DE10117441A1 - 1-indolyl derivatives, their use in the manufacture of medicaments, a process for the preparation of 1-indolyl derivatives and pharmaceutical preparations containing 1-indolyl derivatives - Google Patents

Abstract

The invention relates to novel 1-indolyl derivatives of general formula (II), having an anti-oestrogenic effect, whereby R<1>, R<2>, R<3>, R<4>, 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

The present invention relates to novel 1-indolyl derivatives, a ver drive to the production of 1-indolyl derivatives, their use for Production of pharmaceuticals and phar containing 1-indolyl derivatives pharmaceutical preparations.

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

Many other compounds with antiestrogens are already in the literature Properties have been described, for example tamoxifen [Eur. J. Cancer. 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 (Anti) Steroidal Agents, Raven Press, New York (1987)].

WO 98/07740 A1 describes 7α- (ξ-aminoalkyl) estratrienes which have a very strong antiestrogenic action. 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 N-alkylated in the side chain, this alkyl group being interrupted by a thio- (-S-), a sulfinyl (-SO-) or a sulfonyl group (-SO ₂ -) and optionally fluorinated at the end , Chains of the type (CH ₂ ) _n -SO _x - (CH ₂ ) ₃ -E are specified as N-alkyl chains, where x and _{n are} 0, 1 or 2 and E can be an unsubstituted or mono- to pentafly fluorinated ethyl radical , Specifically, among other things
(CH ₂ ) ₃ -S- (CH ₂ ) ₃ -C ₂ F ₅ ,
(CH ₂ ) ₃ -SO- (CH ₂ ) ₃ -C ₂ F ₅ and
(CH ₂ ) ₃ -SO ₂ - (CH ₄ ) ₅ -C ₂ F ₅ .

WO 99/33855 A1 also describes compounds with strong antiestrogenic activity. It is 11β-Halogenestratri enderivate, which have an alkylamine side chain in the 7α-position. This side chain is also N-alkylated, it being possible for the N-alkyl group to be at least partially fluorinated. For example, the N-alkyl group can be a (CH ₂ ) _m -C _n F _{2n + 1} 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 ) ₆ -C ₂ F ₅
- (CH ₂ ) ₇ -C ₂ F ₅
- (CH ₂ ) ₈ -C ₂ F ₅
- (CH ₂ ) ₂ -C ₄ F ₉
- (CH ₂ ) ₃ -C ₄ F ₉
- (CH ₂ ) ₆ -C ₄ F ₉
- (CH ₂ ) ₂ -C ₆ F ₁₃
- (CH ₂ ) ₆ -C ₆ F ₁₃
- (CH ₂ ) ₃ -C ₈ F ₁₇ and
- (CH ₂ ) ₆ -C ₈ F ₁₇ .

EP 0 348 341 B1 describes aminoalkylindoles which also have strong antiestrogenic properties. These compounds are pure antagonists, ie they have no residual estrogenic activity. 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 (CH ₃ ) ₂ ,
- (CH ₂ ) ₆ -NH (C ₂ H ₅ ) and
- (CH ₂ ) ₆ -N (C ₂ H ₅ ) ₂ .

The invention is based on the problem of further improved antiestro to find gene active ingredients that have an antiproliferative effect on estrogen sensitive cells for the therapy of hormone-sensitive breast carcinoma to have.

The problem is solved by 1-indolyl derivatives according to claim 1 the use of a 1-indolyl radical as a component of compounds of antiestrogenic activity according to claim 11, further by a method for the preparation of these compounds according to claim 12, a use Use of these compounds for the manufacture of medicaments according to An claim 13 and by pharmaceutical preparations according to claim 14. Preferred embodiments of the invention are in the subclaims Chen specified.  

The 1-indolyl derivatives according to the invention have the common structural part with the general formula

as a component of compounds with antiestrogenic activity. Mean in this formula
U is either a straight-chain or branched-chain C ₁ -C ₁₃ -alkylene, -alkenylene or -alkynylene radical or the grouping AB, where A is bonded to the indole nitrogen atom and one via -CH ₂ - to the indole- Nitrogen atom-bonded benzylidene residue, a phenylene residue or a C ₁ - to C ₁₃ -alkylaryl residue bonded via the alkyl group to the indole nitrogen atom and B represents a straight-chain or branched-chain C ₁ - to C ₁₃ -alkylene, -alkylene or -Alkinylene radical and where A and B can also be connected to one another via an oxygen atom,
V is a CH ₂ or a C (O) group,
W is an N (R ⁶ ) or an azolidinylene group, where R ^{6 is} either H or CH ₂ -R ⁷ or C (O) -R ⁷ , where R ⁷ can mean the following:

• a) hydrogen or
• b) a straight-chain or branched-chain, non-fluorinated or at least partially fluorinated C ₁ -C ₁₄ -alkyl, -alkenyl or -alkynyl radical which can be hydroxylated once or more and which is substituted by one to three heteroatoms -O-, -S- and / or groupings -NR ⁹ - can be interrupted, wherein R ^{9 represents} hydrogen or a C ₁ - to C ₃ -alkyl radical, or
• c) an unsubstituted or substituted, preferably mono- or disubstituted, aryl or heteroaryl rest or
• d) an unsubstituted or substituted, preferably mono- or disubstituted, C ₃ - to C ₁₀ -cycloalkyl radical or
• e) an unsubstituted or substituted, preferably mono- or disubstituted, C ₄ - to C ₁₅ -cycloal kylalkylrest or
• f) an unsubstituted or substituted, preferably mono- or disubstituted, C ₇ to C ₂₀ aralkyl radical or
• g) an unsubstituted or substituted, preferably mono- or disubstituted, heteroaryl-C ₁ -C ₆ -alkyl radical or
• h) an unsubstituted or substituted aminoalkyl radical or a biphenyl radical,

X is a straight or branched chain C ₁

- up to C ₁₂

Alkylene, alkylene or alkynylene 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 SO _n and Z or a straight or branched chain C ₁ - to C ₆ -alkylene-, -alkenylene- or -Al represents kinylene radical, or
• b) the grouping OR ¹¹ , where R ¹¹ for
  • a) is a straight-chain or branched-chain C ₁ -C ₅ -alkylene, -alkenylene or -alkynylene radical or
  • b) an unsubstituted or substituted, preferably mono- or disubstituted, aryl radical or heteroaryl radical or
  • c) an unsubstituted or substituted, preferably mono- or disubstituted, C ₃ - to C ₁₀ -cyclalkyl radical or
  • d) an unsubstituted or substituted, preferably monosubstituted or disubstituted, C ₆ - to C ₁₅ -cycloalkylalkyl radical or
  • e) an unsubstituted or substituted, preferably monosubstituted or disubstituted, C ₇ - to C ₂₀ - aralkyl radical or
  • f) is an unsubstituted or substituted, preferably mono- or disubstituted, heteroaryl-C ₁ -C ₆ -alkyl radical,
• 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 or branched chain, at least partially fluorinated C ₁

- to C ₉

-Alky len, alkenylene or alkynylene.

At positions 2, 3, 4, 5, 6 and 7 on the indolyl ring, hydrogen can or any other substituent.  

In particular, those 1-indolyl derivatives with the structural part according to general formula I are suitable in which
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 ver branched chain C ₁ - to C ₃ -alkyl radical,
X stands for (CH ₂ ) _q , where q = 0 or an integer from 1 to 12 and
Y and Z together represent either SO _n - (CH ₂ ) _r -CF ₂ , (CF ₂ ) _s or O-aryl, where n is 0, 1 or 2, r is 0 or an integer from 1 to 6 is 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:

wherein
R ¹ and R ^{2 are} independent of each other

• a) hydrogen or
• b) represent straight-chain or branched-chain C ₁ -C ₄ -alkyl, -alkenyl or -alkynyl radicals or
• c) C (O) -R ⁵ , where R ^{5 is} a straight-chain or branched chain C ₁ -C ₄ -alkyl, -alkenyl or -alkynyl radical,

R ³

and R ⁴

independently of each other

• a) hydrogen or
• b) are 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 be acyl radicals having the general formula C (O) -R ⁵ , where R ^{5 is} preferably a straight-chain or branched-chain C ₁ to C ₄ alkyl, alkenyl or alkynyl radical, namely in particular methyl and its higher homologues, namely ethyl, propyl and butyl.

Furthermore, R ³ and R ^{4 can} also together represent a methylene, ethylene, propylene or butylene bridge and an unsaturated carbon hydrogen chain, for example but-2-en-1,4-ylene or prop-1-ene-1,3 -ylen.

U can especially be a straight or branched chain pentylene, hexylene, heptylene or octylene radical. In particular, U is a (CH ₂ ) ₆ or a (CH ₂ ) 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 (CH ₂ ) ₆ 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 Grouping is bound to the indole nitrogen atom.

W is preferably an NH or N (CH ₃ ) group. In addition, W can also be a group N (R ⁶ ), where R ^{6 can be} CH ₂ -R ⁷ or C (O) -R ⁷ and R ^{7 is} a straight- or branched-chain methylene, ethylene, propylene, Butylene, pentylene, hexylene or an even higher homolo and their unsaturated analog is, 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 (CH ₃ ). For example, ((CH ₂ ) ₂ -O-) _n -CH ₃ , ((CH ₂ ) ₂ -S-) _n -CH ₃ and ((CH ₂ ) ₂ -NH-) _n -CH ₃ or ((CH ₂ ) ₂ -N (CH ₃ )) _n -CH ₃ ge 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 be alkyl derivatives of the aforementioned aryl, heteroaryl and cycloalkyl radicals, for example benzyl, 1-methylene-2-pyridinyl or methylenecyclohexyl. 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 (O) -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 -O-CH ₃ , namely those of C (O) - (CH ₂ ) 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 ₃ and their higher homologues, further benzoyl, 1- and 2-naphthoyl and which correspond to the 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 Piperidiny lenrestes is the nitrogen to the radical V and the radical X in the para position bound to the piperidinylene ring.

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

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 CF ₃ .

Y is particularly preferably an S-propylene group, an SO ₂ -propylene group or a para-O-phenylene group. Basically, instead of the propylene groups in S-propylene and SO ₂ propylene, a higher homolog, 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 SO 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, it is the arylene group preferably phenylene, 1-naphthylene or 2-naphthylene. As heterarylene group are in particular the 2-, 3- or 4-pyridinylene, the 2- or 3-foot rylene radical, the 2- or 3-thienylene radical, the 2- or 3-pyrrolylene radical, the 2-, 4-  or 5-imidazolylene radical, the pyridazinylene radical, the 2-, 4- or 5-pyrimidi nylene radical or the 3- or 4-pyridazinylene radical are suitable. Is preferred para-O-phenylene for Y.

Alternatively, Y can also be an O-alkylene, O-alkenylene or O-alkynylene be a group, for example an O-propylene, O-butylene or O-penty lengruppe and their unsaturated analogues. Besides, too O-cycloalkyl groups included, for example O-cyclohexyl. Fer Y can also mean the meaning of alkyl derivatives of the aforementioned Have groups such as that of benzyloxy.

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

Y can also represent the group HN-C (O) -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 para-C ₆ H ₄ -HN-C (O) -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 ne 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 CH ₂ -CF ₂ -CF _{2, can also be used} . Unsaturated derivatives are also suitable.

Particularly suitable compounds are the 1-indolyl derivatives shown in Table 1:
The corresponding 4 ', 5-dimethoxyindole derivatives of these compounds are also suitable.

In Table 2, specific structural properties for compounds Nos. 1 to 12 are given, namely the lengths of the alkylene chain of the structural element U = (CH ₂ ) _n , the type of structural element V, namely CH ₂ or C = O, the length q of the Alkylene chain (CH ₂ ) _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 SO ₂ - (CH ₂ ) ₃ -CF ₂ or (CF ₂ ) ₃ or (CF ₂ ) ₅ or para-OC ₆ H ₄ .

The compounds according to the invention also include pharmacolo genetically compatible addition salts. This is the equivalent Addition salts with inorganic and organic acids. As Addition salts with inorganic acids come especially the Hy drochloride, hydrobromide, acetate, citrate, oxalate, tartrate and me Thanesulfonate into consideration.

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

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

In contrast to known indoles substituted in the 1-position and having an antiestrogenic effect, the 1-indolyl derivatives according to the invention 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.

Due to the different combination of the indole base, in particular the 2-phenylindole base, the alkylamine or alkylamide group bonded to the indole in the 1-position, and the fluorinated end group, a much stronger estrogen antagonism and a better antitumor effect is achieved than with analogs Active substances that lack the structural elements mentioned. In contrast to non-fluorinated alkylamines and alkylamides, the compounds according to the invention show a complete inhibition of estradiol-stimulated luciferase expression in stably infected human MCF-7-Mam macarcinoma cells. The IC ₅₀ values are usually below 1 µM. The most effective of the compounds found according to the invention exceeds the antiestrogenic activity of known antiestrogenic steroids, although their affinity for the estrogen receptor is clearly lower, for example 7α- {9- (4,4,5,5,5-pentafluoropentylsulfonyl) nonyl } -estradiol, which also has a fluorinated alkyl end group in the side chain of the steroid structure, but not an alkylamine or an alkylamide group.

By fluorinating the chain end of the side chain, a dra Matic increase in effectiveness in the previously known 2-phenyl indole derivatives reached.

Furthermore, the active compounds according to the invention show neither in vitro nor in vivo residual estrogen activity.  

The compounds according to the invention have a pronounced receptor binding affinity RBA to the estradiol receptor and com petitively displace ³ H-17β-estradiol from the receptor.

The indolyl derivatives according to the invention have strong antiestro in vivo gene effects on the uterus of the mouse and inhibit the estrogen-stimulated Uterine growth up to 100%. There are estrogenic effects in these tests undetectable. The compounds inhibit the wax tum of hormone-sensitive tumor cells. In particular, they inhibit that Growth of estrogen sensitive breast tumors (MCF-7).

The non-steroidal antiestrogens were found both in vitro and in vi vo checked for biological activity.

In the in vitro test, the affinities of the invention 1-Indolylderivate to the estrogen receptor RBA, the antiestrogenic activity in a transfection assay and the proliferative effect on hormone-sensitive tive breast carcinoma cells determined. In addition, the invented Active ingredients according to the invention also on estrogenic side effects general cytotoxic properties examined.

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. Cham bon, 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, 2811-2818 (1990)].  

A comparison was made against pure antiestrogens with a steroid basic structure (R1, R2) and against a 1-indolyl derivative (R3) as reference compounds checked. These were the antiestrogens 7α- [9- (4,4,5,5,5- Pentafluoropentylsulfinyl) nonyl] estradiol (compound R1), 11β-fluoro-7α- {5- [N-methyl-N- (3- (4,4,5,5,5-pentafluoropentyl-thio) propyl) -amino] -pentyl} - estradiol (compound R2) and 5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- [10- (pentylsulfonyl) decyl] indole (Compound R3).

To determine the relative binding affinity of RBA to the estrogen receptor, based on 17β-estradiol (= 100), calf uterine cytosol became the source used. Table 3 shows the results of the measurements for 1-Indo lyl derivatives and for the three reference compounds (estradiol derivatives and indole compound). The RBA values fluctuate in Range from 0.05 to 25, with the RBA values corresponding to the anti estrogenic efficacy best 1-indolyl derivatives No. 9, 10, 11 and 12 relative are close together.

As can be seen from Table 4, none of the anti according to the invention shows estrogen an agonistic effect. All values are below the value of the untreated control cells. The drop below the basal value for the 1-indolyl derivatives according to the invention can be attributed to that the serum still contained growth factors and cytokines, which the Could activate estrogen receptor in the absence of a ligand. the This effect can be achieved by blocking the receptor with a pure one Remove antagonists.

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

The antiestrogenic effect was determined in vitro on MCF-7 breast carcinoma cells (see Table 3), which were stably transfected with a Lucifera sereporter plasmid and stimulated with 10 ^-8 M estradiol. On the other hand, the inhibition of the 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. 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 with a spacer length, ie with a length of the alkylene radical U, of six and seven methylene groups. This is evidenced by the low IC ₅₀ 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 IC _{50 are obtained} for these compounds if 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). Compound No. 10 (5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {7- [N-methyl-N- (3- (7,7, 8,8,9,9,10,10,10-nonafluorodecylamino] -heptyl} indole), which has a spacer length of seven carbon atoms in the group U-CH ₂ .

In vitro results of the antiestrogenic activity of the compounds Nos. 13 to 41 are given in Table 1, the values given there for the antiestrogenic activity (IC ₅₀ [nM]) being obtained when 0.1 nM estradiol was added.

Furthermore, the antiproliferative effect in vitro on inhibition of Growth hormone sensitive MCF-7 breast carcinoma cells under examined. To standardize the conditions and make a comparison too to enable the investigation in the transfection assay MCF-7 cells also stimulated with 1 nM 17β-estradiol. The results of this Investigations are shown in Table 4.

In parallel to the studies on the proliferative activity, the substances were also tested on hormone-insensitive MDA-MB-231-Mammacarci nom 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 anti-estrogenic activity, presumably a receptor-mediated antiproliferative effect can be assumed. This assumption is supported by the agreement of the IC ₅₀ values with those obtained in the transfection assay.

Furthermore, in vivo studies on the juvenile NMRI mouse carried out. It became the uterotrophic and the antiuterotrophic effect Compound No. 2 (5-hydroxy-2- (4-hydroxyphenyl) -3-me thyl-1- {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-1- {6- [N- methyl-N- (5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluordecyl) -amino] -hexyl} - indole) tested. Table 5 shows the results of these tests played.

The tested compounds completely antagonize the effect of 0.01 mg estradiol / kg body weight at a dose of 2.5 mg / kg body weight or 0.5 mg / kg body weight. In Fig. 1 and Fig. 2 shows the results of these studies are shown graphically.

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

The 1-indolyl derivatives according to the invention, in particular those in the 1-position with the side chain according to the invention substituted 2-phenylindole deri vate, or the pharmaceutical preparations according to the invention, the these compounds are ideal for therapy breast cancer (second-line therapy instead of tamoxifen), Prostate carcinoma, prostate hyperplasia, anovulatory infertility and Melanoma in humans and in principle also in mammals. Au In addition, the compounds according to the invention can be used for the preparation of drugs for the treatment of endometriosis and endomas trialcarcinomen can be used.

The antiestrogens according to the invention can also be used as a compo used in the products described in EP 0 346 014 B1 that contain an estrogen and a pure antiestrogen, namely for simultaneous, sequential or separate use for this se selective estrogen therapy of peri- and postmenopausal women. The invent Compounds according to the invention can also be used together with antigestagens  (competitive progesterone antagonists) for the treatment of hormone sensitive tumors are used (EP 0 310 542 A).

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

The compounds according to the invention can furthermore be used for the preparation pharmaceutical compositions for male and female Fertility control (male fertility control: DE-A-195 10 862).

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

The compounds can be administered orally and parenterally, for example i. p. (intra peritoneal), i. v. (intravenously), i. m. (intramuscularly) or percutaneously be enough. The connections can also implan into the tissue be animals. The amount of the compounds to be administered can be in fluctuate within a wide range, as far as an effective menu is applied. The duration of treatment depends on what you achieve appropriate purpose.  

Capsules, pills, tablets, coated tablets, creams, Ointments, lotions, liquids, such as syrups, gels, injectable liquids, for example for i. p.-, i. v.-, i. m.- or percutaneous injection, etc. in question, the individual dosage forms the Ver Depending on the type, ties gradually or the entire amount in short give time to the body.

For oral administration, capsules, pills, tablets, coated tablets and Liquids or other oral dosage forms known as phar pharmaceutical preparations are used. In this case, the Medicines should be formulated in such a way that they are either the active ingredients Release in a short time and release to the body or a depot Kung, so that a long-lasting, slow supply of Active ingredient is reached to the body. The dosage units can ne ben the 1-indolyl derivative one or more pharmaceutically acceptable che carriers contain, for example substances for adjusting the rheology of the drug, surfactants, solubilizers, microcap seln, microparticles, granules, thinners, binders such as starch, sugar, Sorbitol and gelatin, and also fillers, such as silica and talc, lubricant medium, dyes, fragrances and other substances.

In particular, the 1-indolyl derivatives according to the invention can also be used in Form a solution to be formulated for oral administration is determined and that in addition to the active 1-indolyl derivative as follows Components a pharmaceutically acceptable oil and / or a phar pharmaceutically acceptable lipophilic, surface-active substance and / or a pharmaceutically acceptable hydrophilic, surface active sub punch and / or a pharmaceutically acceptable water-miscible solvent contains agents. For this purpose, reference is also made to WO-A-97/21440.  

In order to improve the bioavailability of the active compounds according to the invention achieve the compounds as cyclodextrin chlate be formulated. For this purpose, the compounds with α-, β- or γ-Cyclodextrin or their derivatives implemented (PCT / EP 95/02656).

If creams, ointments, lotions and external liquids to be used, they must be such that the he Compounds according to the invention in sufficient quantities be fed. Excipients are included in these dosage forms substances, for example substances for adjusting the rheology of the medicinal products, surfactants, preservatives, solubilizers, ver thinner, substances to increase the permeability for the Invention according to 1-indolyl derivatives 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 ingredients can also be used contained in the drug [Ullmann's Encyclopedia of Technical Chemie, Volume 4 (1953), pages 1-39; J. Pharm. Sci., 52, 918 ff. (1963); H. v. Czetsch-Lindenwald, auxiliaries for pharmacy and neighboring areas te; Pharm. Ind., 2, 72 ff (1961); Dr. H. P. Fiedler, Lexicon of auxiliaries for Pharmacy, cosmetics and related areas, Cantor AG, Aulen Dorf / Württ., 1971].

For parenteral administration, the active ingredients can be in a physiolo cally compatible diluents can be dissolved or suspended. As Diluents are very often oils with or without the addition of one Solubilizer, a surface-active agent, a or emulsifier used. Examples of oils used are oli veno oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil. Any liquid can be used to formulate an injectable preparation  Carrier are used in which the Verbin invention solutions are dissolved or emulsified. These liquids often contain also substances for regulating viscosity, surface-active substances, con preservatives, solubilizers, thinners and other additives, with which the solution is adjusted isotonic. Together with the 1-Indolyl derivatives can also be administered other active ingredients.

The 1-indolyl derivatives can be in the form of a depot injection or egg Use the implant preparation, for example subcutaneously, the so for can be mulated that a delayed release of active ingredient enables becomes. Known techniques can be used for this, for example depots that dissolve or work with a membrane. in the As inert materials, plants can biodegrade, for example bare polymers or synthetic silicones, for example silicone chew chuk, included. The 1-indolyl derivatives can also be used percutaneously Administration can be incorporated into a plaster, for example.

For the production of with active compounds according to the invention loaded intravaginal (e.g. vaginal rings) or intrauterine systems (e.g. pessaries, spirals) are suitable for different buttocks polymers, for example silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene.

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

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-CF ₃ (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 having the general formula

3 (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 [(CH ₂ ) ₅ ] and XYZ is (CH ₂ ) _m -P, where m = 3 if P is S- (CH ₂ ) ₃ -CF ₂ or SO ₂ - (CH ₂ ) ₃ -CF ₂ , and m = 4 if P is C ₅ F ₁₀ or para-O-phenylene stands). R ¹ , R ² and R ³ are especially methyl. Before R ⁴ is preferably hydrogen. U is in particular an unbranched alkylene group [(CH ₂ ) _n ], where n is an integer from 1 to 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 in particular represents an unbranched ethylene, propylene, butylene or He xylengruppe. YZ together are a C ₅ F ₁₀ group, a para-O-phenylene group, an S- (CH ₂ ) ₃ -CF ₂ group or an SO ₂ - (CH ₂ ) ₃ -CF ₂ group.

The usual reactions are available for halogenating the carboxylic acid derivatives Gentien available, for example phosphorus pentachloride, N-chlorine succinimide, dicyclohexylcarbodiimide (DCC), fluorine, chlorine, bromine or Hydroiodic acid, thionyl chloride, thionyl bromide, phosphorus oxychloride, Triphenylphosphine / carbon tetrachloride, HF / pyridine or diamino sweat feltrifluoride and nonaflyl fluoride / 1,5-diazabicyclo [5.4.0] -undecene.  

The acid amides are reacted with the acid chlorides corresponding methylamines formed by the from the reaction the acid chloride crude products formed to a solution of the methylamine added dropwise with exclusion of moisture and to the reak tion and the resulting products by pouring them onto ice water can be hydrolyzed.

The ethers formed are then cleaved by reacting with moisture with aluminum chloride and then with ethanethiol and the product is hydrolyzed so that the 5-hydroxy-2- (4-hydroxyphenyl) indole derivatives are formed (reaction b). This sequence of reactions is used for the compounds with YZ = para-O-phenylene (compounds no. 7 and 8). Alternatively, the ethers can also be cleaved with Bortribro mid. This synthesis option is used for the other compounds (YZ = C ₅ F ₁₀ , S- (CH ₂ ) ₃ -CF ₂ and SO ₂ - (CH ₂ ) ₃ -CF ₂ ; compounds Nos. 1 to 6 and 9 to 12) ,

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

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

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 here for scheme B in FIG. 4: R ₁ , R ₂ and R ₃ there are methyl and R _{4 is} hydrogen, U is pentamethylene [(CH ₂ ) ₅ ], and E is Br).

This 1-indolyl derivative is then converted by nucleophilic substitution with R ⁶ -NH-XYZ-CF ₃ to the 1-indolyl derivative II '''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 (CH ₂ ) ₃ -SO ₂ - (CH ₂ ) ₃ -CF ₂ ).

For nucleophilic substitution of the halogen compound XB with the ent Talking methylamine is combined with the amine in one example implemented ethanolic solution. The resulting product is covered with ice hydrolyzed water.

The ethers then become 5-hydroxy-2- (4-hydroxyphenyl) indole derivative II implemented (reaction b). For this purpose, the aforementioned is again used Ether cleavage with aluminum chloride and ethanethiol and / or with Bortri bromide performed.  

The starting compounds XA are synthesized according to the following reaction scheme (Scheme C in FIG. 5):
1-Bromo-1- (4-methoxy-benzoyl) ethane is reacted with 4-methoxyaniline to give 5-methoxy-2- (4-methoxyphenyl) -3-methylindole (reaction a). The corresponding 1-indolyl derivative is formed by subsequent reaction with sodium hydride and subsequent reaction with n-bromoalkanoic acid ethyl ester 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 for a more detailed explanation the invention:

Synthesis instructions and analytical data General instructions for the preparation of acid amides

1.98 mmol of 1- (5-carboxypentyl) -5-methoxy-2- (4-methoxyphenyl) -3-me 1.98 mmol of phosphorus pentachloride were added to thylindol and the solution was added under Exclusion of moisture for 30 minutes at room temperature and on then stirred at about 60 ° C for 30 minutes. 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 slowly to a solution of 4.94 mmol of the respective second Dropped in methylamine in absolute dichloromethane. The approach was again stirred overnight with the exclusion of moisture.  

The reaction mixture was poured onto ice water for hydrolysis. to finally the aqueous phase was extracted three times with ethyl acetate. Then the combined organic phases became saturated twice ter sodium chloride solution and washed over magnesium sulfate dries. The solvents were removed in vacuo. The Rohpro product was purified by column chromatography on silica gel 60 (various dichloromethane / ethyl acetate mixtures).

example 1 5-methoxy-2- (4-methoxyphenyl) -3-methyl-1- {5- [N-methyl-N- (5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluordecyl) -carbamoyl] -pentyl} -indole (Connection 5A)

Preparation from N-methyl-5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorodecyl amine; Purification by column chromatography on silica gel 60 (dichloromethane / ethyl acetate 5: 1, v / v)
yellow resin; Yield: 40%
C ₃₄ H ₃₇ F ₁₃ N ₂ O ₃ (768.7)
IR (film): 1645 cm ^-1 (s; C = O)
¹ H NMR (CDCl ₃ ): δ (ppm) = 1.15-1.28 (m; 6H; - (CH ₂ ) ₂ -C ₆ F ₁₃ , -C H ₂ - (CH ₂ ) ₂ -CO -); 1.43-1.58 (m; 6H; -C H ₂ -CH ₂ -NCH ₃ -, -C H ₂ -CH ₂ -CO-, indole-N-CH ₂ -C H ₂ -); 2.19 (s; 3H; indole-CH ₃ ); 2.06-2.20 (m; 2H; -CH ₂ -CO-); 2.41 (s; 3H; -CO-NCH ₃ -); 3.22-3.24 and 3.35-3.37 (m; 2H; -C H ₂ -NCH ₃ -, e / z); 3.88 (s; 3H; -OCH ₃ ); 3.89 (s; 3H; -OCH ₃ ); 3.85-3.92 (m; 2H; indole-N-CH ₂ -); 6.87 (dd; ³ J = 8.8 Hz, ⁴ J = 2.4 Hz; 1H; indole-H ⁶ ); 7.01 (dd; ⁴ J = 2.4 Hz, ⁵ J = 0.5 Hz; 1H; indole-H ⁴ ); 7.22 (dd; ³ J = 8.8 Hz, = 0.5 Hz; 1H; 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-tri fluoromethyl-phenyloxy) -ethyl) -corbamoyl] -pentyl} -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%
C ₃₃ H ₃₇ F ₃ N ₂ O ₄ (582.7)
IR (CHCl ₃ ): 1646 cm ^-1 (s; C = O)
¹ H NMR (CDCl ₃ ): δ (ppm) = 1.11-1.62 (m; 6H; - (CH ₂ ) ₃ -); 2.18 (s; 3H; indole-CH ₃ ); 2.17-2.31 (m; 2H; -CH ₂ -CO-); 2.97 and 3.06 (s; 3H; -CO-NCH ₃ -, e / z); 3.62-3.79 (m; 2H; -C H ₂ -NCH ₃ -); 3.87 (s; 3H; -OCH ₃ ); 3.88 (s; 3H; -OCH ₃ ); 3.88-4.11 (m; 2H; -CH ₂ -O-); 4.1-4.16 (m; 2H; indole-N-CH ₂ -); 6.87 (dd; ³ J = 8.8 Hz; ⁴ J = 2.6 Hz; 1H; indole-H ⁶ ); 7.01 (dd; ⁴ J = 2.6 Hz; ⁵ J = 0.5 Hz; 1H; indole-H ⁴ ); 7.21 (dd; ³ J = 8.8 Hz; ⁵ J = 0.5 Hz; 1H; 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 (ver Binding 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%
C ₃₂ H ₄₁ F ₅ N ₂ O ₃ S (628.8)
IR (film): 1644 cm ^-1 (s; C = O)
¹ H NMR (CDCl ₃ ); δ (ppm) = 1.12-1.29 (m; 2H; -C H ₂ - (CH ₂ ) ₂ -CO-); 1.46-1.58 (m; 4H; -C H ₂ -CH ₂ -CO-, -CH ₂ -C ₂ F ₅ ); 1.74-1.92 (m; 4H; indole-N-CH ₂ -C H ₂ -, -C H ₂ -CH ₂ -C ₂ F ₅ ); 2.12-2.23 (m; 4H; -CH ₂ -CO-, -C H 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-NCH ₃ -, 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; -OCH ₃ ); 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; 1H; indole-H ⁶ ); 7.02 (dd; ⁴ J = 2.3 Hz, ⁵ J = 0.5 Hz; 1H; indole-H ⁴ ); 7.22 (dd; ³ J = 8.8 Hz, ⁵ J = 0.5 Hz; 1H; 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-pentafluoropentyl-sulfonyl) propyl) -carbamoyl] -pentyl} -indole (Compound No. 3A)

Preparation from N-methyl-3- (4,4,5,5,5-pentafluoropentylsulfonyl) propyl amine; Purification by column chromatography on silica gel 60 (dichloromethane / ethyl acetate 1: 1, v / v)
yellow resin; Yield: 40%
C ₃₂ H ₄₁ F ₅ N ₂ O ₅ S (660.8)
IR (film): 1643 cm ^-1 (s; C = O)
H-NMR (DMSO-d ₆ ): δ (ppm) = 1.03-1.11 (m; 2H; -C H ₂ - (CH ₂ ) ₂ -CO-); 1.24-1.33 (m; 2H; -CH ₂ -C ₂ F ₅ ); 1.42-1.53 (m; 2H; -C H ₂ -CH ₂ -CO-); 1.78-1.95 (m; 4H; indole-N-CH ₂ -C H ₂ -, -C H ₂ -CH ₂ -C ₂ F ₅ ); 2.03-2.16 (m; 2H; -CH ₂ -CO-); 2.11 (s; 3H; indole-CH ₃ ); 2.30-2.44 (m; 2H; -C H ₂ -CH ₂ -NCH ₃ -); 2.76 and 2.87 (s; 3H; -CO-NCH ₃ -, e / z); 3.02-3.10 (m; 2H; -C H ₂ - (CH ₂ ) ₂ -C ₂ F ₅ ); 3.13-3.26 (m; 2H; -C H ₂ - (CH ₂ ) ₂ -NCH ₃ -); 3.28-3.36 (m; 2H; -CH ₂ -NCH ₃ -); 3.79 (s; 3H; -OCH ₃ ); 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; 1H; In dol-H ⁶ ); 6.99 (dd; ⁴ J = 2.4 Hz, ⁵ J = 0.5 Hz; 1H; indole-H ⁴ ); 7.31-7.35 (m; 1H; indole-H ⁷ ); 7.08 and 7.33 (AA'BB '; ³ J = 8.7 Hz; 4H; phenyl-H).

Ether cleavage with ethanethiol with aluminum chloride catalysis

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

After the aqueous phase had been separated off, it was washed three times with ethyl acetate extracted, the combined organic phases twice with What washed, dried over magnesium sulfate and the solvents in Rotated vacuum. The crude product obtained was column chro Matography cleaned on silica gel 60 (dichloromethane / ethyl acetate 1: 2).

Example 5 5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {5- [N-methyl-N- (2- (4- trifluoromethylphenyloxy) ethyl) carbamoyl] pentyl} indole (compound No. 7)

yellow foam; Yield: 40%
C ₃₁

H ₃₃

F ₃

N ₂

O ₄

(554.7)
IR (CHCl ₃

): 3304 cm ^-1

(s; OH)
1650 cm ^-1

(s; C = O)
¹

H-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; -CH _2nd

-CO-); 2.83 and 2.98 (s; 3H; -CO-NCH ₃

-, e / z); 3.60-3.64 (m; 2H; -C H ₂

-NCH ₃

-); 3.90 (s; br; 2H; -CH ₂

-O-); 4.10 ^-4

, 21 (m; 2H; indole-N-CH ₂

-); 6.64 (dd; ^3rd

J = 8.7 Hz, ⁴

J = 1.9 Hz; 1H; Indole-H ⁶

); 6.78 (dd; ⁴

J = 1.9 Hz, ^5th

J = 0.5 Hz; 1H; Indole-H ⁴

); 7.01 (dd; ³

J = 8.7 Hz, ^5th

J = 0.5 Hz; 1H; Indole-H ⁷

); 6.89 and 7.87 (AA'BB '; ^3rd

J = 8.8 Hz; 4H; Phenylindole-H); 7.05 and 7.18 (AA'BB '; ^3rd

J = 8.4 Hz; 4H; Phenyl-H); 8.66 (s, 1H; -OH); 9.65 (s; 1H; -OH).

Ether cleavage with boron tribromide

A solution of 2.16 mmol boron tribromide in 10 ml absolute dichlorme than was cooled in an ice-sodium salt bath and with nitrogen gas with a solution of 0.54 mmol of the corresponding methoxyphenyl indols (II ") are added dropwise in absolute dichloromethane The cold bath was removed dropwise. The approach was still minimal stirred for at least three hours.

For working up, the reaction mixture was cooled again and through careful dropping with a total of 60 ml of saturated sodium hydrogen carbonate solution hydrolyzed. Stirring continued until no more gas development could be seen. Then ent standing chunks dissolved by adding ethyl acetate. The two Phases have been separated. The aqueous phase was washed twice with ethyl acetate shaken out. The combined organic phases were finally twice with saturated sodium bicarbonate solution as well as washed once with water. After drying over magne siumsulfat, the solvents were removed in vacuo. For cleaning the crude products on silica gel 60 (various dichlorme than / 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-tridecafluordecyl) -carbamoyl] -pentyl} -indole (Compound No. 5)

Preparation from Compound No. 5A (5-methoxy-2- (4-methoxyphenyl) -3-methyl-1- {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%
C ₃₂ H ₃₃ F ₁₃ N ₂ O ₃ (740.7)
IR (film): 3299 cm ^-1 (s, br; OH)
1642 cm ^-1 (s; C = O)
¹ H NMR (DMSO-d ₆ ): δ (ppm) = 1.03-1.51 (m; 12H; - (CH ₂ ) ₃ -C ₆ F ₁₃ , - (CH ₂ ) ₃ -); 2.04 (s; 3H; indole-CH ₃ ); 2.07-2.15 (m; 2H; -CH ₂ -CO-); 2.75 and 2.84 (s; 3H; -CO-NCH ₃ , e / z); 3.20-3.29 (m; 2H; -C H ₂ -NCH ₃ -); 3.91-3.94 (m; 2H; indole-N-CH ₂ -); 6.64 (dd; ³ J = 8.6 Hz, ⁴ J = 2.3 Hz; 1H; indole-H ⁶ ); 6.78 (dd; ⁴ J = 2.3 Hz, ⁵ J = 0.5 Hz; 1H; indole-H ⁴ ); 7.16-7.19 (m; 1H; indole-H 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-1- {5- [N-methyl-N- (3- (4,4,5,5,5- pentafluoropentylthio) propyl) carbamoyl] pentyl} indole (compound Number 1)

Preparation from Compound No. 1A (5-methoxy-2- (4-methoxyphenyl) -3-methyl-1- {5- [N-methyl-N- (3- (4,4,5,5,5-pentafluoropentyl -thio) -propyl) -carbamoyl] -pentyl} -indole); Purification by column chromatography on silica gel 60 (dichloromethane / ethyl acetate 1: 2, v / v)
yellow resin; Yield: 55%
C ₃₀ H ₃₇ F ₅ N ₂ O ₃ S (600.8)
IR (film): 3300 cm ^-1 (s, br; OH)
1642 cm ^-1 (s; C = O)
¹ H NMR (CDCl ₃ ): δ (ppm) = 1.10-1.19 (m; 2H; -C H ₂ - (CH ₂ ) ₂ -CO-); 1.44-1.58 (m; 4H; -C H ₂ -CH ₂ -CO-, -CH ₂ -C ₂ F ₅ ); 1.77-1.92 (m; 4H; indole-N-CH ₂ -C H ₂ -, -C H ₂ -CH ₂ -C ₂ F ₅ ); 2.05-2.25 (m; 4H; -CH ₂ -CO-, -C H 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-NCH ₃ -); 3.32 and 3.44 (t; ³ J = 7.4 Hz; 2H; -C H ₂ -NCH ₃ -, 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; 1H; indole-H ⁴ ); 6.97 (dd; ⁴ J = 2.4 Hz, ⁵ J = 0.5 Hz; 1H; indole-H ⁴ ); 7.14 (dd; ³ J = 8.6 Hz, ⁵ J = 0.5 Hz; 1H; 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-1- {5- [N-methyl-N- (3- (4,4,5,5,5- pentafluoropentylsulfonyl) propyl) carbomoyl] pentyl} indole (compound No. 3)

Preparation from Compound No. 3A (5-methoxy-2- (4-methoxyphenyl) -3-methyl-1- {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%
C ₃₀ H ₃₇ F ₅ N ₂ O ₅ S (632.8)
IR (film): 3286 cm ^-1 (s, br; OH)
1644 cm ^-1 (s; C = O)
¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 1.04-1.50 (m; 6H; - (C H ₂ ) ₂ -CH ₂ -CO-, -CH ₂ -C ₂ F ₅ ); 1.79-1.98 (m; 4H; indole-N-CH ₂ -C H ₂ -, C H ₂ -CH ₂ -C ₂ F ₅ ); 2.04 (s; 3H; indole-CH ₃ ; 2.06-2.17 (m; 2H; -CH ₂ -CO-); 2.29-2.43 (m; 2H; -C H ₂ - CH ₂ -NCH ₃ -); 2.73 and 2.88 (s; 3H; -CO-NCH ₃ -, e / z); 3.03-3.18 (m; 2H; -C H ₂ - ( CH ₂ ) ₂ -C ₂ F ₅ ); 3.20-3.30 (m; 2H; -C H ₂ - (CH ₂ ) ₂ -NCH ₃ -); 3.33-3.36 (m; 2H ; -C H ₂ -NCH ₃ -); 3.89-3.92 (m; 2H; indole-N-CH ₂ -); 6.64 (dd; ³ J = 8.7 Hz, ⁴ J = 2 , 3 Hz; 1H; indole-H ⁶ ); 6.78 (dd; ⁴ J = 2.3 Hz, ⁵ J = 0.5 Hz; 1H; indole-H ⁴ ); 7.19 (dd; ³ J = 8.7 Hz, ⁵ J = 0.5 Hz; 1H; 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 9.11 mmol lithium aluminum hydride in 100 ml absolute  THF was heated to reflux and so out with a solution 3.38 mmol of the corresponding carboxamide in 150 ml of absolute THF added dropwise that the approach always boiled, but did not foam too much. The reaction mixture was completed Addition kept boiling for an hour. Then that was Removed water bath and continued stirring at room temperature overnight.

To work up the resulting product, excess Li thiumaluminiumhydrid with a total of 150 ml of ice water and 25 ml sown saturated sodium bicarbonate solution hydrolyzed and separated te aqueous phase extracted three times with ethyl acetate. The united or ganic phases were washed twice with saturated sodium chloride Solution and washed once with water and over magnesium sulfate dried. The solvents were then removed in vacuo gene.

A separation of unreacted starting material and of secondary products was purified by column chromatography on silica gel 60 (ethyl acetate / methanol 3: 1, v / v) reached.

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-tridecafluorodecyl) amino] hexyl} indole (ver Binding 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)
light brown foam, yield: 53%
C ₃₂ H ₃₅ F ₁₃ N ₂ O ₂ (726.7)
IR (film): 3288 cm ^-1 (s, br; OH)
¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 1.02-1.49 (m; 14H; - (CH ₂ ) ₃ -C ₆ F ₁₃ , - (CH ₂ ) ₄ -); 2.04 (s; 3H; indole-CH ₃ ); 2.04-2.29 (m; 4H; -NCH ₃ - (CH ₂ -) ₂ ); 2.08 (s; 3H; -NCH ₃ -); 3.88-3.95 (m; 2H; indole-N-CH ₂ -); 6.63 (dd; ³ J = 8.6 Hz, ⁴ J = 2.3 Hz; 1H; indole-H ⁶ ); 6.78 (dd; ⁴ J = 2.3 Hz; ⁵ J = 0.5 Hz; 1H; indole-H ⁴ ); 7.18 (dd; ³ J = 8.6 Hz, ⁵ J = 0.5 Hz; 1H; 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; 1H; -OH).

Example 10 5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {6- [N-methyl-N- (2- (4- trifluoromethyl-phenyloxy) 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-trifluoromethylphenyloxy) ethyl) carbamoyl ] -pentyl} indole)
colorless foam; Yield: 45%
C ₃₁ H ₃₅ F ₃ N ₂ O ₃ (540.7)
IR (CHCl ₃ ): 3284 cm ^-1 (s; OH)
¹ H NMR (DMSO-d ₆ ): δ (ppm) = 1.02-1.14 (m; 4H; - (CH ₂ ) ₂ -); 1.17-1.22 (m; 2H; -C H ₂ -CH ₂ -NCH ₃ -); 1.41-1.43 (m; 2H; indole-N-CH ₂ -C H ₂ -); 2.03 (s; 3H; indole-CH ₃ ); 2.15 (s; 3H; -NCH ₃ -); 2.10-2.28 (m; 2H; -C H ₂ -NCH ₃ -); 2.61 (t; ³ J = 5.9 Hz; 2H; -C H ₂ -CH ₂ O-); 3.88-3.99 (m; 4H; indole-N-CH ₂ -, -CH ₂ O-); 6.63 (dd; ³ J = 8.7 Hz; ⁴ J = 2.3 Hz; 1H; indole-H ⁶ ); 6.77 (dd; ⁴ J = 2.3 Hz, ⁵ J = 0.5 Hz; 1H; indole-H ⁴ ); 7.17 (dd; ³ J = 8.7 Hz, ⁵ J = 0.5 Hz; 1H; 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-1- {6- [N-methyl-N- (3- (4,4,5,5,5- pentafluoropentyl-thio) propyl) amino] hexyl} indole (Compound No. 2)

Preparation from Compound No. 1 (5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {5- [N-methyl-N- (3- (4,4,5,5,5- pentafluoropentyl-thio) -propyl) - carbamoyl] -pentyl} -indole)
brownish resin; Yield: 68%
C ₃₀ H ₃₉ F ₅ N ₂ O ₂ S (586.8)
IR (film): 3287 cm ^-1 (s, br; OH)
¹ H NMR (DMSO-d ₆ ): δ (ppm) = 1.03-1.15 (m; 4H; - (C H ₂ ) ₂ - (CH ₂ ) ₂ -NCH ₃ -); 1.18-1.24 (m; 2H; -CH ₂ -C ₂ F ₅ ); 1.43-1.50 (m; 2H; - (CH ₂ ) ₄ -C H ₂ -CH ₂ -NCH ₃ -); 1.57-1.81 (m; 4H; C H ₂ -CH ₂ -C ₂ F ₅ , indole-N-CH ₂ -C H ₂ -); 2.04-2.12 (m; 2H; -SCH ₂ -C H ₂ -CH ₂ -NCH ₃ -); 2.04 (s; 3H; indole-CH ₃ ); 2.12 (s; 3H; -NCH ₃ -); 2.18-2.51 (m; 6H; - (CH ₂ ) ₅ -C H ₂ -NCH ₃ -, -S (CH ₂ -) ₂ ); 2.58 (t; ³ J = 7.2 Hz; 2H; -SCH ₂ -CH ₂ -C H ₂ -NCH ₃ -); 3.93 (t; ³ J = 7.0 Hz; 2H; indole-N-CH ₂ -); 6.64 (dd; ³ J = 8.6 Hz, ⁴ J = 2.3 Hz; 1H; indole-H ⁶ ); 6.78 (dd; ⁴ J = 2.3 Hz, ⁵ J = 0.5 Hz; 1H; indole-H ⁴ ); 7.18 (dd; ³ J = 8.6 Hz, ⁵ J = 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; 1H; -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-pentafluoropentyl-sulfonyl) -propyl) - amino] -hexyl} -indole) by nucleophilic substitution and ether cleavage

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

Example 13 5-methoxy-2- (4-methoxyphenyl) -3-methyl-1- {6- [N-methyl-N- (3- (4,4,5,5,5-pentofluoropentylsulfonyl) propyl) amino] hexyl} indole (ver Binding No. 4A)

yellow resin; Yield: 74%
C ₃₂

H ₄₃

F ₅

N ₂

O ₄

S (646.8)
¹

H-NMR (DMSO-d ₆

): δ (ppm) = 1.00-1.02 (m; 4H; - (C H 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; - (CH ₂

) ₄

-C H ₂

-CH ₂

-NCH ₃

-); 1.70-1.85 (m; 2H; -C H ₂

-CH ₂

-C ₂

F ₅

); 1.88-1.97 (m; 2H; indole N-CH ₂

-C H ₂

-); 2.06-2.15 (m; 2H; -SO ₂

-CH ₂

-C H 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; -SO ₂

-C H ₂

- (CH ₂

) ₂

-C ₂

F ₅

); 3.19-3.31 (m; 2H; -SO ₂

-C H ₂

- (CH ₂

) ₂

-NCH ₃

-); 3.77 (s; 3H; -OCH ₃

); 3.82 (s; 3H; -OCH ₃

); 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; 1H; Indole-H ⁶

); 6.97 (dd; ⁴

J = 2.4 Hz, ^5th

J = 0.5 Hz; 1H; Indole-H ⁴

); 7.31 (dd; ³

J = 8.8 Hz, ⁵

J = 0.5 Hz; 1H; Indole-H ⁷

); 7.07 and 7.31 (AA'BB '; ^3rd

J = 8.7 Hz; 4H; Phenyl-H).

Ether cleavage with ethanethiol / AlCl ₃

The removal 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) performed. The connection was established using Chromatogra purified on silica gel 60 (ethyl acetate / methanol 3: 1, v / v).

Example 14 5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {6- [N-methyl-N- (3- (4,4,5,5,5- pentafluoropentylsulfonyl) propyl) amino] hexyl} indole (compound No. 4)

brown resin; Yield: 73%
C ₃₀

H ₃₉

F ₅

N ₂

O ₄

S (618.8)
IR (CHCl ₃

) 3405 cm ^-1

(s, br; OH)
¹

H-NMR (DMSO-d ₆

): δ (ppm) = 1.03-1.14 (m; 4H; - (C H ₂

) ₂

- (CH ₂

) ₂

-NCH ₃

-); 1.23-1.25 (m; 2H; -CH ₂

-C ₂

F ₅

); 1.41-1.44 (m; 2H; - (CH ₂

) ₄

-C H ₂

-CH ₂

-NCH ₃

-); 1.71-1.83 (m; 2H; -C H ₂

-CH ₂

-C ₂

F ₅

); 1.86-1.98 (m; 2H; indole-N-CH ₂

-C H ₂

-); 2.05 (s; 3H; indole CH ₃

); 2.07 (s; 3H; -NCH _3rd

-); 2.12-2.18 (m; 2H; -SO ₂

-CH ₂

-C H ₂

-CH ₂

-NCH ₃

-); 2.31-2.43 (m; 4H; -NCH ₃

- (CH ₂

-) ₂

); 3.06-3.12 (m; 2H; -SO ₂

-C H ₂

- (CH ₂

) ₂

-C ₂

F ₅

); 3.20-3.34 (m; 2H; -SO ₂

-C H ₂

- (CH ₂

) ₂

-NCH ₃

-); 3.82-3.96 (m; 2H; indole-N-CH ₂

-); 6.64 (dd; ^3rd

J = 8.6 Hz, ^4th

J = 2.3 Hz; 1H; Indole-H ⁶

); 6.78 (dd; ⁴

J = 2.3 Hz, ^5th

J = 0.5 Hz; 1H; Indole-H ⁴

); 7.19 (dd; ³

J = 8.6 Hz, ^5th

J = 0.5 Hz; 1H; Indole-H ⁷

); 6.89 and 7.18 (AA'BB '; ^3rd

J = 8.5 Hz; 4H; Phenyl-H); 8.67 (s, br; 1H; - OH); 9.67 (s, br; 1H; -OH).

Compounds No. 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), No. 10 (5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-1- {7- [N-methyl-N- (7,7,8,8,9,9,10,10,10-nonafluorodecyl) -amino] -heptyl} -indole), No. 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) and No. 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) and the white tere compounds listed in Table 1 Nos. 13 to 41 and their 4 ', 5-dimethoxyindole derivatives can be analogous to the above connections are made.  

Table 1

Indolyl derivatives according to the invention

Continuation of table 1

Continuation of table 1

Continuation of table 1

Table 3

Relative binding affinity to the estrogen receptor / antiestrogenic effectiveness

reference compounds

R1: 7α- {9 - [(4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl} estra-1,3,5 (10) - triene-3,17β-diol
R2: 7α- (5- {N-methyl-N- [3 - ({4,4,5,5,5-pentafluoropentyl} 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 5 (estrogenic and antiestrogenic effects in the mouse)

Claims (14)

1. 1-indolyl derivatives with the general formula
wherein
R ¹ and R ^{2 are} independent of each other

• a) hydrogen or
• b) represent straight-chain or branched-chain C ₁ -C ₄ -alkyl, -alkenyl or -alkynyl radicals or
• c) C (O) -R ⁵ , where R ^{5 is} a straight-chain or branched-chain C ₁ -C ₄ -alkyl, -alkenyl or -alkynyl radical,

R ³ and R ^{4 are} independent of one another

• a) hydrogen or
• b) are 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 may also contain a double bond, and
U represents either a straight-chain or branched-chain C ₁ - to C ₁₃ -alkylene, -alkenylene or -alkynylene radical or AB, where A is bonded to the indole nitrogen atom and one via -CH ₂ - bonded to the indole nitrogen atom Represents benzylidene radical, a phenylene radical or a C ₁ to C ₃ alkylaryl radical bonded via the alkyl group to the indole nitrogen atom and B represents a straight or branched chain C ₁ to C ₁₃ alkylene, alkenylene or alkynylene radical and where A and B can also be connected to one another via an oxygen atom,
V represents a CH ₂ or a C (O) group,
W represents an N (R ⁶ ) or an azolidinylene group, where R ^{6 is} either H or CH ₂ -R ⁷ or C (O) -R ⁷ , in which R ⁷ can mean the following:

• a) hydrogen or
• b) a straight-chain or branched-chain, non-fluorinated or at least partially fluorinated C ₁ -C ₁₄ -alkyl, -alkenyl or -alkynyl radical which can be hydroxylated once or more and by one to three heteroatoms -O-, - S and / or groupings -NR ⁹ - can be interrupted, in which R ^{9 represents} hydrogen or a C ₁ - to C ₃ -alkyl radical, or
• c) an unsubstituted or substituted aryl or hetero aryl radical or
• d) an unsubstituted or substituted C ₃ - to C ₁₀ -cycloal kylrest or
• e) an unsubstituted or substituted C ₄ - to C ₁₅ -cycloal kylalkylrest or
• f) an unsubstituted or substituted C ₇ to C ₂₀ 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 straight-chain or branched-chain C ₁ to 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 SO _n and Z or a straight or ver branched chain C ₁ - to C ₆ -alkylene-, - Represents alkenylene or alkynylene or
• b) the group R ¹¹ or OR ¹¹ , wherein R ¹¹ for
  • a) is a straight-chain or branched-chain C ₁ - to C ₅ -alkylene, -alkenylene or -alkynylene radical or
  • b) is an unsubstituted or substituted aryl radical or heteroaryl radical or for
  • c) represents an unsubstituted or substituted C ₃ to C ₁₀ cyclalkyl radical or
  • d) is an unsubstituted or substituted C ₄ to C ₁₅ cycloalkylalkyl radical or for
  • e) is an unsubstituted or substituted C ₇ to C ₂₀ aralkyl radical or for
  • f) is an unsubstituted or substituted hetero aryl-C ₁ -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, at least partially fluorinated C ₁ -C ₉ -alkylene, -alkenylene or -alkinylene 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 or branched chain C ₁ to C ₃ alkyl radical,
X stands for (CH ₂ ) _q , where q = 0 or an integer from 1 to 12 and
Y and Z together represent either SO _n - (CH ₂ ) _r -CF ₂ , (CF ₂ ) _s or O-aryl, where n = 0, 1 or 2, r = 0 or an integer of 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 records that U is a straight or branched chain pentylene, hexylene, Hep tylene, octylene or Nonylenrest is. 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 records that X is a straight or branched chain ethylene, propylene, butylene, Is pentylene or hexylene. 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 is 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, wherein 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- (5,5,6,6,7,7,8,8,9,9 , 10,10,10-tridecafluordecyl) 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-nonafluorodecyl ) 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- 1H-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-nonafluorundecyl) amino] ethoxy} benzyl) -1H-indole-5-ol,
• 16. 2- (4-Hydroxyphenyl) -3-methyl-1- [6- (methyl- {3 - [(4,4,5,5,5-pentafluorpentyl) sulfinyl] propyl} amino) - hexyl] -1H-indole-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-1H-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-pentafluorpentyl) sulfinyl] propyl} amino) - heptyl-1H-indol-5-ol,
• 20. 2- (4-Hydroxyphenyl) -3-methyl-1- [7- (methyl- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} amino) heptyl ] -1H-indole-5-ol,
• 21. 2- (4-Hydroxyphenyl) -3-methyl-1- [7- (methyl- {3 - [(4,4,5,5,5-pentafluorpentyl) thio] propyl} amino) - heptyl] -1 H-indole-5-ol,
• 22. rac-1- (4- {2 - [(2,3-dihydroxypropyl) (7,7,8,8,9,9,10,10,10-nonafluorodyl) amino] ethoxy} benzyl ) -2- (4-hydroxyphenyl) -3-methyl-1H-indol-5-ol,
• 23. rac-1- {7 - [(2,3-dihydroxypropyl) (7,7,8,8,9,9,10,10,10-nonafluorodecyl) amino] heptyl} -2- (4- hydroxyphenyl) -3-methyl-1H-indol-5-ol,
• 24. rac-1- {b - [(2,3-dihydroxypropyl) (7,7,8,8,9,9,10,10,10-nonafluorodecyl) amino] hexyl} -2- (4- hydroxyphenyl) -3-methyl-1H-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] -1H-indol-5-ol,
• 26. 2- (4-Hydroxyphenyl) -3-methyl-1- {6- [methyl- (8,8,9,9,9-pentafluorononyl) amino] hexyl} -1H-indol-5-ol .
• 27. 1- {6 - [(7,7,8,8,9,9,9-heptafluorononyl) methylamino] hexyl} -2- (4-hydroxyphenyl) -3-methyl-1H-indole-5- oil,
• 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} - 1H-indol-5-ol,
• 30. 2- (4-hydroxyphenyl) -3-methyl-1- {6- [methyl- (6,6,7,7,8,8,9,9,9,9-nonafluorononyl) amino] hexyl} 1H-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-1H-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-1H-indol-5-ol,
• 33. 2- (4-Hydroxyphenyl) -3-methyl-1- {7- [methyl- (8,8,9,9,9-pentafluorononyl) amino] heptyl} -1H-indol-5-ol .
• 34. 1- {7 - [(7,7,8,8,9,9,9-heptafluorononyl) methylamino] heptyl} -2- (4-hydroxyphenyl) -3-methyl-1H-indole-5- oil,
• 35. 1- {7 - [(2-hydroxyethyl) (7,7,8,8,9,9,10,10,10-nonafluorodecyl) amino] heptyl} -2- (4-hydroxyphenyl) -3 methyl-1H-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) -1H-indole-5-ol,
• 38. (RS) -2- (4-hydroxyphenyl) -3-methyl-1- {4- [2- (methyl- {3 - [(4,4,5,5,5,5-pentafluoropentyl) sulfinyl] - propyl} -amino) -ethoxy] -benzyl} -1H-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} -1H-indol-5-ol,
• 40. 2- (4-Hydroxyphenyl) -3-methyl-1- {4- [2- (methyl- {3 - [(4,4,5,5,5-pentafluorpentyl) sulfonyl] propyl} - amino) -ethoxy] -benzyl} -1H-indol-5-ol,
• 41. 1- (4- {2 - [(7,7,8,8,9,9,9-heptafluorononyl) methylamino] ethoxy} benzyl) -2- (4-hydroxyphenyl) -3-methyl- 1H-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 meanings given in claims 1 to 8. 12. Process for the preparation of 1-indolyl derivatives with the general formula
where R ³ , R ⁴ , R ⁶ , U, X, Y and Z have the meanings given in claim 1,
in which, starting from a compound of 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 nucleophilic substitution with R 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
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 meanings given above, the 1-indolyl derivative is formed with the general formula II '''
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 egg nem 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 min at least a pharmaceutically acceptable carrier.