WO2002081444A1

WO2002081444A1 - 1-indolyl derivatives, use thereof for production of medicaments, a method for production of said 1-indolyl derivatives and pharmaceutical preparations containing 1-indolyl derivatives

Info

Publication number: WO2002081444A1
Application number: PCT/EP2002/003646
Authority: WO
Inventors: Erwin Angerer Von; Jens Hoffmann; Rolf Bohlmann; Rolf Jautelat; Nicolaus Heinrich; Rosemarie Lichtner; Thomas Golob; Georg Walter
Original assignee: Schering Aktiengesellschaft
Priority date: 2001-04-03
Filing date: 2002-04-03
Publication date: 2002-10-17
Also published as: DE10117441A1

Abstract

The invention relates to novel 1-indolyl derivatives of general formula (II), having an anti-oestrogenic effect, whereby R?1, R2, R3, R4¿, U, V, W, X, Y and Z have the meanings given in the description, a method for production of said 1-indolyl derivatives, use thereof for production of medicaments and pharmaceutical preparations containing 1-indolyl derivatives.

Description

1-Indolyl derivatives, their use for the production of medicaments, a process for the preparation of 1-indolyl derivatives and pharmaceutical preparations containing 1-indolyl derivatives

Description:

The present invention relates to novel 1-indolyl derivatives, a process for the preparation of 1-indolyl derivatives, their use for the production of medicaments and pharmaceutical preparations containing 1-indolyl derivatives.

Mammacarcinomas as well as the tissue from which they originate are hormone sensitive.

Many other compounds with antiestrogenic properties have already been described in the literature, for example tamoxifen [Eur. J. Concer. Clin. OncoL, 21, 985 (1985) and J.S. Patterson, "10 Years of Tamoxifen in Breast Cancer" in Hormonal Manipulation of Cancer, Peptides, Growth Factors and New (Anfi) Steroidai Agents, Raven Press, New York (1987)].

WO 98/07740 AI describes 7a- (ξ-aminoalkyl) -estratrienes, which have a very strong antiestrogenic effect. On the one hand, there are partial antagonists, ie that these compounds have estrogenic effects in addition to their antiestrogenic activity, and on the other hand they are pure antagonists which have only antiestrogenic properties. The ξ-aminoalkyl group of these compounds is in the side chain N-αlkyliert, wherein this alkyl group is interrupted by a thio- (-S-), a sulfinyl (-SO-) or a sulfonyl group (-SO2-) and optionally fluorinated. Chains of the type (CH ₂ ) n-SO _x - (CH ₂ ) 3-E are indicated as N-alkyl chains, where x and n stand for 0, 1 or 2 and E can be an unsubstituted or mono- to pentas fluorinated ethyl radical. Specifically, among others

(CH ₂ ) 3-SO- (CH2) 3-C ₂ F ₅ and

(CH ₂ ) 3-SO ₂ - (CH ₂ ) 3-C ₂ F5.

WO 99/33855 AI also describes compounds with strong antiestrogenic activity. These are 1 1 ß-halogenestratridine derivatives which have an alkylamine side chain in the 7a position. This side chain is also N-alkylated, whereby the N-alkyl group can be at least partially fluorinated. For example, the N-alkyl group can be a (CH2) mC _n F2n + ι group, where n and m independently of one another represent an integer from 1 to 8. The following are particularly indicated as fluorinated alkyl groups:

- (CH ₂ ) ₃ -C ₂ F ₅

- (CH ₂ ) ₂ -C ₄ F ₉

- (CH ₂ ) ₆ -C ₄ F ₉

EP 0 348 341 B1 describes aminoαcylindoles which also have strong antiestrogenic properties. These compounds are pure antagonists, i.e. they have no residual estrogenic effectiveness. These compounds are 2-phenylindole derivatives which are substituted in the 1 position. The side chain bonded in the 1 position can be a ξ- (N, N-dialkylamino) alkyl chain. Compounds in which the side chain can have the following structure are particularly suitable:

- (CH ₂ ) ₆ -NH (CH ₃ )

- (CH ₂ ) 6-N (C ₂ H ₅ ) 2.

The invention is based on the problem of finding further improved antiestrogenic active substances which have an antiproliferative effect on estrogen-sensitive lines for the therapy of hormone-sensitive breast carcinoma.

The problem is solved by 1-indolyl derivatives according to claim 1, by the use of a 1-indolyl radical as a constituent of compounds having an antiestrogenic action according to claim 1 1, further by a process for the preparation of these compounds according to claim 12, a use of these compounds for the preparation of Medicaments according to claim 13 and by pharmaceutical preparations according to claim 14. Preferred embodiments of the invention are specified in the subclaims. The 1-indolyl derivatives according to the invention have the common structural part with the general formula

I

as a component of compounds with antiestrogenic activity. Mean in this formula

U is either a straight-chain or branched-chain Ci to Ci3-alkylene, alkenylene or alkynylene radical or the grouping AB, where A is bonded to the indole nitrogen atom and a benzylidene bond bonded via -CH2- to the indole nitrogen atom represents a phenylene radical or a Ci to C3 alkylaryl radical bonded via the alkyl group to the indole nitrogen atom and B represents a straight or branched chain Ci to Ci3 alkylene, alkenylene or alkynylene radical and where A and B also can be connected to one another via an oxygen atom,

V is a CH ₂ or a C (0) group,

W is an N (R ⁶ ) - or an azolidinylene group, where R ^{ό is} either H or CH2-R ⁷ or C (0) -R ⁷ , where R ⁷ can mean the following: a) hydrogen or b) a straight or branched-chain non-fluorinated or at least partially fluorinated C to Cu alkyl, alkenyl or alkynyl radical, which may be hydroxylated once or several times and which can be interrupted by one to three heteroatoms -O-, -S- and / or groupings -NR ⁹ -, in which R ^{9 represents} hydrogen or a C 1 -C 3 -alkyl radical, or c) an unsubstituted or substituted, preferably mono- or disubstituted, aryl or heteroaryl or d) an unsubstituted or substituted, preferably mono- or disubstituted, C3- to Cio-cycloalkyl residue or e) an unsubstituted or substituted, preferably mono- or disubstituted, C - to Cis-cycloalkyl alkyl or f) an unsubstituted or substituted, preferably mono- or disubstituted, C7- to C2o-aralkyl radical or g) an unsubstituted or substituted, preferably mono- or disubstituted, heteroaryl-Ci- to -Ci-- alkyl radical or h) an unsubstituted or substituted aminoalkyl radical or a biphenyl radical,

X is a straight-chain or branched-chain C 1 -C 12 -alkylene, -alkenylene or -alkinylene radical,

Y is a direct bond between X and Z or the following: a) a SO _n -R ¹⁰ group, where n = 0.1 or 2 and R ^{10 is} a direct bond between SOn and Z or a straight or branched chain bis C _ό -alkylene, -alkenylene or -AI- kinylene radical, or b) the group OR ¹¹ , where R ^{11 is} i) a gerαd- or branched-chain Ci to Cs-alkylene, alkenylene or alkynylene radical or ii) an unsubstituted or substituted, preferably single or double substituted, aryl or heteroaryl or iii) an unsubstituted or substituted, preferably mono- or disubstituted, C3 to C10- cyclalkyl or iv) unsubstituted or substituted, preferably mono- or disubstituted, C - to C15- - Cycloalkylalkyl radical or represents v) an unsubstituted or substituted, preferably mono- or disubstituted, C7- to C20- aralkyl radical or vi) an unsubstituted or substituted, preferably mono- or disubstituted, heteroaryl -C 1 -C 6 -alkyl radical stands, c) the grouping CH = CF or d) the grouping HN-C (0) -NH-R ¹² , where R ^{12 is} an unsubstituted or substituted is arylene radical and where R ^{12 is} bound to Z, and

Z is a direct bond between Y and CF3 or a straight or branched, at least partially fluorinated Ci to C ₉ alkylene, alkenylene or alkynylene radical.

At positions 2, 3, 4, 5, 6 and 7 on the indolyl ring, hydrogen or any other substituent can be attached. Those 1-indolyl derivatives with the structural part according to general formula I are particularly suitable in which

U stands for (CH2) _P , where p is an integer from 2 to 10,

V represents either CH ₂ or C (O),

W represents N (R ⁶ ), where R ^{6 is} hydrogen or a straight-chain or branched-chain C 1 to C 3 alkyl radical,

X stands for (CH2) q, where q = 0 or an integer from 1 to 12 and

Y and Z together represent either SO _n - (CH2) rCF2, (CF ₂ ) s or O-aryl, where n is 0, 1 or 2, r is 0 or an integer from 1 to 6, s is 0 or an integer from 1 to 10 and aryl is an unsubstituted or substituted, preferably mono- or disubstituted, phenylene radical.

1 -Indolyl derivatives with good antiestrogenic properties are in particular compounds with the following general formula:

II in which

R ¹ and R ² independently of one another represent a) hydrogen or b) straight-chain or branched-chain Ci to C -alkyl, -alkenyl or -alkynyl radicals or c) C (0) -R ⁵ , where R ^{5 represents} a straight-chain or branched-chain Ci to C alkyl, alkenyl or alkynyl radical,

R ³ and R ⁴ independently of one another denote a) hydrogen or b) a straight-chain or branched-chain C 1 -C ₄ -alkyl, -alkenyl or -alkynyl radical or

R ³ and R ⁴ together represent a di, tri or tetramethylene bridge, which can also contain a double bond, and

U, V, W, X, Y and Z have the aforementioned meanings.

R ¹ , R ² and R ⁴ can in particular represent hydrogen or methyl and R ^{3 represent} methyl. In principle, these groups can also include higher homologs. R ¹ and R ² can also be ethyl, propyl and butyl, both the straight-chain and the branched-chain radicals, in particular isopropyl, isobutyl and tert-butyl, being suitable. The same applies to R ³ and R ⁴ .

In addition, R ¹ and R ^{2 can} also represent acyl radicals having the general formula C (0) -R ⁵ , where R ^{5 is} preferably a straight-chain or branched-chain O- to C -alkyl, -alkenyl or -alkynyl radical, namely especially methyl and its higher homologues, namely ethyl, propyl and butyl.

Furthermore, R ³ and R ⁴ together can also represent a methylene, ethylene, propylene or butylene bridge and an unsaturated hydrocarbon chain, for example but-2-en-l, 4-ylene or prop-l-en-1,3 -ylen.

U can especially be a straight or branched chain pentylene, hexylene, heptylene or octylene radical. In particular, U is a (CH2) ό- or egg ne (CH2) 7 group. Of course, U can also represent longer or shorter chains, for example ethylene, propylene, butylene or nonylene, decylene, undecylene and dodecylene, etc. The carbon chain can also be substituted with an aryl radical, for example with a phenylene radical. In addition, a phenylene radical can also be bonded directly to the nitrogen atom of the indole backbone in the 1-position and the aforementioned alkylene chain to the phenylene radical. In this case the alkylene group is shorter. In this case it is preferably a methylene, ethylene or propylene group.

The length of the main chain between the indolyl nitrogen atom to which the side chain is attached and the next chain component V is particularly important. Therefore, higher homologues can also be suitable if the chain is more branched. Chains with a length of six or seven carbon atoms in the main chain are most suitable. This is the case, for example, when U is a (CH2) ό radical and the subsequent group V is CH ₂ . Compounds in which U is a straight-chain or branched alkylene group are particularly suitable. Groups without side chains are preferred.

W can in particular also be p-methyleneoxybenzyl, the benzyl group being bonded to the indole nitrogen atom.

W is preferably an NH or N (CH3) group. W can also be a group N (R ⁶ ), where R ^{6 can be} CH2-R ⁷ or C (0) -R ⁷ and R ^{7 is} a straight-chain or branched-chain methylene, ethylene, propylene or butylene , Pentylene, hexylene or an even higher homologue and their unsaturated analog, for example ethenylene, propenylene, etc. Furthermore, the alkylene, alkenylene or alkynylene chain of R ^{7 can} also be interrupted by the heteroatoms O, S or the group NR ⁹ , for example NH or N (CH3). For example, ((CH2) 2-0-) _n -CH ₃ , ((CH ₂ ) ₂ -S-) n-CH ₃ and ((CH ₂ ) 2-NH-) n-CH ₃ or ((CH2) 2-N (CH ₃ )) n-CH ₃ is suitable, where n is an integer, for example 2, 3, 4, 5 or 6.

In particular, R ⁷ can be a hydroxylated alkyl chain, for example 2-hydroxyethyl, 3-hydroxypropyl and 2-3-dihydroxypropyl.

Furthermore, R ^{7 can} also be phenyl, 1 - or 2-naphthyl or another aryl radical or a heteroaryl radical, for example 2-, 3- or 4-pyridinyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, pyridazinyl, 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl.

Furthermore, R ^{7 can} also stand for alkyl derivatives of the aforementioned aryl, heteroaryl and cycloalkyl radicals, for example for benzyl, l-methylene-2-pyridinyl or methylene cyclohexyl. The alkyl derivatives are bonded via the alkylene group to the C (O) or CH ₂ group of R ⁶ in N (R ⁶ ).

If R ^{6 is} C (0) -R ⁷ , the corresponding acyl derivatives are present, in particular ethanoyl, propanoyl, butanoyl and their higher homologues, their unsaturated analogs, for example ethenoyl, propenoyl etc., and the corresponding acyl derivatives of (CH ₂ ) 2-0-CH3, namely those of C (0) - (CH2) 2-CH ₃ , of (CH ₂ ) 2-S-CH ₃ and of (CH ₂ ) ₂ -NH-CH ₃ or of (CH ₂ ) ₂ -N (CH ₃ ) -CH and their higher homologues, further benzoyl, 1- and 2-naphthoyl and the corresponding heteroaroyl derivatives and the alkylene derivatives, for example the phenylacetamides.

In addition, W can also represent an azolidinylene radical, in particular a piperidinylene or a pyrrolidinylene radical. In the case of the piperidinyl residue, the nitrogen is bonded to the V residue and the X residue in the para position on the pipe idylene ring.

X can in particular be a straight-chain or branched-chain ethylene, propylene, butylene, pentylene or hexylene radical. Of course, other alkylene, alkenylene or alkynylene radicals can also be used in this case, for example a methylene radical and higher homologs, for example a heptylene or octylene radical, both the straight-chain and the branched-chain radicals being suitable. Residues without side chains are preferred.

Y can have different meanings: On the one hand, Y preferably represents a direct bond between X and Z. In this case, Z is preferably not a direct bond between Y and the end group CF3.

Y is particularly preferably an S-propylene group, an S0 ₂ -propylene group or a para-O-phenylene group. Basically, instead of the propylene groups in S-propylene and SO ₂ propylene, a higher homologue, for example butylene, pentylene or hexylene, and also methylene and ethylene are suitable. The alkylene groups can have additional side chains. Unsaturated derivatives are also suitable. A (CH ₂ ) 3 group is preferred as S- (CH ₂ ) 3 or as S0 ₂ - (CH ₂ ) 3. It is also possible for Y to stand for thio, sulfinyl or sulfonyl without an additional carbon chain R ¹⁰ .

If Y has the meaning of an O-arylene group, the arylene group is preferably phenylene, 1-naphthylene or 2-naphthylene. The heterarylene group includes, in particular, the 2-, 3- or 4-pyridinylene radical, the 2- or 3-furylene radical, the 2- or 3-thienylene radical, the 2- or 3-pyrrolylene radical, the 2-, 4- or 5-Imidαzolylenrest, the Pyridαzinylenrest, the 2-, 4- or 5-Pyrimidinylenrest or the 3- or 4-Pyridαzinylenrest suitable. Pαrα-O-phenylene is preferred for Y.

Alternatively, Y can also be an O-alkylene, O-alkenylene or O-alkynylene group, for example an O-propylene, O-butylene or O-pentylene group and their unsaturated analogues. O-cycloalkyl groups are also included, for example O-cyclohexyl. Y can also have the meaning of alkyl derivatives of the abovementioned groups, for example that of benzyloxy.

Y can also stand for the grouping CH = CF. This is particularly the case when Z is an at least partially fluorinated, preferably perfluorinated, carbon residue.

Y can also represent the group HN-C (0) -NH-R ¹² , where R ^{12 is} an unsubstituted or substituted arylene radical and where R ^{12 is} bonded to Z. In particular, Y can represent the radical ara-CόH -HN-C (0) -NH.

Z can be an at least partially, but preferably perfluorinated, methylene, ethylene, propylene, butylene or pentylene group. In principle, the higher homologs are also suitable in this case, for example hexylene, heptylene and octylene. Groups without side chains are preferred. The groups which are only partially fluorinated on the individual carbon atoms of the chains, for example CHF-CHF-CHF, and the groups in which the chains are only partially fluorinated, for example CH2-CF2-CF2, can also be used. Unsaturated derivatives are also suitable. Particularly suitable compounds are the 1-indolyl derivatives shown in Table 1:

The corresponding 4 ^l , 5-dimethoxyindole derivatives of these compounds are also suitable.

Table 2 shows specific structural properties for the compounds Nos. 1 to 12, namely the length n of the alkylene chain of the structural element U = (CH ₂ ) n, the type of structural element V, namely CH ₂ or C = O _t, the length q of the Alkylene chain (CH2) q (structural element X) and the type of element YZ formed by the structural elements Y and Z, namely S- (CH ₂ ) 3-CF ₂ or S0 ₂ - (CH) 3-CF ₂ or (CF ₂ ) soder (CF ₂ ) ₅ or

The compounds according to the invention also include pharmacologically acceptable addition salts. These are the corresponding addition salts with inorganic and organic acids. The hydrochlorides, hydrobromides, acetates, citrates, oxalates, tartrates and methanesulfonates are particularly suitable as addition salts with inorganic acids.

The 1-indolyl derivatives according to the invention with the general formula II are particularly suitable for the production of medicaments.

The invention also relates to pharmaceutical preparations which, in addition to at least one of the aforementioned 1-indolyl derivatives, contain at least one pharmaceutically acceptable carrier.

In contrast to known indoles substituted in the 1-position, which have an antiestrogenic effect, the inventive 1 -Indolyl derivatives have an at least partially fluorinated, preferably perfluorinated, end chain of the substituent in the 1 position. On the one hand, this is already given by the fact that the end group of the side chain is a CF ₃ group. In addition, component Z can also represent an at least partially fluorinated, preferably perfluorinated, carbon chain.

The different combination of the indole base, in particular the 2-phenylindole base, the alkylamine or alkylamide group bonded to the indole backbone in the 1 position, and the fluorinated end group result in a significantly stronger estrogen antagonism and a better antitumor effect than with analogous active ingredients who lack the structural elements mentioned. In contrast to non-fluorinated alkylamines and alkylamides, the compounds according to the invention show complete inhibition of estradiol-stimulated luciferase expression in stably infected human MCF-7 mammamarcinoma cells. The ICso values are usually below 1 μM. The most effective of the compounds according to the invention found exceeds the antiestrogenic action of known antiestrogenic steroids, although their affinity for the estrogen receptor is significantly lower, for example 7a- {9- (4,4,5,5,5-pentafluoropentylsulfonyl) nonyl } -estradiol, which also has a fluorinated alkyl end group in the side chain of the steroid skeleton, but not an alkylamine or an alkylamide group.

The fluorination of the chain end of the side chain dramatically increased the effectiveness of the previously known 2-phenylindole derivatives.

Furthermore, the active compounds according to the invention show no residual estrogen activity either in vitro or in vivo. The compounds according to the invention have a pronounced receptor binding affinity RBA to the estradiol receptor and competitively displace ³ H-17β-estradiol from the receptor.

In vivo, the indolyl derivatives according to the invention have strong antiestrogenic effects on the mouse uterus and inhibit estrogen-stimulated uterine growth by up to 100%. Estrogenic effects are not detectable in these tests. The compounds have an inhibitory effect on the growth of hormone-sensitive tumor cells, in particular they inhibit the growth of estrogen-sensitive breast tumors (MCF-7).

The non-steroidal antiestrogens were tested for biological activity both in vitro and in vivo.

In the in v / fro test, the affinities of the 1-indolyl derivatives according to the invention for the estrogen receptor RBA, the antiestrogenic activity in a transfection assay and the proliferative effect on hormone-sensitive breast carcinoma cells were determined. In addition, the active compounds according to the invention were also examined for estrogenic side effects and for general cytotoxic properties.

The antiestrogenic activity of the compounds according to the invention was determined in transactivation assays [E. Demirpence, M.-J. Duchesne, E. Badia, D. Gagne and M. Pons: MVLN Cells: A Bioluminescent MCF-7-

Derived Cell Line to study the Modulation of Estrogenic Activity; J. Steroid Molec. Biol., 46 (3), 355-364 (1993) and M. Berry, D. Metzger, P. Chambon, Role of the two activating domains of the estrogen receptor in the cell-type and promotor-context dependent agonistic activity of the anti-estrogen 4-hydroxytamoxifene; The EMBO Journal, 9, 281 1 - 2818 (1990)]. For comparison, tests were carried out against pure antiestrogens with a basic steroid structure (R1, R2) and against a 1-indolyl derivative (R3) as reference compounds. These were the antiestrogens 7a- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] estradiol (compound Rl), 11β-fluoro-7a- {5- [N- methyl-N- (3- (4,4,5,5,5-pentafluoropentylthio) propyl) amino] pentyl} - estradiol (compound R2) and 5-hydroxy-2- (4-hydroxyphenyl) - 3-methyl-l - [10- (pentylsulfonyl) decyl] indole (Compound R3).

Calf uterine cytosol was used as the source for determining the relative binding affinity RBA to the estrogen receptor, based on 17β-estradiol (= 100). Table 3 shows the results of the measurements for 1 -indolyl derivatives and for the three reference compounds (estradiol derivatives and indole compound). The RBA values fluctuate in the range from 0.05 to 25, the RBA values of the best 1-indolyl derivatives Nos. 9, 10, 11 and 12 being relatively close to one another in terms of antiestrogenic activity.

As can be seen from Table 4, none of the anti-estrogens according to the invention shows an agonistic effect. All values are below the value of the untreated control cells. The reduction below the basal value for the 1-indolyl derivatives according to the invention is due to the fact that the serum still contained growth factors and cytokines which were able to activate the estrogen receptor in the absence of a ligand. This effect can be eliminated by blocking the receptor with a pure antagonist.

The estrogenic and antiestrogenic activity of the compounds according to the invention and that of the reference compounds were also investigated. The antiestrogenic effect was reduced at the same time Addition of 1 nM or 10 nM estradiol determined to simulate the physiological situation. The values of compounds which were obtained when 10 nM were added (No. 1 to 8, reference compounds R1, R2, R3) are marked with *), the values of compounds No. 9 to 12 which were obtained when 1 nM was added were marked with **). The results of the tests for antiestrogenic activity are also shown in Table 3.

The antiestrogenic effect was determined in vitro on MCF-7 breast carcinoma cells (see Table 3) which were stably transfected with a luciferase reporter plasmid and stimulated with 10 " ⁸ M estradiol. On the other hand, the inhibition of Growth of estrogen-sensitive MCF-7 breast carcinoma cells after incubation for several days in the absence of estradiol was determined by crystal violet staining, and in some cases several values were obtained, all of which are shown.

It can be seen from the results that the compounds according to the invention prove to be particularly effective estrogen antagonists, especially when the spacer length, ie with a length n of the alkylene radical U, of six and seven methylene groups. This is demonstrated by the low IC50 values (determined in in vitro on MCF-7 breast carcinoma cells which have been stably transfected with luciferase reporter plasmid) for these compounds of 13 nM (compound no. 10) and 25 nM (compound no. 11) when the MCF-7 breast carcinoma cells were stimulated with estradiol at a concentration of 1 nM. Lower values for IC50 are obtained for these compounds when estradiol is used in a concentration of 0.1 nM (compound no. 10: 0.59 / 1, 0/1, 0/1, 0 nM, compound no. 11 : 1, 8 nM). The most effective estrogen antagonist has therefore been found to be compound no. 10 (5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-l - {7- [N-methyl-N- (3- (7, 7,8,8,9,9, l 0, 10, 10-nonafluoro decyl-αmino] -heptyl} -indole), which has a spacer length of seven carbon atoms in the group U-CH2.

/ nv / ^' fro results of the antiestrogenic activity of the compounds Nos. 13 to 41 are given in Table 1, the values for the antiestrogenic activity (IC50 [nM]) given there being obtained when 0.1 nM estradiol was added.

Furthermore, the antiproliferative effect in vitro on inhibition of the growth of hormone-sensitive MCF-7 breast carcinoma cells was investigated. In order to standardize the conditions and to make a comparison with the investigation in the transfection assay, the MCF-7 cells were also stimulated with 1 nM 17β-esfradiol. The results of these tests are shown in Table 4.

In parallel to the studies on the proliferative efficacy, the substances were also tested on hormone-insensitive MDA-MB-231 mammacarcinoma cells in order to be able to recognize non-specific cytostatic or cytotoxic effects. The results of these tests are also shown in Table 4. Since cytotoxic effects only occur at a concentration that is a hundred times higher than the concentration required for antiestrogenic activity, a presumably mediated antiproliferative effect can be assumed. This assumption is supported by the agreement of the IC50 values with those obtained in the transfection assay.

V / Vo studies were also carried out on the juvenile NMRI mouse. The uterotrophic and the antiuterotrophic activity of the compounds No. 2 (5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-l- {6- [N-methyl-N- (3- (4, 4,5,5,5-pentafluoropentyl-thio) propyl) amino] - hexyl} indole) and No. 6 (5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-l- {6- [N-methyl-N- (5.5, ό, 6.7.7 , 8,8,9,9, 10, 10, 10-tridecαfluordecyl) -αmino] -hexyl} - indole). Table 5 shows the results of these tests.

The tested compounds antagonize at a dosage of 2.5 mg / kg body weight or 0.5 mg / kg body weight SC. the effect of 0.01 mg estradiol / kg body weight completely. The results of these investigations are shown graphically in FIGS. 1 and 2.

All 1-indolyl derivatives according to the invention show a strong inhibition of the growth of estrogen-sensitive MCF-7 cells.

The 1-indolyl derivatives according to the invention, in particular the 2-phenylindole derivatives substituted in the 1-position with the side chain according to the invention, or the pharmaceutical preparations according to the invention which contain these compounds are outstandingly suitable for the therapy of breast carcinomas (second-line therapy instead of of tamoxifen), prostate carcinoma, prostate hyperplasia, anovulatory infertility and melanoma in humans and in principle also in mammals. In addition, the compounds according to the invention can be used for the production of medicaments for the treatment of endometriosis and endometrial carcinomas.

The antiestrogens according to the invention can also be used as a component in the products described in EP 0346 014 B1, which contain an estrogen and a pure antiestrogen, for simultaneous, sequential or separate use for the selective estrogen therapy of peri- and postmenopausal women. The compounds according to the invention can also be used together with genes (competitive progesterone antagonists) can be used to treat hormone-sensitive tumors (EP 0310542 A).

Further indications in which the compounds according to the invention can be used are male hair loss, diffuse alopecia, alopecia caused by chemotherapy and hirsutism [Hye-Sun Oh and Robert C. Smart, Proc. Natl. Acad. Be. USA, 93, 12525-12530 (1996)].

Furthermore, the compounds according to the invention can be used for the production of pharmaceutical compositions for male and female fertility control (male fertility control: DE-A-195 10862).

Depending on the condition to be treated and the type of administration, the amount of the compound administered can be from 0.01 to 100 mg / kg of body weight, preferably 0.1-20 mg / kg of body weight, per day. In humans, this corresponds to a daily dose of about 0.5 to about 5,000 mg. The preferred daily dosage in humans is about 5 to 1,000 mg. The individual dosage units for oral administration can contain, for example, 10 to 100 mg of the active ingredient. This applies in particular to tumor therapy.

The compounds can be administered orally and parenterally, for example Lp. (intraperitoneally), iv (intravenously), im (intramuscularly) or percutaneously. The connections can also be implanted into the tissue. The amount of the compounds to be administered can vary within a wide range, provided that an effective amount is applied. The duration of treatment depends on the purpose to be achieved. Capsules, pills, tablets, dragees, creams, ointments, lotions, liquids such as syrups, gels, injectable liquids are used, for example for / ^' .p.-, i. .-, im.- or percutaneous injection, etc. in question, the individual dosage forms give the compounds of the invention gradually, depending on their type or the entire amount in a short time to the body.

For oral administration, capsules, pills, tablets, coated tablets and liquids or other known oral dosage forms can be used as pharmaceutical preparations. In this case, the medicaments can be formulated in such a way that they either release the active substances in a short time and release them to the body or have a depot effect, so that a longer-lasting, slow supply of active substance to the body is achieved. In addition to the 1-indolyl derivative, the dosage units can contain one or more pharmaceutically acceptable carriers, for example substances for adjusting the rheology of the medicament, surface-active substances, solubilizers, microcapsules, microparticles, granules, diluents, binders, such as starch, sugar, sorbitol and gelatin , also fillers such as silica and talc, lubricants, dyes, fragrances and other substances.

In particular, the 1-indolyl derivatives according to the invention can also be formulated in the form of a solution which is intended for oral administration and which in addition to the active 1-indolyl derivative as the following constituents is a pharmaceutically acceptable oil and / or a pharmaceutically acceptable lipophilic, surface-active substance and / or contains a pharmaceutically acceptable hydrophilic, surface-active substance and / or a pharmaceutically acceptable water-miscible solvent. For this purpose, reference is also made to WO-A-97/21440. In order to achieve better bioavailability of the active compounds according to the invention, the compounds can also be formulated as cyclodextrin chlate. For this purpose, the compounds are reacted with a-, β- or γ-cyclodextrin or their derivatives (PCT / EP95 / 02656).

If creams, ointments, lotions and liquids which can be used externally are to be used, they must be such that the compounds according to the invention are supplied to the body in sufficient quantities. These dosage forms contain auxiliaries, for example substances for adjusting the rheology of the pharmaceuticals, surface-active agents, preservatives, solubilizers, thinners, substances for increasing the permeability for the 1-indolyl derivatives according to the invention through the skin, dyes, fragrances and skin protection agents, such as conditioners and moisture regulators , Together with the steroids according to the invention, other active substances can also be contained in the medicament [ü7 / Mann's Encyclopedia of Industrial Chemistry, Volume 4 (1953), pages 1-39; J. Pharm. Sei, 52, 918 ff. (1963); H. v.Czetsch-Lindenwald, auxiliaries for pharmacy and neighboring areas; Pharm. Ind., 2, 72 ff (1961); Dr. H. P. Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and related areas, Cantor AG, Aulendorf / Württ., 1971].

For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically compatible diluent. Oils with or without the addition of a solubilizer, a surface-active agent, a suspending or emulsifying agent are very often used as diluents. Examples of oils used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil. Any liquid can be used to formulate an injectable preparation. siger carrier are used in which the compounds of the invention are dissolved or emulsified. These liquids often also contain substances for regulating the viscosity, surface-active substances, preservatives, solubilizers, thinners and other additives with which the solution is adjusted isotonic. Other active substances can also be administered together with the 1-indolyl derivatives.

The 1-indolyl derivatives can be used in the form of a depot injection or an implant preparation, for example subcutaneously, which can be formulated in such a way that a delayed release of the active ingredient is made possible. Known techniques can be used for this purpose, for example depots that dissolve or work with a membrane. As inert materials, implants can contain, for example, biodegradable polymers or synthetic silicones, for example silicone rubber. The 1-indolyl derivatives can also be incorporated into a plaster for percutaneous administration, for example.

Various polymers, for example silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene, are suitable for producing intravaginal (for example vaginal rings) or intrauterine systems (for example pessaries, spirals) loaded with active compounds according to the invention.

There are various ways of synthesizing the 1-indolyl derivatives according to the invention. Two of these approaches are shown below as examples:

In the synthesis for the preparation of 1-indolyl derivatives according to the invention with the general formula

is from a compound with the general formula

XA

went out. By halogenation, first an acid halide (1st step according to reaction a in Scheme A in FIG. 3) and then by nucleophilic substitution with R ⁶ -NH-XYZ-CF3 (2nd step according to reaction a), where R ¹ , R ² , R ³ , R ⁴ , R ⁶ , U, X, Y and Z have the abovementioned meanings, the 1-indolyl derivative with the general formula

II "(see scheme A in Fig. 3: there are methyl for R ¹ , R ² , R ³ and R ⁶ and hydrogen for R ⁴ ; U is pentamethylene [(CH2) s] and XYZ is (CH ₂ ) mP, where m = 3 if P is S- (CH ₂ ) 3-CF ₂ or S0 ₂ - (CH ₂ ) 3-CF ₂ , and m = 4 if P is C ₅ F1 ₀ or para -O-phenylene). R ¹ , R ² and R ³ are in particular methyl. R ⁴ is preferably hydrogen. U is in particular an unbranched alkylene group [(CH ₂ ) _n ], where n is an integer from 1 to Is 13 and preferably 5, 6, 7 or 8. X is preferably an unbranched alkylene group [(CH ₂ ) _m ], where m is an integer from 1 and 12, so that X is in particular for an unbranched ethylene, propylene, YZ are together a CsFio group, a para-O-phenylene group, an S- (CH ₂ ) 3-CF ₂ group or an S0 ₂ - (CH ₂ ) ₃ -CF ₂ group.

The usual reagents are available for halogenating the carboxylic acid derivatives, for example phosphorus pentachloride, N-chlorosuccinimide, dicyclohexylcarbodiimide (DCC), fluorine, chlorine, bromine or hydroiodic acid, thionyl chloride, thionyl bromide, phosphorus oxychloride, triphenylphosphine / tetrachloromethane Pyridine or diamino-sulfur trifluoride and nonaflyl fluoride / 1, 5-diazabicyclo [5.4.0] -undecene. The acid amides are formed by reacting the acid chlorides with the corresponding methylamines by adding the crude acid chloride products formed from the reaction of the carboxylic acids to a solution of the methylamine with exclusion of moisture and causing them to react, and the resulting products are hydrolyzed by pouring them onto ice water.

The ethers formed are then split by reacting with aluminum chloride and then with ethanethiol with exclusion of moisture and the product is hydrolyzed, so that the 5-hydroxy-2- (4-hydroxyphenyl) indole derivatives are formed (reaction b). This reaction sequence is used for the compounds with YZ = para-O-phenylene (compounds Nos. 7 and 8). Alternatively, the ethers can also be cleaved with bortribomide. This synthesis option is used for the other compounds (YZ = C5F10, S- (CH ₂ ) ₃ -CF ₂ and S0 ₂ - (CH ₂ ) ₃ -CF2; compounds Nos. 1 to 6 and 9 to 12).

The amide can be reduced to the amine using conventional reducing agents, for example using lithium aluminum hydride in tetrahydrofuran (THF) (reaction d).

Alternatively, the compounds II can also start from the 1-indolyl derivative with the general formula

XB can be produced, where E is a halogen atom, in particular bromine, a hydroxyl group or a nucleophilic leaving group and R ¹ , R ² , R ³ and R ^{4 have the} same meanings as previously indicated (see scheme B in FIG. 4: Ri, R ₂ where R ₃ is methyl and R _{4 is} hydrogen, U is pentamethylene [(CH2) s], and E is Br).

This 1-indolyl derivative is then converted by nucleophilic substitution with R ⁶ -NH-XYZ-CF3 to the 1-indolyl derivative 11 '"according to the invention (reaction a):

where R ⁶ , U, X, Y and Z have the meanings given above (in scheme B, R ^{6 is} methyl and XYZ is (CH2) ₃ -Sθ2- (CH2) 3-CF ₂ ).

For nucleophilic substitution of the halogen compound XB with the corresponding methylamine, XB is reacted with the amine in an ethanolic solution, for example. The resulting product is hydrolyzed with ice water.

The ethers are then converted to 5-hydroxy-2- (4-hydroxyphenyl) indole derivative II (reaction b). For this purpose, the aforementioned ether cleavage is again carried out with aluminum chloride and ethanethiol and / or with boron tribromide. The starting compounds XA are synthesized according to the following reaction scheme (scheme C in FIG. 5):

1 -Brom-1 - (4-methoxy-benzoyl) -ethane is added to 4-Methoxya nilin

5-methoxy-2- (4-methoxyphenyl) -3-methyl-indole reacted (reaction a). The corresponding 1-indolyl derivative is formed by subsequent reaction with sodium hydride and subsequent reaction with ethyl n-bromoalkanoate or 6-bromo-hexylnitrile (reaction b). This is then hydrolyzed with ethanolic KOH solution or HCl to the acid XA (reaction c). The acid XA can then be processed further in the aforementioned manner.

The examples shown below serve to explain the invention in more detail:

Synthesis instructions and analytical data

General instructions for the preparation of acid amides

1.98 mmol l- (5-carboxypentyl) -5-methoxy-2- (4-methoxyphenyl) -3-methylol were mixed with 1.98 mmol phosphorus pentachloride and with exclusion of moisture for 30 minutes at room temperature and then for 30 minutes stirred at about 60 ° C. After adding 5 ml of benzene, the mixture was concentrated in a water jet vacuum. The

The residue was taken up in 10 ml of dry dichloromethane and the solution was slowly added dropwise to a solution of 4.94 mmol of the respective secondary methylamine in absolute dichloromethane. The mixture was again stirred overnight with the exclusion of moisture. The reaction mixture was poured onto ice water for hydrolysis. The aqueous phase was then extracted three times with ethyl acetate. Then the combined organic phases were washed twice with saturated sodium chloride solution and dried over magnesium sulfate. The solvents were removed in vacuo. The crude product was purified by column chromatography on silica gel 60 (various dichloromethane / ethyl acetate mixtures).

Example 1 :

5-methoxy-2- (4-methoxyphenyl) -3-methyl-l- {5- [N-methyl-N- (5,5,6,6,7,7,8,8,9,9,10 , 10, 10-iridecaflυordecyl) carbamoyl] pentyl} indole (compound 5A)

Preparation from N-methyl-5,5,6, ό, 7,7,8,8,9,9,10,10,10-tridecafluorodecylamine; Purification by column chromatography on silica gel 60 (dichloromethane / ethyl acetate 5: 1, v / v) yellow resin; Yield: 40%

IR (film): 1645 cm- ¹ (s; C = 0) ⁱ H-NMR (CDCI3): δ (ppm) = 1, 15-1, 28 (m; 6H; - (CH ₂ ) ₂ -C ₆ Fι ₃ ,

-CH ₂ - (CH ₂ ) ₂ -CO-); 1, 43-1, 58 (m; 6H; -CH ₂ -CH ₂ -NCH ₃ -, -CH ₂ -CH ₂ -CO-, indole-N-CH ₂ -CH ₂ -); 2.19 (s; 3H; indole CHs); 2.06-2.20 (m; 2H; -CH2-CO-); 2.41 (s; 3H; -CO-NCH3-); 3.22-3.24 and 3.35-3.37 (m; 2H;

-CH ₂ -NCH ₃ -, e / z); 3.88 (s; 3H; -OCH ₃ ); 3.89 (s; 3H; -OCH3); 3.85-3.92 (m; 2H; indole-N-CH ₂ -); 6.87 (dd; ³ J = 8.8 Hz, J = 2.4 Hz; 1 H; indole-H *); 7.01 (dd; J = 2.4 Hz, ⁵ J = 0.5 Hz; 1 H; indole-H ⁴ ); 7.22 (dd; ³ J = 8.8 Hz, sj = 0.5 Hz; 1 H; indole-H ⁷ ); 7.00 and 7.28 (AA'BB '; ³ J = 8.7 Hz; 4H; Phenyl-H)

Example 2:

5-methoxy-2- (4-methoxyphenyl) -3-methyl- 1 - {5- [N-methyl-N- (2- (4-trifluoromethylphenyloxy) ethyl) carbamoyl] -penfyl} -indole (Compound No. 7A)

Preparation from N-methyl-2- (4-trifluoromethylphenyloxy) ethylamine; Purification by column chromatography on silica gel 60 (dichloromethane / ethyl acetate 5: 1, v / v) yellow resin; Yield: 55%

IR (CHCI ₃ ): 1646 cm- '(s; C = 0) ⁱ H-NMR (CDCb): δ (ppm) = 1.1 1-1.62 (m; 6H; - (CH ₂ ) ₃ - ); 2.18 (s; 3H; indole-CH ₃ ); 2.17-2.31 (m; 2H; -CH2-CO-); 2.97 and 3.06

(s; 3H; -CO-NCH3-, e / z); 3.62-3.79 (m; 2H; -CH2-NCH3-);

3.87 (s; 3H; -OCH ₃ ); 3.88 (s; 3H; -OCH ₃ ); 3.88-4.1 1 (m; 2H;

-CH2-O-); 4.1 1-4.16 (m; 2H; indole-N-CH ₂ -); 6.87 (dd; ³ J = 8.8 Hz; ⁴ J = 2.6 Hz; 1 H; indole-H *); 7.01 (dd; ⁴ J = 2.6 Hz; sj = 0.5 Hz; 1 H; indole-H ⁴ ); 7.21 (dd; J = 8.8 Hz; 5J =

0.5 Hz; 1 H; Indole-H ⁷ ); 6.93 and 7.53 (AA'BB '; ³ J = 8.7 Hz;

4H; Phenylindole-H); 6.98 and 7.27 (AA'BB '; ³ J = 8.8 Hz;

4H; Phenyl-H) Example 3:

5-methoxy-2- (4-methoxyphenyl) -3-methyl-1 - {5- [N-methyl-N- (3- (4,4,5,5,5-pentafluoropentylthio) propyl) - carbamoyl] pentyl} indole (Compound No. 1A)

Preparation from N-methyl-3- (4,4,5,5,5-pentafluoropentylthio) propylamine; Purification by column chromatography on silica gel 60 (dichloromethane / ethyl acetate 5: 1, v / v) brown resin; Yield: 37%

IR (film): 1644 cm- '(s; C = OJ ⁱ H-NMR (CDCb); δ (ppm) = 1, 12-1, 29 (; 2H; -CH ₂ - (CH ₂ ) ₂ -CO -); 1, 46-1, 58

(m; 4H; -CH ₂ -CH ₂ -CO-, -CH ₂ -C ₂ F ₅ ); 1.74-1.92 (m; 4H; indole-N-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -C ₂ F ₅ ); 2.12-2.23 (m; 4H;

-CH ₂ -CO-, -CH ₂ -CH ₂ -NCH ₃ -); 2.19 (s; 3H; indole-CH ₃ );

2.45-2.67 (m; 4H; -S (CH ₂ -) ₂ ); 2.88 and 2.90 (s; 3H;

-CO-NCH3-, e / z); 3.30 and 3.41 (t; ³ J = 7.4 Hz; 2H;

-CH ₂ -NCH ₃ -, e / z); 3.88 (s; 3H; -OCH ₃ ); 3.89 (s; 3H; -OCH3); 3.97 (t; ³ J = 7.4 Hz; 2H; indole-N-CH ₂ -); 6.87 (dd;

³ J = 8.8 Hz, ⁴ J = 2.3 Hz; 1 H; Indole-H ⁶ ); 7.02 (dd; ⁴ J =

2.3 Hz, ⁵ J = 0.5 Hz; 1 H; Indole-H ⁴ ); 7.22 (dd; ³ J = 8.8 Hz,

⁵ J = 0.5 Hz; 1 H; Indole-H ⁷ ); 7.00 and 7.28 (AA'BB '; ³ J =

8.8 Hz; 4H; Phenyl-H) Example 4:

5-methoxy-2- (4-methoxyphenyl) -3-methyl- 1 - {5- [N-methyl-N- (3- (4,4,5,5,5-pentafluorpentylsulfonyl) propyl) -carbamoyl] -pentyl} -indole (Compound No. 3A)

Preparation from N-methyl-3- (4,4,5,5,5-pentafluoropentylsulfonyl) propylamine; Purification by column chromatography on silica gel 60 (dichloromethane / ethyl acetate 1: 1, v / v) yellow resin; Yield: 40%

IR (film): 1643 cm- ¹ (s; C = 0)

'H NMR (DMSO-d ₆ ): δ (ppm) = 1, 03-1, 1 1 (m; 2H; -CH ₂ - (CH ₂ ) 2-CO-); 1, 24-

1.33 (m; 2H; -CH2-C2F5); 1.42-1.53 (m; 2H; -CH ₂ -CH ₂ -CO-); 1, 78-1, 95 (m; 4H; indole-N-CH ₂ -CH ₂ -,

-CH ₂ -CH ₂ -CF ₅ ); 2.03-2.16 (m; 2H; -CH ₂ -CO-); 2.1 1 (s; 3H; indole CHs); 2.30-2.44 (m; 2H; -CH2-CH2-NCH3-); 2.76 and 2.87 (s; 3H; -CO-NCH3-, e / z); 3.02-3.10 (m; 2H; -CH2- (CH2) 2-C ₂ F ₅ ); 3.13-3.26 (m; 2H; -CH ₂ - (CH ₂ ) ₂ -NCH ₃ -); 3.28-3.36 (m; 2H; -CH2-NCH3-); 3.79

(s; 3H; -OCH3); 3.83 (s; 3H; -OCH ₃ ); 3.99-4.04 (m; 2H; indole-N-CH ₂ -); 6.78 (dd; ³ J = 8.8 Hz, ⁴ J = 2.4 Hz; 1 H; indole-H *); 6.99 (dd; ⁴ J = 2.4 Hz, sj = 0.5 Hz; 1 H; indole-H ⁴ ); 7.31-7.35 (m; 1 H; H-indole ^7); 7.08 and 7.33 (AA'BB '; ³ J = 8.7 Hz; 4H; phenyl-H)

Ether cleavage with ethanethiol under aluminum chloride catalysis

0.94 mmol of the methoxyphenylindole compound No. 7A (Example 2) were dissolved in 15 ml of dry dichloromethane. 5.66 mmol aluminum chloride was added. The mixture was stirred for 5 minutes and the resulting dark brown mixture was finally mixed with 4.72 mmol ethanethiol. The mixture was stirred for a total of three hours at room temperature and with exclusion of moisture and then hydrolyzed.

After the aqueous phase had been separated off, it was extracted three times with ethyl acetate, the combined organic phases were washed twice with water, dried over magnesium sulfate and the solvents were spun off in vacuo. The crude product obtained was purified by column chromatography on silica gel 60 (dichloromethane / ethyl acetate 1: 2).

Example 5:

5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-l- {5- [N-methyl-N- (2- (4-trifluoromethylphenyloxy) ethyl) carbamoyl] pentyl} - indole (compound no. 7)

yellow foam; Yield: 40%

IR (CHC): 3304 cm- ¹ (s; OH)

1650 cm- ¹ (s; C = 0) TH NMR (DMSO-d ₆ ): δ (ppm) = 1, 03-1, 57 (m; 6H; - (CH ₂ ) ₃ -); 2.04 (s; 3H; indole-CH ₃ ); 1.99-2.29 (m; 2H; -CH2-CO-); 2.83 and 2.98 (s; 3H; -CO-NCH3-, e / z); 3.60-3.64 (m; 2H; -CH2-NCH3-);

3.90 (s; br; 2H; -CH2-O-); 4.10-4.21 (m; 2H; indole-N-CH ₂ -); 6.64 (dd; ³ J = 8.7 Hz, ⁴ J = 1.9 Hz; 1 H; indole-H *); 6.78 (dd; ⁴ J = 1.9 Hz, ⁵ J = 0.5 Hz; 1 H; indole-H ⁴ ); 7.01 (dd; ³ J = 8.7 Hz, ⁵ J = 0.5 Hz; 1 H; indole-H ⁷ ); 6.89 and 7.87 (AA'BB '; ³ J = 8.8 Hz; 4H; phenylindole-H); 7.05 and 7.18 (AA'BB '; ³ J = 8.4 Hz; 4H; Phenyl-H); 8.66 (s, 1H; -OH); 9.65 (s; 1H; -OH)

Ether rinsing with boron tribromide

A solution of 2.16 mmol of boron tribromide in 10 ml of absolute dichloromethane was cooled in an ice-sodium salt bath and a solution of 0.54 mmol of the corresponding methoxyphenylindole (II ") in absolute dichloromethane was added dropwise under nitrogen gas. After the dropwise addition, the mixture was added the cooling bath was removed and the batch was stirred for at least three hours more.

For working up, the reaction mixture was cooled again and hydrolyzed by careful dropping with a total of 60 ml of saturated sodium hydrogen carbonate solution. The stirring was continued until gas evolution was no longer discernible. Chunks formed were then dissolved by adding ethyl acetate. The two phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were finally washed twice with saturated sodium hydrogen carbonate solution and once with water. After drying over magnesium sulfate, the solvents were removed in vacuo. For purification, the crude products were chromatographed on silica gel 60 (various dichloromethane / ethyl acetate mixtures). Example 6:

5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1 - {5- [N-methyl-N- (5,5,6,6,7,7,8,8,9,9,10 , 10, 10-tridecaflυordecyl) carbamoyl] pentyl} indole (Compound No. 5)

Preparation from Compound No. 5A (5-methoxy-2- (4-methoxyphenyl) -3-methyl-l- {5- [N-methyl-N- (5,5,6,6,7,7,8, 8,9,9,10,10,10-tridecafluorodecyl) carbamoyl] pentyl} indole); Purification by column chromatography on silica gel 60 (dichloromethane / ethyl acetate 1: 2, v / v) yellow resin; Yield: 62%

IR (film): 3299 cm- ¹ (s, br; OH)

1642 cm- ¹ (s; C = 0) ^! H NMR (DMSO-d ₆ ): δ (ppm) = 1.03-1.51 (m; 12H;

- (CH ₂ ) ₃ -C ₆ Fi3, - (CH ₂ ) ₃ -); 2.04 (s; 3H; indole-CH ₃ ); 2.07-2.15 (m; 2H; -CH2-CO-); 2.75 and 2.84 (s; 3H; -CO-NCH3, e / z); 3.20-3.29 (m; 2H; -CH2-NCH3-); 3.91-3.94 (m; 2H; indole-N-CH ₂ -); 6.64 (dd; ³ J = 8.6 Hz, ⁴ J = 2.3 Hz; 1 H; indole-H *); 6.78 (dd; J = 2.3 Hz, ⁵ J = 0.5 Hz; 1 H; indole-H ⁴ );

7.16-7.19 (m; 1 H; H-indole ^7); 6.88 and 7.18 (AA'BB '; ³ J = 8.5 Hz; 4H; phenyl-H); 8.65 (s, br; 1H; -OH); 9.64 (s, br; 1H; -OH)

Example 7:

5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-l- {5- [N-methyl-N- (3- (4-5,5,5,5-pentafluorpentylthio) propyl) carbamoyl] pentyl } -indole (Compound No. 1)

Preparation from Compound No. 1A (5-methoxy-2- (4-methoxyphenyl) -3-methyl-l- {5- [N-methyl-N- (3- (4,4,5,5,5- pentafluoropentylthio) propyl) carbamoyl] pentyl} indole); Purification by column chromatography on silica gel 60 (dichloromethane / ethyl acetate 1: 2, v / v) yellow resin; Yield: 55%

IR (film): 3300 cm- ¹ (s, br; OH)

1642 cm- ¹ (s; C = 0) Η NMR (CDC): δ (ppm) = 1, 10-1, 19 (m; 2H; -CH ₂ - (CH ₂ ) ₂ -CO-); 1, 44-1, 58

(m; 4H; -CH2-CH2-CO-, -CH2-C2F5); 1.77-1.92 (m; 4H; indole-N-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -C ₂ F ₅ ); 2.05-2.25 (m; 4H; -CH ₂ -CO-, -CH ₂ -CH ₂ -NCH ₃ -); 2.12 (s; 3H; indole-CH ₃ ); 2.46-2.63 (m; 4H; S (CH ₂ -) ₂ ); 2.93 (s; 3H; -CO-NCH3-); 3.32 and 3.44 (t; ³ J = 7.4 Hz; 2H; -CH2-NCH3-, e / z); 3.93 (t; ³ J =

7.4 Hz; 2H; indole-N-CH ₂ -); 5.31 (s, br; 2H; -OH); 6.77 (dd; ³ J = 8.6 Hz, ⁴ J = 2.4 Hz; 1 H; indole-H *); 6.97 (dd; ⁴ J = 2.4 Hz, ⁵ J = 0.5 Hz; 1 H; indole-H ⁴ ); 7.14 (dd; ³ J = 8.6 Hz, sj = 0.5 Hz; 1 H; indole-H ⁷ ); 6.94 and 7.18 (AA'BB '; ³ J = 8.6 Hz; 4H; phenyl-H) Example 8:

5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-l- {5- [N-methyl-N- (3- (4,4,5,5,5-pentafluoropentylsulfonyl) propyl} - carbamoyl] pentyl} indole (Compound No. 3)

Preparation from Compound No. 3A (5-methoxy-2- (4-methoxyphenyl) -3-methyl-l- {5- [N-methyl-N- (3- (4,4,5,5,5-pentafluoropentyl -sulfonyl) -propyl) -carbamoyl] -pentyl} -indole); Purification by column chromatography on silica gel 60 (dichloromethane / ethyl acetate 1: 8, v / v) yellow foam; Yield: 50%

IR (film): 3286 cm- ¹ (s, br; OH)

1644 cm- ¹ (s; C = 0) H-NMR (DMSO-dό): δ (ppm) = 1, 04-1, 50 (m; 6H; - (CH ₂ ) -CH ₂ -CO-,

-CH2-C2F5); 1.79-1.98 (m; 4H; indole-N-CH ₂ -CH ₂ -, CH ₂ -CH ₂ -C ₂ F ₅ ); 2.04 (s; 3H; indole-CH ₃ ); 2.06-2.17 (m; 2H; -CH2-CO-); 2.29-2.43 (m; 2H; -CH2-CH2-NCH3-); 2.73 and 2.88 (s; 3H; -CO-NCH3-, e / z); 3.03 to 3.18 (m; 2H; -CH2- _(CH2) 2-C ₂ F5); 3.20-3.30 (m; 2H;

-CH ₂ - (CH ₂ ) 2-NCH ₃ -); 3.33-3.36 (m; 2H; -CH2-NCH3-); 3.89-3.92 (m; 2H; indole-N-CH ₂ -); 6.64 (dd; ³ J = 8.7 Hz, ⁴ J = 2.3 Hz; 1 H; indole-H *); 6.78 (dd; ⁴ J = 2.3 Hz, ⁵ J = 0.5 Hz; 1 H; indole-H ⁴ ); 7.19 (dd; ³ J = 8.7 Hz, ⁵ J = 0.5 Hz; 1 H; indole-H ⁷ ); 6.89 and 7.18 (AA'BB '; ³ J = 8.5 Hz; 4H;

Phenyl-H); 8.66 (s; 1H; -OH); 9.65 (s; 1H; -OH)

Reduction of the amide function to the amine

A suspension of 9.1 1 mmol lithium aluminum hydride in 100 ml abso- lutem THF was heated to reflux and a solution of 3.38 mmol of the corresponding carboxamide in 150 ml of absolute THF was added dropwise so that the batch always boiled but did not foam too much. The reaction mixture was kept boiling for one hour after the addition. The water bath was then removed and stirring was continued at room temperature overnight.

To work up the resulting product, excess lithium aluminum hydride was hydrolyzed with a total of 150 ml of ice water and 25 ml of saturated sodium hydrogen carbonate solution and the separated aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed twice more with saturated sodium chloride solution and once with water and dried over magnesium sulfate. The solvents were then removed in vacuo.

Separation of unreacted starting material and by-products was achieved by column chromatography on silica gel 60 (ethyl acetate / methanol 3: 1, v / v).

Example 9:

5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1 - {6- [N-methyl-N- (5,5,6,6,7,7,8,8,9,9,10 , 10, 10-tήdecaflυordecyl) amino] hexyl} indole (Compound No. 6)

Preparation from compound no. 5 (5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-1 - {5- [N-methyl-N- (5,5,6,6,7,7,8, 8,9,9, 10, 10, 10-tridecafluorodecyl) - carbamoyl] -pentyl} -indole) slightly brownish foam, yield: 53%

IR (film): 3288 cm- ¹ (s, br; OH)

'H NMR (DMSO-d ₆ ): δ (ppm) = 1, 02-1, 49 (m; 14H; - (CH ₂ ) 3-C _ό F ₁₃ , - (CH ₂ ) ₄ -);

2.04 (s; 3H; indole-CH); 2.04-2.29 (m; 4H; -NCH - (CH ₂ -) ₂ ); 2.08 (s; 3H; -NCH3-); 3.88-3.95 (m; 2H; indole-N-CH ₂ -);

6.63 (dd; ³ J = 8.6 Hz, ⁴ J = 2.3 Hz; 1 H; indole-H *); 6.78 (dd;

⁴ J = 2.3 Hz; ⁵ J = 0.5 Hz; 1 H; Indole-H ⁴ ); 7.18 (dd; ³ J =

8.6 Hz, ⁵ J = 0.5 Hz; 1 H; Indole-H ⁷ ); 6.88 and 7.17 (AA'BB ';

³ J = 8.5 Hz; 4H; Phenyl-H); 8.66 (s, br; 1H; -OH); 9.67 (s, br; l H; -OH)

Example 10:

5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-l- {6- [N-methyl ~ N- (2- (4-trifluoromethylphenyloxy) ethyl) amino] hexyl} indole ( Compound No. 8)

Preparation from compound no. 7 (5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {5- [N-methyl-N- (2- (4-trifluoromethyl-phenyloxy) -ethyl) carbamoyl ] -pentyl} -indole) colorless foam; Yield: 45%

IR (CHC): 3284 cm- ¹ (s; OH)

¹ H NMR (DMSO-d ₆ ): δ (ppm) = 1, 02-1, 14 (m; 4H; - (CH) ₂ -); 1, 17-1, 22

(m; 2H; -CH ₂ -CH ₂ -NCH ₃ -); 1.41-1.43 (m; 2H; indole-N-CH ₂ -CH ₂ -); 2.03 (s; 3H; indole-CH ₃ ); 2.15

(s; 3H; -NCH3-); 2.10-2.28 (m; 2H; -CH2-NCH3-); 2.61 (t; ³ J = 5.9 Hz; 2H; -CH ₂ -CH ₂ 0-); 3.88-3.99 (m; 4H; indole-N-CH ₂ -, -CH2O-); 6.63 (dd; ³ J = 8.7 Hz; ⁴ J = 2.3 Hz; 1 H; indole-H *); 6.77 (dd; ⁴ J = 2.3 Hz, sj = 0.5 Hz; 1 H; indole-H ⁴ ); 7, 17 (dd; ³ J = 8.7 Hz, ⁵ j = 0.5 Hz; 1 H; Indole-H ⁷ ); 6.84 and 7.19 (AA'BB '; ³ J = 8.6 Hz; 4H; phenylindole-H); 6.88 and 7.16 (AA'BB '; ³ J = 8.5 Hz; 4H; phenyl-H); 8.65 (s, br; 1H; -OH); 9.66 (s, br; 1H; -OH)

Example 11:

5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-l- {6-IN-methyl-N- (3- (4,4,5,5,5-pentafluoropentylthio) propyl) aminoj -hexyi mdol (compound no. 2)

Preparation from compound no. 1 (5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-l- {5- [N-methyl-N- (3- (4,4,5,5,5 -pentafluorpentyl-thio) -propyl) - carbamoyl] -pentyl} -indole) brownish resin; Yield: 68%

IR (film): 3287 cm- '(s, br; OH) ⁱ H-NMR (DMSO-dό): δ (ppm) = 1, 03-1, 15 (m; 4H; - (CH2) 2- ( CH) 2-NCH ₃ -);

1.18-1, 24 (m; 2H; -CH ₂ -C ₂ F ₅ ); 1, 43-1, 50 (m; 2H;

- (CH2) 4-CH2-CH ₂ -NCH ₃ -); 1.57-1.81 (m; 4H;

CH2-CH2-C2F5, indole N-CH ₂ -CH ₂ -); 2.04-2.12 (m; 2H;

-SCH2-CH2-CH2-NCH3-); 2.04 (s; 3H; indole-CH ₃ ); 2.12 (s;

3H; -NCH3-); 2.18-2.51 (m; 6H; - (CH ₂ ) 5-CH2-NCH ₃ -,

-S (CH ₂ -) ₂ ); 2.58 (t; ³ J = 7.2 Hz; 2H;

-SCH2-CH2-CH2-NCH3-); 3.93 (t; J = 7.0 Hz; 2H; indole-N-CH ₂ -); 6.64 (dd; ³ J = 8.6 Hz, ⁴ J = 2.3 Hz; 1 H;

Indole-H *); 6.78 (dd; J = 2.3 Hz, ⁵ J = 0.5 Hz; 1 H; indole-H ⁴ );

7.18 (dd; ³ J = 8.6 Hz, sj = 0.5 Hz; 1 H; indole-H ⁷ ); 6.90 and 7.17 (AA'BB '; ³ J = 8.5 Hz; 4H; phenyl-H); 8.68 (s, br; 1H; -OH); 9.70 (s, br; l H; -OH)

Example 12:

Direct Preparation of Amine No. 4 (5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1 - {6- [N-methyl-N- (3- (4,4,5,5,5- pentαfluorpentyl-sulfonyl) -propyl) - αmino] -hexyl} -indole) by nucleophilic substitution and ether cleavage

1.32 mmol l - (6-bromohexyl) -5-methoxy-2- (4-methoxyphenyl) -3-methylindole, 2.70 mmol N-methyl- [3- (4,4,5,5,5- pentαfluorpentyl-sulfonyl) - propyl] -αmin and 30 ml of pure ethαnol were heated to reflux overnight. After hydrolysis with ice water, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed once each with water and saturated sodium chloride solution and dried over magnesium sulfate. The solvents were removed in vacuo. For purification, the reaction mixture obtained was chromatographed on silica gel 60 (ethyl acetate / methanol 3: 1, v / v).

Example 13:

5-methoxy-2- (4-methoxyphenyl) -3-methyl-l- {6- [N-methyl-N- (3- (4,4,5,5,5-pentafluoropentylsulfonyl) propyl) - amino] hexyl} indole (Compound No. 4A)

yellow resin; Yield: 74%

¹ H NMR (DMSO-d ₆ ): δ (ppm) = 1.00-1.02 (m; 4H; - (CH ₂ ) ₂ - (CH ₂ ) ₂ -NCH ₃ -);

1, 20-1, 22 (m; 2H; -CH ₂ -C ₂ F ₅ ); 1, 41 -1, 43 (m; 2H; - _(CH2) 4-CH2-CH2-NCH ₃ -); 1.70-1.85 (m; 2H;

-CH ₂ -CH ₂ -C2F ₅ ); 1, 88-1, 97 (m; 2H; indole-N-CH ₂ -CH ₂ -); 2.06-2.15 (m; 2H; -S0 ₂ -CH ₂ -CH ₂ -CH ₂ -NCH ₃ -); 2.06 (s; 3H; indole-CH ₃ ); 2.10 (s; 3H; -NCH ₃ -); 2.32-2.42 (m; 4H; -NCH ₃ - (CH ₂ -) ₂ ); 3.04-3.10 (m; 2H; -Sθ2-CH2- (CH2) 2-C ₂ F ₅ ); 3.19-3.31 (m; 2H; -Sθ2-CH ₂ - (CH2) 2-NCH ₃ -); 3.77 (s; 3H; -OCH); 3.82 (s; 3H;

-OCH3); 3.98 (t; ³ J = 7.1 Hz; 2H; indole-N-CH ₂ -); 6.77 (dd; ³ J = 8.8 Hz, ⁴ J = 2.4 Hz; 1 H; indole-H *); 6.97 (dd; ⁴ J = 2.4 Hz, ⁵ J = 0.5 Hz; 1 H; indole-H ⁴ ); 7.31 (dd; ³ J = 8.8 Hz, ⁵ J = 0.5 Hz; 1 H; indole-H ⁷ ); 7.07 and 7.31 (AA'BB '; ³ J = 8.7 Hz; 4H; phenyl-H)

Etherspαltung with Ethαnthiol / AIC

The cleavage of the methoxy groups was carried out analogously to the synthesis of compound no. 7 (5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-1 - {5- [N-methyl-N- (2- (4-trifluoromethyl- phenyloxy) ethyl) carbamoyl] pentyl} indole) (Example 5). The compound was purified by chromatography on silica gel 60 (efhylacetaf / methanol 3: 1, v / v).

Example 14:

5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl- l- {6- [N-methyl-N- (3- (4,4,5,5,5-pentafluoropentylsulfonyl) propyϊ) - amino] hexyl} indole (Compound No. 4)

brown resin; Yield: 73%

IR (CHCb) 3405 cm- ¹ (s, br; OH)

^T H NMR (DMSO-d ₆ ): δ (ppm) = 1, 03-1, 14 (m; 4H; - (CH ₂ ) 2- (CH2) 2-NCH ₃ -); 1, 23-1, 25 (m; 2H; -CH2-C2F5); 1.41-1.44 (m; 2H; - (CH ₂ ) 4-CH ₂ -CH2-NCH3-); 1.71-1.83 (m; 2H;

-CH2-CH2-C2F5); 1.86-1.98 (m; 2H; indole-N-CH ₂ -CH ₂ -);

2.05 (s; 3H; indole-CH); 2.07 (s; 3H; -NCH3-); 2.12-2.18 (m;

2H; -SO2-CH2-CH2-CH2-NCH3-); 2.31-2.43 (m; 4H; -NCH3- (CH ₂ -) ₂ ); 3.06 to 3.12 (m; 2H; -Sθ2-CH2- _(CH2) 2-C2F _5); 3,20

3.34 (m; 2H; -S0 ₂ -CH ₂ - (CH ₂ ) ₂ -NCH ₃ -); 3.82-3.96 (m; 2H; indole-N-CH ₂ -); 6.64 (dd; ³ J = 8.6 Hz, ⁴ J = 2.3 Hz; 1 H;

Indole-H *); 6.78 (dd; ⁴ J = 2.3 Hz, sj = 0.5 Hz; 1 H; indole-H ⁴ );

7.19 (dd; ³ J = 8.6 Hz, sj = 0.5 Hz; 1 H; indole-H ⁷ ); 6.89 and 7.18 (AA'BB '; ³ J = 8.5 Hz; 4H; phenyl-H); 8.67 (s, br; 1H; -

OH); 9.67 (s, br; l H; -OH)

Compounds No. 9 (5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-l - {6- [N-methyl-N- (7,7,8,8,9,9, 10, 10 , 10-nonαf luordecyl) -αmino] hexyl} indole), No. 10 (5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-l- {7- [N-methyl-N-

(7,7,8,8,9,9,10,10,10-nonαfluordecyl) -αmino] -heptyl} -indole), No. 1 1 (5-

Hydroxy-2- (4-hydroxyphenyl) -3-methyl-l - {8- [N-methyl-N-

(7,7,8,8,9,9, 10,10,10-nonαfluordecyl) -αmino] -octyl} -indole) and No. 12 (5-

Hydroxy-2- (4-hydroxyphenyl) -3-methyl-l - {9- [N-methyl-N- (7,7,8,8,9,9, 10,10,10-nonαfluorodecyl) αmino] -nonyl} indole) and the further compounds Nos. 13 to 41 listed in Table 1 and their 4 ', 5-dimethoxyindole derivatives can be prepared analogously to the compounds described above.

Table 1: Indolyl derivatives according to the invention

*) Transfection assay with the addition of 0.1 nM estradiol to stimulate MCF-7 breast carcinoma cells Continuation of table 1:

*) Transfection assay with the addition of 0.1 nM estradiol to stimulate MCF-7 mammacarcinoma cells Continuation of table 1:

*) Trαnsfekfionsαssαy with the addition of 0.1 nM estradiol to stimulate MCF-7 breast carcinoma cells Continuation of table 1:

*) Transfection assay with the addition of 0.1 nM estradiol to stimulate MCF-7 breast carcinoma cells Table 2: 1 structure properties of indolyl derivatives Nos. 1 to 12

Indole - UVWXYZ-CF3 = (CH2) nVN (CH ₃ ) - (CH2) qYZ-CF ₃

Continuation of table 2:

Table 3: Relative binding affinity to the estrogen receptor / antiestrogenic activity

1) Relative binding affinity to the estrogen receptor (RBA value for 17ß-estradiol = 100)

2) Antiestrogenic activity, determined in vitro, on MCF-7 breast carcinoma cells which have been stably transfected with luciferase reporter plasmid and stimulated with estradiol, namely with an estradiol concentration of 10 nM (*) or 1nM (* *)

3) Inhibition of the growth of estrogen-sensitive MCF-7 breast carcinoma cells after incubation for several days in the absence of estradiol, determined by crystal violet staining.

R1: 7α- {9 - [(4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl} estra-1,3,5 (10) -triene-3,17ß-diol

R2: 7α- (5- {N-methyl-N- [3 - ({4,4,5,5,5-pentafluorpentyl} thio) propyl] amino} pentyl) estra-1, 3, 5 (10) - triene-3,17β-diol

R3: 5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- [10- (pentylsulfonyl) decyl] indole Table 4: Estrogens, antiproliferative and cytotoxic effects

m TJ

CΛ

>

H N CD

73 m o m r

*) no addition of estradiol

**) Add 1 nM estradiol

R1: 7α- {9 - [(4,4,5,5,5-pentafluoropentyl) sulfyl] nonyl} estra-1,3,5 (10) -triene-3,17β-diol

R2: 7α- (5- {N-methyl-N- [3 - ({4,4,5,5,5-pentafluorpentyl} thio) propyl] amino} pentyl) estra-1, 3, 5 (10) -triene-3,17ß-diol

R3: 5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1 - [10- (pentylsulfonyl) decyl] indole

Table 5 (estrogenic and antiestrogenic effects in the mouse):

a) daily dose; applied subcutaneously in the solvent olive oil (5% EtOH) for three consecutive days b) relative uterine weight, based on 100 g body weight (MW V σ _n -ι); information not marked is not significant compared to the control c) EW: estrogenic effect; H: inhibition d) application of the test substances together with 0.01 mg estradiol / kg e) significant p <0.025 compared to the control f) significant p <0.01 compared to the estradiol control group g) significant p <0.05 compared to the estradiol - Control group h) significantly p <0.05 compared to the control

Claims

claims:

1. 1 -Indolyl derivatives with the general formula

wherein R ¹ and R ² independently of one another represent a) hydrogen or b) straight-chain or branched-chain C to C ₄ -alkyl, -alkenyl or -alkynyl radicals or c) C (O) -R ⁵ , where R ^{5 is} a straight line - or branched chain C 1 -C ₄ -alkyl, -alkenyl or -alkynyl radical,

R ³ and R ⁴ together represent a di, tri or tetramethylene bridge, which can also contain a double bond, and U represents either a straight-chain or branched-chain C 1 -C 3 -alkylene, -alkenylene or -alkynylene radical or AB, where A is bonded to the indole nitrogen atom and a benzylidene radical bonded via -CH∑- to the indole nitrogen atom, one Phenylene radical or a Ci to C3 alkylaryl radical bonded via the alkyl group to the indole nitrogen atom and B represents a straight or branched chain Ci to Ci3 alkylene, alkenylene or alkynylene radical and where A and B also have one Oxygen atom can be connected to each other,

V represents a CH2 or a C (0) group,

W represents an N (R ⁶ ) - or an azolidinylene group, where R ^{6 is} either H or CH ₂ -R ⁷ or C (0) -R ⁷ , where R ⁷ can mean the following: a) hydrogen or b) one straight-chain or branched-chain, non-fluorinated or at least partially fluorinated C _r to C 1 -alkyl, alkenyl or alkynyl radical which can be hydroxylated once or more and through one to three heteroatoms -O-, -S- and / or groups - NR ⁹ - can be interrupted, in which R ^{9 represents} hydrogen or a Ci to C3 alkyl radical, or c) an unsubstituted or substituted aryl or heteroaryl radical or d) an unsubstituted or substituted C3 to Oo-cycloalkyl radical or e) an unsubstituted or substituted C - to Cis-cycloalkylalkyl or f) an unsubstituted or substituted C - to C ₂ o-aralkyl or g) an unsubstituted or substituted heteroαryl-Ci bis

-Cό-αlkylrest or h) an unsubstituted or substituted Aminoαlkylrest or a biphenyl residue,

X is a linear or branched chain C 1 -C 12 -alkylene, -alkenylene or -alkynylene radical,

Y is a direct bond between X and Z or can mean the following: a) a SO _n -R ¹⁰ group, where n = 0.1 or 2 and R ^{10 is} a direct bond between SOn and Z or a straight or branched chain Ci to Cό alkylene, alkenylene or alkynylene or b) the group R "or OR", where R ^π for i) a straight or branched chain Ci to Cs alkylene,

-Alkenylene or -alkinylene radical or ii) an unsubstituted or substituted aryl radical or

Heteroarylrest stands for or iii) an unsubstituted or substituted C3 to Cio-

-Cyclalkyl radical or represents iv) an unsubstituted or substituted C ₄ - to C15-

Cycloalkylalkylrest stands for or v) an unsubstituted or substituted C7 to C20

Aralkyl radical or represents vi) an unsubstituted or substituted heteroaryl-C to -C ₆ alkyl radical, or c) the grouping CH = CF or d) the grouping HN-C (O) -NH-R ¹² , where R ^{12 is} an unsubstituted or substituted arylene radical and where R ^{12 is} bonded to Z, and

Z is a direct bond between Y and CF ₃ or a straight-chain or branched-chain, at least partially fluorinated d to C ₉ alkylene, alkenylene or alkynylene radical,

which also include pharmacologically acceptable acid addition salts.

2. 1 -Indolyl derivatives according to claim 1 with the general formula II, characterized in that

U stands for (CH ₂ ) _P , where p is an integer from 2 to 10,

V represents either CH ₂ or C (O),

W represents N (R ⁶ ), where R ^{6 is} hydrogen or a straight-chain or branched-chain C ₁ -C ₃ -alkyl radical, X represents (CH ₂ ) _q , where q = 0 or an integer from 1 to 12 and Y and Z together either for SO _n - (CH ₂ ) r-CF _2l for (CF ₂ ) _S or for

Are O-aryl, where n = 0, 1 or 2, r = 0 or an integer from 1 to 6, s = 0 or an integer from 1 to 10 and aryl is an unsubstituted or substituted phenylene radical.

3. 1 -Indolyl derivatives according to one of claims 1 and 2, characterized in that U is a straight- or branched-chain pentylene, hexylene, heptylene, octylene or nonylene radical.

4. 1 -Indolyl derivatives according to claim 3, characterized in that U is a (CH ₂ ) ₆ - or a (CH ₂ ) ₇ radical.

5. 1 -Indolyl derivatives according to one of claims 1 to 4, characterized in that W is an N (CH ₃ ) group.

6. 1 -Indolyl derivatives according to one of claims 1 to 5, characterized in that X is a straight or branched chain ethylene, propylene, butylene, pentylene or hexylene radical.

7. 1 -Indolyl derivatives according to one of claims 1 to 6, characterized in that Y is a direct bond between X and Z or an S- (CH ₂ ) ₃ radical or an SO ₂ - (CH ₂ ) ₃ radical or a para-O-phenylene radical.

8. 1 -Indolyl derivatives according to one of claims 1 to 7, characterized in that Z is a (CF ₂ ) _S radical, in which s is an integer from 1 to 5.

9. 1 -Indolyl derivatives according to one of claims 1 to 8, characterized in that R 1, R ₂ and R _{4 are} hydrogen or methyl and R _{3 is} methyl.

10. 1 -Indolyl derivatives of the general formula II, namely

1) 5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1 - {5- [N-methyl-N- (3- (4,4,5,5,5-pentafluoropentylthio) propyl ) -carbamoyl] -pentyl} indole,

2) 5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {6- [N-methyl-N- (3- (4,4,5,5,5-pentafluoropentylthio) propyl ) -amino] -hexyl} indole,

3) 5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {5- [N-methyl-N- (3- (4,4,5,5,5-pentafluoropentylsulfonyl) propyl ) -carbamoyl] -pentyl} indole,

4) 5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {6- [N-methyl-N- (3- (4, 4,5,5,5-pentafluoropentylsulfonyl) propyl ) -amino] -hexyl} indole,

5) 5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1 - {5- [N-methyl-N- (5 _I 5 _I 6 _> 6.7 _l 7.8.8.9 _> 9.10 _f 10 _> 10-triclθcafluorodecyl) -carbamoyl] -pentyl} -indole,

6) 5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1 - {6- [N-methyl-N- (5,5,6,6,7,7,8,8,9,9 , 10,10,10-tridecafluordecyl) amino] -hexyl} indole,

7) 5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {5- [N-methyl-N- (2- (4-trifluoromethylphenyloxy) ethyl) carbamoyl] pentyl } indole,

8) 5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {6- [N-methyl-N- (2- (4-trifluoromethylphenyloxy) ethyl) amino] hexyl } indole,

9) 5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {6- [N-methyl-N- (7,7,8,8,9,9,10,10,10-nonafluorodecyl ) -amino] -hexyl} -indole, 10) 5-hydroxy ~ 2- (4-hydroxyphenyl) -3-methyl-1- {7- [N-methyl-N-

(7,7,8,8,9,9,10,10,10-nonafluordecyl) amino] heptyl} indole,

11) 5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {8- [N-methyl-N- (7,7,8,8,9,9,10,10,10-nonafluorodecyl ) -amino] -octyl} indole,

12) 5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {9- [N-methyl-N- (7,7,8,8,9,9,10,10,10-nonafluorodecyl ) -amino] -nonyl} indole,

13) 1- (4- {2 - [(8,8,9,9,10,10,10-heptafluorodecyl) methylamino] ethoxy} benzyl) - 2- (4-hydroxyphenyl) -3-methyl- 1 H-indol-5-ol,

14) 1- [4- (2 - {[7,8,8,8-tetrafluoro-7- (trifluoromethyl) octyl] methylamino} ethoxy) benzyl] -2- (4-hydroxyphenyl) -3- methyl-1H-indol-5-ol, 15) 2- (4-hydroxyphenyl) -3-methyl-1- (4- {2- [methyl- (8,8,9,9,10,10,11 , 11, 11-nonafluorundecyl) amino] ethoxy} benzyl) -1 H-indole-5-ol,

16) 2- (4-Hydroxyphenyl) -3-methyl-1 - [6- (methyl- {3 - [(4,4,5,5,5-pentafluorophenyl) sulfinyl] propyl} amino) -hexyl] -1 H -indol-5-ol,

17) 1- (4- {2 - [(2-hydroxyethyl) (7,7,8,8,9,9, 10,10, 10-nonafluorodecyl) amino] - ethoxy} benzyl) -2- ( 4-hydroxyphenyl) -3-methyl-1H-indol-5-ol,

18) 1 - [5 - ({6- [5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-1 H -indol-1-yl] -hexyl} - methylamino) -pentyl] -3- [ 3- (trifluoromethyl) phenyl] urea,

19) 2- (4-Hydroxyphenyl) -3-methyl-1 - [7- (methyl- {3 - [(4,4,5,5,5-pentafluorophenyl) sulfinyl] propyl} amino) -heptyl-1 H-indol-5-ol, 20) 2- (4-Hydroxyphenyl) -3-methyl-1 - [7- (methyl- {3 - [(4, 4,5,5,5-pentafluoropentyl) sulfonyl] propyl} amino) heptyl ] -1 H-indol-5-ol,

21) 2- (4-hydroxyphenyl) -3-methyl-1 - [7- (methyl- {3 - [(4,4,5,5,5-pentafluoropentyl) thio] propyl} amino) -heptyl] -1 H-indol-5-ol,

22) rac-1- (4- {2 - [(2,3-dihydroxypropyl) (7,7,8,8,9,9,10,10,10-nonafluorodecyl) amino] ethoxy} benzyl) -2- (4-hydroxyphenyl) -3-methyl-1H-indol-5-ol.

23) rac- 1 - {7 - [(2,3-dihydroxypropyl) (7,7,8,8,9,9, 10,10,1 O-nonafluorodecyl) - amino] -heptyl} -2- (4th -hydroxyphenyl) -3-methyl-1H-indol-5-ol, 24) rac-1- {6 - [(2,3-dihydroxypropyl) (7,7,8,8,9,9,10,10 , 10-nonafluorodecyl) amino] hexyl} -2- (4-hydroxyphenyl) -3-methyl-1 H-indol-5-ol,

25) 2- (4-Hydroxyphenyl) -3-methyl-1- [6- (4- {2 - [(4,4,5,5,5-pentafluoropentyl) -oxy] ethyl} piperidine-1 - yl) hexyl] -1 H-indol-5-ol,

26) 2- (4-Hydroxyphenyl) -3-methyl-1- {6- [methyl- (8,8,9,9,9-pentafluomonyl) amino] hexyl} -1 H -indol-5-ol .

27) 1- {6 - [(7,7,8,8,9,9,9-heptafluomonyl) methylamino] hexyl} -2- (4-hydroxyphenyl) -3-methyl-1H-indole -5-ol,

28) 1- (6 - {[7,8,8,8-tetrafluoro-7- (trifluoromethyl) octyl] methylamino} hexyl) -2- (4-hydroxyphenyl) -3-methyl-1H-indole -5-ol, 29) 2- (4-hydroxyphenyl) -3-methyl-1- {6- [methyl- (8,8,9,9, 10,10,11, 11, 11-nonafluorundecyl) amino ] -hexyl} -1 H-indol-5-ol

30) 2- (4-Hydroxyphenyl) -3-methyl-1- {6- [methyl- (6,6,7,7,8,8,9,9,9-nonafluorononyl) amino] hexyl } -1 H-indole-5-ol,

31) 1- {6 - [(2-hydroxyethyl) (7,7,8,8,9,9,10,10,10-nonafluorodecyl) amino] hexyl} - 2- (4-hydroxyphenyl) -3 -methyl-1 H -indol-5-ol

32) 2- (4-hydroxyphenyl) -1- {6 - [(3-hydroxypropyl) (7,7,8,8,9,9 ₎ 10,10,10-nonafluorodecyl) amino] hexyl} -3-methyl-1 H-indol-5-ol,

33) 2- (4-Hydroxyphenyl) -3-methyl-1- {7- [methyl- (8,8,9,9,9-pentafluorononyl) amino] heptyl} -1 H-indol-5-ol , 34) 1- {7 - [(7,7,8,8,9,9,9-heptafluorononyl) methylamino] heptyl} -2- (4- hydroxyphenyl) -3-methyl-1 H-indol-5-ol,

35) 1- {7 - [(2-hydroxyethyl) (7,7,8,8,9,9,10,10,10-nonafluorodecyl) amino] heptyl} -2- (4-hydroxyphenyl) -3 -methyl-1 H-indol-5-ol,

36) 2- (4-Hydroxyphenyl) -1- (7 - [(3-hydroxypropyl) (7,7,8,8,9,9,10,10,10-nonafluorodecyl) amino] heptyl} -3 methyl-1H-indol-5-ol,

37) 2- (4-Hydroxyphenyl) -3-methyl-1- (4- {2- [methyl- (7,7,8,8,9,9,10,10,10-nonafluorodecyl) amino] - ethoxy} benzyl) -1 H-indol-5-ol,

38) (RS) -2- (4-Hydroxyphenyl) -3-methyl-1- {4- [2- (methyl- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfinyl ] -propyl} -amino) -ethoxy] -benzyl} -1 H-indol-5-ol,

39) 2- (4-Hydroxyphenyl) -3-methyl-1- {4- [2- (methyl- {3 - [(4,4,5,5,5-pentafluoropentyl) thio] propyl} amino ) -ethoxy] -benzyl} -1 H-indol-5-ol,

40) 2- (4-hydroxyphenyl) -3-methyl-1- {4- [2- (methyl- {3 - [(4,4,5,5,5-pentafluorophenyl) sulfonyl] propyl} -amino) -ethoxy] -benzyl} -1 H-indol-5-ol

41) 1- (4- {2 - [(7,7,8,8,9,9,9-heptafluorononyl) methylamino] ethoxy} benzyl) -2- (4-hydroxyphenyl) -3-methyl- 1 H-indol-5-ol,

11. Use of the structural part

as a component of compounds with antiestrogenic activity,

where U, V, W, X, Y and Z have the loading given in claims 1 to 8 have interpretations.

12. Process for the preparation of 1-indyl derivatives with the general formula

wherein R ³ , R ⁴ , R ⁶ , U, X, Y and Z have the meanings given in claim 1, in which, starting from a compound having the general formula

where R ¹ and R ^{2 have} the meanings given in claim 1,

by halogenation first an acid halide and then by Kleophilic substitution with R ^{6 6} -NH-XYZ-CF ₃ the 1 -indolyl derivative with the general formula II "is formed:

and in this compound the 5-hydroxy-2- (4-hydroxyphenyl) indolyl derivative is formed first by ether cleavage and then the compound II is formed by selective reduction of the amide group, or

starting from the 1 -indolyl derivative XB with the general formula

XB

where E is a halogen atom, a hydroxyl group or a nucleophilic leaving group and R ¹ , R ² , R ³ , R ⁴ and U have the abovementioned meanings, by nucleophilic substitution with R ⁶ -NH-XYZ-CF ₃ , where R ⁶ , X, Y and Z have the abovementioned meanings, the 1 -indolyl derivative having the general formula II '"is formed

and compound II is formed from this compound by ether cleavage.

13. Use of the 1 -indolyl derivatives with the general formula II according to one of claims 1 to 10 for the manufacture of medicaments.

14. Pharmaceutical preparations containing at least one 1-indolyl derivative with the general formula II according to one of claims 1 to 10 and at least one pharmaceutically acceptable carrier.