DE102008004100A1 - New metallocene compounds are estrogen receptor modulators useful e.g. to treat preferably cancer, manic disorder, gynecomastia and/or female infertility, and to prevent mamma carcinoma - Google Patents

Abstract

The present invention relates to a new class of metallocenophanes. it further relates to the synthesis of such compounds and their use as cytostatic agents. The metallocenophanes according to the invention are derived from a metallocenophanone. By reductive coupling with another carbonyl compound, the compounds can be obtained. Assayed compounds showed cytotoxic activity in the MTT assay against L929 mouse fibrolasts and MCF-7 breast cancer cells.

Description

The The present invention relates to metallocenophanes. It continues to apply the synthesis of such compounds as well as these Metallocenophane comprehensive Drug.

Since the discovery by Rosenberg of the effect of cis- [PtCl ₂ (NH ₃ ) ₂ ] (cisplatin) in 1969, the cancerostatic properties of certain metal compounds have been increasingly investigated. Köpf and Köpf-Maier first investigated the antitumor properties of titanocene dichloride in 1979. Another pharmacologically used metallocene compound is ferrocifen. This is a tamoxifen analogue in which a tyoxifene phenyl ring is replaced by a ferrocenyl moiety. The pharmacologically active metabolite of tamoxifen is 4-hydroxytamoxifen. This is used as a selective estrogen receptor modulator (SERM) for the treatment of hormone-dependent breast cancer. The introduction of the ferrocenyl moiety into the tamoxifen scaffold leads to an extension of the spectrum of action to non-hormone-dependent breast cancer cells. Ferrocifen and its derivatives are the subject of patent applications, for example WO 1996/11935 A1 and WO 2006/005856 A1 ,

metallocenes whose cyclopentadienyl ligands are linked together in analogy to the usual nomenclature in organic chemistry the cyclophane called metallocenophanes. Compared to the unbridged metallocenes have the metallocenophanes a more rigid structure. This can turn into a permanent one steric hindrance of certain areas of the molecule to make noticable. Other properties in terms of reactivity and their interaction with other molecules are the Consequence of the bridging in the metallocenophane.

So far, only a few metallocenophanes have been disclosed in the prior art, which have a cytotoxic activity. So concerns DE 34 04 443 A1 Metallicium salts of the general formula [(η ⁵ -C ₅ H _5-x R _x ) M (η ⁵ -C ₅ H _5-y R ' _y )] ^{m +} _a [A] ^n- b, in M Fe, Co, Ni , Ru or Os is. In these cations, the radicals R and R 'can together form an alkylene bridge having 2 to 4 bridge atoms. The claimed Metalliceniumsalze be used as drugs, especially as cytostatics in the fight against cancer.

by virtue of the wide range of biological recognition processes, which lead to the action of a cytostatic agent, persists the need for metallocenophanes with cytostatic properties. The present invention has the object, at least to solve one of the disadvantages of the prior art. Especially It has set itself the task to provide novel metallocenophanes. She has continued to set the task, a method for synthesis specify such metallocenophanes and their use in medicines.

M ist Fe, Ru, Os, Co, Rh oder Ir;
R1a, b, c, d sind unabhängig voneinander H, Alkyl, Halogen, OH, NH₂, SH, CH₂(CH₂)_0-20OH, CH₂(CH₂)_0-20NH₂, CH₂(CH₂)_0-20SH, C(O)OH, P(Alkyl)_rH_3-r, oder P(Aryl)_sH_3-s; oder R1a, b, c, d bilden aromatische, olefinische und/oder aliphatische Carbo- oder Heterocyclen aus;
R2a, b, c, d sind unabhängig voneinander H, Alkyl, Halogen, OH, NH₂, SH, CH₂(CH₂)_0-20OH, CH₂(CH₂)_0-20NH₂, CH₂(CH₂)_0-20SH, C(O)OH, P(Alkyl)_rH_3-r oder P(Aryl)_sSH_3-s;
oder R2a, b, c, d bilden aromatische, olefinische und/oder aliphatische Carbo- oder Heterocyclen aus;
X, Y und Z sind unabhängig voneinander:

wobei gilt:
R3, R4 sind gemeinsam ein O-Atom, eine Iminogruppe oder eine alkylsubstituierte Iminogruppe;
oder sie sind unabhängig voneinander H, Halogen, Pseudohalogen, OH, NH₂, SH, Alkyl, Alkoxy, Alkylamino, Dialkylamino, Alkylthio, Aryl, Arylalkyl, Aryloxy, Arylalkyloxy, Heteroaryl oder Heteroarylalkyl;
R5, R6 sind gemeinsam ein O-Atom, eine Iminogruppe oder eine alkylsubstituierte Iminogruppe;
oder sie sind unabhängig voneinander H, Halogen, Pseudohalogen, OH, NH₂, SH, Alkyl, Alkoxy, Alkylamino, Dialkylamino, Alkylthio, Aryl, Arylalkyl, Aryloxy, Arylalkyloxy, Heteroaryl oder Heteroarylalkyl;
R7, R8 sind unabhängig voneinander Cycloalkyl, Cycloalkenyl, Aryl, Arylalkyl, Aryloxy, Arylalkyloxy, Heteroaryl oder Heteroarylalkyl;
wobei R7 und R8 unabhängig voneinander zusätzlich in einfacher oder mehrfacher Weise substituiert sein können;
n, m und o sind unabhängig voneinander 0, 1, 2 oder 3, jedoch nicht gleichzeitig alle 0; und wobei weiterhin in der Metallocenverbindung gemäß Formel (I) mindestens eine der Gruppen X, Y oder Z für

steht.This object is achieved by a metallocene compound of the formula I: where

M is Fe, Ru, Os, Co, Rh or Ir;
R1a, b, c, d are independently H, alkyl, halogen, OH, NH _2, SH, CH ₂ (CH _{2) 0-20} OH, CH ₂ (CH _{2) 0-20} NH _2, CH ₂ (CH ₂ ) _0-20 SH, C (O) OH, P (alkyl) _r H3 _-r , or P (aryl) _s H3 _-s ; or R1a, b, c, d form aromatic, olefinic and / or aliphatic carbo or heterocycles;
R 2a, b, c, d are independently H, alkyl, halogen, OH, NH _2, SH, CH ₂ (CH _{2) 0-20} OH, CH ₂ (CH _{2) 0-20} NH _2, CH ₂ (CH ₂ ) _0-20 SH, C (O) OH, P (alkyl) _r H3 _-r or P (aryl) _s SH3 _-s ;
or R2a, b, c, d form aromatic, olefinic and / or aliphatic carbo- or heterocycles;
X, Y and Z are independent of each other:

where:
R3, R4 together are an O atom, an imino group or an alkyl-substituted imino group;
or they are independently H, halogen, pseudohalogen, OH, NH ₂ , SH, alkyl, alkoxy, alkylamino, dialkylamino, alkylthio, aryl, arylalkyl, aryloxy, arylalkyloxy, heteroaryl or heteroarylalkyl;
R5, R6 together are an O atom, an imino group or an alkyl-substituted imino group;
or they are independently H, halogen, pseudohalogen, OH, NH ₂ , SH, alkyl, alkoxy, alkylamino, dialkylamino, alkylthio, aryl, arylalkyl, aryloxy, arylalkyloxy, heteroaryl or heteroarylalkyl;
R7, R8 are independently cycloalkyl, cycloalkenyl, aryl, arylalkyl, aryloxy, arylalkyloxy, heteroaryl or heteroarylalkyl;
wherein R7 and R8 may be independently substituted in single or multiple ways;
n, m and o are independently 0, 1, 2 or 3, but not all 0 at the same time; and wherein furthermore in the metallocene compound of the formula (I) at least one of the groups X, Y or Z represents

stands.

The cyclopentadienyl ligands can be unsubstituted or, according to the specifications for R 1a, b, c, d and R 2a, b, c, d, each independently carry 1, 2, 3 or 4 further substituents. For example, they may be substituted with alkyl groups instead of hydrogen substituents. "Alkyl" in the context of the present invention means a linear or branched C ₁ -C ₂₀ -alkyl, preferably methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl. For example, by means of the substituents R1a, b, c and d on the one hand or R2a, b, c, d, one, two, three or four methyl groups can be synthesized on one or both of the cyclopentadienyl ligands.

Farther The cyclopentadienyl ligand may also be part of a larger Ring system, which is otherwise aromatic, olefinic or aliphatic. The ring system may be carbocyclic or heterocyclic. Examples of inventively designed Ring systems are indenyl or fluorenyl systems. In the context of present invention includes the term "cyclopentadienyl" also the aforementioned fused ring systems containing the cyclopentadienyl subunit exhibit.

It is also provided that the cyclopentadienyl ligands having the substituents OH, NH _2, SH, CH ₂ (CH _{2) 0-20} OH, CH ₂ (CH _{2) 0-20} NH _2, CH ₂ (CH _{2) 0-20} SH, C (O) OH, P (alkyl) _r H _3-r and / or P (aryl) _s H _3-s . Selected examples are CH ₂ CH ₂ OH, CH ₂ (CH ₂ ) ₂ OH, CH ₂ (CH ₂ ) ₃ OH, CH ₂ CH ₂ NH ₂ , CH ₂ (CH ₂ ) ₂ NH ₂ , CH ₂ (CH ₂ ) ₃ NH ₂ , CH ₂ CH ₂ SH, CH ₂ (CH ₂ ) ₂ SH or CH ₂ (CH ₂ ) ₃ SH. All these substituents have the common feature that they have an active hydrogen atom and are therefore available for subsequent reactions. As a result, the metallocenophanes can for example be immobilized on surfaces or attached to other biological molecules. Preferably, at least one of the aforementioned substituents is ortho to one of the carbon atoms which forms the bridge between the cyclopentadienyl ligands. The substituents may be introduced via metalation of the cyclopentadienyl ligand followed by trapping of the intermediate with an electrophile. Conveniently, the functionalization is carried out already in a synthesis intermediate. For example, alkyl lithium compounds such as n-butyllithium, tert-butyllithium or methyllithium may be lithiated and CO ₂ trapped to introduce the C (O) OH substituent. Preferably, a directional ortho-metalation takes place.

is one of the substituents R1 a, b, c, d of the other of these substituents differently, the cyclopentadienyl ligand becomes a level of chirality introduced. The same applies to the substituents R2a, b, c, d. Consequently, depending on the substitution pattern total metallocenophane, enantiomers or diastereomers of the Molecule occur. Both enantiomerically pure and diastereomerically pure Compounds as well as mixtures of the enantiomers and / or diastereomers in any proportions are included in the present invention.

The Metallocenes according to the invention have a bridge the cyclopentadienyl ligands. Thus, they are called metallocenophanes to characterize. Another, in the metallocenes of the late transition metals less common name is ansa metallocene.

The Subunits X, Y and Z are the constituents that make up the bridge can be built. According to the specifications the backbone of the bridge of carbon atoms built, which can be further substituted. These Substituents can be grouped together as in the case that the bridging carbon atom Part of a carbonyl group or an imino group. The bridge carbon atoms can also have a single bond with substituents be connected.

The subunits X, Y and Z may, due to the further specification that the counters n, m and o assume values of 0, 1, 2 or 3, a bridge having at least one and at most nine carbon atoms in represent the bridge. An example of such a bridge would also be a [3] metallocenophane such as a [3] ferrocenophane.

With regard to the substituents, it should further be noted that "pseudohalogen" denotes the group comprising CN, -CN, OCN, N ₃ , CNO and / or SeCN. "Aryl" denotes aromatic compounds having a molecular weight of ≤ 300 g / mol. Examples of aryl substituents are phenyl, biphenyl, naphthalenyl, anthracenyl and / or phenanthrenyl. "Heteroaryl" refers to the corresponding aryl compounds in which the aromatic system comprises O, N and / or S atoms.

gebildet wird, wobei R7 und R8 nach den obigen Definitionen weiterhin einfach oder mehrfach substituiert sein können. Dieses kann unabhängig voneinander geschehen, so dass R7 beispielsweise ein unsubstituierter Phenylring ist und R8 ein substituierter Phenylring. Allgemein treten bei unterschiedlichen R7 und R8 an der C=C-Doppelbindungen E- und Z-Isomere auf. Ausdrücklich eingeschlossen im Rahmen der vorliegenden Erfindung sind die E-Isomere und die Z-Isomere der erfindungsgemäßen Metallocenverbindungen sowie Gemische dieser Isomere in beliebigen Anteilen.According to the invention it is provided that at least one element of the bridging between the cyclopentadienyl ligands by the following unit

is formed, wherein R7 and R8 according to the above definitions can be further mono- or polysubstituted. This can be done independently of each other so that R7 is, for example, an unsubstituted phenyl ring and R8 is a substituted phenyl ring. In general, E and Z isomers occur at different R7 and R8 on the C = C double bonds. Expressly included in the context of the present invention are the E isomers and the Z isomers of the metallocene compounds according to the invention and mixtures of these isomers in any proportions.

in the Within the scope of the present invention, the metallocene compounds also in cationic form together with pharmaceutically acceptable Anions are present.

wobei M, die Substituenten R1 a, b, c, d, die Substituenten R2a, b, c, d sowie die Substituenten R3, R4, R5, R6, R7 und R8 dieselbe Bedeutung wie vorstehend definiert innehaben. Hierbei handelt es sich um ein [3]Metallocenophan. Aufgrund der sterischen Verhältnisse bei späten Übergangsmetallen weisen die [3]Metallocenophane eine geringe Ringspannung in der Brücke zwischen den Cyclopentadienylliganden auf. Gleichzeitig ist die Konformation der Brücke stabil.In one embodiment of the present invention, the metallocene compound is represented by the formula II:

wherein M, the substituents R1 a, b, c, d, the substituents R2a, b, c, d and the substituents R3, R4, R5, R6, R7 and R8 have the same meaning as defined above. This is a [3] metallocenophane. Because of the steric situation in late transition metals, the [3] metallocenophanes have a low ring strain in the bridge between the cyclopentadienyl ligands. At the same time, the conformation of the bridge is stable.

wobei M, die Substituenten R1a, b, c, d, die Substituenten R2a, b, c, d sowie die Substituenten R3, R4, R5, R6, R7 und R8 dieselbe Bedeutung wie vorstehend definiert innehaben; und
wobei weiterhin gilt:
R9, R10 sind unabhängig voneinander:

• a) H, Halogen, Pseudohalogen, OH, NH₂, SH, Alkyl, Alkoxy, Alkylamino, Dialkylamino, Alkylthio, Aryl, Arylalkyl, Aryloxy oder Arylalkyloxy; oder:
• b) die folgende Gruppe: -X1-(CH₂)_p-CH₂–N(R11)(R12) wobei X1 für O, NH oder S steht wobei p 1, 2, 3 oder 4 sein kann wobei R11 und R12 unabhängig voneinander H, C₁ bis C₄-Alkyl, -CH₂C=CH oder -CH₂CH₂OH sind oder R11 und R12 einen N-haltigen fünf- oder sechsgliedrigen Ring bilden; oder:
• c) die folgende Gruppe: -Y1-(CH2)_qCH₂-O-R13 wobei Y1 für O, NH oder S steht wobei q 1, 2, 3 oder 4 sein kann wobei R13 H, -CH₂CH₂OH oder -CH₂CH₂Cl sein kann; oder:
• d) 2,3-Dihydroxypropoxy, 2-Methylsulfamylethoxy, 2-Chloroethoxy, 1-Ethyl-2-hydroxyethoxy, 2,2-Diethyl-2-hydroxyethoxy oder Carboxymethoxy.

In a further embodiment of the present invention, the metallocene compound is represented by formula III:

wherein M, the substituents R1a, b, c, d, the substituents R2a, b, c, d and the substituents R3, R4, R5, R6, R7 and R8 have the same meaning as defined above; and
where furthermore applies:
R9, R10 are independent of each other:

• a) H, halogen, pseudohalogen, OH, NH ₂ , SH, alkyl, alkoxy, alkylamino, dialkylamino, alkylthio, aryl, aryl alkyl, aryloxy or arylalkyloxy; or:
• b) the following group: -X1- (CH ₂ ) _p -CH ₂ -N (R 11) (R 12) where X 1 is O, NH or S where p can be 1, 2, 3 or 4 where R 11 and R 12 are independently each is H, C ₁ to C ₄ alkyl, -CH ₂ C = CH or -CH ₂ CH ₂ OH or R 11 and R 12 form an N-containing five- or six-membered ring; or:
• c) the following group: -Y1- (CH ₂ ) _q CH ₂ -O-R 13 where Y 1 is O, NH or S where q can be 1, 2, 3 or 4 where R 13 is H, -CH ₂ CH ₂ OH or -CH ₂ CH ₂ Cl can be; or:
• d) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or carboxymethoxy.

An example of such a compound is when R 9 is H or OH and R 10 is the group -O-CH ₂ -CH ₂ -N (CH ₃ ) ₂ or -O-CH ₂ -CH ₂ -CH ₂ -N (CH ₃ ) ₂ . R9 and R10 may be para to their phenyl rings.

In a further embodiment of the present invention, the metallocene compound is a [3] ferrocenophane, wherein the carbon atom bearing the C = C double bond is located at the 1 position in the C ₃ bridge and CH ₂ groups at 2- and at 3-position. It is in the metallocene compound: M is Fe; R1 a, b, c, d is H; R2a, b, c, d is H; R3 is H; R4 is methyl; R5 is H; R6 is H. Examples of such [3] ferrocenophane systems are given by the following formulas IV and V. Here, the substituents R7, R8, R9 and R10 assume the meanings defined above.

In another embodiment of the present invention, a cyclopentadienyl ligand is further functionalized. In this metallocene compound: M is Fe; R1a, b, c, d is H; R2a, b, c is H; R2d is Br, OH, SH, NH _2, CH ₂ OH, CH ₂ NH ₂ or C (O) OH; R3 is H; R4 is methyl; R5 is H; R6 is H. Preferably, R2d is positioned ortho to the cyclopentadienyl ligand-bridging subset of the compound. As already mentioned, the substituents can be introduced via a metallation of the cyclopentadienyl ligand with subsequent interception of the intermediate with an electrophile. Conveniently, the functionalization is carried out already in a synthesis intermediate. For example, alkyl lithium compounds such as n-butyllithium, tert-butyllithium or methyllithium may be lithiated and CO ₂ trapped to introduce the C (O) OH substituent. Suitable coordinating groups in the synthesis intermediate such as a dimethylamino group in the bridge between the cyclopentadienyl ligands can effect directional metallation. Preferably, this is a directed ortho-metalation. Examples of [3] ferrocenophanones according to the invention are represented by the following formulas Na, b, c and Va, b, c. Here, the substituents R7, R8, R9 and R10 assume the meanings defined above.

In general, the bridging carbon atom bearing the methyl group is a stereogenic center. If the methyl group in the representation according to formulas IV, IVa, b, c, V, Va, b, c protrudes from the plane of the drawing, the configuration of the carbon atom carrying the methyl group is (S). If the methyl group is behind the drawing plane, the configuration is accordingly (R). In one embodiment of the present invention, the absolute configuration of R4, that is, the methyl group, is carrying carbon (R) and the compound is present in an enantiomeric excess of ≥90%. In a further embodiment, the absolute configuration of R4, that is, the methyl group, carrying carbon atom (S) and the compound is present in an enantiomeric excess of ≥ 90%. Enantiomerically enriched or as part of the measurement accuracy enantiomerically pure precursor compounds for the metallocenophanes according to the invention are disclosed in the publication of L. Tebben, M. Neumann, G. Kehr, R. Frohlich, G. Erker, S. Losi, P. Zanello, Dalton Transactions 2006, 1715-1720 available. This publication is referred to in its entirety.

In the synthesis of the metallocenophanes of the invention it makes sense to consider the C = C double bond in which one of the carbon atoms Part of the bridge between the cyclopentadienyl rings, to build up in a late synthesis stage and thus two Link molecular fragments to the target molecule. This is possible, for example, an olefin metathesis or a Wittig reaction. Advantageously, the double bond by means of a titanium-mediated reductive coupling of two carbonyl groups introduced. This coupling is also under the generic term the McMurry reaction known.

• a) Bereitstellen einer Metallocenverbindung der Formel I, wobei mindestens eine der Gruppen X, Y oder Z eine Carbonylgruppe darstellt;
• b) Hinzufügen einer Carbonylverbindung der Formel O=C(R7)(R8), wobei R7 und R8 dieselbe Bedeutung wie vorstehend definiert innehaben;
• c) Hinzufügen von Titantetrachlorid und Reduktionsmittel.

The invention therefore furthermore relates to a process for the preparation of metallocene compounds according to the present invention, comprising the steps:

• a) providing a metallocene compound of the formula I, wherein at least one of the groups X, Y or Z represents a carbonyl group;
• b) adding a carbonyl compound of formula O = C (R7) (R8), wherein R7 and R8 have the same meaning as defined above;
• c) adding titanium tetrachloride and reducing agent.

consequently become the required in step a) carbonyl group and the carbonyl group the compound from step b) is linked to one another, that a C = C double bond is built up between their carbon atoms becomes. Suitable reducing agents for use in step c) are, for example, lithium aluminum hydride, alkali metals such as Lithium, sodium or potassium, alkaline earth metals such as magnesium, zinc, Zinc-copper alloy or graphite potassium.

und R9 und R10 weisen dieselbe Bedeutung wie vorstehend definiert auf.In one embodiment of the process according to the invention, the carbonyl compound in step b) is constructed according to the following formula:

and R9 and R10 have the same meaning as defined above.

In a further embodiment of the invention Method is the metallocene compound in step a) according to the of general formula III and it also applies: M is Fe; R1 a, b, c, d is H; R2a, b, c, d is H; R3 is H; R4 is methyl; R5 is H; R6 is H.

In a further embodiment of the process according to the invention, the metallocene compound in step a) is constructed according to general formula III and furthermore: M is Fe; R1 a, b, c, d is H; R2a, b, c is H; R 2d is Br, OH, SH, NH ₂ , CH ₂ OH, CH ₂ NH ₂ or C (O) OH or one of the aforementioned substituents which is provided with a protecting group; R3 is H; R4 is methyl; R5 is H; R6 is H. Protecting groups may be used if the presence of the H atoms of the substituents during the reductive coupling would lead to undesirable side reactions.

One Another object of the invention is a medicament comprising a metallocene compound according to the present invention Invention. Likewise, the invention relates to the use of a metallocene compound according to the present invention for the manufacture of a medicament.

One Another object of the invention is a medicament for treatment of diseases selected from the group comprising cancer, Mania, gynecomastia and / or female infertility, comprising a metallocene compound according to present invention. In particular, the drug may be suitable to treat breast cancer. Likewise, the invention relates the use of a metallocene compound according to the present invention for the preparation of a medicament for the treatment of diseases selected from the group comprising cancer, in particular breast cancer, mania, gynecomastia and / or female Infertility.

One Another object of the invention is a medicament for the prevention breast cancer, comprising a metallocene compound according to the present invention. Likewise, the invention relates to the use a metallocene compound according to the present invention Invention for the preparation of a medicament for the prevention of Breast cancer.

One Another object of the invention is a cytostatic preparation, comprising a metallocene compound according to present invention. Likewise, the invention relates to the use a metallocene compound according to the present invention Invention for the preparation of a cytostatic preparation.

One Another object of the invention is an estrogen receptor modulating A composition comprising a metallocene compound according to present invention. Likewise, the invention relates to the use a metallocene compound according to the present invention Invention for producing an estrogen receptor modulating Composition.

One Another object of the invention is an inventive Metallocene compound for use as a medicament.

One Another object of the invention is an inventive Metallocene compound for use as a medicament for the treatment of diseases selected from the group comprising cancer, Mania, gynecomastia and / or female infertility.

One Another object of the invention is an inventive Metallocene compound for use as a preventive medicine of breast cancer.

The Invention will be further illustrated by the following examples.

Example 1:

• Synthesis of carbonyl compound VI as a precursor for the reductive coupling ( L. Tebben, M. Neumann, G. Kehr, R. Frohlich, G. Erker, S. Losi, P. Zanello, Dalton Transactions 2006, 1715-1720 )
  

Sodium bicarbonate (13.224 g, 157 mmol) was added to a solution of 1,1 '- [1- (dimethylamino) -butane-1,3-diyl] -ferrocene (6.990 g, 24 mmol) in toluene (100 mL). The reaction mixture was stirred for 30 minutes at room temperature. Then, methyl chloroformate (9.3 mL, 120 mmol) was added and stirred for 5 hours. Solids were filtered off and the filtrate was freed from the solvent in vacuo. The resulting red oil was dissolved in 150 mL of a 1: 1: 1 mixture of ethanol, acetic acid and water. Hexamethylenetetramine (6.696 g, 47 mmol) was then added and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and neutralized with aqueous sodium bicarbonate solution. It was extracted with dichloromethane (3 x 20 mL) and the combined organic phases were dried over magnesium sulfate. After filtration and concentration of the filtrate in vacuo, the residue was purified by column chromatography (silica gel, diethyl ether). 4.563 g (76%) of product VI were obtained as a red solid.
¹ H-NMR _(CDCl3, 300 MHz): δ = 1.24 (d, 3H), 2:59 (dd, 1H), 3.19 (dd, 1H), 3.21 (m, 1H), 3.89 (m, 1H), 4:09 -4.89 (m, 7H). MS (ESI) m / z: calculated for C ₁₄ H ₁₄ FeO: 254.04; Found: 277.0 [M + Na ⁺ ], 255.0 [M + H ⁺ ].

Example 2:

Synthesis of compound VII by reductive coupling

Titanium tetrachloride (3 mL) was added to a suspension of zinc powder (4.632 g, 71.0 mmol) in 70 mL THF at 0 ° C. Subsequently, a solution of Compound VI (3.017 g, 11.8 mmol) available from Example 1 and 4,4'-dihydroxybenzophenone (2.449 g, 11.4 mmol) in 20 mL of THF was added. The mixture was heated to reflux for 2.5 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added. Extraction with chloroform followed by column chromatography (silica gel, diethyl ether: pentane 1: 1) gave Compound VII as a yellow solid (1.307 g, 25%). HRMS (ESI) m / z: calculated for C ₂₇ H ₂₄ FeO ₂ : 436.1126; found: 459.1026 [M-Na ⁺ ], 436.1124 [M ⁺ ]. Single crystal data: C ₂₇ H ₂₄ FeO ₂ .CH ₂ C ₁₂ , M = 521.24, T = 223 K, monoclinic, P2 ₁ / n (no. 14), a = 11.1096 (2) Å, b = 12 , 8660 (2) Å, c = 16.8908 (4) Å, β = 98.315 (1) °, V = 2388.93 (8) Å ³ , Z = 4, D _calculates = 1.449 gcm ^-3 , μ = 8.79 cm 1, [(sinθ) / λ] = 0.66 Å ^-1 , 15593 reflectances measured, 5654 independent reflections, 301 refined parameters, goodness-of-fit = 1.024, R = 0.048, wR ₂ = 0.121, largest difference peak / hole 1.22 / -0.42 eÅ ^-3 .

Example 3:

Synthesis of compound VIII (mixture of E and Z isomers)

To a solution of Compound VII (1.7011 g, 3.9 mmol) available in Example 2 in 40 mL of ethanol was added sodium ethanolate (7.7 mmol). The mixture was refluxed for 1 hour. 2-Chloroethyl dimethylamine hydrochloride (600.0 mg, 4.1 mmol) was added and heated to reflux again for 3 hours. After cooling to room temperature, the reaction mixture was hydrolyzed with water and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate. After filtration and concentration of the filtrate in vacuo, the residue was purified by column chromatography (silica gel, triethylamine: chloroform 1:10). The product VIII (421 mg) was obtained as a mixture of the E and Z isomers. Both isomers were separated by fractional crystallization. HRMS (ESI) m / z: calculated for C ₃₁ H ₃₄ FeNO ₂ : 508.1934; found: 508.1927 [M ⁺ ]. Single crystal data for (E) -VIII: C ₃₁ H ₃₃ Fe-NO _2, M = 507.43, triclinic T = 223 K, P1bar (no. 2), a = 10.7374 (2) Å, b = 11.4093 (2) Å, c = 12.3076 (4) Å, a = 66.036 (1) °, β = 83.189 (1) °, γ = 71.850 (2) °, V = 1309.18 (5) Å ³ , Z = 2, D _calculates 1.287 gcm ^-3 , μ = 6.04 cm ^-1 , [(sinθ) / λ] = 0.66 Å ^-1 , 12546 reflections measured, 6231 independent reflections, 320 refined parameters, goodness-of -fit = 1.020, R = 0.067, wR ₂ = 0.163, largest difference peak / hole 0.87 / -0.65 e Å ^-3 .

Example 4:

Synthesis of Compound IX (mixture of E and Z isomers)

Analogously to the synthesis instructions from Example 3, compound VII (936.2 mg, 2.15 mmol), sodium ethanolate (4.3 mmol) and 3-chloropropyldimethylamine hydrochloride (330.1 mg, 2.3 mmol) were reacted together. After work-up, the product IX (316 mg) was obtained as a mixture of the E and Z isomers. Both isomers were separated by fractional crystallization. HRMS (ESI) m / z: calculated for C ₃₂ H ₃₆ FeNO ₂ : 522.2090; found: 522,2094 [M ⁺ ].
(Z) -IX: ¹ H NMR (DMSO, 600 MHz, 298 K): δ = 9.38 (br, 1H, OH), 6.95, 6.73 (each m, 2H, C ₆ H ₄ ^B ), 6.82, 6.59 (each m, 2H, C ₆ H ₄ ^A ), 4.35, 4.07, 3.85, 3.60 (each m, 1H, C ₅ H ₄ ^A ), 4.34, 4.25, 4.01, 3.82 (each m, 1H, C ₅ H ₄ ^B), 3.85, 1.75, 2.28 (each m, 2H, ^A O- (CH _{2) 3} -N), 2.62, 2:47 (each m, 1H, CH _2), 2:51 (m, 1H, CH), 2:09 ( s, 6H, N (CH _{3) 2),} 1:09 (d, 3H, CH _3). ¹³ C-NMR (DMSO, 150 MHz, 298 K): δ = 156.6 (i), 135.5 (i), 131.2, 113.1 (C ₆ H ₄ ^A ), 156.0 (i), 133.9 (i), 130.1, 114.8 (C ₆ H ₄ ^B ), 139.8, 132.7 (C = C), 85.6 (i), 70.4, 69.0, 68.5, 68.0 (C ₅ H ₄ ^A ), 91.6 (i), 70.8, 68.9, 66.8, 66.3 ( C ₅ H ₄ ^B), 65.4, 26.9, 55.6 ^(A O- (CH _{2) 3} -N), 49.1 _(CH2), 45.1 (N (CH _{3) 2),} 34.7 (CH), 22.0 (CH ₃ ).
(E) -IX: ¹ H-NMR (DMSO, 600 MHz, 298 K): δ = 9.19 (br, 1H, OH), 7.05, 6.90 (each m, 2H, C ₆ H ₄ ^B ), 6.72, 6.43 (each m, 2H, C ₆ H ₄ ^A ), 4.35, 4.07, 3.86, 3.61 (each m, 1H, C ₅ H ₄ ^A ), 4.34, 4.25, 4.01, 3.82 (each m, 1H, C ₅ H ₄ ^B), 3.98, 1.84, 2:36 (each m, 2H, ^A O- (CH _{2) 3} -N), 2.61, 2:44 (each m, 1H, CH _2), 2:51 (m, 1H, CH), 2.15 ( s, 6H, N (CH _{3) 2)} 1.08 (d, 3H, CH _3). ¹³ C-NMR (DMSO, 150 MHz, 298 K): δ = 157.2 (i), 135.6 (i), 130.1, 113.9 (C ₆ H ₄ ^A ), 155.4 (i), 133.9 (i), 131.2, 114.1 (C ₆ H ₄ ^B ), 139.8, 132.6 (C = C), 85.1 (i), 70.4, 69.0, 68.5, 68.0 (C ₅ H ₄ ^A ), 91.6 (i), 70.8, 69.0, 66.8, 66.0 ( C ₅ H ₄ ^B), 65.6, 26.9, 55.7 ^(A O- (CH _{2) 3} -N), 49.0 _(CH2), 45.2 (N (CH _{3) 2),} 34.7 (CH), 22.1 (CH ₃ ).

Example 5:

Synthesis of Compound X by Reductive Coupling

Analogously to the synthesis instructions from Example 3, 1,1 '- (propane-1-3-diyl-1-one) ferrocene, which was prepared according to the procedure in TD Turbitt, WE Watts, J. Organomet. Chem. 1972, 46, 109 available is used. After reaction of titanium tetrachloride (1.65 mL) and zinc powder (1.9259 g, 23.5 mmol) in 20 mL THF, this [3] ferrocenonephanone (1.1825 g, 4.9 mmol) and 4.4 ' Dihydroxybenzophenone (0.9371 g, 4.3 mmol). After work-up, the compound X (784 mg, 43%) was obtained as a yellow crystalline solid.

Example 6:

Synthesis of compound XI (mixture of E and Z isomers)

Analogously to the synthesis instructions from Example 3, the compound X obtainable from Example 5 (594.3 mg, 1.4 mmol), sodium ethanolate (2.8 mmol) and 2-chloroethyl-dimethylamine hydrochloride (202.9 mg, 4.1 mmol) used. After work-up, the compound XI (218 mg) was obtained as product as a mixture of the E and Z isomers. The isomers were separated by fractional crystallization.
(Z) -XI: ¹ H NMR (DMSO, 400 MHz, 298 K): δ = 9.42 (broad, 1H, OH), 6.96, 6.83, 6.73, 6.62 (m, 2H, 2 ×, respectively) C ₆ H ₄ ), 4.26, 3.98, 3.95, 3.92 (each m, 2H, 2 × C ₅ H ₄ ), 3.90, 2.53 (each m, 2H, O- (CH ₂ ) ₃ -N, 2.62, 2.28 (m, 2H, CH ₂ CH ₂ ), 2.15 (s, 6H, N (CH ₃ ) ₂ ) Single-crystal data for (Z) -XI: C ₃₀ H ₃₁ FeNO ₂ · CH ₂ Cl ₂ , M = 578 , 33, T = 223 K, orthorhombic, Pbca (no. 61), a = 19.8635 (5) Å, b = 11.3190 (3) Å, c = 26.7053 (10) Å, V = 6004 , 3 (3) Å ³ , D _calculates 1.20 gcm ^-3 , μ = 7.07 cm ^-1 , [(sinθ) / λ] = 0.60 Å ^-1 , 32152 measured reflections, 5285 independent reflections, 337 refined parameters, goodness-of-fit = 1.045, R = 0.073, wR ₂ = 0.199, largest difference peak / hole 0.46 / -0.60 e Å ^-3 .

Example 7: Cytotoxic action against mouse fibroblasts

Compounds VIII and IX, each as a racemate and mixture of (E) and (Z) isomers, were tested for their cytotoxic activity against L929 mouse fibroblasts. The assay used was the MTT assay. The inhibition concentration IC ₅₀ was 400 ng / mL for compound VIII (corresponding to 0.79 μM) and for compound IX to 250 ng / mL (corresponding to 0.48 μM). Compared with cisplatin, whose IC _{50 is} about 2 μM in this assay, the compounds have a potent antiproliferative effect.

Example 8: Cytotoxic action against breast cancer cells

Compounds VIII and IX, each as a racemate and mixture of the (E) and (Z) isomers, were tested for their cytotoxic activity against estrogen-dependent MCF-7 breast cancer cells. The assay used was the MTT test. Results of the assay are in the 1 played. The inhibitory concentration IC ₅₀ was 15 ng / mL for compound VIII (corresponding to 26.9 nM) and for compound IX was 9 ng / mL (corresponding to 17.3 nM). One could observe a biphasic inhibition curve. The first phase goes up to a plateau at 40% and has an IC ₅₀ of 5 ng / mL. The second phase starts at concentrations above 400 ng / mL and then reaches complete inhibition. Without being bound by theory, it is believed that the inhibition in the first phase is specific for the breast cancer cells and that in the second phase corresponds to the inhibition also observed in the mouse fibroblasts of Example 7. Compared with HO tamoxifen, whose IC _{50 is} about 3 μg / mL (7.7 μM) against MCF-7 cells, the compounds have a potent antiproliferative effect.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• WO 1996/11935 A1 [0002]
• WO 2006/005856 A1 [0002]
• - DE 3404443 A1 [0004]

Cited non-patent literature

• - L. Tebben, M. Neumann, G. Kehr, R. Fröhlich, G. Erker, S. Losi, P. Zanello, Dalton Transactions 2006, 1715-1720 [0022]
• - L. Tebben, M. Neumann, G. Kehr, R. Frohlich, G. Erker, S. Losi, P. Zanello, Dalton Transactions 2006, 1715-1720 [0037]
• TD Turbitt, WE Watts, J. Organomet. Chem. 1972, 46, 109 [0042]

Claims (20)

Metallocene compound of the formula I: where:

M is Fe, Ru, Os, Co, Rh or Ir; R1 a, b, c, d are independently H, alkyl, halogen, OH, NH _2, SH, CH ₂ (CH _{2) 0-20} OH, CH ₂ (CH _{2) 0-20} NH _2, CH ₂ ( CH ₂ ) _0-20 SH, C (O) OH, P (alkyl) _r H _3-r , or P (aryl) SH _3-s ; or R1 a, b, c, d form aromatic, olefinic and / or aliphatic carbo- or heterocycles; R 2a, b, c, d are independently H, alkyl, halogen, OH, NH _2, SH, CH ₂ (CH _{2) 0-20} OH, CH ₂ (CH _{2) 0-20} NH _2, CH ₂ (CH ₂ ) _0-20 SH, C (O) OH, P (alkyl) _r H3 _-r or P (aryl) SH3 _-s ; or R2a, b, c, d form aromatic, olefinic and / or aliphatic carbo- or heterocycles; X, Y and Z are independent of each other:

where R3, R4 together are an O atom, an imino group or an alkyl-substituted imino group; or they are independently H, halogen, pseudohalogen, OH, NH ₂ , SH, alkyl, alkoxy, alkylamino, dialkylamino, alkylthio, aryl, arylalkyl, aryloxy, arylalkyloxy, heteroaryl or heteroarylalkyl; R5, R6 together are an O atom, an imino group or an alkyl-substituted imino group; or they are independently H, halogen, pseudohalogen, OH, NH ₂ , SH, alkyl, alkoxy, alkylamino, dialkylamino, alkylthio, aryl, arylalkyl, aryloxy, arylalkyloxy, heteroaryl or heteroarylalkyl; R7, R8 are independently cycloalkyl, cycloalkenyl, aryl, arylalkyl, aryloxy, arylalkyloxy, heteroaryl or heteroarylalkyl; wherein R7 and R8 may be independently substituted in single or multiple ways; n, m and o are independently 0, 1, 2 or 3, but not all 0 at the same time; and wherein furthermore in the metallocene compound of the formula (I) at least one of the groups X, Y or Z represents

stands. Metallocene compound according to claim 1, represented by formula II:

wherein M, the substituents R1a, b, c, d, the substituents R2a, b, c, d and the substituents R3, R4, R5, R6, R7 and R8 have the same meaning as defined in claim 1. Metallocene compound according to claim 1, represented by formula III:

wherein M, the substituents R1a, b, c, d, the substituents R2a, b, c, d and the substituents R3, R4, R5, R6, R7 and R8 have the same meaning as defined in claim 1; and with the further proviso: R9, R10 are independently: a) H, halogen, pseudohalogen, OH, NH _2, SH, alkyl, alkoxy, alkylamino, dialkylamino, alkylthio, aryl, arylalkyl, aryloxy or arylalkyloxy; or: b) the following group: -X1- (CH ₂ ) _p -CH ₂ -N (R 11) (R 12) where X 1 is O, NH or S where p can be 1, 2, 3 or 4 where R 11 and R12 are independently H, C ₁ to C ₄ alkyl, -CH ₂ C = CH or -CH ₂ CH ₂ OH or R 11 and R 12 form an N-containing five- or six-membered ring; or: c) the following group: -Y1- (CH ₂ ) _q CH ₂ -O-R 13 where Y 1 is O, NH or S where q can be 1, 2, 3 or 4 where R 13 is H, -CH ₂ CH _{2 can be} OH or -CH ₂ CH ₂ Cl; or: d) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or carboxymethoxy. Metallocene compound according to claim 2 or 3, wherein: M is Fe; R1 a, b, c, d is H; R2a, b, c, d is H; R3 is H; R4 is methyl; R5 is H; R6 is H. A metallocene compound according to claim 2 or 3, wherein M is Fe; R1a, b, c, d is H; R2a, b, c is H; R2d is Br, OH, SH, NH _2, CH ₂ OH, CH ₂ NH ₂ or C (O) OH; R3 is H; R4 is methyl; R5 is H; R6 is H. Metallocene compound according to claim 5 wherein R2d is ortho to the cyclopentadienyl ligands bridging subgroup of the compound is arranged. Metallocene compound according to one of claims 4 to 6, wherein the absolute configuration R4 bearing carbon (R) is and wherein the compound is present in an enantiomeric excess of ≥ 90%. Metallocene compound according to one Claims 4 to 6, wherein the absolute configuration of the R4 carrying carbon (S) is wherein the compound is present in an enantiomeric excess of ≥ 90%. Process for the preparation of metallocene compounds according to claim 1, comprising the steps: a) Providing a metallocene compound of the formula I, wherein at least one of X, V or Z represents a carbonyl group; b) Addition of a carbonyl compound of the formula O =C (R 7) (R 8), wherein R7 and R8 have the same meaning as defined in claim 1; c) Add titanium tetrachloride and reducing agent. A process according to claim 9, wherein the carbonyl compound in step b) is constructed according to the following formula:

and wherein R9 and R10 have the same meaning as defined in claim 3. A method according to claim 9 or 10, wherein the metallocene compound in step a) according to the is general formula III and further applies: M is Fe; R1 a, b, c, d is H; R2a, b, c, d is H; R3 is H; R4 is methyl; R5 is H; R6 is H. A process according to claim 9 or 10, wherein the metallocene compound in step a) is constructed according to general formula III and furthermore: M is Fe; R1 a, b, c, d is H; R2a, b, c is H; R 2d is Br, OH, SH, NH ₂ , CH ₂ OH, CH ₂ NH ₂ or C (O) OH or one of the aforementioned substituents which is provided with a protecting group; R3 is H; R4 is methyl; R5 is H; R6 is H. A pharmaceutical composition comprising a metallocene compound according to one of claims 1 to 8. Medicines selected for the treatment of diseases from the group comprising cancer, mania, gynecomastia and / or female infertility, comprising a metallocene compound according to one of claims 1 to 8. Medicines for the prevention of breast cancer, comprising a metallocene compound according to one of claims 1 to 8. A cytostatic preparation comprising a metallocene compound according to one of claims 1 to 8. Estrogen receptor modulating composition, comprising a metallocene compound according to one of claims 1 to 8. Metallocene compound according to one of claims 1 to 8 for use as a medicament. Metallocene compound according to one of claims 1 to 8 for use as a medicament for Treatment of diseases selected from the group comprising Cancer, mania, gynecomastia and / or female infertility. Metallocene compound according to one of claims 1 to 8 for use as a medicament for Prevention of breast cancer.