AU2006202187B2 - 17alpah-alkyl-17beta-oxy-estratrienes and intermediate products for their production, uses thereof and pharmaceutical preparations - Google Patents

Description

23-05-'06 17:23 FROM-DCC SYDNEY +61292621080 T-196 P006/068 F-200 Va c Our Ref:12677861 P/00/01 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Address for Service: Invention Title: Schering Aktiengesellschaft Mullerstrasse 178 13353 Berlin Germany DAVIES COLLISON CAVE Patent Trade Mark Attorneys 255 Elizabeth Street Sydney, New South Wales, Australia, 2000 17alpha-alkyl-17beta-oxy-estratrienes and intermediate products for their production, uses thereof and pharmaceutical preparations The following statement is a full description of this invention, including the best method of performing it known to me:- 5951 COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:24 FROM-DCC SYDNEY +61292621080 T-196 P007/068 F-200

O

0 S1 7m-Alkyl-17p-oxy-estratrienes and Intermediate Products for their Production, Uses thereof and Pharmaceutical Preparations Cl This application is a divisional application of Australian patent application No.

2004202428, itself a divisional application of AU 2002360949, the disclosures of which are 00 incorporated herein in their entirety. The invention subject of this application is set out in the

N

O claims which follow, whilst the invention as originally disclosed is set out in the description

I-,

Sbelow.

C" The invention relates to 17a-alkyl-17p-oxy-estratrienes and intermediate products for their production, use of the 17a-alkyl- 171-oxy-estratrienes for the production of pharmaceutical agents as well as pharmaceutical preparations that contain these compounds.

The compounds according to the invention have antiestrogenic action, these substances exert inhibiting actions relative to estrogens. Such substances have already been described extensively.

For example, compounds that have an antiestrogenic action are known from EP 0 138 504 B1. These are then essentially estra-1,3,5(10)-triene derivatives, which are substituted in 3-position, with hydroxy or alkoxy, in 173-position with hydroxy, and in 17a-position, with hydrogen or alkyl. In 7a-position, these compounds also have an alkyl side chain that can be partially fluorinated and that can be interrupted by, amido, amino, amine-Noxide, oxy, sulfanyl, sulfinyl and/or sulfonyl groups.

In WO 99/33855 Al, 11 3-halogen-7c-substituted estra-l,3,5(10)-trienes are described that can have hydroxy groups in 3-position and in 17-position. The 7a-side chain is a partially fluorinated, optionally unsaturated hydrocarbon chain that is interrupted by an amine-nitrogen atom or a sulfany, sulfinyl or sulfonyl group.

COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:24 FROM-DCC SYDNEY +61292621080 T-196 P08/068 F-200 2

O

o Other compounds are described in WO 98/07740 Al. In this connection, these are substituted 7a-( -aminoalkyl)-estra-l,3,5(10)-trienes. These compounds preferably have a hydroxy, methoxy or acetyloxy group in 3-position and preferably a methyl or trifluoromethyl Ce C1 group in 17c-position and/or 17p-position. In 11 -position, a fluorine atom is preferably provided, and in 7a-position, an alkyl side chain that is at least partially fluorinated in the 00 terminal position and that is interrupted by an amine-N atom and by a sulfanyl, sulfinyl or 0 sulfonyl group is provided.

o In WO 97/45441 Al, 7ca-(5-methylaminopentyl)-estra-1,3,5(10)-trienes are disclosed 0 cl that have a hydroxy group in 3-position and in 17-position. In 17a-position, a methyl or ethynyl group can be provided. The estratriene skeleton can also be substituted in 2-position with a fluorine atom.

It has turned out that the known compounds in the application form a variety of biologically very active metabolites. The formation of these metabolites results in undesirable actions and thus in an uncontrollable spectrum of action. In particular, side effects can be adjusted or the desired primary action (antiestrogenic action) is uncontrollable by spontaneous formation of these metabolites. In addition, the compatibility of the known compounds in the case of oral administration is unsatisfactory. It has turned out in particular that the known compounds promote the build-up of alveolar macrophages.

The present invention seeks to provide antiestrogenic compounds whose metabolism can be controlled and that therefore form little or no biologically active metabolites. In addition, it is desired that the compatibility of the compounds that are sought is satisfactory in the case of oral administration and in the case of their dispensing, alveolar macrophages do not build up or at least build up only to a small extent.

Accordingly, the present invention as claimed provides 17a-alkyl-17p-oxyestratrienes of formula I according to claim 1. The invention as claimed also provides 17p- COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:24 FROM-DCC

SYDNEY

+61292621080 T-196 P009/068 F-200 3

\O

0 oxy-estratrienes according to claim 16 and 17-oxo-estratrienes according to claim 18, which can be used as intermediate products. The invention as claimed also provides 17a-alkyl-17poxy-estratrienes for the production of pharmaceutical agents and pharmaceutical compositions containing compounds according to the invention.

The 17a-alkyl-173-oxy-estratrienes according to the invention have general formula I: 00 00 OR17 Hal ,\R17"

IN

Vo

I

0RO

'SK

Here, in particular: Hal F or Cl; this radical is bonded in 11 P-position to the estratriene skeleton; R hydrogen, Ci- C 4 -alkyl, -alkanoyl or, in more cyclic terms, C 3

C-

ether with an O atom,

R

17 hydrogen, Ci- C 4 -alkyl and Ci- C 4 -alkanoyl, RI CI- -C 4 -alkyl, Ci-C 4 -alkynyl as well as an at least partially fluorinated alkyl radical, whereby R 17 means -O in 17p-position and R 17 in -7-position-is-bonded-to-the-estratrieneskeleton; SK whereby this grouping is bonded via U in 7aposition to the estratriene skeleton.

In the side chain, the symbols U, V, W, X, Y, Z and E have the following meanings: U represents either a straight-chain or branched-chain C C 3-alkylene, -alkenylene or -alkynylene radical or the group A-B, whereby A is bonded to the estratriene skeleton and represents a benzylidene radical that is bonded via -CH2- to the estratriene COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:24 FROM-DCC SYDNEY +61292621080 T-196 P010/068 F-200 4

NO

0 skeleton, a phenylene radical or a C 1 C3-alkylaryl radical that is bonded via the alkyl group to the estratriene skeleton, and B stands for a straight-chain or branhed-chaino C) C 3 -alkylene, CM -alkenylene or -alkynylene radical, and whereby A and B also can be connected to one another via an 0 atom.

O V represents a CH 2 group or a C(0) group.

c W is an N(R) group or an group or an azolidinylene ring or an LO azolidinylene-N-oxide ring, 0 O whereby the azolidinylene ring or azolidinylene-N-oxide ring includes at least one C atom of grouping X, whereby R 6 is also either H or CH2-R 7 or C(0)-R 7 in which R 7 can mean, as follows: a) hydrogen or b) a straight-chain or branched-chain, non-fluorinated or at least partially fluorinated Ci- C 1 4 -alkyl, -alkenyl or-alkynyl radical, which can be hydroxylated in one or more places and which can be interrupted by one to three of the heteroatoms and and/or the groupings -NR 9 in which

R

9 stands for hydrogen or a C 1

C

3 -alkyl radical, or c)-a-munsubstituted or substituted-aryl or heteroaryl radical-or-- d) an unsubstituted or substituted C 3 Cio-cycloalkyl radical, or e) an unsubstituted or substituted C 4 Cis-cycloalkylalkyl radical, or f) an unsubstituted or substituted C 20 -aralkyl radical, or g) an unsubstituted or substituted heteroaryl-C1- -Cs-alkyl radical or h) an unsubstituted or substituted aminoalkyl radical or a biphenyl radical, X is preferably a straight-chain or branched-chain C Cl2-alkylene, -alkenylene or -alkynylene radical.

COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:25 FROM-DCC

SYDNEY

+61292621080 T-196 P011/068 F-200 a Y can be a direct bond between X and Z. Y can also mean the following, however: Sa) an SOn-R' 1 group, only ifW is an group or an azolidinylene-N-oxide ring and not an N(R) group or an azolidinylene ring, whereby n 0, 1 or 2, and whereby R' represents a direct bond between SO, and Z or a straight-chain or branched-chain CI- C6-alkylene, -alkenylene or -alkynylene radical, or b) the group R" or whereby R" stands for 00 Si) a straight-chain or branched-chain Ci- Cs-alkylene-, 0 -alkenylene- or -alkynylene radical or for

NO

Sii) an unsubstituted or substituted aryl radical or heteroaryl radical or for iii) an unsubstituted or substituted

C

3 Clo-cycloalkyl radical or for iv) an unsubstituted or substituted

C

4 Cs-cycloalkylalkyl radical or for v) an unsubstituted or substituted

C

7 C2o-aralkyl radical or for vi) an unsubstituted or substituted heteroaryl-C -C6-alkyl radical, or c) the grouping CH CF or d) the grouping

HN-C()-_NH-R

12 whereby

R

12 stands for an Unsubstituted or substituted arylene radical and whereby

R

12 is bonded to Z.

Z represents a direct bond between Y and E or a straight-chain or b r Calkylnhede -aly-chainQlalkmyylene radical, which can be partially or completely fluorinated.

E is a CF 3 group or an at least partially fluorinated aryl group, in particular a phenyl group.

Moreover, preferably hydrogen atoms are bonded to positions 1, 2, 4, 6 to 9 and 11 to 16 in the estratriene skeleton. In principle, however, the estratriene skeleton can also be modified, for example by a hydrocarbon bridge, for example a 15P,163-methano group.

Hal in particular stands for fluorine.

COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:25 FROM-DCC

SYDNEY

+61292621080 T-196 P012/068 F-200 6 O

R

3 can be hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-

O

butyl, a corresponding alkanoyl (acetyl, propionyl, butanoyl) or a cyclic ether. R S in particular stands for hydrogen, CH 3 CH3CO or C 5 HoO.

R

17 and R 17 are in particular methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl, whereby

R'

7 in addition can also be hydrogen, acetyl, propionyl and butanoyl, and whereby in this case, the corresponding isomers can be included. In addition, R17" can be 00 Sethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl as well as S trifluoromethyl, pentafluoroethyl, heptafluoropropyl and nonafluorobutyl, whereby in this ocase, the corresponding isomers are also included. R 17 is in particular hydrogen, CH3 or

CH

3 CO. R 17 preferably stands for methyl, ethynyl and trifluoromethyl.

U can be in particular a straight-chain or branched-chain alkylene radical and in particular a methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene or tridecylene radical. U preferably stands for (CH 2 whereby p is an integer from 2 to 10. In particular, U is preferably a butylene, pentylene, hexylene or heptylene radical. U is quite especially preferably an nbutylene radical, in the formula (CH 2 )p for U, p 4.

In particular, V stands for CH2. The grouping U-V thus can be n-pentylene in a quite preferred embodiment.

In particular, W stands for the amine-N-oxide

N+(O)(R

6 or for the amine_(l) 4 whereby R 6 is preferably hydrogen or CH2-R 7 in which R 7 stands in particular for hydrogen or methyl or ethyl. R 6 is thus preferably hydrogen or a Ci- C3-alkyl radical, thus in particular a methyl, ethyl, n-propyl or iso-propyl radical. In an especially preferred embodiment, W represents an N(O-)(CH 3 group (N-methylamine-N-oxide).

X preferably stands for (CH2)q, whereby q 0 or an integer from 1 to 12, thus for a direct bond between W and Y or for a straight-chain or branched methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:25 FROM-DCC SYDNEY +61292621080 T-196 P013/068 F-200 7 Io undecylene or dodecylene radical. In an especially preferred embodiment, X is an ethylene,

O

N n-propylene, n-butylene, n-pentylene, n-hexylene, n-heptylene or n-octylene radical.

In particular, Y can rrepresent a direct bond between X and Z. If this is the case, X c stands for a longer alkylene chain, thus in particular, X stands for n-hexylene, n-heptylene or n-octy]ene. In a preferred embodiment, Y can also be an SOn group, whereby n 0, 1 or 2, thus a sulfanyl group, a sulfinyl group or a sulfonyl group. IfY is an SO, group, X represents Sa rather shorter alkylene chain, in particular an n-propyl chain.

Z is preferably a direct bond between Y and E or a straight-chain or branched-chain S Ci- C 7 -alkylene radical, which can be at least partially fluorinated. In particular, Z can be a methylene, ethylene, propylene or butylene radical, which can be at least partially fluorinated.

In particular, Z is difluoromethylene or a straight-chain alkylene radical, which is perfluorinated on one end, thus, for example, a 1,1-difluoroethylene, 1,1, 2 2 -tetrafluoro-npropylene or 1,1,, 2 ,2,3, 3 -hexafluoro-n-butylene radical. Alkylene radicals that carry only two fluorine atoms on a terminal C-atom are especially advantageous, whereby this CF 2 group is bonded to radical E. In this case, side chain SK is terminated with C 2 Fs.

In particular, E stands for CF 3 or for pentafluorophenyl. The grouping Z-E thus preferably represents one of the groups that is selected from the group that comprises C 2

F

5

C

3

F

7 and C 4

F

9 as well as C 6

F

s According to this invention pharmacologicalyo mpatible acid addition saltsas well..

as esters of 17ax-alkyl-17p-oxy-estratrienes are also included. The addition salts are the corresponding salts with inorganic and organic acids. As addition salts, in particular the hydrochlorides, hydrobromides, acetates, citrates, oxalates, tartrates and methanesulfonates are considered. If R 3 and R 7 are hydrogen, such that a 3,17p-diol is present, the esters of these hydroxy compounds can also be formed. These esters are preferably formed with organic acids, whereby the same acids as for forming the addition salts are suitable, namely in COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:25 FBOtI-DCC SYDNEY +61292621030 T-196 P014/068 F-200 8 INO particular acetic acid, but also higher carboxylic acids, such as, propionic, butyric, O isobutyric, valeric, isovaleric or pivalic acid, The novel I 7a-alkyl- 1 7P-oxy-estratrjenes have several chiral centers, for example also on an N atom that is optionally oxidized to form N-oxide. There are therefore several stercoisomeric forms of each compound in each case. The compounds of fonnula I can be present as tautomers, stereoisomers or geometric isomers. The invention also comprises all 00 possible isomers such as E- and Z-isomers, S- and R-enantiomers, diastereorners, racemates and mixtures thereof including the tautomeric compounds. All of these isomeric compounds O are even if not expressly indicated in each case components of this invention. The isomeric mixtures can be separated into enantiomers or E-/Z-isomers according to commonly used methods, such as, for example, crystallization, chromatography or salt formation.

Especially suitable compounds as defined by the invention are estratrienes with general formula L, namely 1) 11 P-Pluoro-7a- 5[ehl77,,,,,-etaloooy ann~etl-17atmethylestra- 1.3,5(1 O)-triene-3, 1 7f-diol N-oxide 2) 11 p-Fluoro-7a- {5-[methyl(8,s,9,9, 10,10,1 O-heptafluorodecyl)axinojpentylp 17amethylestra- 1,3,5(l 0)-triene-3, 17p-dio1 N-oxide 3) I I P-Pluoro-7cc- f(5-[methyl(7,7,8,8,9,9, 10,10, 1 O-nonafluorodecyl)aminoppentyl) -l7ct-nethylestra-i1.

3 ,$(lO)-triene-3,I1713:iol N-oxide-...

4) 11 g-Fluoro-7a- {S-[methyl(88,9.9,9-pentanluorononyl)amaino~pentyl} -17atmethylestra- 1,3,5( lO)-triene-3, 1 7-dio1 N-oxide 1i J-Fluoro-7cz- {-[methyl(9,9, 10,10,1 O-pentafluorodecyl)aminojpentyp 1 7cmethylestra- 1,3>5(1 O)-triene-3,1I7f3-diol N-oxide 6) 11 1-Fluoro-7cc- 5-[methyI(8,8,9,9,9..pentafluorouonyl)arnjno]penyl}-1 7cznethylestra-1.3,5(1o)-triene-3,171-diol COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-' 05 17:25 FHOM-DGC SYDNEY 19513 +61292621080 T-196 P015/068 F-200 9 INO7) 110J-Fluoro-7at-{5-[methyl(7,7,8,8,9,9,10,10,1 O-nonrafluorodecyl)aminojjpwtyl} -17acc-I methylestra- 1,3,5(1 O)-triene-3, 1 71-diol 8) 11 P-Fluoro-7a- f-mty(,,,,,,-etfurnnlaiopny)-I7c methylestra- 1,3,5(1 0)-triene-3, 1 7f3-diol 9) 1i7a-E-thynyl-1 11-fluoro-7a- f{S-methyl(7,1,8,s9,99 0, 10 1 0l-nonafluorodecyl).

amninojpentyl} -estra- 1,3,5(l O)-triene-3, 1 7J-diol 00 1 7c-Ethynyl-1 I 5 -fluoro-3-(2-tetra11ydropyranoy 0 yy.7a [methyl(7,7,s,8,99, 10,10,1 O-nonafluorodecy1)aaiino]penty1} -estra- 1,3,5(1 O)-trien- 17p-oI 11) 11 P-Fluoro-3-(2-tetrahydropyranyloxy)-7at {5-[methyl(7,7,S, 8,9,9, 10,10, nonafluorodecyl)amino~pentyiy. 11c-methylestra. 1 3 ,5(1O0)-trien- 1 7A3 -ol 12) 11 1-Fluoro-7a- {5-[methyl(7,7,8,89,910,10,1 O-nonatlorcdecyl)amino]pentylp 1 7atrifluoromethylestra-1,3,5(1 O)-triene-3, 17p-dio1 13) 11 I-Fluoro-7ac- 5[atyl6677,,,-etaloI tlaio~etl7czmethylestra- 1,3,5(1 O)-triene-3, 1 7-dio1 14)11 j3-Pluoro-7a- {5-[inethyl(8,8,9,9, 10,10,1 O-heptafluorodecyl)amninojpentyly. I7axmethyiestra,3,5(10)trjcne-317p-dio1 1 5)11 1-Fuoro-7c- {5-[methyi(6,6,7,7,8,,9,9,10,10,i O-undecaflucrodecyl)amino}.pentyl} -1 7ct-methylestra- 1,3,5(1 O)-triene-3, 1 7f-diol 16) 1] j-Fluoro-7at(-mty(,,,,,,,-noal rotl~rio etl-I7c&methylestra-1 lO)-triene-3, 1 7f-diol 17)1 I3p-Fluoro-7cc- {Sfmethyl(9,9, 10,10,11,1 1,11 -heptafluorcundecy)ino]-penty} I 7a-methylestra- 1,3,5(1 0)-triene-3, 1 7J-diol COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:26 FROM-DCC SYDNEY +61292621080 T-196 P016/068 F-200 INO 18) 110-Fluoro-7a-{5-[methyl(9,9,10,10,10-pentafluorodecyl)amino]pentyl}-17a- 0 C methylestra-1,3, 5 (10)-triene-3,17p-diol SPhysical properties of some of these compounds are indicated in Table 1.

The 17a-alkyl-17p-oxy-esatatrienes according to the invention are distinguished from 0' known compounds primarily in that a halogen atom is bonded in 1 la-position, and/or an alkyl 00 radical is bonded in 17ac-position. In addition, preferred compounds in the 7a-side chain can 0 have an amine-N-oxide grouping.

o In contrast to 3,17-dihydroxy-estratrienes, which are unsubstituted in 17a-position, virtually no metabolites are formed from the 17a-alkyl-17-oxy-estratrienes according to the invention. Metabolites can also be biologically active. It has namely been revealed that the estratriene derivatives that are produced by oxidation of the hydroxy group that is bonded in 17P-position, whereby a 17-oxo derivative is produced, have very strong biological activity.

By blocking the 17a-position by an alkyl radical, especially by a Ci- C 4 -alkyl group, this oxidation reaction is stopped, such that a metabolic variety is also suppressed. The estratrienes according to the invention that are used as active ingredients therefore exhibit a species-independent effectiveness and activity. The advantage of these compounds therefore exists in that the full effectiveness of the active ingredient is achieved in a single compound.

For this reason, advantages arise in the development of pharmaceutical agents, since owing to a lack of formation of biologically active metabolites, the effectiveness can more simply be ascribed to certain structural principles, such that a targeted search for active ingredients is made possible.

In addition, the 17a-alkyl-17p-oxy-estratrienes according to the invention inhibit the action ofestradiol to approximately 100%. They therefore represent antiestrogens.

COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:26 FROM-DCC

SYDNEY

+61292621080 T-196 P017/068 11 were To study the effectiveness of the compounds according to the invention, in-vivo tests were performed on infant rats. To this end, the uterus growth was performed with peroral administration of the pharmaceutical agent (test on antiestrogenic action).

The principle of this method consists in examining what influence the administration of compounds that have an antiestrogenic action has in the simultaneous administration of estrogens. In the case of rodents, the uterus reacts to the dispensing of estrogens namely with 00 a weight increase (both by proliferation and by water retention). This growth can be inhibited ci in a dose-dependent manner by simultaneous administration of compounds that have an oantiestrogenic action.

For the tests, infant female rats with a weight of 35-45 g at the beginning of the test were studied. Five to six animals were tested per dose. For the p.o. administration, the substances were dissolved in one portion of ethanol and were filled out with nine portions of peanut oil For acclimation, the young rats just dropped by the mothers were delivered one day before the beginning of treatment and immediately supplied with food right in the cage. The animals were then treated in combination with 0.5 gg of estradiolbenzoate (EB) once daily for three days. EB was always administered subcutaneously while the test substance was administered p.o. 24 hours after the last administration, the animals were weighed, killed, and the uteri were removed. The moist weights (less contents) were determined from the -prepared uteri..The following control studies were performed: for a negative control, 0.2-mlof_an EEO mixture per animal and day was added. For a positive control study, 0.5 ig of EB/O. 1 ml per animal and day was administered, From the relative organ weights (mg/100 g of body weight), the average values with standard deviation (X SD) as well as the significance of the differences in the control group (EB) in the Dunnett Test (p 0.05) were determined for each group. The inhibition (in COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:27 FROM-DCC SYDNEY +61292621080 T-196 P018/068 F-200 12 IN relative to the EB control was determined with a computer program. The relative

O

Seffectiveness of the test substances was calculated by a covariance and regression analysis.

STest results for selected compounds are reproduced in Table 2. Test results for the uterus growth with simultaneous administration of 0.5 jpg of EB/0, 1 ml as well as peroral dispensing of the compounds that have an antiestrogenic action in an amount in the range of 0.03 mg/kg of body weight and 0.3 mg/kg of body weight are reproduced there, 00 It can be seen from Table 2 that the antiestrogenic action is nearly 100% when a 0 CN dosage of about 0.3 mg/kg in the case of peroral administration was added.

The compounds according to the invention are as effective as or even more effective than the corresponding compounds that are not substituted in 17a-position. Compared to the compounds that are not substituted in 17a-position, the estratrienes according to the invention in addition have a better compatibility, such that the latter are to be preferred. The better compatibility can be attributed in particular to the fact that the formation of metabolites is largely limited.

Determination of metabolic stability: in-vitro 17J3-HSD test 17#/-HSD2 mediates the intestinal enzymatic dehydrogenization of an OH group in 17position of the sterane skeleton into a ketone group.

For this test, the following materials are used: Na-Phsphate-buffer: 100 mmol of Na2HPO4 x 2420 arid-100 mmol o-fNaHI2PO 4 x H 2 0 Test substance solution of 11 p-Fluoro-7a- {5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}-17amethylestra-1, 3 5 (10)-triene-3,170-diol (compound 1, as a representative of the compounds of general formula I) and COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:27 FROM-DCC SYDNEY +61292621080 T-196 P019/068 F-200 13 SO 11 -Fluo r o -71-5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyI-estra 1,3,5(10)- N triene-3,17-diol (compound 15 jimol in MeOH (0.3 umol in the test batch).

t Cofactor solution: 2 ml of glucose-6-phosphate (160 mmol)/MgCl 2 (80 mol) c mixture is added to 400 pl of a glucose-6-phosphate-dehydrogenase solution, and then 15.6 mg of NADP and 13.4 mg of NAD are added.

Microsome solution: intestinal microsomes (InVitroTechnologies; protein content: 24 mg/ml; CYP450 content: 0.058 nmol/mg of protein) I In the water bath, it is thawed at 37 0 C (-60 seconds) and diluted with Naphosphate buffer to a concentration of 5 mg/ml of protein.

In each case, 170 l/well of the buffer and 5 RI/well of the test substance solutions are introduced into the corresponding wells, whereby double values are applied for each measuring time 10, 20, 30, 45 and 60 minutes).

In each case, 250 pl of ice-cold MeOH is added to the 0-minute values. Then, 25 p of microsome solution and 50 pl of cofactor solution are added immediately to all wells. The samples of the 0-minute values are stored without incubation at -20 0 C for about 24 hours.

The other samples are incubated in each case for 10, 20, 30, 45 and 60 minutes at 37°C, and the dehydrogenation reaction is stopped after these times by the addition of 250 pl of ice-cold MeOH in each case. The samples are stored until measurement per LC/MS/MS at -20oC is done-fot g abo ut-24-hours-andcentrifage-at -000pm-before-analysis-whereby the supernatant is measured.

The concentrations of the test substances measured per LC/MS/MS and the resulting 17 ketone product are reproduced in Figures 2a-2f Compound 1 is metabolically stable in intestinal microsomes but not in liver microsomes, which indicates that different phase-1 reactions occur in both tissues. The putative product of the 178HSD-reaction, 11 -fluoro-7a- {5-[methyl(8,8,9,9,9- COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:27 FROM-DCC SYDNEY +61292621080 T-196 P020/068 F-200 14 N pentafluorononyl)amino]pentyl}-estra-1,3,5(10)-trien-3-ol-17-one, compound 3, does not 0 occur in any of the tissues, however. In contrast to this, compound 2, which does not have any 17 methyl group, is degraded in intestinal microsomes, whereby the corresponding 17c ketone is produced. Consequently, the high metabolic stability of compound 1 can be explained by the blocking of the 17BHSD reaction, which is completely stopped by a 178methyl group. It therefore has to be assumed from this that an alkyl group, for example a 00 Smethyl group, or else an alkenyl or alkynyl group, for example an ethinyl group, in the 0 vicinity of the 17-OH group, prevents the intestinal (in contrast to the hepatic) oxidation

O

S thereof to ketone, surprisingly enough, which should have the result of higher oral bioavailability.

In addition, the compounds according to the invention are thus distinguished by an extraordinarily high bioavailability, such that high serum levels can be reached by the administration of the compounds according to the invention to the affected patients. In connection with the already mentioned high compatibility, a successful and reliable therapy can thus be performed since it is possible with the compounds according to the invention to set a serum level of the active compound that has a sufficient distance to the effect level of the corresponding compound. Effect level means the serum concentration of the active ingredient that is necessary at the least to achieve the desired effect in the respective indication.

The 17a-alkyl-Lg-oxy-estratrienes with.generalformula I according.to the-invention_are suitable in particular for the production of pharmaceutical agents. The invention therefore relates in addition to the pharmaceutical preparation that in addition to at least one 17ac-alkyl- 17p-oxy-estratriene with general formula I, which has the substituents Hal, R 3

R'

7

R

1 7

U,

V, W, X, Y, Z and E according to the definitions above, contains at least one pharmaceutically compatible vehicle.

COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:27 FROM-DCC SYDNEY +61292621080 T-196 P021/068 F-200 No The pharmaceutical preparations or compositions according to the invention are 0 Cl produced with commonly used solid or liquid vehicles or diluents and commonly used pharmaceutical and technical adjuvants according to the desired type of administration with a suitable dosage in a way that is known in the art. Preferred preparations consist of a Cl dispensing form that is suitable for oral, enteral, or parenteral administration, for example i.p.

(intraperitoneal), i v. (intravenous), i.m. (intramuscular) or percutaneous administration. Such 00 dispensing forms are, for example, tablets, film tablets, coated tablets, pills, capsules, 0 Cl powders, creams, ointments, lotions, liquids, such as syrups, gels, injectable liquids, for Sexample for i.m. or percutaneous injection, etc. In addition, depot forms, such as implantable preparations, as well as suppositories, are also suitable. In this case, depending on their type, the individual preparations release to the body the estratrienes according to the invention gradually or all at once in a short time.

For oral administration, capsules, pills, tablets, coated tablets and liquids or other known oral forms for dispensing can be used as pharmaceutical preparations. In this case, the pharmaceutical agents can be formulated in the way that they release the active ingredients either in a short time and pass on to the body or have a depot action, so that a longer-lasting, slow supply of active ingredients to the body is achieved. In addition to at least one estratriene, the dosage units can contain one or more pharmnnaceutically compatible vehicles, for example substances for adjusting the rheology-of-the pharmaceutical agent, surfactants, solubilizers, microcapsules, microparticles, granulates, diluents, binders, such as starches, sugar, sorbitol and gelatins, also fillers, such as silicic acid and talc, lubricants, dyes, perfumes and other substances.

Corresponding tablets can be obtained, for example, by mixing active ingredient with known adjuvants, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinyl pyrrolidone, explosives such as corn starch or alginic acid, binders such as starch or COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:28 FROM-DCC SYDNEY +61292621080 T-196 P022/068 F-200 16 Sgelatin, lubricants such as carboxypolymethylene, carboxy methyl cellulose, cellulose acetate

O

phthalate or polyvinyl acetate. The tablets can also consist of several layers.

Coated tablets can be produced accordingly by coating cores that are produced c analogously to the tablets with agents that are commonly used in coated tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. In this Scase, the shell of the coated tablet can also consist of several layers, whereby the adjuvants 00 that are mentioned above in the case of the tablets can be used.

0 Capsules that contain active ingredients can be produced, for example, by the active

O

S ingredient being mixed with an inert vehicle such as lactose or sorbitol and encapsulated in gelatin capsules.

The estratrienes according to the invention can also be formulated in the form of a solution that is intended for oral administration and that in addition to the active estratriene contains as components a pharmaceutically compatible oil and/or a pharmaceutically compatible lipophilic surfactant and/or a pharmaceutically compatible hydrophilic surfactant and/or a pharmaceutically compatible water-miscible solvent.

To achieve better bio-availability of the active ingredients according to the invention, the compounds can also be formulated as cyclodextrin clathrates. To this end, the compounds are reacted with 1- or -y-cyclodextrin or derivatives thereof.

f cream ointments, lofions and liquids that cn e applie toiall are be used the latter must be constituted so that the compounds according to the invention are fed to the body in adequate amounts. In these forms for dispensing, adjuvants are contained, for example substances for adjusting the rheology of pharmaceutical agents, surfactants, preservatives, solubilizers, diluents, substances for increasing the permeability of the estratrienes according to the invention through the skin, dyes, perfumes and skin protection agents, such as conditioners and moisturizers. Together with the compounds according to the invention, other active ingredients can also be contained in the pharmaceutical agent COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:28 FROM-DCC SYDNEY +61292621080 T-196 P023/068 F-200 17 IN [Ullmanns Enzyklopddie der technischen Chemie [Ullmann's Encyclopedia of Technical 0 ^C Chemistry], Volume 4 (1953), pages 1-39; J Pharm. Sci., 52, 918 ff. (1963); issued by Czetsch-Lindenwald, Hilfsstoffe far Pharmazie und angrenzende Gebiete [Adjuvants for SPharmaceutics and Related Fields]; Pharm. Ind., 2, 72 ff(1961); Dr. H. P. Fiedler, Lexikon der Hilfsstoffefiir Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary ofAdjuvants for Pharmaceutics, Cosmetics and Related Fields], Cantor AG, Aulendorf/Wilrtt., 1971].

00 SThe substances according to the invention can also be used in suitable solutions, such C as, for example, physiological common salt solution, as infusion or injection solutions. For Va S parenteral administration, the active ingredients can be dissolved or suspended in a physiologically compatible diluent. As diluents, in particular oily solutions, such as, for example, solutions in sesame oil, castor oil and cottonseed oil, are suitable. To increase solubility, solubilizers, such as, for example, benzyl benzoate or benzyl alcohol, can be added.

To formulate an injectable preparation, any liquid vehicle can be used in which the compounds according to the invention are dissolved or emulsified. These liquids frequently also contain substances to regulate viscosity, surfactants, preservatives, solubilizers, diluents and other additives, with which the solution is set to isotonic. Other active ingredients can also be administered together with the estratrienes.

The estratrienes according to the invention can also be applied in the form of a depot injection or an implant reparation for example subcutaneously _Such_pparations can be formulated in such a way that a delayed release of active ingredients is made possible. To this end, known techniques can be used, for example depots that dissolve or operate with a membrane. Implants can contain as inert materials, for example, biodegradable polymers or synthetic silicones, for example silicone gum. The estratrienes can also be incorporated in, for example, a patch, for percutaneous administration.

It is also possible to incorporate the substances according to the invention in a transdermal system and thus to administer them transdermally.

COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:28 FROM-DCC SYDNEY +61292621080 T-196 P024/068 F-200 18 S To achieve an improved transdermnnal skin flow that produces therapeutically effective 0 C, blood levels, the compounds according to the invention can also be incorporated in Stransdermal systems analogously to what is described for other antiestrogens in WO 01/76608. These transdermnal systems are distinguished by a special ratio of 2 penetration intensifiers, in particular laurie acid and propylene glycol.

The dosage of the substances of general formula I according to the invention is 00 determined by the attending physician and depends on, the substance that is administered, ci the method of administration, the disease that is to be treated and the severity of the disease.

o The amount of the compounds to be administered fluctuates within a wide range and can cover any effective amount. Based on the condition to be treated and on the type of administration, the amount of administered compound can be 0.1-25 mng/kg of body weight, preferably 0.5-5 mg/kg of body weight, per day. In humans, this corresponds to a daily dose of 5-1250 mg. The preferred daily dosage in humans is 50-200 mg. This applies in particular to tumor therapy. The dose can be given as a single dose to be administered once or divided into two or more daily doses.

The compounds of general formula I represent, as already mentioned, compounds with very strong antiestrogenic action.

The compounds are suitable for therapy of estrogen-dependent diseases, for example, breast cancer (secondline theapyoftamoxifen-resistant breast cancer; for adjuvant treatment of breast cancer instead oftamoxifen), endometrial carcinoma, prostate hyperplasia, anovulatory infertility and melanoma.

The compounds of general formula I can also be used as components in the products that are described in, EP 346 014 B1, whereby said products contain an estrogen and a pure antiestrogen, namely for simultaneous, sequential or separate use for the selective estrogen therapy ofperimnenopausal or postmenopausal women.

COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:29 FROM-DCC SYDNEY +61292621080 T-196 P025/068 F-200 19 N The compounds of general formula I can be used together with antigestagens

O

(competitive progesterone antagonists) to treat hormone-dependent tumors (EP 310 542 A).

SOther indications in which the compounds of general formula I can be used is male Shair loss, diffuse alopecia, an alopecia caused by chemotherapy as well as hirsutism (Hye-Sun Oh, and Robert C. Smart, Proc. Natl. Acad. Sci. USA, 93 (1996) 12525-12530).

In addition, the compounds of general formula I can be used for the production of 00 medications for treating endometriosis.

0 The compounds of general formula I can also be used for the production of cO o pharmaceutical compositions for male and female birth control (male birth control: DE 195 862.0

A).

The estratrienes according to the invention can be produced analogously to the known process: In Figure 1, a reaction diagram is reproduced, according to which the compounds according to the invention can be produced. In this diagram, the 17a-alkyl-17-oxyestratrienes according to the invention are referred to with the term "17a-methyl-amine" and "1 7 a-methyl-amine-oxide." However, the compounds with the designation "17a-methyl" in 7a-position have a side chain without an amine grouping. The compounds that carry a hydroxy or alkoxy group in 171-position, an alkyl group in 17a-position as well as a 7a-side chain with an amine grouping are referred to as -methyl-amine." n a corresponding way, the compounds that are referred to as "1 7 a-methyl-amine-oxide" are the amine-Noxides according to the invention of the previously referenced "I7a-methyl-amine" compounds.

If R 3 H, an etherification is performed with a reagent R 3 in which X means a leaving group.

COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:29 FROM-DCC SYDNEY +61292621080 T-196 P026/068 F-200 S Compounds that are referred to as "17p-OH" are also estratrienes that have a hydroxy

O

C group or alkoxy group in 17p-position but have neither a 17a-alkyl grouping nor an amine grouping in the side chain in 7a-position. Compounds that are referred to as "17-keto" are C estratrienes that carry an oxo group in 17-position but do not carry any amine grouping in the side chain in 7a-position. The other compounds that are referred to as "17p-OH-amine," "17keto-amine," "170-OH-amine-oxide" and "17-keto-amine-oxide" have corresponding C, substitution patterns.

0 c\ In principle, all cited compounds, starting from the 17-oxo compound, can be 0 O produced. The production of the 17-oxo compounds is described by way of example in, for example, WO 99/33855 Al. Derivatives other than the compounds that are disclosed expressly in this document with the same substitution pattern can be produced analogously.

In the same way, the estratrienes according to the invention can also be produced starting from the 17p-hydroxy compounds or the 17p-alkoxy compounds The production of these derivatives is also indicated in, for example, WO 99/33855 Al. In the same way, the production of the 17p-hydroxy compounds or 17p-alkoxy compounds as well as the 17-oxo compounds with an amine grouping in the side chain in 7ac-position is disclosed in this document. If the production of the starting compounds is not described, the starting compounds are known and commercially available, or the compounds are synthesized analogously to the described processes. Below, the production of a few precursors, intermediate products and products is described by way of example.

In the production of the substances according to the invention, for example, the following processes are employed (see also, in this respect, EP 0138 504 Bl; WO 97/45441 Al; WO 98/07740 Al; WO 99/33855 Al): The 17a-alkyl-17p-oxy-estratrienes according to the invention can be produced starting from the corresponding 17p-oxy-estratrienes The synthesis of these COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:29 FROM-DCC SYDNEY +61292621080 T-196 P027/068 F-200 21 o starting substances is also described in, for example, WO 97/45441 Al and WO 98/07740 Al.

O

N The side chain in 7a-position can be built up, for example, according to the procedure that is indicated in WO 98/07740 Al.

Cc, Then, the 173-hydroxy compound or the 17p-alkoxy compound that is produced can be oxidized with an amine grouping in the side chain in 7a-position by oxidation to form the corresponding 17-oxo compound ("17-keto-amine"), To this end, commonly used oxidizing 00 C agents, for example chromium(VI) compounds (Jones oxidation), nitric acid, manganese dioxide, selenium dioxide and SO 3 in pyridine can be used. The ketones can also be produced 0 by catalytic dehydrogenation with metallic copper, silver, copper chromate and zinc oxide at elevated temperature or by dehydrogenation with ketones, for example cyclohexanone, by Oppenauer oxidation. If the group reducing the side chain contains, for example, S or SO groups, the latter can optionally be selectively reduced again after an over-oxidation.

In another process variant, the 17 P-oxy-estratrienes without amine-purging in the side chain can be oxidized directly to the 1 7 -oxo-estratrienes ("17-keto"), and the latter are then aminated in a known way in the 7a-side chain.

Then, an alkyl group can be introduced in 17a-position. To this end, commonly used nucleophilic alkylating reagents can be used, for example Grignard reagents or alkyllithium compounds. In this reaction, the desired 17a-alkyl-17p-oxy-estratrienes are produced ("17cmethyl," if a start is made from the corresponding 171-hydroxy-estratrienes without an amine grouping in the side chain in 7a-position or "17a-methyl-amine," if a start is made from the corresponding 7 -hydroxy-estratrienes with an amine grouping in the side chain in 17-position ["17P-OH-amine"]). In addition, the 17-oxo-estratrienes that are obtained as intermediate products can first be alkylated in a known way and then aminated in the 7a-side chain.

COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:29 FROM-DCC SYDNEY +61292621080 T-196 P028/68 F-200 22 o If the amine-N-oxide compounds ("17p-OH-amine-oxide" or "17-keto-amine-oxide" or "17a-methyl-amine-oxide") are to be produced, the corresponding estratrienes are oxidized with an amine grouping in the 7a-side chain ("17p-OH-amine" or "17-keto-amine" or "17a- Cf methyl-amine"), for example with hydrogen peroxide. In this reaction, the secondary OH group in 17P-position is not oxidized.

00 In an alternative procedure for the production of the 17ot-alkyl-17p-oxy-estratrienes o according to the invention, the previously-mentioned 17p-hydroxy-estratrienes with an amine IO grouping in the side chain in 7a-position ("17p-OH-amine") are also used as starting C substances.

The latter are first reacted to form the corresponding amine-N-oxide compounds 7-OH-amine-oxide"), whereby, as indicated above, commonly used oxidizing agents, for example, hydrogen peroxide, are used.

Then, the formed amine-N-oxide compounds ("17p-OH-amine-oxide") can be oxidized to the corresponding ketone ("17-keto-amine-oxide"), whereby the same oxidizing agents, as indicated above, can be used. In this case, the 17-oxo compounds with an amine- N-oxide grouping in the 7a-side chain are produced.

For the production of the 17a-alkyl-17-oxy-estratrienes according to the invention, the keto group is in turn reacted according to the instructions above with suitable nucleophilic alkylating reagents. In this case, the 17ac-alkyl-17p-oxy-estratrienes with an amine-N-oxide grouping in the 7a-side chain ("17ca-methyl-amine-oxide") are produced.

For the production of the 17ac-alkyl-17p-oxy-estratrienes according to the invention, intermediate products with the following general formula II are thus also formed, which also are the subjects of this invention: COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:30 FROM-DCC SYDNEY +61292621080 T-196 P029/068 F-200 23

NO

(N OR 1 0

II

RO ^'SK Here, in turnm: Ci Hal F or Cl, whereby this radical in 11 p-position is bonded to the estratriene skeleton, SR hydrogen, Ci- C4-alkyl, Ci- C4-alkanoyl or, in more cyclic terns, a

C

3

C

7 -ether with an O Atom, R hydrogen, Cl- C 4 -alkyl and Ci- C 4 -alkanoyl, whereby R 1 7 in 17pposition is bonded to the estratriene skeleton, and SK U-V-W-X-Y-Z-E, whereby this grouping is bonded to the estratriene skeleton via U in 7a-position, and whereby U, V, X, Y, Z and E have the meanings that are further indicated above, and W stands for or for an azolidinylene-N-oxide ring, whereby the azolidinylene-N-oxide ring includes at least one C atom of grouping X, whereby R 6 otherwise has the meaning that is further indicated above.

In positions 1, 2, 4, 6 to 9 and 11 to 16 on the estratriene skeleton, hydrogen atoms are preferably bonded in turn, moreover. In principle, the estratriene skeleton can also be modified, however, by one hydrocarbon bridge, for example by a 151,1 group.

Especially preferred 17a-alkyl-17p-oxy-estratrienes with an amine-N-oxide grouping in the 7c-side chain with general formula II are the following compounds: COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23

I

23-05-' 06 17:30 FHOCM-DCC SYDNEY+619500 +61292621080 T-196 P030/068 F-200 24 INOXl) I1 f-Fluoro-7cx- {$-[mnethyl(S,8,9,9,9-pentafluorononyl)aminolpenty1}esfra-1,3,5(10)- Cl triene-3,l 7p-diol N-oxide X2) Ii j 3 -Fluoro-7cc-[5-(methyl 3 2 3 4 5,6-pentafluorophenyl)sulfanyI]propylyrn amino)pentyl)estra- 1,3,5(1 O)-triene-3, 1 7)-diol N-oxide X3) 1 3 0-Fluoro-7c-[5-4nethyl 3 -{(4,4.5,5,5-pentafluoropentyl)sulfany].

propyl} amino)pentyl]estra- 1,3,5(1 0)-triene-3 ,1 7j-diol N-oxide 0 NOpropyl} amino)pentyllestra- 1,3,5(1 O)-triene-3,1I7J3-diol N-oxide Cl X5) 1i f-Fluoro-7i- {5-[methyl(7,7,8,S,9,9, 10,10, lO-nonafluorodecyl)anuino]pentyllestra.

l,3,5(10)-triene-3, 1 7f-diol N-oxide X6) 1 P-Fluoro-7cz-{5-[methyl(7,7,s,s 1Q10,1 O-nonafluorodecyl)aminojpentyl)> 1 7ct-methylestra- 1,3,5(1 0)-triene-3, 1 7-dio1 N-oxide Ii f-Fluoro-7a- {5-[methyl(7,7,8,8,9,9, 10,10,1 O-nonafluorodecyl)amino]pentyl} 1 7a-methylestra- 1,3,5(1 0)-triene-3, 1 71-diol N-oxide X(8) I 1-Pluoro-7x- {5-fmethyl(9,9, 10,10,1 O-pentafluorodecyl)amino]pentyl} estra- 1,3,5(1 O)-triene-3, 1 7j-diol N-oxide.

Physical properties of these compounds are indicated in Table 3.

~In addition, the 1 7 -oxo-cshrstrieno with n mink-N!-oxidegxpn that aretnnredin the production of the llcc-alkyl-17f3-oxy-estratrienes according to the invention in the 7aside chain as intenmediate products are also subjects of this invention. These compounds have general formula III: 0 Ha ttl fIII COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:30 FROM-DCC SYDNEY +61292621080 T-196 P031/068 F-200 Va 00

INO

Here: Hal F or Cl, whereby this radical is bonded in 110-position to the estratriene skeleton,

R

3 hydrogen, Ci- C 4 -alkyl, Ci- C4-alkanoyl or, in more cyclic terms, a C- C 7 -ether with an O atom, and SK U-V-W-X-Y-z-E, whereby this grouping is bonded via U in 7ccaposition to the estratriene skeleton and whereby U, V, X, Y, Z and E have the meanings that are further indicated above, and W stands for an N group or for an a2olidinylene-N-oxide ring, whereby the azolidinylene-Noxide ring includes at least one C atom of grouping X, whereby R6 also has the meaning that is further indicated above.

In positions 1, 2, 4, 6 to 9 and 11 to 16 on the estratriene skeleton, moreover, preferably hydrogen atoms are bonded in turn. In principle, the estratriene skeleton can also be modified, but, by a hydrocarbon bridge, for example a 15 P,160-methano group.

Especially preferred 17-oxo-estratrienes with an amine-N-oxide grouping in the 7aside chain with general formula III are the following compounds: Y1 i I1-Fluoro-7c-[5-(methyl (3-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]propyl) amnino)pentyl]estra- 1,3,5(10O)-trien-3-ol-17-one N-oxide T2 i 1 -Fluoro-7a-[5-(aethylT3-[(4,4,5,,55peinTafluoropentyl)§ulfanypropyjamino)pentyl]estra- 1,3,5(1 O)-trien-3-ol- 17-one N-oxide Y3 11 0-Fluoro-7- (5-[methyl(7,7,8,8,9,9, 10,10, 10-nonafluorodecyl)amino]pentyl} estra-1,3,5(10 )-trien-3-ol-] 7-one N-oxide.

Physical properties of these compounds are indicated in Table 4.

T

COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:30 FROM-DCC SYDNEY +61292621080 T-196 P032/068 F-200 26 O The compounds of general formula II and the compounds of general formula III are 0 C1 also compounds with antiestrogenic action. They can therefore be used in principle in the types of indications indicated above for the compounds of general formula I.

SBelow, the process steps for the production of the compounds according to the invention are described in more detail.

Without further elaboration, it is believed that one skilled in the art can, using the 00 C preceding description, utilize the present invention to its fullest extent. The following 0 C preferred specific embodiments are, therefore, to be construed as merely illustrative, and not Va S limitative of the remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius, and all parts and percentages are by weight, unless otherwise indicated.

Process Variant 1.1 (Production of 17-oxo-estratrienes with amine-N-oxide grouping in the side chain, starting from 17p-hydroxy-estratrienes with an amine grouping in the side chain via the corresponding 17-oxoestratrienes): a) Ell uora--{5meth.yl(,2,8,89,9,94,104,1 -onafluorodecyl)aminolpentyl}estra-1,3,5(10)-trien-3-ol-17-one (angle of rotation oxD of this compound (No. Z14) is indicated in Table ml of ethyldiisopropylamine is added in drops at 10°C to a solution of 1.23 g of pyridine sulfur trioxide complex in 10 ml of dried dimethyl sulfoxide. Then, 1.72 g of 1P-fluoro-7a-{5-[methyl(7,7,8,8, 9 ,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-triene-3,170-diol (compound No. Z9) as well as another 10 ml of dried COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:31 FROM-DCC SYDNEY +61292621080 T-196 P033/068 F-200 27 o dimethyl sulfoxide are added and stirred for 30 minutes at room temperature. Then, it 0 N is diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and sodium chloride solution, dried odn sodium sulfate, evaporated to the dry state in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 11- Fluoro-7a- {5-[methyl(7,7,8,8,9,9, 10,10,1 O-nonafluorodecyl)amino]pentyl) estra- 1, 3 ,5(10)-trien-3-ol-17-one, [oID in chloroform, is obtained.

0 b) ip-Fluoro-7a-{5-(methy(7,7,8,8,9,9,10,10,10-nonafluorodecyl)aminoj-

NO

O pentyl}estra-1,3,5(10)-trieno-3-ol-17-one N-oxide A solution of 0.5 g of 1 1P-fluoro-7a- s5-fmethyl(7,7,8,8,9,9,10,10,10nonafluorodecyl)amino]pentyl) estra-l ,3,5(10)-trien-3-ol-17-one in 11 ml of methanol and 11 ml of chloroform is mixed with 3.5 ml of 30% hydrogen peroxide solution and stirred for five days at room temperature. Then, it is mixed with sodium thiosulfate, added to water, extracted three times with dichloromethane, washed neutral, dried on sodium sulfate, evaporated to the dry state in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 401 mg of 11 -fluoro-7a- [methyl(7,7,8,8,9,9,1010,IO-nonafluorodecyl)aminojpentyl} estra-1,3,5(10)-trien-3-ol- 17-one N-oxide is obtained as a solid with a melting point of 84-86 0 C; [a]D +53.60, in chloroform, c) 11 P-Fluoro-7a- {5-[methyl(7,7,8,,9,9,1 0,10,1 0-nouafluorodecyl)amino.pentyl)1 71-methylestra-1,3,5(10)-triene-3,1 7-diol N-oxide A suspension of 2.3 g of cerium(III) chloride in 23 ml of tetrahydrofuran is mixed at o 0 C with 3.19 ml of a 3-molar methylmagnesium bromide solution in diethyl ether, and it is stirred for 30 minutes. A solution of 250 mg of 1 10-fluomro-7a- COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:31 FROM-DCC SYDNEY +61292621080 T-196 P034/068 F-200 28 O [methyl(7,7,8,8,9,9,10,0,10-nonafluorodecyl)amino]pentyl} estra-1,3,5(10)-trien-3-ol-

O

17-one N-oxide in 5 ml of tetrahydrofuran is added in drops thereto and then stirred Sfor 24 hours at room temperature, mixed at o°C with 10 ml of ammonium chloride Ssolution, extracted with ethyl acetate, washed with water, dried with sodium sulfate, concentrated by evaporation in a vacuum, taken up with 5 ml of methanol and 5 ml of chloroform, mixed with 2 ml of 30% hydrogen peroxide solution, mixed and stirred 00 Sfor 5 days at room temperature. Then, it is mixed with sodium thiosulfate, added to 0 C-i water, extracted three times with dichloromethane, washed neutral, dried on sodium Va sulfate, evaporated to the dry state in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 165 mg of 11 [methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl} -17-methylestra- 1,3,5(10)-triene-3,17p-diol N-oxide with a melting point of 122C is obtained.

Process Variant 1.2: (Production of 1 7-oxo-estratrienes with amine-N-oxide groupings in the side chain, starting from 17p-hydroxy-estratrienes with amine groupings in the side chain via the corresponding 17p-hydroxy-estratrienes with amine-N-oxide groupings in the side chain): a) 11 -Fluoro-7a-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino] pentyl}-estra-l ,3,5(10)-triene-3,17-diol N-oxide A solution of 50 g of 11 0-fluoro-7a- {5-[methyl(7,7,8,8,9,9,10,10,10nonafluorodecyl)amino]pentyl}-estra-1,3,5(10)-triene-3,17p-diol in 500 ml of methanol and 500 ml of chloroform is mixed with 7.3 g of sodium bicarbonate as well as 45 ml of 30% hydrogen peroxide solution, and it is stirred for 3 days at room temperature. Then, it is mixed with sodium thiosulfate, added to water, extracted three COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:31 FROM-DCC SYDNEY +61292621080 T-196 P035/068 F-200 29 N times with dichloromethane, washed neutral, dried on sodium sulfate, evaporated to N the dry state in a vacuum and absorptively precipitated from diethyl ether. 48.3 g of 11 -fluoro-7c- {5-[methyl(7,7,8,8,9,9,.10,10,10-nonafluorodecyl)amino]pentyl} -estra- 1, 3 ,5(10)-triene-3,17P-diol N-oxide with a melting point of 131.7 0 C is obtained.

b) 11 1-Floro-7a-(5-methyI(7,7,8,8,9,9,10,10,10-nonafloorodecyl)- 0 iamino]pentyl}-estra-1,3,5(10)-trien-3-ol-17one N-oxide ml of ethyldiisopropylamine is added in drops at 10 0 C to a solution of 1.23

NO

o g of pyridine sulfur trioxide complex in 10 ml of dried dimethyl sulfoxide. Then, 1.62 g of 11 -fluoro-a- {5-[methyl(7,7,8,8,9,9,10,101 O-nonafluorodecyl)amninojpentyl}estra-1,3,5(10)-triene-3,17p-dio N-oxide as well as another 10 ml of dried dimethyl sulfoxide are added and stirred for 30 minutes at room temperature. Then, it is diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and sodium chloride solution, dried on sodium sulfate, evaporated to the dry state in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 1.32 g of 11 -fluoro-7a- {5-[methyl(7,7,8,8,9,9,10,10,10 O-nonafluorodecyl)amino]pentyl}-estra- 1, 3 ,5(10O)-trien-3-ol-17one N-oxide is obtained as a solid with a melting point of 84- 86 0 C; [aoc]D +53.60 in chlorofonnrm.

Process Variant 2.1: (Production of 1 7a-methyl-estratrienes with amine-N-oxide groupings in the side chain, starting from 17-oxo-estratrienes with amine groupings in the side chain via the corresponding 17-oxo-estratrienes with amine-N-oxide groupings in the side chain): a) 11 f-Fluoro-7ta-(5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amlino- COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:31 FROM-DCC SYDNEY +61292621080 T-196 P036/068 F-200 INO pentyl)-17a-methylestra-1,3,5(10)-triene-3,17p-dio (physical properties of 0 Ci this compound (No. 7) are indicated in Table 1) A suspension of 230 g of cerium(III) chloride in 2.3 1 of tetrahydrofuran is mixed at 0 0 C with 320 ml of a 3-molar methylmnagnesium bromide solution in dicthyl ether and stirred for 30 minutes. A solution of 25 g of 1 1J-fluoro-7a-{5- [methyl(7,7,8,8,9,9,10.10,1 O-nonafluorodecyl)amino]pentyl} estra-1,3,5(1 O)-trien-3-ol- 0 17-one (angle of rotation aD of this compound (No. Z14) is indicated in Table 5) in 250 ml of tetrahydrofuran is added in drops thereto and then stirred for 24 hours at 0 o room temperature, mixed at o 0 C with amnimonium chloride solution, extracted with ethyl acetate, washed with water, dried with sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/ methanol. 19.1 g of 11 -fluoro-7a- {5-[methyl(7,7,8,8,9,9,10,10,10nonafluorodecyl)amino]pentyl}-17a-methylestra-1,3,5(10)-triene-3, 170-diol with a melting point of 82-85 0 C and [a]D +21.8* in chloroform is obtained.

b) 11P-Fluoro-7a-{5-[methyl(77,8,8,9,9,10,10,10-nouafluorodecyl)aminolpentyl-17a-methylestra-1,3,5(10)-triene-3, 70-dioI N-oxide A solution of 18 g of I 1I0-fluoro-7a-(5-[methyl(7,7,8,8,9,90,10,100nonafluorodecyl)amino]pentyl}-17 c-methylestra-1,3,5(10)-trine-3,1 70-diol in 180 ml of chloroform and 180 ml of methanol is mixed with 2.57 g of sodium bicarbonate and 16.2 ml of a 30% hydrogen peroxide solution, and it is stirred for 48 hours at room temperature. Then, it is diluted with dichloromethane, washed with water and sodium thiosulfate solution, dried on sodium sulfate, evaporated to the dry state in a vacuum and absorptively precipitated with diethyl oether. 18.4 g of 11 0-fluoro-7a- COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:32 FROM-DCC SYDNEY +61292621080 T-196 P037/068 F-200 31 SN [methyl(7,7,8,8,9,9,10,10,1 0-nonafluorodecyl)adino]pentyl -17a-methylestra- CN 1, 3 5 (10)-triene-3,17p-diol N-oxide with a melting point of 122'C is obtained.

Process Variant 2.2: c (Production of 17a-methyl-estratrienes with amine groupings in the side chain, starting from 1 7 -oxo-estratrienes via.the corresponding 17a-methyl-estratrienes): 00 Cl a) 7a-(5-Bromopentyl)-i 10-fluoro-17a-methylestra-1,3,5(10 O)-triene-3,17p-diol

NO

O A suspension of 46.8 g of cerium(III) chloride in 0.47 1 of tetrahydrofuran is mixed at OC with 63.8 ml of a 3-molar methylmagnesium bromide solution in diethyl ether, and it is stirred for 1 hour. A solution of 25 g of 7 a-(5-bromopentyl)- fluoro-estra-1, 3 ,5(10)-trien-3-ol-17-one in 200 ml oftetrahydrofuran is added in drops thereto and then stirred for 28 hours at room temperature, mixed at o 0 c with ammonium chloride solution, extracted with ethyl acetate, washed with water, dried with sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 15.1 g of 7a-(5-bromopentyl)- fluoro-I 7ca-mnethylestra- 1,3,5(10)-triene-3,1 7p-diol with a melting point of 48.6 0 C is obtained.

b) 1lp-Fnluoro-7a-5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)andnopentyl-17a-cmethylestra-1,3,5(10)-triene-3,1 70-diol (physical properties of this compound (No. 7) are indicated in Table 1) A solution of 18 g of 7a-(5-bromopentyl)- 11 I-fluoro-1 7 ca-methylestra- 1, 3 ,5(10O)-triene-3,17p-diol in 180 ml of dimethylformamide is mixed with 15.9 g of (7,7,8,8,9,9,10,10,10-nonafluorodecyl)-methyl-aine and 5 g of sodium carbonate and COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:32 FROM-DCC SYDNEY +61292621080 T-196 P038/068 F-200 32 IO then stirred for 8.5 hours at a bath temperature of 800C. Then, it is added to water, 0 extracted with ethyl acetate, washed with water and saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 22.9 g of 11 P-fluoro- 7a- {5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}-17a-methylestra- 1,3,5(10)-triene-3,17p3-diol with a melting point of 82-85°C and laio +21.80 in 00 chloroform is obtained.

c Additional compounds according to the invention can be produced analogously. To this end, additional intermediate products are presented in Table In addition, physical properties of these compounds are also partially indicated.

COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 2006202187 23 May 2006 Table 1: 2 Ii -Fluoro-7a-f.{s[mehy1(ss7 ,9,,9~-heptafluooy)niio]pen}-17cmethylestra- 1,3,5(1 O)-trienc-3, 17p-dio1 N-oxide IMelting Point j Angle of Rotation loq aD 1) 152-154 R j3 P u r o 7 a 5 [m e t h 7 ,7 ,8 ,8 9 9 1 0 ,1 0 l O-n o n a fl h z o d e c lA min o lp e n ty q lVa-methylestra- 1, 3,5(1 0)-trien 3,1 7j-diol N-oxide lilp-Fluoro-7 cc-f l88999pnaloooy~mnjetl-7-atyeta 3 5(1O)-triee-.3,17pi-dioI N-o cide 1 1J-Fluoro-7ca (5-[methyl(9,9, ,010, O0I-pentafluorodecy)mino~pentyl1 7 a-methylestra- 1,3,5(1 O)-triene-3, 1 7j3-dicl N-o ide l10-Fluoro-7a- (5-[methyl(s,s, 9 9 -penafluoronony)minoJpentyl}-1 7 a-muethylestra- 11 f-Fluoro-7cr-{5-[methyl(7,7,s,,9,910,10, lO-nonafluorodecyl)aminolpentylpi 7ccmethylestra- 1,3,5(1 0)-triene-3, 17f-diol 1485 25.30 -68-71 +320' 82-85 +-21.8 34 2006202187 Melting Point 23 May 2006 Angle of Rotation

QD)I

I

methylestra- 1,3,5 (1 0)-triene-3,1 17J-diol 9: 17a-E th y nyl 1 -fluoro-7a- {Sn~m ethyl(7,7, g,8,9 9 10 0,10-12 3 moniafluorodecyl)axnino]pentyl} 'estra-1 3 7 5 (l0)-triene-3,1I713-dioI mionafluorodecyl)aininolpentyl} -estra-I 3 7 5 (I0)-trien-1 703 -01 11 1llP-Fuoro-3-(2..tetrahydropyyjoxy)-7a {5-[methyl(7,7,8,s,9,9,lo, 10,10o- 13 i 1 3 Fluoro27ya.minel 71 7amtyeta -135( 7a-metyiewa 96.3 tzfurmyeta1,3,5(10O)-trierie3,l 713-dio 14 10-luoro-7cc. 5-[methiyl(s,s, 4,9,10,10,1 O-heptafiuorodecy)aminolpentyl} I Yc- 137 methylestra.- 1,3,5(1 O)-triene-3,1 79-die] +13. +18.80 "-Fuoo-7a(5-Crnetyl(66,1,,8,8 9 l10010-undecafluorodecy1)amino~penty} 1.6+13 lc-methylestra-1,3,( O)-ten-17-il 2006202187 23 May 2006 Melting Point I Angleof Rota-ton fci'I aD

I)

16 1 1P-Fluoro-7cz- {5-[meth-yl(5,5, methylestra- 1, 3,5(1 0)-triene-3, I I11 f-Puoro- 7cc- {5-[methyl(9,9, 5,6,7, 7 8 ,8,-,ionatluorooctyl)amino]pentyly 1 7a- 713-diol 0,10,11411,11 -heptfluorouxndecy)amino]pentyl)17a 17 18 'nethylestra- 1,3,5(1 0)-triene-3, 171-dial 11p 3luoro-7a-{5-[methyl(9,9,'010, O0l-pentafluorodecyi)aminojpety}- 1 7cmethylestra- l, 3 1 5(l0)-triene-3, 17f3-diol 884-9 +32.50, 3) Ia]D in Chloroform 2006202187 23 May 2006 Table 2: Antiuterotropic Action S.C. 1 In hi b.

-P-0.

Inhib.

3 (RS)-1IP-Fluoro-7a-{54[r P.O. Inhib. I- I I I nethyli 7 I 7c-methylestra- 1,3,5(1 0)-triene, 11 fl-Fluoro-7cc- {5-[nethyl(7,7,82 methylestra- l, 3 ,5(10)-triene-3, 17 Ii I 3 -Flucro-7a-{f5-[methyj(7,7,s, methyiestra-1,3,5(10)trinez3, 17 78,89,910,0,1-nonafluorodecyl)amino]pentyl}.- 3,I7P-dioI N-oxide 9,9,9, 10, 10,1 O-nonafluorodecyl) amino] pentyl) -I17a- -diol

S,

9 9 9 -heptafluorononyl)armino]pentyl} -1 7cc- 3-diol I9* 76 0.03 j 59 0.3 94 2006202187 23 May 2006 37 Table 3: xl {-uoo7o-54[met1)yI(8,8S{9,9-pe-ntafluoronony1)aniind1penyl}esta1 ,3,5(10)triene-3,1I7J3-diol N-oxide X2 liP-Fluoro-7x-[5-(methyl {3-I 42,,4 5 6 -penafluoropheny1)sulrany1IpwopyI I aino)pentyllestra-1 5(1 0)-triene-3, 7J3-diol N-oxide Melting Point Angle of Rotation [CC] a 1) 158-160+33.60 X3- X4 11 I3 -Fluoro-7ct-[5-(methyl {34[({,4i5,5,5-pentafluopenty)su~cany11propy} amino)pentyl]estra- 1,3,5(l 0)-triene-3,1 I 3-dial N-oxide 1 1-Fluoro-7a- [5-(methyl 4 ,5,5,5-pentafluoropentylsulfanyljpropyl} 114-116 I I F- 03 -105 amino)pentyllestr-l,3,5(1 0)-triene-3,1 7j-diol N-oxide 11 lp-Fluoro-7w., {5-[methyl(7,7,8,8,9,9, 10,10,1 O-nonafluorodecyl)aminojpentyl} estr- 147-150 +30.20 1,3,5(1 0)-triene-3,173-diol N-oxide (S)-I1 -vuoro-7a- [methiyI(77,8,s,9,9, 10,10,1 O-nonafluorodeeyl)anino]pentyl} -1 ic- 128.5 +32.50 X6 2006202187 23 May 2006 38 L71 SMeiting Point Angle of Rotation CJu mnethylestra-1 ,3,5(1)tie3, 0do N-oxide X7~ J()I 1-Fluoro-7ax-{5-[meffiy( 7,7,83,8,9,9,1I 0,10,1 O-non a fluorodecy1) aminojpe~tylj.1 7- 144.0 +31.30 x8 metliylestra- 1,3,5(1 O)-triene-3,117fv-dio1 N-oxide 1 1-Pluoro-7cc- (5-[methyl(9,9, 1 0,10, 1 O-pentyfluorodecyl)aminolpmtyl} estra- 1,3,5(10)- 99-1 01 +28.5triene-3, 1 7j-diol N-oxide D in chloroform

I

2006202187 23 May 2006 Table 4 Y1 YN2_ I IP-Fluoro-7a-15-(znethylf {-R4(,4,5,5 5 -PeItafluoropenty)sufiny1popyI}amino)pentyl] estra- 1,3,5 (1 0)-tri en- 3-o Lf 17-one N-oxide 11PFur-a[-mty pnalooetlslay~rpl aminop)pentyfl]estra- 1,3,5 (1 0)-trien- 3 -oiL 1 7-one N-oxide 1 I1-laoro-7a- 5-[methyl(7,7,8,s,9,9, 10,10, lO-nonafluorodecy)aninopentylesra 1,3,5(1 0)-trien-3-olI-1I 7-one N-oxide Melting Point1 [1Ccl Angle of Rotation +45.6" +52.80 Y3 84-86+53.6i) MaD in chlorof'orn I 200 Table 6202187 23 May 2006 0C]

ZI

Z2 Z3 110-Fluoro-7a- {5IntY(,,,,-etfur nnlaiopnylsr-,,(0)triene-3,17p-dio] 11 f3-Fluoro-7&. 5-mtil88§99pnaloo~ty~mnletl estz-a-1,3,5(lO)-trien- Z4 3 -ol-17-one 1 l3-Fuor-7a {S[meh~l3~34~45,s6,67,7,8,s S-tridecafluoroocty1)aminopentyl} estratrien-3 -ci-17-one 11 j-Pluoro-7ct. 5-[methyl(9,9, 10,1 OiI-pentafluorodcyl)aino Ipentyl) estra-1,3,5(l0)y triene-3,170-diol 11 P-Eluoro-7ct- {5-[methyl(3,3,4,4, St5s 6 6 6 -nonafluorchexyl)amnino]pentyly estra- +48.4C 2006202187 23 May 2006 Melting Point JAngle of Rotation cD'1) foci l, 3 ,S(l0)-triene.3,1 7f-diol Z7 Z8 11 I -Fluoro-7cc- {5-[methyl(4,4,{5,66,7,7,8g89,9 9 -ticdecafluoronony])aznino]pentylp.

esta-I ,3,5(1 O)-tiierie-3,17p-fiol Ii I3-Fluoro-7c- {5-[methy(77f Is88-PentafluorooctY)minolpmtl) estra- 1,3,5(1 0)-triene- 3,113-diol Z9 I iiPFjuoro-7c- (S-[methyl(7,7, ,S,9,9,1O, 10,1 O-nonafluorodeeyl)amino]peny) estraz1i Zi1 Z12 b13,5(10)-triene-3, 1 7-dio1 Ii j-Fluowo-7cc- (5-(methyl(7,7,8,s,,9,9,lo, 10,11711,12,12,1 2 -tridecafiuowododeeyi)aminoypentyl}estra- 1,3,5(1 0)-triene-3,1 7p-dio1 IIP-.Fuoro7a-(-[rethY 1(44 t6,67789,9,10,1,11,11,11hePtadecafluoroundecy)aminopentyl~estnl 1, 3 5 (10)-triene-3,1 7p-dio1 lfr-Fluoro-7cc-(5-[methyl(7,7,,,9,9,Iolol 11,1 1,12,12,13413,14,14,14heptadecafluorotetradecyl)amimo~pentyl estra- 1,3,5(1 0)-tuiene-3,1 7f-diol 2006202187 23 May 2006 i Melting Point JAngle of Rotation rcj Z1 3 11 I3-Fluoro-7cc. (5-[methyl(5,5i),6,7,'7,,39,9 10, 10, 1 O-tridecaluorodecyl)aminolpeatylp.

Z14 fj11-Fluoro.7c- (5-[rnethyl(7,7, 10,10, 1 O-nonafluorodecyl)amuinojpentyllestra- 1,3,5(10)-trien-3-ol-1 -one +58.20 +39.20 5 110 Ifuoro-3-methoxy-7a- nethyl(7, 7,8,8,9,9,10,1 Ol-nonafluorodecy)anino]pentyl} estra-1,3,5(I0)-trieiu7 ol Z16 Ii IP-Fluoro-3 -methxyc7a..pentyl)estra-1 ,J,5(10)-trien-17 Z 1701-Acetylloxy-1 I fl-fluoro-7acpentyl) estra-1 ,3,5(I 0)-trien-34o Z18 I I P -Fluoro-7a- {5-[mnethy1(7,7,i iethy1(7,7,8,8,9,9,10, 10,1 O-nonafluorodecyl)amino]mne S-fmethyl(7,7,8,,9,lo1, 10,1 O-nonafluorodevyl)aniinop- ,8,9,9,1O, 10,IO0-nonafluorodecy)aipoJpetyl}tra +55.90, +21.0c' +66, 1 c [,3i5(10)-triene-3-(2-tetrahydojyranoyloxy)4 7-one ZI 9 3 -tert-Butanoyloxy. 11 P-fluemjlcc- {5-rmethyl(7,7,8,8,9,9, 10, 10, 1 O-nonafluorodecyl).

2006202187 23 May 2006 zQ r Melting Point Angle of Rotation Wj 1 ami-nolpentyl} estra-1,3,5(1 0)-hx 3-Acetyloxy-1 1 I -fluoro-7a- (5.

pentyl) estra-1,3,5(10)-trien-17r SI P -Fluoro-7ct- {5-[niethyl(6,6,' l,3,5(IO)-triene-3,17p-diol ~en-17p -ol t

I

[tuethyl(7,7,8,8,9,9,1o, 10,1 0-no~nafluorodecyl) aminto]- -ol 7,7, SiS 2 9 99-nonafluoronony)atnino]pentyl}cstr- -t f +330 -1i Z22 I 10-Fluoro-7c- {54[methyI(8,8,I),9,10,1 0,11,11,1 1-nonafluoroundecyl)amninolpentyl) estral,3,5(lO)-triene-3,173-diol

I

Z23 I IP-Ftuoro-7cc- (5-(methyl(7,7, ,S, 9 9 9 -heptafluorononyI)aninolpenty }est-a-1 125.0 triene-3,1I7j3-diol Z4 11f-Fuoro-7a-{(5- [methyI(7,7,1 ,s,9,9 9 -heptafluorononyl)axinopentyl) estsa135(lo0) ±70,2V trien-3-ol-1I 7-one li J-Fluoro-7c- {-Lmethyl( 6 6,7,7,8,8,8-heptafluorooctl)aminoJperitytlestra-1,35( +71.60 trien-3 -oI- 1 7-one 2006202187 23 May 2006 1 1 7 Melting Point Angle of Rotation a 0 Z56 Z27 110-luoo-7af5-methl(66,1,,8,,8-hptaluoroetl~amno~ entea- 1,3,5(10)triene-3,1753-dio1 I1 3-Fluoro-7a- {5-[methiyl(8,8,9,9, 10,10,1 O-heptafluomodecy)aminolpenty}esr-~.

1,3,5(1 0)-trien-3-ol- 1 7-one i 1 112.8 +42.6D -4 4.

+56.20 +34.90 Z29 11 P-Fluoro-7a-{5-[methyl(s,s,9,10,10,1 O-heptafluorodecyl)aniino]penty1}esra- 1,3,5(1 0)-triene-3,1 7f-diol ii j-Fluoro-7a- {5-[methyl(6,6,7, 7,8,8,9,9,10,1 ,lO-undecafluorodecyl)amino]pentyl) esta-i ,3,5(1 0)-trien-3-oI-1 7-one

I

+64.60 IPFluro-a-1-[mthy(6,67,79,89,910,0,1-unecafuordecl~ainc- 9-96+36.80 pentyl) estra-1 3 7 5 (1O)-triene-3, 1 7Wdiol 3110 I-Fluoro-7a- {-[rethyl(S$56677,88nonauowoocty1)amino]pety1}ctra- 1 ,3,5SGO)-trien-3-ol- 17-one Z32 II P-Fluoro-7c- f-mtyl55 fuoocy~ann entea- 2006202187 200622187 23 May 2006 [aD in chloroform 23-05-' 06 17:35 FEON-DCC SYDNEY+612608 +61292621080 T-196 P052/068 F-200 46 INO The entire disclosure of all applications, patents and publications, cited herein and of corresponding German Application No. 101 59 217.5, filed November 27, 2001 is incorporated by reference herein.

The preceding examples can be repeated with similar success by substituting the ci generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

00 From the foregoing description, one skilled in the art can easily ascertain the essential ci characteristics of this invention and, without departing from the spirit and scope thereof, can o make various changes and modifications of the invention to adapt it to various usages and conditions.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is8 not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23

Claims (2)

1. 23-05-'06 17:35 FROM-DCC SYDNEY +61292621080 T-196 P053/068 F-200 47 IO The claims defining the invention are as follows: O c 1. A 1 7a0-alkyl-17-oxy-estratriene of formula I OR I T Hal I oO "SK in which O O Hal stands for F or and is in 11 P-position, R 3 stands for hydrogen, Ci- C 4 -alkyl, Ci- C 4 -alkanoyl or a cyclic C 3 C 7 -ether with an O atom, R 17 stands for hydrogen, Ci- C 4 -alkyl or Ci- C 4 -alkanoyl, R' 7 stands for Ci- C 4 -alkyl, C2- C 4 -alkynyl or at least partially fluorinated Cj- C 4 -alkyl, wherein R17'-O is in 17p-position and R 7 is in 17a-position, and SK stands for U-V-W-X-Y-Z-E, which is bonded via U in 7a-position, in which U represents either a straight-chain or branched-chain C 1 3 alkylene-, -alkenylene- or -alkynylene radical or the group A-B, wherein A is bonded in the 7a-position and represents a benzylidene radical that is bonded via -CH 2 in the 7a-position, a phenylene radical, or a Ci- C3-alkylaryl radical that is bonded via the alkyl group in the 7a-position, and B stands for a straight-chain or branched-chain C1- Cnl-alkylene-, -alkenylene- or -alkynylene radical, and wherein A and B are optionally connected to one another via an 0 atom, V represents a CH2- or a C(O) group, COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:35 FROM-DCC SYDNEY +61292621080 T-196 P054/068 F-200 48 S W is an N(OXR)( 6 group or an azolidinylene-N-oxide ring, wherein the C' azolidinylene-N-oxide ring includes at least one C atom of X, wherein R 6 is H or CHz-R 7 or C(O)-R 7 in which R 7 is: a) hydrogen or b) a straight-chain or branched-chain, non-fluorinated or at least partially fluorinated Ci- C 14 -alkyl-, -alkenyl- or -alkynyl radical, any of which can 00 be hydroxylated in one or more places and can be interrupted by one to 0 C. three of the heteroatoms and/or -NR in which R 9 stands for \O Shydrogen or a C 1 C 3 -alkyl radical, or c) an unsubstituted or substituted aryl- or heteroaryl radical or d) an unsubstituted or substituted C 3 Clo-cycloalkyl radical or e) an unsubstituted or substituted C 4 Cls-cycloalkylalkyl radical or f) an unsubstituted or substituted C 7 C 2 0 -aralkyl radical or g) an unsubstituted or substituted heteroaryl-C 1 -C 6 -alkyl radical or h) an unsubstituted or substituted aminoalkyl radical or a biphenyl radical, X is a direct bond between W and Y or is straight-chain or branched-chain C Ci 2 -alkylene-, -alkenylene- or -alkynylene radical, Y is a direct bond between X and Z or is: SO.-R 10 wherein n 0, 1 or.2, wherein represents a direct bond between SO, and Z or a straight-chain or branched-chain C 1 C 6 -alkylene-, -alkenylene- or -alkynylene radical, or b) R" or O-R, wherein R" stands for i) a straight-chain or branched-chain C 1 C 5 -alkylene-, -alkenylene- or -alkynylene radical or ii) an unsubstituted or substituted aryl radidal or heteroaryl radical or iii) an unsubstituted or substituted Ca- Cio-cycloalkyl radical or COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:35 FROM-DCC SYDNEY +61292621080 T-196 P055/068 F-200 49 O iv) an unsubstituted or substituted 4- C-yloalkylalky radical or iv) an unsubstituted or substituted C7- Cs-cycloalkylalky l radical or ci v) an unsubstituted or substituted heter- Coar alkyl radical radical or vi) an unsubstituted or substituted heteroaryl-C- -QC-alkyl radical, or c) CH CF or d) HN-C(O)-NH-R, wherein R' 2 stands for an unsubstituted or substituted arylene radical, and wherein R 1 2 is bonded to Z, 00 Z is a direct bond between Y and E or a straight-chain or branched-chain C- Cg-alkylene-, -alkenylene- or -alkynylene radical, any of which can be Spartially or completely fluorinated, and E is a CF 3 group or an at least partially fluorinated aryl group, or a pharmacologically compatible acid addition salt thereof or an ester thereof formed in the 3- or 17P-position. 2. An estratriene according to claim 1, wherein R stands for hydrogen, CH 3 CH3CO or CsH]oO. 3. An estratriene according to one of the preceding claims, wherein R 1 7 stands for hydrogen, CH3 or CH3CO, and wherein R 17 stands for methyl, ethynyl or trifluoromethyl. 4. An estratriene according to one of the preceding claims, wherein Hal stands for fluorine. An estratriene according to one of the preceding claims, wherein U stands for (CH 2 wherein p is an integer of 2 to 6. An estratriene according to one of the preceding claims, wherein p 4. COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:35 FROM-DCC SYDNEY +61292621080 T-196 P056/068 F-200 VO 0 0 en ci 7. An estratriene according to one of the preceding claims, wherein V stands for CH 2 8. An estratriene according to one of the preceding claims, wherein W stands for wherein R 6 is hydrogen or a C1- C 3 -alkyl radical. 9. An estratriene according to one of the preceding claims, wherein Rf stands for methyl. An estratriene according to one of the preceding claims, wherein X stands for (CH2)q, wherein q 0 or is an integer of 1 to 12. 11. An estratriene according to one of the preceding claims, wherein Y is a direct bond between X and Z or an SO, group, wherein n 0, 1 or 2. 12. An estratriene according to one of the preceding claims, wherein Z is a straight- chain or branched-chain C C 7 -alkylene radical, which is at least partially fluorinated. 13. An estratriene according to one of theprccedingselaim4. w_herein EstandsforCE3 or pentafluorophenyl. 14. An estratriene according to one of the preceding claims, wherein Z-E stands for C 2 F 5 C 3 F 7 C 4 F 9 or C 6 An estratriene according to claim 1 which is: COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:36 FHOII-DCC SYDNEY 62610 T96P7/6F-0 +61292621080 T-196 P057/068 F-200 51 8 11 f3-Flnoro-7ct- {5-[methyl(7,7,8,8,9,9,9-heptafluorononyl)amino]pentyl}- -1 Cl methyle stra- 1,3,5(1 0)-triene-3, 1 7(-dial N-oxide Ii f3-Fluoro-lt- {5-[methyl(8,S,9,9, 10,10,1 0-heptafluorodecyl)aminolpentyl} -17ev n rnethylestra-1 ,3,5(1 0)-triene-3 ,17(3-diol N-oxide (P3)-I 1 J-Fluoro-7ax- (5-[methyl(7,7,8,8,9,9,1 0, 10,1 0-nonafluorodccyl)amino]- 00pentyl}- I 7cz-zethylestra- 1,3,5(1 0)-triene-3, 17(3-dial N-oxide 11 P-Fhioro-7a- {5-[inethyl(8,8,9,9,9-pentafluorononyflamninojpentyl} 1 7a INOmethylestra-1 ,3,5(l 0)-triene-3,l 71-dial N-oxide 0 1 -Fluoro-7c- {5-[rnethyl(9,9, 10,10, 10-pentafluorodeoyl)amino]pentyl-17a- methylestra-l 10)-triene-3,1 7(3-dial N-oxide 16. An 17(-oxy-estratriene of fornula II ORIT in which fltL stands far F or&Land is-inA 1(3-position, i 3 stands for hydrogen, Cr C 4 -alkyl, Cj- C 4 -alkanoyl or a cyclic Cr C 7 -ether with an 0 atom, Rt' 7 stands for hydrogen, CI C 4 -alkyl or for C, C 4 -alkanoyl and is in 17(3-position, and SR stands for U-V-W-X-Y-Z-E, which is bonded via COMS ID No: SBMI-03674292 Received by P1 Australia: Time 17:35 Date 2006-05-23 23-05-' 06 17:36 FHOM-DCC SYDNEY 19613 +61292621080 T-196 P058/068 F-200 52 SN U in 7a-position, and wherein U, V, X, Y, Z and E have the meanings Cl indicated in any one of claims 1- 15, provided that W stands for an N t (Oy(R') group or for an azolidinylene-N-oxide -ring, wherein the azolidinylene-N-oxide ring includes at least one C atom of X, in which R' has the meaning indicated in any one of claims 1 00 Cl 17. An I'4-oxy-estratriene according to claim 16 which is: 1 P-Fluoro-7cc- {S-[mnethyl(8,8,9,9,9..pentafluoronony)&ino]pety} estra- 1,3,5(10)- o triene-3,17P-diol N-oxide 11 P-Fluoro-7c4-[5-{methyl 3 -[(2,3,4,5,6-pentafluorophenyl)sulfanyl]propyl} amino)pentyl]estra-1,3,5(1 0)-triene-3, 1 7-dio1 N-oxide 11 1-Fluoro-7cc-[5-(methyl 3 4 4 .,,,-pentatluoropentyl)sulfanyl]propyl) amino)- pentyl]estra- 1,3,5(1 0)-triene-3, 1 71-diol N-oxide 11 -Fluoro-7a-[5-(methyl 3 4 ,4,5,5,5-pentafluoropentyl)sulniny]propy} amino)- pentyl~estra- 1,3,5(1 0)-triene-3, 17j3-diol N-oxide 1 1-Fluoro-7z- {5-[rnethyt(7,7,8,8,9,9, 10,10,1 O-nonafluorodecyl)aniino]pentyl} estra- 1,3,5(1 0)-triene-3,1713-diol N-oxide I1-Fluoro-7a-{5-[methyl(7,7,s,s,g 10,10,1 O-nonafluorodecyl)arrino]pentylp. I 7ct-methylestra- 1,3,5 (1 0)-triene-3, 1 7f-diol N-oxide (R)-11 1-Fluoro-7a-w {5-(miethyl(7,7,8,8,9,9, 10, 10, 1 O-nonafluorodecyl)aminojpentylpI. 1 7a-methylestra- 1,3 ,5(10)-triene-3, 1 7j-diol N-oxide 11 f3-Fluoro-7c- {5-[methyl(9,9, 10,10,1 O-pentyiluorodecy1)amino~penty} estra- l,3,5(1O)-trienc-3,1
2. 71-diol N-oxide. COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 T-196 P059/068 F-200 23-05-'06 17:36 FROM-DCC SYDNEY +61292621080 Va c 18. An 17-oxo-estratriene of formula III in which Hal stands for F or Cl and is in 11 P-position, R 3 stands for hydrogen, CI- Ca-alkyl, Ci- C 4 -alkanoyl or a cyclic C3- C7-ether with an O atom, and SK stands for U-V-W-X-Y-Z-E, which is bonded via U in 7a-position, and wherein U, V, X, Y, Z and E have the meanings indicated in any one of claims 1 15, provided that W stands for an N(0O)(R') group or for an azolidinylene-N-oxide ring, wherein the azolidinylene-N-oxide ring includes at least one C atom of X, in which R6 has the meaning indicated in any one of claims I 19. An 17-oxo-estratriene according to claim 18 which is; 11fRl=n-7arM tnthyl J(4A A q5 e nt-fl ro t L tlf l J amino)pentyl]estra-1,3,5(10)-trien-3-ol- 17-one N-oxide 11 -Fluoro-7a-[5-(methyl 3 -t(4,4,5,5,5-pentafluoropentyl)sulfanyl]propyl} amino)- pentyl]estra-1,3,5(1 O)-trien-3-ol- 17-one N-oxide 11 P-Fluoro-7ac- {5-[methyl(7,7,8,8,9,9, 10,10,1 0-nonafluorodecyl)amino]pentyl) estra- 1,3,5(1O)-trien-3-ol-1 7-one N-oxide COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23 23-05-'06 17:36 FROM-DCC SYDNEY +61292621080 T-196 P060068 F-200 54 o 20. Use of a 17ac-alkyl-17p-oxy-estratriene according to any one of claims 1 15 for O Cl the production of a pharmaceutical agent. S21. A pharmaceutical preparation that contains at least one estratriene according to any one of claims 1 15 in associates with at least one pharmaceutically compatible vehicle. 00 DATED this 23rd day of May 2006 0 g SCHERING AKTIENGESELLSCHAIT SBy its Patent Attorneys DAVIES COLLISON CAVE COMS ID No: SBMI-03674292 Received by IP Australia: Time 17:35 Date 2006-05-23