DE102008012435A1 - New quinazoline compounds are tyrosin-kinase inhibitors e.g. to treat cancer, hematologic or solid tumors, non-Hodgkin tumors or T-cell lymphoma; and for the modulation of the cell cycle, cell differentiation, apoptosis or angiogenesis - Google Patents

Abstract

Quinazoline compounds (I) and their salts with counter ions are new. Quinazoline compounds of formula (I) and their salts with counter ions are new. R 1>, R 2>H, OH, halo, CN, NO 2, one or more times saturated 1-10C-alkyl (which is optionally 1-3 times substituted by OH, halo or 1-5C-alkoxy, and interrupted by one or more O, S, N, carbonyl or sulfonyl group, aliphatic or aromatic 5-7 membered homo or heterocyclic ring system), one or more times saturated 1-10C-alkoxy (which is optionally 1-3 times substituted by OH, halo or 1-5C-alkoxy, and interrupted by one or more O, S, N, carbonyl or sulfonyl group, aliphatic or aromatic 5-7 membered homo or heterocyclic ring system), one or more times saturated 1-10C-alkylthio (which is optionally 1-3 times substituted by OH, halo or 1-5C-alkoxy, and interrupted by one or more O, S, N, carbonyl or sulfonyl group, aliphatic or aromatic 5-7 membered homo or heterocyclic ring system), or 1-5C-perfluoroalkyl (optionally one or more times unsaturated); R 3>, R 4>H, halo, CN, NO 2, CF 3or 1-4C-alkyl; R 5>an aliphatic or aromatic 5-7 membered homo- or heterocyclic ring system, which can be condensed with 1 or 2 further aliphatic or aromatic 5-7 membered homo- or heterocyclic ring systems, which is optionally substituted by halo, CN or NO 2, or 1-4C-alkyl or 1-4C-alkoxyl, 2-4C-alkenyl, 2-4C-alkynyl (all optionally one or more times saturated and substituted by phenyl or halogenated phenyl group); L : N(R 6>), O, C(=O)-, -O-C(=O)- or -C(=O)-O-, -N(R 6>)-C(=O)- or -C(=O)-N(R 6>)-, -N(R 6>)-O- or -N(R 6>)-O-, -O-N(R 6>)-C(=O)- or -C(=O)-N(R 6>)-O-, -N(R 6>)-C(=O)-O- or -O-C(=O)-N(R 6>)-; and R 6>H or 1-4C-alkyl. Provided that: at least one residue of R 1>or R 2>is not H. An independent claim is included for the preparation of (I). [Image] ACTIVITY : Cytostatic; Angiogenesis Modulator; Antiinflammatory; Antiasthmatic; Antiallergic; Ophthalmological; Dermatological; Antiarthritic; Osteopathic; Antirheumatic; Gastrointestinal-Gen.; Antibacterial; Immunosuppressive; Antidiabetic; Hemostatic; Neuroprotective; Muscular-Gen.; Antipsoriatic; Nephrotropic; Respiratory-Gen.; Anabolic; Anorectic; Cardiant; Antiapoptotic. MECHANISM OF ACTION : Tyrosin-kinase inhibitor.

Description

The The present patent application relates to new pharmaceuticals, for example based on novel substituted quinazolines, method too Their preparation and their use in therapy, for example in the therapy of cancers.

Background and state of the art

cancers are still a common cause of death of humans in the industrialized countries. Alone in Germany annually about 395,000 new cancers diagnosed. The cure rate is 30-60%. Despite a number of known drugs For the treatment of cancer is to be noted that there are a number of There are tumors that do not respond to therapeutics. Next to it are the known therapies characterized by a variety of side effects.

It There is therefore a need for further cancer therapeutics.

Description of the invention

in der
R¹ und R² unabhängig voneinander, ein Wasserstoffatom,
eine Hydroxy-Gruppe, ein Halogenatom, eine Cyanogruppe,
eine Nitrogruppe
oder
eine gegebenenfalls 1-3-fach Hydroxy-, Halogen- oder C₁-C₅-Alkoxy substituierte (C₁-C₁₀)-Alkylgruppe, die ein oder mehrfach durch Sauerstoff-, Stickstoff- oder Schwefelatome oder durch Carbonyl- oder Sulfonylgruppen oder durch aliphatische oder aromatische 5-7 Ringatome enthaltende homo- oder heterocyclische Ringsysteme unterbrochen sein kann, die unverzweigt oder verzweigt sein kann und die gegebenenfalls auch ein- oder mehrfach ungesättigt sein kann,
eine gegebenenfalls 1-3-fach Hydroxy-, Halogen- oder C1-C5-Alkoxy substituierte (C₁-C₁₀)-Alkoxygruppe,, die ein oder mehrfach durch Sauerstoff-, Stickstoff- oder Schwefelatome oder durch Carbonyl- oder Sulfonylgruppen oder durch aliphatische oder aromatische 5-7 Ringatome enthaltende homo- oder heterocyclische Ringsysteme unterbrochen sein kann, die unverzweigt oder verzweigt sein kann und die gegebenenfalls auch ein- oder mehrfach ungesättigt sein kann,
eine gegebenenfalls 1-3-fach Hydroxy-, Halogen- oder C1-C5-Alkoxy substituierte (C₁-C₁₀)-Alkylthiogruppe, die ein oder mehrfach durch Sauerstoff-, Stickstoff- oder Schwefelatome oder durch Carbonyl- oder Sulfonylgruppen oder durch aliphatische oder aromatische 5-7 Ringatome enthaltende homo- oder heterocyclische Ringsysteme unterbrochen sein kann, die unverzweigt oder verzweigt sein kann und die gegebenenfalls auch ein- oder mehrfach ungesättigt sein kann,
eine (C₁-C₅)-Perfluoralkyl-gruppe, die unverzweigt oder verzweigt sein kann und die gegebenenfalls auch ein- oder mehrfach ungesättigt sein kann,
mit der Maßgabe dass mindestens einer der Reste R¹ oder R² nicht gleich Wasserstoff ist,
R³ und R⁴ unabhängig voneinander ein Wasserstoffatom, ein Halogenatom, eine Cyanogruppe, eine Nitrogruppe, eine CF₃-Gruppe oder eine C₁-C₄-Alkylgruppe, die unverzweigt oder verzweigt sein kann, oder
R⁵ ein aliphatisches oder aromatisches 5-7 Ringatome enthaltendes homo- oder heterocyclisches Ringsystem, welches mit 1 oder 2 weiteren aliphatischen oder aromatischen 5-7 Ringatome enthaltenden homo- oder heterocyclischen Ringsystemen kondensiert sein kann,
und
welches ein oder mehrfach mit einer Halogenatom, eine Cyanogruppe, eine Nitrogruppe
oder einer C₁-C₄-Alkylgruppe, oder einer C₁-C₄-Alkoxylgruppe, einer C₂-C₄-Alkenylgruppe einer C₂-C₄-Alkinylgruppe substituiert sein kann, die verzweigt oder unverzweigt und gegebenenfalls auch ein- oder mehrfach ungesättigt sein kann wobei die C₁-C₄-Alkylgruppe, die C₁-C₄-Alkoxylgruppe, die C₂-C₄-Alkenylgruppe oder die C₂-C₄-Alkinylgruppe ihrerseits mit Phenylgruppen oder halogenierten Phenylgruppen substitiert ist,
L für
-N(R⁶)-
-O-
-O-C(=O)- oder -C(=O)-O-
-N(R⁶)-C(=O)- oder -C(=O)-N(R⁶)-, -N(R⁶)-O- oder -N(R⁶)-O-,
-O-N(R⁶)-C(=O)- oder -C(=O)-N(R⁶)-O-
worin
R⁶ Wasserstoff oder eine verzweigte oder unverzweigte C₁-C₄-Alkylgruppe bedeutet,
steht sowie ihre Salze mit physiologisch verträglichen Gegenionen,
überraschenderweise hervorragende Eignung als Pharmazeutika, insbesondere als Krebstherapeutika aufweisen. Diese sind dabei durch ein günstiges Wirkungs-/Nebenwirkungsprofil gekennzeichnet.It has now been found that compounds of general formula I

in the
R ¹ and R ² independently of one another, a hydrogen atom,
a hydroxy group, a halogen atom, a cyano group,
a nitro group
or
an optionally 1-3-fold hydroxy, halogen or C ₁ -C ₅ -alkoxy-substituted (C ₁ -C ₁₀ ) -alkyl group which is mono- or polysubstituted by oxygen, nitrogen or sulfur atoms or by carbonyl or sulfonyl groups or may be interrupted by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems, which may be unbranched or branched and may optionally also be mono- or polyunsaturated,
an optionally 1-3-fold hydroxy, halogen or C ₁ -C 5 -alkoxy-substituted (C ₁ -C ₁₀ ) -alkoxy group which is mono- or polysubstituted by oxygen, nitrogen or sulfur atoms or by carbonyl or sulfonyl groups or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems may be interrupted, which may be unbranched or branched and which may optionally also be mono- or polyunsaturated,
an optionally 1-3-fold hydroxy, halogen or C ₁ -C 5 -alkoxy-substituted (C ₁ -C ₁₀ ) -alkylthio group which is mono- or polysubstituted by oxygen, nitrogen or sulfur atoms or by carbonyl or sulfonyl groups or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems may be interrupted, which may be unbranched or branched and which may optionally also be mono- or polyunsaturated,
a (C ₁ -C ₅ ) perfluoroalkyl group which may be unbranched or branched and which may optionally also be mono- or polyunsaturated,
with the proviso that at least one of R ¹ or R ^{2 is} not the same as hydrogen,
R ³ and R ⁴ independently represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a CF ₃ group or a C ₁ -C ₄ alkyl group, which may be unbranched or branched, or
R ^{5 is} an aliphatic or aromatic 5-7 ring atoms-containing homo- or heterocyclic ring system which may be condensed with 1 or 2 further aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems,
and
which one or more times with a halogen atom, a cyano group, a nitro group
or a C ₁ -C ₄ -alkyl group, or a C ₁ -C ₄ -alkoxyl group, a C ₂ -C ₄ -alkenyl group of a C ₂ -C ₄ -alkynyl group which may be branched or unbranched and optionally also one or may be polyunsaturated with the C ₁ -C ₄ -alkyl group, the C ₁ -C ₄ -alkoxyl group, the C ₂ -C ₄ -alkenyl group or the C ₂ -C ₄ -alkynyl group being in turn substituted by phenyl groups or halogenated phenyl groups,
L for
-N (R ⁶ ) -
-O-
-OC (= O) - or -C (= O) -O-
-N (R ⁶ ) -C (= O) - or -C (= O) -N (R ⁶ ) -, -N (R ⁶ ) -O- or -N (R ⁶ ) -O-,
-ON (R ⁶ ) -C (= O) - or -C (= O) -N (R ⁶ ) -O-
wherein
R ⁶ denotes hydrogen or a branched or unbranched C ₁ -C ₄ -alkyl group,
and their salts with physiologically compatible counterions,
surprisingly excellent suitability as pharmaceuticals, especially as cancer therapeutics. These are characterized by a favorable effect / side effect profile.

The Invention is based on the finding that compounds with -C-O-N- or -C-N-O- groups (for example -C-O-N (H) -C (= O) - or -C-N (H) -O-C (= O) -) on the one hand competitively bind with natural ligands, but on the other hand can not be metabolized. The Inhibitory effect is thus significantly increased. These Recognition is the compounds described in this document based.

Detailed description of the invention and preferred embodiments

The compounds of general formula I according to the invention are novel substituted linear quinazolines. The radicals R ¹ and R ² are chains which may contain cyclic units. The chains in R ¹ and R ² may in particular contain terminal N-containing aliphatic rings, such as piperidine or morpholine. Preferably, one of the two radicals R ¹ and R ^{2 is} a methoxy group. The optional radicals R ³ and R ⁴ are preferably hydrogen, fluorine or CH ₃ or CF ₃ groups. The radical R ⁵ is preferably a substituted aromatic, for example a phenyl group with halogen substituents, or a substituted heteroaromatic, for example a substituted indole group. As a substituent of the aromatic or heteroaromatic also another (in turn substituted) phenyl group comes into question, which is linked via a short alkyl or Oxyalkylkette.

The linker L represents an ether, ester, amine, amide, carbonyl or hydroxamate group. Preferably L is -N (R ⁶ ) -, -O-, -C (= O) -, -N (R ⁶ ) -C (= O) - or -C (= O) -N (R ⁶ ) -, -ON (R ⁶ ) -C (= O) - or -C (= O) -N (R ⁶ ) -O-.

Most preferably, L is -ON (R ⁶ ) -C (= O) - or -C (= O) -N (R ⁶ ) -O-.

The Compounds according to the invention can by the presence of asymmetric centers as stereoisomers available. The subject of the present invention are all possible ones Stereoisomers both as racemates, as well as in enantiomerically pure Shape. The term stereoisomers also includes all possible diastereomers and regioisomers and tautomers (e.g., keto-enol tautomers) in which the compounds according to the invention can be present, which are therefore also the subject of the invention.

Particularly preferred radicals R ¹ and R ² are below and in the 1 displayed.

Particularly preferred radicals R ⁵ are below and in the 2 displayed:

Very particularly preferred embodiments of compounds of general formula I are in the 3 - 99 displayed.

Most preferred are the compounds

uses

The Compounds of general formula I are suitable as medicaments. They are particularly suitable for the treatment of cancer. They come in particular for the treatment of hematological or solid tumors, such. Non-Hodgkin's tumors, or from T-cell lypmhomas.

The Effect of the compounds of the invention as Cancer therapeutics may be appropriate to their suitability Attributed to inhibition of tyrosine kinase.

The Suitability as cancer therapeutics is still on the effect of these Compounds on the modulation of the cell cycle, the modulation of Cell differentiation, apoptosis and angiogenesis.

The compounds of the general formula I lead to a dose-dependent inhibition of colony formation in the colony assay of the company Oncotest (Freiburg). IC ₅₀ values in 25 different cell culture lines (including MCF-7, HT-29, BxPC-3, MDA-MB-453, NK1) were generally between 4 and 40 μM. Outstanding selectivity was found in small cell lung carcinoma (LXFS650), followed by renal carcinoma (RXF 1393).

The Invention therefore teaches the use of an inventive Compound for the preparation of a pharmaceutical composition for the treatment of one or more diseases from the group cancer, such as lung cancer, leukemia, ovarian cancer, Sarcomas, meningioma, colon cancer, lymph node cancer, brain tumors, breast cancer, Pancreatic cancer, prostate cancer, skin cancer, gastric and esophageal cancer, T-cell lymphoma, CTLC, but also chronic inflammation, Asthma, Allergy, Rhinitis, Uveitis, Urticaria, Arthritis, Osteoarthritis, Chronic Polyarthritis, Rheumatoid Arthritis, Inflammatory Bowel disease, degenerative joint disease, rheumatic diseases Formenkreises with cartilage degradation, sepsis, autoimmune diseases, type I diabetes, Hashimoto's thyroiditis, autoimmune thrombocytopenia, multiple sclerosis, Myasthenia gravis, chronic inflammatory bowel disease, Crohn's disease, uveitis, psoriasis, atopic dermatitis, collagenosis, Goodpasture syndrome, disorders with impaired leucocyte adhesion, Cachexia, diseases due to increased TNFalpha concentration, Diabetes, obesity, bacterial infections, especially with resistant bacteria, heart failure and the chronic cardiac Failure (CCF) "The term treatment also covers prophylaxis.

formulations

The present invention teaches a pharmaceutical composition containing at least one compound of the invention. Optionally, one or more physiologically acceptable excipients and / or carriers may be mixed with the compound and the mixture galenically prepared for local or systemic administration, especially orally, parenterally, for infusion, for injection. The choice of additives and / or adjuvants will depend on the chosen dosage form. The galenic preparation of the pharmaceutical composition according to the invention is carried out in the usual way. Free carboxylic acid groups can also be used in the form of their salts with physiologically acceptable counterions, such as. As Mg ⁺⁺ , Ca ⁺⁺ , Na ⁺ , K ⁺ , Li ⁺ or ammonium derivatives, such as cyclohexylammonium present. Amino-containing compounds may also be in the form of an ammonium salt, for. As chloride, bromide, mesylate, tosylate, oxalate, orotate or tartrate. Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, microcapsules, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection (iv, ip, im, sc) or nebulization (aerosols), forms of preparation for Dry powder inhalation, transdermal systems as well as preparations with sustained-release release, in the production of which conventional auxiliaries such as carriers, blasting agents, binders, coating substances, swelling or lubricants, flavorings, sweeteners and solubilizers are used. Examples of excipients which may be mentioned are magnesium carbonate, titanium dioxide, lactose, manidine and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile water and monohydric or polyhydric alcohols, for example glycerol.

A inventive pharmaceutical composition is producible by at least one used according to the invention Substance combination in a defined dose with a pharmaceutically suitable and physiologically acceptable carriers and optionally other suitable active ingredients, additives or excipients with defined Dose mixed and to the desired dosage form is prepared.

When Diluents include polyglycols, ethanol, water and Buffer solutions in question. Suitable buffer substances are for example N, N-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, Sodium bicarbonate and sodium carbonate. But it can also be without a diluent to be worked.

Preferably the pharmaceutical composition is in dosage units and administered, each unit as an active ingredient a defined dose of the compound of the invention according to formula I contains. For solid dosage units such as tablets, Capsules, dragees or suppositories can dose this 0.1-1000 mg, preferably 10-50 mg, and for injection solutions in the form of ampoules 0.01-1000 mg, preferably 10-40 mg.

For the clinical application is the production of infusion solutions another preferred embodiment.

For the treatment of an adult, 50-100 kg heavy, for example 70 kg patients, for example, daily doses of 0.1-1000 mg active ingredient, preferably 10-50 mg, indicated. In certain circumstances however, higher or lower daily doses may be used to be appropriate. The administration of the daily dose can be carried out both by Single dose in the form of a single dosage unit or several smaller Dosage units as well as by multiple subdivided doses done at certain intervals.

in the Frameworks of pharmaceutical compositions can be used according to the invention Compounds combined with other drugs known per se become. For example: Aldesleukin, Amifostine, atrasentan, bevacizumab, bexarotene, bortezomib, capecitabine, Carboplatin, chlorambucil, cisplatin, cladribine, cyclophosphamide, Cytamid, dacarbazine, docetaxel, droloxifene, edrecolomab, epothilone, Erlotinib, etoposide, exemestane, flavopiridol, fludarabine, fluorouracil, Formestane, fulvestrant, gefitinib, gemcitabine, idarubicin, irinotecan, Ixabepilone, Lonafarnib, Miltefosine, Mitomycin, Neovastat, Oxaliplatin, Pemetrexed, porfimer, rituximab, tegafur, temozolomide, tipifarnib, Topotecan, trimetrexate, vorozole, vinblastine, and mixtures of two or more such agents. In this case, the inventive Connection in the context of a single galenic dressing with the active substance to be mixed. But it is also possible that the pharmaceutical composition of two (or more) different galenic preparations, whereby in a first preparation the compound of the invention and in a second Preparation of the active ingredient are included. It can under the first preparation also one of the active ingredient of the second preparation be set up different active ingredient.

production method

The Preparation of the other compounds of the invention the general formula I is carried out by those skilled in the art known methods of organic chemistry, the introduction of the C-O-N-C group preferred (but not exclusive) by reaction with tert-butyl-dimethylsilylhydroxylamine (or its analogs) runs.

outgoing of this provision, the expert in the field of organic Chemistry the derivatives of the general formula I (as well as the below mentioned alternative embodiments) in simpler Make way.

The synthetic schemes for preparing the most preferred compounds 1861 and 887 are described in U.S. Patent Nos. 4,199,391 and 4,199,247 11 and 12 shown.

The synthetic schemes for preparing the still preferred compound 1304 are described in U.S.P. 14 shown.

outgoing Of these representations, those skilled in the art of organic Chemistry the derivatives of general formula I in a simple manner produce.

The skilled person further recognizes that the in 14 exemplified method is suitable to produce hydroxamates that were previously inaccessible synthetically. For this purpose, the "amine-imine tautomerism" of the educt is exploited: the imine form is intercepted here with O- (2,4-dinitrophenyl) hydroxylamine or mesytlenesulfonylhydroxylamine. Further reaction with any desired acid chlorides (or activated esters) leads to novel hydroxamates (US Pat. 15 ). Preference cyclic compounds can be used, as exemplified in 16 are shown. Other possible starting materials are nucleic bases, such as thymine, uracil or cytosine

The Usability of the compounds of the invention in the therapy of cancer can be studied as follows:

proliferation assay

Cultured human tumor cells, for example, hormone-independent human mammary carcinoma cells, MCF7, human non-small cell lung carcinoma cells, e.g. DU145, hormone independent human prostate carcinoma cells, e.g. B. ATCC HTB-81 or MaTu-MDR, can be prepared in a density of about 5,000 cells per measurement point in 96-well multi-well plates in 200 ul of the appropriate growth medium. After 24 hours, the cells of one plate can be stained with crystal violet while the medium of the other plates is replaced by fresh culture medium containing the test substances in different concentrations concentrations (0 μmol, as well as in the range 0.01-30 μmol) can be replaced. The cells can then be incubated for four days in the presence of the test substances. Cell proliferation can be determined by staining the cells with crystal violet.

XTT test for mitochondrial activity living line.

Principle of the method:

At the XTT assay is the yellow tetrazolium salt XTT (sodium 3 '- [1- (phenylaminocarbonyl) -3,4-tetrazolium] -bis (methoxy-6-nitro) benzenesulfonic acid) by metabolism active cells transformed into orange formazan (cleavage the tetrazolium ring of the XTT). The bioreduction of the XTT is going through the addition of PMS (electron coupling phenazine methosulfate) potentiated. The color intensity correlates with the mitochondrial dehydrogenase activities and the number of living cells. The quantification of the color intensity is carried out spectrophotometrically with the aid of an ELISA reader.

Establishment at ScheBo Biotech

at The establishment of the procedure was for each cell lines the optimal starting cell number per well for an ideal Measurement of the optical density can be determined. additionally were for each cell line correlation curves between the OD and the underlying cell number created. Was continued for each cell line the optimal time of substance addition and the cultivation time (see implementation).

execution

In Dependence on the cell line becomes the second point t0 between 500 and 5000 cells in 100 μl of nutrient medium per well of a 96-well plate auspassagiert.

It 50 μl of substance or in the control 50 μl Solvent added.

To 4 (NK, MCF-7, BxPC-3, WI-38) or according to 6 (MDA-MB-453, HT 29, KB-V1) Cultivation days in the incubator are 75 .mu.l fresh prepared XTT solution (1 mg / ml XTT, 0.383 mg / ml PMS: in the ratio 1:50).

• Literatur: Scudiero, D. et al.: Cancer Res. (1988), 48: 4827-4833 .
• Zelllinien, Übersicht ScheBo Biotech AG, Gießen

MCF-7: humane Brustkrebs-Zelllinie MDA-MB-453: humane Brustkrebs-Zelllinie HT 29: humane Colonkarzinom-Zelllinie BxPC-3: humane Pancreastumor-Zelllinie KB-V1: Multidrug-resitenter Abkömmling von HeLa-Zellen KBV600: interne Bezeichnung: KB-V1, kultiviert mit 600 ng/ml Vinblastin KBVO: interne Bezeichnung; KB-V1, ohne Virnblastin WI 38: humane, fetale Fibroblasten-ähnliche Zelllinie der Lunge NK: Novikoff-Ratten-Hepatoma-Zelllinie After an incubation period of 3 h in the incubator at 37 ° C., the ODs in the ELISA reader are measured at a wavelength of 450 nm (reference wavelength 620 nm).

• Literature: Scudiero, D. et al .: Cancer Res. (1988), 48: 4827-4833 ,
• Cell Lines, Overview ScheBo Biotech AG, Gießen

MCF-7: human breast cancer cell line MDA-MB-453: human breast cancer cell line HT 29: human colon carcinoma cell line BxPC-3: human pancreatic tumor cell line KB-V1: Multidrug-resistant derivative of HeLa cells KBV600: internal name: KB-V1, cultured with 600 ng / ml vinblastine KBVO: The internal term; KB-V1, without Virnblastin WI 38: human, fetal fibroblast-like cell line of the lung NK: Novikoff rat hepatoma cell line

QUOTES INCLUDE IN THE DESCRIPTION

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

Cited non-patent literature

• Scudiero, D. et al .: Cancer Res. (1988), 48: 4827-4833 [0039]

Claims (17)

Compound of the general formula I

in which R ¹ and R ² independently of one another, a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, a nitro group or an optionally 1-3-fold hydroxy, halogen or C ₁ -C ₅ alkoxy substituted (C C ₁ -C ₁₀ ) -alkyl group which may be interrupted one or more times by oxygen, nitrogen or sulfur atoms or by carbonyl or sulfonyl groups or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems which are unbranched or branched and optionally may also be monounsaturated or polyunsaturated, an optionally 1-3-fold hydroxy, halogen or C ₁ -C 5 -alkoxy-substituted (C ₁ -C ₁₀ ) -alkoxy group which is mono- or polysubstituted by oxygen , Nitrogen or sulfur atoms or by carbonyl or sulfonyl groups or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems may be interrupted, which may be unbranched or branched kan n and optionally also mono- or polyunsaturated, an optionally 1-3-fold hydroxy, halogen or C ₁ -C 5 -alkoxy-substituted (C ₁ -C ₁₀ ) -alkylthio group which is monosubstituted or polysubstituted by oxygen, Nitrogen or sulfur atoms or by carbonyl or sulfonyl groups or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems may be interrupted, which may be unbranched or branched and which may optionally also be mono- or polyunsaturated, a (C ₁ -C ₅ ) -Perfluoralkyl group which may be unbranched or branched and which may optionally also be mono- or polyunsaturated, with the proviso that at least one of R ¹ or R ^{2 is} not the same hydrogen, R ³ and R ⁴ independently represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a CF ₃ group or a C ₁ -C ₄ alkyl group, which may be unbranched or branched, or R ⁵ an al iphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring system, which may be fused with 1 or 2 further aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems, and which one or more times with a halogen atom, a cyano group, a Nitro group or a C ₁ -C ₄ -alkyl group, or a C ₁ -C ₄ -alkoxyl group, a C ₂ -C ₄ -alkenyl group of a C ₂ -C ₄ -alkynyl group which may be branched or unbranched and optionally also a or is polyunsaturated, the C ₁ -C ₄ -alkyl group, the C ₁ -C ₄ -alkoxyl group, the C ₂ -C ₄ -alkenyl group or the C ₂ -C ₄ -alkynyl group being in turn substituted by phenyl groups or halogenated phenyl groups, L for -N (R ⁶ ) - -O- -C (= O) - -OC (= O) - or -C (= O) -O- -N (R ⁶ ) -C (= O) - or -C (= O) -N (R ⁶ ) -, -N (R ⁶ ) -O- or -N (R ⁶ ) -O-, -ON (R ⁶ ) -C (= O) - or -C ( = O) -N (R ⁶ ) -O- wherein R ^{6 is} hydrogen or a branched or un branched C ₁ -C ₄ alkyl group is, and their salts with physiologically acceptable counterions. Compounds of the general formula I according to Claim 1, characterized in that at least one of the radicals R ¹ and R ^{2 represents} one of the following radicals:

Compounds of general formula I according to claim 1, characterized in that at least one of R ³ and R ^{4 is} hydrogen, fluorine or a CH ₃ or CF ₃ group. Compounds of general formula I according to Claim 1, characterized in that L represents one of the following groups: L for -N (R ⁶ ) -, -O-, -C (= O) -, -N (R ⁶ ) - C (= O) - or -C (= O) -N (R ⁶ ) -, -N (R ⁶ ) -O- or -N (R ⁶ ) -O- -ON (R ⁶ ) -C (= O ) - or -C (= O) -N (R ⁶ ) -O-. Compounds of general formula I according to Claim 1, characterized in that L represents one of the following groups: -ON (R ⁶ ) -C (= O) - or -C (= O) -N (R ⁶ ) -O- , Compounds of general formula I according to Claim 1, characterized in that R ^{5 represents} one of the following groups:

Compounds of general formula I according to claim 1, namely

Use of at least one compound according to at least any one of claims 1-7 for the preparation of medicaments. Use of at least one compound according to at least any one of claims 1-7 for the preparation of medicaments for the treatment of cancer. Use according to claim 9 for Production of medicaments for the manufacture of a medicament for Treatment of hematological or solid tumors, from non-Hodgkin's tumors or T-cell lymphomas. Use according to claim 9 for Production of medicaments for the manufacture of a medicament for for modulation of the cell cycle, cell differentiation, apoptosis or angiogenesis. Use according to claim 8 to Preparation of a tyrosine kinase inhibitor. Process for the preparation of a hydroxamate, characterized in that a compound of general formula II,

which is present in "amine-imine tautomerism" and where R and R 'represent any organic radicals, is reacted with an O-aminating reagent to give a compound of general formula III,

and subsequently with an acid chloride (or an activated ester) of the general formula VI

wherein R '''is any organic radical to a hydroxamate of the general formula V

is reacted, wherein R, R 'and R''' have the above meanings. A process for producing a hydroxamate according to claim 13, characterized in that the O-aminating reagent O- (2,4-dinitrophenyl) hydroxylamine or mesytlenesulfonylhydroxylamine is. Process according to Claim 13, characterized in that the starting compounds of the general formula II used are one of the following compounds:

wherein R ¹ and R ^{2 have} the meanings mentioned in claim 2. A method according to claim 13, characterized characterized in that as starting compounds of the general formula II thymine, uracil or cytosine can be used. A method according to claim 13, characterized in that as starting compounds of general formula II

which is converted by reaction with O- (2,4-dinitrophenyl) hydroxylamine or Mesytilensulfonylhydroxylamin to a compound

which is converted by reaction with benzoic acid chloride

is implemented.