MXPA96004158A - Amidas de acido 2-ciano-3-mercaptocroton - Google Patents

Abstract

The present invention relates to the use of a compound of the formula I: a stereoisomeric form thereof or a physiologically tolerable salt thereof, wherein R 1 represents a) a hydrogen atom, b) (C 1 -C 17) alkyl, c) alkyl (C1-C4), mono- or polysubstituted with fluorine, chlorine, bromine or iodine ... etc. R2 represents a) a hydrogen atom, b) (C1-C4) alkyl, c) phenyl, etc., R3 represents a) an unsaturated heterocyclic radical, with one, two or three nuclei, with 3 to 13 carbon atoms and 1 to 4 heteroatoms of the group consisting of oxygen, sulfur and nitrogen, of which in the ring system at most one of the heteroatoms is different from nitrogen, and is not replaced or is mono- or polysubstituted, etc. for the preparation of a medically for the treatment of immune or autoimmune disorders, alterations with an increased cell growth, rejection reactions of transplants, skin alterations selected from the group consisting of psoriasis, vulgar psoriasis, eruptive psoriasis, erythrodermic psoriasis , postulative psoriasis, erythrodermic dermatitis, postular psoriasis, dermatitis, atopic dermatitis, allergic dermatitis, photoallergic dermatitis, medicated dermatitis and eczema, and asthma, urticaria, rhinitis, ureitis, type II diabetes, hepatic fibrosis, cystic fibrosis, colitis or allergies

Description

Amides of 2-cyano-3-mercaptocrotonic acid The invention relates to derivatives of 2-cyano-3-mercaptocrotonic acid amides, to a process for their preparation and to the use thereof as a medicament. Some of the compounds usable according to the invention have already been described, but nothing is known about their use as a medicine (Hartke et al., Arch Pharm, (1968), 301 (8), pages 601-610; Yokoyama et al. ., J Org Chem, (1984), 49, pages 74-78). The invention relates to a compound of the formula I, SH 0 and / or to an optionally stereoisomeric form of the compound of the formula I and / or to a physiologically compatible salt of the compound of the formula I, wherein R 1 represents a) a hydrogen atom, b) alkyl (CX-CX 7), c) alkyl (Cx-C4), substituted once or several times with fluorine, chlorine, bromine or iodine, d) phenyl, e) phenyl, substituted once or several times with 1) fluorine, chlorine, bromine or iodine, 2) nitro, 3) cyano, 4) alkyl (Cx-C4), 5) alkyl (Cx-C4), substituted once or several times with fluorine, chlorine, bromine or iodine, 6) alkoxy (Cx-C4), 7) alkoxy (CX-C4) ), substituted once or several times with fluorine, chlorine, bromine or iodine, f) benzyl, g) cycloalkyl (C3-C7), h) alkenyl with 2 or 3 C atoms or i) alkynyl with 2 or 3 C atoms, R > 2 * represents a) a hydrogen atom, b) alkyl (Cx-C4), c) phenyl, d) phenyl-alkyl (Cx-C2) oe) alkenyl having 2 to 3 carbon atoms, or R3 represents a) a unsaturated heterocyclic radical, with one, two or three nuclei, with 3 to 13 C atoms and 1 to 4 heteroatoms of the oxygen, sulfur and nitrogen group, of which in the ring system at most one of the heteroatoms is different from nitrogen, and is unsubstituted or substituted one or several times with l) fluorine, chlorine, bromine or iodine, 2) alkyl (Cx-C4), 3) alkyl (Cx-C4), substituted one or more times with fluorine, chlorine, bromine or iodine, alkoxy (Cx-C4), alkoxy (Cx-C4), substituted once or several times with fluorine, chlorine, bromine or iodine, nitro, hydroxy, carboxy, carbamoyl or 10) an oxo group , b) a radical of formula II (ID in which R4, R5 and R6 can be the same or different and represent 1) a hydrogen atom, 2) alkyl (Cx-C4), 3) alkyl (Cx-C4), substituted once or several times with fluorine, chlorine , bromine or iodine, 4) in which R4 represents a hydrogen atom and R5 and R6, together with the phenyl ring of the formula II, form a naphthalene ring, 5) in which R4 represents a hydrogen atom and R5 and R6 form a methylenedioxy radical, 6) (Cx-C4) alkoxy, 7) (Cx-C4) alkoxy, substituted once or several times with fluorine, chlorine, bromine or iodine, 8 (8)) alkyl (CX-C4) -mercapto, 9) alkyl (Cx-C4) -mercapto, substituted one or more times with fluorine, chlorine, bromine or iodine, ) fluorine, chlorine, bromine or iodine, 11) nitro, 1 122)) cyano, 13) hydroxy, 14) carboxy, 15) alkyl (Cx-C4) -sulfonyl, 16) carboalkoxy with 1 to 3 carbon atoms in the alkyl chain, 17) benzoyl, 18) benzoyl, substituted one or more times with 18. 1 fluorine, chlorine, bromine or iodine, 18.2 alkyl (Cx-C4) or 18.3 alkoxy (Cx-C4), 19) phenyl, 20) phenyl, substituted one or more times with 20.1 alkoxy (Cx-C4), 20.2 fluorine, chlorine, bromine or iodine, or 20.3 alkyl (Cx-C4), 21) phenoxy, or 22) phenoxy, substituted once or several times with (Cx-C3) alkoxy, substituted once or several times with 22.1 fluorine, chlorine, bromine or iodine, 22.2 alkyl (Cx-C3), substituted once or several times with fluorine, chlorine, bromine or iodine, or 22.3 fluorine, chlorine, bromine or iodine, c) a radical of formula III - (CH2) n-COOR10 (III) wherein R10 represents 1) a hydrogen atom or 2) alkyl (Cx-C4) and n represents an integer from 1 to 12, or d) R2 and R3 form, together with the nitrogen to which they are attached, a ring of 4 to 7 members, which is unsubstituted or substituted with carbonyl at the C atom adjacent to the N atom, or e) R2 and R3 form, together with the nitrogen to which they are attached, a 5-6 membered ring of the formula IV in which it represents 1) -CH3 -, 2) - CH2 - CH2 -, 3) - CH2 - CH -, 2 1 1 CH3 4) - CH2 - CH -, C, H, 6) - CH2 - 0 - c 7) - CH2 - S -, with the condition that a compound of the formula I in which R2 and R3 are a hydrogen atom and R1 is phenyl, ethyl or methyl is excluded. Preferred is a compound of the formula I and / or a physiologically compatible salt of the compound of the formula I and / or an optionally stereoisomeric form of the compound of the formula I, wherein R 1 represents a) a hydrogen atom, b) alkyl ( Cx-C3), c) alkyl (Cx-C4), substituted once or several times with fluorine, chlorine, bromine or iodine, d) phenyl, e) alkenyl with 2 or 3 C atoms of) cycloalkyl (C3-C4) , R2 represents a) a hydrogen atom, b) (Cx-C4) alkyl, c) benzyl, or d) alkenyl with 2 to 3 C atoms, R3 represents a) pyridyl, substituted one or more times with 1) one atom of hydrogen, 2) fluorine, chlorine, bromine or iodine, 3) nitro, 4) alkyl (Cx-C3), or 5) alkoxy (Cx-C3), b) a radical of formula II, wherein R4, Rs and R6 may be the same or different and represent 1) a hydrogen atom, 2) alkyl (Cx-C3), '3) alkyl (Cx-C3), substituted once or several times with fluorine, chlorine, bromine or iodine, ) in which R4 represents an atom d and hydrogen and R5 and R6 form a methylenedioxy radical, 5) (Cx-C3) alkoxy, 6) (Cx-C3) alkoxy, substituted once or several times with fluorine, chlorine, bromine or iodine, 7) alkyl (Cx-C3) ) -mercapto, 8) alkyl (Cx-C3) -mercapto, substituted one or more times with fluorine, chlorine, bromine or iodine, 9) fluorine, chlorine, bromine or iodine, 10) nitro, 11) cyano, 12) alkyl (Cx-C3) -sulfonyl, 13) benzoyl, 14) benzoyl, substituted one or more times with 14.1 fluorine, chlorine, bromine or iodine, 14.2 alkyl (Cx-C3) or 14.3 alkoxy (Cx-C3), 15) phenoxy, or 16) phenoxy, substituted one or more times with 16.1 alkoxy (Cx-C3), substituted once or several times with fluorine, chlorine , bromine or 16.2 fluorine, chlorine, bromine or iodine, 16.3 alkyl (Cx-C3), substituted once or several times with fluorine, chlorine, bromine or iodine, c) a radical of formula III, in which R10 represents 1) a hydrogen atom, 2) alkyl (Cx-C4) and n represents an integer from 1 to 12, od) R2 and R3 form, together with the nitrogen to which they are attached, a ring of 4 to 7 members, which is substituted with carbonyl in the C atom adjacent to the N atom. A compound of the formula is particularly preferred I and / or a physiologically compatible salt of the compound of the formula I and / or an optionally stereoisomeric form of the compound of the formula I, wherein R 1 represents alkyl (C x C 3), R 2 represents a hydrogen atom, R 3 represents a) pyridyl, substituted one or more times with fluorine, chlorine, bromine or iodine or b) a radical of formula II, in which R4, R5 and Re can be the same or different and represent l) a hydrogen atom or 2) alkyl (CL) -C3), 3) alkyl (Cj-C3), substituted once or several times with fluorine, chlorine, bromine or iodine, 4) in which R4 represents a hydrogen atom and Rs and R6 form a methylenedioxy radical, 5) alkoxy ( Cx-C3), 6) alkoxy (Cx-C3), substituted once or several times with fluorine, chlorine, bromine or iodine, 7) fluorine, chlorine, bromine or iodine, 8) nitro, 9) benzoyl, 10) benzoyl, replaced one or more times with 10.1 fluorine, chlorine, bromine or iodine, 10.2 alkyl (Cx-C3) or 10.3 alkoxy (C? -C3), 11) phenoxy, or 12) phenoxy, substituted one or more sometimes with 12.1 alkoxy (Cx-C3), substituted once or several times with fluorine, chlorine, bromine or iodine, 12.2 fluorine, chlorine, bromine or iodine, or 12.3 alkyl (Cx-C3) substituted once or several times with fluorine, chlorine , bromine or iodine. Particularly preferred are 2-cyano-3-mercapto-N- (4-trifluoromethylphenyl) -crotonic acid amide or 2-cyano-N- (4-trifluoromethylphenyl) -cro-tonic-3-thiolate acid amide. of sodium.

By the term "alkyl" or "alkoxy" are meant radicals whose carbon chain may be linear, branched or cyclic. The cyclic alkyl radicals are, for example, 3- to 7-membered monocycles, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In addition, cyclic alkyl radicals also include polycyclics, such as adamantane, t-istan or diama radicals. The expression "R2 and R3 form, together with the nitrogen atom to which they are attached, a ring of 4 to 7 members" belong, for example, radicals which are derived from azetidine, pyrrolidine, piperidine or azepine. The term "unsaturated heterocyclic radicals, with one, two or three nuclei, with 3 to 13 C atoms" belong, for example, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, thiazolinyl, oxazolyl, thiadiazolyl, benzoxazolyl. , benzimidazolyl, quinolyl, pyrazolyl, acridinyl, indolyl, tetrazolyl or indazolyl.

Physiologically compatible salts of the compound of the formula I which are suitable are, for example, alkali metal, alkaline earth metal or ammonium salts, including those of organic ammonium bases. The invention also relates to a process for the preparation of the compound of the formula I and / or a physiologically compatible salt of the compound of the formula I and / or an optionally stereoisomeric form of the compound of the formula I, which is characterized in that a) an amide of cyanoacetic acid of the formula V R2 NC- CH, - CO - N (v) is reacted in the presence of a basic compound with a dithiocarboxylic acid of the formula VI R'-CH.-CS-S-R7 (VI) having R1, R2 and R3 the meanings mentioned for the compound of the formula I and representing R7 CX-C6 alkyl, or b) a compound of the formula I, prepared according to process a), which, by virtue of its chemical structure, occurs in enantiomeric forms, is separated into the pure enantiomers by formation of salts with pure acids or bases with respect to the enantiomers, chromatography in chiral station phases or derivatization by chiral compounds, pure in terms of the enantiomers, such as amino acids, separation of the diastereoisomers obtained thereby and dissociation of the chiral auxiliary group, or c) the compound of the formula I, prepared according to process a) or b) is isolated in free form or, in the case of the presence of acidic or basic groups, it is optionally converted into physiologically compatible salts. The preparation of physiologically compatible salts from compounds of formula I capable of forming salts, including their stereoisomeric forms, is carried out in a manner known per se. The carboxylic acids form alkali metal, alkaline earth or ammonium salts optionally substituted with basic reactants, such as hydroxides, carbonates, hydrogencarbonates, alcoholates as well as ammonia or organic bases, for example trimethylamine or triethylamine, ethanolamine or also basic amino acids , for example lysine, ornithine or arginine.

If the compounds of the formulas I have basic groups in the radical R3, salts can also be prepared by the addition of stable acids with strong acids. For this purpose, both inorganic and organic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p -toluenesulfonic, 4-bromobenzenesulfonic, cyclohexylamido-sulfonic, trifluoromethylsulfonic, acetic, oxalic, tartaric or trifluoroacetic.

The preparation and reaction of the compounds of the formula I is conveniently carried out in a partition agent or solvent which behaves indifferently under the reaction conditions with respect to the reaction participants. For this purpose, it is possible, for example, to use nitryls, such as acetonitrile, ethers, such as diethyl ether, tetrahydrofuran or dioxane, and alcohols, such as methanol, ethanol, propanol and isopropanol. As basic compounds, in this case, for example, alkali metal hydrides, sodium or potassium alcoholates of lower alcohols, alkali metal amides, sodium or potassium carbonate or bicarbonate and alkali metal hydroxides can be used. In a preferred embodiment, a cyanoacetic acid amide of the formula V is thioacylated with a dithiocarboxylic acid ethyl ester of the formula VI in the presence of a sodium or potassium alcoholate. The alcohol used for the preparation of the alcoholate is used as solvent or delivery agent in this case. The cyanoacetic acid amides of the formula V, required as starting materials, are known or can be prepared analogously from cyanoacetic acid and from the amines of the formula VII R2 HN Vi l wherein R2 and R3 have the meanings indicated above. The preparation of the dithiocarboxylic acid esters of the formula VI is carried out by alkylation of the dithiocarboxylic acids with alkyl halogenamides or dialkylsulfates. The invention also relates to medicaments, characterized by an effective content of at least one compound of the formula I ) and / or a physiologically compatible salt of the compound of the formula I and / or an optionally stereoisomeric form of the compound of the formula I, the radicals R 1, R 2 and R 3 being defined as in the formula I, but the conditions being included, together with a pharmaceutically suitable and physiologically compatible support substance, additive and / or other active substances and adjuvants. By virtue of their pharmacological properties, the compounds according to the invention are extremely suitable for the treatment and prophylaxis of immune or autoimmune diseases, diseases with an increased development of the cells, such as cancer or restinosis, rejection reactions in transplants, diseases of the skin of the group of psoriasis, vulgar psoriasis, eruptive psoriasis, erythrodermic psoriasis, pustular psoriasis, dermatitis, atopic dermatitis, allergic dermatitis, photoalergic dermatitis, drug dermatitis, and eczema, asthma, urticaria, rhinitis, ureitis, type II diabetes , pulmonary fibrosis, cystic fibrosis, colitis or allergy. The immune or autoimmune diseases include systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, nephrotic syndrome, in particular glomerulonephritis, ulcerative colitis or juvenile diabetes. Cancer diseases include lung cancer, leukemia, ovarian cancer, sarcoma, Kaposi's sarcoma, meningioma, bowel cancer, cancer of the lymph nodes, glioblastoma, prostate cancer or skin cancer. In the case of organ transplants or transplants, rejection reactions of the organ recipient against the implanted organ or rejection reactions of the implanted organ against the recipient may occur (host reactions versus graft or graft versus host reaction). Rejection reactions are understood to mean all the reactions of the recipient organism or the transplanted organ that, ultimately, they lead to the decay of the cell or tissue of the transplanted organ or impair the functionality and life capacity of the transplanted organ or the recipient. In particular, they mean acute rejection reactions as well as chronic ones. By the term organ is meant all organs or parts of organs (also several) in mammals, in particular man, for example kidney, heart, skin, liver, muscle, cornea, bone, bone marrow, lung, pancreas, intestine or stomach. The invention also relates to the use of the compound of the formula I for the preparation of medicaments for the prophylaxis and therapy of immune or autoimmune diseases, diseases with an increased development of the cells, such as cancer or restinosis, rejection reactions in transplants, skin diseases of the psoriasis group, psoriasis vulgaris, eruptive psoriasis, erythrodermal psoriasis, pustular psoriasis, dermatitis, atopic dermatitis, allergic dermatitis, photoallergic dermatitis, drug dermatitis, and eczema, asthma, urticaria, rhinitis, ureitis, type II diabetes, pulmonary fibrosis, cystic fibrosis, colitis or allergy. The invention also relates to a process for the preparation of a medicament, characterized in that at least one compound of the formula I is brought into a suitable administration form with a pharmaceutically suitable and physiologically compatible carrier and optionally other active substances, additives or suitable adjuvants. Forms of suitable solid or galenic preparations are for example granulates, powders, dragees, tablets, (micro) -capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, as well as preparations with a prolonged release of the active principle, in the preparation of which conventional auxiliary agents, such as support substances, disintegrating agents, binders, coating agents, expansion agents, glidants or lubricants, flavoring substances, sweeteners and dissolution inducers are used. Magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talcum, milk albumin, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, can often be used as coadjuvants used. sunflower, peanut or sesame oil, polyethylene glycol and solvents, such as for example sterile water and monovalent or polyvalent alcohols, such as glycerol. Preferably, the pharmaceutical preparations are produced and administered in dosage units, each unit containing, as an active component, a certain dose of the compound of the formula I according to the invention. In the case of solid dosage units, such as tablets, capsules, dragees or suppositories, this dose may be up to about 1000 mg, but preferably up to about 50 to 300 mg, and in the case of solutions for injection in the form of an ampoule , up to about 300 mg, but preferably up to about 10 to 100 mg.

For the treatment of an adult patient of approximately 70 kg of weight, they are indicated - depending on the activity of the compounds according to formula I, daily doses of about 20 mg to 1000 mg of active principle, preferably about 100 mg to 500 mg. In certain circumstances, however, higher or lower daily doses may also be suitable. The administration of the daily dose can be effected either by single administration in the form of a single dosage unit or several smaller dosage units, as well as by multiple administration of subdivided doses at certain intervals.

Example 1 Amide of 2-cyano-3-mercapto-N- (4-trifluoromethylphenethyl) crotonic acid a) N- (4-trifluoromethylphenyl) cyanoacetic acid amide In a solution of cyanoacetic acid (34.0 g, 0.40 mol) in 1.2 1 dichloromethane, phosphorus pentachloride (83.3 g, 0.40 mol) is added and the mixture is refluxed for 30 minutes. After cooling to 20 ° C, the reaction mixture is combined with 500 ml of water and stirring is continued for 30 minutes. The aqueous phase is neutralized with sodium carbonate and the precipitate is filtered off with suction. The filter cake is washed with water and dried. In this way, 55.2 g of N- (4-trifluoromethylphenyl) -cyanoacetic acid amide in crystalline form are obtained. Melting point: 194-195, 5 ° C. b) N- (4-tri luoromethylphenyl) cyanoacetic acid amide (9.1 g, 0.04 mol) is suspended in ethanol (150 ml) and combined at 0 ° C to 5 ° C with tere. potassium butylate (4.8 g, - 0.04 moles). Subsequently, ethyl dithioacetic acid ester (4.9 g, 0.04 mol) is added dropwise with stirring at 15 ° C to 20 ° C. The reaction mixture is heated to 70 ° C to 75 ° C. After completion of the mercaptan release, it is still stirred for 30 minutes at 65 ° C to 70 ° C. After cooling to room temperature, 100 ml of water are added dropwise in the reaction mixture and the mixture is continued for 15 minutes at room temperature. The reaction mixture is poured into 400 ml of 0.1 N hydrochloric acid and extracted with stirring 4 times, in each case with 100 ml of dichloromethane. The combined organic phases are washed 2 times in each case with 300 ml of water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue (10.5 g) is crystallized from 260 ml of ethanol. In this way, 5.6 g of 2-cyano-3-mercapto-N- (4-trifluoromethylphenyl) crotonic acid amide are obtained in the form of yellowish crystals. Melting point: 183 ° C to 184 ° C.

Example 2 Amide of 2-cyano-N- (4-trifluoromethylphenyl) crotonic-3-thiolate sodium acid; Amide of 2-cyano-3-mercapto-N- (4-trifluoromethylfe-nyl) crotonic acid (2.6 g, 0.09 mole) of Example 1 is suspended in water (450 ml) and, dropwise and with stirring, it is combined with a solution of sodium hydroxide (0.35 g, 0.009 mol) in water (10 ml) up to 45 ° C, until the reaction mixture has a pH value of 5.4. It is filtered, and the filtrate is concentrated to dryness under reduced pressure at 50 ° C. In this way, 3.0 g of 2-cyano-N- (4-tri-fluoromethylphenyl) crotonic-3-thiolate sodium amide are obtained in the form of pale yellow crystals. Melting point: 235 ° C to 240 ° C (with decomposition) Pharmacological tests 1. Adjuvant induced arthritis, modification according to Perper (Proc. Soc. Exp. Biol. Med. 137, 506 (1971)) As test animals, male rats of a race istar-Le is with a body weight of 130 to 200 g. The animals receive a subcutaneous injection in the tail of 0.1 ml of a suspension of Mycobacterium butyricum on day 1 (Difco, 6 mg / kg in paraffin oil, Merck). The compounds to be compared are applied intraperitoneally twice a day from the 1st to the 12th day of the test; then the determination is made on the 18th day as the leg volume. Animals of a control group receive only the solvent. By dosage and in the control group, 6 animals are used in each case. The decrease in the increase in the volume of the paw compared to the untreated control group serves as activity criterion. A dose of 25 mg of the compound according to Example 2 per kg of live weight of a Wistar-Lewis rat provides an inhibition of 83% (38% inhibition in the case of 12.6 mg / kg) of the increase in the volume of the paw compared to an untreated control group.

Claims (8)

1. - Compound of formula I and / or a possibly stereoisomeric form of the compound of the formula I and / or a physiologically compatible salt of the compound of the formula I, wherein Ra represents a) a hydrogen atom, b) alkyl (Cx-C17), c) alkyl (C - ^ - C ^), substituted once or several times with fluorine, chlorine, bromine or iodine, d) phenyl, e) phenyl, substituted once or several times with 1) fluorine, chlorine, bromine or iodine, 2) nitro , 3) cyano, 4) alkyl (Cx-C4), 5) alkyl (CLC ^), substituted once or several times with fluorine, chlorine, bromine or iodine, 6) alkoxy (Cx-C4), 7) alkoxy (Ci) -Ct), substituted once or several times with fluorine, chlorine, bromine or iodine, f) benzyl, g) C ^ -C ^ cycloalkyl, h) alkenyl with 2 or 3 C atoms, or i) alkynyl with 2 or 3 atoms of C, R2 represents a) a hydrogen atom, b) alkyl (Cx-C4), c) phenyl, d) phenyl-alkyl (C ^ -C2) oe) alkenyl with 2 to 3 C atoms, or R3 represents a) an unsaturated heterocyclic radical, with one, two or three nuclei, with 3 to 13 carbon atoms C and 1 to 4 heteroatoms of the oxygen, sulfur and nitrogen group, of which in the ring system at most one of the heteroatoms is other than nitrogen, and is unsubstituted or substituted one or more times with 1) fluorine , chlorine, bromine or iodine, 2) alkyl (Cx-C4), 3) alkyl (CX-C?), substituted once or several times with fluorine, chlorine, bromine or iodine, 4) alkoxy (CL-C *), 5) alkoxy (CLC, substituted one or more times with fluorine, chlorine, bromine or iodine, 6) nitro, 7) hydroxy, 8) carboxy, 9) carbamoyl or 10) an oxo group, b) a radical of the formula II wherein R4, Rs and Rβ may be the same or different and represent 1) a hydrogen atom, 2) alkyl (Cx-C4), alkyl (Cx-C4), substituted once or several times with fluorine, chlorine, bromine or iodine,) in which R 4 represents a hydrogen atom and Rs and R 6, together with the phenyl ring of the formula II form a naphthalene ring, 5) in which R4 represents a hydrogen atom and R5 and R6 form a methylenedioxy radical, 6) (Cx-C4) alkoxy, 7) (Cx-C4) alkoxy, substituted once or several times with fluorine, chlorine, bromine or iodine, 8) alkyl (Cx-C4) -mercapto, 9) alkyl (Cx-C4) ) -mercapto, substituted one or more times with fluorine, chlorine, bromine or iodine, 10) fluorine, chlorine, bromine or iodine, 11) nitro, 12) cyano, 13) hydroxy, 14) carboxy, 15) alkyl (Cx-C4) -sulfonyl, 16) carboalkoxy with the 3 carbon atoms in the chain of alkyl, 17) benzoyl, 18) benzoyl, substituted one or more times with 18.1 fluorine, chlorine, bromine or iodine, 18.2 alkyl (Cx-C4) or 18.3 alkoxy (Cx-C4), 19) phenyl, 20) phenyl, substituted one or several times with 20.1 alkoxy (Cx-C4), 20.2 fluorine, chlorine, bromine or iodine, or 20.3 alkyl (Cx-C4), 21) phenoxy, or 22) phenoxy, substituted once or several times with alkoxy (Cx- C3), substituted once or several times with 22.1 fluorine, chlorine, bromine or iodine,

22. 2 alkyl (Cx-C3), substituted once or several times with fluorine, chlorine, bromine or iodine, or

22. 3 fluorine, chlorine, bromine or iodine, c) a radical of formula III - (CH2) n-COOR10 (III) wherein R10 represents 1) a hydrogen atom or 2) alkyl (Cx-C4) and n represents an integer from 1 to 12, or d) R2 and R3 form, together with the nitrogen to which they are attached, a ring of 4 to 7 members, which is unsubstituted or substituted by carbonyl at the C atom adjacent to the N atom, or e) R2 and R3 form, together with the nitrogen to which they are attached, a ring of 5 to 6 members of the formula IV G - N (IV) where W represents l) - CH2 -, 2) - CH2 - CH2 -, 3) - CH2 - CH -, 1 1 CH3 6) -CH2 -0- or 7) -CH2-S-, with the proviso that a compound of the formula I in which F2 and R3 are a hydrogen atom and R1 is phenyl, ethyl or methyl is excluded.

2. Compound of the formula I according to claim 1 and / or a physiologically compatible salt of the compound of the formula I and / or an optionally stereoisomeric form of the compound of the formula I, wherein R1 represents a) a hydrogen atomb) alkyl (Cx-C6), c) alkyl (Cx-C4), substituted once or several times with fluorine, chlorine, bromine or iodine, d) phenyl, e) alkenyl with 2 or

3 C atoms of) cycloalkyl (C3-C4), R represents a) a hydrogen atom, b) alkyl (Cx-C4), c) benzyl, or od) alkenyl with 2 to 3 carbon atoms, R3 represents a) pyridyl, substituted one or more sometimes with 1) a hydrogen atom, 2) fluorine, chlorine, bromine or iodine, 3) nitro, 4) alkyl (Cx-C3), or 5) alkoxy (Cx-C), b) a radical of formula II , wherein R4, R5 and R6 may be the same or different and represent 1) a hydrogen atom, 2) alkyl (Cx-C3), 3) alkyl (Cx-C3), substituted once or several times with fluorine, chlorine, bromine or iodine, 4) in which R4 represents a hydrogen atom and Rs and R6 form a radicayl methylenedioxy, 5) alkoxy (Cx-C3), 6) alkoxy (Cx-C-, substituted one or more times with fluorine, chlorine , bromine or iodine, 7) alkyl (Cx-C3) -mercapto, 8) alkyl (Cx-C3) -mercapto, substituted one or several times with fluorine, chlorine, bromine or iodine, 9) fluorine, chlorine, bromine or iodine, 10) nitro, 11) cyano, 12) alkyl (Cx-C3) -sulphonyl, 13) benzoyl, 14) benzoyl, substituted one or several times with 14.1 fluorine, chlorine, bromine or iodine, 14.2 alkyl (Cx-C3) or 14.3 alkoxy (Cx-C3), 15) phenoxy, or 16) phenoxy, substituted once or several times with 16.1 alkoxy (Cx-C3 ), substituted once or several times with fluorine, chlorine, bromine or 16.2 fluorine, chlorine, bromine or iodine, 16.3 alkyl (Cx-C3), substituted once or several times with fluorine, chlorine, bromine or iodine, c) a radical of formula III, in which R10 represents 1) a hydrogen atom, 2) alkyl (Cx-C4) and n represents an integer from 1 to 12, or d) R2 and R3 form, together with the nitrogen to which they are attached, a 4 to 7 membered ring, which is substituted with carbonyl at the C atom adjacent to the N. 3 atom. - Compound of the formula I according to claims 1 or 2, wherein R 1 represents alkylene (C x -C 6), R 2 represents a hydrogen atom, R1 represents a) pyridyl, substituted once or several times with fluorine, chlorine, bromine or iodine or b) a radical of formula II, in which R

4, R5 and R6 may be the same or different and represent 1) a hydrogen atom or 2) alkyl (Cx-C3), 3) alkyl (Cx-C3), substituted once or several times with fluorine, chlorine, bromine or iodine, 4) in which R4 represents a hydrogen atom and R? and Rβ form a radiceyl methylenedioxy, 5) alkoxy (Cx-C3), 6) alkoxy (Cx-C,), substituted once or several times with fluorine, chlorine, bromine or iodine, 7) fluorine, chlorine, bromine or iodine, 3) nitro, 9) benzoyl, 10) benzoyl, substituted one or more times with 10.1 fluorine, chlorine, bromine or iodine, 10.2 alkyl (Cx-C3) or 10.3 alkoxy (Cx-C3), 11) phenoxy, or 12) phenoxy, substituted one or more times with 12.1 (Cx-C3) alkoxy, substituted once or several times with fluorine, chlorine, bromine or iodine, 12.2 fluorine, chlorine, bromine or iodine, or 12.3 alkyl (Cx-C3), substituted or several times with fluorine, chlorine, bromine or iodine. 4.- 2-Cyano-3-mercapto-N- (4-trifluoromethylphenyl) -crotonic acid amide or 2-cyano-N- (4-trifluoromethylphenyl) -crotonic-3-thiolate sodium amide.

5. Process for the preparation of the compound of the formula I, wherein a) a cyanoacetic acid amide of the formula V R2 NC- CH2- C0 - N (V) is reacted in the presence of a basic compound with a dithiocarboxylic acid of the formula VI Rl-CH, -CS-S-R7 (VI) having R1, R2 and R3 the meanings mentioned for the compound of the formula I and representing R7 CX-C6 alkyl, or b) a compound of the formula I, prepared according to process a), which, by virtue of its chemical structure, is present in enantiomeric forms, it is separated into pure enantiomers by formation of salts with pure acids or bases as regards the enantiomers, chromatography on chiral stationary phases or derivatization by chiral compounds, pure as regards the enantiomers, such as amino acids, separation of the diastereoisomers obtained thereby and dissociation of the chiral auxiliary group, or c) the compound of the formula I, prepared according to process a) or b), is isolated in free form or, in the case of the presence of acidic or basic groups , it is eventually transformed into physiologically compatible salts.

6. Medicaments, which contain an effective amount of at least one compound of the formula I according to claim 1 and / or a physiologically compatible salt of the compound of the formula I and / or an optionally stereoisomeric form of the compound of the formula I, the radicals R1, R2 and R3 being defined as in claim 1, but the conditions being included, together with a pharmaceutically suitable and physiologically compatible support substance, additive and / or other active substances and / or adjuvants.

7. - Use of at least one compound of formula I according to one or more of claims 1 to 4, for the preparation of medicaments for the treatment and prophylaxis of immune or autoimmune diseases, diseases with an increased development of cells, such as cancer or restinosis, rejection reactions in transplants, skin diseases of the psoriasis group, psoriasis vulgaris, eruptive psoriasis, erythrodermic psoriasis, pustular psoriasis, dermatitis, atopic dermatitis, allergic dermatitis, photoallergic dermatitis, drug dermatitis, and eczema, asthma, urticaria, rhinitis, ureitis, type II diabetes, pulmonary fibrosis, cystic fibrosis, colitis or allergy.

8. Process for the preparation of a medicament according to claim 6, characterized in that at least one compound of the formula I according to claim 1 and / or a compound obtained according to the process according to claim 5 is brought into a suitable administration form with adjuvants and physiologically acceptable support substances and optionally other additives and / or other active substances.