EP2167459A1 - Novel triazine compounds for treatment of cancer - Google Patents

Abstract

The present invention relates to novel triazine compounds, to processes for preparing them, to a pharmaceutical composition comprising them, and to the use thereof for the treatment of human cancers. The novel triazine compounds are notable, compared to the known triazine compounds, for improved efficacy with simultaneously reduced toxicity, i.e. for lower side effects.

Description

 NEW TRIAZEN COMPOUNDS FOR THE TREATMENT OF CANCER

DESCRIPTION

The present invention relates to novel pharmaceutical compounds, to processes for their preparation, to pharmaceutical compositions comprising them, and to the use thereof for the treatment of human cancers. The novel Tπazen compounds are distinguished from the known Tπazen compounds by an improved therapeutic breadth, ie by lower side effects with high anti-tumor activity

INTRODUCTION

Triacendivates were extensively researched in the 1970s for their cytostatic efficacy and the potential for the treatment of cancer. However, due to their potent side effects and toxicity of these cytochemicals, they have never been widely used in tumor treatment. An exception is dacarbazine (DTIC), which is a prodrug of monomethyl-tπazeno-imidazole-carboxamide (MTIC) and is mainly used to combat melanoma (Montgomery JA (1 976) Cancer Treat Rep 60, 205-21 1).

Because of the photosensitivity of dacarbazine, and particularly its side effects, in which nausea, vomiting, and leukoemia and thrombocytopenia are particularly noteworthy, a large number of arylalkyltnacenes have been synthesized with the aim of developing more potent and better contracted tπazenes (Montgomery JA (1,976) Cancer Treatment reports 60,125-13,4, Spassova MK and Golovinsky EV (1,985) Pharmac Ther 27,333,352, Derry EV Wilman and Phyllis M Goddard, J Med Chem 1,980,253, 1,052-1,024) To date, dacarbazine and temozolomide (for the treatment of glioblastomas) have remained the only triazine or tπazene prodrugs in clinical use

THOMAS A CONNORS, PHYLLIS M GODDARD, KANTI MERAI, WALTER CJ ROSS and DERRY EV WILMAN, Biochemical Pharmacology, Vol. 25 Pp 241-246 Pergαmon Press 1,976 described the structural requirements for an antitumor effect When the Tπαzen trαgende group is Imidαzolrest, the compounds are unstable and decompose spontaneously When replacing the imidazole by other and especially aromatic-bearing groups increases the stability of Tπazene without their activity to anaern experiments to develop novel and therapeutically more effective Tπazene for tumor therapy by structure-activity relationships, but showed that differences in the antitumor effect not correlated with the physico-chemical properties of aromatic Tπazen model compounds aggravating added that depending on substituents alkylating agents with different properties No improvement in the therapeutic index was found within the compounds tested

An approach for overcoming the problem of compatibility of selected Tπazenen was described in DE 1 793 1 1 5 and DE 21 47 781, by the introduction of highly polar functional groups not only the water solubility of triazine derivatives but also the rapid excretion of the substances could be greatly improved. The above-mentioned typical side effects, in particular the suppression of the hematopoietic system, could be greatly reduced, However, this was due to a strong metabolic burden on the excretory liver and kidney Due to contractual problems with long-term administration, the contractual dose range was limiting, so that the promising therapeutic potential of this compound class However, since such Tπazeπe have a relatively high cytostatic activity, they were still interesting to combat tumors, provided that the above side effects could be reduced or even eliminated,

Other documents relating to Tπazene, which are mentioned here for completeness, are the following DE 1 768 720, WO91 / 1 7753 and WO2004 / 1 06258 A1 (also relate to the use of triazene derivatives for the treatment of tumors), EP-A-0627325 (relates the use of Tπazenen as dyes), EP-A-0037948 and EP-AO 071 901 (relate to processes for the preparation Tπazenylverbindungen), and F Schmidt et al, J Med Chem 1 994, 37, 381 2 381 8 (relates to the antineoplastic effect of peptide-bound 1, 3-dialkyl-3-acyltrιazenen)

TASK

The object of the present invention was thus to find cytostatic Triazendeπvate with reduced toxicity with improved efficacy in order to make them available for therapy in humans, in particular for the treatment of human cancers

DESCRIPTION OF THE INVENTION

The inventors found new Tπazenyl compounds with high cytostatic activity, whose toxicity is significantly reduced. The invention therefore relates to compounds of the formula (1)

wherein

R ¹ and R ^{2 are the} same or different and are each selected from the group consisting of. optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted alkylaryl,

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ^{10 are the} same or different and are each selected from the group consisting of

Hydrogen,

Halogen, Cyαno,

nitro,

Cαrboxyl

Aminocαrbonyl,

Sulfonic acid residue (-SO ₃ H),

Aminosulfonyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted aryl, optionally substituted alkylaryl;

R ^{1 1} is optionally substituted alkanediyl or alkenediyl optionally substituted;

R ^{12 is} hydrogen and R ^{1 3 is} optionally substituted alkyl or

Hydroxy is, or

R ^{13 is} hydrogen and R ^{1 2 is} optionally substituted alkyl or

Hydroxy is, or

R ^{1 2} and R ^{1 3 are} each alkyl, wherein at least one of the alkyl groups has at least one substituent, or

R ^{1 2} and R ^{1 3} together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 5 to 8-glιedrιgen Cyclus, which may optionally contain further heteroatoms, and

X ^{1 is} selected from the group consisting of a single bond Carbonyi, sulfur, oxygen, sulfoxy, sulfonyl, azo, and an optionally substituted, saturated or _ ^

unsaturated αhphαtischen divαlenten radical having 1 to 6 Kohlenstoffαtomen,

or pharmaceutically-acceptable salts thereof

in the general formula (1), R ¹ and R ^{2 are the} same or different, and are each selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, and optionally substituted alkylaryl

Optionally substituted alkyl includes in the context of the entire invention, ie also in connection with the other substituent groups (where indicated, as in the case of R ¹² and R ¹³ , other possibilities may be included), preferably a straight-chain or branched alkyl having 1 to 8 , preferably 1 to 6, carbon atoms, cycloalkyl having 3 to 8, preferably 5 or 6 carbon atoms, or alkyl having 1 to 4 carbon atoms, which is substituted by cycloalkyl, which may optionally each preferably carry 1 to 3 substituents, preferably from the group be selected, which consists of. Hydroxy, halogen and cyano Halogen here and in the context of the present invention includes fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine. Furthermore, one or more, preferably 1 to 3, carbon atoms can be substituted by heteroanalogical groups which contain nitrogen, oxygen or This means in particular that, for example, one or more methylene groups in the alkyl radicals may be replaced by NH, O or S.

Examples of alkyl radicals having 1 to 8 carbon atoms include a methyl group, an ethyl group, an n-propyl group, a ι-propyl group, an n-butyl group, a ι-butyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, a 1-pentyl group, a sec-pentyl group, an f-pentyl group, a 2-methylbutyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-pentyl group, a Methylpentyl group, a 4-methylpentyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 3-ethylbutyl group, a 1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3, 3-dimethylbutyl group, a 1-ethyl-1 methylpropyl group, n-heptyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 1-ethylpentyl group, 2-ethylpenty group, 3-ethylpentyl group, a 4-ethylpentyl group, a 1, 1-dimethylpentyl group, a 2,2-dimethylpentyl group, a 3,3-methylpentyl group, a 4,4-dimethylpentyl group, a 1-propylbutyl group, an n-octyl group, a 1-methylheptyl group, a 2-methylheptyl group, a 3-

Methylheptyl group, a 4-methylheptyl group, a 5-methylheptyl group, a 6-methylheptyegroup, a 1-ethylhexyl group, a 2-ethylhexyl group, a 3-ethylhexyl group, a 4-ethylhexyl group, a 5-ethylhexyl group, a 1, 1-dimethylhexyl group, a 2, 2-

Dimethylhexyl group, a 3,3-dimethylhexyl group, a 4,4-dimethylhexyl group, a 5,5-dimethylhexyl group, a 1-propylpentyl group, a 2-propylpentyl group, etc. Preference is given to those having 1 to 6 carbon atoms, in particular methyl, ethyl and n- Propyl Most preferred is methyl

Examples of alkyl groups resulting from exchange with one or more heteroanalogous groups, such as -O-, -S- or -NH-, are preferably those in which one or more methylene groups are replaced by -O- to form an ether group, such as methoxymethyl , Ethoxymethyl, 2-methoxyethylene, etc. According to the invention, polyether groups are also included in the definition of alkyl

Cycloalkyl radicals having 3 to 8 carbon atoms preferably include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc. Preferred are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group are heterocyclic alkyl groups by exchanging methylene with hetero analogues Groups are formed from Cycloalkyi, for example, 5- or 6-glιedπge heterocyclic radicals, such as tetrahydrofuryl, pyrrolidmyl, piperidyl or tetrahydrophyrenyl, which may optionally be condensed with aromatic rings, etc

Specifically, examples of a halogen-substituted linear or branched alkyl group having 1 to 8 carbon atoms include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a chloromethyl group, a bromomethyl group, a dibromomethyl group, a tribromomethyl group, a 1-fluoroethyl group, a 1-chloroethyl group, a 1-bromethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 1, 2-difluoroethyl group, a 1, 2-Dιchlorethylgruppe, a 1, 2-dibromoethyl group, a 2,2, 2-Trιfluorethylgruppe, a

Heptafluoroethyl group, a 1-fluoropropyl group, a 1-chloropropyl group, a 1-bromopropyl group, a 2-fluoropropyl group, a 2-chloropropyl group, a 2-bromopropyl group, a 3-fluoropropyl group, a 3-chloropropyl group, a 3-bromopropyl group, a 1, 2-difluoropropyl, a 1, 2-Dιchlorpropylgruppe, a 1, 2-dibromopropyl, a 2,3-Dιfluorpropylgruppe, a 2,3-dichloropropyl, a 2, 3-Dιbrompropylgruppe, a 3,3, 3-Tπfluorpropylgruppe, a 2nd , 2,3,3,3-pentafluoropropyl group, a 2-fluorobutyl group, a 2-chloro-butyl group, a 2-bromobutyl group, a 4-fluorobutyl group, a 4-chlorobutyl group, a 4-bromobutyl group, a 4,4,4 Trifluorobutyl group, a 2, 2, 3, 3, 4, 4, 4-heptafluorobutyl group, a perfluorobutyl group, a 2-fluoropentyl group, a 2-chloropentyl group, a 2-bromopentyl group, a 5-fluoropentyl group, a 5-chloropentyl group, a 5 ~ Bromopentyl group, a perfluoropentyl group, a 2-fluorohexyl group, a 2-chlorohexy a 2-bromohexyl group, a 6-fluorohexyl group, a 6-chlorohexyl group, a 6-bromohexyl group, a perfluorohexyl group, a 2-fluoroheptyl group, a 2-chloroheptyl group, a 2-bromoheptyl group, a 7-fluoroheptyl group, a 7-chlorohexyl group, a 7 Bromoheptyl group, a perfluoroheptyl group, etc , Q _

Examples of a hydroxy-substituted alkyl group include the above-mentioned alkyl groups having 1 to 3 hydroxyl groups, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc

Optionally substituted alkenyl preferably includes a ¹ throughout the scope of the invention

Straight-chain or branched-chain alkenyl having 2 to 8 carbon atoms and cycloalkenyl having 3 to 8 carbon atoms, which may be optionally substituted by preferably 1 to 3 substituents, such as hydroxy, halogen or alkoxy, examples include vinyl, 1-methylvinyl, allyl, 1-butenyl , Isopropenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl. Vinyl or allyl are preferred

Optionally substituted aryl preferably includes throughout the scope of the invention

Aromatic hydrocarbon radicals having 6 to 1 4 carbon atoms (wherein the carbon atoms of the substituents are not included) and 5- to 10-membered aromatic heterocyclic radicals having up to 3 heteroatoms from the series S, O, N, which may be mono- or bicyclic and which may be substituted by preferably 1 to 3 substituents selected from hydroxy, halogen, cyano, alkyl, acyl and alkoxy. Reference may be made to the above definitions or examples for the definition of alkyl and halogen.

Alkoxy as a substituent of aryl here and hereinafter includes, for example, an Em mentioned above alkyl which is bonded to aryl via an oxygen atom, such as a linear or branched alkoxy radical having up to 6 carbon atoms, such as a methoxy group, an ethoxy group, an n-propyloxy group, a ι-propyloxy group, an n-butyloxy group, a ι-butoxy group, a sec-butoxy group, a t-butoxy group, an n-pentyloxy group, a ι-pentyloxy group, a sec-pentyloxy group, a t-pentyloxy group, a 2-methylbutoxy group, an n-hexyloxy group, an ι-hexyloxy group, a t-hexyloxy group, a sec-hexyloxy group, a 2-methylpentyloxy group, a 3-methylpentyloxy group, a 1-ethylbutyloxy group, a 2-Efhylbutyloxygruppe, a 1, 1 -

Dimethylbutyloxy group, a 2,2-dimethylbutyloxy group, a 3,3- Dimethylbutyloxy group, a 1-ethyl-1-methylpropyloxy group, etc. Preferred are a methoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxy group, an n-Butyloxygi uppe, a ι-butyloxy group, a sec-butyloxy group, a t- butyloxy group, etc acyl as the substituent of aryl includes here and hereinafter an aiiphatisches acyl, aromatic Acy ¹ as C l to Co alkanoyl, such as formyl, acetyl, Prop'onyl butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc, as well as C6 to C10 O aroyl, such as benzoyl, toluoyl, xyloyl, etc

Aromatic hydrocarbon radicals having from 6 to 14 carbon atoms include, for example, phenyl, naphthyl, phenanthrenyl and anthracenyl, which may be optionally substituted. Phenyl is preferred.

Heteroaromatic radicals include, for example, ^1- pyridyl, pyridyl-N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indinyl, indolyl, benzo [b] thienyl, benzo [b] furyl, indazolyl, quinolyl, isoquinolyl, Naphthyπdinyl, quinazolmyl 5- or ό-glιedrιge aromatic heterocycles such as pyridine, Pyπdyl N-oxide, Pyπmidyl, Pyπdazinyl, furyl and thienyl are preferred

Optionally substituted alkylaryl preferably includes throughout the scope of the invention:

Straight-chain or branched alkyl having 1 to 8, preferably 1 to 4 carbon atoms, as described above, which is substituted by aryl, as described above. Preferred arylalkyl is benzyl

More preferably, R ¹ and R ^{2 are} each alkyl, and are preferably the same or different and each is straight or branched alkyl of 1 to 6, preferably 1 to 4, more preferably 1 to 3 carbon atoms, with linear alkyl being preferred ¹ and R ^{2 are} methyl or ethyl Most preferably, R ¹ and R ^{2 are} methyl

in the general formula (1), R ^3, R ^4, R ^5, R ^6, R ^7, R ^8, R ⁹ and R ^{1 0} are identical or different and are each selected from the group consists

Hydrogen,

Halogen,

Cyaπo,

nitro,

carboxyl,

aminocarbonyl,

Sulfonic acid (-SO ₃ H),

Ammosulfonyl, optionally substituted aikyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted aryl, optionally substituted alkylaryl

With regard to the definition of said substituents and their preferred meanings, reference may be made to the statements made above on the corresponding substituents in connection with the definition of R ¹ and R ^2. In addition, aminocarbonyl preferably represents carbamoyl (H ₂ NCO-) or mono in the context of the entire invention - or Diaikylammocarbonyl (H (alkyl) NCO- or (alkyl) ₂ NCO-), which can be referred to the above explanations with regard to the definition of alkyl and also optionally substituted alkyl includes Furthermore, ammosulfonyl in the context of the invention as a whole Sulfamoyl (H ₂ N-SO ₂ -) or mono- or dialkylaminosulfonyl (alkyl) ₂ N-SO ₂ , wherein reference may be made to the above explanations for the definition of alkyl and also includes optionally substituted alkyl. Optionally substituted alkoxy is included above mentioned exemplified as a substituent of aryl it alkoxy, which may optionally be substituted by preferably 1 to 3 substituents, which are preferably selected from the group of halogen, hydroxy and cyano

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are preferably selected from hydrogen, Halogen,

cyano,

nitro,

carboxyl,

aminocarbonyl,

Sulfonic acid (-SO ₃ H),

Aminosulfonyl, optionally substituted alkyl, and optionally substituted alkoxy

More preferably, R ^3, R ^4, R ^5, R ^6, R ^7, R ^8, R ^9, and R ¹⁰ are selected from ¹ is hydrogen, halogen, and optionally substituted alkoxy

Preferably, at least 6, more preferably at least 7 of the radicals R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ^{10 are} hydrogen. Most preferably, all radicals R ³ , R ⁴ , R ^ö , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ° are hydrogen.

R ^{1 1} is in the general formula (1) optionally substituted alkanediyl or optionally substituted alkenediyl Optionally substituted alkanediyl is preferably a bivalent straight or branched alkanediyl radical having 1 to 7 preferably 1 to 6, more preferably 1 to 4 carbon atoms, which is optionally 1 to 3 May carry substituents which are selected from the group consisting of hydroxy, halogen and cyano and may be mentioned by way of example and preferably methylene, 1, 2-ethanediyl, ethane-1, 1-diyl, 1, 3-propylene, propane-1, 1 -diyl, propane-1, 2-dιyl, propane-2, 2-dιyl, 1, 4-butylene, butane-1, 2-dιyl, butane-1, 3-dιyl, butane-2, 3-dιyl, Pentan-1, 5-dιyl, pentane-2,4-dιyl, 3-methyl-pentane-2,4-dιyl and hexane-1 6-diyl A preferred, substituted alkanediyl radical is a hydroxy-substituted aikandiyl radical is optionally substituted alkenediyl preferably a divalent straight-chain or branched alkenediylres t of 2 to 7 more preferably 2 to 6, more preferably 2 to 4 carbon atoms which may optionally bear 1 to 3 substituents selected from the group consisting of hydroxy, halogen and cyano Examples which may be mentioned are ethene-1, 1-dιyl, ethene-1, 2-dιyl, propene-1, 1-diyl, prope-1, 2-dιyl, propene-1, 3-dιyl, but-1-ene -i, 4-diyl, but-1-ene-1,3-diyl, but-2-ene-1, 4-diyl, buta-1,3-diol-1,4-diyl, pent-2-ene-1 , 5-dιyl, hex-3-en-l, 6-dιyl and hexa-2,4-dιen-l, 6-dιyl.

In the context of the present invention, R ¹¹ is particularly preferably alkanediyl, more preferably alkanediyl having 1 to 3 carbon atoms, more preferably 1, 2-ethanediyl (-CH ₂ CH ₂ -) or 1, 3-propanediyl (-CH ₂ CH ₂ CH ₂ Most preferably R ^{11 is} 1,2-ethanediyl (-CH ₂ CH ₂ -)

In the general formula (1), X ^{1 is} selected from the group consisting of a single bond

Carbonyl (-CO-),

Sulfur (-S-),

Oxygen (-O-),

Sulfoxy (-SO-),

Sulfonyl (-SO ₂ -),

Azo (-N = N-), and an optionally substituted, saturated or unsaturated aliphatic radical having 1 to 6 carbon atoms

An optionally substituted, saturated or unsaturated ahphatic radical having 1 to 6 carbon atoms for X ¹ in the context of the present invention includes an optionally substituted alkanediyl as defined above, optionally substituted alkenediyl as defined above, and alkynediyl. Preferred is X ¹ alkanediyl, alkenediyl or alkynediyl of up to 4, having up to 2 carbon atoms, such as methylene (-CH ₂ -), which may optionally be substituted by hydroxyl (such as -CH (OH) -).

Most preferred are compounds of the general formula (1) in which X ^{1 is} carbonyl (-CO-)

The groups R ¹² and R ¹³ in the general formula (1) are used in the context of the present invention is selected from the following alternatives

1) R ^1? is hydrogen and R ¹³ is optionally substituted alkyl or hydroxyl, or

R ^{1 3} is hydrogen and R ^{1 2} is optionally substituted alkyl or hydroxyl,

The alternatives mentioned under 1) are equivalent per se They correspond to the case where one substituent of R ¹² or R ^{13 is} hydrogen and the other substituent is optionally substituted alkyl or hydroxyl

2) R ^{1 2} and R ^{1 3} are each alkyl, wherein at least one of the alkyl groups has at least one substituent, R ^{1 2} and R ^{1 3 are} thus substituted alkyl, or

3) R ^{1 2} and R ^{1 3} form, together with the nitrogen atom to which they are bonded, a saturated or unsaturated, optionally substituted 5 to 8-glιedrιgen cycle, which may optionally contain further heteroatoms

Alternative 1):

The above-mentioned alternative 1) is a preferred alternative in the context of the present invention. It is even more preferable in the context of this alternative ¹

R ^{1 2 is} hydrogen, and R ^{1 3} is substituted alkyl, or R ^{1 3 is} hydrogen, and R ^{1 2} is substituted alkyl

Alkyl here includes straight-chain or branched alkyl having 1 to 8, preferably 1 to 6, carbon atoms, cycloalkyl having 3 to 8, preferably 5 or 6 carbon atoms, or alkyl having 1 to 4 carbon atoms which is substituted by cycloalkyl, a possible examples of alkyl Reference may be made to the examples mentioned above for R ¹ and R ^2. Alkyl is particularly preferably a C 1 to Co, preferably C 1 to C 5, alkyl group which may be branched or straight-chain, in particular Methyl ethyl, propyl, 2-methylpropanol, butyl, such as n-butyl, 2-methylbutyl, 3-methylbutyl, pentyl, such as p-pentyi, or n-hexyl. Said alkyl groups are substituted by at least one substituent. Preferred substituents on alkyl are polar functional groups which contain one or more heteroatoms, which are preferably selected from N, O, S, halogen, such as Cl, F, Br and I substituents on alkyl include in the definition of R ¹² and R ¹³ in particular

A group of the formula

_- .y2 " _R ¹⁴ is where

X ^{2 is} selected from the group that consists of

carbonyl,

Sulfoxv, and

Sulfonyl, and R ^{1 4 is} selected from the group consisting of

Hydroxy, optionally substituted Ammo, and optionally substituted alkoxy

X ² is preferably carbonyl and R ^{1 4} is hydroxy

When R ^{1 4 is} hydroxy, the substituent group -X ² R ^{1 4} = carboxy is given. If R ^{1 4 is} optionally substituted ammo, this results, for example, in the substituent group -X ² R ^{1 4} = -CONH ₂ thus carbamoyl im Case of R ^{1 4} = ammo, or -X ² R ^{1 4} = mono- or dialkylammocarbonyl in the case R ^{1 4} = - alkylamino or dialkylamino When R ^{1 4 is} optionally substituted alkoxy, this results, for example, in the substituent group -X ² R ^{1 4} = alkoxycarbonyl in the case of R ^{1 4} = alkoxy, ie an ester group Substituents for alkyl in the definition of R ^{1 2} and R ^{1 3} preferably have at least one group, preferably one or two groups of the formula -X ² R ^{1 4}

More preferred substituents on alkyl in the definition of R ^{1 2} and R ^{1 3} include, besides the preferred existing group -X ² R ^{1 4,} the following Substituents

Guαnidmo,

Thiol (-SH),

Alkylthio, in particular methylthio,

Amino (-NH ₂ )

Mono- or dialkylalkylmmo,

Acylammmo, where Acy! in particular as defined above, saturated, unsaturated or aromatic, mono- or bicyclic, optionally substituted heterocyclic radicals, for example those mentioned above, optionally substituted heteroaromatic radicals, preferably imidazolyl, such as imidazol-5-yl, 1H-indolyl, such as 1H- indole-3-yl, optionally substituted aryl as described above, in particular phenyl, hydroxyphenyl, such as 4-hydroxyphenyl,

Alkoxyphenyl, such as methoxyphenyl,

hydroxyl,

Alkoxy as described above.

Alkyl in the definition of R ^{1 2} and R ^{1 3} preferably has one or two substituents, of which preferably at least one substituent is the group -X ² R ¹⁴ represents

In a preferred embodiment of the aforementioned alternative 1)

R ^{1 2 is} hydrogen and R ^{1 3 is} a radical A of a compound of the formula H ₂ NA or

R ^{l λ is} hydrogen and R ^{2 is} a radical A of a compound of the formula

H ₂ NA is where

A is a radical which is formally removed by cleavage of an amino group

(-NH ₂ ) from a natural or synthetic amino acid, a natural or synthetic Aminosauredeπvat or a

Polyammosaure or a Polyaminosauredeπvat derived For the sake of disappointment

For example, the amino acid H ₂ NA is glycine

, then A = R or R ^{1 3 is} a radical of the formula

More preferred compounds according to the invention are those in which A is the radical which is derived formally by cleavage of the amino group from an amino acid or an amino acid derivative (for clarification The formal cleavage of the amino group from an amino acid does not mean the cleavage of an amino group from a possibly present amide group (H ₂ N-CO-) but an amino group which is bonded to a carbon atom, that except H or C carries no further substituents Thus, the corresponding resulting by cleavage of an amino group of asparagine radical R ^{1 2} or R ¹³ would be

(the arrow symbolizes the binding site) and mcM

COOH

O NH

² (the arrow symbolizes the binding site))

More preferably, the residue A is derived from the cleavage of an H ₂ N group from the group of the following amino acids Alαnin, according to the case where R ^{1 2} or R ^{1 3} ethyl, substituted with

Carboxy, is

Arginine (less preferred) corresponding to the case where R ^{1 is 2} or R ^{1 is 3}

Butyl substituted with Carboxv and Guamdino is,

Asparagine, corresponding to the case where R ^{1 2} or R ^{1 3 is} ethyl substituted with aminocarbonyl (carbamoyl) and carboxy,

Aspartic acid corresponding to the case where R ^{1 2} or R ^{1 3 is} ethyl substituted with two carboxy groups,

Cysteine (less preferred) corresponding to the case where R ^{1 is 2} or R ^{1 is 3}

Ethyl substituted with thio (-SH) and carboxy,

Glutamine, corresponding to the case where R ^{1 2} or R ^{1 3 is} propyl substituted with aminocarbonyl (carbamoyl) and carboxy,

Glutamic acid, corresponding to the case where R ^{1 2} or R ^{l 3 is} propyl substituted with two carboxy groups,

Glycine, corresponding to the case where R ^{1 2} or R ^{1 3 is} methyl substituted with carboxy,

Histidine, corresponding to the case where R ^{1 2} or R ^{1 3 is} ethyl substituted with carboxy and imidazolyl,

Isoleucine, corresponding to the case where R ^{1 is 2} or R ^{1 is 3} 2-methylbutyi substituted with carboxy,

Leucine, corresponding to the case where R ^{1 2} or R ^{1 3 is} 3-methylbutyl substituted with carboxy,

Lysine, according to the case where R ^{1 2} or R ^{1 3} n-pentyl, substituted with carboxy and amino, wherein the bond via the

Carboxyl group neighborable amino group

(Arrow points to the binding line or the

Binding site) or via the terminal amino group

(Arrow points to the binding line or the

Binding site), the corresponding compounds of the formula (1) thus appear as follows , ]

respectively

analogous to other basic amino acids with more than one

Amino)

Methionine corresponding to the case where R ^{1 2} or R ^{1 3 is} n-propyl substituted with carboxy and methylthio,

Phenylalanine, corresponding to the case where R ^{1 2} or R ^{1 3 is} ethyl substituted with carboxy and phenyl,

Senn, corresponding to the case where R ^{1 2} or R ^{1 3} ethyl, substituted with

Carboxy and hydroxy, is Threonine, corresponding to the case where R ¹² or R ^{13 is} n-propyl substituted with carboxy and hydroxy

Tryptophan, corresponding to the case when R ¹² or R ^{13 is} ethyl substituted with carboxy and indolyl

Tyrosine, according to the case where R ^{1 2} or R ^{1 3} ethyl, substituted with

Carboxy and Hydroxyphenyi, is, and

VaIm, corresponding to the case where R ¹² or R ^{13 is} 2-methylpropyl substituted with carboxy, or derivatives, in particular esters or amides thereof, corresponding to the case where R ^{14 is} alkoxy or optionally substituted amino, or derivatives or Polyamiπosauren thereof, which arise by peptidic linkage with one or more further amino acids to the above or below mentioned amino acids

Other amino acid compounds or derivatives thereof which formally form an R ^{1 2} or R ^{1 3} radical by cleavage of an amino group include creatine (less preferred), creatinine, tauπn, or derivatives or polyamino acids thereof, which are linked by peptidic linkage with one or more several other amino acids to the above or below mentioned amino acids emerge. Furthermore, so-called non-proteinogenic amino acids are included, such as. 4-aminobutyric acid (GABA), L-homoseπn (2-amino-4-hydroxybutyric acid), ornithine (2,5-diamino novaleric acid), L- (+) - -Cιtrullin (N5- (aminocarbonyl) -L-ornithine), 5- Hydroxytryptophan (5-HTP), ß-Aianιn (3-aminopropionic acid), ß-methylammo-Alanιn, D-VaIm, D-Alanιn, D-glutamic acid and 2,6-Dιamιnopιmelιnsaure

The derivatives of the aforementioned amino acid compounds H ₂ NA are in particular those which have arisen by exchange of a hydrogen atom for a hydroxyl function

Very particular preference is given to compounds of the invention in which the radical A is derived formally by cleavage of the H ₂ N group from the group of the amino acids glycine and its derivatives and histidine and derivatives thereof Most preferred are compounds according to the invention in which the radical A is derived by cleavage of the H ₂ N group from the group of the following amino acids or amino acid derivatives: glycine,

corresponding to R ^{1 2} or R ^{1 3} =

Glycinamide: (2-amino-acetamide), corresponding to R ^{1 2} or R ^{1 3} =

glycine:

(Amino-acetic acid ethyl ester), corresponding to R ^{1 2} or R ^{1 3}

Histidine. correspondingly R or R ^{1 3} =

or the Hislidinamide

(2-Amιno-3- (1 H -ιιιιιιαι) -propιonamιd), corresponding to R ^{1 2} or R ^{1 3} =

With the exception of glycine, all amino acids have asymmetric Kohlenstoftatome The erfmdungsgemaßen compounds in which R ¹² or R ^{13 is} a radical A, which results formally by cleavage of an amino group from a natural amino acid, therefore, has the natural configuration (L-Konfιguratιon) of the amino acid This also applies to the compounds which formally form by cleavage of an amino group from an amino acid derivative, a polyamino acid and a polyamino acid derivative. According to the invention, however, the FAN is also suitable included, in which the amino acids have the non-natural D configuration, such as D-Alanιn, D-Glutamιnsaure etc ..

Erfmdungsgemaß are the compounds wherein the amino acids H ₂ NA have the L-configuration, or wherein R ^1? or R ^{1 3 represent} the radical A of such an amino acid, and preference is given to those compounds in which the underlying Aminosauredπvate, the polyamino acids and the Polyaminosauredπvate derived from amino acids H ₂ NA, which have the L configuration

In view of their better Wasserloshchkeit further compounds are preferred in which the radical R ^{1 2} or R ^{1 3} formally by elimination of an NH ₂ group from an acidic Ami nosäure with at least two carboxyl groups such as aspartic acid, glutamic acid also results in the use of hydroxyl Group-containing amino acids such as threonine may be preferred in this aspect

Alternative 2

In the above-mentioned alternative 2) wherein R ^{1 3} alkyl are each ^{1 2} and R, wherein at least one of the alkyl groups one, preferably one or two substituents comprising at least, can be in terms of the definitions or examples of alkyl to the above for R ¹ or R indicated in alternative 1) ² or R ^{1 2} and R ^{1 3} are referenced substituents on alkyl include thus, for "optionally substituted alkyl" in the definition of R ¹ and R ² given example, such as hydroxy, halogen and cyano Additionally, close potential Substituents of alkyl in the alternative 2) also the examples given for R ^{1 2} and R ^{1 3} in the above-described alternative 1), such as

Guanidmo,

Thiol (-SH),

Alkylthio, in particular methylthio,

Amino (-NH ₂ )

Mono or dialkylamino,

Acylamino, in which acyl is in particular as defined above, saturated, unsaturated or aromatic, mono- or bicyclic, optionally substituted heterocyclic radicals, such as, for example, the above-mentioned optionally substituted heteroaromatic radicals, preferably imidazolyl, such as lmιdazol-5-yl, 1 H-indolyl, such as IH indol-3-yl, optionally substituted Aryl, as described above, in particular phenyl, hydroxyphenyl, such as 4-hydroxyphenyl,

Alkoxyphenyl, such as methoxyphenyl,

hydroxy,

Alkoxy as described above, and a group of the formula:

2, -, 14

- X R, wherein XV ² 2 un _^ d, ~ ι R ¹ n i ⁴ 4 are as defined above, and in particular the radicals which formally from the cleavage of the NH ₂ - group resulting from the amino acids NH ₂ -A

Alternative 31

In the above-mentioned alternative 3), in which R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 5 to 8-glifluorinated cycle which may optionally contain further heteroatoms, include possible ring systems, consisting of R ^{1 2} and R ¹³ and the nitrogen atom to which they are attached, preferably 5- or 6-membered, optionally substituted rings such as Pιperιdιn- 1 -yl, Morpholιn-4-yl, rhιomorpholιn-4 yl, pyrrolidine! -yl, oxazolιdιn-3-yl, thiazolidin-3-yl, 2-carboxy-pyrrolιdιnι-l -yl (prolyl), 3- or 4-hydroxy-carboxy-Pyrrolιdιn- l - yl (3- or 4-hydroxy prolyl), etc. Particularly preferred here are prolyl or hydroxy-prolyl

Tπazene compounds which are particularly preferred according to the invention are those in which R ¹ and R ^{2 are} each alkyl, preferably alkyl having 1 to 6 carbon atoms, more preferably methyl

According to the invention particularly preferred Tπazenverbindungen are those wherein R ^3, R ^4, R ^5, R ^6, R ^7, R ^8, R ⁹ and R ^{1 0} are each hydrogen Triαzenverbmdungen particularly preferred according to the invention are those in which X ¹ Cαrbonyl

Particularly preferred coupling compounds according to the invention are those in which R ^{1 is} alkynyl, preferably linear alkanediyl having 1 to 6 carbon atoms, more preferably methylene (-CH ₂ -) or ethane-1, 2-diyl.

According to the invention, particularly preferred triazene compounds are those in which the radicals

X ¹ and the rest on the phenylene radical para each other.

According to the invention, particularly preferred triazene compounds are those in which the radicals

X ¹ and the rest on the phenylene radical para each other.

According to the invention, particular preference is given to compounds of the formula (2):

According to the invention, particular preference is given to compounds of the formulas or (2) in which R ¹ and R ^{2 are} each Aikyl,

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ^{10 are} each hydrogen,

R ^{1 1 is} alkanediyl,

R ^{12 is} hydrogen and R ^{1 3 is} a radical A of a compound of the formula H ₂ NA or

R ^{13 is} hydrogen and R ' ^{2 is} a radical A of a compound of the formula H ₂ N

A is where

A is a radical which is derived by cleavage of the amino group (-NH ₂ ) from a natural or synthetic amino acid, a natural or synthetic Aminosauredπvat or a Polyaminosaure or a Polyaminosaurederivat, and

X ^{1 is} carbonyl (-CO-).

Most preferred are the compounds selected from the group consisting of ¹

(Example 1 (Example 5)

^' (Example 6) (Example 3)

^' or pharmaceutically-acceptable salts thereof.

Furthermore, pay the following connections

(free acid of

Example 9),

(free acid of Example 7) and 9R -

(Example 8)

and their pharmaceutically acceptable salts to the preferred compounds

(In these structural formulas, by way of example, this means a structural element

the formula a dimethylamino group, ie the methyl groups are represented by simple dashes, a notation familiar to those skilled in the art

Well known is analogue poses a shortened spelling of a

Methylene radical (-CH ₂ -) represents)

According to the invention, compounds of the formula (1) are furthermore preferred in which

R ^{1 2 is} hydrogen and R ^{13 is} substituted alkyl, or R ^{13 is} hydrogen and R ^{12 is} substituted alky! is in which

substituted alkyl is an alkyl group which has at least one sulfonic acid radical, sulfonic acid ester radical or a sulfonamido radical In this connection, compounds in which substituted alkyl in the definition of R ¹² or R ^{1 3 is} a radical of the forms are particularly preferred!

H,

.SO ₃ H

H 2, which is derived from Tauπn (2-Aminoethansulfonsaure) Tπαzen compounds of the invention containing basic groups can be used in the form of their pharmaceutically acceptable salts with pharmaceutically acceptable acids such as salts with mineral acids, carboxylic acids and sulfonic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, tartaric , Methanesulfonic acid, hydroxyethanesulfonic acid, aceturic acid (acetylglycine), maleic acid, propionic acid, fumaric acid, toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, naphthalenedisulfonic acid 1, 5, sahcylic acid, benzoic acid, lactic acid, malic acid, 3-hydroxy-2-naphthoic acid-2, citric acid or acetic acid,

Triazene compounds of the invention containing acidic groups may be employed in the form of their pharmaceutically acceptable salts with pharmaceutically acceptable bases, such as, for example, salts with alkali or alkaline earth hydroxides, such as NaOH, KOH, Ca (OH) ₂ , Mg (OH) ₇ etc., amine compounds such as ethylamine, diethylamine, trimethylamine, ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine, methylglycine, dicyclohexylamine, dimethylammoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine 2-amino-2-methyl- propanoi (I), 2-amino-2-methyl-propanediol (1,3), 2-amino-2-hydroxyl-methyl-propanediol (1,3) (TRIS) etc.

The water solubility or the solubility in physiological saline solution and thus possibly also the activity of the compounds according to the invention can be significantly influenced by salt formation in general, especially by the choice of the counterion. For example, the sodium salt of the compound

(Example 4α) a looseness in water at 25 ° C of about 4 g / L, whereas the TRIS salt has a similarity in water at 25 ° C of about 250 g / L

The waterlessness or the detachment in physiological saline solution and thus possibly also the activity of the compounds according to the invention may also depend significantly on the basic structure of the compounds themselves. For example, the compound of example 2 a) surprisingly has a very good water-solubility of 500 g / L at room temperature (25 ° C) which is much higher than that of the compound of Example 4a) (4g / L) even though it has one more methylene group

A high Wasserloshchkeit of the compounds of the invention is not necessarily crucial, since in the bloodstream probably the vast majority of the substance present protein bound is of importance in general rather that the substances are recognized as a substrate for an endogenous transport system in the context of the present invention probably, in particular, the so-called OATs (organic anion transporters) and OATPs (organic anion transporter proteins) of importance But these have no 1 00% specificity for anions Example of this is the digitoxin Similarly, also peptide transporters as relevant uptake and excretion mechanisms, the amino acid or amino acid amide -Rest recognize, be discussed

The use of 2-amino-2-hydroxyl-methyl-propanediol (1, 3) (TRIS) - and Natnum salts is preferred against the background of increasing the Wasserloshchkeit of the invention Vernindungen

The invention compounds, depending on their structure, may exist in the presence of asymmetric carbon atoms in stereoisomeric forms (enantiomers, diastereomers). The invention therefore includes the use of the enantiomers or diastereomers and their respective mixtures. The enantiomerically pure forms may optionally be prepared by conventional optical resolution methods such as fractionated crystallization of diastereomers thereof can be obtained therefrom by reaction with optically active compounds. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses the use of all tautomeric forms

The present invention further relates to a process for the preparation of the compounds of formula (1) which comprises the step

Reaction of a compound of the formula (3)

ode ^r a salt such as in particular the sodium or Kahum Cσlciumsalz thereof, with a compound of formula (4)

wherein R ¹ to R ^{1 are 3} and X are as defined above

The preparation of the Tπazenverbindungen (3) can be obtained analogously to the method described in DE 1 7931 1 5 Al by diazotization of the underlying amino compound, which in turn is obtained by reduction from the corresponding nitro compound The following scheme illustrates the preparation method using the example of {2- 4- (4- [(IE) -3-dimethyl-1-triazenyl] -benzoyl) -phenoxy] -propιonylamιno} essιgsaure

Step 1

The steps shown represent known reaction types (Friedeis Grafts Acyiierung, hydrogenation or, reduction of the nitro group, diazotization, amidation and saponification), which can be carried out in a conventional manner, By reacting with a pharmaceutically acceptable base to obtain the corresponding salt , Anilen of Methylglycinats can also other amino compounds of the formula:

In particular, other amino acids or derivatives thereof are used in step 5

Analogously to the above scheme one obtains

{2- [4- (4 - [(L E) -3, 3-Dimethyl-triazenyl] -benzoyl) -phenoxy] - acetylamino} acetic acid and salts thereof starting from phenoxyacetic acid, which in step 2 with p-nitrobenzoyl chloride in a Fπedels -Craft reaction is implemented

With regard to the stilbene derivatives in which X ¹ = -CH = 1 CH-, reference may be made, for example, to WO2004 / 1 06358. The preparation of further starting compounds is described in the already mentioned DE 1 7931 1 5 A1, DE 21 47781 A1 and in US Pat DE 1 768 720 A1

With regard to preferred reaction conditions, reference is made to the examples

The hydroxamic acid derivatives in which one of R ^1? or R ^{13 is} hydrogen and the other hydroxyl can, for example, analogously to US 200701 35424 A (for example, intermediate 24) by reacting the acid

with O- (tetr-ahydro-2H-pyrαn-2-yl) -hydroxylαmm to the compound of the formula

can be subsequently converted recordable by reaction with Tπfluoressigsaure in the corresponding hydroxamic acid

Some of the intermediates used according to the invention are novel and contribute to the properties of the end products via the structural elements contributed by them. Accordingly, the invention also relates to new intermediates, in particular of the formula (3 ')

where x is from 2 to 6, preferably 2, and their salts

The present invention furthermore relates to compounds of the formula (1) for use as medicaments and to the use of the compounds of the formula (1) for the preparation of a medicament, in particular for the treatment of cancers

The compounds according to the invention can be used, for example, for the treatment of the following tumor types: adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neuroma, ampoule carcinoma, anal carcinoma, astrocytomas, basalioma, pancreatic cancer, connective tissue tumor, bladder cancer, bronchial carcinoma, non-small cell lung carcinoma, breast cancer, Burkitt's lymphoma, corpus carcinoma, CUP - syndrome, colon cancer, small intestine cancer, small intestine tumors, ovarian cancer, endornetrium carcinoma, ependymoma, epithelial cancers, Ewmg tumors, gastric tumors, gall bladder cancer, bile carcinomas, uterine cancer, cervical cancer, glioblastomas, gynecological tumors, ear, nose and throat tumors, hematological neoplasias, Hairy cell leukemia, urinary cancers, cancer of the head, brain tumors (gliomas), brain metastases, testicular cancer, pituitary, carcinoids, Kaposi's sarcoma, throat cancer, germ cell tumor, bone cancer, colorectal carcinoma, head and neck tumors (tumors of the ear, nose and throat ereichs), colon carcinoma, craniopharyngiomas, cancer of the mouth and on the lip, liver cancer, liver metastases, leukemia, lid tumor, lung cancer, lymph node cancer (Hodgkin / Non-Hodgkm), lymphoma, gastric cancer, malignant melanoma, malignant neoplasm, gastrointestinal murmur Tracts, breast cancer, rectal cancer, medulloblastoma, melanoma, meningiomas, Merkelzell carcinoma, Hodgkin's disease, mycosis fungoides, nasal cancer, neuroma, neuroblastoma, kidney cancer, renal cell carcinoma, non-Hodgkm lymphoma, oligodendroglioma esophageal carcinoma, osteolytic carcinoma and osteoplastic carcinoma, osteosarcoma, ovaπal- Carcinoma, pancreatic carcinoma, penile cancer, plasmocytoma, squamous cell carcinoma of the head and neck, prostate cancer, Rectal cancer, Rectal cancer, Retinoblastoma, Vaginal cancer, Thyroid carcinoma, Schneeberger's disease, Rice cancer, Spinalioma, T cell lymphoma (Mycosis fungoides), Thymoma, Tubal carcinoma, Tumors of the eye, Ureteral cancer, Urological tumors, Urothelial carcinoma, Vulvar cancer Warts involvement, Soft tissue tumors, Soft tissue sarcoma, Wilms tumor, Cervical carcinoma and tongue cancer In addition, reference can also be made to the uptake of the cancers, for example in WO2007061 978 (page 16, line 22 to page 18, line 2) or in US20071 35424A1 (page 9, left column, section 12), which The compounds of the present invention can also be used in other indications, such as those mentioned in US20071 35424A1 in sections 1 23 to 1 42 mentioned

The compounds according to the invention are particularly preferably used for the treatment of breast cancer, colon cancer or melanoma

The compounds according to the invention are particularly preferably used for the treatment of breast cancer

The invention further relates to the use of the compounds of the formula (1) in combination with at least one further chemotherapeutic agent for the treatment of cancer

Accordingly, 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 with drugs which are administered concomitantly with the chemotherapeutic agents during chemotherapy. Examples of such chemotherapeutic agents which may be used in combination and others in US Pat Chemotherapy used drugs can be found for example in WO2007061 978 under the keyword "Combmation Therapy" (page 23, line 1 to page 30, line 1 8) or in US20071 35424A1 (sections 1 53 to 1 71), to which also in full extent Reference is made The present invention furthermore relates to pharmaceutical compositions comprising at least one of the compounds of the formula (1) together with at least one pharmacologically acceptable carrier, excipient or solvent. These are customary pharmaceutical carriers, excipients or solvents. Named pharmaceutical compositions are suitable, for example for inhalation or intravenous, intraperitoneal, intramuscular, intravaginal, intrabuccal, percutaneous, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, intragasal or intracutaneous administration and are in the form of pills, tablets, enteric-coated tablets, film-coated tablets, for example. Layered tablets, sustained-release formulations for oral, subcutaneous or cutaneous administration (in particular as a patch), depot formulation, dragees, suppositories, gels, ointments, syrups, inhalable powders, granules, suppositoπs, emulsions, dispersio NEN, microcapsules, microforming, nanoformulations, liposomal formulations, capsules, enteric capsules, powders, inhalation powders, microcrystalline formulations, inhalation sprays, powders, drops, nose drops, nasal sprays, aerosols, ampoules, solutions, juices, suspensions, emulsions, infusion solutions or injection solutions, etc .. ,

The compounds of the invention may be administered in pharmaceutical composition which may contain various organic or inorganic carriers and / or auxiliary materials commonly used for pharmaceutical purposes, in particular solid drug formulations, such as excipients (such as sucrose, starch, mannitol, sorbitol, Lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate), binders (such as cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch), disintegrants (such as starch, hydrolyzed starch, carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropyl starch , Sodium glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate), lubricants or lubricants (such as Mineral acid, talc, sodium lauryl sulfate), a flavoring agent (such as citric acid, menthol, glycine, orange powder), preservatives (such as sodium benzoate, sodium bisulfite, methylparaben, propylparaben), stabilizers (such as citric acid, sodium citrate, acetic acid, and multicarboxylic acids of the titanium series such as B , Diethylentπaminpentaessigsaure (DTPA), suspending agents (such as methylcellulose, Polyviπylpyrrohdon, Aiuminiumstearat), dispersants, diluents (such as water, organic solvents), beeswax, cocoa butter, polyethylene glycol, white petrolatum, etc.

Liquid drug formulations, such as solutions, suspensions and gels, usually contain a liquid carrier, such as water and / or pharmaceutically-acceptable organic solvents. Furthermore, such liquid formulations may also contain pH adjuvants, emulsifiers or dispersing agents, buffering agents, preservatives, wetting agents, gelling agents ( The compositions may be isotonic, that is, they may have the same osmotic pressure as blood. The isotonicity of the composition may be enhanced by the use of sodium chloride or other pharmaceutically acceptable agents such as dextrose, maltose, boric acid , Sodium tartrate, propylene glycol or other inorganic or organic soluble substances. The viscosity of the liquid compositions can be adjusted using a pharmaceutically acceptable thickener such as methylcellulose. Other suitable thickening agents include, for example, xanthan, carboxymethylcellulose, hydroxypropylcellulose, carbomer and the like. The preferred concentration of thickening agent will depend on the agent chosen. Pharmaceutically acceptable preservatives may be used to obtain benzyl alcohol may be suitable although a variety of preservatives including, for example, paraben, thimerosal, chlorobutanol or bezalkonium chloride may also be used to enhance the durability of the liquid composition; As Stαbilisierungsmittel for the pharmaceutical solid or liquid formulations of the compounds of the invention, in particular the compound of Example 2a), proves in particular the Diethylentπaminpentaessigsaure (DTPA)

The active ingredient may be administered, for example, at a unit dose of 0.01 mg / kg to 500 mg / kg of body weight, for example up to 1 to 4 times a day. However, the dosage may vary depending on the age, weight, condition of the patient, severity of the disease or type increased or decreased

The invention is further illustrated by the following examples. The examples are merely exemplifications and the person skilled in the art is capable of extending the specific examples to other claimed compounds

EXAMPLES:

STARTING PREPARATIONS: Preparation 1.:

The preparation of the starting compound

is carried out according to the following reaction scheme:

CICHoCHXl

Na ₇ SH ₉ O

1. HClHoO

2.NaXOo

Na ₂ CO ₃ H ₂ O HN (CH ₃ );

All output products are well known and documented. The NMR spectra of all synthesized products are consistent with the structure

step

MG 301. C 1 5H 1 1 NO6

0.5 mol

To a suspension of 235g AICI ₃ in 1 liter of dichloroethane is added dropwise

Stirring at 0 ° -5 ° C 1 02 g p-nitrobenzoyl chloride (0.55 mol) dissolved in 300 ml

Dichloroethane slowly added in this solution is carried at 5 ° C 76 g

Phenoxyessigsaure in portions then one 4 h at 1 ^{0 0} C u 1 0 Std. followed at room temperature

refurbishment;

600 ml of dichloroethane are distilled off 600 ml ligroin added The

Mixture is then poured onto 2 l of ice / water, the aqueous phase is separated off and the precipitated crystalline product is filtered off with suction, washed with water and dried.

Yield. 1 00 g, mp. 1 86 ° C, white product

Stage II

MG 27 1; C 1 5H 1 3NO4, Lit Houben Weyl 1 1/1 p. 41 7

0, 5 mol

320 g of I are boiled in 1 liter of ethanol while stirring under reflux. A solution of 350 g of Na ₂ S is carefully added dropwise to 350 ml of water (strongly exothermic, H ₂ S absorption). The mixture is refluxed for 2 hours The reaction mixture is then allowed to stand for about 10 hours

Room temperature,

Work-up:

The alcohol is distilled off u, the residue under stirring with 3 l hot

Extracted water and filtered off with suction while hot. The filtrate is acidified with glacial acetic acid and the precipitated product is filtered off with suction, washed with water, again filtered off with suction and dried

Purification, from ethanol

Yield: 200 g = 74%, pale yellow product;

Mp: 1 72 ° C,

step

MG; 349; C I 7H 1 6N3O4Nα

0.1 mol

A solution of 6.9 g of NaNO ₂ in 20 ml of water is added dropwise with stirring at 0 ⁰ C to a solution of 27, 1 g Il, 350 ml of water u, 1 0.4 g concentrated HCl (37%) u , at ⁰ ° C. for another 15 minutes, stirred,

The resulting diazonium salt solution is added to a solution of 1 5 g of Na ₂ CO ₃ u, 10 g of a 45% strength aqueous dimethylamine solution and 50 ml

Water without stirring at 0 - 5 ° C added dropwise.

Work-up:

The reaction mixture is kept cold, the precipitated salt is filtered off and recrystallized from water,

Cleaning:

Reconfiguration from water Solubility: 1 g in 25 ml of water

Yield: 10 g = 28%, beige; Fp of the acid: 1 60 ° C. The acid gets through

Get lots of salt in water and precipitate with acetic acid, PREPARATION 2 "

The preparation of the phenoxypropionyl Ausgαngsverbindung

^' takes place as shown in the diagram in the description section

Step 1 :

The following Mateπalen were used in the specified amounts

Phenol and ethyl acrylate were placed in a 5 L 3N glass flask equipped with a thermocouple, and a top cherish ligand stirrer, added Triton B was added, and under reflux (1 20 ⁰ C) was heated for 48 hours The TLC showed that a small amount of phenol still present The reaction composition was worked up as follows. Ethyl acrylate was removed and the residue was dissolved in ethyl acetate, washed with aq. NaOH (10%) followed by water (3.0 L) and dried over anhydrous sodium sulfate. The dried organic layer became a residue concentrated, and the residue was put into a 1 0.0 LRB glass flask conc HCl added and heated for 24 hours under reflux the TLC was checked and the reaction composition is cooled to 25 ⁰ C. the solids were filtered and washed with water (I 5) washed well the Product was dried in an oven in vacuo at 30 ⁰ C overnight

Yield 450 g (27% of theory) Purity (HPLC); 98.32%,

(Alternatively, the product can also be prepared by saponification of the underlying nitrite according to the following scheme:

Step 2 :

The following materials were used in the indicated amounts:

In a 3 I 4 N (neck) flask were added 4-nitrobenzoic acid, thionyl chloride and DMF and heated at 78 ⁰ C for 2 hours under reflux. The end of the reaction was monitored by the clarity of the reaction composition. It was a kiare solution at the end of the reaction. Thionyl chloride was removed under reduced pressure, dichloroethane (1 L) was added and evaporated to give 4-nitrobenzoyl chloride as a solid. The solid was dissolved in dichloroethane (1 L). Dichloroethane (1 0 I) was placed in a 20 L glass flask and cooled to 0 ° C, aluminum chloride was added at 0-5 ° C, then the above prepared 4-nitrobenzoylchloride dissolved in dichloroethane was added dropwise at 0-5 ⁰ C, Phenoxypropionic acid was added in portions to

Reaction composition at 0, 5 ⁰ C and overnight at 25 ° C. The TLC was checked and the reaction composition was quenched in a mixture of hexane (8 L) and ice-water (15 L). The composition was stirred and the solids were filtered off. The product was washed with hexane and dried

Yield 400 g (70% of theory) Purity 92, 8% at HPL C

step 3

The following Mateπalen were used in the specified amounts

The product from step 2 was taken up in ethanol and cooled to 1 0 ⁰ C. Aqueous solution of the sodium sulfide was added dropwise at 1 0- 1 5 ⁰ C and stirred overnight at 25 ⁰ C ethanol was removed and water [AI] was under reduced pressure added acetic acid was added to adjust the pH to 6. The pH of the filtrate was adjusted to 3 with acetic acid and extracted with ethyl acetate (3 L). The organic layer was dried and concentrated to a residue

Yield 1 68 g purity> 70% in HPLC

A similar batch was made with 230 g of the product from step 2

Yield 1 08 g

Purity 66, 1% at H LPC The two above lots of product were mixed and reprecipitated from ethanol.

Combined Yield I T O g (I 9.3 of theory) Purity. 95.6% for HPLC,

Step 4:

The following Mateπalen were used in the specified amounts

Mixed product from Step 3, water (2 L) and conc HCl were cooled to 0 ^° C. Sodium nitrite was dissolved in water (150 ml), added at 0-5 ⁰ C and stirred for 30 minutes.

In another glass flask Natπumcarbonat was dissolved in water (1 60 ml), added dimethylamine and cooled to 0 ⁰ C. The sodium diazonium salt was added slowly to the above prepared solution at 0-5 ⁰ C and stirred for 1 hour. The TLC was checked and the reaction was completed. The pH of the reaction composition was adjusted to 3 with acetic acid and extracted with ethyl acetate (1.2 L). The organic layer was washed with water (200 ml x 2), dried over anhydrous sodium sulfate and concentrated to a solid.

Ron yield: 1 09.5 g Purity: 84, 7% The crude product was purified by column chromatography (20% THF in ethyl acetate)

Yield 85 g (64.6 of theory) purity 93.3% in HPLC

The product of preparation 2 has a melting point of 1 24 5 to 1 25, 8 ° C.

Figure 1 9 shows the 1 H-NMR spectrum of the compound obtained

Example 1 ;.

(Step 5 of the above scheme):

The following materials were used in the indicated amounts.

The product from step 4 was dissolved in DCM and cooled to 1 0 ⁰ C. To the EDC HCl and HOBT were added and stirred for 30 minutes Methyiglycinat has been added at 1 0 ⁰ C and stirred overnight at 27 ⁰ C. The TLC was checked and the reaction was found to be complete. Water (1 L) was added and the layer separated. The organic layer was dried over sodium sulfate and concentrated to a residue.

Raw yield: 1 1 0 g purity 91, 3% at H PLC

The Ron product was further purified by column chromatography (10% ethyl acetate in hexane),

Yield: 89 g (86% of theory) Purity: 95.4% for H PLC. The product is a pink powder with a melting point of 1 04.0 to 1 05.0 ⁰ C, in the mass spectrum a main peak is observed at 41 3.5 (M + 1)

Figure 1 shows the ¹ H-NMR spectrum (400 MHz) of the compound of Example 1.

Figure 2 shows the ^{1 3} C-NMR spectrum (1 00 MHz) of the compound of Example 1,

Example 2:

(Step 6 of the above schema)

The following materials were used in the indicated amounts:

The product from Step 5, THF and water were mixed and cooled to 0 ^° C. Lithium hydroxide (4.5 g) was added portionwise at 0 ^° C and stirred for 20 minutes. The TLC was checked, the reaction had not started. Another batch of LiOH (4.5 g) was added and stirred for 30 minutes. The TLC was checked and found to have begun the reaction. The reaction composition was held for 1 hour and the TLC was checked. A very small amount of substrate remained. Yet another batch of lithium hydroxide (0.5 g) was added The TI C was checked after 30 minutes and the substrate was gone. THF was removed in vacuo and the residue diluted with ethyl acetate (2 L). The pH was adjusted to 5-6, a clear solution was obtained. It was washed with water (200 ml × 2), dried over sodium sulfate and concentrated to a residue

Yield ¹ 72 g

The crude product was further processed by column chromatography (DCM / methanol)

Yield: 46 g (53.5% of theory) Purity: 95.9%,

The product is a yellow hygroscopic solid. In the mass spectrum, a major peak is observed at 399.1 (M + 1).

Figure 3 shows the ¹ H-NMR spectrum (400 MHz) of the compound of Example 2,

Example 2 q):

To 7 g of the compound obtained in Example 2 was added a solution of sodium carbonate (1.49 g, 0.01-40 mol) in water (3.75 mL). To this was added ethyl acetate (50 mL) and stirred. The precipitated product was stirred with tetrahydrofuran (1 00 mL) overnight (ca, 1 2 hours) at room temperature (25 ° C), the solid was filtered off and washed with dichloromethane (50 mL) and ethyl acetate (100 mL), the solid Was dried in Vαkkum at 50 ⁰ C overnight (about 1 2 hours) and the sodium salt of the compound of Example? has been received

Yield 5 7 g (56% of theory) Purity HPLC 97.4%

The product is a pale orange crystalline powder. It surprisingly has a very good water solubility of 500 g / L at room temperature (25 ^° C.), which is in particular much higher than that of the compound of Example 4a), even though it has one more methylene group

Figure 4 shows the λ NMR spectrum (400 MHz-D ₂ O) of the compound obtained in Example 2a)

Figure 5 shows the ¹³ C-NMR spectrum (1 00 MHz - d ⁶ -DMSO) of the compound obtained in Example 2a)

Example 3

Analogously to Example 1, the following compound was obtained starting from Preparation 1 with ethyl glycinate as a yellow powder in a purity of> 95% (HPLC)

Figure 6 shows the result of HPLC of the compound obtained in Example 3 Example 4

Analogously to Example 2, the following compound was obtained starting from Example 3

Yellow solid, purity (HPLC)> 99%, melting point 1 30, 7 to 1 31, 2 ⁰ C.

Figure 7 shows the ^ NMR spectrum (400 MHz -d ⁶ -DMSO) of the compound obtained in Example 4

Figure 8 shows the ¹³ C-NMR spectrum (1 00 MHz - d ⁶ -DMSO) of the compound obtained in Example 4

Example 4a)

Analogously to Example 2a), the sodium salt of the compound of Example 4 was obtained by reaction with Natπumcarbonat

It is a cream-colored powder with a melting point of 253, 2 to 253.9 ⁰ C.

Figure 9 shows the 'H-NMR spectrum (400 MHz - D ₂ O) of the compound obtained in Example 4a)

Figure 1 0 shows the ¹³ C-NMR spectrum p θθ MHz - d ° -DMSO) of the compound obtained in Example 4a)

Analogously, by reaction with other bases such as TRIS (Trιs (hydroxymethyl) ammomethane or 2-amino-2- (hydroxymethyl) -propane-1,3-dinol), further salts of the compound of Example 4 can be obtained In particular, the TRIS SaIz has a significantly higher

Water-solubility at room temperature as the sodium salt aut (250 g / L corresponding to a factor of about 60 in relation to the sodium hydroxide), which also has a pronounced salting-out effect in 0.9% NaCl

Example 5

Analogously to Example 1, the following compound was obtained starting from Preparation 1 with histidine amide as a yellow powder in a purity of> 95% (HPLC)

Figure 1 1 shows the result of HPLC of the compound obtained in Example 5

Example 6

Analogously to Example 1, the following compound was obtained starting from glycinamide as a light brown powder in a purity of> 95% (HPLC)

Figure 1 2 shows the result of HPLC of the compound obtained in Example 6 Example .7

(4-Cαrbαmoyl-2- {3- [4- (4 - [(L E) -3,3-dιmethyH-tπαzenyl] -benzoyl) -phenoxy] -propιonylαmιno} -butαnsαure-Nαtπumsαlz)

was based on

(3- {4- {4- [(I E) -3, 3-Dimethyl-1-t-zenazyl] -benzoyl} -phenoxy} -propionic acid)

prepared as follows

In a 1 L three-necked round bottom flask with thermocouple pocket and riorer were on an ice-water bath (3- {4- {4 - [(l E) -3,3-dimethyl-l -tπazenyl] - benzoyl} -phenoxy} propιonsaure) (40g, 0.1 liter, 73 mol) as starting compound, HOBt (3, 7g, 0.0274 mol) and dioxane (300 mL). To this was added a solution of DCC (40.66 g, 0.1970 mol) in dioxane ( 10 ml) was added dropwise over a period of 5 to 6 hours, the temperature being kept between 20 and 25 ° C. In another 2 l three-necked round-bottomed flask with thermocouple pocket and Ruhrer, L-glutamine (43, 20 g of 0.2956 mol) and saturated sodium bicarbonate solution (432 mL) were added to the above prepared dioxane solution and for 1 6 hours at 1 0 to 1 5 ° C. The progress of the reaction was monitored by TLC (thin layer chromatography) (MDC MEOH 1 L). After 16 hours, the TI C gave complete conversion of the starting compound. The pH of the reaction mixture was adjusted to 6 8 using HCl (1.5 N ) are set and the reaction mixture was concentrated under reduced pressure at 50 ⁰ C and concentrated the residue was added with water (20OmL) and stirred at 25 ⁰ C the slurry was filtered and the pH of the filtrate was adjusted to 3 08 (using HCl 1 5N The reaction mixture was extracted with ethyl acetate (200mL) and the phases were separated. The organic layer was dried over sodium sulfate (25g). The organic layer was rinsed with dry ammonia for 2 hours (a gummy residue was formed) and the supernatant liquid became Decanted The residue was spooled with a mixture of THF EtOAC (1 L, 10 mL) and decanted. The procedure was repeated five times (after this treatment, the residue was a flexible solid) and then (78 to 80 ⁰ C) was filtered The crude solid was dissolved in ethanol (1 00 mL) at under reflux for held for 1 hour, the hot slurry was filtered una the filtrate cooled to 20 ^° C. for 2 hours After 2 hours, the slurry was filtered and the filter cake (1 g) dissolved in water (1 20 mL). The pH of the solution was adjusted to 3 using HCl (1.5 N). The phases were separated and the organic layer was washed with water (6OmL). The organic layer was dried over sodium sulfate (20 g) and a solution of sodium carbonate (2.6 g) in water ( 8mL) was added thereto by THF (1 2OmL) was added and stirred for 2 hours, the slurry was filtered and (VTD in Vaccum tray Dπer) at 50 ⁰ C for 1 6 hours dried The dried product was anal ysiert Yield 1 1 2 g (1 9 44% of theory)

The compound is obtained as a pale orange powder having a melting point of 1 81 0 to 1 82 5 ⁰ C.

The solution in water at 25 ⁰ C is about 400 g / L Similarly, other salts can be obtained by reaction with corresponding bases, such as TRIS, instead of Natπumcarbonat

Figure 1 3 shows the 'H-NMR spectrum of the compound obtained in Example 7

Figure 1 4 shows the ¹³ C-NMR spectrum of the compound obtained in Example 7

Belsfil ^β LΘ.

was based on

(Compound of Example 2α))

prepared as follows

A 5 L three-neck round bottom flask equipped with a thermocouple and a stirrer was placed on an ice-water bath. To this was added the compound of Example 2a) (200 g, 0.476 mol) and water (2.0 L). The reaction mixture was stirred until a clear solution was obtained. and the pH of the solution was adjusted to 35 using 1.5N HCl. Dananch was added to ethyl acetate (2.0 L). The reaction mixture was allowed to stand for 30 minutes Washed water (1.0 L) was added to the organic layer (ie, the ethyl acetate layer). The organic layer was dried over sodium sulfate (100 g) and concentrated in vacuo at 50 ° ^C The reaction mass was transferred to a 2.0 L three-neck round bottomed flask equipped with thermocouple and riori The reaction mass was cooled to 0-5 ° C using an ice bath. EDC HCl (1 Ethyl 3- (3-dimethylaminopropyl) carbodiimide - 10g5g, 0.571 4mol) was added, followed by the addition of HOBT (11g, 0.7mol) at 0-5 ° C. Dry ammonia was added 2 hours, and then the reaction mixture was checked by TLC (MDC MEOH - 8 2) for the presence of the starting compound. The reaction was concentrated to dryness in vacuo at a temperature of less than 50 ⁰ C to ethyl acetate (1, 0 L ) And water (1 0 L) and the layers were separated, washing water (1 0 L) was added to the organic layer, the organic layer (about Natπumsulfat 1 00 g) and dried in vacuo at 5O ⁰ C concentrated isopropanol (800 mL) was added to the residue (80 g) and heated to 80 ° C to give a clear solution. The solution was gradually cooled to 25 ° C. The product was filtered off and washed with isopropanol (50 mL) dried at 5O ⁰ C for 1 2 hours in VTD yield 56 g (29.6% of theory)

The compound was obtained as a yellow to orange solid having a melting point of from 1 45.2 to 147.0 ° C. The dissociation in DMSO at room temperature was 833 g / L

Figure 1 5 shows the ^" Η-NMR spectrum of the obtained in Example 8

connection

Figure 1 6 shows the ^{1 3} C-NMR spectrum of that obtained in Example 8

connection Example 9:

The compound of the formula:

was based on the compound of preparation 2:

made as follows:

Tauπn (5.5 g, 0.044 mol) and 4N NaOH (1.76 g of NaOH in 1 1 mL of water) was added to a 50 ml round bottom flask and stirred to obtain a clear solution, the solution was in vacuo at 50 ⁰ C. evaporated to obtain a white residue. The residue was repeatedly (2 x 1 00 ml) stripped with methanol at 58 ⁰ C.

Into another 2 L three-necked round-bottomed flask connected to an overhead stirrer and with a thermocouple pocket were added the sodium salt of taurine and methanol (750 ml) prepared above. To this was added 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ, 16; 31 g, 0.066 mol) and stirred at 25 ⁰ C (it formed a clear solution) was added to the compound of Preparation 2 (1 5 g, 0.044 mol) and stirred at 25 ⁰ C for 48 hours, The progress of Reaction was monitored by thin layer chromatography (TLC) (MDC: MEOH 8: 2). After 48 hours TLC showed complete conversion of the starting compound To the reaction mixture was concentrated in vacuo at 50 ⁰ C to give a yellow solid rothch-

The crude product was dissolved in methanol (150 ml) and to this was added methyl tert-butyl ether (MTBE, 1500 ml) slowly over a period of 30 minutes. The precipitated solids were filtered and treated with MTBE (100 ml). The product was washed in a vacuum dryer tub (vaccum tray dryer - VTD) for 1 2 hours at 50 ⁰ C dried and then analyzed

The product was obtained as an orange powder. The dissociation in water at room temperature was 666 g / L.

Yield: 1 2.5 g (60.46% of theory)

Figure 1 7 shows the 'H-NMR spectrum of that obtained in Example 9

Connection.

Figure 1 8 shows the ¹³ C-NMR spectrum of that obtained in Example 9

Connection.

PHARMACOLOGICAL ACTIVITIES '

All experiments were carried out using female inhalers under controlled illumination and temperature conditions of animal husbandry. The animals were fed water and food at will

Breast tumors (MAXF 401) were transplanted subcutaneously into the hind limbs of the mouse at the age of 10 weeks. The volume increase of the individual tumors was measured with micro graspers and the tumor size was calculated according to the formula a * b ^2/2 (where a was the largest diameter of the tumor and b is the vertical axis) When the tumor volume had risen to 80-120 mm ³ , the animals were randomly placed in experimental groups of 6 animals each

The test compounds (as natural strains) were dissolved in a saline solution and 5% Klucel (hydroxypropylcellulose) was added to dissolve all test compounds in the same carrier. The compounds were administered in equimolar doses equivalent to 350 mg / kg of the comparative composition (according to Example 30 of DE 1 7931 1 5A) by intraperitoneal injection. This dose level was selected according to a dose of the comparator which resulted in a 50% reduction in tumor volume development under the experimental conditions. A volume of 10 ml / kg body weight was injected animals receiving only the carrier , served as control The test compounds were treated according to the schedule of a weekly twice administration over a period of 5 weeks The tumor volume and the body weight were checked twice a week, and the relative tumor volumes were calculated as ratio tumor size vs body weight The experiment was terminated when the tumor volume of the control group reached a level which required dead of the animals to comply with the animal welfare regulations

On the bosis of the relative tumor volumes of the animals treated with the test compounds compared with the tumor volumes of only with the wearer In the treated controls, the T / C values were used as an index of antitumour activity (The T / C index here represents the ratio of tumor size of treated and untreated animals. The smaller the ratio, the better the activity. 100% would be no activity Tumor of the same size)

As shown in Table 1, the substances of Examples 2 and 4 have improved antitumor activity under the experimental conditions. Significant tumor remission was observed within 4 weeks of treatment with the two derivatives. Furthermore, the compositions were well tolerated Compared to the control group, animals treated in the substance treated animals over the experimental period no death trap

LαbeilθJL Antitumor Vergleichsworksαmkeit and mortality in tumor heterotrαnsplαntierten mice

Test composition T / C mortality

value

Example 30 from DE 1 7931 1 5A 48.5 2/6

Example 2 3.4 0/6

Example 4 1 2.6 0/6

Figure 20 shows a comparison of the antitumor activity of the Nαtπumsαlzes (Ex 4α) and the TRIS Sαlzes the compound of Bsp 4 in the MAXF 401 Xenogrαft model in the Nαcktmαus The subcutaneous implantation of the tumor and the determination of the tumor volume was carried out as previously described The above salts of Prufsubstanz were administered as wassπge solution in the mentioned dosages twice weekly by ιp injection over a period of 4 weeks in the figure, the time course of the antitumor effect of Prufsubstanz as T / C value is dose-dependent given with 400 mg / kg of the sodium salt Compound from Example 4, a T / C value of 1 2 was achieved after 4 weeks of therapy, after In the case of administration of 500 mg / kg of the salt, a complete remission was achieved within 3 weeks of treatment. On the other hand, if the same substance was administered as TRIS-Saiz in equimolar doses of 360, 400 and 500 mg / kg of the sodium salt, one was administered at all doses used complete remission observed. These results suggest that both salts differ in their bioavailability. It is probable that the differential antitumor effect of sodium and TRIS salt is due to different peak concentrations of the compound from Bsp 4 after administration of the different salts

MORE WIRKDATEN;

From the test compounds (Nαtriumsαlze) further pharmacological activity data were obtained.

SELECTIVITY OF ANTI-TUMORACTIVITY:

Figure 21 shows the selectivity of the anti-tumor activity of the substance of Example 2a (sodium salt) on various tumors.

The antitumour activity of the substance of Example 2a (sodium salt) was tested in a Xenograft Fumorpanel. Xenografts of human tumors derived from the prostate, uterus, lung, pancreas, bladder, and head and neck cancers were implanted in nude mice, and as previously described, implantation and tumor volume determination were performed in groups of 5-8 animals The test substance was administered as a sodium salt as an aqueous solution in the stated dosages twice a week by injection.

The tumor xenografts used, the dosages used, the duration of the therapy and a classification of observed antitumor effects are summarized in the following Table 2,

Table 2:

(* The control group was stopped as soon as the tumor volume in individual animals exceeded> 1500 mm2, N = 5-8, statistical significance, ns ^■ not significantly different from the control, *: p <0.05, ** p <001, ***. p> 0.005)

In the graph of Figure 21, the dose-dependency of the antitumor effect and the different responses of different tumors are shown 0% Antitumor effect corresponds! In this case the growth of control tumors and 100% of the complete remission of tumors under therapy. The antitumor effect of the test substance increased in the Order MEXF 462>> CXF 280 - MAXF 401> UXF 1 1 38 ~ MEXF 276 - PRXF 22RV1 ~ PRXF DU 1 45> LXFL 529 ~ HNXF536> BXF 1 21 8 - PAXF 1 657 ab The results show a pronounced (ie remission inducing) and specific anti-tunneling activity of the test substance, particularly in tumor arenas comprising melanoma, breast cancer and colon carcinoma

Figure 22 shows the dose-dependency of the anti-tumor effect of the substance from Example 2a in breast tumors (MAXF 401 - xenograft in nude mice)

The antitumor activity of the substance from example 2a (sodium salt) in the MAXF-401 xenograft tumor model in the nude mouse was investigated. The subcutaneous implantation of the tumor and the determination of tumor volume were carried out as described above. The test substance was twice as sodium salt as aqueous solution in the mentioned doses administered weekly by injection over a period of 4 weeks The figure shows the time course of the antitumor effect of the test substance as a dose-dependent T / C value. A dose of 300 mg / kg was given as a threshold dose, 450 mg / kg as ED50 and 500 mg / kg determined as ED90 of antitumor administration In the highest dose, a remission of the tumors was observed under therapy. The substance was well contracted in the dose range used

Figure 23 shows the anti-tumor effect of the substance of Example 2a (sodium salt) in a colon carcinoma xenograft model

In this case, the antitumor activity of the substance of Example 2a in CXF280 xenograft tumor model in the nude mouse was determined The subcutaneous implantation of the tumor and the determination of tumor volume was carried out as previously described The Prufsubstanz was as sodium salt as wassπge solution in the dosages mentioned twice weekly Injection over a period of 4 weeks administered Groups of 8 animals were used After administration in doses of 450 500 or 540 mg / kg Example 2a was observed in all dosages used a pronounced antitumor effect with a complete inhibition ED20, ED50 and ED90 Doses were extrapolated to 330, 390 and 490 mg / kg of active substance The substance was well tolerated in the dose range used and with no significant weight loss connected to the animals

The following Table 3 shows the comparison of the anti-tumor effect of two further selected compounds, which are referred to below as the compound of Example 6 and compound of Example 7, compared to compound <n Bsp 2a in a melanoma xenograft model

The antitumor activity of the compounds was determined in the MEXF 462 xenograft tumor model in the nude mouse. The subcutaneous implantation of the tumor and the determination of tumor volumes were carried out as previously described. Groups of 8 animals each were used

The test substance according to Ex 7 and Ex 2 were administered as aqueous solution in equimolar doses twice a week by injection over a period of 4 weeks. Aquimolar amounts of the compound from Ex 8 was administered as 5% DMSO solution ιp twice weekly over the above period

The time course of the antitumor effect expressed in% of tumor volume at the beginning of the experiment over the therapy period is shown in Table 3

Table 3;

The control group was terminated after day 1 1 for ethical reasons due to the high tumor volume. In the treatment groups, partial remission with the compound of Exa 2a, complete remission on treatment with the compound of Ex 7, and severe retardation of tumor growth with treatment with the compound of Ex 8 were observed when treated with equimolar doses. All substances were found to be well tolerated in the dose range used, and significant weight gain was observed in all animals on therapy.

In summary, the compounds of the invention or the pharmaceutical compositions thereof are shown to be potent antitumor drugs with an improved therapeutic range and fewer side effects. Example 2 (Nephrological Compatibility)

Tumortrαgende mice were treated with the comparison compound from Example 30 of DE 1 7931 1 5A or with the novel derivative of Example 2a at an equimolar dose level corresponding to 450 mg of parent composition by iP-injekf ιon as described above. A control group was only with the wearer after a twice treated weekly treatment regimen

After completion of the 28-day treatment period, the mice were autopsied. In the animals treated with the stock composition, macroscopic changes (swelling, local discoloration) of the kidneys were observed, while the kidneys of the other treatment group receiving the substance of Example 2a and the Control group without pathological findings remained The kidneys of all animals of the experimental groups were surgically removed, fixed in the mold using standard methods, embedded in paraffin and processed for HE staining The histological results of the tissue slices of the experimental groups are summarized in Table 4

Table 4:

Noticeable focal tubular necrosis of the kidneys was observed in the animals treated with the reference compound. No necrotic changes were noted in the kidneys of the animals treated with the compound of the invention. This emphasizes that administration of the reference compound is associated with changes in renal histology who use them as an antitumor agent for the time distribution is limited and confirms the excellent compatibility profile of the compounds according to the invention,

Claims

PATE CLAIMS

Compounds of the formula

wherein

R ¹ and R ^{2 are the} same or different and are each selected from the group consisting of ¹ optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted alkylaryl;

R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ^{10 are the} same or different and are each selected from the group consisting of

Hydrogen,

Halogen,

cyano,

nitro,

carboxyl,

aminocarbonyl,

Sulfonic acid residue (-SO ₃ H),

Aminosulfonyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted aryl, optionally substituted alkylaryl, R ^{1 1 is} optionally substituted alkanediyl or optionally substituted alkenediyl,

R ^{1 2 is} hydrogen and R ^{13 is} optionally substituted alkyl or

Hydroxyl is, or

R ^{1 3 is} hydrogen and R ^{1 2} optionally substituted Alky! or

Hydroxyl is, or

R ^{1 2} and R ^{1 3} each Alky! in which at least one of the alkyl groups has at least one substituent, or

R ^{1 2} and R ¹³ together with the nitrogen atom to which they are attached are a saturated or unsaturated, optionally substituted

Form 5 to 8-glιedrιgen Cycius, optionally further

Heferoatome may contain, and

X ^{1 is} selected from the group consisting of a single bond carbonyl, sulfur, oxygen, sulfoxy, sulfonyl, azo, and an optionally substituted, saturated or unsaturated aliphatic radical of 1 to 6 carbon atoms,

or pharmaceutically-acceptable salts thereof

Compounds according to claim 1, wherein

R ^{1 2} is hydrogen and R ¹ is ^{3-substituted} alkyl, or

R ^{1 3} is hydrogen and R ¹² substituted alkyl

Compounds according to claim 2, wherein substituted alkyl, an alkyl group which is at least one group of the formula

-Y ^A - R ^π14 , wherein

X ^{2 is} selected from the group that consists of

carbonyl,

Sulfoxy, and

Sulfonyl, and R ^{14 is} selected from the group consisting of

Hydroxy, optionally substituted amino, and optionally substituted alkoxy

4. Compounds according to any one of claims 1, 2 or 3, wherein

R ^{12 is} hydrogen and R ^{1 3 is} a radical A of a compound of the forms! H ₂ NA or

R ^{13 is} hydrogen and R ^{12 is} a radical A of a compound of the formula H ₂ N-

A is where

A is a radical which is derived by cleavage of the amino group (-NH ₂ ) from a natural or synthetic amino acid, a natural or synthetic amino acid derivative or a polyamino acid or a polyamino acid derivative.

5. Compounds according to one or more of claims 1 to 4, of the formula (2)

Compounds according to any one of claims 1 to 5, wherein

R ¹ and R ^{2 are} each Aikyl,

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ R ⁸ , R ⁹ , and R ^{10 are} each hydrogen,

R ^{1 1 is} Aikandiyi,

R ^{12 is} hydrogen and R ^{1 3 is} a radical A of a compound of the formula H ₂ NA or

R ^{1 3 is} hydrogen and R ^{1 2 is} a radical A of a compound of the formula H ₂ N-

A is where

A is a radical which is derived by cleavage of the amino group (-NH ₂ ) from a natural or synthetic amino acid, a natural or synthetic Aminosauredeπvat or a Poiyaminosaure or a Polyaminosauredeπvat, and

X ^{1 is} carbonyi (-CO-)

Compounds according to one or more of claims 1 to 6, selected from the group consisting of

(Example 4)

(Example 2) ^* (Example 1 (Example 5) (Example 6) (Example 3)

or pharmaceutically-acceptable salts thereof

A process for the preparation of the compounds of formula (1) according to one or more of claims 1 to 7, which comprises the step:

Reaction of a compound of formula (3):

(3) or a salt thereof, with a compound of the formula (4)

wherein R ¹ to R ^{1 3} and X ^{1 are} as defined in one or more of claims 1 to 7

Compounds of formula (1) according to one or more of claims 1 to 7 for use as medicaments. 0. Use of the compounds of formula (1) according to one or more of claims 1 to 7 for the manufacture of a medicament for the treatment of cancer.