FI68820B - ADJUSTMENT OF THERAPEUTIC HEATING AMNOTIAZOLER - Google Patents

Description

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C (45) Patent, ti r.r .: t ty 11 11 1935 (51) Kv.lk.1 / lnt.CI. 'C 07 D 277/42, A17 / 04, 417/12 1 FINLAND —Fl NLAND (21) Patent application - Patentansöknlng 79 1 754 (22) Filing date — Ansökningsdag 01 06 79 ✓Fl) * '(23) Starting date - Giltighetsdag qj 06 79 (41) Published public - Blivit offentlig j 2 79

National Board of Patents and Registration Date of publication and publication. - ""

Patent- oeh registerstyrelsen '' Ansökan utlagd och utl.skriften publicerad 3 i. u /. ö 5 (32) (33) (31) Privilege claimed - Begärd priority 02.06.78 USA (US) 911830 (71) Pfizer Inc., 235 East 42nd Street, New York, NY, USA (US) (72) Joseph George Lombardino, New London, Connecticut, Jasjit Singh Bindra,

New London, Connecticut, USA (74) Oy Kolster Ab (54) Process for the preparation of therapeutically useful aminothiazoles -Forfarande för framstälIning av terapeutiskt användbara ami notiazoler

The application concerns the manufacture of new substituted aminothiazoles suitable for the treatment of inflammation and the regulation of immunity.

A number of agents used to treat inflammation have been found in the literature, for example corticosteroids, phenylbutazone, indomethacin and various 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxides, such as , which are discussed in U.S. Patent No. 3,591,584. Thus, these agents have been used in the treatment of arthritis and other inflammations, such as rheumatoid arthritis. These conditions have also been treated with immunoregulatory agents, such as levamisole, which is treated e.g. Arthritis Rheumatism, 20, 1445 (1977) and Lancet, 1, 393 (1976). In an attempt to find new and better pharmaceutical agents for the treatment of these conditions, the novel aminothiazoles discussed in this application have been found to have very good pharmacological properties, as they are both anti-inflammatory and immune-regulating in the body. They are therefore particularly // (C 07 D 417/04, 277: 42, 333: 14), (C 07 D 417/12, 277: 42, 333: 14), (C 07 D 417/12, 277 : 42, 307: 52)

2 6 "P 2 O

useful in the treatment of rheumatoid arthritis and other diseases aimed at relieving inflammation and regulating the immune response.

The literature discusses the preparation of a limited set of 2-aralkylaminothiazoles, such as 2-phenylaminothiazole, 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 discuss the pharmacological properties of these compounds.

This invention relates to substituted aminothiazoles used as anti-inflammatory agents and regulators of the body's immune response. In particular, the following compounds are involved:

R? --OF

R J. jL-NH-R, 3 \ s 1 and the corresponding pharmaceutically acceptable acid addition salts, wherein

/ X

R. is -CHV, - (CH «) ,, - X, -CH„ -CH ,, -NH-X or (CH „) Y, wherein X is 1 '22 22 2 m phenyl or monosubstituted phenyl having a substituent is an alkyl group having 1 to 3 carbons, a hydroxy group, an alkoxy group having 1 to 3 carbons, chlorine, bromine or fluorine; Y is thienyl, monosubstituted thienyl, furyl or monosubstituted furyl, said substituents being an alkyl group having 1 to 3 carbons, chlorine, bromine or fluorine; m is 1 or 2; is a phenyl, thienyl or monosubstituted phenyl group in which the substituent is a 1-3 carbon alkyl group, a hydroxy group, a 1-3 carbon alkoxy group, chlorine, bromine or fluorine; and R 1 is hydrogen, a 1-3 carbon alkyl group, phenyl or monosubstituted phenyl substituted with 1-3 carbon alkyl, 1-3 carbon alkoxy, chlorine, bromine or fluorine. Suitable substituents for R 0 are phenyl and p-fluorophenyl and for R 1 are hydrogen and phenyl.

A suitable group of compounds is one in which R 1 is - (CH 2) 2 -X. Most preferred are compounds wherein X is phenyl or p-methoxyphenyl, R 2 is phenyl or p-fluorophenyl, R 1 is phenyl, methyl or hydrogen, such as 2-phenethylamino-4-phenylthiazole, 3,60320 2-phenethylamino- 4,5-Diphenylthiazole and 2-phenethylamino-5-methyl-4-phenylthiazole.

Another group of interest is one in which R 1 is - (Cl 2) -Y 2, especially when m is 1. Suitable Y groups include thienyl and furyl, especially compounds wherein R? is phenyl or p-fluorophenyl and R is hydrogen, methyl or phenyl. v

A third group of interest are compounds wherein R is -CH 2, the best of which are those wherein X is phenyl, R 2 is phenyl and R 1 is hydrogen or phenyl.

Also of interest is the group of compounds wherein R 1 is -C 1 -C 4 -NH-X, especially compounds wherein X is phenyl, R 2 is phenyl and R 1 is hydrogen.

According to the present invention, novel aminothiazoles can be prepared

S

II

appropriately substituted N-aryl lithiourea compounds of formula R 1 NHCNH 2 wherein R 1 is the same as above. The latter compounds can be readily prepared from known and readily available amines of formula R 2 N 1 · 2. For example, when R 1 is unsubstituted or appropriately substituted phenethylamines. Tenyl or furyl compounds corresponding to these amines are used in the preparation of compounds wherein R is - (Cl

/ X

When R. is -CH>. , are unsubstituted or substituted diphenyl

X

methylamines are suitable starting materials, while when R 1 is -CH 2 -CH 2 -NH-X unsubstituted or substituted n-phenethylenediamines are used. Above, X, Y and m are the same as previously described. The starting amine is first converted to the hydrochloride or other hydrogen halide salt by a hydrogen chloride or other hydrogen halide reaction, generally by introducing a gas into an amine in an inert organic solvent, usually an ether such as diethyl ether, at a temperature between about -10 and 10 ° C. The amine hydrogen halide is then reacted with ammonium thiocyanate or an alkali metal thiocyanate such as potassium thiocyanate in an inert organic solvent, generally an aromatic solvent such as bromobenzene, chlorobenzene, xylene and the like to give the desired N-aralkylthiourea. The reaction is preferably carried out in an inert atmosphere, such as a nitrogen atmosphere, at a temperature of about 110-250 ° C, preferably between 150-200 ° C, for example at the reflux temperature of bromobenzene. The reaction time is generally from half an hour to six hours, depending on the temperature used, usually about 1 to 3 hours at a temperature between 150 and 200 ° C. When N-aralkylthiourea is prepared by the method described above, some bis-aralkyl-substituted thiourea is generally obtained, but this can be readily removed from the desired monosubstituted product, e.g., by recrystallization. However, it has been found that the reaction between substituted or unsubstituted diphenylmethylamine hydrogen halides and ammonium thiocyanate yields predominantly bis-substituted thiourea, although smaller amounts of monosubstituted compounds are obtained in this reaction and can be used as starting materials for novel amino acids.

However, it has also been found that bis-substituted thiourea compounds can be used as starting materials for the desired diphenylmethylaminothiazoles because the bis-substituted thiourea decomposes in situ to form a monosubstituted compound.

The appropriate N-aralkylthiourea can be converted to the desired aminothiazole by reaction of an appropriately substituted o-haloketone or an aldehyde of the form R 1 COCH 2 Z 1 R 2, wherein R 1 and R 2 are the same as above and Z is halogen, preferably chlorine or bromine. For example, when phenyl is hydrogen, X-bromoacetophenone may be used, but when R 1 and R 2 are each phenyl, a suitable reagent is a desyl halide, e.g. 2-chloro-2-phenylacetophenone. Other suitable x-halogenetones are readily selected to provide suitable R 6 and R 2 substituents on the thiazole ring. The reaction is allowed to proceed in an inert organic solvent, usually an n-alkanol containing 1 to 6 carbons, preferably absolute ethanol. The reaction temperature may be in the range of 50 to 175 ° C, preferably the reflux temperature of the solvent. The reaction is preferably carried out in an inert atmosphere, for example nitrogen or another inert gas. The reaction generally takes 1 to 15 hours depending on the temperature used, for example 1 to 4 hours when ethanol is used at reflux temperature. The desired product is obtained as the hydrogen halide salt from which the free base is obtained by conventional methods, for example by treatment with an excess of base such as alkali metal hydroxide or carbonate, followed by extraction of the desired free basic aminothiazole as a suitable organic solvent, for example ether.

This application also encompasses pharmaceutically acceptable acid addition salts corresponding to novel aminothiazoles, and can be readily prepared by reacting the free base with a suitable mineral or organic acid, either in aqueous solution or in a suitable organic solvent. The solid salt is then obtained by crystallization or evaporation of the solvent. Pharmaceutically acceptable acid addition salts which are the subject of this application include, but are not limited to, e.g. hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfate, bisulfate, nitrate, phosphate, acetate, lactate, maleate, fumarate, oxalate, citrate, tartrate, succinate, gluconate, methanesulfonate, and the like.

The novel aminothiazoles of this invention and their pharmaceutically acceptable acid addition salts are useful as anti-inflammatory agents and regulators of the immune response of warm-blooded animals. The anti-inflammatory and immune-regulating property is particularly valuable in the treatment of rheumatoid arthritis and other diseases involving a decrease in immunity and subsequent inflammation. Thus, the compounds of this invention alleviate the pain and swelling associated with this condition, and at the same time regulate the immune response of the subject, thereby reducing the immune disorder that caused the disease and maintaining immune competence. Thus, the compounds of this invention may be used in a method of treating rheumatoid arthritis in a warm-blooded animal by administering to the subject a sufficient anti-arthritis-enhancing amount of the aminothiazole of the invention or a corresponding pharmaceutically acceptable acid addition salt. In this method, the compounds may be administered to a subject in need of treatment by conventional means, such as orally or parenterally, and daily doses may range from about 0.1 f) to 50 mg / kg individual weight, with a dose of about 0.15 to 15 mg / kg being most suitable. . However, the person in charge of treatment will decide on the most appropriate dose for each individual to be treated, and will usually initially be given a fairly small dose from which to increase it until the best dose size is found. This depends on the compound used and the individual being treated.

6 60820

The compounds may be used as pharmaceutical preparations containing the compound or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid excipients or solvents and sterile aqueous or organic solutions. The amount of pharmaceutically active ingredient in the active ingredient is such that a dosage of the desired size within the above limits is obtained. Thus, for oral administration, the compounds may be in association with a suitable solid or liquid carrier or diluent to form capsules, cachets, powders, syrups, solutions, slurries, or the like. The pharmaceutical composition may, if desired, contain additives such as flavoring agents, sweetening agents, excipients or the like. The compounds for parenteral administration may be associated with a sterile aqueous phase or organic medium which forms a solution or slurry for injection. For example, solutions of aminothiazoles in sesame or nut oil, in aqueous propylene propylene glycol, or the like can be used as well as aqueous solutions of water-soluble, pharmaceutically acceptable acid addition salts of the compounds. The injections thus prepared can thus be administered intravenously, intraperitoneally, intradermally or intramuscularly, of which intravenous and intraperitoneally administered are best. For the topical treatment of inflammation, the compound may also be administered topically as an ointment, fat, paste or the like in combination with conventional pharmaceutical methods.

The anti-inflammatory efficacy of the compounds discussed in this application can be measured by pharmacological tests, e.g., a carrageenan-induced rat paw edema test, using C.A. The general method described by Winter et al., In Proceedings of the Society of Experimental Biology in Medicine, vol. 111, pp. 544 (1962). In this experiment, the anti-inflammatory activity is determined as the percentage inhibition of hindpaw swelling in a male albino rat (usually weighing about 150-190 g) when carrageenan is injected through the sole of the foot. Carrageenan is injected as a 1% aqueous slurry one hour after the drug, which is usually administered as an aqueous solution or slurry, is administered orally. Swelling is assessed three hours after carrageenan injection by comparing the volume of the paw to be examined before the experiment to the volume it has three hours after injection. The increase in volume three hours after injection of carrageenan is the reaction in question. Compounds are considered effective if the reaction between drug-treated animals (six rats in each group) and a control group, i.e. animals receiving only the mediator, is significant compared to the result obtained with standard compounds such as 10 mg / kg acetylsalicylic acid or 33 mg / kg kg of phenylbutazone, each orally administered.

The ability of the compounds of this invention to regulate immunity can be determined by pharmacological experiments such as accelerating the lymphocyte proliferation of mouse thymus cells cultured in the presence of Conca-Naval A (Con A), in vitro, using V.J. The evaluation method known from Merluzzin et al., Published in the Journal of Clinical and Experimental Immunoloy, Vol. 22, pp. 486 (1975). In this method, four different lymphocyte stimulation assay (LSA) activity ranges were obtained for test compounds, which are: activity equal to Con A; Higher than Con A activity but lower levamisole activity, the best standard solution in this range; compounds with the same activity as levamisole and those with higher activity than levamisole. Compounds are considered effective in this case if their activity is higher than that of Concanavalin A.

The study is illustrated by the following examples.

Example_1_ (Preparation of starting material)

Phenethylamine (479 g, 3.96 mol, Eastman Scintillation Grade) was dissolved in 3,500 mL of diethyl ether, and the solution was cooled to 0 ° C. Dry hydrogen chloride was bubbled into the stirred solution for 10 minutes, and the resulting precipitate was filtered. The filtrate was cooled, hydrogen chloride was bubbled into the solution for 10 minutes, and the formed crystals were collected. This was continued until no more crystals were formed by increasing the acidity of the filtrate with hydrogen chloride. The combined crystals were dried first in air and then in vacuo over phosphorus pentoxide to give 514 g (<2%) of phenethylamine chloride, m.p. 216-218 ° C.

Phenethylamine hydrochloride (257 g, 1.63 mol) and ammonium thiocyanate (123.6 g, 1.63 mol) were heated to 160 ° C in 340 ml of bromobenzene under a nitrogen atmosphere. The mixture was heated for 90 minutes, then cooled to room temperature and then to 5 ° C.

68820

The same was repeated with a second dose of 257 g of phenethylamine hydrochloride. The crystals obtained in the reactions were combined and stirred in 1.5 liters of water and filtered. Recrystallization from isopropyl alcohol gave 261.5 g (45%) of N-phenethylthiourea, m.p. 132-134 ° C.

Example 2 1,500 mL of absolute ethanol with N-phenethylthiourea (225 g, 1.25 mol) and cX-bromoacetophenone (250 g, 1.25 mol, Aldrich Chem. Co.) was heated to reflux for 2 1/2 hours under nitrogen. in the atmosphere. 10% of the solvent was evaporated, after which the reaction mixture was cooled to room temperature and then to 0 ° C with an ice bath. The crystals were filtered, redissolved in 2,500 ml of absolute ethanol and heated to reflux. The solution was evaporated to 2000 ml and the reaction mixture was cooled to 0 ° C. The same was repeated, and after a second recrystallization, the crystals were filtered and dried in vacuo over phosphorus pentoxide to give 365 g (81%) of 2-phenethylamino-4-phenylthiazole hydrogen bromide, m.p. 169-172 ° C.

Analysis * for HBr:

Calculated: C 56.50 H 4.74 N 7.68

Found: C 57.35 H 5.04 N 7.83.

Example 3 N-Phenethylthiourea (140 g, 1.779 mol) and desyl bromide (225 g, 0.82 mol, Eastman Chem. Co.) were heated under reflux in 833 ml of absolute ethanol to reflux temperature for 2 hours and during the reaction further 300 ml of absolute ethanol. The reaction mixture was cooled to 10 ° C, the crystals were filtered, recrystallized from absolute ethanol and dried over phosphorus pentoxide to give 281.0 g (83%) of 2-phenethylamino-4,5-diphenylthiazole hydrobromide, m.p. 171-174 ° C.

Analysis for C23H2QN2S-HBr:

Calculated: C 63.14 H 4.84 N 6.40

Found: C 62.62 H 4.82 N 6.48.

Example 4 10 mL of absolute ethanol with N-phenethylthiourea (2.0 g, 0.011 mol) and N-bromopropiphenone (2.34 g, 0.011 mol,

Aldrich Chem. Co.) was heated to reflux for 90 minutes under a nitrogen atmosphere. The ethanol was removed in vacuo, excess ethyl acetate was added to the mixture and the crystals were filtered off and dried over phosphorus pentoxide. Recrystallization from absolute ethanol gave 2.86 g (70%) of 5-methyl-2-phenethylamino-4-phenylthiazole hydrobromide, m.p. 172-175 ° C.

Analysis for gH ^ gN2S · HBr:

Calculated: C 57.59 H 5.10 N 7.46

Found: C 57.67 H 5.11 N 7.39.

Example 5

Hydrogen halides of the following compounds were prepared by the methods of Examples 1 and 2:

R „—- N

j 1

R 2 R 2 sAh-CH 2 -C "2 -X

Salt X R2 m.p. ° C

HBr phenyl p-methoxyphenyl hydrogen 135-139 HCl phenyl p-fluorophenyl hydrogen 163-165 HBr p-bromophenyl phenyl hydrogen 171-174 HBr p-bromophenyl phenyl methyl 150-151.5 HBr p-methoxyphenyl phenyl hydrogen 169-171 HBr p- methoxyphenyl phenyl methyl 149-150.5 HBr p-methoxyphenyl phenyl phenyl 201-205 HCl p-methoxyphenyl p-fluorophenyl hydrogen 156-158

Example 6 (Preparation of starting material) 2-Tenylamine (30 g, 0.265 mol, Fairfield Chemical Co.) was dissolved in 400 ml of diethyl ether and cooled to 0 ° C with an ice bath. Dry hydrogen chloride gas was bubbled through the mixture for 5 minutes. The formed crystals were filtered and dried over phosphorus pentoxide to give 26.7 g (61%) of 2-phenylamine hydrochloride, m.p. 186-190 ° C.

2-Phenylamine hydrochloride (13.35 g, 0.089 mol) and ammonium thiocyanate (7.4 g, 0.089 mol) in 20 ml of bromobenzene were heated to reflux for 90 minutes. The reaction mixture was cooled, and the filtered crystals were washed three times with water. The product was recrystallized from chloroform and dried over phosphorus pentoxide to give 5.0 g (33%) of N-phenylthiourea, m.p. 99-101 ° C.

10 6 S 8 2 0

Analysis for C6HgN2S2::

Calculated: C 41.83 H 4.68 N 16.26

Found: C 41.56 H 4.58 N 16.07.

Example 7 15 ml of absolute ethanol containing N-phenylthiourea (2.0 g, 0.0116 mol) and O * -bromoacetophenone (2.3 g, 0.0116 mol, Aldrich Chem. Co.) was heated under reflux under nitrogen. for 90 minutes. The reaction mixture was cooled and the ethanol was removed in vacuo. When the residue was dissolved in hot isopropyl alcohol and diluted with diethyl ether, an oil formed. The diethyl ether was decanted, the oil was dissolved in a small amount of ethanol and cooled. The formed crystals were filtered and dried over phosphorus pentoxide to give 3.20 g (78%) of 2-tenylamino-4-phenylthiazole hydrobromide, m.p. 115-118 ° C.

Analysis for ci4H; L2N2S2 'HBr:

Calculated: C 47.58 H 3.71 N 7.93

Found: C 47.75 H 3.74 N 7.90.

Example 8 11 ml of absolute ethanol with N-phenylthiourea (0.80 g, 0.0046 mol) and OC-chloro-p-fluoroacetophenone (0.80 g, 0.0046 mol, Aldrich Chem. Co.) were heated under nitrogen. in the atmosphere to reflux temperature for 90 minutes. After cooling, the ethanol was removed in vacuo, and the crystals were triturated with ethanol, filtered and vacuum dried over phosphorus pentoxide to give 0.848 g (56%) of 2-tenylamino-4- (p-fluorophenyl) -thiazole hydrochloride, m.p. 184-187 ° C.

Analysis of ci4HnN2S2F’HCl:

Calculated: C 51.45 H 3.70 N 8.57

Found: C 51.41 H 3.63 N 8.39.

Example 9

Hydrogen halides of the following compounds were prepared by the methods of Examples 7 and 8: 11,68820

I II II

Salt R2 R3 Sp. ° C

HBr p-methoxyphenyl hydrogen 154-158 HBr phenyl methyl 179.5 - 181.5 HCl thienyl hydrogen 137-142

Example 10 (Preparation of starting material)

Furfurylamine (25.0 g, 0.257 mol, Pfaltz & Bauer Co.) was dissolved in 1300 ml of diethyl ether and cooled to 0 ° C with an ice bath. Dry hydrogen chloride gas was bubbled into the solution until no more crystallization occurred. The crystals were filtered and dried in vacuo over phosphorus pentoxide to give 33.46 g (97%) of furfurylamine hydrochloride, m.p. 147-149 ° C.

71 ml of bromobenzene with furfurylamine hydrochloride (33.46 g, 0.250 mol) and ammonium thiocyanate (38.14 g, 0.501 mol) were heated to reflux under nitrogen for 20 minutes, after which it was cooled to room temperature. The reaction mixture was stirred in a solution of 125 ml of water and 100 ml of ethyl acetate and left at room temperature overnight. The mixture was then diluted with 500 ml of ethyl acetate and 350 ml of water, and the aqueous layer was separated. The organic layer was washed with water and dried over sodium sulfate. After filtration, the organic layer was evaporated to dryness and the bromobenzene was removed in vacuo. The remaining crystals were ground in a mortar, and the ground particles were mixed with diethyl ether to remove residual bromobenzene. The crystals were then filtered, washed with diethyl ether in vacuo and dried over phosphorus pentoxide to give 12.06 g (30%) of N-furfurylthiourea, m.p. 80-91 ° C.

Analysis for C ^ Hg ^ OS:

Calculated: C 46.14 H 5.16 N 17.93

Found: C 46.91 H 4.90 N 17.57.

12 68820

Example 11 11 ml of absolute ethanol containing N-furfuryl urea (0.82 g, 0.005 mol) and O-bromopropiophenone (1.07 g, 0.005 mol, Aldrich Chem. Co.) was heated to reflux under nitrogen for three After the mixture was cooled to room temperature, the solvent was removed in vacuo to give a thick brown oil which was triturated with five 35 mL portions of refluxing ethyl acetate, reduced to 25 mL and cooled to room temperature, and the crystals formed were filtered, washed with ethyl acetate. dried in vacuo over phosphorus pentoxide to give 0.585 g (33%) of 2-furfurylamino-5-methyl-4-phenylthiazole hydrobromide, mp 150-153 ° C.

Analysis for c15H14N2OS * HBr:

Calculated: C 51.29 H 4.30 N 7.97

Found: C 51.97 H 4.47 N 8.42.

Example 12

Hydrogen halides of the following compounds were prepared by the methods of Examples 10 and 11: R 2 'h-n 1

I il I

r3 S

Salt R2 R3 Sp. ° C

HBr phenyl hydrogen 123-1236 HBr phenyl phenyl 192-194

Example 13 (Preparation of starting material)

Diphenylmethylamine (25 g, 0.136 mol, Matheson, Coleman Bell Co.) was dissolved in 660 mL of diethyl ether and cooled to 0 ° C. Dry hydrogen chloride poured into the solution over 10 minutes, during which time a further 300 ml of diethyl ether was added to the mixture. The crystals were filtered, washed with diethyl ether and dried in vacuo over phosphorus pentoxide to give 28.3 g (95%) of diphenylmethylamine hydrochloride, m.p. 303-310 ° C (decomposition range).

37 mL of bromobenzene with diphenylmethylamine hydrochloride (28.3 g, 0.129 mol) and ammonium thiocyanate (9.81 g, 13,68820 0.129 mol) was heated to reflux under nitrogen for 3 1/2 hours, then cooled to room temperature. temperature. The crystals were filtered and triturated twice with 200 ml of water. The crystals were then dissolved in 850 ml of ethanol, filtered and evaporated to about 350 ml. After cooling, the crystals were filtered, washed with ethanol and dried in vacuo over phosphorus pentoxide to give 14.72 g (56%) of Ν, Ν'-bis- (diphenylmethyl) thiourea, m.p. 216 to 217.5 ° C.

Analysis for C27H24N2S:

Calculated: C 79.37 H 5.92 N 6.86

Found: C 79.84 H 6.05 N 6.93.

Example 14 11 ml of absolute ethanol with N, N'-bis- (diphenylmethyl) thiourea (1.21 g, 0.005 mol) and decyl chloride (1.21 g, 0.005 mol, Aldrich Chem. Co.) were heated under nitrogen. in the atmosphere to reflux temperature for three hours. After cooling, the reaction mixture was evaporated to dryness and the residual oil was taken up in about 40 ml of diethyl ether. The crystals were filtered, cooled with diethyl ether and dried in vacuo over phosphorus pentoxide to give 1.01 g (75%) of 4,5-diphenyl-2-diphenylmethylaminothiazole hydrochloride, m.p. 195-198 ° C.

Analysis for C28H22N2S

Calculated: C 73.91 H 5.09 N 6.16

Found: C 73.12 H 5.28 N 6.06.

Example 15

By the methods of Examples 13 and 14, 4-phenyl-2-diphenylmethylaminothiazole hydrobromide was prepared, m.p. 166-168 ° C.

Example 16 (Preparation of starting material) N-phenylethylenediamine (25 g, 0.184 mol, Aldrich Chem. Co.) was dissolved in diethyl ether, cooled to 0 ° C and dry hydrogen chloride was bubbled into the solution until no more crystallization occurred. The filtered crystals were dried over phosphorus pentoxide to give 31.2 g (98%) of N-phenylethylenediamine hydrochloride.

N-phenylethylenediamine hydrochloride (31.2 g, 0.149 mol) and ammonium thiocyanate (11.3 g, 0.149 mol) mixed with 31,148,820 ml of bromobenzene were heated to reflux under nitrogen for two hours. After cooling, the formed crystals were filtered off and the bromobenzene was removed from the filtrate in vacuo. The remaining crystals were mixed with 250 ml of water, filtered and dissolved in hot isopropyl alcohol. After cooling, the crystals were filtered and dried over phosphorus pentoxide to give 2.8 g (8%) of N- (2'-anilinoethyl) thiourea, m.p. 137-140 ° C.

Analysis for C 9 H 7 N 3 S: He:

Calculated: C 55.35 H 6.71 N 21.52

Found: C 55.64 H 6.75 N 21.03.

Example 17 6 ml of absolute ethanol containing N- (2'-anilinoethyl) thiourea (0.90 g, 0.0046 mol) and Ofc-bromoacetophenone (0.92 g, 0.0046 mol, Aldrich Chem. Co. ) was heated in a nitrogen atmosphere to reflux temperature for two hours. After cooling the reaction mixture, the solvent was removed in vacuo. The residual oil was dissolved in hot isopropyl alcohol, filtered and cooled. The crystals were filtered and dried over phosphorus pentoxide to give 1.25 g (73.5%) of 2- (2'-anilinoethylamino) -4-phenylthiazole, m.p. 161-165 ° C.

Analysis for C ^ H ^ N ^ S-HBr:

Calculated: C 54.24 H 4.82 N 11.16

Found: C 54.51 H 4.59 N 11.02.

Example 18

Hydrogen halides of the following compounds were prepared by the methods of Examples 16 and 17:

^ 2 -N

R3 -! ^ S ^ J ^ NH-CH2-CH2-NH - ^ ^ ^

Salt R2 R3 Sp. ° C

HCl phenyl phenyl 139-143 HBr phenyl methyl 133-136, 5,68820

Example I

The immunoregulatory capacity of the aminothiazoles described in Examples 2,3, 4, 5, 7, 8, 9, 11, 12, 15, 17, and 18 was evaluated by determining their ability to stimulate, in vitro, lymphocytes of mouse thymus cells cultured in the presence of Concanavalin A (Con A). formation of VJ By the method of Merluzzin et al., Described in Journal and Experimental Immunology, Vol. 22, pp. 486 (1975). Cells were derived from 6-8 week old male C57B1 / 6 mice obtained from Jackson Laboratories in Bar Habor, Maine, and Con A was obtained from Sigma Chemicals, St. Louis, Missouri. Each cell culture (comprising 0.10 ml of thymus cell stock solution, 0.05 ml of Con A stock solution, 0.05 ml of Corn A stock solution and 0.05 ml of drug) was grown in quadruplicate, and additional cell growth was measured for 48 hours at 37 ° C. After incubation in C, 3 by vibrating each culture with H-thymidine (0.01 ml potency is 1.9 C / mM, obtained from Schwarz-Mann, Orangeburg, N.Y.) and 3 by determining the H-thymidine association with cellular deoxyribonucleic acid (DNA) by liquid scintillation counter radioactivity measurements.

The results obtained by this method are quantified in terms of the average number of beats per minute (cpm) delivered to the cell cultures in quadruplicate at the highest activity level of the drug by β-thymidine. These fourfold measurements have been made on eight drug concentrations ranging from 0.02 to 50 ug / ml. The highest cpm value obtained has been used for scoring, compounds with the same activity as a negative value for Con A (6,000-300 cpm), or a score of 0; Activity higher than Con A (10,000 - 700 cpm) but lower than levamisole was +; the same activity with levamisole (22,000 to 900 cpm) was denoted by ++, and those with higher activity than levamisole (27,000 to 1,000 cpm) received +++. The LSA value of all the compounds shown in the previous examples was +++.

Example II

The anti-inflammatory efficacy of aminothiazoles in this patent application was determined by C.A. Swelling of the carrageenan-induced rat paw, as described by Winter et al., In a standard experiment described in Proceedings of the Society for Experimental Biology and, 6,68820

Medicine, Vol. 111, pp. 544 (1962). The compounds were administered in oral forms of their previously disclosed hydrogen halide salts at doses of about 33 mg / kg. The results obtained by this method are presented in the table below as the percentage inhibition of edema by test substances compared to the untreated control group (i.e., administration of an aqueous solution without test compounds):

H - RK

| OF

R., - L ^ LnH-R

S ^ HZ 1 R. R? R 2% anti-edema (33% mg / kg p.o.) 2-tenyl 4-fluorophenyl hydrogen 49 2-phenethyl phenyl hydrogen 47 2-phenethyl phenyl phenyl 48 4-methoxyphenethyl 4-fluorophenyl hydrogen 29

Claims (5)

A process for the preparation of a therapeutically useful compound of formula I '- N R 3 \ J - NH-R, / X wherein is one of the groups -CH 2, "C 2 -Cl 2 -NH-X and - (CH 2 ) Y, X where X is phenyl or monosubstituted phenyl, wherein said substituent may be alkyl of 1-3 carbon atoms, hydroxy, alkoxy of 1-3 carbon atoms, chlorine, bromine or fluorine; Y is thienyl, monosubstituted thienyl, furyl or monosubstituted furyl, said substituent being alkyl having 1-3 carbon atoms, chlorine, bromine or fluorine; m is one or two; R 2 is phenyl, thienyl or monosubstituted phenyl, wherein said substituent may be alkyl of 1-3 carbon atoms, hydroxy, alkoxy of 1-3 carbon atoms, chlorine, bromine and fluorine; and R 2 is hydrogen, alkyl of 1-3 carbon atoms, phenyl or monosubstituted phenyl, wherein said substituent may be alkyl of 1-3 carbon atoms, alkoxy of 1-3 carbon atoms, bromine, chlorine or fluorine, characterized thereof, wherein a suitably substituted N-aralkyl-S „li-X is substituted by the formula R ^ NHCNI ^, or, if desirable, when R R1 is CH ^, SX and X are as previously defined, reacted with an alpha-halogen compound of formula R 2 COCH (Z) R 3, wherein R 2 and R 3 pharmaceutically acceptable acid addition salt. Process according to claim 1, characterized in that the reaction is carried out in an n-alkanol having from 1 to 6 carbon atoms and at a temperature between 50 and 175 ° C.