FI105680B - Process for preparing therapeutically utilizable hydroxyalkylidenecyanoacetamides - Google Patents

Description

..1 105680

A process for the preparation of therapeutically useful hydroxyalkylidene-cyanoacetic acid amides * Separated from FI application 925211.

5

The invention relates to a process for the preparation of a therapeutically useful compound of the formula Ia or Ib "/ R 3 nz · * 3 10 - c - C - N NC - CH - C - C X R 8 c 1 - 7 /% 0 da) (Ib) For the preparation of its stereoisomeric forms and / or its physiologically tolerable salts, wherein R 3, R 7 and R 8 in a) R 7 are 1) hydrogen, 20 2) alkyl having 2 to 4 carbon atoms, R 8 is 1) hydrogen , 2) methyl, R 3 is 1) phenyl, 2) phenyl, singly or multiply substituted by 2.1 halogen, 2.2 alkyl having from 1 to 3 carbon atoms and singly or multiply substituted by halogen such as fluorine , chlorine, bromine or iodine, 2.3 nitro b) R 7 is 1) alkyl of 1 to 4 carbon atoms, 35 2) hydrogen, 2 105680 R 8 is 1) hydrogen, 2) methyl, 3) alkenyl of 2 - 3 C atoms, 5 R 3 is 1) pyridyl, 2) pyridyl, singly or multiply substituted by 2.1 halogens such as fluorine, chlorine, bromo or iodine. 1a, 2.2 with alkyl of 1 to 3 C atoms, 2.3 with nitro 3) pyrimidinyl substituted as in 2) 4) thiazolyl substituted as in 2) and 4.1 with alkoxycarbonylmethyl having 1 to 3 carbon atoms in the alkyl chain. 3 C atoms, 5) benzothiazolyl substituted as in 20 2), 6) benzimidazolyl substituted as in 2), 7) indazolyl substituted as in 2), 8) phenyl alone - or polysubstituted with 8.1 benzoyl, 8.2 benzoyl mono- or polysubstituted. 8.2.1 halogen such as fluorine, chlorine, bromine or iodine, 8.2.2 alkyl having 1 to 3 C atoms, 8.2.3 alkoxy having 1 to 3 C atoms, 8.2.4 alkoxy having having 1 to 3 C atoms and 35 singly or multiply substituted by halogen such as fluorine, chlorine, bromine or iodine, 3 105680 8.3 carboxy, • 8.4 hydroxy, 8.5 alkylsulfonyl, having 1 to 3 C atoms in the alkyl chain, 8.6 phenoxy, singly or multiply substituted by (C1-3) alkyl, singly or multiply substituted by halogen such as fluorine, chlorine, bromine or iodine, 8.7 methylenedioxy ring group 10 c) R7 is 1) hydrogen, 2) alkyl, having 1 to 4 carbon atoms, R 8 is 1) hydrogen, 15 2) methyl, R 3 is 1) a group of formula III, - (CH 2) 4 -COOR 10 wherein R 10 is 1.1 hydrogen, 1.2 alkyl having 1 to 4 C atoms,

A number of processes for the preparation of isoxazole-4-carboxylic acid amides have been described in the literature (DE-2524 959; DE-2 655 009; DE-3 405 727).

It is known from EP-A-13,376 that 5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl) anilide can be used for its pharmacological properties as an antirheumatic agent, an anti-inflammatory agent, an anti-inflammatory agent, and for the treatment of multiple sclerosis. It also describes methods for preparing this compound.

It has now been discovered that hydroxyalkylidene cyanoacetic acid 35-kaapoamides of the formula Ia and their tautomeric form Ib have an antitumor effect. Many known antitumor agents cause side effects during treatment, such as nausea, vomiting or diarrhea, which also require medical attention in hospital. In addition, these substances also change the rate of growth of other cells in the body, which in turn leads to symptoms such as hair loss or anemia. These symptoms could not be observed in the treatment of humans and animals with compounds of formula Ia and Ib. These active compounds do not possess the ability to suppress the immune system compared to hitherto known cytotoxic anticancer agents (Bartlett, Int. J. Immunopharmac. 8: 199-204 (1986)). This opens new avenues for the tumor blade soon, as the body's own defense system is not weakened by 15 yrs while the growth of tumor cells is prevented. Surprisingly, these active substances inhibit a large number of tumor murine cells, whereas cells of the immune system, such as T lymphocytes, are inhibited at concentrations up to about 50 times only.

The invention thus relates to a method of formula Ia and Ib

which is characterized in that the compound of formula I

° R3 kΧΧΛ, 7 is reacted in the presence of a basic substance. 30 to a compound of formula Ia or Ib.

Known structures of the compounds of formulas I, Ia and Ib are known compounds: 5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl) anilide (compound 1) and N- (4-trifluoromethyl) -35 2-cyano. 3-Hydroxycrotonic acid amide (Compound 2).

5, 105680

Suitable physiologically tolerable formulas of formulas Ia and Ib. The salts of the compounds of the invention are, for example, alkali, alkaline earth and ammonium salts including organic salts. salts of ammonium bases.

The compounds of formula Ia and Ib and their physiologically tolerable salts are particularly suitable for the treatment of many cancers. The types of cancer that are specifically inhibited by these compounds include, for example, leukemia, especially chronic T and B cell type leukemia, lymph node cancer, e.g., Hodgkin's disease or non-Hodgkin's disease, carcinomas, sarcomas or skin cancer. The active ingredients may be administered alone, for example in the form of microcapsules, admixtures or in association with suitable excipients and / or carriers.

The preparation of a compound of formula I, Ia or Ib is carried out in a known manner (DE-2 524 959; DE-2 655 009; DE-3 405 727; DE-2 524 929; DE-2 555 789; DE-2 557 003) .

The compounds of formula Ia or Ib and / or at least one of their physiologically tolerable salts can be used in the manufacture of medicaments for the prophylaxis and / or treatment of rheumatic diseases.

It is possible to prepare medicaments consisting of at least one compound of the formulas Ia and Ib and / or at least one physiologically tolerable salt of yeast or containing at least one of these active ingredients with pharmaceutically acceptable and physiologically tolerated carriers, diluents and / or other excipients. .

Such drugs may be administered orally, topically. , · Rectally, rectally or possibly parenterally, with oral administration being preferred.

Suitable solid or liquid galenic dosage forms include, for example, granules, powders, granules, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, and 6,105,680 formulations with sustained release, which may be formulated with conventional excipients such as carriers, disintegrants, binders, coatings, swellers, lubricants, lubricants, flavors, sweeteners or solubilizers. Commonly used excipients are, for example, magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycols and solvents such as sterile water and mono- or mono- alcohols, for example glycerin.

Preferably, the pharmaceutical preparations are prepared and dispensed in dosage units, each unit containing as active ingredient at least one dose of at least one compound of formula Ia or Ib and / or at least one of its physiologically tolerable salts. In the case of solid dosage units such as tablets, capsules, granules or suppositories, this dose may be up to about 300 mg, preferably about 10-50 mg.

For the treatment of an adult patient (70 kg) with leukemia, depending on the human effect of the compounds of formula Ia or Ib and / or their physiologically tolerable salts, daily doses of about 5 to 300 mg of active ingredient, preferably about 25 to 100 mg, are required. oral route of administration. However, higher and lower daily doses may also be used. The daily dose may be administered in a single dose. 30 ng as a single dosage unit or in several smaller dosage units and in divided doses given at multiple intervals.

Finally, the compounds of formula Ia and Ib and / or at least one of their physiologically tolerable salts can also be formulated with other suitable active ingredients, for example other antineoplastic agents, immunoglobulins, monoclonal antibodies, in the preparation of the above mentioned galenic formulations. • substances, immunostimulants or antibiotics 5. These compounds may also be administered in conjunction with radiation therapy.

Pharmacological tests and results

As an efficacy assay for chemotherapeutic agents, a cell culture proliferation assay was performed in vitro. The results are shown in Table 4.

Example 1

Prolif private exam

Clicks / RPMI 1640 in powder form (50:50) containing L-glutamine without NaHCO 3 for 10 liters (Seromed, Biochrom, Berlin, Federal Republic of Germany) is dissolved in 9 liters of aqua bidest and sterile filtrate. place in 900 ml bottles.

Detergent 900 ml of the stock is buffered with 9.5 ml of 7.5-20% sodium bicarbonate solution and 5 ml of HEPES (N-2-hydroxyethylpiperazine-N-2-ethanol sulphonic acid) (Gibco, Eggenstein, Federal Republic of Germany).

Working solution 900 ml of stock and 19 ml of NaHCO 3 solution (7.5%; 10 ml of HEPES solution and 10 ml of L-glutamine solution (200 mM)).

Medium for mitogen-induced proliferation of lymphocytes The working solution is mixed with 1% heat-activated (30 mil.76.6 ° C) fetal calf serum -. · 30 (FCS).

Tumor Cell Media = To preserve tumor cells and hybridoma cells, mix the working solution with 5% FCS.

8 105680

Cell culture medium

To maintain cell lines, 900 ml of working solution is mixed with 10% FCS, 10 ml of NEA (Gibco) solution, 10 ml of 5% sodium pyruvate (100 mM, Gibco) and 5 ml with 10 "2 M mercaptoethanol.

Spleen cell production and processing for mitogen-induced lymphocyte proliferation

The mice are sacrificed by dissecting the neck and the spleens are sterile removed. Spleens are ground using a sterile 80 mesh sieve and carefully pipetted into a petri dish with the working solution using a plunger syringe (10 ml). To remove erythrocytes from the spleen cell suspension, the mixture is incubated for approximately 1 min with shaking-15 randomly in a hypotonic 0.17 M ammonium chloride solution at room temperature. In this case, the erythrocytes are degraded, whereas the lymphocyte vitality and reactivity are not impaired. After centrifugation (7 min / 340 g), the lye is discarded, the cells are washed twice and then transferred to the appropriate test medium.

Mitogen-Induced Lymphocyte Proliferation 5x105 prepared splenocytes of NMRI female mice, together with various mitogens and preparation, were pipetted in 200 µl of test medium per well of flat-bottomed micro-titre plates. The following concentrations of mitogen and preparations were used:

Concanvalin A [Serva]: 0.5 - 0.12 pg / ml

Lipopolysaccharide [Calbiochem]: 1.0 - 0.5 - 0.1 pg / ml,? 30 Phytohagagglutinin [Gibco]: 0.5 - 0.25 - 0.12% stock solution

Pokeweed Mitogen [Gibco] Compound 1 or 2: 50, 25, 10, 7.5, 5, 2.5, 1, 0.5, 0.1 pmol

Positive control samples were defined as a group of 35 containing mitogen additions without preparation. Negative control samples were cells in the culture medium with no preparation of mitogen. Each mitogen concentration was tested several times at each preparation concentration.

After 48 hours incubation at 37 eC / 5% CO 2, 25 μΐ / well tritium thymidine (Amersham) with activity 0.25 Ci / well (9.25 x 10 7 Bq) is added to the cells. Further incubation was then performed under the same conditions for 16 hours. To evaluate the test batch, cells 10 are harvested on a filter paper using a cell harvester (Flow Laboratories), whereupon unbound thymidine is collected in a special waste bottle. The filter paper is dried, punched, and placed with 2 ml of scintillant (Rothisint 22, manufactured by Roth) into small vials, which are then cooled for an additional 2 hours at 4 ° C. The amount of radioactivity in the cells is measured in a beta counter (manufactured by Packard, Tricarb-460c).

Finalization of tumor cells and cell lines for proliferation assay

The tumor cells or cell cells used in the assay are removed during the logarithmic growth phase of strain preservation, washed twice with detergent and suspended in the appropriate medium.

25 Performing and evaluating a proliferation assay

The proliferation assay was performed in round-bottom microtiter plates. Compound 1 and interleukin were dissolved in 50 μΐ per well of each respective medium, and cell number C5x105) was adjusted with 100 μ1: η per sy-30 wrist to obtain a final volume of 200 μΐ / sy-wrist. In all experiments, values were determined several times. Non-formulation growth factor preparations were defined as negative control samples, and non-formulation but growth factor-containing cells gave values for positive control samples. The value of N 10 105680 positive control samples was obtained from all reported values, and the difference between positive control samples and 100 The plates were incubated for 72 hours at 37 ° C / 5% CO 2 and the rate of proliferation determined similarly to mitogen-induced lymphocyte proliferation.

Cell lines were taken from the American Type Culture Collection (ATCC).

Table 1 shows the concentrations at which 10 50% inhibition occurs:

table 1

Cell line Origin ED50 CTLL Mouse T cell line (Tc ~ Clon IL-2) 40-50 µm HT-2 Mouse T cell line (IL-2) 40-50 Jim 15 CTL-JK Mouse T cell line (Tc, IL-) 2) 40-50 pm

Cl 9/4 Mouse T Cell Line (IL-4 Dep.) 25 pm K III 5 Mouse T Cell Line (Th, IL-2) 1-3 pm

Spleen T Mouse (Con A and PWM) 10 pm

Spleen B Mouse (LPS) 10 µm 20 A20 2J Mouse B Cell Tumor (BALB / c) 1-3 µM TRK 4 Mouse B Cell Hybridoma 5 µm TRK 5 Mouse B Cell Hybridoma 5 µm

Bone Marrow Mouse (M-CSF, GM CSF) 5 µM WEHI 279 Mouse B Cell Lymphoma <1 pm 25 p 388 Dl Mouse M0 Tumor 10 pm 7TD1 Mouse B Cell Hybridoma (IL-6) 10 G53 Mouse T Cell Clone PB- 3C Mouse Mast Cell Line {IL-3) 20 µM DA-1 Mouse Tumor (IL-3) 5 pm 30 7D4 Rat Hybridoma <1 ^ pm A431 Human Cutaneous Cell Carcinoma 15 µM Human Cutaneous Carcinoma Fibroblast 40 µM ^ im 35 HL-60 Human Promyelomonocytic Leukemia 25 pm 11 105680

Example 2

Acute Oral Toxicity Compound 1 was administered to mice and rats to determine acute toxicity. LD50 values were determined according to Litchfield and Wilcoxon. NMRI mice (NMRI: Naval Medical Research Institute) weigh 20 to 25 g and SD rats (SD: Sprague-Dawley) weigh 110 to 165 g. Prior to the experiment, the mice were fasted for approximately 18 hours. Five hours after administration of the compounds tested, 10 are again fed normally. After three weeks, the animals were killed with chloroform and dissected. For each dose, 6 animals were used. The results are summarized in Table 2:

Table 2 15

Compound 1 Compound 2

Acute toxicity Acute toxicity

via OS via OS

LD50 (mg / kg) LD50 (mg / kg) 20 NMRI mice 445 (362-546) SD rat 160 (133-193) SD rat 235 (167-332)

Example 3

Acute toxicity after intraperitoneal administration

The acute toxicity of the test substances following intraperitoneal administration of <25 ton was performed using NMRI mice (20-25 g) and SD rottis (120-195 g). The test substance was suspended in a 1% sodium carboxymethyl cellulose solution. Different doses of test substance were administered to mice in a volume of 10 ml / kg body weight and. · 30 rats in a volume of 5 ml / kg body weight. Ten animals were used per dose. After three weeks, 'acute toxicity was determined according to Litchfield and Wilcoxon. The results are summarized in Table 3.

12 105680

Table 3

Compound 1 Compound 2

Acute toxicity Acute toxicity 5 intraperitoneally intraperitoneally LD50 (mg / kg) LD50 (mg / kg) NMRI mouse 185 (163-210) NMRI mouse (100-200) SD rat 170 (153-189)

Proliferation Assay 10 The following proliferation assays were performed as described on pages 9-10 of the specification. Table 5 shows the concentrations at which 50% inhibition is obtained.

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Example 4 A) Preparation of 5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl) anilide

A solution of 0.05 mol of 5-methylisoxazole-5 4-carboxylic acid chloride (7.3 g) in 20 ml of acetonitrile is added dropwise at room temperature to a solution of 0.1 mol of 4-trifluoromethylaniline (16.1 g). g) in 150 ml of acetonitrile. After stirring for 20 minutes, the 4-trifluoromethylaniline hydrochloride formed is filtered off with suction, washed twice with 20 ml of acetonitrile each time, and the combined filtrates are evaporated under reduced pressure. 12.8 g of white crystalline 5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl) anilide are obtained (compound 1).

B) Preparation of N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxycrotonic acid amide (non-compliant compound) 0.1 mol of 5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl) anilide is dissolved in 100 ml methanol 20 and stirred at a temperature of + 10 ° C with a solution of 0.11 mol (4.4 g) of sodium hydroxide solution in 100 ml of water. Stir for 30 min and after dilution with water, acidify with concentrated hydrochloric acid. The crystalline mass formed is separated by suction filtration, washed with water and air-dried. The yield is 24.4 g of N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxycrotonic acid amide (compound 2). Melting point of methanol 205-206 ° C.

Preparation Examples:

The structure of each of the compounds described below was confirmed by elemental analysis and IR and 1 H NMR spectra.

5. N- (4-Trifluoromethoxyphenyl) -2-cyano-3-hydroxycrotonic acid amide

0.1 mol (28.6 g) of N- (4-trifluoromethoxy-35-phenyl) -5-methylisoxazole-4-carboxamide was dissolved in 100 ml of 15 105680 ethanol and stirred at 20 ° C with a solution of 0 , 11 mol (4.4 g) of sodium hydroxide solution in 100 ml of water. Stir for 30 min and after dilution with water, acidify with concentrated hydrochloric acid. The formed Ki-5 dema is separated by suction filtration, washed with water and air-dried. 27.7 g (97.1% of theory) of N- (4-trifluoromethoxyphenyl) -2-cyano-3-hydroxycrotonic acid amide are obtained, m.p. 171-176 ° C (from ethanol).

According to the example described above, the following compounds of formula Ia or Ib are prepared.

6. 2-Cyano-3-hydroxy-N- (4- (1,1,2,2-tetrafluoroethoxy) phenyl] crotonic acid amide (m.p. 166,164 eCN- [4- (1,1,2,2-tetrafluoroethoxy) ) phenyl] -5-methylsoxazole-4-carboxamide.

7. N- (5-chloro-2-pyridyl) -2-cyano-3-hydroxy-crotonic acid amide [m.p. 213-215 ° C (dec.)] N- (5-chloro-2-pyridyl) -5-methyl -isoxazole-4-O-karboksiamidis.

8. N- (2-chloro-3-pyridyl) -2-cyano-3-hydroxycrotonic acid amide (melting point 128-131 ° C) N- (2-chloro-3-pyridyl) -5-methylisoxazole 4-carboxamide.

9. N- (4-Benzoylphenyl) -2-cyano-3-hydroxycrotonic acid amide (m.p. 186-188 ° C) from N- (4-benzoyl- (phenyl) -5-methylisoxazole-4-carboxamide.

10. N- [4- (4-Chlorobenzoyl) phenyl] -2-cyano-3-hydroxy-4-methylcrotonic acid amide (m.p. 157-159 ° C) N- [4- (4-chlorobenzoyl) phenyl] -5-ethyl -isoksat-tetrazole-4-carboxamide.

11. N- [4- (4-Bromobenzoyl) phenyl] -2-cyano-3-hydroxycrotonic acid amide (m.p. 221-223 ° C) N- [4- (4-bromobenzoyl) phenyl] -5-methyl- isoxazole-4-carboxy-amide.

12. N- [4- (4-Methoxy-benzoyl) -phenyl] -2-cyano-3-35-hydroxycrotonic acid amide (m.p. 74-75 ° C) N- [4- (4- 105680,16-methoxybenzoyl) phenyl] -5-methyl- isoxazole-4-carboxylic amide.

13. N- [4- (4-methylbenzoyl) phenyl] -2-cyano-3-hydroxycrotonic acid amide (m.p. 177-179 ° C) N- [4- 5- (4-methylbenzoyl) phenyl] -5-methylisoxazole 4-kar-carboxamides.

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

15. N- (5-bromo-2-pyridyl) -2-cyano-3-hydroxy-4-methylcrotonic acid amide [melting point 200-202 ° C (dec.)] N- (5-bromo-2-pyridyl) -5 ethyl-isoxazole-4-karboksiami-oxide.

16. 2-Cyano-3-hydroxy-4-methyl-N- (4-nitrophenyl) -crotonic acid amide [m.p. 202-203 ° C (dec.)] N- (4-nitrophenyl) -5-ethylisoxazole -4-carboxamide.

17. N- (3,4-methylenedioxyphenyl) -2-cyano-3-hydroxy-4-methylcrotonic acid amide (melting point 99-100 ° C) 20 N- (3,4-methylenedioxyphenyl) -5-ethylisoxazole 4-carboxamide.

18. N- (4-Benzoylphenyl) -2-cyano-3-hydroxy-4-propylcrotonic acid amide from N- (4-benzoylphenyl) -5-butylisoxazole-4-carboxamide.

19. N-5-Bromo-2-pyridyl) -2-cyano-3-hydroxycrotonic acid amide [melting point 220-223 ° C (dec)] N- (5-bromo-2-pyridyl) -5- methyl-isoxazole-4-carboxamide.

20. N- [4- (4-Chlorobenzoyl) phenyl] -2-cyano-3-hydroxycrotonic acid amide [m.p. 219-223 ° C

«30 (dec)] from N- [4- (4-chlorobenzoyl) phenyl] -5-methylisoxazole-4-carboxamide.

21. N- [4- (4-Fluorobenzoyl) phenyl] -2-cyano-3-hydroxycrotonic acid amide [m.p. 229-231 ° C (dec.)] N-4- (4-fluorobenzoyl) phenyl] -5-methyl- isoxazole-4-carboxamide.

17 105680 22. N- [4- (4-Chlorobenzoyl) phenyl] -2-cyano-4-methyl-3-hydroxycrotonic acid amide (m.p. 147-148 ° C) N- [4- (4-fluorobenzoyl) phenyl] -5-ethyl-iso-ksatso-yl-4-carboxamide.

23. N- [4- (4-Bromobenzoyl) phenyl] -2-cyano-3-hydroxy-4-methylcrotonic acid amide (m.p. 153-155 ° C) N- [4- (4-bromobenzoyl) phenyl] -5- isoksat-ethyl-tetrazole-4-carboxamide.

24. N- (4-Trifluoromethoxy) phenyl-2-cyano-3-hydroxy-4-methylcrotonic acid amide (m.p. 166-167 ° C) N- (4-trifluoromethoxy) phenyl-5-ethylisoxazole-4- carboxamide.

25. N- (4-Fluorophenyl) -2-cyano-3-hydroxy-4-methylcrotonic acid amide (m.p. 145 ° C) from N- (4-fluoro-phenyl) -5-ethylisoxazole-4-carboxamide.

26. N- (3,4-methylenedioxyphenyl) -2-cyano-3-hydroxy-4-methylcrotonic acid amide (melting point 99-100 ° C) N- (3,4-methylenedioxyphenyl) -5-ethylisoxazole-4 -carboxamide.

27. N- (4-Methylsulfonyl) phenyl-2-cyano-3-hydroxycrotonic acid amide (m.p. 196-188 ° C) from N- (4-methylsulfonyl) phenyl-5-methylisoxazole-4-carboxamide .

28. N-Allyl-N-phenyl-2-cyano-3-hydroxycrotonic acid amide (m.p. 57-50 ° C) from N-allyl-N-phenyl-5-methylisoxazole-4-carboxamide.

29. N- (4-Ethoxycarbonylmethyl-2-thiazolyl) -2-cyano-3-hydroxycrotonic acid amide (m.p. 147 ° C) N- (4-Ethoxycarbonyl-1-methyl-2 -1-thiophenyl) -5 - 1 µl to 30% of xazole-4-carboxamide.

«30. N- (2-Benzimidazolyl) -2-cyano-3-hydroxycarboxylic acid amide (dec. Point> 300 DEG C.) from N- (2-benzimidazolyl) -5-methylisoxazole-4-carboxamide.

31. N- (4-Methyl-2-thiazolyl) -2-cyano-3-hydroxy-35-cyclonic acid amide [m.p. 210-212 ° C (dec.)] 18 105680 N- (4-methyl-2-thiazolyl) - 5-methyl-isoxazole-4-carboxylic carboxamides.

32. N- (4-chloro-2-benzothiazolyl) -2-cyano-3-

hydroxycrotonic acid amide [m.p. 211-213 ° C

5 (dec) from N- (4-chloro-2-benzothiazolyl) -5-methylisoxazole-4-carboxylic acid.

33. N- (3-Pyridyl) -2-cyano-3-hydroxycrotonic acid, m.p. 240-250 ° C (dec.)] From N- (3-pyridyl) -5-methylisoxazole-4-carboxamide.

34. N- (4,6-dimethyl-2-pyridyl) -2-cyano-3-hydroxycrotonic acid amide (m.p. 184-186 ° C) N- (4,6-dimethyl-2-pyridyl) -5- methyl-isoxazole-4-carboxy-amide.

35. N- (4,6-Dimethyl-2-pyrimidyl) -2-cyano-3-hydroxycrotonic acid amide (m.p. 221 ° C) N- (4,6-dimethyl-2-pyrimidyl) -5-methyl- isoxazole-4-karboksiami-oxide.

36. N- (6-Indazolyl) -2-cyano-3-hydroxycrotonic acid amide (melting point> 300 ° C) from N- (6-indazolyl) -5-methylisoxazole-4-carboxamide.

37. N- (5-Indazolyl) -2-cyano-3-hydroxycrotonic acid amide (melting point 220-223 ° C) from N- (5-indazolyl) -5-methylisoxazole-4-carboxamide.

38. N- (4-Carboxy-3-hydroxyphenyl) -2-cyano-3-

25 hydroxycrotonic acid amide [m.p. 242-246 ° C

(dec.)] N- (4-carboxy-3-hydroxyphenyl] -5-methyl-isooxazole-4-carboxamide.

39. N- (3-Carboxy-4-hydroxyphenyl) -2-cyano-3-hydroxycrotonic acid amide [m.p. 248-252 ° C (dec.)] 30 N- (3-carboxy-4-hydroxyphenyl) -5- methyl isoxazole-4-carboxamide.

40. N- (4-Carboxy-3-chlorophenyl) -2-cyano-3-hydroxycrotonic acid amide [m.p. 218-224 ° C (dec)] N- (4-carboxy-3-chlorophenyl] -5-methyl- isoxazole-4-carboxamide.

19 105680 41. N- (4-Hydroxyphenyl) -2-cyano-3-hydroxycrotonic acid amide [m.p. 184-186 ° C (dec.)] From N- (4-hydroxyphenyl) -5-methylisoxazole-4-carboxamide .

42. N- [4- (4-trifluoromethylphenoxy) phenyl] -2-cyano-3-hydroxy-4-methylcrotonic acid amide (m.p. 147-149 ° C) N- [4- (4-trifluoromethylphenoxy) phenyl] -5-ethyl -isoxazole-4-carboxamide.

43. N- [4- (4-Trifluoromethylphenoxy) phenyl] -2-cyano-3-hydroxycrotonic acid amide (melting point 171-173 ° C)

10 N- [4- (4-Trifluoromethylphenoxy) phenyl] -5-methylisoxazole-4-carboxamide.

44. N-Methyl-N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxycrotonic acid amide (m.p. 69-70 ° C) N-Methyl-N- (4-trifluoromethylphenyl) -5-methylisoxazole. Of 4-carboxamide, (non-compliant compound).

45. 2-Hydroxyethylidenecyanoacetic acid piperidine-di- (5-methyl-4-isoxazolylcarbonyl) piperidine.

46. 2-Hydroxyethylidene cyanoacetic acid 4-methylpiperidide from N- (5-methyl-4-isoxazolylcarbonyl) -4-hydroxypiperidine.

47. N- (4-Carboxybutyl) -2-cyano-3-hydroxycrotonic acid amide (m.p. 92 ° C) from N- (5-methyl-4-isoxazolylcarbonyl) -5-aminovaleric acid.

*? 48. N- (4-ethoxycarbonylbutyl) -2-cyano-3-hydroxycrotonic acid amide N- (4-ethoxycarbonylbutyl) -5-methylisoxazole-4-carboxamide.

49. N- (6-Carboxyhexyl) -2-cyano-3-hydroxycrotonic acid amide (m.p. 93-94 ° C) from N- (5-methyl-4- (3-isoxazolylcarbonyl) -7-aminoheptanoic acid, (not required) compound).

Claims (3)

A process for the preparation of a therapeutically useful compound of formula Ia or Ib 5? / r3 0 / r3 NC - C - C - H-f NC. CU - C - N r \ BS '\ o C RB r XCH, S0 10 _______ its optionally stereoisomeric forms and / or possibly its physiologically acceptable salts, the groups R3, R7 and R8 being at point 15 a) R7 1. hydrogen , 2. alkyl of 2-6 C atoms, R8 is 1. hydrogen, 2) methyl, R3 is 1. phenyl, 2.phenyl, which is mono- or poly-substituted. 2.1 halogen, 2.2 alkyl of 1-3 C atoms, mono- or poly-substituted with halogen, such as fluorine, chlorine, bromine or iodine, 2.3 nitro, b) R7 is "30 1) alkyl of 1-4 C atoms ,! 2) hydrogen, ------ - - - R8 is 1. hydrogen, 2. methyl, 3) alkenyl with 2 - 3 C atoms, R 26 is 1. pyridyl, 2. pyridyl, or multiply substituted with 2.1 halogen, such as fluorine, chlorine, bromine or iodine, T 2.2 alkyl with 1-3 C atoms, 2.3 nitro, 3. pyrimidinyl, which is substituted as in paragraph 2) 4. thiazolyl, which is substituted as in paragraph 2) and 4.1 with alkoxycarbonylmethyl having 1-3 C atoms in the alkyl chain, 5. benzothiazolyl, which is substituted as in paragraph 2) 6. benzimidazolyl, which is substituted as in paragraph 15 2) 7. indazolyl, which is substituted as in paragraph 2) 8. phenyl, mono- or poly-substituted with 8.1 benzoyl, 8.2 benzoyl, mono- or poly-substituted with 8.2.1 halogen, such as fluorine, chlorine, bromine or iodine, 8.2.2 alkyl with 1 -3 C atoms, 8.2.3 alkoxy with 1-3 C atoms, 8.2.4 alkoxy with 1-3 C atoms and which are one- or; plurally substituted with halogen, such as fluorine, chlorine, bromine or iodine, 8.3 carboxy, 8.4 hydroxy, 8.5 alkylsulfonyl having 1-3 C atoms in the alkyl chain, 8.6 phenoxy, mono- or plurally substituted with 30 (C10) alkyl, which is mono- or poly-substituted by the halogen, such as fluorine, chlorine, bromine or iodine, 8.7 methylenedioxy ring group c) R7 is 1. hydrogen, 2) alkyl of 1-4 C atoms, 2710680 R8 is 1. hydrogen, 2. methyl, R 3 Mr 5 1) a group of formula III - (CH 2) 4-COOR 10 where R 10 is 1.1 hydrogen, 1.2 alkyl having 1-4 C atoms characterized in that a compound of formula I 15 ° R 3 wherein R 7, R 3 and R 8 are the same as above, is reacted in the presence of an alkaline agent to a compound of formula Ia or Ib. . 2. A process according to claim 1, characterized in that the groups R7, R8 and R3 are at point a) R7 is an alkyl of 2-6 C atoms, R8 is 1) hydrogen R3 is _____ phenyl,! 2) phenyl which is mono- or poly-substituted with 2.1 halogen, such as fluorine, chlorine, bromine or iodine, 2.2 alkyl of 1-3 C atoms, mono- or poly-substituted with halogen, such as fluorine, chlorine, bromine or 35 iodine, 105680 2.3 nitro, b) R7 is alkyl of 1-4 C atoms, R8 is hydrogen, R3 is 1) pyridyl, 2. pyridyl, mono- or poly-substituted with 2.1 halogen, such as fluorine, chlorine, bromine or iodine, 2.2 alkyl of 1-3 C atoms, 3. phenyl, mono- or poly-substituted with 3.1 benzoyl, 3.2 benzoyl, mono- or poly-substituted with 3.2.1 halogen, such as fluorine, chlorine, bromine or iodine, 3.2 .2 alkyl of 1-3 C atoms, 3.2.3 alkoxy of 1-3 C atoms, 3.2.4 alkoxy of 1-3 C atoms and which is mono- or poly-substituted with halogen, such as fluorine, chlorine , bromine or iodine. 3. A process according to claim 1, characterized in that N- (4-trifluoro-methoxyphenyl) -2-cyano-3-hydroxy-crotonic acid amide is prepared, N- [4- (1,2,2) 2-Tetrafluoroethoxy) phenyl] -2-cyano-3-hydroxy-crotonic acid amide, N- [4 (4-fluorobenzoyl) phenyl] -2-cyano-3-hydroxy-crotonic acid amide, N- (3,4-methylene -dioxiphenyl) -2-cyano-3-hydroxy-4-methyl-crotonic acid amide. 2-cyano-3-hydroxy-4-methyl-N- (4-nitrophenyl) crotonic acid amide or N- [4- (4-trifluoromethylphenoxy) phenyl] -2-cyano-3-hydroxy-4-methyl -krotonsyramid.