<17>' is in the a-position. 17. Østratriener ifølge krav 16, karakterisert ved at R<17>' er et hydrogenatom.17. Austratrien according to claim 16, characterized in that R<17>' is a hydrogen atom. 18. Østratriener ifølge krav 1, karakterisert ved at SK er en rest med delformel der x er lik 0, 1 eller 2.18. Austratriene according to claim 1, characterized in that SK is a remainder with partial formula where x is equal to 0, 1 or 2. 19. Østratriener ifølge krav 10, karakterisert ved at m = 5, E er en perfluoretylrest og konformasjonen av 2-karbonatornet i den heterosykliske ring er R.19. Austratriene according to claim 10, characterized in that m = 5, E is a perfluoroethyl residue and the conformation of the 2-carbon atom in the heterocyclic ring is R. 20. Østratriener ifølge krav 10, karakterisert ved at m = 5, E er en perfluoretylrest og konformasjonen av 2-karbonatornet i den heterosykliske ring er S.20. Austratriene according to claim 10, characterized in that m = 5, E is a perfluoroethyl residue and the conformation of the 2-carbon atom in the heterocyclic ring is S. 21. Østratriener ifølge krav 1, karakterisert ved at de er 110-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio) propylamino]pentyl}østra-1,3,5(10)-trien-3,170-diol, 110-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulf inyl) propylamino] pentyl Jøstra- 1,3, 5 (10)-trien-3,170-diol , 110-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulf onyl) propylamino] pentyl}østra-l,3,5(10)-trien-3,170-diol, 16a-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyl tio) propylamino]pentylJøstra-1,3,5(10)-trien-3,170-diol, 16a-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyl tio) propylamino] pentyl Jøstra- 1,3, 5(10)-trien-3,17a-diol, 16a-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulf inyl)propylamino]pentylJøstra-1,3,5(10)-trien-3,170-diol , 16a-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulf onyl) propylamino] pentyl}østra-1,3,5(10)-trien-3,170-diol , 7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)-pyrrolidin-l-yl]-pentyl}-østra-1,3,5(10)-trien-3,170-diol, 7a-{5-[(2R)-2-(4,4,5,5,5-pentafluorpentyltiometyl)-pyrrolidin-l-yl]-pentyl}-østra-1,3,5(10)-trien-3,170-diol, 17a-metyl-7a-{5-[2-(4,4,5,5,5-pentafluorpentyltiometyl) pyrrolidin-l-yl] pentyl}-østra-1,3,5(10)-trien-3,170-diol , 110-fluor-7a-{5-[2-(4,4,5,5,5-pentafluorpentyltiometyl)pyrrolidin-l-yl]pentyl}-østra-l,3,5(10)-trien-3,170-diol , 110-fluor-17a-metyl-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl)pyrrolidin-1-yl]pentyl}-østra-1,3,5(10)-trien-3,170-diol, 110-fluor-17a-metyl-7a-{5-[(2S)-2-(4,4,5,5,5-penta-fluorpentansulfinylmetyl)pyrrolidin-l-yl]pentyl}-østra-1,3,5(10)-trien-3,170-diol, 110-f luor-17a-metyl-7a- {5 - [ (2S) -2- (4,4, 5, S^-penta-fi luorpentansulf onylmetyl) pyrrolidin-l-yl] pentyl }-østra-1,3,5(10)-trien-3,170-diol, 7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentansulfinyl-metyl) pyrrolidin-l-yl] pentyl }-østra-1,3,5(10)-trien-3,170-diol, 7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentansulfonyl-metyl) pyrrolidin-l-yl] pentyl-østra-1,3,5(10)-trien-3,170-diol, 110-fluor-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio)propylamino]-pentyl}-østra-1,3,5(10)-trien-3,170-diol, 110-fluor-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentansulfinyl)propylamino]pentyl}-østra-1,3,5(10) - trien-3,170-diol, 110-fluor-17a-metyl-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulfonyl)propylamino]pentyl}-østra-1,3,5(10)-trien-3,170-diol, 110-fluor-7a-{5-[N-metyl-N-2-(4,4,5,5,5-pentafluor-pentansulf onyl) etylamino] pentyl}-østra-1,3,5(10)-trien-3,170-diol , 110-fluor-7a-{5-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio) propylamino]pentyl}-3-hydroksy-østra-1,3,5 (10)-trien-17-on, 110-fluor-7a-{6-[N-metyl-N-3-(4,4,5,5,5-pentafluorpentyltio) propylamino]heksyl}-østra-1,3,5(10)-trien-3,170-diol , 110-fluor-7a-{6-[N-metyl-N-3-(4,4,5,5,5-pentafluor-pentansulf inyl) propylamino] heksyl}-østra-1,3,5(10)-trien-3,170-diol, 110-fluor-7a-(5-{[N-3-(furan-2-ylmetyltio)propyl]-N-metylaminojpentyl)-østra-1,3,5(10)-trien-3,170-diol, 110-fluor-7a-(5-{N-metyl-[N-3-(tiofen-2-ylmetyltio)-propyl]aminojpentyl)-østra-1,3,5(10)-trien-3,170-diol, 110-fluor-7a-{5-[(2S)-2-(4-trifluormetylfenyltiometyl )pyrrolidin-l-yl]pentyl}østra-1,3,5(10)-trien-3,170-diol, 110-fluor-17a-metyl-7a-{5-[(2S)-2-(4,4,5,5,5-penta-fluorpentansulfinylmetyl)pyrrolidin-l-yl]pentyl}-østra-1,3,5(10)-trien-3,170-diol, llp-fluor-17a-metyl-7a-{5-[(2R)-2-(4,4,5,5,5-pentafluorpentyltiometyl)pyrrolidin-l-yl]pentyl}-østra-1,3,5(10)-trien-3,170-diol, 110-fluor-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentyltiometyl) pyrrolidin-l-yl] pentyl} -østra-1, 3 ,5(10)-trien-3,170-diol , 110-fluor-17a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentan-sulf inyl metyl) pyrrolidin- 1 -yl] pentyl }-østra-1,3,5(10)-trien-3,170-diol, 110-fluor-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluorpentan-sulfonylmetyl)pyrrolidin-l-yl]pentyl}-østra-l,3,5(10)-trien-3,170-diol.21. Austratriene according to claim 1, characterized by the fact that they are 110-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}oestra-1,3,5(10)-trien-3,170- diol, 110-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfinyl)propylamino]pentyl Jøstra- 1,3,5 (10)-trien- 3,170-diol, 110-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfonyl)propylamino]pentyl}oestra-1,3,5(10)-triene -3,170-diol, 16a-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentyl thio)propylamino]pentylJostra-1,3,5(10)-triene-3,170-diol , 16a-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentyl thio)propylamino]pentyl Jöstra-1,3, 5(10)-trien-3, 17a-diol, 16a-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentylJostra-1,3,5(10)-triene-3,170 -diol, 16a-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfonyl)propylamino]pentyl}oestra-1,3,5(10)-triene -3,170-diol, 7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-3,170 -diol, 7a-{5-[(2R)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-3,170 -diol, 17α-methyl-7α-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}-oestra-1,3,5(10)-triene-3,170-diol , 110-fluoro-7a-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}-estra-1,3,5(10)-triene-3,170-diol , 110-fluoro-17a-methyl-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}-estra-1,3,5( 10)-triene-3,170-diol, 110-fluoro-17a-methyl-7a-{5-[(2S)-2-(4,4,5,5,5-penta-fluoropentanesulfinylmethyl)pyrrolidin-1-yl]pentyl}-estra-1,3, 5(10)-triene-3,170-diol, 110-fluoro-17α-methyl-7α-{5-[(2S)-2-(4,4,5,S^-penta-fluoropentanesulfonylmethyl)pyrrolidin-1-yl]pentyl}-oestra-1 3,5(10)-triene-3,170-diol, 7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentanesulfinyl-methyl)pyrrolidin-1-yl]pentyl }-oestra-1,3,5(10)-trien-3,170 -diol, 7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentanesulfonyl-methyl)pyrrolidin-1-yl]pentyl-estra-1,3,5(10)-trien-3,170- diol, 110-fluoro-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]-pentyl}-estra-1,3,5(10 )-triene-3,170-diol, 110-fluoro-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}-estra-1,3,5(10) - triene-3,170-diol, 110-fluoro-17a-methyl-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfonyl)propylamino]pentyl}-estra-1,3,5( 10)-triene-3,170-diol, 110-fluoro-7a-{5-[N-methyl-N-2-(4,4,5,5,5-pentafluoro-pentanesulfonyl)ethylamino]pentyl}-estra-1,3,5(10)- triene-3,170-diol, 110-fluoro-7a-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}-3-hydroxy-estra-1,3,5 (10) -trien-17-one, 110-fluoro-7a-{6-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]hexyl}-estra-1,3,5(10)-triene-3,170 -diol, 110-fluoro-7a-{6-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentanesulfinyl)propylamino]hexyl}-estra-1,3,5(10)- triene-3,170-diol, 110-fluoro-7a-(5-{[N-3-(furan-2-ylmethylthio)propyl]-N-methylaminojpentyl)-estra-1,3,5(10)-triene-3,170-diol, 110-fluoro-7a-(5-{N-methyl-[N-3-(thiophen-2-ylmethylthio)-propyl]aminojpentyl)-estra-1,3,5(10)-triene-3,170-diol, 110-fluoro-7a-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)pyrrolidin-1-yl]pentyl}oestra-1,3,5(10)-triene-3,170-diol, 110-fluoro-17a-methyl-7a-{5-[(2S)-2-(4,4,5,5,5-penta-fluoropentanesulfinylmethyl)pyrrolidin-1-yl]pentyl}-estra-1,3, 5(10)-triene-3,170-diol, 11p-fluoro-17a-methyl-7a-{5-[(2R)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}-estra-1,3,5( 10)-triene-3,170-diol, 110-fluoro-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}-estra-1,3,5(10)-triene -3,170-diol, 110-fluoro-17a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentane-sulfinyl methyl)pyrrolidin-1-yl]pentyl }-estra-1,3,5( 10)-triene-3,170-diol, 110-fluoro-7a-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentane-sulfonylmethyl)pyrrolidin-1-yl]pentyl}-estra-1,3,5(10) -triene-3,170-diol. 22. Farmasøytisk preparat, karakterisert ved at det inneholder minst én forbindelse med generell formel I ifølge krav l, så vel som en farmasøytisk forenlig bærer.22. Pharmaceutical preparation, characterized in that it contains at least one compound of general formula I according to claim 1, as well as a pharmaceutically compatible carrier. 23. Anvendelse av forbindelser med generell formel I ifølge krav 1 for fremstilling av legemidler.23. Use of compounds of general formula I according to claim 1 for the manufacture of medicinal products.
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Families Citing this family (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE20000129A1 (en) * 1997-12-23 2000-03-11 Schering Ag 11 BETA-HALOGEN-STRATRIENS SUBSTITUTED IN 7 ALPHA, AS WELL AS THE PROCEDURE TO PREPARE PHARMACEUTICAL PREPARATIONS CONTAINING SUCH 11 BETA-HALOGEN-STRATRENS SUBSTITUTED IN 7 ALPHA
US6503896B1 (en) 1997-12-24 2003-01-07 Sri International Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use
US6054446A (en) 1997-12-24 2000-04-25 Sri International Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use
US6548491B2 (en) 1997-12-24 2003-04-15 Sri International Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use
DE19807791A1 (en) 1998-02-19 1999-08-26 Schering Ag Combination preparation of estrogen with 7-aminoalkyl-estratriene antiestrogen, useful in hormone replacement therapy, e.g. for treatment osteoporosis, Alzheimer's disease and hot flushes
DE19833786A1 (en) * 1998-07-18 2000-01-20 Schering Ag New diphenyl-benzocycloheptene derivatives, are tissue-selective estrogens and antiestrogens useful e.g. for treating osteoporosis or hormone-dependent tumors or in hormone replacement therapy
DE19842123C1 (en) * 1998-09-05 2000-07-13 Schering Ag 11beta-fluoro-7alpha- (14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl) estra-1,3,5 (10) - triene-3,17beta-diol as crystalline solvate
DE19906159A1 (en) * 1999-02-09 2000-08-10 Schering Ag 16-hydroxyestratrienes as selectively active estrogens
WO2001012622A1 (en) * 1999-08-18 2001-02-22 Schering Aktiengesellschaft Piperidine and pyrrolidine derivatives displaying neuronal activity
GB0000313D0 (en) * 2000-01-10 2000-03-01 Astrazeneca Uk Ltd Formulation
DE10019171A1 (en) * 2000-04-07 2001-10-18 Schering Ag Compositions for use as penetration enhancers in transdermal formulations for highly lipophilic active ingredients
DE10159217A1 (en) * 2001-11-27 2003-06-05 Schering Ag 17alpha-alkyl-17ß-oxy-estratrienes and intermediates for their preparation, use of 17alpha-alkyl-17ß-oxy-estratriene for the preparation of medicaments and pharmaceutical preparations
AU2006202187B2 (en) * 2001-11-27 2008-11-06 Bayer Schering Pharma Aktiengesellschaft 17alpah-alkyl-17beta-oxy-estratrienes and intermediate products for their production, uses thereof and pharmaceutical preparations
US20040242551A1 (en) * 2003-05-28 2004-12-02 Schering Ag Composition comprising antiprogestins and pure antiestrogens for prophylaxis and treatment of hormone-dependent diseases
CA2574967A1 (en) * 2004-07-27 2006-02-09 Sicor, Inc. A process for the preparation of 7.alpha.-alkylated 19-norsteroids
CN101312944B (en) 2005-11-22 2013-03-06 住友化学株式会社 Organic sulfur compounds and use thereof as arthropodicides
DE102007049630A1 (en) 2007-10-11 2009-10-29 Bayer Schering Pharma Aktiengesellschaft New amide compounds used for therapy and/or prophylaxis of gynecological diseases e.g. endometriosis, for female fertility control and female hormone replacement therapy
DE102007023614A1 (en) 2007-05-21 2008-11-27 Bayer Schering Pharma Aktiengesellschaft New amide compounds used for treatment of gynecological diseases e.g. endometriosis, for female fertility control and female hormone replacement therapy, has general formula
TW200904329A (en) 2007-05-18 2009-02-01 Sumitomo Chemical Co Organic sulfur compound and its use for controlling harmful arthropod
JP2009001551A (en) 2007-05-18 2009-01-08 Sumitomo Chemical Co Ltd Organic sulfur compound and its use for controlling harmful arthropod
JP5298631B2 (en) 2007-05-18 2013-09-25 住友化学株式会社 Organic sulfur compounds and their use for controlling harmful arthropods
DE102007032800A1 (en) 2007-07-10 2009-01-15 Bayer Schering Pharma Aktiengesellschaft Nonsteroidal progesterone receptor modulators
CN102940619A (en) 2007-10-16 2013-02-27 利普生物药剂公司 Trans-clomiphene for metabolic syndrome
DE102007058747A1 (en) 2007-12-05 2009-06-10 Bayer Schering Pharma Aktiengesellschaft Nonsteroidal progesterone receptor modulators
EP2070909A1 (en) 2007-12-15 2009-06-17 Bayer Schering Pharma AG Non-steroidal progesterone receptor modulators
EP2070941A1 (en) 2007-12-14 2009-06-17 Bayer Schering Pharma Aktiengesellschaft Stereoselective synthesis of selective estrogen receptor down-regulators
DE102008057230A1 (en) * 2008-11-11 2010-05-12 Bayer Schering Pharma Aktiengesellschaft Synergistic pharmaceutical combination with an estrogen receptor antagonist and a progestin
JP5212350B2 (en) * 2008-12-24 2013-06-19 住友化学株式会社 Halogen-containing organic sulfur compounds and uses thereof
EP2258375A1 (en) 2009-06-04 2010-12-08 Bayer Schering Pharma Aktiengesellschaft 17B-alkyl-17alpha-oxy-estratrienes
DE102009034368A1 (en) 2009-07-20 2011-01-27 Bayer Schering Pharma Aktiengesellschaft 17-Hydroxy-17-pentafluoroethyl-estra-4,9 (10) -diene-11-acyloxyalkylenephenyl derivatives, process for their preparation and their use for the treatment of diseases
DE102009034367A1 (en) 2009-07-20 2011-01-27 Bayer Schering Pharma Aktiengesellschaft 17-Hydroxy-17-pentafluoroethyl-estra-4,9 (10) -diene-11-benzylidene derivatives, process for their preparation and their use for the treatment of diseases
DE102009034366A1 (en) 2009-07-20 2011-01-27 Bayer Schering Pharma Aktiengesellschaft 17-Hydroxy-17-pentafluoroethyl-estra-4,9 (10) -diene-11-methyleneoxyalkylene aryl derivatives, process for their preparation and their use for the treatment of diseases
DE102009034362A1 (en) 2009-07-20 2011-01-27 Bayer Schering Pharma Aktiengesellschaft 17-Hydroxy-17-pentafluoroethyl-estra-4,9 (10) -diene-11-aryl derivatives, process for their preparation and their use for the treatment of diseases
DE102009034526A1 (en) 2009-07-21 2011-02-10 Bayer Schering Pharma Aktiengesellschaft 17-Hydroxy-17-pentafluoroethyl-estra-4,9 (10) -diene-11-ethynylphenyl derivatives, process for their preparation and their use for the treatment of diseases
DE102009034525A1 (en) 2009-07-21 2011-01-27 Bayer Schering Pharma Aktiengesellschaft 17-Hydroxy-17-pentafluoroethyl-estra-4,9 (10) -diene-11-aryl derivatives, process for their preparation and their use for the treatment of diseases
WO2011092127A1 (en) 2010-01-26 2011-08-04 Bayer Schering Pharma Aktiengesellschaft 14,17-bridged estratriene derivatives comprising heterocyclic bioisosteres for the phenolic a-ring
DE102010007722A1 (en) 2010-02-10 2011-08-11 Bayer Schering Pharma Aktiengesellschaft, 13353 Progesterone receptor antagonist
DE102010007719A1 (en) 2010-02-10 2011-08-11 Bayer Schering Pharma Aktiengesellschaft, 13353 Progesterone receptor antagonist
US11576891B2 (en) 2010-06-16 2023-02-14 Endorecherche, Inc. Methods of treating or preventing estrogen-related diseases
DE102010030538A1 (en) 2010-06-25 2011-12-29 Bayer Schering Pharma Aktiengesellschaft 6,7-Dihydro-5H-benzo [7] annulene derivatives, process for their preparation, pharmaceutical preparations containing them and their use for the preparation of medicaments
DE102011004899A1 (en) 2011-03-01 2012-09-06 Bayer Pharma Aktiengesellschaft New 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl-derivatives are progesterone receptor antagonists useful to treat and prevent e.g. uterine fibroids, endometriosis, heavy menstrual bleeding and meningioma
DE102011087987A1 (en) 2011-12-08 2013-06-13 Bayer Intellectual Property Gmbh 6,7-Dihydro-5H-benzo [7] annulene derivatives, process for their preparation, pharmaceutical preparations containing them and their use for the preparation of medicaments
US20150031656A1 (en) 2012-02-29 2015-01-29 Repros Therapeutics Inc. Combination therapy for treating androgen deficiency
TR201817995T4 (en) 2013-03-13 2019-02-21 Sage Therapeutics Inc NEUROACTIVE STEROIDS AND METHODS OF USE
EP2983671B1 (en) 2013-04-11 2018-10-24 Bayer Pharma Aktiengesellschaft Progesterone receptor antagonist dosage form
WO2014169462A1 (en) * 2013-04-18 2014-10-23 西安力邦医药科技有限责任公司 Ester derivative of 7-alpha-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17beta-diol having antitumour activity and preparation method thereof
CN108348605B (en) 2015-11-10 2023-06-09 帕拉卡林治疗公司 Treatment of ER-negative breast cancer with PDGF-CC inhibitors and antiestrogens
HUE059491T2 (en) 2016-04-01 2022-11-28 Sage Therapeutics Inc Oxysterols and methods of use thereof
WO2017193046A1 (en) 2016-05-06 2017-11-09 Sage Therapeutics, Inc. Oxysterols and methods of use thereof
JP6966486B2 (en) 2016-07-07 2021-11-17 セージ セラピューティクス， インコーポレイテッド Oxysterols and how to use them
CN115850361A (en) 2016-09-30 2023-03-28 萨奇治疗股份有限公司 C7 substituted oxysterol and methods of using same as NMDA modulators
JP2019532079A (en) 2016-10-18 2019-11-07 セージ セラピューティクス， インコーポレイテッド Oxysterols and methods of use
CN115505019B (en) * 2022-11-07 2024-01-26 南宁师范大学 7-amide substituted estrogenic compounds, and preparation method and application thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8327256D0 (en) * 1983-10-12 1983-11-16 Ici Plc Steroid derivatives
HU208150B (en) * 1988-10-31 1993-08-30 Endorecherche Inc Process for producing new estrogen derivatives having steroid hormone inhibitor activity and pharmaceutical compositions comprising such derivatives
DE3925507A1 (en) * 1989-07-28 1991-01-31 Schering Ag 14,17 (ALPHA) ETHENO AND ETHANOESTRATRIA, METHOD FOR PRODUCING THESE COMPOUNDS, AND THEIR USE FOR PRODUCING MEDICINAL PRODUCTS
DE4218743C2 (en) * 1992-06-04 2001-10-25 Schering Ag Process for the preparation of C (7) -substituted Estra-1,3,5 (10) -trienes and new starting products for this process

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