SE438333B - NEW AMINOTIAZOLS - Google Patents

Description

7904798-1 inflammation and regulation of the body's immune response.

The synthesis of a limited number of 2-aralkylaminothioazoles has been described, for example 2-phenethylaminothiazole, Chem. Abs. 59, 1613e (1963); 2-benzylaminothiazole, J.A.C.S., 74, 2272 (1952) and 2-benzylamino-4-phenylthiazole, J. Ind. Chem. Soc., 44, 57 (1967).

However, these articles do not disclose any pharmacological activity of such compounds.

The present invention relates to substituted aminothiazoles useful as anti-inflammatory agents and as regulators of the body's immune response. More particularly, the novel compounds of the invention fall under the general formula RN / S and the compounds also include pharmaceutically acceptable acid addition salts of these compounds, the general symbols of the above formula having the following meanings: R 1 is -CH, - (C -X, -CH 2 -CH 2 -NH-X or - (CH 2) m Y, where X is phenyl X or phenyl substituted with alkoxy having 1f 3 collomer or bromine; Y is thienyl or furyl; m is an integer 1 or 2; R 2 is phenyl, thienyl or phenyl substituted with alkoxy having 1-3 carbon atoms or fluorine, and R 3 is hydrogen or alkyl having 1-3 carbon atoms Preferred values for R 2 are phenyl and p-fluorophenyl and for R 3 hydrogen.

A preferred group are those compounds in which R 1 is - (CH 2) 2 -X. Most preferred are those compounds in which X is phenyl or p-methoxyphenyl, R 2 is phenyl or p-fluorophenyl, R 3 is methyl or hydrogen, i.a. 2-phenethylamino-4-phenyl-thiazole and 2-phenethylamino-5-methyl-4-phenyl-thiazole.

Another group of interest is those compounds in which R1 is - (CH2) m-Y, especially when m is 1. Preferred are especially in those compounds; wherein R 2 is phenyl or p-fluorophenyl and R 3 is hydrogen or methyl. Containing a novel 7904798-1 Another group of compounds are those in which R 1 is / X -CH, wherein preferred compounds are those in which X is phenyl, R 2 X is phenyl and R 3 is hydrogen. Another group of compounds of interest are those in which R 1 is -CH -CH -NH-X, in particular those compounds in which X is phenyl, R 2 is phenyl and R 5 is hydrogen.

Also within the scope of the invention are pharmaceutical preparations substituted aminothiazole according to the invention or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable substance, as carrier or diluent. Preferred pharmaceutical preparations are those containing the compounds preferred above and most preferably 2-phenethylamino-4-phenyl-thiazole, 2-tenylamino-4- (p-fluorophenyl) -thiazole or 2- (p-methoxyphenethylamino) -4- (p -fluorophenyl] -thiazole or pharmaceutically acceptable acid addition salts of these compounds.

Also within the scope of the invention is a method of treating rheumatoid arthritis including the administration of an effective antiarthritic amount of a novel aminothiazole of the present invention, in particular the preferred compounds described above and most preferably 2-phenethylamino-4-phenylthiazole, 2- (p-methoxyphenethylamino) -4- (p-fluorophenyl) -thiazole or 2-tenylamino-4- (p-fluorophenyl) -thiazole or pharmaceutically acceptable acid addition salts thereof.

The novel aminothiols of the present invention are prepared from an appropriately substituted N-arylthiourea of the formula R 1 NHNH 2, where R 1 has the meaning given above. These latter compounds can be readily prepared from known and readily available amines of the formula R1NHz. unsubstituted or suitably substituted phenethylamines. The corresponding tenyl or furyl analogs of these amines are used to prepare compounds. When, for example, the group R 1 - is - (CH 2) 2 -X, -f10 D 25 '40 79o479a-1 -11 l / X 1 which R 1 is - (cH 2) m Y . When R 1 is -ca, unsubstituted phenyl-, X-substituted diphenylmethylamines are suitable starting materials, while when R 'is -CH -CH -NH-X, unsubstituted or substituted n-phenethylenediamines are used. The general symbols X, Y, .n and m used above have the meanings previously given above.

The amine used as starting material is first converted to the hydrochloride or other hydrohalide by reaction with HCl or another hydrogen halide, generally by bubbling the gaseous halide through a solution of the amine in an inert organic solvent, typically an ether. , for example diethyl ether, at a temperature between about -10 and about: + 10 ° C. The amine hydrohalide is then reacted with ammonium thiocyanate or an alkali metal thiocyanate, for example potassium thiocyanate, in an inert organic solvent, generally an aromatic solvent such as bromobenzene, chlorobenzene, zylene and the like. to form the desired N-aralkylthiourea {The reaction is conveniently carried out in an inert atmosphere, for example under nitrogen, at a temperature between about 110 and about 250 ° C, preferably at 150 DEG-100 DEG C., for example at the reflux temperature of bromobenzene. generally completed in a time between about 30 minutes and about 6 hours depending on the temperature applied. Generally, about 1-3 hours at 150 DEG-100 DEG C. are required. In the preparation of the N-aralkylthioureas described above, it has generally been found that a small amount of bis-aralkyl-substituted thiourea is formed, but this can be easily separated from the desired monosubstituted product, for example by recrystallization. However, it has been found that the reaction between substituted or unsubstituted diphenylmethylamine hydrohalides and ammonium thiocyanate predominantly yields bis-substituted thiourea, although minor amounts of the mono-substituted compounds may be obtained in this reaction, and after separation used as starting material for the new aminothiazoles. However, it has also been found that the bis-substituted thioureas can be used as starting materials for the preparation of the desired diphenylmethylaminothiazoles of the invention, the bis-substituted thiourea decomposing in situ to form the monosubstituted compound.

The appropriate N-aralkyl-thiourea is converted to the desired aminothiazole by reaction with an appropriately substituted 11β-haloketone or aldehyde of the formula R2CCHCH (Z) R3, where 40 ...- fv -.- v.> ... .. .. 7904798-1 R2 and R3 have the meanings given above and Z is halogen, preferably chlorine or bromine. For example, when R 2 is phenyl and R 3 is hydrogen, bromoacetophenone can be used.

Other suitable alpha- or aldehydes can be readily selected to give the desired substituents R 2 and R 3 on the thiazole ring. The reaction is carried out in an inert organic solvent, typically in n-alkanol having 1-6 carbon atoms, preferably in absolute ethanol. Reaction temperatures between about 50 ° C and about 175 ° C are applied, preferably the reflux temperature of the solvent. The reaction is conveniently carried out in an inert atmosphere, for example under nitrogen or other inert gas. The reaction is generally substantially complete in between about 1 and about 15 hours depending on the temperature applied, for example within 1-4 hours using ethanol at reflux temperature. The desired compound is obtained in the form of the hydrohalide and the free base can then be prepared from the salt in a conventional manner, for example by contacting it with an excess base, for example alkali metal hydroxide or carbonate, followed by extraction of the desired free base aminothiazole. with a suitable organic solvent, for example an ether, such as diethyl ether.

Pharmaceutically acceptable acid addition salts of the novel aminothiazoles are also included in the present invention and are readily prepared by contacting the free base with a suitable mineral acid or organic acid in aqueous solution or in a suitable organic solvent. The solid salt can then be recovered by precipitation or by evaporating the solvent. Pharmaceutically acceptable acid addition salts according to the invention are e.g. hydrochlorides, hydrobromides, hydroiodides, sulfate, bisulfate, nitrate, phosphate, acetate, lactate, maleate, fumarate, oxalate, citrate, tartrate, succinate, gluconate, methanesulfonate and the like, although the invention is not limited to these acid addition salts. The novel aminothiazoles of the invention and pharmaceutically acceptable acid addition salts thereof are useful as anti-inflammatory agents and as regulators of the immune response of warm-blooded animals. The combination of anti-inflammatory and immunoregulatory activity is particularly valuable in the treatment of conditions such as rheumatoid arthritis and other diseases, which are associated with insufficient immunity and are accompanied by inflammation. Thus, the compounds of the invention relieve the pain and swelling associated with such conditions while regulating the patient's immune response and thereby alleviating the underlying immune disease by maintaining immune competence. Accordingly, the invention also includes a method of treating rheumatoid arthritis in warm-blooded animals by administering an effective antiarthritic amount of an aminothiazole of the present invention or a pharmaceutically acceptable acid addition salt thereof.

According to this method, the compounds of the invention may be administered to the patient in need of treatment in a conventional manner, for example orally or parenterally in doses between about 0.10 and about 50 mg / kg body weight and day, preferably between about 0.15 and about 15 mg / kg body weight and day. The optimal dose for an individual patient is, of course, determined by the person responsible for the treatment and, in general, smaller doses are initially administered and then gradually increasing doses to determine the most appropriate dosage.

This varies according to the compound used and the patient being treated; The compounds may be used in pharmaceutical preparations containing the compound or a pharmaceutically acceptable acid addition salt thereof in combination with a pharmaceutically acceptable substance as carrier or diluent. Suitable pharmaceutically acceptable carriers are inert, solid fillers or diluents and sterile aqueous or organic solutions. The active compound is included in such pharmaceutical preparations in amounts sufficient to provide the desired dose within the range indicated above. Thus, for oral administration, the compounds may be combined with a suitable solid or liquid substance as a carrier or diluent for the manufacture of capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical preparations may, if desired, contain additional components, such as flavors, sweeteners, excipients and the like. For parenteral administration, the compounds may be combined with sterile, aqueous or organic media into injectable solutions or suspensions. Examples are solutions of the aminothiazoles in sesame or peanut oil, aqueous propylene glycol and the like. as well as aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts of the compounds. The injectable solutions, prepared in this manner, may then be administered intravenously, intraperitoneally, subcutaneously or intramuscularly, with intravenous and intraperitoneal administration being preferred. For local treatment of inflammation, the compounds may also be administered topically in the form of ointments, creams, pastes and the like, all in accordance with conventional pharmaceutical practice.

The activity of the compounds of the invention as anti-inflammatory agents can be determined by pharmacological tests, for example the standard test with carrageenan-induced rat edema using the general procedure described by C.A. Winter and co-workers in the Proceedings of the Society of Experimental Biology in Medicine, Volume 111, p. 544 (1962). In this test, the anti-inflammatory activity is determined as a percentage inhibition of edema in the hind paw of albino male rats (which generally weighs between about 150 and about 190 g) in response to a subplantar injection of carrageenan. The carrageenan is injected in the form of a 1% aqueous suspension one hour after oral administration of the drug, which is normally administered in the form of an aqueous solution or suspension. The training is assessed 3 hours after the carrageenan injection by comparing the original volume of the injected paw with the volume after 5 hours. The volume increase 3 hours after the carrageenan injection constitutes the individual response and the compounds are considered active, if this response in the drug-treated experimental animals (6 rats in each group) in comparison with the control group (ie the experimental animals on which only the vehicle was administered ), proves to be significant in comparison with the results obtained with the standard compounds, for example acetylsalicylic acid at a dose of 100 mg / kg or phenylbutazone at a dose of 33 mg / kg, both by oral administration.

The immunoregulatory activity of the compounds of the invention can be determined by such pharmacological tests as in vitro stimulation of the proliferation of rat or mouse thymus cells when cultured in the presence of Concanavalin A (Con A) using the general estimation procedure prepared by V.J. Merluzzi et al., Journal of Clinical and Experimental Immunology, Vol. 22, p. 486 (1975). For this study, 4 different activity levels of lymphocyte stimulation test (LSA) were used for the tested compounds, namely (1) those having the same activity as Con A alone, (Z) those having greater activity than Con A but less activity than levamisole, which is an excellent standard compound in the art in question, (3) those having the same activity as levamisole, l0 1 15 79Û4798-1- and (4) those having higher activity than levamisole. Compounds are considered to be active for the present purpose if they are better than Concanavalin A. The invention is illustrated in the following examples, but it is of course not limited to the details given in the examples.

Example 1: Phenethylamine (479 g, 3.96 mol, Eastman Scintillation Grado) was dissolved in 3500 ml of diethyl ether and the solution was cooled to UOC.

Dry HCl was bubbled through the stirred solution for 10 minutes and the precipitate formed was filtered off. The filtrate was then cooled and HCl was bubbled through the solution for a further 10 minutes, after which the solid was collected. This was repeated until acidification of the filtrate with dry HCl no longer gave any precipitate. The combined solids were dried in air and then over phosphorus pentoxide in vacuo to give 514 g (82%) of phenethylamine hydrochloride, m.p. 216-21896.

, Phenethylamine hydrochloride (257 g, 1.63 mol) and ammonium riocyanate (1z3.6 g, 1.63 mol) were heated to 160 ° C in 134 ml of bromobenzene under nitrogen. After heating for 90 minutes, the mixture was cooled to room temperature and then to SOC. The process was repeated with an additional batch of 257 g of phenethylamine hydrochloride. The combined solids obtained in the above-described reaction were stirred in 1.5 L of water and filtered off.

Recrystallization from isopropyl alcohol gave 261.5 g (45%) of N-phenethylthiourea, melting point 132 DEG-144 DEG.

Example 2: N-Phenethyl-thiourea (225 g, 1.25 mol) and cX-bromo-acetophenone (250 g, 1.25 mol, Aldrich Chem. Co.) in 1500 ml of absolute ethanol were heated to reflux temperature in 2.5 hours under nitrogen. The volume of the solvent was reduced by 10%, after which the reaction mixture was cooled to room temperature and then to 0 ° C in an ice bath. The solids were filtered off, redissolved in 2500 ml of absolute ethanol and heated to reflux.

The volume of solvent was reduced to 2000 ml and the reaction mixture was cooled to 0 ° C. This procedure was repeated and after the second recrystallization the solids were collected and dried in vacuo over phosphorus pentoxide. 365 g (81%) of 2-phenethylamino-4-phenylthiazole hydrobromide were obtained, m.p. 169-172 ° C. -, - p-v ..-; ._......._.-_ ... ..- i .9 Analysis -% C calculated for cnnl fi nzs-Hßr: 56.50; Found: 57:35 7904798-1% H% N 4.74 7.68, 04 7.83.

Example gel 3 = N-phenethyl-thiourea (2.0 g, 0.011 mol) and c 1-4 bromopropylphenone (2.34 g, 0.011 mol, Aldrích Chem. Co.) in 10 ml of absolute ethanol were heated to reflux temperature for 90 h minutes under nitrogen. The ethanol was then removed in vacuo, ethyl acetate was added in excess and the solids were filtered off, dried over phosphorus pentoxide and recrystallized from absolute ethanol. 2.86 g (70%) of 5-methyl-2-phenethylamino-4-phenyl-thiazole hydrobromia were obtained, m.p. 172 DEG-172 DEG.

Analysis - 0% C% H% N calculated for c 18 H 18 N 2 S-Hzrz 57.59 5.19 7.46 Found: 57.67 5.11 7.39.

Example 14 = In the manner set forth in Examples 1 and 2, the hydrohalides were prepared from the following compounds: R 2 N} - -CH -X Ra S NH C112 2 eal: x 52 53 enlarge Has phenyl p-meroxyphenyl hydrogen 1: 5-1s9 ° c Hcl phenyl p-fluorophenyl hydrogen * 163-16s ° c HBr p-bromophenyl phenyl hydrogen 171 ~ 174 ° C HBr p-bromophenyl phenyl methyl 150-151.5 ° C 'Salt Ä 32 33 melting point HBr P “methoxyphenyl phenyl hydrogen l6q_l7l0C HBr p-methoxyphenyl phenyl 1 - methyl 149 "15n ° c _ .. _ 0 Hcl p-methoxyphenyl p-flHorphenyl Vate 156 158 C lm 7904798-1 '- 10 phgemgel 5: 2-tenylamine (30 g, 0.265 mol, Fairfield Chemical Co .) was dissolved in 400 ml of diethyl ether and the solution was cooled to 0 ° C in an ice bath Dry HCl was bubbled through the solution for 5 minutes, then the formed solids were filtered off and dried over phosphorus pentoxide to give 26.7 g (61%) 2-tenylamine hydrochloride, m.p. 186 DEG-180 DEG C. 2-tenylamine hydrochloride (13.35 g, 0.089 mol) and ammonium thiocyanate (7.4 g, 0.009 mol) in 20 ml bromobenzene was heated at reflux temperature for 90 minutes ter. The reaction mixture was cooled, the solids were filtered off and washed 3 times with water. Recrystallization from chloroform and drying over phosphorus pentoxide gave 5.0 g (33% of 1N-tenylthiourea, m.p. 99-101 ° C).

Analysis -C% C% H% N calculated for C 6 H 8 N 2 S 2: 41.83 4.68 16.26 Found: 41.56 4.58 16.07.

Example gel 6: N-tenylthiourea (2.0 g, 0.0116 mol) and. Ok bromoacetophenone (2.3 g, 0.0116 mol, Aldrich Chem. Co.) in 15 ml of absolute ethanol was heated at reflux temperature to 90 ° C under nitrogen.

The reaction mixture was cooled and the ethanol was removed in vacuo. Upon dissolution of the evaporation residue in hot isopropyl alcohol and dilution with diethyl ether, an oil formed. The diethyl ether was decanted off, the oil was dissolved in a small amount of ethanol and the solution was cooled. The solids formed were filtered off and dried over phosphorus pentoxide to give 3.20 g (78%) of 2-tenylamino-4-phenylthiazole hyarobromia, m.p. 115 DEG-115 DEG.

Analysis -% C% H% N calculated for C 14 H 12 N 2 S 2 · HBr: 47.58 3.71 7.93 Found: 47.75 3.74 7.90.

Example 72 N-tenyl-thiourea (0.80 g, 0.0046 mO1) 0Ch 6Å-chloro- 40 --- wv -_- 1 - Ã-w - »-» --- »~ - ~ -.- _-. _. . 7904798-1 μl of p-fluoroacetophenone (0.80 g, 0.0046 mol, Aldrich Chem. Co.) in 11 ml of absolute ethanol was heated at reflux temperature under nitrogen for 90 minutes. minutes. After cooling, the ethanol was removed in vacuo and the solid residue was triturated with ethanol, filtered off and vacuum dried over phosphorus pentoxide to give 0.848 g (56%) of 2-tenylamino-4- (p-fluorophenyl) -thiazole hydrochloride, m.p. 184-1 ° C.

Analysis - 50% c a one calculated for C 14 H 11 B 2 S 2 F 1 HCl: 51.45 3.70 8.57 found: 51.41 5.63 8.39.

Example 8; In the manner set forth in Examples 6 and 7, the hydrochlorides were prepared from the following compounds: âílí E; E; Example 9 = Furfurylamine (25.0 g, 0.257 mol, Pfaltz & Bauer Co., p.) P-methoxyphenyl hydrogen 154-158 ° C Her phenylmethyl 179.5-1s1, s ° c aci .t1enyl1 hydrogen 137-142 ° cu. ) was dissolved in 1300 ml of diethyl ether and the solution was cooled to 0 ° C in an ice bath. Dry HCl was bubbled through the solution until no more precipitate formed. The solids were filtered off and dried in vacuo over phosphorus pentonide to give 33.46 g (97%) of furfurylamine hydrochloride, m.p. 147-149 ° C. Furfurylamine hydrochloride (33.46 g, 0.250 mol) and ammonium thiocyanate (38.14 g, 0.501 mol) in 71 ml of bromobenzene were heated under nitrogen at reflux temperature for 20 minutes, after which the reaction mixture was cooled to room temperature, mixed with a solution of 125 ml of water and 100 ml of ethyl acetate and allowed to stand at room temperature overnight. The mixture was then diluted to contain 500 ml of ethyl acetate and 350 ml of water, after which the aqueous phase was separated. The organic phase was washed with water, dried over sodium sulfate, filtered and evaporated to dryness, then the bromobenzene was removed in vacuo. The solids thus obtained were ground with a pistil in a mortar and the fine V.-........_, - ..._.._..___.___. B ____ .., _._. ..-._.-. _,. 40. ' The particles were stirred in diethyl ether to remove residual bromobenzene. The solids were filtered off, washed with diethyl ether and dried in vacuo over phosphorus pentoxide to give 12.06 g (30%) of N-furfuryl-thiocarbamide, m.p. '~' Ana1ys - p e 'c - æc%. 1,% N calculated for c6H8n2os = 46.14 5.16 17.93, 46.91 4.90 17.57. Found Example 10: N-Furfuryl thiourea (0.82 g, 0.005 mol) and C% bromopropiophenone (1.07 g, 0.005 mol, Aldrich Chem. Co.) in 11 ml of absolute ethanol were heated at reflux temperature under nitrogen hours and then cooled to room temperature, after which the solvent was removed in vacuo. A thick, brown oil was obtained. This was triturated with 5 portions of 35 ml each under reflux of boiling ethyl acetate. The volume of ethyl acetate was reduced to young. 25 ml and cooled to room temperature. The precipitated solids were filtered off, washed with ethyl acetate and dried in vacuo over phosphorus pentoxide. 0.585 g (33%) of 2-furfurylamino-5-methyl-4-phenyl-thiazole hydrobromide were obtained, m.p. 150-153 ° C.

Analysis -% C% H% N calculated for C 15 H 12 N 2 OS.SHBr: 51.29 4.30 7.97 Found: - 51.97 1.47 8.42 Example 11: In the manner set forth in Examples 9 and 10, hydrobromides were prepared from the following compound: R2 1 N - N E34 / 'ß ~ NH-CH2 - (/ es' Salt - E32 7 33' melting point Has hydrogen 123-126 ° c phenyl Example 12: Diphenylmethylamine (25.0 g, 0.136 mol, Matheson, Coleman & Bell Co.) was dissolved in 660 ml of diethyl ether and the solution was cooled to 0 [deg.] C. Dry HCl was bubbled through the solution for 10 minutes, during which a further 300 ml of diethyl ether were added, the precipitate was filtered off, washed with diethyl ether and vacuum-dried over phosphorus pentoxide to give 28.3 g (95%) of diphenylmethylamine hyarochioria, m.p. 50 DEG-50 DEG C. decomposition.

Diphenylmethylamine hydrochloride (28.3 g, 0.129 mol) and ammonium phthiocyanate (9.81 g, 0.129 mol) in 37 ml of bromobenzene were heated at reflux temperature under nitrogen for 3.5 hours and then cooled to room temperature. The solids were filtered off, triturated twice with 200 ml of water and dissolved in 850 ml of ethanol. The solution was filtered and evaporated to about 350 ml. After cooling, the solids were filtered off, washed with ethanol and dried in vacuo over phosphorus pentoxide to give 14.72 g (56%) of N, N'-bis- (diphenylmethyl) thiourea, m.p. 216-217 , S ° C.

Analysis -% C% H% N calculated for C 27 H 24 N 2 St 79.37 5.92 6.86 79.84 6.05 6.93. Found: Example gel 13: N, N'-bis- (diphenylmethyl) -thiourea (1.21 g, 0.005 mol) and acyl chloride (1, z1 g, 0.005 mol, A1dr1ch chem. co.) 1 11 ml absolute ethanol was heated at reflux temperature under nitrogen for 3 hours. After cooling, the reaction mixture was evaporated to dryness and the oil thus obtained was mixed with young. 40 ml of diethyl ether. The solids were filtered off, washed with diethyl ether and vacuum dried over phosphorus pentoxide to give 1.01 g (75%) of 4,5-diphenyl-2-diphenylmethylamino-thiazole-hyalurea, mp 195-19 ° C.

Analysis - 9% c,% n% N calculated for C 28 H 22 N 2 S · HCl: 73.91 5.09 6.16 found 73.12 5.28 6.06.

Example Gel 14: In the manner set forth in Examples 12 and 13, 4-phenyl-2-diphenylmethylamino-thiazole hydrobromide was prepared, m.p. 166-16 ° C.

Example Gel 15: N-Phenylethylenediamine (25 g, 0.184 mol, Aldrich Chem.

Co.) was dissolved in diethyl ether, the solution was cooled to 0 ° C and dry HCl was bubbled through until no more precipitate formed. The solids were filtered off and dried over phosphorus pentoxide to give 31.2 g (98%) of N-phenylethylenediamine hydrochloride. g of N-phenylethylenediamine hydrochloride (31.2 g, 0.149 mol) and z '40' ammonium thiocyanate (11.3 g, 0.149 mol) in 31 ml of bromobenzene were heated at reflux temperature under nitrogen for 2 hours and then cooled. The formed solids were filtered off and the bromobenzene was removed from the filtrate in vacuo. The solids formed were stirred in 250 ml of water, filtered off and dissolved in hot isopropyl alcohol. After the solution cooled, the solids were filtered off and dried over phosphorus pentoxide to give 2.8 g (8%) of N- (2'-anilinethyl) -thiourea, m.p. 137 DEG-140 DEG C.; Analysis J _ a ac an% N calculated for C 90 g, 0.0046 mol) and absolute ethanol were heated at reflux temperature and under nitrogen for 2 hours. After the reaction mixture cooled, the solvent was removed in vacuo and the oil thus formed was dissolved in hot isopropyl alcohol. The solution Eíltrcrades and chilledcs. The solids were filtered off and dried over phosphorus pentoxide to give 1.25 g (73.5%) of 2- (2'-anilinethylamino) -4-phenylthiazole, m.p. 461-16 ° C.

Analysis -: P_% c an% N calculated for C17H17N3S.HBr: 54.24 4.82 11.16 Found: 54.51 4.59 11.02 Example gel 17 = In the manner set forth in Examples 15 and 16, hYår0bFÖmi¿ was prepared ê fl of the following compound = _13. N 'R3 // / ɧ-NH-cH2-cH2-nH- s _ ”_,. §Al§_, §2 '33 melting point HBr 7 phenyl vmethyl 133-136 ° C.

Example Gel 18: The immunoregulatory activity of the aminothiazoles according to Examples 2, 3, 4, 6, 3, 10, 11, 13, 14, 16CC 17 was evaluated by determining their ability to stimulate lymphocyte proliferation in vitro. in rat or mustache cells cultured in the presence of Concanavalin A (Con A); applying it by V.J. Merluzzi and co-workers developed the procedure, as mainly described in the Journal of Clinical and Experimental Immunology, Vol. 22, pp. 486 (1975). The cells were obtained from 6-8 week old male mice C57B1 / 6, purchased from Jackson's Laboratories of Bar Harbor, Maine and Con A had been obtained from Sigma Chemicals of St. Louis, 1 Missouri. Each cell culture (which consisted on the one hand of two stock solutions, namely 0.10 ml of thymus cell solution and .05 ml of Con A solution and on the other hand 0.05 ml of drug) was divided into quadruplicate and the cell proliferation was determined after 48 hour incubation at 37 ° C by pulsing each of the cultures with SH-thymidine (0.1 ml with specific activity 1.9 c / nn, obtained from sehwatz-Mann, Inc. of Orangeburg, NY) after which the incorporation of 3H -thymidine in cell deoxyribonucleic acid (DNA) was determined by measuring the radioactivity using a liquid instillation counter.

The results obtained in this way are expressed quantitatively as the average pulse rate per minute (cpm) for 3 H-thymidine, which has been incorporated with maximum activity at the drug level of the quadruplicate cell cultures. These quadruplicate determinations were applied at 8 different drug concentrations between -02 and 50 μm / ml. The highest cpm value obtained was used in the marking system. On this basis, 4 different activity levels were established in the present lymphocyte stimulation experiment (LSA) and these are defined as follows, namely levels corresponding to those for Con A alone (6; 000 3,300 cpm) were assigned a negative value or marking 0; activity levels above those for Con A (10,000 É 700 cpm) but less than those for levamisole were designated as +; the levels corresponding to those for levamisole (22,000 É 900 cpm) were designated as ++ and those with activity above levamisole (27,000 f 1,000 cpm) were designated as +++. The LSA activity for the compounds according to the above example was +++ in all cases.

Example 19: The anti-inflammatory activity of the aminothiazoles of the invention was determined using the standard test involving carrageenan-induced rat edema essentially according to the procedure described by C.A. Winter and co-workers, Pro- _ceedings of the Society for Experimental Biology and Medicine, Vol. 111, pp. 544 (1962). The compounds were orally administered at a dose of 33 mg / kg in the form of their above-described hydrogen hydrogen doses of 33 mg / kg.

The results obtained in this way are summarized in the table below in the form of a percentage inhibition of edema formation, which is produced by each test compound, using as a non-drug-treated control, ie. experimental animals on which an aqueous solution was administered without compound: -NH-R1 U? v \\\ UI \ / É RI R2 RSÜ Hz 'øaeminhibiti0n,% __ __ __ __. (33 mg / kg, 2.0.) 4-fluorobenzyl phenyl hydrogen HBr 41 2-tenyl1 4-fluorienyl hydrogen HBr 49 ¶ 2-phenethylphenyl hydrogen HBr 47 4-methoxy-4-fluorophenyl hydrogen HBr »29 phenethyl

Claims (10)

10 15 20 25 30 35 -fl- w- fi- »w --- -,; '1 1 7904798-1 -Patentkrav A compound characterized by the general formula and pharmaceutically acceptable ear addition salts thereof, in which formula R 1 is x / Y .. - -C 2 -N 2, - (cH 2) 2 -x, -CH 2 -CH 2 -NH -X or - (cH2) m, where X is phenyl or phenyl substituted with bromine or alkoxy having 1-3 carbon atoms, Y is thienyl or furyl; m is an integer 1f2; R 2 is phenyl, thienyl or phenyl substituted with alkoxy having 1-3 carbon atoms or fluorine; and R 3 is hydrogen or alkyl of 1-3 carbon atoms. A compound according to claim 1, wherein R 1 is - (CH 2) 2 -X, wherein simultaneously X, R 2 and R 3 are as follows: X = phenyl; R2 = phenyl; and R 3 = hydrogen or methyl, preferably hydrogen. A compound according to claim 1, wherein R 1 is - (CH 2) 2 -X; X = p-methoxyphenyl; R 2 = p-fluorophenyl; and R 3 = hydrogen. A compound according to claim 1, wherein R 1 is - (CH 2) m -Y, wherein at the same time Y, m, R 2 and R 3 are as follows: Y = thienyl; m = 1; R2 = phenyl or p-fluorine- _ k ä n n e t e c k n a d 'k ä n n e t e c k n a d k ä n n e t e c k n a d phenyl; and R 3 = hydrogen. A compound according to claim 1, n a d in that R 1 is - (CH 2) m -Y 1 Y 2 = furyl; m = 1; R2 = phenyl; and R 3 = hydrogen or methyl. A compound according to claim 1, characterized in that R 1 is known in k / - / X 'i' -CH; X = phenyl; R2 = phenyl and R3 = hydrogen. * x 10 I phenyl; and R 79047984, |% A compound according to claim 1, wherein R is -CH -CH 2 -NH 4 X; X = phenyl; R2 = 1 2 3 = hydrogen. 8; A pharmaceutical preparation containing an immunoregulatory amount of a compound according to claim 1, preferably 2-phenylethylamino-4-phenylthiazole, and a pharmaceutically acceptable carrier. A preparation according to claim 8, wherein the compound is 2-tenylamino-4- (p-fluoro-k e n n e t e c k-n a d phenyl) -thiazole. 9. I A preparation according to claim 8, in that the compound is 2- (p-methoxyphenethylamino) - k e n n e t e c k - n a d -4- (pifluorophenyl] thiazole.