HK1187330A

HK1187330A - Substituted diphenyl derivatives

Info

Publication number: HK1187330A
Application number: HK14100428.6A
Authority: HK
Inventors: 亨氏．福斯特
Original assignee: 创新治疗有限公司
Priority date: 2011-03-16
Filing date: 2012-03-12
Publication date: 2014-04-04

Description

Substituted biphenyl derivatives

Technical Field

The present invention relates to substituted biphenyl derivatives comprising at least (i) a dialkyltriazenyl group, (ii) at least one sulfonyloxy (sulfoxy) group and/or at least one sulfamoyloxy (sulfoxy) group per molecule, their salts, solvates and solvates of these salts. The invention also relates to processes for the preparation of these compounds and their use as medicaments.

For the purposes of the present invention, biphenyl derivatives are benzene rings connected by single bonds or bridging bonds.

Background

Triazene-substituted biphenyl derivatives are known. Thus, DE1793115a1, DE2147781a1 and WO2004/106358a1 disclose biphenyl derivatives substituted in particular by triazene radicals and, for example, by sulfonic acid or oxycarboxylic acid radicals.

The cell growth inhibitory effect of triazene derivatives has been examined extensively over the past few decades. These traditional triazene cytostatics belong to the group of alkylated compounds and have never found wide clinical application due to their serious side effects and toxicity. One exception is Dacarbazine (DTIC), which is a prodrug of monomethyltriazeneimidazole carboxamide (MTIC) and is used primarily against Hodgkin's lymphoma and soft tissue sarcoma (Cancer Treatment reports60,205-211 (1976)). Because of the mild hypersensitivity and especially the side effects of dacarbazine, of which leukopenia and thrombocytopenia are particularly important, a large number of arylalkyl triazenes have been investigated in order to synthesize more efficient and well tolerated triazenes (Cancer Treatment Reports60:125-134(1976); J.Med.chem.23,1052-1024 (1980)). Despite these efforts, to date, only dacarbazine and temozolomide have been the remaining triazenes that are capable of treating malignant gliomas in clinical applications, despite their non-negligible side effects, like myelosuppression, neurotoxicity and hepatotoxicity, vomiting, hair loss and skin rashes.

A first attempt to overcome the tolerance problem of selected triazenes for selective use in breast cancer is described in DE1793115a1 and DE2147781a 1.

A second attempt to overcome the serious side effects of selected triazenes is described in WO2004/106358A 1. Some serious side effects of triazenes are known to be reduced by the introduction of oxycarboxylic acid groups. However, they are not suitable for long-term use due to undesirable side effects on the kidney.

It is an object of the present invention to provide a pesticidally (oncocidal) active compound which is suitable for long-term treatment, has virtually no toxic side effects and at the same time has an increased efficacy.

We have found that novel biphenyl derivatives contain (i) at least one dialkyltriazene group and (ii) at least one sulfonyloxy group and/or at least one sulfamoyloxy group per molecule, and their salts, solvates and solvates of these salts.

Compared with similar known active compounds (WO 2004/106358a1, DE1793115a1 and DE2147781a 1), the novel biphenyl derivatives according to the invention surprisingly have a greatly improved antitumor effect on tumors of important target organs (e.g. colon, lung, liver, pancreas, kidney), in particular as selective killers (oncocids) against tumors of skin, breast, prostate and testis and organ-dependent target organs. They have virtually no toxic side effects compared with analogous known active compounds and are therefore suitable for long-term therapy.

They are medically useful, either as monotherapy or in combination with other anti-cancer agents, tumor-specific antibodies or antibodies linked to the compounds according to the invention by linkers, due to their better tolerability and higher efficacy.

Inside the cell, they release a principle of reproduction inhibition/killing, which can stop the uncontrolled replicative metabolism of the tumor cells and even lead to the degeneration of the tumor.

The novel biphenyl derivatives are useful as active compounds in medicaments for humans and animals.

Biphenyltriazenes having sulfonic acid and sulfonic acid amide groups in the molecule have not been disclosed and their particular utility has not been pointed out.

For the purposes of the present invention, preference is given to substituted biphenyl derivatives of the formula, and their salts, free acids, solvates and solvates of these salts and solvates of these free acids.

Wherein

X is a direct C-C bond between rings a and b, CH₂、CHOH、CO、S、SO、SO₂、-N=N-、-CR⁷=CR⁸Or X is a divalent radical-C (O) -C = CH-O-which is adjacent to the two rings a on which it is locatedTogether form a pyrone ring, and ring b is located on the C atom of the radical,

R³、R⁶are independent of each other and are each hydrogen, hydroxy, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, C₁-C₄alkyl-S-, C₁-C₄-alkyl-SO-, C₁-C₄-alkyl-SO₂-, where alkyl is preferably methyl or ethyl, halogen (F, Cl, Br, I), nitro, cyano or-OSO₂The radical Y is a radical of the formula,

R⁴、R⁵are independent of each other and are each-N = N-N (R)²)₂Radical or-OSO₂The radical Y is a radical of the formula,

R⁷is a hydrogen, methyl, ethyl or phenyl radical, formed from the radical R⁹、R¹⁰Is substituted and is directly connected to R⁷-a support for carbon atoms,

R⁸is hydrogen, ethyl, CN, NO₂、-CH₂CH₂Halogen (F, Cl, Br, I) or CH₂CH₂OH，

R⁹、R¹⁰Are independent of each other and are each hydrogen, hydroxy, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, where alkyl is preferably methyl or ethyl, halogen (F, Cl, Br, I), nitro, cyano, -N = N-N (R)²)₂Radical or-OSO₂The radical Y is a radical of the formula,

y is OH or N (R)¹)₂，

R¹Is hydrogen, methyl or ethyl, and

R²is a methyl group or an ethyl group,

wherein one or two-N = N-N (R) per whole molecule (1)²)₂Radicals and one or two-OSO₂With the Y radical in any ring of the aromatic ringOn the carbon atom, the carbon atom is,

we have also developed processes for the preparation of novel biphenyl derivatives comprising per molecule (i) at least one dialkyltriazenyl group and (ii) at least one sulfonyloxy group and/or at least one sulfamoyloxy group, characterized by aminophenyl derivatives of formula

Wherein

X is a direct C-C bond, CH₂、CHOH、CO、S、SO、SO₂、-N=N-、-CR⁷=CR⁸Or X is a divalent-C (O) -C = CH-O-radical which, together with the two adjacent carbon atoms of ring a, forms a pyrone ring, while ring b is located on the C atom of the radical,

R⁴、R⁵are independent of one another and are each-NH₂Radical or-OSO₂The radical Y is a radical of the formula,

R⁸is hydrogen, ethyl, CN, NO₂、-CH₂CH₂Halogen (F, Cl, B)r, I) or CH₂CH₂OH，

R⁹、R¹⁰Are each, independently of one another, hydrogen, hydroxy, C₁-C₄Alkyl, preferably methyl or ethyl, C₁-C₄Alkoxy, preferably methoxy or ethoxy, halogen (F, Cl, Br, I), nitro, cyano, -NH₂Radical or-OSO₂The radical Y is a radical of the formula,

y is OH or N (R)¹)₂And is and

R¹is hydrogen, methyl or ethyl, and is,

wherein, per whole molecule (2), one or two NH groups₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring,

they are diazotized by diazotizing agents in the presence of strong acids at low temperatures, preferably at from 0 ℃ to 8 ℃, particularly preferably from 0 ℃ to 5 ℃ and in particular from 0 ℃ to 2 ℃, in aqueous acid solutions to form diazonium salts of the formula

Wherein

X is a direct C-C bond, CH₂、CHOH、CO、S、SO、SO₂、-N=N-、-CR⁷=CR⁸-or X is a divalent-C (O) -C = CH-O-radical which, together with the two adjacent carbon atoms of ring a on which it is located, forms a pyrone ring, while ring b is located on the C atom of the radical,

R⁴、R⁵are independent of one another and are each-N₂ ⁺AN^-Radical or-OSO₂The radical Y is a radical of the formula,

R⁹、R¹⁰Are each, independently of one another, hydrogen, hydroxy, C₁-C₄-alkyl radical, C₁-C₄Alkoxy, where alkyl is preferably methyl or ethyl, halogen (F, Cl, Br, I), nitro, cyano, -N₂ ⁺AN^-Radical or-OSO₂The radical Y is a radical of the formula,

An^-is a halogen anion (Cl)^-，Br^-) Or 1/2 Sulfate (SO)₄ ^2-) An anion of the compound (I) is selected,

y is OH or N: (¹R)₂And is and

R¹is hydrogen, methyl or ethyl, and is,

wherein, per whole molecule (3), one or two diazo groups and one or two-OSO groups₂The Y group is located on any ring carbon atom of the aromatic ring,

and the diazonium salt (3) obtained is subsequently reacted with a dialkylamine of the formula

H N(R²)₂ (4)

Wherein R is₂Is a methyl group or an ethyl group,

followed by optionally preparing salts from the compounds obtained and then optionally liberating hydroxyl and/or acidic groups from these salts.

Suitable diluents for the diazotisation are all polar solvents which are inert under the reaction conditions, for example alcohols such as methanol, ethanol, and also dimethylformamide and dimethyl sulphoxide, and in particular water or mixtures of these solvents.

As the strong acid in the diazotization reaction, a hydrohalic acid, preferably hydrochloric acid, or sulfuric acid, can be used.

As the diazotizing agent, potassium nitrite and sodium nitrite are preferable.

As acid acceptors in the coupling reaction, all customary acidic binders can be used. Preferably sodium carbonate and potassium carbonate are included.

For the purposes of the present invention, salts are preferably physiologically acceptable salts. They include conventional base salts such as alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), and salts derived from ammonia or organic C₁-C₁₆Ammonium salts of amines (such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, arginine, lysine, ethylenediamine and methylpiperidine).

For the purposes of the present invention, solvates are in the form of compounds which form complexes by coordination of solvent molecules in the solid or liquid state. Hydrates are a particular form of solvates in which water is coordinated.

Alternatively, the biphenyl derivatives of the present invention may also be prepared by first introducing a triazene group and subsequently introducing only a sulfonyloxy group and/or a sulfamoyloxy group. For this purpose, the triazenylphenols of the formula may subsequently be sulfated or sulfonylaminated

Wherein

X is a direct C-C bond, CH₂、CHOH、CO、S、SO、SO₂、-N=N-、-CR₇=CR⁸-or X is a divalent-C (O) -C = CH-O-radical which, together with the two adjacent carbon atoms of ring a on which it is located, forms a pyrone ring, while ring b is located on the C atom of the radical,

R³、R⁶are independent of each other and are each hydrogen, hydroxy, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, C₁-C₄alkyl-S-, C₁-C₄-alkyl-SO-, C₁-C₄-alkyl-SO₂-where alkyl is preferably methyl or ethyl, halogen (F, Cl, Br, I), nitro, cyano or an OH group,

R⁴、R⁵are independent of each other and are each-N = N-N (R)²)₂A group or an OH group, or a group,

R⁹、R¹⁰Are independent of each other and are each hydrogen, hydroxy, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, where alkyl is preferably methyl or ethyl, halogen (F, Cl, Br, I), nitro, cyano, -N = N-N (R)²)₂A group or an OH group, or a group,

y is OH or N (R)¹)₂And is and

R¹is hydrogen, methyl or ethyl, and is,

wherein one or two-N = N-N (R) per whole molecule (2)²)₂The radicals and one or two OH groups are located on any ring carbon atom of the aromatic ring.

The biphenyl derivatives of the present invention are described in detail below according to the definition of X:

1. cis-and trans-diphenylethylenes of formula (5)

When X in the formula (1) is-CR⁷=CR⁸-when the compounds of the invention, and their salts, free acids, solvates and solvates of these salts and solvates of these free acids have the formula:

wherein

R⁷is a hydrogen, methyl, ethyl or phenyl radical, formed from the radical R⁹、R¹⁰Is substituted and is directedIs linked to R⁷-a support for carbon atoms,

y is OH or N (R)¹)₂，

R¹Is hydrogen, methyl or ethyl, and

R²is a methyl group or an ethyl group,

wherein, in each whole molecule (5), one or two-N = N-N (R)²)₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

Preference is given to compounds of the formula (5) and their salts, free acids, solvates and solvates of these salts and solvates of these free acids, where

R⁴、R⁵In the 3 and 3' positions, respectively (CH)₃)₂N-N = N-group,

R³、R⁶is-OSO in the 4-and 4' -positions, respectively₂The radical Y is a radical of the formula,

R⁷、R⁸are each an ethyl group, an

Y is OH or NH₂，

Wherein one or two-N = N-N (CH) in each entire molecule (5)₃)₂Radicals and one or two-OSO₂Radical YThe radicals are located on any ring carbon atom of the aromatic ring.

Furthermore, preference is given to compounds of the general formula (5) and their salts, free acids, solvates and solvates of these salts and solvates of these free acids, in which,

R⁴、R⁵are independent of one another and are each hydrogen, (CH)₃)₂N-N = N-group or-OSO₂Y radical, R³、R⁶Independently of one another, are each hydrogen, fluorine, chlorine, hydroxyl, methyl, methoxy or-OSO₂The radical Y is a radical of the formula,

R⁷、R⁸are each hydrogen and

y is OH or NH₂，

Wherein one or two-N = N-N (CH) in each entire molecule (5)₃)₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

Particular preference is given to compounds of the formula (5) and their salts, free acids, solvates and solvates of these salts and solvates of these free acids, in which,

R³is hydrogen in the 4-position, hydroxy or-OSO₂The radical Y is a radical of the formula,

R⁴is-OSO in the 2 position₂The radical Y is a radical of the formula,

R⁵is in the 4' position (CH)₃)₂N-N = N-group,

R⁶is hydrogen or methyl in the 2' -position,

R⁷、R⁸are each hydrogen, and

y is OH or NH₂，

Wherein one or two-N = N-N (CH) per whole molecule (5)₃)₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

Diphenylethylene (5), which is particularly preferred for the purposes of the present invention, relates to the following compounds, as well as their salts, free acids, solvates and solvates of these salts and solvates of these free acids:

(Z + E)4- (3, 3-dimethyltriazenyl-1) -4 '-sodiosulfonyloxy-2' -sulfamoyloxydiphenylethylene

(Z + E)4- (3, 3-dimethyltriazenyl-1) -4 '-hydroxy-2' -sodiosulfonyloxydiphenylene

(Z and E)4- (Dimethyltriazinenyl-1) -2-methyl-4 '-hydroxy-2' -sodiosulfonyloxydiphenylethylene

3,3 '- [ bis- (3, 3-dimethyltriazenyl-1) ] -4, 4' - (disodium sulfonyloxy) -1, 2-diethyldiphenylethylene

Compound (5) can be prepared from an aromatic amine in a manner similar to compound (1),

wherein the content of the first and second substances,

R⁹、R¹⁰Are independent of each other and are each hydrogen, hydroxy, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, where alkyl is preferably methyl or ethyl, halogen (F, Cl, Br, I), nitro, cyano, -NH₂Radical or-OSO₂The radical Y is a radical of the formula,

y is OH or N (R)¹)₂，

R¹Is hydrogen, methyl or ethyl, and is,

wherein, per whole molecule (6), one or two-NH groups₂Radicals and one or two-OSO₂Position of Y groupOn any ring carbon atom of the aromatic ring.

For example, if 3,3 '-diamino-4, 4' -dipotassium sulfonyloxy-1, 2-diethyldiphenylethylene, potassium nitrite and dimethylamine are used as starting materials, the reaction process can be expressed by the following reaction scheme

The 3,3 ' -diamino-4, 4 ' -dipotassium sulfonyloxy-1, 2-diethyldiphenylethylene shown in reaction formula (7) can be prepared from known 3,3 ' -dinitrodiethyldiethylstilbestrol (Arch. pharm. (Weinheim)311,184-195 (1978)) which is first sulfated and then reduced to a diamine.

The aromatic amines (6) can be prepared in a known manner from the corresponding nitrosulfonyloxy or nitrosylsulfonyloxy aromatic compounds, for example by catalytic reduction of hydrogen on palladium on carbon in ethanol or on platinum oxide in methanol (chem. Berichte.72,839, [ (1939) ]) or using Raney nickel in THF (chem. Berichte.91,1905 (1958)).

The synthetic methods mentioned herein can also be used to synthesize the aromatic amines used in sections 2-4.

Examples of converting aromatic amines into diazonium salts and combining them with dialkylamines to form (3, 3-dialkyltriazen-1) -aryls are fully disclosed in DE1793115a1, DE2147781a1, GB1371969 and WO 2004/106358.

The preparation of new starting materials with sulfonyloxy or sulfamoyloxy groups can be carried out by reaction of the corresponding aromatic phenols with alkali metal hydrogen sulfates (Na, K) as disclosed in EP0722455a1/US5,703,261, optionally alternatively with chlorosulfonic acid/pyridine as described in WO02/134715a1, or with sulfamoyl chloride in dimethylacetamide as described in WO2008/003378 and US2003/0225051 page 44.

The syntheses mentioned here can also be used in reactions according to sections 2-4 for converting phenolic hydroxyl groups into starting materials or end products according to the invention containing sulfonyloxy or sulfamoyloxy groups.

The synthesis of compounds according to the present invention can be illustrated by reaction schemes 8 and 9:

2. triphenylethylene derivatives of formula (10)

In the formula (1), when

X is-CR⁷=CR⁸-, and R⁷Is represented by R⁹、R¹⁰Substituted phenyl radical, and is directly linked to R⁷When it is supporting a carbon atom,

these compounds, as well as their salts, free acids, solvates and solvates of these salts and solvates of these free acids have the formula

Wherein

y is OH or N (R)¹)₂，

R¹Is hydrogen, methyl or ethyl, and

R²is a methyl group or an ethyl group,

wherein one or two of-N = N-N (R) per whole molecule (10)²)₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

Preference is given to compounds of the formula (10), and also to their salts, free acids, solvates and solvates of these salts and solvates of these free acids, where

R³Is hydrogen, hydroxy, methoxy, -OSO in the 3 or 4 position₂Y radicals, halogen (F, Cl, Br, I), CHO or CH₂OH，

R⁴Is hydrogen in position 3 or-N = N-N (CH)₃)₂The radical(s) is (are),

R⁵is hydrogen in the 3 'or 4' position or-N = N-N (CH)₃)₂The radical(s) is (are),

R⁶is hydrogen, hydroxy, methoxy or-OSO in the 3 'or 4' position₂The radical Y is a radical of the formula,

R⁸is hydrogen, ethyl, CH₂CH₂Halogen (F, Cl) or CH₂CH₂OH，

R⁹、R¹⁰Independently of one another, are hydroxyl, methoxy or-OSO in the 3 'or 4' position, respectively₂Y is a radical of

Y is OH or NH₂，

Particular preference is given to compounds of the formula 10, and their salts, free acids, solvates and solvates of these salts and solvates of these free acids, where

R³Is hydrogen, hydroxy, methoxy or-OSO in the 4-position₂The radical Y is a radical of the formula,

R⁴is hydrogen in position 3 or-N = N-N (CH)₃)₂The radical(s) is (are),

R⁶is hydrogen, hydroxy, methoxy or-OSO in the 4' position₂The radical Y is a radical of the formula,

R⁸is hydrogen or an ethyl group, and the compound is,

Y is OH or NH₂，

Wherein one or two-N = N-N (CH) per whole molecule (10)₃)₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

As particularly preferred triphenylethylene derivatives (10), the following compounds are mentioned, as well as their salts, free acids, solvates and solvates of these salts and solvates of these free acids:

1,1- [ bis-3, 4 ' ' - (disodium sulfonyloxyphenyl) ] -2-ethyl-2- [4 ' - (3, 3-dimethyltriazenyl-1) -phenyl ] ethylene

1- (4-hydroxyphenyl) -1- (4 ' ' - (sodiosulfonyloxyphenyl) -2-ethyl-2- [4 ' - (3, 3-dimethyltriazenyl-1) -phenyl ] ethylene

1- [3- (3, 3-Dimethyltriazino-1) -4-methoxyphenyl ] -1- (4 ' ' -sodiosulfonyloxyphenyl) -2-ethyl-2- (4 ' -hydroxyphenyl) ethene

1,1- [ bis-4- (sodiosulfonyloxyphenyl) ] -2-ethyl-2- [ 4' - (3, 3-dimethyltriazenyl-1) -phenyl ] ethylene

Compound (10) can be prepared from the corresponding aromatic amine in a similar manner to Compound (1),

wherein the content of the first and second substances,

R⁸is hydrogen, ethyl, CN, NO₂、-CH₂CH₂-, halogen (F, Cl, Br, I) or CH₂CH₂OH，

R⁹、R¹⁰Are independent of each other and are each hydrogen, hydroxy, C₁-C_4-Alkyl radical, C₁-C₄Alkoxy, where alkyl is preferably methyl or ethyl, halogen (F, Cl, Br, I), nitro, cyano, -NH₂Radical or-OSO₂The radical Y is a radical of the formula,

y is OH or N (R)¹)₂And is and

r1 is hydrogen, methyl or ethyl,

wherein each whole molecule: (11) In (2), one or two-NH₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

For example, if 1- (4-aminophenyl) -1- (4 '' -sodiosulfonyloxyphenyl) -2-ethyl-2-phenylethene, sodium nitrite and dimethylamine are used as starting materials, the course of the reaction can be expressed by the following reaction scheme

Here, the diazonium salt is first prepared and immediately reacted with dimethylamine to form 1- (4- (3, 3-dimethyltriazenyl-1-phenyl) -1- (4 '' -sodiosulfonyloxyphenyl) -2-ethyl-2-phenylethene.

The aromatic amines (11) can be prepared from the corresponding nitrosylsulfonyloxy aromatic compounds or nitrosylsulfonyloxy aromatic compounds by customary known methods, for example by catalytic reduction of hydrogen on palladium on carbon in ethanol or using Ra-Ni in THF.

The triphenylethylene derivative of formula (10) can be prepared by the method shown in reaction scheme (13). Here, the synthesis is carried out according to known methods, for example the Wittig reaction, reduction of the nitro group by Raney nickel/hydrazine, cleavage of the ether bond, preparation of the triazenylphenol and its reaction with alkali metal hydrogen sulfate or sulfamoyl chloride. In addition to the alkali metal hydrogen sulfate in DMF, chlorosulfonic acid in pyridine is also possible.

3. Isoflavones of formula (14)

In the formula (1), when

X is a divalent-C (O) -C = CH-O-radical, forming a pyrone ring together with two adjacent carbon atoms of the ring a, and the ring b is located on the C atom of the radical, the formula (1) being changed to the formula

Wherein

y is OH or N (R)¹)₂，

R¹Is hydrogen, methyl or ethyl, and

R²is a methyl group or an ethyl group,

wherein one or two of-N = N-N (R) per whole molecule (14)²)₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring,

and their salts, free acids, solvates and solvates of these salts and solvates of these free acids.

Preference is given to compounds of the formula (14), and also to their salts, free acids, solvates and solvates of these salts and solvates of these free acids, where

R³、R⁶Independently of one another, are each hydroxy, methoxy or-OSO₂The radical Y is a radical of the formula,

R⁴、R⁵are each, independently of one another, hydrogen, hydroxy, methoxy or-N = N-N (CH)₃)₂A group of

Y is OH or NH₂，

Wherein one or two-N = N-N (CH) per whole molecule (14)₃)₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

Particular preference is given to compounds of the formula (14), and also their salts, free acids, solvates and solvates of these salts and solvates of these free acids, where

R³Is hydroxy, methoxy or-OSO in the 5-or 7-position₂The radical Y is a radical of the formula,

R⁴is hydrogen in position 6 or-N = N-N (CH)₃)₂The radical(s) is (are),

R⁵is hydroxy, methoxy or-OSO in the 4' position₂The radical Y is a radical of the formula,

R⁶is-N = N-N (CH) at the 2 'or 3' position₃)₂A group of

Y is OH or NH₂，

Particularly preferred isoflavones (14) are the following compounds, as well as their salts, free acids, solvates and solvates of these salts and solvates of these free acids:

7-hydroxy-3- [3 '- (3, 3-dimethyltriazenyl-1) -4' -sodiosulfonyloxy ] isoflavones

6- (3, 3-Dimethyltriazinenyl-1) -7-methoxy-3- (4' -sodiosulfonyloxy) isoflavone

7-methoxy-3 '- (3, 3-dimethyltriazenyl-1) -4' -sodiosulfonyloxy-isoflavones

7-sodiosulfonyloxy-2 '- (3, 3-dimethyltriazenyl-1) -4' -sulfamoyloxyisoflavone

The isoflavones (3) according to the present invention can be prepared in a similar manner to the compounds (1) from the corresponding aromatic amines

Wherein

y is OH or N (R)¹)₂And is and

R¹is hydrogen, methyl or ethyl, and is,

wherein, per whole molecule (15), one or two-NH groups₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

For example, if 6-amino-7, 4' -dipotassium sulfooxyisoflavone, sodium nitrite and dimethylamine are used as raw materials, the reaction process can be expressed by the following reaction scheme.

Here, the diazonium salt is first prepared and immediately reacted with dimethylamine to form the 7, 4' -dipotassium sulfonyloxy-6- (3, 3-dimethyltriazenyl-1) -isoflavone according to the invention.

Previously unknown aromatic amines (15) can be prepared from the corresponding nitrosulfonyloxy aromatic ring or nitrosylsulfonyloxy aromatic compound by methods known to those skilled in the art, for example by catalytic reduction of Ra-Ni with hydrogen on palladium on carbon in ethanol or in THF.

Nitroisoflavones of this type, which are used as starting materials in reaction scheme (17) below, are known and can be prepared by known methods (z. kristallogr. ncss 222,293-294 (2007)).

The preparation of new starting materials with sulfonyloxy or sulfamoyloxy groups can be carried out by reaction of the corresponding aromatic phenols with chlorosulfonic acid in pyridine or with alkali metal hydrogen sulfate in DMF or with sulfamoyl chloride in dimethylacetamide. The individual reaction steps are illustrated in reaction scheme (17):

4. biphenyl derivatives of formula (18) unbridged or bridged by an atomic or diatomic group:

according to the invention, the formula (1), and also their salts, free acids, solvates and solvates of these salts and solvates of these free acids, can also be in the form of the formula

Wherein

X is a direct C-C bond, CH₂、CHOH、CO、S、SO、SO₂or-N = N-,

y is OH or N (R)¹)₂，

R¹Is hydrogen, methyl or ethyl, and

R²is a methyl group or an ethyl group,

wherein one or two-N = N-N (R) per whole molecule (18)²)₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

Preference is given to compounds of the formula (18), and also to their salts, free acids, solvates and solvates of these salts and solvates of these free acids, where

X is CH₂CO, SO or SO₂，

R³、R⁶Are independent of one another and are each hydrogen, hydroxy, methyl, ethyl, methoxy, CH₃S-、CH₃SO-、CH₃SO₂-, halogen (F, Cl, Br, I), nitro, cyano or-OSO₂The radical Y is a radical of the formula,

R⁴、R⁵are independent of each other and are each-N = N-N (CH)₃)₂Radical or-OSO₂Y is a radical of

Y is OH or NH2,

wherein one or two-N = N-N (CH) per entire molecule (18)₃)₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

Particular preference is given to compounds of the formula (18), and also their salts, free acids, solvates and solvates of these salts and solvates of these free acids, where

X is CH₂CO, SO or SO₂，

R³、R⁶Independently of one another, are each hydrogen, hydroxy, methyl, fluorine, chlorine, bromine or-OSO₂The radical Y is a radical of the formula,

R⁴is a hydrogen atom, and is,

R⁵is (CH)₃)₂N-N = N group, and

y is OH or NH₂，

Wherein one or two-N = N-N (CH) per whole molecule (18)₃)₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

Very particular preference is given to compounds of the formula (18), and also their salts, free acids, solvates and solvates of these salts and solvates of these free acids, where

X is CH₂CO, SO or SO₂，

R³Is hydroxy, methyl, chlorine or bromine in the 2, 3 or 4 position,

R⁴is-OSO in the 2, 3 or 4 position₂The radical Y is a radical of the formula,

R⁵is in the 4' position (CH)₃)₂N-N = N group, and the group,

R⁶is hydrogen, methyl, fluorine, chlorine or bromine in the 2 ', 3 ' or 5 ' position, and

y is OH or NH₂，

The most preferred biphenyl derivatives bridged by diatomic or triatomic groups include the following compounds, as well as their salts, free acids, solvates and solvates of these salts and solvates of these free acids:

4- (3, 3-dimethyl triazenyl-1) -4 '-hydroxy-2' -sodium sulfonyloxy diphenyl ketone

4- (3, 3-dimethyl triazenyl-1) -4 '-hydroxy-3' -sodiosulfonyloxydiphenyl ketone

4- (3, 3-Dimethyltriazinenyl-1) -3 '-hydroxy-4' -sodiosulfonyloxydiphenyl methanone

4- (3, 3-Dimethyltriazinenyl-1) -4 '-sodiosulfonyloxy-3' -sulfamoyloxybenzophenone

4- (3, 3-Dimethyltriazinenyl-1) -4' -sodiosulfonyloxydiphenylmethane

2-chloro-4- (3, 3-dimethyltriazenyl-1) -4' -sodiosulfonyloxy (diphenyl sulfone)

It is particularly preferred that

4- (33-dimethyl triazenyl-1) -4' -sodium sulfonyl diphenyl ketone

The starting materials for the synthesis of compound (18) are known and can be prepared by the methods described in GB1371969, which synthesizes compound (18) by converting a hydroxytriazole derivative (19) of the type described herein into a final product such as (20), shown by way of example by reaction scheme (21).

Wherein Y has the meaning indicated in the formulation of formula (18).

The invention also provides biphenyl derivatives comprising (i) at least one dialkyltriazene group and (ii) at least one sulfonyloxy group and/or at least one sulfamoyloxy group per molecule, as well as their salts, solvates and solvates of these salts, their use as and in the manufacture of a medicament, preferably for the treatment of cancers of estrogen-dependent tissues, in particular of estrogen receptor negative and positive tumors of the sexual organs and melanoma.

In a preferred embodiment of the invention, the substituted biphenyl derivatives of the invention may be used in conjunction with monoclonal antibodies.

According to The invention, monoclonal antibodies with high selectivity for tumor cells are preferably used (Discovery Medicine, Alain Beck, "The next generation of Antibody-drug conjugates of Age", October16, 2010).

The substituted biphenyl derivatives of the present invention are linked to monoclonal antibodies and introduced into tumor cells.

In general, biphenyl derivatives and monoclonal antibodies of the invention are used in a ratio of 0.5:1 to 4:1 (biphenyl derivative: antibody).

Monoclonal antibodies are known per se. Monoclonal antibodies are immunologically active proteins that are produced by cell lines traced back to a single B-lymphocyte and are directed against a single epitope (e.g., a tumor cell).

The compounds of the invention can be used, for example, for the treatment of tumors of the following type: breast cancer, uterine cancer (endometrial cancer, uterine corpus cancer), cervical cancer, ovarian cancer (ovarian cancer), vaginal cancer, prostate cancer, skin cancer, melanoma (malignant melanoma).

The invention also provides the use of a compound of the invention in combination with at least one other chemotherapeutic agent for the treatment of cancer. Thus, the compounds of the present invention may also be used in combination with other chemotherapeutic agents known in the treatment of cancer or tumors, and/or in combination with agents administered with chemotherapeutic agents during chemotherapy.

Examples of such chemotherapeutic agents that can be used in Combination with other agents used in chemotherapy are disclosed, for example, in WO/2007/061978, the keyword of which is "Combination Therapy" (page 23, line 1 to page 30, line 18), or in US2007/135424a1 (paragraph 153 to paragraph 171).

For these methods of administration, the active compounds can be administered in the appropriate form of administration. For oral administration, administration forms which are known to release the active compound rapidly and/or in modified form, for example tablets (coated and uncoated, for example tablets with a coating resistant to gastric juice or film tablets), capsules, dragees, granules, microspheres, powders, emulsions, suspensions, solutions and aerosols, are suitable.

Parenteral administration can take place either avoiding the resorption step (intravenous, intra-arterial, intracardiac, intraspinal or intralumbar) or involving resorption (intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). In particular, administration forms suitable for parenteral administration are solutions, suspensions, emulsions, lyophilisates and injectable and leachable preparations in the form of sterile powders.

For other methods of administration, suitable forms are, for example, inhaled medicaments (including powder inhalers, sprays), nasal drops/solutions, sprays; tablets or capsules for lingual, sublingual or buccal administration, suppositories, otic and ophthalmic preparations, uterine caps, aqueous suspensions (lotions, mixtures to be shaken), lipophilic suspensions, ointments, creams, emulsions, pastes, powders or implants to be sprayed.

The active compounds can be converted in a known manner into the administration forms described. This can be effected using inert, non-toxic, pharmaceutically suitable auxiliaries. In particular, this includes supports (for example microcrystalline cellulose), solvents (for example liquid polyethylene glycol), emulsifiers (for example sodium lauryl sulfate), dispersants (for example polyvinylpyrrolidone), synthetic and natural biopolymers (for example albumin), stabilizers (for example antioxidants like ascorbic acid), colorants (for example inorganic pigments like iron oxide) or flavors and/or fragrances.

In general, in the case of parenteral administration, an amount of about 1 to 40mg/kg, preferably about 2.5 to 15mg/kg, is recommended depending on body weight, thereby obtaining effective results. In the case of oral administration, the amount is about 1 to 70mg/kg, preferably about 1 to 50mg/kg, depending on body weight.

However, it is also necessary to deviate from the amounts mentioned, depending on the body weight, the method of administration, the individual response to the active compound, the type of preparation and the point in time or interval at which the administration takes place. Thus, in some cases it may be desirable to use less than the minimum amount, while in other cases the upper limit may be exceeded. In the case of relatively large amounts of administration, it is also possible to dispense them in a plurality of individual doses during the day.

The invention also provides a pharmaceutical composition comprising at least one compound according to the invention and at least one pharmaceutically acceptable carrier, adjuvant or solvent. These are conventional pharmaceutical carriers, adjuvants or solvents. The pharmaceutical compositions of the invention are suitable, for example, for inhalation or intravenous, intraperitoneal, intramuscular, intravaginal, intraoral, transdermal, subcutaneous, mucocutaneous, buccal, rectal, transdermal, topical, intradermal, intragastric or intradermal administration, and are present, for example, in the form of pills, tablets resistant to gastric juice, film tablets, coated tablets, oral delayed-action formulations, subcutaneous or transdermal administration (in particular as plasters), depot preparations, dragees, emboli, gels, ointments, syrups, inhalation powders, microparticles, suppositories, emulsions, dispersions, microcapsules, micro-dosage forms, nano-dosage forms, liposome dosage forms, capsules resistant to gastric juice, powders, inhalation powders, micro-crystalline dosage forms, inhalation sprays, powders, drops, nasal sprays, aerosols, ampoules, solutions, juices, suspensions, emulsions, infusions or injections, etc.

Detailed Description

Unless otherwise indicated, the percentages in the examples below are percentages by weight; the parts are parts by weight. In each case, the solvent ratio, dilution ratio and concentration of the liquid/liquid solution are by volume.

1. Diphenylethylene derivatives of formula (5)

Raw material

Example 1.1: 2-sodium sulfooxybenzaldehyde

The following process serves as a mode of sulfation by alkali metal bisulfates

12.2g (0.1 mol) of 2-hydroxybenzaldehyde and 33.3g (0.15 mol) of sodium hydrogensulfate were mixed together with 100ml of dimethylformamide and 130ml of tetrahydrofuran and stirred at room temperature for 30 hours. 200ml of a 1N aqueous sodium carbonate solution are subsequently added to the reaction mixture, the mixture is stirred, filtered and the filtrate is evaporated under reduced pressure. The residue was dissolved in the minimum amount of water required, filtered through activated carbon and the filtrate evaporated on a rotary evaporator.

The title material may be further processed as a crude product.

Example 1.2 4-sodium sulfonyloxybenzaldehyde

This compound is prepared in a similar manner to example 1.1 and the crude product is subjected to further processing.

3-sodium sulfooxybenzaldehyde can be obtained in a similar manner.

Example 1.3 2-Aminosulfonyloxybenzaldehyde

The methods below use sulfamoyl chloride as the mode of sulfamylation.

12.46g (0.11 mol) of sulfamoyl chloride are added dropwise to a solution of 12.2g (0.1 mol) of 2-hydroxybenzaldehyde in 200ml of anhydrous dimethylacetamide at 0 to 5 ℃. The reaction mixture is stirred at room temperature for 3 hours and then extracted with 1000ml of ethyl acetate, the organic phase is washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and the solvent is removed on a rotary evaporator. The residue is triturated with a mixture of ethyl acetate/petroleum ether, crystallized and filtered off with suction.

Example 1.4-Aminosulfonyloxybenzaldehyde

Synthesis analogous to example 1.3

The 3-sulfamoyloxy derivative of 3-hydroxybenzaldehyde can be obtained in a similar manner.

Example 1.5 (4-nitrobenzyl) triphenylphosphine chloride

[O₂N-C₆H_4-CH₂-P⁺Ph₃]Cl^-

A solution of 263g (1 mol) of triphenylphosphine and 172g (1 mol) of 4-nitrobenzyl chloride in 2L of toluene is stirred at the boiling point for 15 hours. The reaction mixture is cooled, and the crystals are filtered off with suction and rinsed with toluene.

Example 1.6 (Z-and E) -2-sodiosulfonyloxy-4' -nitrodiphenylethylene.

0.04mol of sodium methoxide in methanol solution and a 40ml methanol solution of 17.3g of phosphonium salt from example 1.5 are simultaneously added dropwise in small portions to a 50ml methanol solution of 8.9g (0.04 mol) of benzaldehyde-2-sodium sulfate at 0 ℃ with stirring. After decolorizing the reaction solution, the solvent was distilled off on a rotary evaporator. The solid product was extracted with 100ml of ethyl acetate with stirring to remove triphenylphosphine oxide, filtered off with suction, dried in air, subsequently boiled with nitromethane and separated from the insoluble residue (trans compound) by filtration with suction. On cooling, the cis-compound crystallizes out of the filtrate and optionally recrystallizes again.

Example 1.7 (Z-and E) -4-methoxy-2-sodiosulfonyloxy-4' -nitrodiphenylethylene

Synthesis analogous to example 1.6

Example 1.8 (Z-and E) -4-nitro-2' -sulfamoyloxydiphenylethylene

13.15g (0.05 mol) of the phosphonium salt from example 1.5 and 0.05mol of sodium methoxide solution are added simultaneously, in small amounts each time (in each case after decolorization), to a solution consisting of 10.4g (0.05 mol) of acetaldehyde from example 1.3 and 75ml of ethanol at from 0 to 5 ℃. After decolorizing the reaction solution, the solvent was removed on a rotary evaporator and the residue was stirred with 50ml of toluene to remove triphenylphosphine and filtered off with suction. The residue remaining was heated with 75ml of acetonitrile and filtered off by suction while maintaining the elevated temperature. The trans compound is retained. The cis-compound crystallizes from acetonitrile under cooling and may optionally be recrystallized from acetonitrile or isopropanol.

Example 1.9 (Z) -4-amino- (2-sodiosulfonyloxy) diphenylethylene

3.4g (0.01 mol) of the Z-nitro compound from example 1.8 are hydrogenated at room temperature and 2atm in 300ml of methanol or THF and 20ml of water using 4g of Ra-Ni. After the desired amount of hydrogen has been taken up, the catalyst is filtered off under suction and the solvent is distilled off. The residue was further reacted as a crude product.

The following amino compounds were obtained analogously:

example 1.10 (E) -4-amino-2' -sodiosulfonyloxydiphenylethylene (from example 1.6E)

Example 1.11 (Z) -4-amino-2' -sulfamoyloxydiphenylethylene (from example 1.8Z)

Example 1.12 (E) -4-amino-2' -sulfamoyloxydiphenylethylene (from example 1.8E)

Final product

Example 1.13 (Z) -4- (3, 3-Dimethyltriazino-1) -2' -sodiosulfonyloxydiphenylene

A solution consisting of 3.5g of sodium nitrite and 5ml of water is added dropwise to a solution consisting of 15.6g (0.05 mol) of cis-aminodiphenylethylene from example 1.9, 100ml of water and 13ml of concentrated hydrochloric acid at 0 ℃ and the mixture is stirred for a further 10 minutes. Subsequently, the diazonium salt solution obtained is rapidly added dropwise to a solution consisting of 30g of sodium carbonate, 60ml of water and 7g of a 40% strength aqueous dimethylamine solution. The mixture was stirred for an additional 40 minutes and the reaction solution was evaporated on a rotary evaporator. The residue was dissolved in the required minimum amount of water at 50 ℃ and the title compound was precipitated by a saturated aqueous solution of sodium chloride, filtered off with suction and dried. The product can be recrystallized from sodium chloride solution or methanol/water.

The following compounds were prepared in a similar manner:

example 1.14 (E) -4- (3, 3-Dimethyltriazino-1) -2' -sodiosulfonyloxydiphenylene

(from example 1.10 in a manner analogous to example 1.13)

Example 1.15 (Z) -4- (3, 3-Dimethyltriazino-1) -2' -sulfamoyloxydiphenylethylene

A solution consisting of 3.5g of sodium nitrite and 5ml of water is added dropwise to a solution consisting of 15.6g (0.05 mol) of Z-aminodiphenylethylene, 100ml of water and 10ml of concentrated hydrochloric acid from example 1.11 at 0 ℃ and the mixture is stirred for a further 10 minutes. Subsequently, the diazonium salt solution obtained is rapidly added dropwise to a solution consisting of 30g of sodium carbonate, 60ml of water and 7g of 40% strength aqueous dimethylamine solution. The mixture was stirred for an additional 40 minutes, 50ml of water were added and the mixture was extracted with 300ml of ethyl acetate. The organic phase is separated, washed with 300ml of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. The product is purified by chromatography and optionally subsequently recrystallized from ethanol/cyclohexane.

Example 1.16:

(E) -4- (3, 3-Dimethyltriazinenyl-1) -2' -sulfamoyloxydiphenylethylene (from example 1.12)

2. Triphenylethylene derivatives of formula (12)

Raw material

Example 2.1 [ bis (4-methoxyphenyl) ] bromomethane

(CH₃O-C₆H₄-)₂CH-Br

Hydrogen bromide was fed to a suspension of 100g of bis (4-methoxyphenyl) methanol and 46g of calcium chloride in 2L of toluene to saturation. The precipitated salts are filtered off under suction and the filtrate is evaporated. The yellow oily residue is further processed in crude form.

Example 2.2 [ bis (4-methoxyphenyl) methyl ] triphenylphosphonium bromide

The title compound is prepared from the bromide of example 2.1 in analogy to example 1.5.

Example 2.3 1,1- [ bis (4-methoxyphenyl) ] -2- (4-nitrophenyl) ethylene

4.5g (0.1 mol) of sodium hydride (53% concentration, dispersed in oil) are supplied in 50ml of DMSO under absolutely dry conditions. The mixture was heated to 70-80 ℃ until the evolution of hydrogen ceased. While cooling in ice, 57g (0.1 mol) of the phosphonium salt of example 2.2 dissolved in 150ml of DMSO are added dropwise and the mixture is stirred for an additional 1 hour. 15.1g (0.1 mol) of 4-nitrobenzaldehyde dissolved in 50ml of DMSO are then added dropwise and the mixture is stirred at room temperature for an additional 15 hours. 600ml of water are subsequently added, the mixture is extracted with 500ml of ethyl acetate, the solvent is removed on a rotary evaporator and the product is isolated from the triphenylphosphine oxide by means of an alumina column. Toluene/ethyl acetate (9: 1) was used as eluent. The second fraction is freed of solvent on a rotary evaporator and worked up further as crude product.

Example 2.4:1,1- [ bis (4-methoxyphenyl) ] -2- (4-amino-phenyl) ethene

15.26g (0.042 mol) of the nitro compound from example 2.4 are heated to the boiling point in 500ml of ethanol and admixed with 66g of 80% hydrazine hydrate solution (1.06 mol N)₂H₄) Mixed and rapidly cooled to 50 ℃ and then stirred with freshly prepared raney nickel suspended in neutral ethanol medium while mixing until no further evolution of gas is observed when more catalyst is added. The mixture was then heated under reflux for an additional 1 hour and the hot reaction mixture was filtered. After washing the residue on the filter with 250ml of hot ethanol, the combined filtrates are evaporated to dryness under reduced pressure and the residue is optionally recrystallized from ethanol.

Example 2.5 1,1- [ bis (4-hydroxyphenyl) ] -2- (4-amino-phenyl) ethane

84g of concentrated hydrochloric acid are added dropwise to a mixture of 33g (0.1 mol) of the compound from example 2.4 and 66ml of pyridine. The reaction solution was subsequently heated at 150 ℃ for 3 hours and subsequently evaporated to dryness on a rotary evaporator, 200ml of water were taken and neutralized. The solid reaction product is filtered off with suction and dried. The crude product is reacted further.

Example 2.6 1,1- [ bis (4-hydroxyphenyl) ] -2- [4- (3, 3-dimethyltriazenyl-1) phenyl ] ethylene

13.55g (0.05 mol) of 1.1- [ bis (4-hydroxyphenyl) ] -2- (4-aminophenyl) ethylene from example 2.5 were dissolved in a solution consisting of 13ml of concentrated hydrochloric acid and 80ml of water. A solution consisting of 10ml of water and 3.5g of sodium nitrite was slowly added dropwise at 0 to 5 ℃ while stirring. The diazonium salt solution obtained is then rapidly added dropwise at 0 to 5 ℃ to a solution consisting of 15g of sodium carbonate, 60ml of water and 7g of 40% strength aqueous dimethylamine solution. The mixture is subsequently stirred for an additional 30 minutes, neutralized and the title material is filtered off as a solid under suction, optionally recrystallised from nitropropane and dried. The crude product is further processed.

Final product

Example 2.7 1,1- [ bis-4- (sodiosulfonyloxyphenyl) ] -2- [4- (3, 3-dimethyltriazenyl-1) phenyl ] ethylene

3.60g (0.01 mol) of the compound from example 2.6 and 6.6g (0.03 mol) of sodium hydrogensulfate are mixed with 10ml of dimethylformamide and 13ml of tetrahydrofuran and stirred at room temperature for 30 minutes. Subsequently 20ml of 1N aqueous sodium carbonate solution were added to the reaction mixture, the mixture was stirred, the solid was filtered off under suction and the filtrate was evaporated under reduced pressure. The residue was dissolved in the minimum amount of water required, filtered through activated carbon, the filtrate was evaporated on a rotary evaporator and the residue was recrystallized from methanol/water.

Example 2.8 1,1- [ bis-4- (sulfamoyloxyphenyl) ] -2- [4- (3, 3-dimethyltriazenyl-1) -phenyl ] ethylene

4g (0.033 mol) of sulfamoyl chloride are added dropwise to a solution of 3.60g (0.01 mol) of the compound from example 2.6 in 20ml of anhydrous dimethylacetamide at 0 to 5 ℃. The reaction mixture was stirred at room temperature for 3 hours. The mixture is subsequently extracted with 100ml of ethyl acetate, the organic phase is washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and the solvent is distilled off on a rotary evaporator. The residue is triturated with an ethyl acetate/petroleum ether mixture, crystallization is induced and filtered off by suction.

3. Flavonoid derivative of general formula (14)

Raw material

Example 3.17, 4 '-dihydroxy-3' -nitroisoflavone

20ml of a mixture of concentrated sulfuric acid and nitric acid (3: 1) was added dropwise to a solution of 1g daidzein in 200ml of absolute ethanol at room temperature, while stirring vigorously. The mixture was stirred for an additional 2 hours and then 400ml of water was added. The compound precipitate was filtered off by suction and washed with water until neutralized. The yellow product was recrystallized from alcohol.

2' -Nitroisoflavone was obtained according to the electronic paper by S.Tappmeye: http:// www.diss.fu-berlin.de/2004/287/index.html.

Synthesis of sulfate salts

The following examples were carried out in a similar manner to example 1.1. The title compound was further reacted as crude product.

Example 3.2 sodium 7-sulfonyloxy-4 '-methoxy-2' -nitroisoflavone

Example 3.3 disodium 7,4 '-Disonyloxy-2' -nitroisoflavone

Example 3.4 disodium 7,4 '-Disonyloxy-3' -nitroisoflavone

Example 3.5 7-methoxy-3 '-nitro-4' -sodiosulfonyloxyisoflavone

Example 3.6 sodium 7-Sulfonyloxy-3 '-nitro-4' -methoxyisoflavone

Synthesis of oxyaminosulfonates

The following examples were carried out in a similar manner to example 1.3. The title compound was further reacted as crude product.

Example 3.7 7,4 '-Disulfamoyloxy-2' -nitroisoflavone

Example 3.8 7,4 '-Disulfamoyloxy-3' -nitroisoflavone

Reduction of nitroisoflavones to aminoisoflavones

The reduction of the nitro compound is carried out by catalytic reduction in ethanol using hydrogen/Pd/C.

Example 3.9 sodium 7-sulfonyloxy-2 '-amino-4' -methoxyisoflavone

The following was prepared in a similar manner:

example 3.107, 4 '-disodium-sulfonyloxy-2' -aminoisoflavones

3.117, 4 '-disodium sulfonyloxy-3' -aminoisoflavones

3.127-methoxy-3 '-amino-4' -sodiosulfonyloxy isoflavone

3.137-Narcosulfonyloxy-3 '-amino-4' -methoxyisoflavone

3.147-Nalsulfonyloxy-2 '-amino-4' -methoxyisoflavone

3.157, 4 '-Disulfamoyloxy-3' -aminoisoflavones

3.167, 4 '-disulfamoyloxy-2' -aminoisoflavones

3.177-sulfamoyloxy-3 '-amino-4' -methoxyisoflavone

Final product

Example 3.18 sodium sulfonyloxy-3 '- [ (3, 3-dimethyltriazenyl-1) -4' -methoxy ] isoflavone

A solution consisting of 2g of sodium nitrite and 20ml of water is added dropwise at 0 ℃ to a solution consisting of 4g (0.02 mol) of aminoisoflavone from example 3.14, 30ml of water and 5ml of concentrated hydrochloric acid, the mixture is stirred for an additional 10 minutes, and the diazonium salt solution obtained is rapidly added dropwise to a solution consisting of 8g of sodium carbonate, 15ml of water and 2g of 40% strength aqueous dimethylamine solution. The mixture is stirred for an additional 60 minutes, and the crystalline reaction product is filtered off by suction and recrystallized from a small amount of water.

According to the present invention, the following triazenyl isoflavones are prepared in a manner analogous to example 3.18 from the aminoisoflavones mentioned above.

Example 3.19 disodium 7,4 '-Disulfonyloxy-2' - (3, 3-dimethyltriazenyl-1) isoflavone

Example 3.20 disodium 7,4 '-Disulfonyloxy-3' - (3, 3-dimethyltriazenyl-1) isoflavone

Example 3.21 7-methoxy-3 '- (3, 3-dimethyltriazenyl-1) -4' -sodiosulfonyloxyisoflavone

Example 3.22 sodium 7-sulfonyloxy-3 '- (3, 3-dimethyltriazenyl-1) -4' -methoxyisoflavone

Example 3.23 7,4 '-sulfamoyloxy-3' - (3, 3-dimethyltriazenyl-1) isoflavone

Example 3.24-sulfamoyloxy-2 '- (3, 3-dimethyltriazenyl-1) -4' -methoxyisoflavone

4. Biphenyl derivatives (18) unbridged or bridged by an atom or a diatomic group:

raw materials:

example 4.1 3-methyl-4-nitro-4' - (3-methyl-4-nitro-benzoyloxy) benzophenone

A mixture of 122g of phenetole (1 mol), 400g of 3-methyl-4-nitrobenzoyl chloride (2 mol) and 1500ml of 1, 2-dibromoethane is placed in a reaction vessel. 400g of aluminum chloride are added in portions at 15 ℃ to 20 ℃ (exotherm!) while cooling. The reaction mixture was then stirred stepwise at 20-30 deg.C, 40 deg.C and 80 deg.C for 2 hours each.

And (3) reprocessing: the reaction mixture was cooled to 0 ℃ and slowly introduced into 1.6kg of ice. Then 100ml of concentrated hydrochloric acid was added to the reaction mixture, stirred and maintained. The supernatant was decanted and the solid product was filtered off with suction and rinsed with water.

The filter residue is slurried with 400ml of acetone, cooled to 0 ℃, filtered off with suction and dried.

And (3) purification: recrystallization from nitropropane

Example 4.2 4-hydroxy-3 '-methyl-4' -nitrobenzophenone

322g (1 mol) of 4-nitro-4' - (4-nitrobenzoyloxy) benzophenone (example 4.1) are heated in 1.3L of water, 200ml of ethanol and 85g of sodium hydroxide until the solid is dissolved.

And (3) reprocessing: the reaction mixture was filtered hot through activated carbon/celite with suction. Onko0640 was precipitated from the filtrate together with 4-nitrobenzoic acid by addition of 120ml of concentrated hydrochloric acid. The solid was filtered off under suction and rinsed with water. The filtered residue is stirred with 140g of sodium bicarbonate and 900ml of water at 70 ℃ for 1 hour, filtered off hot under suction, rinsed with 4ml of hot water and dried.

Example 4.3 4-amino-3-methyl-4' -hydroxydiphenylmethanone

25.8g (0.1 mol) of 4-hydroxy-3' -methyl-4-nitrobenzophenone (example 4.2) are dissolved in 200ml of ethanol. At 80 ℃, 35g of an aqueous solution of sodium sulfide in 40ml was slowly added dropwise with stirring. The reaction solution was then refluxed for 2 hours.

And (3) reprocessing: the reaction solution is poured into 1L of water, cooled to 20 ℃ and the precipitated product is filtered off under suction, dried and recrystallized from toluene.

Example 4.4-hydroxy-4' - (3, 3-dimethyltriazenyl-1) diphenylmethanone

57g (0.25 mol) of 4-amino-3-methyl-4' -hydroxydiphenylmethanone are dissolved in a solution consisting of 75ml of concentrated hydrochloric acid and 400ml of water. Subsequently, a solution consisting of 25ml of water and 17.25g of sodium nitrite was slowly added dropwise at 0 to 5 ℃ while stirring. Subsequently, the diazonium salt solution was added dropwise to a solution made from 75g of sodium carbonate, 150ml of water and 35g of 40% strength aqueous dimethylamine solution at 0 to 5 ℃ while stirring. The mixture is stirred for 1 hour, neutralized and the precipitated solid is filtered off with suction, dried and crystallized from n-hexane/toluene.

Final product

Example 4.5- (3, 3-Dimethyltriazino-1) -4' -sodium sulfonyloxy (biphenyl sulfone)

4g (0.01 mol) of 4-hydroxy-4' - (3, 3-dimethyltriazenyl-1) - (diphenylsulfone) and 3.3g (0.15 mol) of sodium hydrogensulfate were mixed with 20ml of dimethylformamide and 25ml of tetrahydrofuran and stirred at room temperature for 30 hours. Subsequently 20ml of 1N aqueous sodium carbonate solution were added to the reaction mixture, the mixture was stirred, the solid was filtered off under suction and the filtrate was evaporated under reduced pressure. The residue is dissolved in the minimum amount of water required, filtered through activated carbon, the filtrate is evaporated on a rotary evaporator and the residue is recrystallized from methanol/water or sodium chloride solution.

The following may be prepared in a similar manner:

example 4.6 4- (3, 3-Dimethyltriazino-1) -2' -sodiosulfonyloxydiphenylketone

Example 4.7 2, 6-dibromo-4-sodiosulfonyloxy-4' - (3, 3-dimethyltriazenyl-1) -diphenylmethanone

Example 4.8 2, 6-dimethyl-4-sodiosulfonyloxy-4' - (3, 3-dimethyltriazenyl-1) -diphenylmethanone

Example 4.9 4- (3, 3-Dimethyltriazino-1) -4' -sodiosulfonyloxybiphenyl

Example 4.10- (3, 3-Dimethyltriazinenyl-1) -4' -sodiosulfonyloxy (diphenyl sulfide)

Example 4.11- (3, 3-Dimethyltriazino-1) -4' -sodiosulfonyloxy (diphenylsulfoxide)

Example 4.12- (3, 3-Dimethyltriazino-1) -4' -sodiosulfonyloxy (diphenylsulfone)

Example 4.13 4- (3, 3-Dimethyltriazino-1) -4' -sulfamoyloxybenzophenone

8.6g (0.075 mol) of sulfamoyl chloride are added dropwise at 0 ℃ to a solution of 13.4g (0.05 mol) of 4- (3, 3-dimethyltriazenyl-1) -4' -hydroxybenzophenone (example 4.6) in 100ml of dimethylacetamide. The mixture was stirred at 0 ℃ for 1 hour, and then at room temperature for an additional 12 hours. Saturated aqueous ammonium chloride solution was then added, the mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and the solvent was removed. The product was recrystallized from cyclohexane/ethyl acetate.

The following may be prepared in a similar manner:

example 4.14- (3, 3-Dimethyltriazino-1) -2' -sulfamoyloxybenzophenone

Example 4.15- (3, 3-Dimethyltriazino-1) -4' -sulfamoyloxy (diphenylsulfoxide)

Example 4.16- (3, 3-Dimethyltriazino-1) -4' -sulfamoyloxy (diphenylsulfone)

Claims

1. A biphenyl derivative comprising per molecule (i) at least one dialkyltriazene group, (ii) at least one sulfonyloxy group and/or at least one sulfamoyloxy group, and salts, solvates and solvates of these salts.

2. Biphenyl derivatives as claimed in claim 1, having the formula

Wherein

X is a direct C-C bond between rings a and b, CH₂、CHOH、CO、S、SO、SO₂、-N=N-、-CR⁷=CR⁸Or X is a divalent-C (O) -C = CH-O-radical which, together with the two adjacent carbon atoms of ring a, forms a pyrone ring, while ring b is located on the C atom of the radical,

R³、R⁶are independent of each other and are each hydrogen, hydroxy, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, C₁-C₄alkyl-S-, C₁-C₄-alkyl-SO-, C₁-C₄-alkyl-SO₂-, halogen, nitro, cyano or-OSO₂The radical Y is a radical of the formula,

R⁸is hydrogen, ethyl, CN, NO₂、-CH₂CH₂-halogen or CH₂CH₂OH，

R⁹、R¹⁰Are independent of each other and are each hydrogen, hydroxy, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, halogen, nitro, cyano, -N = N-N (R)²)₂Radical or-OSO₂The radical Y is a radical of the formula,

y is OH or N (R)¹)₂，

R¹Is hydrogen, methyl or ethyl, and

R²is a methyl group or an ethyl group,

wherein one or two-N = N-N (R) per whole molecule (1)²)₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

3. Biphenyl derivatives according to claim 1 or 2, and their salts, free acids, solvates and solvates of these salts and solvates of these free acids, having the formula

Wherein

R⁸is hydrogen, ethyl, CN, NO₂、-CH₂CH₂-halogen or CH₂CH₂OH，

y is OH or N (R)¹)₂，

R¹Is hydrogen, methyl or ethyl, and

R²is a methyl group or an ethyl group,

wherein one or two-N = N-N (R) per whole molecule (5)²)₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

4. Biphenyl derivatives according to claim 1 or 2, and their salts, free acids, solvates and solvates of these salts and solvates of these free acids, having the formula

Wherein

R⁸is hydrogen, ethyl, CN, NO₂、-CH₂CH₂-halogen or CH₂CH₂OH，

y is OH or N (R)¹)₂，

R¹Is hydrogen, methyl or ethyl, and

R²is a methyl group or an ethyl group,

5. Biphenyl derivatives according to claim 1 or 2, and their salts, free acids, solvates and solvates of these salts and solvates of these free acids, having the formula

Wherein

y is OH or N (R)¹)₂，

R¹Is hydrogen, methyl or ethyl, and

R²is a methyl group or an ethyl group,

wherein one or two of-N = N-N (R) per whole molecule (14)²)₂Radicals and one or two-OSO₂The Y group is located on any ring carbon atom of the aromatic ring.

6. Biphenyl derivatives according to claim 1 or 2, and their salts, free acids, solvates and solvates of these salts and solvates of these free acids, having the formula

Wherein

X is a direct C-C bond, CH₂、CHOH、CO、S、SO、SO₂or-N = N-,

y is OH or N (R)¹)₂，

R¹Is hydrogen, methyl or ethyl, and

R²is a methyl group or an ethyl group,

7. Biphenyl derivatives according to any of claims 1,2 and 6, having the formula 4- (3, 3-dimethyltriazenyl-1) -4' -sodiosulfonyloxydiphenylketone.

8. A process for the preparation of biphenyl derivatives comprising per molecule (i) at least one dialkyltriazenyl group, (ii) at least one sulfonyloxy group and/or at least one sulfamoyloxy group, characterized in that the aminophenyl derivative has the formula

Wherein

X is a direct C-C bond, CH₂、CHOH、CO、S、SO、SO₂、-N=N-、-CR⁷=CR⁸-, or

X is a divalent-C (O) -C = CH-O-radical which, together with the two adjacent carbon atoms of ring a, forms a pyrone ring, whereas ring b is located on the C atom of the radical,

R⁸is hydrogen, ethyl, CN, NO₂、-CH₂CH₂-halogen or CH₂CH₂OH，

R⁹、R¹⁰Are independent of each other and are each hydrogen, hydroxy, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, halogen, nitro, cyano, -NH₂Radical or-OSO₂The radical Y is a radical of the formula,

y is OH or N (R)¹)₂And is and

R¹is hydrogen, methyl or ethyl, and is,

they are diazotized by a diazotizing agent in the presence of a strong acid at low temperatures to form diazonium salts of the formula

Wherein

X is a direct C-C bond, CH₂、CHOH、CO、S、SO、SO₂、-N=N-、-CR⁷=CR⁸-or (ii) either of,

R⁸is hydrogen, ethyl, CN, NO₂、-CH₂CH₂-halogen or CH₂CH₂OH，

R⁹、R¹⁰Are independent of each other and are each hydrogen, hydroxy, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen, nitro, cyano, -N₂ ⁺An^-Radical or-OSO₂The radical Y is a radical of the formula,

An^-as halide anions or 1/2 Sulfate (SO)₄ ^2-) An anion of the compound (I) is selected,

y is OH or N: (¹R)₂And is and

R¹is hydrogen, methyl or ethyl, and is,

HN(R²)₂ (4)

Wherein R is₂Is a methyl group or an ethyl group,

salts are then optionally prepared from the compounds obtained and hydroxyl and/or acidic groups are then optionally liberated from these salts.

9. Use of biphenyl derivatives comprising (i) at least one dialkyltriazene group, (ii) at least one sulfonyloxy group and/or at least one sulfamoyloxy group per molecule and salts, solvates and solvates of these salts for combating skin tumors and organ-dependent tumors of humans and animals.

10. A method of combating skin tumours and sex hormone-dependent organ-targeted tumours in humans and animals by applying a sufficient amount of at least one biphenyl derivative containing (i) at least one dialkyltriazene-based group, (ii) at least one sulphonyloxy group and/or at least one sulphamoyloxy group per molecule, and salts, solvates and solvates of such salts.

11. Use of biphenyl derivatives comprising (i) at least one dialkyltriazene group, (ii) at least one sulfonyloxy group and/or at least one sulfamoyloxy group per molecule, and salts, solvates and solvates of these salts thereof, in the manufacture of a biocide for skin, breast, prostate and testicular tumors and organ-dependent tumors of humans and animals.

12. A pharmaceutical agent comprising at least one biphenyl derivative containing (i) at least one dialkyltriazene group, (ii) at least one sulfonyloxy group and/or at least one sulfamoyloxy group per molecule and salts, solvates and solvates of such salts, optionally further comprising one or more pharmacologically acceptable adjuvants or supports.