WO2009036753A2 - Novel pharmaceuticals, method for the production thereof and use thereof in medical therapy - Google Patents

Abstract

The present invention relates to novel pharmaceuticals based on novel substituted 4-pyridine-3yl-pyrimidine, to a method for the production thereof, and to the use thereof in medical therapy, in particular cancer diseases.

Description

 New pharmaceuticals, process for their preparation and their use in medical therapy

The present patent application relates to novel pharmaceuticals, for example based on novel substituted 4-pyridin-3yl-pyrimidines, processes for their preparation and their use in therapy, for example in the therapy of cancer. The application claims priority from the German prior application DE 102007046266 (filing date: 20.9.07).

Background and state of the art

Cancers are still a common cause of death for people in industrialized countries. In Germany alone, about 395,000 new each year

Cancer diagnosed. The cure rate is 30-60%. Despite a number of known drugs for the treatment of cancer, there are a number of tumors that do not respond to therapeutics. In addition, the known therapies are characterized by a variety of side effects.

There is therefore a need for further cancer therapeutics.

Description of the invention

It has now been found that compounds of general formula I

in der R¹ und R² unabhängig voneinander ein Wasserstoffatom, ein Halogenatom, eine Cyanogruppe, eine Nitrogruppe, eine CF₃-Gruppe oder eine C₁-C₄- Alkylgruppe, die unverzweigt oder verzweigt sein kann

in the R ¹ and R ² 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

R ^{3 is} an optionally 1-3-fold hydroxy, halogen or Ci-C ₅ alkoxy substituted (Ci-C-io) alkyl group, the one or more times by

Oxygen, nitrogen or sulfur atoms or by carbonyl or sulfonyl or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic, saturated or unsaturated ring systems may be interrupted, which may be unbranched or branched and optionally also one or more times can be unsaturated,

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, saturated or unsaturated 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-containing homo- or heterocyclic, saturated or unsaturated ring systems may be interrupted, which may be unbranched or branched and 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, L ¹ and L ^{2 are} independently of one another -N (R ⁴ ) - -O-

-C (= O) -

-O-C (= O) - or -C (= O) -O-

-N (R ⁴⁾ -C (= O) - or -C (= O) - N (R ⁴⁾ -, -N (R ⁴⁾ -O- or -N (R ⁴⁾ -O-, -ON (R ⁴ ) -C (= O) - or -C (= O) - N (R ⁴ ) -O-

embedded image in which

R ^{4 is} hydrogen or a branched or unbranched CrC ₄ -

Alkyl group means

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 -CON or -CNO groups (for example -CON (H) -C (= O) - or -CN (H) -OC (= O) -) on the one hand competitively with natural Ligand bind, but on the other hand can not be metabolized. The inhibitory effect is thus significantly increased. This finding is based on the compounds described in this document.

Detailed description of the invention and preferred embodiments

The compounds of general formula I according to the invention are novel substituted 4-pyridin-3yl-pyrimidines. The optional radicals R ¹ and R ² are preferably hydrogen, fluorine or CH ₃ or CF ₃ groups.

The radical R ³ is a chain which may contain cyclic moieties. The chains in R ³ may contain in particular terminal N-containing aliphatic rings, such as piperidine or morpholine. Alternatively, the chain in R ^{3 can} also heterocycles, such as pyrrole, furan, thiophene, pyridine, pyrimidine, quinoline, isoquinoline, pyrazine, Containing quinazoline, quinoxaline. Preferably R _{3 is} a phenyl radical which in turn is monosubstituted or polysubstituted with F, CF ₃ , Me, Het, O-Het, - (CH ₂ ) _X -Het, - (CH ₂ ) _X -O-Het, wherein X is 0, 1, 2, 3 or 4 and wherein Het is a saturated or unsaturated heterocycle (such as piperidine, pyridine, thiazole, oxazo, pyrrole, imidazole, piperazine) which in turn has one or more substituents (such as methyl , Methoxy, ethyl, ethoxy). Particularly preferred radicals R ³ are shown in FIGS. 1 and 2.

The linkers L ¹ and L ² are an ether, ester, amine, amide, carbonyl or

Hydroxamate. Preferably, L1 and L2 is -N (R ⁴⁾ -, -O-, -C (= O) -, -N (R ⁴⁾ -C (= O) - or -C (= O) - N (R ⁴ ) -,

-ON (R ⁴ ) -C (= O) - or -C (= O) - N (R ⁴ ) -O-.

Most preferably, at least one of the groups L ¹ and L ^{2 stands} for

-ON (R ⁴ ) -C (= O) - or -C (= O) - N (R ⁴ ) -O-.

The radical R ⁴ optionally present in the linker groups is hydrogen or a branched or unbranched C 1 -C ₄ -alkyl group, preferably for

-H, -CH ₃ or -CH ₂ -CH ₃ . Most preferably, R ^{4 is} hydrogen.

The compounds of the invention may exist as stereoisomers due to the presence of asymmetric centers. The present invention relates to all possible stereoisomers both as racemates, as well as in enantiomerically pure form. The term stereoisomers also includes all possible diastereomers and regioisomers and tautomers (e.g., keto-enol tautomers) in which the compounds of the invention may be present, which are also subject of the invention.

Particularly preferred radicals R ³ are shown in FIGS. 1 and 2.

und die Verbindung 34

sowie die Verbindung 1862-791

Very particularly preferred embodiments of compounds of the general formula I are shown in FIGS. 3-12. Most preferred is compound 1862

and the connection 34

and the compound 1862-791

uses

The compounds of the general formula I are suitable as medicaments. They are particularly suitable for the treatment of cancer. They are particularly useful for the treatment of hematological or solid tumors, e.g. non-Hodgkin's tumors, or of T-cell lymphomas.

The effect of the compounds according to the invention as cancer therapeutics may possibly be due to their suitability for the inhibition of tyrosine kinase.

The suitability as cancer therapeutics is further on the effect of these compounds on the modulation of the cell cycle, the modulation of the

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 a compound of the invention for the preparation of a pharmaceutical composition for the treatment of one or more diseases selected from the group consisting of cancer such as lung cancer, leukemia, ovarian cancer, sarcoma, meningioma, colorectal 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's syndrome, disorders with impaired leukocyte adhesion, cachexia, increased TNFalpha concentration, diabetes , Obesity, bacterial infections, especially with resistant bacteria, heart failure and Chronic Cardiac Failure (CCF). "The term treatment also includes 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 may also be present in the form of their salts with physiologically acceptable counterions such as Mg ⁺⁺ , Ca ⁺⁺ , Na ⁺ , K ⁺ , Li ⁺ or ammonium derivatives such as cyclohexylammonium. Amino-containing compounds may also be present in the form of an ammonium salt, for example as chloride, bromide, mesylate, tosylate, oxalate, orotate, maleate 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), preparation forms for Trockenpulverinhalation, transdermal systems and preparations with sustained release drug, in the preparation of conventional auxiliaries such as carriers, blasting, binding, coating, swelling, lubricants or lubricants, flavorings, sweeteners and Solvent finder use. 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 pharmaceutical composition according to the invention can be prepared by mixing at least one substance combination used according to the invention in defined doses with a pharmaceutically suitable and physiologically acceptable carrier and optionally further suitable active ingredients, additives or excipients with a defined dose and prepared to the desired administration form.

Suitable diluents are polyglycols, ethanol, water and buffer solutions. Suitable buffer substances are, for example, N, N-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, sodium bicarbonate and sodium carbonate. However, it is also possible to work without a diluent.

Preferably, the pharmaceutical composition is prepared and administered in dosage units, each unit containing as active ingredient a defined dose of the compound of formula I according to the invention. In the case of solid dosage units such as tablets, capsules, dragees or suppositories, this dose may be from 0.1 to 1000 mg, preferably from 10 to 50 mg, and in the case of injection solutions in the form of ampoules from 0.01 to 1000 mg, preferably from 10 to 40 mg.

For clinical use, the preparation of infusion solutions is another preferred embodiment.

For example, for the treatment of an adult, patients weighing 50-100 kg, for example 70 kg, daily doses of 0.1-1,000 mg active ingredient, preferably 10 -50 mg, are indicated. However, higher or lower daily doses may be appropriate. The administration of the daily dose can be achieved by single administration in the form of a single dose Dosiθrungseinhθit or several smaller dosage units as well as by multiple subdivided doses at intervals.

The preparations according to the invention can be prepared, for example, as follows:

Dragees (with 75 mg active substance)

1 Drageekem contains:

• Active substance 75.0 mg

• Calcium phosphate 93.0 mg

• corn starch 35.5 mg • polyvinylpyrrolidone 10.0 mg

• hydroxypropylmethylcellulose 15.0 mg

• Magnesium stearate 1, 5 mg total weight: 230.0 mg

production:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone,

Hydroxypropylmethylcellulose and half of the specified amount of magnesium stearate mixed. On a tableting machine compacts are produced with a diameter of about 13 mm, these are ground on a suitable machine through a sieve with 1, 5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tabletting machine into tablets of the desired shape. Core weight: 230 mg

Stamp: 9 mm, curved

The coated dragee cores are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film dragees are shined with beeswax. Dragee weight: 245 mg.

Tablets (with 100 mg active substance)

Composition: 1 tablet contains: • Active substance 100.0 mg

• lactose 80.0 mg

• corn starch 34.0 mg

• polyvinylpyrrolidone 4.0 mg • magnesium stearate 2.0 mg

Total weight: 220.0 mg

Hersteliungverfahren:

Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the wet mass (2.0 mm mesh size) and drying in a rack oven at 50 ⁰ C is sieved again (1, 5 mm mesh size) and admixed with the lubricant. The ready-to-use mixture is processed into tablets.

Tablet weight: 220 mg

Tablets (with 150 mg active substance) Composition:

1 tablet contains:

• Active substance 150.0 mg

• lactose powdered 89.0 mg

• Corn starch 40.0 mg • Colloidal silica gel 10.0 mg

Polyvinylpyrrolidone 10.0 mg

• Magnesium stearate 1, 0 mg total weight: 300.0 mg

Production: The active substance mixed with milk sugar, corn starch and silica is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and beaten through a sieve of 1.5 mm mesh size.

The dried at 45 ⁰ C granules are rubbed again through the same sieve and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture. Tablet weight: 300 mg

Hard gelatine capsules (with 150 mg active substance)

1 capsule contains:

• active ingredient 150.0 mg • corn starch drink. about 180.0 mg

• lactose powder approx. 87.0 mg

Magnesium stearate 3.0 mg approx. 420.0 mg Preparation:

The active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and mixed homogeneously in a suitable device.

The final mixture is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg

Suppositories (with 150 mg active substance) 1 suppository contains:

• Active ingredient 150.0 mg

• Polyethylene glycol 1500 550.0 mg

• polyethylene glycol 6000 460.0 mg

• Polyoxyethylene sorbitan monostearate 840 mg total weight: 2000.0 mg

production:

After the suppository mass has melted, the active ingredient is distributed homogeneously therein and the melt is poured into pre-cooled molds.

Suspension (with 50 mg active substance) 100 ml suspension contain:

• Active ingredient 1, 00 g

Carboxymethylcellulose Na salt 0.10 g

P-Hydroxybenzoic acid methyl ester 0.05 g

• propyl p-hydroxybenzoate 0.01 g • cane sugar 10.00 g • Glycerine 5.00 g

• Sorbitol solution 70% 20.00 g

• Aroma 0.30 g

• dist. Water. ad 100 ml

production:

Dest. Water is heated to 7O ⁰ C. Herein, p-hydroxybenzoic acid methyl ester and propyl ester and also glycerol and carboxymethylcellulose sodium salt are dissolved with stirring. It is cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After adding and loosening the

Sugar, the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring.

5 ml of suspension contain 50 mg of active ingredient.

Ampoules (with 10 mg active substance)

Composition:

• Active ingredient 10.0 mg

• 0.01 n hydrochloric acid s.q.

• Aqua bidest ad 2,0 ml Production:

The active substance is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 2 ml ampoules.

Ampoules (with 50 mg active substance) Composition:

• Active ingredient 50.0 mg

• 0.01 n hydrochloric acid s.q.

• Aqua bidest ad 10.0 ml Production: The active ingredient is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 10 ml ampoules.

Corresponding formulations can be prepared for the compounds mentioned below of the alternative embodiments mentioned in this document. In the context of pharmaceutical compositions, compounds of the invention may be combined with other drugs known per se. For example, aldesleukin, amifostine, atrasentan, bevacizumab, bexarotene, bortezomib, capecitabine, carboplatin, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytamide, dacarbazine, docetaxel, droloxifene, edrecolomab, epothilone, erlotinib, etoposide,

Exemestane, Flavopiridol, Fludarabine, Fluorouracil, Formestane, Fulvestrant, Gefitinib, Gemcitabine, Idarubicin, Irinotecan, Ixabepilone, Lonafamib, Miltefosine, Mitomycin, Neovastat, Oxaliplatin, Pemetrexed, Porfimer, Rituximab, Tegafur, Temozolomide, Tipifamib, Topotecan, Trimimetrexate, Vorozole, Vinblastine, and mixtures of two or more such agents. In this case, the compound according to the invention can be mixed with the active substance in the context of a single galenic preparation. However, it is also possible that the pharmaceutical composition consists of two (or more) different galenic preparations, wherein in a first preparation the compound according to the invention and in a second preparation of the active ingredient are included. In the context of the first preparation, it is also possible to set up a substance which is different from the active ingredient of the second preparation.

production method

The further compounds of the general formula I according to the invention are prepared by the methods of organic chemistry known to those skilled in the art, the introduction of the C-O-N-C group preferably (but not exclusively) by reaction with tert-butyl-dimethylsilylhydroxylamine (or its analogs).

The synthetic schemes for making the most preferred compounds 1862, 2748 and 1832-791 are shown in Figs. 13-15.

Based on these representations and his general expertise can those skilled in the art of organic chemistry, the derivatives of the general formula I and the various alternative embodiments in a simple manner.

The utility 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. DIM 45, hormone independent human prostate carcinoma cells, e.g. ATCC HTB-81 or MaTu-MDR, can in one

Density of about 5,000 cells per measurement point in 96-l_och multi-well plates in 200 .mu.l of the appropriate growth medium are prepared. After 24 hours, the cells of one plate can be stained with crystal violet while replacing the medium of the other plates with fresh culture medium to which the test substances are added at various concentrations (0 μmol and in the range 0.01-30 μmol). 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 of live line.

Principle of the method:

In the XTT assay, the yellow tetrazolium salt XTT (sodium 3 '- [1- (phenylaminocarbonyl) -3,4-tetrazolium] -bis (methoxy-6-nitro) benzenesulfonic acid) is converted to orange-colored formazan by metabolically active cells (cleavage the tetrazolium ring of the XTT). The bioreduction of XTT becomes potential by the addition of PMS (electron coupling phenazine methosulfate). 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 In establishing the method, the optimal starting cell count per well for each cell line was determined for an ideal measurement of the optical density. In addition, correlation curves between the OD and the underlying cell number were generated for each cell line. Furthermore, the optimal time of substance addition and culture time was determined for each cell line (see implementation).

execution

Depending on the cell line, between 500 and 5000 cells in 100 μl of nutrient medium per well of a 96-well plate are passed through at the second point tθ.

50 μl of substance or 50 μl of solvent are added to the control.

After 4 (NK, MCF-7, BxPC-3, WI-38) or after 6 (MDA-MB-453, HT 29, KB-V1) cultivation days in the incubator, 75 μl of the freshly prepared XTT solution (1 mg / ml XTT, 0.383 mg / ml PMS: in the ratio 1:50).

After an incubation time of 3 h in an incubator at 37 ⁰ C, the OD in the ELISA reader (620 nm reference wavelength) was measured at a wavelength of 450 nm.

References: 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: internal name; KB-V1, without Virnblastin

Wl 38: human, fetal fibroblast-like cell line of the lung

NK: Novikoff rat hepatoma cell line Alternative embodiments of the invention

Within the scope of the invention, a number of further alternative embodiments have been found. These are substances that can also be used as pharmaceuticals. These are also characterized by a favorable effect / side effect profile.

The general formulas of the alternative embodiments as well as preferred embodiments of these alternative embodiments are shown in FIGS. 16 ff. The terms used herein of chemical substituents have the following meanings:

R ⁶ is hydrogen or a branched or unbranched C ₁ -C ₄ - alkyl group

R ⁷ represents a halogen atom, a cyano group, a nitro group, a CF 3 or a -C ₂ F ₅ group

R ⁸ represents a halogen atom (preferably fluorine or chlorine), a cyano group, a hydroxy group, a C 1 -C ₄ -alkoxy group, a nitro group, a CF 3 or a C ₂ F ₅ group,

R ⁹ represents a hydroxy group, a C 1 -C ₄ alkoxy group, a

Amino group, a group -N (H) -R ₆ or -N (H) -OR ₆ ,

represents a group - (CHa) _n - in which n has the meaning given below,

Z is independently a direct bond or an oxygen atom, with the proviso that at least one Z is an oxygen atom, preferably exactly one Z is an oxygen atom L stands for

-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-, -ON ^(R6) -C (= O) - or -C (= O) - N (R ⁶⁾ -O-, -N (R ⁶⁾ -C (= O) -O- or - OC (= O) - N (R ⁶ ) - wherein R ^{6 has} the abovementioned meaning

n stands for integers from zero to four, eg for zero, one, two, three or four

Quite surprisingly, the compounds of the alternative embodiments are effective in particular in the following indications:

Indication alternative

embodiment

Cancer V, VI, VII, IX, X

Psychoses Xl

CML (chronic myeloma leukemia) IX

Alzheimer XII

Dementia, schizophrenia, epilepsy XII

Hypercholesterolemia, hyperlipidemia Il

Stroke Il

Parkinson's Disease IM ₁ XII

Bacterial Infections IV, V

Moreover, surprisingly, the compounds of the alternative embodiments are effective in the production of inhibitors of specific proteins - and thus in the therapy of associated diseases -:

Protein inhibitor alternative embodiment

Serotonin receptor Xl

Dopamine receptor Xl

Tyrosine kinase inhibitor IX ₁ X

3-hydroxy-3-methylglutaroyl-coenzyme A (HMG-CoA) -II inhibitor

Dopamine agonist III

Kinase inhibitor (e.g., EGFR tyrosine kinase) VI

Kinase inhibitor (e.g., bcr-abl or c-kit or PDGF-R V tyrosine kinase

Cholinesterase inhibitor XIII

Claims

 Claims: 1. Compound of general formula I.

in the R ¹ and R ² 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 R ^{3 is} an optionally 1-3-fold hydroxy, halogen or Ci-Cs-alkoxy-substituted (Ci-Cio) alkyl group, 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, saturated or unsaturated 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 6 -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 May be interrupted interrupted ring-containing homo- or heterocyclic, saturated or unsaturated ring systems, which may be unbranched or branched and which may optionally also be mono- or polyunsaturated, an optionally 1-3-fold hydroxy, halogen or C-ι-C ₅ alkoxy substituted (Ci-Cio) -alkylthio group, one or more times by oxygen, nitrogen or sulfur atoms or by carbonyl or sulfonyl groups or by aliphatic or aromatic 5-7 Ring-containing homo- or heterocyclic, saturated or unsaturated ring systems may be interrupted, which may be unbranched or branched and 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, L ¹ and L ² independently of one another represent --N (R ⁴ ) - -O- -CO = O) - -O-C (= O) - or -C (= O) -O- -N (R ⁴⁾ -C (= O) - or -C (= O) - N (R ⁴⁾ -, -N (R ⁴⁾ -O- or -N (R ⁴⁾ -O-, -ON (R ⁴ ) -C (= O) - or -C (= O) - N (R ⁴ ) -O- wherein R ^{4 is} hydrogen or a branched or unbranched C 1 -C ₄ - Alkyl group means and their salts with physiologically compatible counterions. 2. Compounds of general formula I according to claim 1, characterized in that at least one of R ¹ and R ^{2 is} one of the following radicals: hydrogen, fluorine, methyl or trifluoromethyl. 3. Compounds of general formula I according to claim 1, characterized in that R ^{3 represents} one of the following radicals:

15

20 1. Compounds of general formula I according to claim 1, characterized in that L represents one of the following groups: -N (R ⁴ ) -, -O-, -C (= O) -, -N (R ⁴⁾ -C (= O) - or -C (= O) - N (R ⁴⁾ -, -N (R ⁴⁾ -O- or -N (R ⁴⁾ -O- -one ( R ⁴ ) -C (= O) - or -C (= O) -N (R ⁴ ) -O-, wherein R ^{4 is} hydrogen or a branched or unbranched C ₁ -C ₄ - alkyl group. 5. Compounds of general formula I according to claim 1, characterized in that L represents one of the following groups: -ON (R ⁴ ) -C (= O) - or -C (= O) - N (R ⁴ ) - O- wherein R ⁴ is hydrogen or methyl. 6. Compounds of general formula I according to claim 1, namely

or

7. Use of at least one compound according to any one of claims 1-6 for the preparation of medicaments. 8. Use of at least one compound according to any one of claims 1-6 for the preparation of medicaments for the treatment of cancer. 9. Use according to claim 8 for the manufacture of a medicament for the treatment of hematological or solid tumors, non-Hodgkin tumors or T-cell lymphomas. 10. Use according to claim 9 for the preparation of medicaments for the modulation of the cell cycle, cell differentiation, apoptosis or Angiogenesis. 11. Use according to claim 7 for the preparation of a tyrosine kinase inhibitor. 12. Use according to claim 7 for the manufacture of a medicament for the treatment of chronic inflammation, asthma, Allergy, Rhinitis, Uveitis, Urticaria, Arthritis, Osteoarthritis, Chronic Polyarthritis, Rheumatoid Arthritis, Inflammatory Bowel Disease, Degenerative Joint Diseases, Rheumatoid Related Diseases with Cartilage Degradation, Sepsis, Autoimmune Diseases, Type I Diabetes, Hashimoto's Thyroiditis, Autoimmune Thrombocytopenia, Multiple Sclerosis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, uveitis, psoriasis, atopic dermatitis, collagenosis, goodpasture syndrome, disorders with impaired leukocyte adhesion, cachexia, diseases due to increased TNFalpha concentration, diabetes, obesity, bacterial infections, especially with resistant ones Bacteria, Heart Failure or Chronic Cardiac Failure (CCF)