LT3416B - Isoxazole-4-carboxamides, hydroxyalkylidene-cyanoacetamides, drugs containing these compounds and method for the preparation of such drugs - Google Patents

Abstract

The isoxazol-4-carbonic acid amide derivatives and hydroxyalkylidene cyanoacetic acid amide derivatives are suitable for curing cancerous diseases. These compounds can be obtained by known methods. A part of these compounds is new and is suitable for curing rheumatic diseases.

Description

The present invention relates to isoxazole-4-carboxylic acid amides and hydroxyalkylidene cyanoacetamide derivatives which are proposed for use as medicaments for the treatment of cancer, to pharmaceutical compositions thereof and to processes for their preparation.

The compounds may be prepared by known methods. Some of these are novel compounds and may also be used in the treatment of rheumatic diseases.

Several processes for the preparation of isoxazole-4-carboxylic acid amides have been described in the literature (DE 25 24 959; DE 26 55 009; DE 34 05 727). It is known from European Patent 13,376 that 5-methylisoxazole-4-carboxylic acid 4-trifluoromethylanilide can be used as an antirheumatic, anti-inflammatory, anti-inflammatory, analgesic, and in the treatment of multiple sclerosis due to its pharmacological properties. This patent also describes a process for preparing this compound.

Recently, isoxazole -; - carboxylic acid amides of formula (I) and hydroxyalkylidene-cyanoacetic acid amides of formula (Ia) and their tautomeric form (Ib) have antitumor activity. Many known anticancer agents cause side effects such as nausea, vomiting or diarrhea during treatment, which require hospital treatment. In addition, these drugs alter the rate at which other autogenous cells metabolize and cause symptoms such as hair loss or anemia. Such symptoms are not observed in the treatment of humans and animals with compounds of formula (I). In contrast to hitherto known cytotoxic anticancer agents, these agents do not compromise the immune system (Bartlett, Int. J. Immunopharmac., 1986, pp. 199-204). This opens up new pathways for tumor therapy without compromising the autogenous defense system and inhibiting tumor cell growth. Unexpectedly, these substances have been found to inhibit most tumor cells, whereas cells of the immune system, such as thymphocytes, are inhibited only at concentrations 50 times higher.

Thus, the present invention relates to the use of a medicament for the treatment of cancerous diseases comprising at least one compound of formula I, Ia or Ib

(I)

(Ia)

(Ib) and optionally in stereoisomeric form and / or at least one of its physiologically acceptable salts, wherein:

R is

T-. ²

R is n ³

R is

a) hydrogen, b) C 1-8 alkyl, c) C ₁ . _4- alkyl substituted with one or more substituents such as 1) halogen, such as fluorine, chlorine, or iodine; bromine d) phenyl; a) hydrogen; b) C ₁ . _4- alkyl; c) phenyl-C ₁ . _2- alkyl, especially benzyl; d) C ₂ _ ₃ alkenyl; a) mono-, bi- or tricyclic unsaturated

a heterocyclic group having 3 to 13 C atoms and 1 to 4 heteroatoms such as oxygen, sulfur and nitrogen, of which at most one atom is different from nitrogen which is unsubstituted or has one or more substituents such as:

(1) halogen such as fluorine, chlorine, bromine or iodine;

2) C ₁ . ₄ alkyl,

3) C ₁ _ ₃ alkyl in which one or more substituents such as:

3.1) halogen, such as fluorine, chlorine, bromine or iodine,

4) C ₁ . _3- alkoxy, 5) C _x _ ₃ -alkoxy, multiple substituents, containing one or more of the following: 5.1) halogen, bromine or like fluorine, chlorine, iodine, 6) nitro group, 7) hydroxyl, 8) carboxyl, 9) carbamoyl, 10) oxo group; (b) a group of the formula II

(II) wherein R ⁴ , R ⁵ and R ⁶ may be the same or different and are:

1) hydrogen,

2) C 1-6 alkyl,

3) C _l - ₃ alkyl, in which one or more substituents such as:

3.1) halogen, bromine or like their skins, fluorine, chlorine, 4) R ⁴ is present hydrogen and R ⁵ and R ⁶ together with II of the formula phenyl ring consists of of naphthalene

ring,

5) R ⁴ is hydrogen and R ⁵ and R ⁶ form a methylenedioxy group,

6) C ₁ _ ₃ -alkoxy,

7) C ₁ _ ₃ alkoxy group bearing one or more substituents such as:

7.1) halogen, such as fluorine, chlorine, bromine or iodine,

8) C ₁ . _3- alkylmercaptic group,

9) C ₁ . _{A 3-} alkylmercaptic group containing one or more substituents such as:

9.1) halogen, such as fluorine, chlorine, bromine or iodine,

10) halogen, such as fluorine, chlorine, bromine or iodine,

11) nitro group,

12) cyano group,

13) hydroxyl,

14) carboxyl

15) C _x . _3- alkylsulfonyl,

16) a carbalkoxy group having 1-3 C atoms in the alkyl chain,

17) benzoyl,

18) benzoyl, mono- or polysubstituted, such as:

18.1) halogen such as fluorine, chlorine, bromine or iodine,

18.2) C _x . ₃ alkyl,

18.3) C _x . _3- alkoxy,

19) phenyl,

20) phenyl substituted with one or more substituents such as:

20.1) C _x . _3- alkoxy,

20.2) halogen such as fluorine, chlorine, bromine or iodine,

20.3) C _x - ₃ alkyl

21) phenoxy group,

(22) phenoxy, substituted with one or more substituents such as:

22.1) A C 1-3 alkoxy group having one or more substituents such as:

22.1.1) halogen such as fluorine, chlorine, bromine or iodine,

22.2) halogen such as fluorine, chlorine, bromine or iodine,

22.3) C ₁ . _3- alkyl substituted with one or more substituents such as:

22.3.1) halogen, such as fluorine, chlorine, bromine or iodine;

(c) a group of formula III

- (CH ₂ ) _n -COOR io (III) in which

R ¹⁰ is 1) hydrogen;

2) C ₁ _ ₄ alkyl, n is an integer from 1 to 12,

3

d) R and R together with the nitrogen to which they are attached form a 4- to 9-membered ring containing substituents such as:

1) carbonyl at the C-atom adjacent to Natom;

e) R and R together with the nitrogen to which they are attached form a 5-6 membered ring of formula IV r ~ \

-M W xz (IV) wherein W is:

D -ch ₂ -,

2) -CH ₂ -CH ₂ -,

3) -CH ₂ -CH-,

I

CH ₃

4) -CH ₂ -CH-,

I

C ₂ H _s

5) -CH ₂ -CH-,

I

OH

6) -CH ₂ -O- or

7) -CH ₂ -S-;

R ⁷ is a) hydrogen,

b) C 1-4 alkyl,

c) C 1-6 alkyl, in the process of being substituted with one or more substituents such as halogen, such as fluorine, chlorine, bromine or iodine,

d) phenyl-C ₁ . _2- alkyl, especially benzyl;

θ

R is a) hydrogen;

b) methyl

c) the C ₂ _ ₃ alkenyl.

5-Methylisoxazole-4-carboxylic acid 4-trifluoromethylanilide (Compound 1) and 2-cyano-3-hydroxycrotonic acid N- (4-trifluoromethyl) amide (Compound 2) are most suitable.

Physiologically acceptable salts of the compounds of formula I include, for example, alkali metals, alkaline earth metals and ammonium salts, including salts of organic ammonium bases.

The mono-, di- or tricyclic unsaturated heterocyclic group having 3 to 13 C atoms is, for example, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, thiazolinyl, oxazolyl, thiadiazolyl, benzoxazolyl, benzimidazolyl, ch , acridinyl, indolyl, tetrazolyl or indazolyl.

The compounds of formula I and their physiologically acceptable salts are suitable, inter alia, for the treatment of many cancers. Cancers that are particularly well suppressed by these compounds include leukemia, namely chronic T- and B-cell leukemia, lymph node cancer such as Hodgkin's or non-Hodgkin's lymphoma, carcinomas, sarcoma and skin cancer. The active ingredients may be used either alone, for example in microcapsules, or in mixtures thereof, or in combination with suitable excipients and / or carriers.

The compounds I, Ia and Ib are synthesized by known methods (DE 2 524 959; DE 2 655 099; DE 3 404 727; DE 2 524 929; DE

557,003).

io

Compounds of formula I, Ia or Ib are prepared by action

(a) a compound of formula V:

(V) wherein X is halogen, preferably chlorine or bromine, and R ¹ is as defined for Formula I, an amine of Formula VI:

H-N <

R * (VI) wherein R ² and R ³ have the meanings given in the formula I;

or

(b) Compound of Formula VI:

ho-or * r *

CH3-C0-C-C0NH - ^) - R ^{f <VI)} β * wherein R ¹ is C ₁ . _4- alkyl, while R ⁴ , R ⁵ and R ⁶ have the meanings indicated in the description of formula I, preferably at least in equimolar amounts in the hydroxylamine organic solvent;

or

c) reacting a compound of formula V wherein X and R ¹ have the meanings given above, with a primary aliphatic amine of formula VII:

H ₂ N- (CH ₂ ) _n -COOR ¹⁰ (VII) wherein n and R ¹⁰ have the meanings given in the formula I;

or

d) in the presence of a compound of formula V wherein X and R ¹ have the meanings given above, of a lactam of formula VIII:

(VIII) wherein m is an integer from 1 to 6;

or

e) treating a compound of formula V wherein X and R ¹ have the meanings given above with an amine of formula IX:

H-N ti (IX) wherein W has the meanings given in the formula I;

or

f) The compounds of formula I are converted into the corresponding compounds of formula Ia or Ib in the presence of bases.

Another object of the present invention are novel compounds of formula (I)

(I) where appropriate, their stereoisomeric forms and / or, under certain conditions, their physiologically acceptable salts, wherein

R ¹ is a) hydrogen,

b) C ₂ _ ₆ -alkyl,

c) C 1-6 alkyl substituted with one or more substituents such as:

1) halogen, such as fluorine, chlorine, bromine or iodine,

d) phenyl;

R ² is a) hydrogen;

b) C _2-3 alkenyl,

c) benzyl;

R ³ is a) pyridyl substituted with one or more substituents such as:

1) hydrogen,

2) halogen such as fluorine, chlorine, bromine or iodine,

(3) nitro group,

4) C ₁ . ₃ alkyl,

5) C ₁ . _3- alkoxy;

(b) a group of formula II,

R * (II) wherein R ⁴ , R ⁵ and R ⁶ are the same or different and are 1) halogen such as fluorine, chlorine, bromine or iodine,

2) nitro group,

3) hydrogen,

4) benzoyl substituted with one or more substituents such as:

4.1) halogen, such as fluorine, chlorine, bromine or iodine,

4.2) methyl,

4.3) methoxy group,

5) C ₁ . _{A 3-} alkoxy group containing one or more substituents such as:

5.1) halogen, such as fluorine, chlorine, bromine or iodine;

6) C _x . _4- alkyl substituted with one or more substituents such as:

6.1) halogen, such as fluorine, chlorine, bromine or iodine,

7) hydroxyl,

8) alkylsulfonyl having 1-3 C atoms in the alkyl chain,

9) R ⁴ is hydrogen and R ⁵ and R ⁶ together form a methylenedioxy group,

10) cyano group,

11) C ₁ _ ₃ -alkilmerkaptogrupė,

12) benzoyl,

13) C ₁ _ ₃ alkyl;

(c) pyrimidinyl, mono- or polysubstituted, such as:

1) C _x _ ₃ alkyl;

(d) indolyl,

e) indazolinyl.

Another object of the invention are novel compounds of formula Ia or Ib:

NC-c-c-rv («« M

R ⁷ 'OH (Ia)

S

NC-CH-C-Λ / ζ.

(Ib) optionally in stereoisomeric forms and / or, if necessary, in physiologically acceptable salts thereof, containing 3 r-7. _8

R, R and R are:

a) R is 1) hydrogen,

2) C ₂ . ₄ alkyl,

R is 1) hydrogen,

2) methyl,

R is 1) phenyl,

2) phenyl substituted by one or more substituents such as:

2.1) halogen,

b) R ⁷ is _, 8

R is n ³

R is

2.2) C 1-6 alkyl substituted with one or more substituents such as halogen, such as fluorine, chlorine, bromine or skin;

1) hydrogen,

2) C 1-6 alkyl,

3) CF ₃ ,

1) hydrogen,

2) methyl,

3) C _2-3 ~ alkenyl,

1) pyridyl,

(2) pyridyl substituted by one or more substituents such as:

2.1) halogen as fluorine,

chlorine, bromine or iodine, 2.2) C 1-6 alkyl, 3) pyrimidinyl wherein the substituents described in 2), is 4) thiazolyl substituted by

described in 2) and

4.1) alkoxycarbonyl having 13 C atoms in the alkyl chain,

5) benzothiazolyl substituted with 2),

6) benzimidazolyl substituted with 2),

7) indazolyl substituted with 2),

8) phenyl containing one or

several alternates, 8.1) benzoyl, such as: 8.2) benzoyl, containing alternates, such

how:

8.2.1) halogen such as fluorine, chlorine, bromine or iodine,

8.2.2) C 1-6 alkyl,

8.2.3) C ₁ _ ₃ -alkoxy,

8.2.4) C _r . _{A 3-} alkoxy group containing one or more substituents such as halogen such as fluorine, chlorine, bromine or iodine,

8.3) carboxyl,

18th c) R ⁷ is present 8.4) hydroxyl; 1) hydrogen, 2) C ₁ . ₄ alkyl, R is 1) hydrogen, R ³ is present 2) methyl, 1) a group of formula III: -CH ₂ ) ₄ COOR ¹⁰ (III) wherein R ¹⁰ is 1.1) hydrogen, d) R ⁷ is present 1.2) C ₁ _ ₄ alkyl; 1) hydrogen, 2) C 1-6 alkyl, R ⁸ and R ³ together with the nitrogen to which they are attached form a 4- to 9-membered ring, containing a substituent 2.1) carbonyl at the C-atom, adjacent to the N-atom; or

R ⁸ and R ³ together with the nitrogen to which they are attached form a piperidine ring optionally substituted with C ₁ -C ₃ alkyl.

Another object of the invention is the use of novel compounds of formula I, Ia or Ib and / or at least one of their physiologically acceptable salts for the preparation of a medicament for the prophylaxis and / or treatment of rheumatic diseases.

The invention also relates to medicaments comprising at least one compound of the formula I and / or at least one of its physiologically acceptable salts, or at least one of these active substances together with a suitable physiologically acceptable carrier, diluent and / or other excipients.

The medicaments of the invention may be administered orally, topically, or, if desired, parenterally, but oral administration is preferred.

Suitable solid or liquid dosage forms are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection, as well as sustained release dosage forms; conventional excipients such as carriers, binders, coating materials, swelling agents, emollients and moisturizers, flavor enhancers, sugars and solvents are used to make these forms. The most commonly used excipients are, for example, magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol and solvents such as sterile water. and monopolyatomic alcohols such as glycerol.

Pharmaceutical formulations are prepared and used in the most commonly administered dosage forms and each dosage unit contains a suitable dose of at least one compound of formula I and / or at least one physiologically acceptable salt thereof. For solid dosage units such as tablets, capsules, dragees, or suppositories, this dose may be up to about 300 mg, but is preferably about 10 to 50 mg.

Depending on the efficacy of the formula I and / or its physiologically acceptable salt in humans, the daily dose is approximately 5 to 100 mg for treatment of adult patients (70 kg) with leukemia. Higher or lower daily doses may also be used, depending on the circumstances. This daily dose may be a single dose, consisting of one or more dosage units, or may be divided at appropriate intervals.

In addition, the compounds of the formula I and / or at least one of their physiologically acceptable salts contained in said dosage forms may also be formulated in a formulation with other suitable active ingredients, for example other anticancer drugs, immunoglobulins, monoclonal antibodies, immunostimulants or antibiotics. These compounds can also be used as an adjunct to radiation therapy.

Pharmacological tests and results

An in vitro assay for cell culture proliferation was used as an effective chemotherapy assay.

example

Proliferation test

Clicks- / RPMI 1640 (50:50) medium containing NaHCO ₃ Lglutamine (powder, 10 liters) (Seromed, Biochrom, Berlin, VFR) was dissolved in 9 l of water (doubly distilled) and sterile filtered into 900 ml vials.

Rinse medium

900 ml of stock medium is mixed with 9.5 ml of 7.5% sodium bicarbonate solution and 5 ml of HEPES (N-2-hydroxy-ethylpiperazine-N-2-ethanol sulfuric acid) (Gibco, Eggenstein, VFR)

Working medium

900 ml stock medium plus 19 ml NaHCO ₃ solution (7.5%, 10 ml HEPES solution and 10 ml L-glutamine solution (200 mM)).

Medium for mitogen-induced lymphocyte proliferation

The medium is mixed with 1% thermally activated (30 min, 56 ° C) fetal calf serum.

Tumor cell medium

The working medium is mixed with 5% calf fetal serum (FCS) to maintain tumor cells and hybridoma cells.

Culture medium for cell lines

For maintenance of cell lines, 900 ml of medium are mixed with 10% FCS, 10 ml of NEA (Gibco) solution, 10 ml of pyruvate sodium solution (100 mM, Gibco) and 5 ml of 10 ' ² M mercaptoethanol .

Production and processing of spleen cells for mitogen-induced lymphocyte proliferation

Cervical dislocation kills mice and aseptically removes their spleens. Sponges are ground on a sterile mesh of 80 mesh and carefully injected into a Petri dish with working medium using a plastic syringe (10 ml). For removal of erythrocytes from the spleen cell suspension, the mixture is incubated for approximately 1 minute at room temperature with periodic shaking in a hypotonic 0.17 M ammonium chloride solution. Erythrocytes lyse and lymphocyte viability and reactivity remain. Centrifuge (7 min / 340 g), lysate is discarded, cells are washed twice with water and added to appropriate test medium.

Mitogen-induced proliferation of lymphocytes x 10 ⁵ treated spleen cells from NMRI female mice, together with various mitogens and preparation, in 200 µl of working medium was pipetted into wells of a flat bottom microtiter plate. The following concentrations of mitogens and preparation are used:

concanavalin A (Servo): 0.5-0.25-0.12 µg / ml lipopolysaccharide (Calbiochem): 1.0-0.5-0.1 µg / ml phytohemagglutinin (Gibco): 0.5-0 25 - 0.12% stock solution of Pokeweed mitogen (Gibco), compound 1 or 2:

50, 25, 10, 7.5, 5, 2.5, 1, 0.5, 0.1 μΜ.

The group in which mitogen-free product was added was considered a positive control. The group where mitogen-free medium was present in the cell culture medium was considered a negative control. Mitogen concentrations were tested 4 times at all concentrations. After incubation for 48 hours at 37 ° C / 5% CO ₂ , 25 μΙ / well of tritium-thymidine (Amersham) at 0.25 pCi / i (9.25 x 10 ³ Bq) was added to the cells. . Subsequently, incubate under the same conditions for 16 hours. Cells are harvested on filter paper using a cell harvesting device (Flow Laboratories) and the unbound thymidine is collected in a vial. The filter paper is dried, stamped and, after addition of 2 ml of scintillator (Rotiszint 22 Roth firm), placed in a flask which is cooled for another 2 hours at 4 ° C. The amount of radioactivity released from the cells is measured with a beta counter (Packard firm, Tricarb-460c).

Preparation of tumor cells and cell lines for proliferation assays

The tumor cells or cell lines used in the assay are harvested in the logarithmic growth phase, washed twice in the leaching medium and suspended in the appropriate medium.

Performance and Analysis of Proliferation Test

The proliferation assay is performed on round bottom titration plates, compound 1 and interleukin are dissolved in 50 μΐ of the appropriate medium / well and the cell volume (5 x ^{10 5} ) is determined by addition of 100 μΐ / well, ie a total volume of 200 μΐ / well. All tests were repeated 4 times. Cells without preparation and without growth factor were considered as negative controls and cells without preparation but with growth factor were considered as positive controls. Negative controls were subtracted from all values found and the difference between positive control and negative control was assumed to be 100%.

Cells were incubated for 72 hours at 37 ° C / 5% 0D ₂ , and the rate of proliferation was determined as in the case of mitogen-induced proliferation of lymphocytes.

Cell lines were obtained from stock ATCC (American Type Culture Collection) solution.

The following table gives the concentrations at which 50% braking is obtained:

table

Cell line Origin ED (pM) CTLL Mouse T cell line (T _c -Clon IL-2) 40-50 HT-2 Mouse T cell line (IL-2) 40-50 CTL-J-K Mouse T cell line (T _c , IL-2) 40-50 Cl 9/4 Mouse T cell line (dep. IL-4) 25th K III 5 Mouse T cell line (T _h , IL-2) 1-3 Spleen T Mice (Con A and PWM) 10th Spleen B Mice (FTA) 10th A20 2J Mouse B cell tumor (BALB / c) 1-3 TRK 4 Mouse B cell hybridoma 5 TRK 5 Mouse B cell hybridoma 5 Bone Marrow Mice (M-CSF, GM CSF) 5 WEHI 279 Mouse cell lymphoma <1 P 388 DI Mouse M tumor 10th 7TDI Mouse B Cell Hybridoma (IL-6) 10th G 53 A mouse T cell clone 10th PB-3C Mouse Mast Cell Line (IL-3) 20th DA-I Mouse Tumor (IL-3) 5 7D4 Rat Hybridoma <1 A431 Human Epidermal Carcinoma 15th KB Human Epidermal Carcinoma 15th HFF Human skin surface fibroblast 40 HL-60 Human promyelomonocytic leukemia 25th

example

Acute oral toxicity Mice and rats were used to determine the acute oral toxicity of the compound.

LD ₅₀ values were determined according to Litchfield and Wilcoxon.

NMRI-mice (NMRI: Navai Medical Research Institute) weighed between 20 and 25 g and SD-rats (SD: SpragueDawley) weighed between 120 and 165 g. Mice were fasted for 18 hours prior to the experiment. Mice were resumed normal nutrition 5 hours after administration of the test substance. After 3 weeks, the animals were killed with chloroform and gutted. Six animals were used per dose. The results are summarized in Table 2.

table

NMRI-mouse SD-rat

Acute toxicity, LD ₅₀ (mg / kg) Compound 1 Compound 2

445 (362-546)

235 (167-332) 160 (133-193) Example

Acute toxicity by ingestion

Acute oral toxicity of the test compounds was determined using NMRI mice (20-25 g) and SD rats (120-195 g). The test substance is suspended in a 1% sodium carboxymethylcellulose solution. Different amounts of test substance were administered to mice at 10 ml / kg and rats at 5 ml / kg. 10 animals were used per dose. Acute toxicity after 3 weeks was determined by Litchfield and Wilcoxson. The results of the tests are summarized in Table 3.

table

NMRI-mouse SD-rat

Acute toxicity, LD ₅₀ (mg / kg) Compound 1 Compound 2

185 (163-210) (100-200)

Example 170 (153-189)

A. Preparation of 5-methylisoxazole-4-carboxylic acid 4-trifluoromethylanilide

A solution of 0.05 mol of 5-methylisoxazole-4-carbonic acid chloride (7.3 g) in 20 ml of acetonitrile was added dropwise at room temperature to a solution of 0.1 mol of 4-trifluoromethylaniline (16.1 g) in 150 ml of acetonitrile, stirred for 20 minutes. After precipitation, the precipitate is filtered off with 4-trifluoromethylaniline hydrochloride and the precipitate is washed with acetonitrile (2 x 20 mL). The filtrate and the acetonitrile used for the washing are evaporated in vacuo. 12.8 g of white crystalline 5-methylisoxazole-4-carbonic acid 4-trifluoromethylanilide (Compound 1) are obtained.

B. Preparation of N- (4-trifluoromethylphenyl) amide of 2-cyano-3-hydroxycrotonic acid

Dissolve 0, 1 mol of 5-methylisoxazole-4-crotonic acid 4-trifluoromethylanilide in 100 ml of methanol and stir at 0 ° C with 0.11 mol (4.4 g) of caustic soda in 100 ml of water. The mixture is stirred for 30 minutes, diluted with water and acidified with concentrated hydrochloric acid. The precipitated crystals are suctioned off, washed with water and air dried.

24.4 g of 2-cyano-3-hydroxycrotonic acid N- (4-trifluoromethylphenyl) amide (compound 2) are obtained. Melting point (from methanol): 205-206 ° C.

Examples of synthesis

In the following structure of the compounds was determined by means of elemental analysis, IR spectra and ¹ H-BMRspektrų methods.

5. N- (4-Chlorodifluoromethoxy) phenyl-5-ethylisoxazole-4-carboxamide

0.1 mol (19.4 g) of 4-chlorodifluoromethoxyaniline dissolved in 150 ml of acetonitrile are added dropwise at room temperature to a solution of 0.05 mol (7.3 g)

5-Methylisoxazole-4-carbonic acid chloride in 30 mL of acetonitrile. After stirring for another 20 minutes, the precipitated salt is filtered off and the filtrate is evaporated to the dry state in a vacuum. 28.5 g (94.2% of theory) of the crystalline product are obtained. Melting point (from 20: 1 (v / v) cyclohexane: acetone): 112-113 ° C.

The following formula I compounds are obtained according to the procedure described above:

6. N- (4-Fluorophenyl) -isoxazole-4-carboxamide (m.p. 162-164 ° C) from isoxazole-4-carbonic acid chloride and 4-fluoroaniline.

7. N- (4-Chlorophenyl) -isoxazole-4-carboxamide (m.p. 175-177 ° C, decomposes) from isoxazole-4-carbonic acid chloride and 4-chloroaniline.

8. N- (4-Bromophenyl) -isoxazole-4-carboxamide (m.p. 185-186 ° C, decomposes) from isoxazole-4-carbonic acid chloride and 4-chloroaniline.

9. N- (4-Iodophenyl) -isoxazole-4-carboxamide (m.p. 207-208 ° C) from isoxazole-4-carbonic acid chloride and 4-iodanyl.

N- (4-nitrophenyl) -isoxazole-4-carboxamide (m.p. 208-210∞C, decomposed) from isoxazole-4-carbonic acid chloride and 4-nitroaniline.

N- (3,4-methylenedioxyphenyl) -isoxazole-4-carboxamide (m.p. 168-169 ° C) from isoxazole-4-carboxylic acid chloride and 3,4-methylenedioxyaniline.

12. N- (4-Benzoylphenyl) -isoxazole-4-carboxamide (m.p. 197-199∞C, decomposed) from isoxazole-4-carboxylic acid chloride and 4-aminobenzophenone.

13. N- (4-Fluorophenyl) -5-ethylisoxazole-4-carboxamide (m.p. 75-77 ° C) from 5-ethylisoxazole-4-carboxylic acid chloride and 4-fluoroaniline.

14. N- (4-Chlorophenyl) -5-ethylisoxazole-4-carboxamide (m.p. 102-105 ° C) from 5-ethylisoxazole-4-carbonic acid chloride and 4-chloroaniline.

15. N- (4-Bromophenyl) -5-ethylisoxazole-4-carboxamide (m.p. 117-118 ° C) from 5-ethylisoxazole-4-carbonic acid chloride and 4-bromoaniline.

N- (4-nitrophenyl) -5-ethylisoxazole-4-carboxamide (m.p. 139-141 ° C) from 5-ethylisoxazole-4-carboxylic acid chloride and 4-nitroaniline.

17. N- (3,4-Methylenedioxyphenyl) -5-ethylisoxazole-4-carboxamide (m.p. 105-106 ° C) from 5LT 3416 B Ethylisoxazole-4-carboxylic acid chloride and 3,4-methylenedioxyaniline.

18. N- (4-Trifluoro-toxic phenyl) -5-ethylisoxazole-4-carboxamide (m.p. 52-54 ° C) from 5-ethylisoxazole-4-carboxylic acid chloride and 4-trifluoromethoxyaniline.

19. N- (4-Benzoylphenyl) -5-ethylisoxazole-4-carboxamide (m.p. 168-170 ° C) from 5-ethylisoxazole-4-carboxylic acid chloride and 4-aminobenzophenone.

N- (4- (4-fluorobenzoyl) phenyl) -5-ethylisoxazole-4-carboxamide (m.p. 153-155 ° C) from 5-ethylisoxazole-4-carboxylic acid chloride and 4- (4-fluorobenzoyl) aniline.

21. N- (4- (4-chlorobenzoyl) phenyl-5-ethylisoxazole-4-carboxamide (m.p. 159-161 ° C) from 5-ethylisoxazole-4-carboxylic acid chloride and 4- (4-chlorobenzoyl) aniline.

N- (4- (4-Bromobenzoyl) phenyl) -5-ethylisoxazole-4-carboxamide (m.p. 178-181 ° C) from 5-ethylisoxazole-4-carboxylic acid chloride and 4- (4-bromobenzoyl) aniline.

23. N- (4-Benzoylphenyl) -5-propylisoxazole-4-carboxamide (m.p. 134-135 ° C) from 5-propylisoxazole-4-carbonic acid chloride and 4aminobenzophenone.

24. N- (4-chlorophenyl) -5-butylisoxazole-4-carboxamide (m.p. 91-92∞C) from 5-butylisoxazole-4-carbonic acid chloride and 4-chloroaniline.

25. N- (4-Benzoylphenyl) -5-butylisoxazole-4-carboxamide (m.p. 108-110 ° C) from 5-butylisoxazole-4-carboxylic acid chloride and 4-aminobenzophenone.

26. N- (4-Fluorophenyl) -5-trifluoromethylisoxazole-4-carboxamide (m.p. 97 ° C) from 5-trifluoromethylisoxazole-4-carbonic acid chloride and 4-fluoroaniline.

27. N- (4-Chlorophenyl) -5-trifluoromethylisoxazole-4-carboxamide (m.p. 90-92 ° C) from 5-trifluoromethylisoxazole-4-carboxylic acid chloride and 4-chloroaniline.

28. N- (4-Nitrophenyl) -5-trifluoromethylisoxazole-4-carboxamide (m.p. 136-138 ° C) from 5-trifluoromethylisoxazole-4-carbonic acid chloride and 4-nitroaniline.

29. N- (3,4-Methylenedioxyphenyl) -5-trifluoromethylisoxazole-4-carboxamide (m.p. 114-116 ° C) from 5-trifluoromethylisoxazole-4-carboxylic acid chloride and 3,4-methylenedioxyaniline.

30. N- (4-Trifluoromethylphenyl) -5-chloromethylisoxazole-4-carboxamide (m.p. 136-137 ° C) from 5-chloromethylisoxazole-4-carboxylic acid chloride and 4-trifluoromethylaniline.

31. N- (4-Trifluoromethylphenyl) -5-phenylisoxazole-4-carboxamide (m.p. 159-160 ° C) from 3-phenylisoxazole-4-carboxylic acid chloride and 4-trifluoromethylaniline.

32. N- (4-Fluorophenyl) -5-phenylisoxazole-4-carboxamide (m.p. 151-153∞C) from 5-phenylisoxazole-4-carboxylic acid chloride and 4-fluoroaniline.

33. N- (4-Rethylsulfonylphenyl) -5-methylisoxazole-4-carboxamide (m.p. 170-172 ° C) from 5-methylisoxazole-4-carboxylic acid chloride and 4-methylsulfonylaniline.

34. N-Benzyl-N- (4-trifluoromethylphenyl) -5-methylisoxazole-4-carboxamide (m.p. of 5-methylisoxazole-4-carboxylic acid chloride and N-benzyl-4-trifluoromethylaniline).

35. N- (3,5-di-tert-butyl-4-hydroxyphenyl) -5-methylisoxazole-4-carboxamide (m.p. 199-203, decomposes) from 5-methylisoxazole-4-carboxylic acid chloride and 3, 5-di-tert-butyl-4-hydroxyaniline.

36. N- (5-chloro-2-pyridyl) -isoxazole-4-carboxamide (m.p. 254-255 ° C) from isoxazole-4-carbonic acid chloride and 2-amino-5-chloropyridine.

37. N- (5-chloro-2-pyridyl) -5-ethylisoxazole-4-carboxamide (m.p. 133-136 ° C) from 5-ethylisoxazole-4-carboxylic acid chloride and 2 amino-5-chloropyridine.

38. N- (5-bromo-2-pyridyl) -5-ethylisoxazole-4-carboxamide (m.p. 144-145 ° C) from 5-ethylisoxazole-4-carboxylic acid chloride and 2 amino-5-bromopyridine.

39. N- (5-nitro-2-pyridyl) -5-ethylisoxazole-4-carboxamide (m.p. 236-237 ° C) from 5-ethylisoxazole-4-carboxylic acid chloride and 2 amino-5-nitro-pyridine.

40. N- (5-chloro-2-pyridyl) -5-phenylisoxazole-4-carboxamide (m.p. 160-161 ° C) from 5LT 3416 B phenylisoxazole-4-carbonic acid chloride and 2 amino-5-chloropyridine.

41. N- (5-Indolyl) -5-methylisoxazole-4-carboxamide (m.p. 155-157 ° C) from 5-methylisoxazole-4-carboxylic acid chloride and 5-aminoindole.

42. N- (6-Indazolyl) -5-raethylisoxazole-4-carboxamide (m.p. 198-202 ° C) from 5-methylisoxazole-4-carboxylic acid chloride and 6-aminoindazole.

43. N- (5-Indazolyl) -5-methylisoxazole-4-carboxamide (m.p. 218-220 ° C) from 5-methylisoxazole-4-carboxylic acid chloride and 5-aminoindazole.

44. Na-Allyl-N-phenyl-5-methylisoxazole-4-carboxamide (m.p. 79-85 ° C) from 5-methylisoxazole-4-carbonic acid chloride and N-alanyl aniline.

45. N- [3- (1,1,2,2-Tetrafluoroethoxy) phenyl] -5-methylisoxazole-4-carboxamide (m.p. 97 ° C) from 5-Methylisoxazole-4-carboxylic acid chloride and 3 (1,1) , 2,2-tetrafluoroethoxy) -aniline.

46. N- (4-Cyanophenyl) -5-methylisoxazole-4-carboxamide (m.p. 197-200 ° C) from 5-methylisoxazole-4-carboxylic acid chloride and 4-cyanoaniline.

47. N- (4-methylmercaptophenyl) -5-methylisoxazole-4-carboxamide (m.p. 134-136 ° C) from 5-methylisoxazole-4-carboxylic acid chloride and 4-methylmercaptoaniline.

48. N- (4,6-Dimethyl-2-pyridyl) -5-methylisoxazole-4-carboxamide (m.p. 210 ° C) from 5-methylisoxazole-4-carboxylic acid chloride and 2-amino-4,6-dimethylpyridine.

49. N- (4,6-Dimethyl-2-pyrazinyl) -5-methylisoxazole-4-carboxamide (m.p. 222-226 ° C) from 5-methylisoxazole-4-carboxylic acid chloride and 2 amino-4,6-dimethylpyrazine.

50. 2-Cyano-3-hydroxycrotonic acid N- (4'-fluoro-toxic) -phenylamide

Dissolve 0.1 mol (28.6 g) of N- (4-trifluoromethoxyphenyl) -5-methylisoxazole-4-carboxamide in 100 ml of ethyl alcohol and stir at room temperature with 0.11 mol (4.4 g) of sodium hydroxide solution in 100 ml water. The mixture is stirred for 30 min, diluted with water and acidified with concentrated hydrochloric acid. The precipitated crystals are suctioned off, washed with water and air dried. 7.7 g (97.1% of theory) are obtained.

Of 2-cyano-3-hydroxycrotonic acid N- (4-trifluoromethoxy) phenylamide having a melting point of 171176 ° C) from ethyl alcohol).

According to the procedure described above, the following compounds of formula la or lc are obtained:

51. 2-Cyano-3-hydroxycrotonic acid N- (4- (1,1,2,2-tetrafluoroethoxy) phenylamide (m.p. 164-166 ° C) from N- (4- (1,1,2, 2-Tetrafluoroethoxy) phenyl) -5-methylisoxazole-4-carboxamide.

52. 2-Cyano-3-hydroxycrotonic acid N- (6-chloro-2-pyridyl) -amide (m.p. 213-215 ° C, decomposes) from N- (5-chloro-2-pyridyl) -5-methylisoxazole. Of 4-carboxamide.

53. 2-Cyano-3-hydroxycrotonic acid N- (2-chloro-3-pyridyl) -amide (m.p. 128-131 ° C) from N- (2-chloro-3-pyridyl) -5-methylisoxazole-4- carboxamide.

54. 2-Cyano-3-hydroxycrotonic acid N- (4-benzoylphenyl) amide (m.p. 186-188 ° C) from N- (4-benzoylphenyl) -5-methylisoxazole-4-carboxamide.

55. 2-Cyano-3-hydroxycrotonic acid N- / 4- (4-chlorobenzoyl) -phenyl / amide (m.p. 157-159 ° C) from N- / 4- (4-chlorobenzoyl) phenyl / -5- ethylisoxazole-4-carboxamide.

56. 2-Cyano-3-hydroxycrotonic acid N- [4- (4-bromobenzoyl) -phenyl] -amide (m.p. 221-223 ° C) from N- 4- (4-bromobenzoyl) phenyl / -5-methylisoxazole -4-carboxamide.

57. N- [4- (4-Methoxybenzoyl) phenyl] -amide (m.p. 74-75 ° C) from 2-Cyano-3-hydroxycrotonic acid from N- [4- (4-methoxybenzoyl) phenyl] -5-methylisoxazole 4carboxamide.

58. 2-Cyano-3-hydroxycrotonic acid N- [4- (4-methylbenzoyl) phenyl] -amide (m.p. 177-179 [deg.] C.) from N- [4- (4-methylbenzoyl) phenyl] -5-methylisoxazole 4carboxamide.

59. 2-Cyano-3-hydroxy-4-methylcrotonic acid N- (5chloro-2-pyridyl) amide (m.p. 206-208 ° C) from N- (5chloro-2-pyridyl) -5-ethylisoxazole -4-carboxamide.

60. 2-Cyano-3-hydroxy-4-methylcrotonic acid N- (5-bromo-2-pyridyl) amide (m.p. 200-202 ° C, decomposes) from N- (5-bromo-2-pyridyl) -5-ethylisoxazole-4-carboxamide.

61. 2-Cyano-3-hydroxy-4-methylcrotonic acid N- (4-nitrophenyl) -amide (m.p. 202-203 ° C, decomposes) from N (4-nitrophenyl) -5-ethylisoxazole-4-carboxamide .

62. 2-Cyano-3-hydroxy-4-methylcrotonic acid N- (3,4-methylenedioxyphenyl) amide (m.p. 99-100 ° C) from N- (3,4-methylenedioxyphenyl) -5-ethylisoxazole-4-carboxamide.

63. 2-Cyano-3-hydroxy-4-propylcrotonic acid N- (4-benzoylphenyl) amide from N- (4-benzoylphenyl) -5-butyloxazole-4-carboxamide.

64. 2-Cyano-3-hydroxycrotonic acid N- (5-bromo-2-pyridyl) -amide (melting point: 220-223 ° C, decomposes) from N- (5-bromo-2-pyridyl) -5-methylisoxazole. Of 4-carboxamide.

65. 2-Cyano-3-hydroxycrotonic acid N- / 4- (4-chlorobenzoyl) -phenyl / amide (m.p. 219-223 ° C, decomposes) from N- 4- (4-chlorobenzoyl) phenyl / -5 -methylisoxazole-4-carboxamide.

66. 2-Cyano-3-hydroxycrotonic acid N- / 4- (4-fluorobenzoyl) -phenyl / amide (m.p. 229-231 ° C, decomposes) from N- (4- (4-fluorobenzoyl) phenyl) - 5-Ethylisoxazole-4-carboxamide.

67. 2-Cyano-4-methyl-3-hydroxycrotonic acid N- [4- (4-fluorobenzoyl) phenylamide (m.p. 147-148 [deg.] C.) from N- [4- (4-fluorobenzoyl) phenyl] -5-. ethylisoxazole-4-carboxamide.

68. 2-Cyano-3-hydroxy-4-raethylcrotonic acid N- [4- (4-bromobenzoyl) phenyl] -amide (m.p. 153-155 [deg.] C.) from N- [4- (4-bromobenzoyl) phenyl] - 5-Ethylisoxazole-4-carboxamide.

69. 2-Cyano-3-hydroxy-4-methylcrotonic acid N- (4-trifluoromethoxyphenyl) amide (m.p. 166-167 ° C) from N- (4-trifluoromethoxyphenyl-5-ethylisoxazole-4-carboxamide).

70. 2-Cyano-3-hydroxy-4-methylcrotonic acid N- (4-fluorophenyl) -amide (m.p. 145 ° C) from N- (4-fluorophenyl) -5-ethylisoxazole-4-carboxamide.

71. 2-Cyano-3-hydroxy-4-methylcrotonic acid N- (3,4-methylenedioxyphenyl) amide (m.p. 99-100 ° C) from N (3,4-methylenedioxyphenyl) -5-ethylisoxazole-4- carboxamide.

72. 2-Cyano-3-hydroxycrotonic acid N- (4-methylsulfonyl) phenylamide (m.p. 196-198 ° C) from N (4-methylsulfonyl) phenyl-5-methylisoxazole-4-carboxamide.

73. 2-Cyano-3-hydroxycrotonic acid N-allyl-N-phenylamide (m.p. 50-57 ° C) from N-allyl-N-phenyl-5-methylisoxazole-4-carboxamide.

74. 2-Cyano-3-hydroxycrotonic acid N- (4-ethoxycarbonylmethyl-2-thiazolyl) amide (m.p.

147 DEG C. from N- (4-ethoxycarbonylmethyl-2-thiazolyl) -5-methylisoxazole-4-carboxamide.

75. N- (2-Benzimidazolyl) -amide of 2-cyano-3-hydroxycrotonic acid (melting point: 300 °) from N- (2-benzimidazolyl) -5-methylisoxazole-4-carboxamide.

76. 2-Cyano-3-hydroxycrotonic acid N- (4-methyl-2-thiazolyl) amide (m.p. 210-212 ° C, decomposed) from N- (4-methyl-2-thiazolyl) -5-methylisoxazole-4 -carboxamide.

77. 2-Cyano-3-hydroxycrotonic acid N- (4-chloro-2-benzothiazolyl) -amide (m.p. 211-213 ° C, decomposes) from N- (4-chloro-2-benzothiazolyl) -5- methylisoxazole-4-carboxamide.

78. 2-Cyano-3-hydroxycrotonic acid N- (3-pyridyl) amide (m.p. 240-250 ° C, decomposes) from N- (3-pyridyl) -5-methylisoxazole-4-carboxamide.

79. 2-Cyano-3-hydroxycrotonic acid N- (4,6-dimethyl-2-pyridyl) amide (m.p. 184-186 ° C) from N- (4,6-dimethyl-2-pyridyl) -5-methylisoxazole -4-carboxamide.

80. 2-Cyano-3-hydroxycrotonic acid N- (4,6-dimethyl-2-pyrimidinyl) amide (m.p. 221 ° C) from N- (4,6-dimethyl-2-pyrimidinyl) -5-methylisoxazole-4 -carboxamide.

81. 2-Cyano-3-hydroxycrotonic acid N- (6-indazolyl) amide (m.p. 300 ° C) from N- (5-indazolyl) -5-methylisoxazole-4-carboxamide.

82. 2-Cyano-3-hydroxycrotonic acid N- (5-indazolyl) -amide (melting point: 220-223 ° C) from N- (5-indazolyl) -5-methylisoxazole-4-carboxamide.

83. 2-Cyano-3-hydroxycrotonic acid N- (4-carboxy-3-hydroxyphenyl) amide (m.p. 242-246 ° C, decomposes) from N- (carboxy-3-hydroxyphenyl) -5-methylisoxazole-4-carboxamide .

84. 2-Cyano-3-hydroxycrotonic acid N- (3-carboxy-4-hydroxyphenyl) amide (m.p. 248-252 ° C, decomposes) from N- (3-carboxy-4-hydroxyphenyl) -5-methylisoxazole -4-carboxamide.

85. 2-Cyano-4-hydroxycrotonic acid N- (4-carboxy-3-chlorophenyl) amide (m.p. 218-224 ° C, decomposes) from N- (4-carboxy-3-chlorophenyl) -5-methylisoxazole. Of 4-carboxamide.

86. 2-Cyano-3-hydroxycrotonic acid N- (4-hydroxyphenyl) -amide (m.p. 184-186 ° C, decomposed) from N- (4-hydroxyphenyl) -5-methylisoxazole-4-carboxamide.

87. 2-Cyano-3-hydroxy-4-methylcrotonic acid N- [4- (4-trifluoromethylphenoxy) phenyl] -amide (m.p.

149 ° C) from N- [4- (4-trifluoromethylphenoxy) phenyl] -5-ethylisoxazole-4-carboxamide.

88. 2-Cyano-3-hydroxycrotonic acid N- [4- (4-trifluoromethylphenoxy) phenyl] -amide (m.p. 171173 ° C) from N- [4- (4-trifluoromethylphenoxy) phenyl] -5-methylisoxazole-4-carboxamide .

89. 2-Cyano-3-hydroxycrotonic acid N-methyl-N- (4-trifluoromethylphenyl) amide (m.p. 69-70 ° C) from N-methyl-N- (4-trifluoromethylphenyl) -5-methylisoxazole-4-carboxamide.

90. 2-Hydroxyethylidene-cyanoacetic acid piperidide from

N- (5-methyl-4-isoxazolylcarbonyl) piperidine.

91. 2-Hydroxyethylidene cyanoacetic acid 4-methylpiperidide from N- (5-methyl-4-isoxazolylcarbonyl) 4-hydroxypiperidine.

92. 2-Cyano-3-hydroxycrotonic acid N- (4-carboxybutyl) amide (m.p. 93 ° C) from N- (5-methyl4-isoxazolylcarbonyl) -5-aminovaleric acid.

93. 2-Cyano-3-hydroxycrotonic acid N- (4e-carbonylbutyl) amide from N- (4-ethoxycarbonylbutyl) -5-methylisoxazole-4-carboxamide.

94. 2-Cyano-3-hydroxycrotonic acid N- (6-carboxyhexyl) -amide (m.p. 93-94 ° C) from N- (5-methyl-4-isoxazolylcarbonyl) -7-aminoheptanoic acid.

table

Compounds of formula I

For example, R ² R ²

No.

H

For example, R ² R ²

No.

H

For example, R ² R ² R ³

No.

For example, R ² R ²

No.

C ₂ H ₅

C, H

6 CF ₃

For example, R ² R ² R ³

No.

CF.

CF ₃

³¹ Ό

“Oh

For example, R ² R ² R ³

No.

CHo

CH ₃

H

C ₂ H ₅

C ₂ H ₅

C ₂ H ₅

For example, R ² R ² R ³

No.

H

For example, R ² R ²

No.

Claims (22)

DEFINITION OF INVENTION 1. At least one compound of formula I, Ia or Ib, N (I) o II N _C -cc- _W ą _e , (Ia) II NC-CH-C- _g (Ib) 5 and optionally stereoisomeric forms and / or, where appropriate, at least one of its physiologically acceptable salts for the preparation of a medicament for the treatment of cancer and rheumatic diseases, wherein R ¹ is a) hydrogen; (b) C ₁ . _6- alkyl; c) C 1-6 alkyl substituted with one or more substituents such as 1) halogen, such as fluorine, chlorine, bromine or iodine; d) phenyl; R ² is a) hydrogen; b) C ₁ _ ₄ alkyl; c) phenyl-C _l _ ₂ alkyl, in particular benzyl; d) C _2-3 alkenyl; R ³ is a) a mono-, di- or tricyclic unsaturated heterocyclic group containing 3 to 13 C atoms and 1 to 4 heteroatoms such as oxygen, sulfur and nitrogen, of which at most one atom is different from nitrogen, which is unchanged, or has one or more substituents such as: 1) halogen, such as fluorine, chlorine, bromine or iodine, 2) C 1-6 alkyl, 3) C 1-6 alkyl substituted with one or more substituents such as: 3.1) halogen, such as fluorine, chlorine, bromine or iodine, 4) C 1-4 alkoxy, 5) C ₁ . _{A 3-} alkoxy group having one to several substituents such as: or 5.1) halogen as fluorine, chlorine, bromine or iodine, 6) nitro group, 7) hydroxyl, 8) carboxyl, 9) carbamoyl, 10) oxo group; (b) a group of formula II (II), R ¹ * wherein R ⁴ , R ⁵ and R ⁶ may be the same or different and are: D hydrogen, 2) Cx- ₃ alkyl, 3) C ₁ . _3- alkyl containing one or a few substitutes such as: 3.1) halogen, such as fluorine, chlorine, bromine or iodine; 4) R ⁴ is hydrogen and R ⁵ and R ⁶ together with the phenyl ring of formula II form a naphthalene ring, 5) R ⁴ is hydrogen and R ⁵ and R ⁶ form a methylenedioxy group, 6) C ₁ . _3- alkoxy, 7) C 1-6 alkoxy substituted with one or more substituents such as: 7.1) halogen, such as fluorine, chlorine, bromine or iodine, (8) C 1-4 alkyl mercapto group, 9) a C 1-4 alkyl mercapto group containing one or more substituents such as: 9.1) halogen, such as fluorine, chlorine, bromine or iodine, 10) halogen, such as fluorine, chlorine, bromine or iodine, 11) nitro group, 12) cyano group, 13) hydroxyl, 14) carboxyl; 15) C 1-6 alkylsulfonyl, 16) a carbalkoxy group having 1-3 C atoms in the alkyl chain, 17) benzoyl, 18) benzoyl, mono- or polysubstituted, such as: 18.1) halogen such as fluorine, chlorine, bromine or iodine, 18.2) C ₁ _ ₃ alkyl, 18.3) C ₁ . _3- alkoxy, 19) phenyl, 20) phenyl substituted with one or more substituents such as: 20.1) C 1-4 alkoxy, 20.2) halogen such as fluorine, chlorine, bromine or iodine, 20.3) C ₁ . ₃ alkyl, 21) phenoxy group, (22) phenoxy, substituted with one or more substituents such as: 22.1) C ₁ _ ₃ alkoxy group which contains one or more of the substituents, such as: 22.1.1) halogen such as fluorine, chlorine, bromine or iodine, 22.2) halogen such as fluorine, chlorine, bromine or iodine, 22.3) C ₁ _ ₃ alkyl in which one or more of the substituents, such as: 22.3.1) halogen, such as fluorine, chlorine, bromine or iodine; (c) a group of formula III - (CH ₂ ) _n -COOR io (III) in which R ¹⁰ is 1) hydrogen; 2) C ₁ _ ₄ alkyl, n is an integer from 1 to 12, d) R ² and R ³ together with the nitrogen to which they are attached form a 4- to 9-membered ring containing substituents such as: 1) carbonyl at the C-atom adjacent to Natom; e) R ² and R ³ together with the nitrogen to which they are attached form a 5- to 6-membered ring of formula IV (IV) wherein W is: D -ch ₂ -, 2) -CH ₂ -CH ₂ -, 3) -CH ₂ -CH-, I CH ₃ 4) -CH ₂ -CH-, I c ₂ h ₅ 5) -CH ₂ -CH-, I OH 6) -CH ₂ -O-, or 7) -CH ₂ -S-; R ⁷ is a) hydrogen; (b) C ₁ . ₁₇ alkyl; c) C ₁ _ ₃ alkyl in which one or more of the substituents, such as halogen like fluorine, chlorine, bromine or iodine; d) phenyl-C 1-6 -alkyl, especially benzyl; R is a) hydrogen; b) methyl; c) C ₂ . _3- alkenyl. Use according to claim 1, characterized in that R ¹ is a) hydrogen; b) C 1-8 alkyl; c) C ₁ _ ₄ alkyl, in which one or more of the substituents, such as: 1) halogen such as fluorine, chlorine, bromine and iodine; d) phenyl; R ² is a) hydrogen; b) C _{1 4} alkyl; c) phenyl-C ₁ _ ₂ alkyl, in particular benzyl; d) C ₂ . _3- alkenyl; R ³ is a) pyridyl substituted with one or more substituents such as: 1) hydrogen, 2) halogen such as fluorine, chlorine, bromine or iodine, (3) nitro group, 4) C ₁ . ₃ alkyl, 5) Cx- ₃ alkoxy; (b) a group of formula II R ⁶ wherein R ⁴ , R ⁵ and R ⁶ may be the same or different and are: 1) hydrogen, 2) C ₁ . ₃ alkyl, 3) C ₁ . _3- alkyl substituted with one or more substituents such as: 3.1) halogen, such as fluorine, chlorine, bromine or iodine, 4 5 6 4) R is hydrogen and R and R are methylenedioxy, 5) C ₁ . _3- alkoxy, 6) C ₁ . _{A 3-} alkoxy group containing one or more substituents such as: 6.1) halogen, such as fluorine, chlorine, bromine or iodine, 7) C ₁ _ ₃ -alkilmerkaptogrupė, 8) C ₁ -C ₃ alkyl mercapto group having one or more substituents such as: 8.1) halogen, such as fluorine, chlorine, bromine or iodine, 9) halogen, such as fluorine, chlorine, bromine or iodine, (10) nitro group, 11) cyano group, 12) C 1-3 alkylsulfonyl group; 13) benzoyl, (14) benzoyl substituted with one or more substituents such as: 14.1) halogen such as fluorine, chlorine, bromine or iodine, 14.2) C ₁ _ ₃ alkyl, 14.3) C ₁ . _3- alkoxy, 15) phenoxy group, (16) phenoxy, substituted with one or more substituents such as: 16.1) C ₁ . _{A 3-} alkoxy group containing one or more substituents such as: 16.1.1) halogen such as fluorine, chlorine, bromine or iodine, 16.2) halogen such as fluorine, chlorine, bromine or iodine, 16.3) C ₁ . _3- alkyl substituted with one or more substituents such as: 16.3.1) halogen, chlorine, iodine; (c) a group of formula III as fluorine, bromine or - (CH ₂ ) _n -COOR ¹⁰ (III) in which R ¹⁰ is 1) hydrogen; 2) C ₁ _ ₄ alkyl, n is an integer from 1 to 12; 2 3 d) R and R together with the nitrogen to which they are attached form a 4- to 9-membered ring containing substituents such as: 1) carbonyl at the C-atom adjacent to Natom; R ⁷ is a) hydrogen; t *) C ₁ -C ₁₇ alkyl; c) C ₁ _ ₃ alkyl in which one or more substitutes, such chlorine, bromine like halogen, like fluorine, or iodine; d) phenyl-C 1-6 -alkyl, especially benzyl; is a) hydrogen; b) methyl; c) C _2-3 alkenyl. 3. Use according to Item 1, b e s i s k i r i a n - t i s in that R ^l is present C 1-4 alkyl; 2 R is hydrogen; R ³ is present (a) pyridyl, containing one or a few alternates, such as halogen, how fluorine, chlorine, bromine or iodine; (b) a group of formula II R ⁴ wherein R ⁴ , R ⁶ and R ⁵ may be the same or different and are: 1) hydrogen, 2) C ₁ . ₃ alkyl, 3) C ₁ . _3- alkyl substituted with one or more substituents such as: 3.1) halogen, such as fluorine, chlorine, bromine or iodine, 4) R ⁴ is hydrogen and R ⁵ and R ⁶ form ethylenedioxy, 5) C ₁ . _3- alkoxy, 6) C _{L. A 3-} alkoxy group containing one or more substituents such as: 6.1) halogen, such as fluorine, chlorine, bromine or iodine, 7) halogen such as fluorine, chlorine, bromine or iodine, 8) nitro group, 9) benzoyl, 10) benzoyl substituted with one or more substituents such as: 10.1) halogen such as fluorine, chlorine, bromine or iodine, 10.2) C ₁ . ₃ alkyl, 10.3) C 1-3 alkoxy, 11) phenoxy group, (12) phenoxy, substituted with one or more substituents such as: 12.1) C,. _{A 3-} alkoxy group containing one or more substituents such as: 12.1.1) halogen such as fluorine, chlorine, bromine or iodine, 12.2) halogen such as fluorine, chlorine, bromine or iodine, 12.3) C ₁ . _3- alkyl substituted with one or more substituents such as: 12.3.1) halogen such as fluorine, chlorine, bromine or iodine; R ⁷ is C ₁ . ₁₇ alkyl; R ⁸ is hydrogen. Use of methyl isoxazole-4-carboxylic acid 4-trifluoromethylanilide or 2-cyano-3-hydroxycrotonic acid N (4-trifluoromethylphenyl) amide for the preparation of a medicament for the treatment of cancerous diseases. A process for the preparation of a medicament for the treatment of cancer, characterized in that at least one compound of formula I, Ia or Ib according to claim 1, under certain conditions, in a stereoisomeric form and / or at least one of its physiologically acceptable salts together with physiologically acceptable carriers and, where appropriate, other additives and / or adjuvants for administration to the body. Compounds of formula I ΙΓΊΓ R * (I), R * and, where appropriate, their stereoisomeric forms and / or, where appropriate, their physiologically acceptable salts, wherein R ¹ is a) hydrogen; b) C _2-6 alkyl; c) C _{L. 4-} alkyl substituted with one or more substituents such as: 1) halogen, such as fluorine, chlorine, bromine or iodine; d) phenyl; R is a) hydrogen; b) C _2-3 alkenyl; c) benzyl; R is (a) pyridyl substituted with one or more substituents such as: 1) hydrogen, 2) halogen such as fluorine, chlorine, bromine or iodine, (3) nitro group, 4) C ₁ _ ₃ alkyl, 5) C 1-4 alkoxy; (b) a group of formula II wherein R ⁴ , R ⁵ and R ⁶ may be the same or different and are: 1) halogen, such as fluorine, chlorine, bromine or iodine, 2) nitro group, 3) hydrogen, 4) benzoyl substituted with one or more substituents such as: 4.1) halogen, such as fluorine, chlorine, bromine or iodine, 4.2) methyl, 4.3) methoxy group 4.4) benzoyl, 5) C ₁ . _{A 3-} alkoxy group containing one or more substituents such as: 5.1) halogen, such as fluorine, chlorine, bromine or iodine, 6) C ₁ . _3- alkyl substituted with one or more substituents such as: 6.1) halogen, such as fluorine, chlorine, bromine or iodine, 7) hydroxyl, 8) alkylsulfonyl having 1-3 C atoms in the alkyl chain; 9) R ⁴ is hydrogen and R ⁵ and R ⁶ together form a methylenedioxy group, 10) cyano group, 11) C ₁ . _3- alkylmercaptic group, 12) benzoyl, 13) C ₁ _ ₃ alkyl; (c) pyrimidinyl, mono- or polysubstituted, such as: 1) C _{L. 3} alkyl, (d) indolyl; or e) indazolinyl. Compounds according to claim 6, characterized in that R ¹ is a) hydrogen; b) C _2-6 ^- alkyl; c) _Y ^ C -alkyl, in which one or more of the substituents, such as: 1) halo like fluoro, chloro, bromo or iodo; d) phenyl; 2 R is a) hydrogen; b) ₂ -3 ~ C alkenyl; c) benzyl; R ³ is a) pyridyl substituted with one or more substituents such as: 1) hydrogen, 2) halogen such as fluorine, chlorine, bromine and iodine, 3) nitro, 4) C ₁ . _3- alkyl, 5) C 1-6 -alkoxy; (b) a group of formula (II) R * wherein R ⁴ , R ⁵ and R ⁶ may be the same or different and are: 1) halogen, such as fluorine, chlorine, bromine or iodine, 2) nitro group, 3) hydrogen, benzoyl substituted with substituents such as: one or more 4.1) halogen, as bromine or iodine, fluorine, chlorine, 4.2) methyl, 4.3) methoxy group, 4.4) benzoyl; 5) C 1-4 alkoxy substituted with one or more substituents such as: 5.1) halogen, such as fluorine, chlorine, bromine or iodine, 6) C 1-4 alkyl substituted with one substituent such as: or several 6.1) halogen such as fluorine, bromine or iodine; chlorine, 7) hydroxyl, » 8) alkylsulfonyl with alkyl 1-3 C atoms, part contains 9) R ⁴ is hydrogen and R ⁵ and R ⁶ together form a methylenedioxy group, 10) cyano group, 11) C ₁ . _3- alkylmercaptic group, 12) benzoyl, 13) C ₁ . _3- alkyl; c) pyrimidinyl monosubstituted such as: or several D C ₁ _ ₃ alkyl; d) indolyl or e) indenolinyl. Compounds according to claim 6, characterized in r i a n - t y s that R ¹ is C ₂ . _6- alkyl, is hydrogen, R ³ is a) pyridyl substituted with one or more substituents such as: 1) hydrogen, 2) halogen, such as fluorine, chlorine, bromine or iodine; (b) a group of formula II β * wherein R ⁴ , R ⁵ and R ⁶ may be the same or different and are: 1) halogen, as or iodine, fluorine, chlorine, bromine 2) nitro group, 3) benzoyl, 4) benzoyl substituted with one or more substituents such as: 4.1) halogen, such as fluorine, chlorine, bromine or iodine, 4.2) methyl, 5) C ^ -al what an igroup containing one or several substituents such as: 5.1) halogen, such as fluorine, chlorine, bromine or iodine, 6) C 1-6 alkyl, 7) C _{1 3} alkyl, wherein one or more of the substituents, such as: 7.1) halogen as fluorine, chlorine. bromine or iodine 8) hydrogen 9) R ⁴ is hydrogen, and R ⁵ and R ⁶ together form a methylenedioxy group. Compounds of formula Ia or Ib (Ia) "» ·. com ³ CH-CI '' '(Ib) and, where appropriate, their stereoisomeric forms and / or, where appropriate, their physiologically acceptable salts, wherein R ⁷ , R ⁷ and R ³ are: a) R is 1) hydrogen, 2) C ₂ _ ₄ alkyl, θ R is 1) hydrogen, 2) methyl, R ³ is 1) phenyl, (2) phenyl, singly or substituted, such as: 2.1) halogen, 2.2) C 1-6 alkyl, singly or substituted, such as halogen, fluorine, chlorine, bromine or iodine; b) R ⁷ is 1) C ₁ . ₄ alkyl, 2) hydrogen, 3) CF ₃ , θ R is 1) hydrogen, 2) methyl, 3) C ₂ . _3- alkenyl, R ³ is 1) pyridyl, (2) pyridyl, mono- or polysubstituted, such as: several as few as several 2.1) halogen, such as fluorine, chlorine, bromine or iodine, 2.2) C ₁ _ ₃ alkyl, 3) pyrimidinyl substituted with 2), 4) thienyl substituted with 2) and 4.1) alkoxycarbonyl having 1-3 C atoms in the alkyl chain, 5) benzothiazolyl substituted with 2), 6) benzimidazolyl substituted with 2), 7) indazolyl substituted with 2), 8) phenyl substituted by one or more substituents such as: 8.1) benzoyl, 8.2) Benzoyl substituted with one or more substituents such as: 8.2.1) halogen such as fluorine, chlorine, bromine or iodine, 8.2.2) C ₁ . ₃ alkyl, 8.2.3) C ₁ _ ₃ -alkoxy, 8.2.4 a) C ₁ _ ₃ alkoxy group which contains one or more of the substituents, such as halogen like fluorine, chlorine, bromine or iodine, 8.3) carboxyl or 8.4) hydroxyl; c) R ⁷ is 1) hydrogen; 2) C 1 -C 4 alkyl, θ R is 1) hydrogen, 2) methyl, R is 1) a group of formula III - (CH ₂ ) ₄ -COOR ¹⁰ (III) wherein R ¹⁰ is: 1.1) hydrogen, 1.2) C 1-6 alkyl; d) R ⁷ is 1) hydrogen; 2) C 1-4 alkyl; Θ · 3 R and R together with the nitrogen to which they are attached form a 4- to 9-membered ring containing substituents such as: 2.1) carbonyl at the C-atom adjacent to Natomas, or R and R together with the nitrogen to which they are attached form a piperidine ring, optionally substituted with C ₁ . ₃ alkyl. Compounds according to claim 9, characterized in that R ⁷ , R ⁸ and R ³ are: a) R ⁷ is C ₂ _ ₄ alkyl, R ⁸ is hydrogen, R ³ is 1) phenyl, 2) phenyl, a substituent such as: one or more 2.1) halogen, such as fluorine, chlorine, bromine or iodine, 2.2) C ₁ _ ₃ alkyl in which one or more of the substituents, such as halogen like fluorine, chlorine, bromine or iodine; b) R ⁷ is C ₁ . ₄ alkyl, R ⁸ is hydrogen, R ³ is 1) pyridyl, (2) pyridyl substituted by one or more substituents such as: 2.1) halogen, such as fluorine, chlorine, bromine or iodine, 2.2) C ₁ _ ₃ alkyl; 3) phenyl substituted by one or more substituents such as: 3.1) Benzoyl 3.2) benzoyl substituted with one or more substituents such as: 3.2.1) halogen such as fluorine, chlorine, bromine or iodine, 3.2.2) C ₁ . ₃ alkyl 3.2.3) C 1-4 alkoxy, 3.2.4) C 1-4 -alkoxy substituted with one or more substituents such as halogen, such as fluorine, chlorine, bromine or skin. 11. Compounds: N- (4-Chlorodifluoromethoxy) phenyl-5-ethylisoxazole-4-carboxamide N- (4-methylsulfonylphenyl) -5-methylisoxazole-4-carboxamide, N- (5-indolyl) -5-methylisoxazole-4-carboxamide, N- (6-indenoyl) -5-methylisoxazole-4-carboxamide, N- (5-indazolyl) -5-methylisoxazole-4-carboxamide, N-allyl-N-phenyl-5-methylisoxazole-4-carboxamide, N- (4,6-dimethyl-2-pyridyl) -5-methylisoxazole-4-carboxamide, N- (4,6-dimethyl-2-pyrimidinyl) -5-methylisoxazole-4-carboxamide, 2-Cyano-3-hydroxycrotonic acid N- (4-trifluoromethoxyphenyl) -amide, 5 2-cyano-3-hydroxycrotonic acid N- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -amide, 2-Cyano-3-hydroxycrotonic acid N- / 4- (4-fluorobenzoyl) phenyl / amide, or 2-Cyano-3-hydroxy-4-methylcrotonic acid N- (3,4-methylenedioxyphenyl) amide. 12. A medicament comprising at least one compound of formula I, Ia or Ib according to claims 6-11, optionally in stereoisomeric form and / or at least one of its pharmacologically acceptable salts.