DK150068B - METHOD OF ANALOGUE FOR THE PREPARATION OF AMINOTHIAZOLES - Google Patents

Description

'150068 i

The invention relates to an analogous method for the preparation of novel substituted amino-thiazoles useful for the relief of inflammatory disorders and as immune regulators.

A number of compounds have been known as being useful as anti-inflammatory agents, e.g. the corticosteroids, phenylbutazone, indomethacin, and various 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-4-carboxamide-1,1-dioxides such as those described in U.S. Pat. 3591584. As a result, these compounds have been of therapeutic value in the treatment of arthritic and other inflammatory disorders such as rheumatoid arthritis. Such disorders have also been treated by the administration of immunoregulatory agents such as levamisole, as described in e.g. "Arthritis Rheumatism" 20, 1445 (1977) and "Lancet" 1, 393 (1976).

In the effort to find novel and improved therapeutic agents for the treatment of these disorders, it has now been found that the novel amino-thiazoles prepared according to the invention have a particularly desirable combination of pharmacological properties, namely that they both act as anti-inflammatory agents. agents and as regulators of the immune responses in the body. As a result, they are of particular value in the treatment of rheumatoid arthritis and other disorders in which inflammation and regulation of the body's immune response are desired.

The synthesis of a limited number of 2-aralkylamino-thiazoles has been described previously, e.g. 2-phenethylethylaminothiazole, Chem. Abs. 59, 1613e (1963), 2-benzylaminothiazole, J.A.C.S., 74, 2272 (1952) and 2-benzyl-. amino-4-phenyl-thiazole, J. Ind. Chem. Soc., 44, 57 (1967).

However, these articles do not describe any pharmacological effect of such compounds.

The substituted aminothiazoles prepared by the process of the invention are useful as anti-inflammatory agents and as regulators of the body's immune response. The compounds of the present invention have 2 150068

the general formula I (see claim 1), or are pharmaceutically acceptable acid addition salts thereof, wherein X

ice

R is -CH, - (CH 2) 2-X 7 -CH 2 -CH 2 -NH-X or - (CH 2 Y,

5 ^ Y

wherein X is phenyl, p-bromophenyl or p-methoxyphenyl, γ 2 is thienyl or furyl, m is 1 or 2, R is phenyl, 3

thienyl, p-fluorophenyl or p-methoxyphenyl, and R

is hydrogen or alkyl having from 1-3 carbon atoms.

Preferred substituents for R are phenyl and p-fluoro-3-phenyl and for R hydrogen.

A preferred group of compounds is that wherein R 1 is - (CH 2) - X. Most preferred are those compounds of 2 wherein X is phenyl or p-methoxyphenyl, R is phenyl or p-fluorophenyl, R is methyl or hydrogen, including 2-phenethylamino-4-phenylthiazole and 2-phenethylamino -5-methyl-4-phenyl-thiazole.

A further group of interest is that wherein R 1 is · (CH 2) -Y, especially where m is 1. Y is thienyl or furyl, especially those compounds where R 1 is phenyl or p-fluorophenyl, and R is hydrogen or methyl.

Yet another group of compounds are those 25 i / x wherein R is -CH: f, with preferred compounds being 23 where X is phenyl, R is phenyl and R is hydrogen.

Another group of compounds of interest are those wherein R 1 is -CH 2 -CH 2 -NH-X, especially those compounds wherein X is phenyl, R 2 is phenyl and R 3 is hydrogen.

The present novel aminothiazoles are prepared according to the invention as set forth in the characterizing part of claim 1.

The starting materials are readily prepared from known and readily available amines of the formula R 2 NH 2 · 150068 3 For example. if the group is - (CH 2) 2 "X, unsubstituted or appropriately substituted phenethylamines are used. Similarly, thenyl or furyl analogs of these amines are used to prepare compounds wherein R" "" is 5 'in - (CH') - Y. Where R is -CH 2, unsubstituted or substituted diphenylmethyxamines are suitably starting materials, whereas when R is -CH 2 -CH 2 -NH-X unsubstituted or substituted n-phenethylene-10 diamines are used. X, Y and m defined as before The starting amine is first converted to hydrochloride or another hydrohalide salt by reaction with hydrogen chloride or other hydrogen halide, generally by bubbling a solution of the amine 15 in an inert organic solvent, typically an ether such as diethyl ether, with the gas at a temperature of approx.

-10 ° C to approx. 10 ° C. The amine hydrohalide salt 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-arophylthiourethane. The reaction is preferably carried out in an inert atmosphere, f-. eg under nitrogen, at a temperature of approx. 110 ° C to 25 approx. 250 ° C, preferably 150 ° C to 200 ° C, e.g. at the reflux temperature of bromobenzene. The turnover will generally be completed from approx. 30 minutes to approx.

6 hours, depending on the temperature used, in general of from approx. 1-3 hours at 150-200 ° C. In the preparation of N-aralkylthiourea as described above, it is generally found that some bis-aralkyl substituted thiourea is formed, but this can be readily separated from the desired monosubstituted product, e.g. by recrystallization. However, it has been found that the reaction of substituted or unsubstituted diphenylmethylamine hydrohalides and ammonium thiocyanate essentially gives the bis-substituted thiourea, although smaller amounts of the monosubstituted compound can be obtained in this reaction and which, after separation, can be used. as a starting material for these 5 novel aminothiazoles. However, it has also been found that the bis-substituted thioureas can be used as starting materials for the formation of the desired diphenylmethylaminothiazoles of the invention, the bis-substituted thiourea being degraded in situ to form the monosubstituted compound.

The appropriate N-aralkylthiourea according to the invention is converted to the desired aminothiazole by reaction with a suitably substituted α-halo carbonyl compound of formula 2 3 2 3 R COCH (Z) R, wherein R and R are as defined previously, and Z is halogen, preferably chlorine or bromine. Eg.

2 3, if R is phenyl and R is hydrogen, α-bromoacetophenone can be used. Other appropriate α-halocarbonyl compounds can be readily selected to obtain the desired R and R substituents in the thiazole ring.

The reaction is carried out in an inert organic solvent, typically an n-alkanol having from 1-6 carbon atoms, preferably in absolute ethanol. Reaction temperatures between ca.

50 and 175 ° C are used, preferably the reflux temperature of the solvent. The reaction is preferably carried out in an inert atmosphere, e.g. under nitrogen or another inert gas. Generally, the turnover is substantially completed from about. 1-15 hours, depending on the temperature used, e.g. of 1-4 hours when using ethanol at reflux temperature.

The desired product is obtained in the form of the hydrohalide salt, and the free base can then be prepared from the salt by ordinary means, e.g. contact with an excess of a base such as an alkali metal hydroxide or carbonate, followed by extraction of the desired free base aminothiazole with a suitable organic solvent, e.g. an ether such as diethyl ether.

5 1500δ8

The pharmaceutically acceptable acid addition salts of the novel aminothiazoles prepared by the present process are readily prepared by contacting the free base with a suitable mineral or organic acid either in aqueous solution or in a suitable organic solvent. The solid salt can then be obtained by precipitation or by evaporation of the solvent. The pharmaceutically acceptable acid addition salts include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, acetate, lactate, maleate, fumarate, oxalate, citrate, tartrate, succinate, gluconate or methane .

The novel aminothiazoles prepared according to the invention and their pharmaceutically acceptable acid addition salts are useful as anti-inflammatory agents and as regulators of the immune response in warm-blooded animals. The combination of anti-inflammatory and anti-inflammatory effects is particularly valuable in the treatment of disorders such as rheumatoid arthritis and other diseases associated with immune failure and accompanied by inflammation. Thus, the present compounds act to reduce the pain and swelling associated with such disorders while regulating the individual's immune response, thereby alleviating the underlying immune disorder by maintaining immune competence.

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 carrier or diluent.

The effect of the compounds of the invention as anti-inflammatory agents can be determined by pharmacological studies, e.g. standard carrageenin-induced rat foot edema using the general procedure described by C.A.Winter et.al. in 6 150068 "Proceedings of the Society of Experimental Biology in Medicine" Volume 111, page 544 (1962). In this test, the anti-inflammatory effect is determined as the percentage inhibition of edema in the hind paw of male albino rats (generally weighing from 150-190 g) in response to a subplantar injection of carra genin. The carrageenin is injected in the form of a 1% aqueous suspension 1 hour after oral administration of the drug, which is usually administered in the form of an aqueous solution or suspension. Edema formation is determined 3 hours after carrageenin injection by comparing the initial volume of the paw receiving the injection and the volume after a 3 hour period. The increase in volume 3 hours after carrageenin injection constitutes the individual reaction. Compounds are considered to be active if the reaction among drug-treated animals (6 rats per group) and the control group, ie. animals receiving the vehicle alone are found to be significant in comparison with results obtained 2o by standard compounds such as acetylsalicylic acid at 100 mg / kg or phenylbutazone at 33 mg / kg both by oral administration.

The immunoregulatory effect of the compounds of this invention can be determined by such pharmacological studies as the in vitro stimulation of lymphocyte formation by mouse typhoid cells grown in the presence of Con-canavalin A (Con A) using VJMerluzzi et al. For general assessment method, see "Journal of Clinical and Experimental Immunology" Volume 22, page 486 30 (L975). In this study, 4 different levels of lymphocyte stimulation assay (LSA) activity were established for the compounds evaluated, namely those that were similar to Con A alone, those that had a greater effect than Con A but less than levamisole, the standard compound 35 in this area, those that had an effect that was equal to levamisole and those that had a greater effect than levamisole. For the purpose of this invention, compounds are considered to be active if they are better than Con-150068 7 canavalin A.

From the subsequent biological tests, it is clear that the compounds prepared by the process according to the invention are surprisingly effective in far better than closely related known compounds both as anti-inflammatory and immune-regulating agents.

The process of the invention is further illustrated by the following examples.

10

Example 1.

a) Phenethylamine (479 g, 3.96 mol, Eastman Scintillation grade) was dissolved in 3500 ml of diethyl ether and the solution cooled to 0 ° C. The stirred solution 15 was bubbled with dry hydrogen chloride gas for 10 minutes and the resulting solid was filtered off. The filtrate was then cooled and the solution was bubbled with hydrogen chloride for 10 minutes and the solid collected.

This procedure was repeated until acidification of the filtrate 20 with dry hydrogen chloride did not lead to precipitation. The combined solid was dried in air and then over phosphorus pentoxide in vacuo to give 514 g (82%) of phenethylamine hydrochloride, m.p. 216-218 ° C.

b) Phenethylamine hydrochloride (257 g, 1.63 mole) and 25 ammonium thiocyanate (123.6 g, 1.63 mole) were heated to 160 ° C in 340 ml of bromobenzene under nitrogen. After 90 minutes of heating, the mixture was cooled to room temperature and then to 5 ° C. This procedure was repeated with an additional portion of 257 g of phenethylamine hydrochloride.

The total solid obtained in the above reaction was stirred in 1.5 L of water and filtered. Recrystallization in isopropyl alcohol gave 261.5 g (45%) of N-phenethylthiourea, m.p. 132-134 ° C.

c) N-phenethylthiourea (225 g, 1.25 mole) and α-bromoacetophenone (250 g, 1.25 mole, Aldrich Chem. Co.) in 1500 ml of absolute ethanol were heated to reflux for 2 1/2 hours under nitrogen. After reducing the solvent volume by 10%, the reaction mixture was cooled to room temperature and then to 0 ° C in an ice bath. The solid was filtered off, redissolved in 2500 ml of absolute ethanol and heated to reflux. The solvent volume was reduced to.

5,000 ml, and the reaction mixture was cooled to 0 ° C. This procedure was repeated and after the second recrystallization, the solid was collected and dried in vacuo over phosphorus pen toxide to give 365 g (81%) of 2-phenethylamino-4-phenylthiazole hydrobromide, m.p. 169-172 ° C.

Analysis: Calculated for C ^H ^ g gS SHBr: C, 56.50; H, 4.74; N, 7.68.

Found: C, 57.36; H, 5.04; N, 7.83.

Example 2.

N-phenethylthiourea (2.0 g, 0.011 mole) and α-bromopropionphenone (2.34 g, 0.011 mole, Aldrich Chem.

CO.) In 10 ml of absolute ethanol was heated to reflux for 90 minutes under nitrogen. The ethanol was then removed in vacuo and excess ethyl acetate was added and the solid filtered and dried over phosphorus pentoxide. Recrystallization in absolute ethanol gave 2.86 g (70%) of 5-methyl-2-phenethylamino-4-phenylthiazole hydrobromide, m.p. 172-175 ° C.

Analysis: Calculated for C ^ gE ^g ^S'HBr: C 57.59; H 5.10; 25 N 7'46

Found: C, 57.67; H, 5.11; N, 7.39.

Example 3

By the procedures of Example 1 30, hydrohalide salts were prepared from the following compounds: R2 150068 9

Salt X Mp. ° 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 HCl p-methoxyphenyl p-fluorophenyl hydrogen 156-158 Example 4.

a) 2-Thenylamine (30 g, 0.265 mol, Fairfield Chemical Co.) was dissolved in 400 ml of diethyl ether and cooled to 0 ° C in an ice bath. The solution was bubbled with dry hydrogen chloride gas for 5 minutes. The resulting solid was filtered and dried over phosphorus pentoxide to give 26.7 g (61%) of 2-thenylamine hydrochloride, m.p. 186-190 ° C.

b) 2-Thenylamine 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 solid washed three times with water. Recrystallization in chloroform and drying over phosphorus pentoxide gave 5.0 g (33%) of N-thenylthiourea, m.p. 99-101 ° C.

Analysis: Calculated for C, 41.83; H, 4.68; N 16.26

Found: C, 41.56; H, 4.58; N, 16.07.

c) N-Thenylthiourea (2.0 g, 0.0116 mol) and α-bromoacetophenone (2.3 g, 0.0116 mol, Aldrich Chem. Co.) in 15 ml of absolute ethanol were heated to reflux temperature for 90 minutes under nitrogen. The reaction mixture was cooled and the ethanol removed in vacuo. By dissolving the residue in hot isopropyl alcohol and diluting with diethyl ether, an oil was formed. The diethyl ether was decanted, the oil dissolved in a small amount of ethanol 35 and cooled. The resulting solid was filtered and dried over phosphorus pentoxide to give 3.20 g of 150068 or 78% of 2-thenylamino-4-phenylthiazole hydrobromide, m.p.

115-118 ° C.

Analysis: Calculated for C 14 H 12 N 2 S 2 * HBr: C 47'58 'H 3.71; N, 7.93.

Found: C, 47.75; H, 3.74; N, 7.90.

Example. 5 N-Thenylthiourea (0.80 g, 0.0046 mol) and 10 α-chloro-p-fluoroacetophenone (0.80 g, 0.0046 mol, Aldrich Chem. Co.) in 11 ml of absolute ethanol were heated at reflux temperature under nitrogen for 90 minutes.

After cooling, the ethanol was removed in vacuo and the solid triturated with ethanol, filtered and vacuum dried over phosphorus pentoxide to give 0.848 g (56%) of 2-thenylamino-4 (p-fluorophenyl) thiazole hydrochloride, m.p. 184-187 ° C.

Analysis: calculated for C 14 H 12 N 2 S 2 F · HCl: C, 51.45; H 3.7Q? N, 8.57.

Found: C, 5.41; H, 3.63; N, 8.39.

Example 6

By the methods of Examples 4 and 5, hydrohalide salts were prepared from the following compounds: R2

Salt R2 R3 Mp. ° C

HBr p-methoxyphenyl hydrogen 154-158 HBr phenyl methyl 179.5-181.5 HCl thienyl hydrogen 137-142 150068 11

Example 7 a) Furfurylamine (25.0 g, 0.257 mol, Pfaltz & Bauer Co.) was dissolved in 1300 ml of diethyl ether and cooled to 0 ° C in an ice bath. The solution was bubbled with dry hydrogen chloride gas until no further precipitation occurred. The solid was filtered and dried in vacuo over phosphorus pentoxide to give 33.46 g (97%) of furfurylamine hydrochloride, m.p. 147-149 ° C.

b) Furfurylamine hydrochloride (33.46 g, 0.250 mol) and 10 ammonium thiocyanate (38.14 g, 0.501 mol) in 71 ml of bromobenzene were heated under nitrogen at reflux for 20 minutes and then cooled to room temperature. The reaction mixture was 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 500 ml of ethyl acetate and 350 ml of water and the aqueous layer was removed. The organic layer was washed with water and dried over sodium sulfate.

After filtration, the organic layer was evaporated to dryness and bromobenzene was removed in vacuo. The resulting solid was bumped into a pestle mortar and the fine particles were stirred in diethyl ether to remove residual bromobenzene. The solid was then filtered, washed with diethyl ether and vacuum dried over phosphorus pentoxide to give 12.06 g (30%) of N-furfuryl thiourea, m.p. 80-91 ° C.

Analysis: Calculated for: C 6 H 9 N 2 OS: C 46.14; H, 5.16; N, 17.93.

Found: C, 46.91; H, 4.90; N, 17.57.

C) N-furfurylthiourea (0.82 g, 0.005 mol) and α-bromopropionphenone (1.07 g, 0.005 mol, Aldrich Chem.

Co.) in 11 ml of absolute ethanol was heated to reflux temperature under nitrogen for 3 hours. After cooling to room temperature, the solvent was removed in 35 vacuo to give a thick brown oil which was triturated with five 35 ml portions of reflux ethyl acetate. The ethyl acetate was reduced in volume to approx. 25 ml and cooled to room temperature. The precipitated solid 12 was filtered, washed with ethyl acetate and vacuum dried over phosphorus pentoxide to give 0.585 g (33%) of 2-furfurylamino-5-methyl-4-phenyl-thiazole hydrobromide, m.p. 150-153 ° C.

Analysis: Calculated for C-HH₂ OSO.HBr: C, 51.29; H, 4.30; N, 7.97.

Found: C, 5, 97; H, 4.47; N, 8.42.

Example 8 10 Using the procedure of Example 7, hydrohalide salts were prepared from the following compound:

Salt R? _._ mp ° C

HBr phenyl hydrogen 123-126 Example 9 a) Diphenylmethylamine (25.0 g, 0.136 mol, Matheson,

Coleman & Bell Co.) was dissolved in 660 ml of diethyl ether and cooled to 0 ° C. The solution was bubbled with dry hydrogen chloride gas for 10 minutes while adding an additional 300 ml of diethyl ether. The precipitate was filtered, washed with diethyl ether and vacuum dried over phosphorus pentoxide to give 28.3 g (95%) of diphenylmethylamine hydrochloride, m.p. 303-310 ° C (decomposition).

b) Diphenylmethylamine hydrochloride (28.3 g, 0.129 mol) and ammonium thiocyanate (9.81 g, 0.129 mol) in 37 ml of bromobenzene were heated at reflux temperature under nitrogen for 3 1/2 hours and then cooled to room temperature. The solid was filtered and triturated twice with 200 ml of water. The solid was then dissolved in 850 ml of ethanol, filtered and evaporated to a volume of ca. 350 ml. After cooling, the solid was filtered, washed with ethanol and vacuum dried over phosphorus pentoxide to give 14.72 g (56%) of Ν, Ν'-bis (di-phenylmethyl) thiourea, m.p. 216-217.5 C.

Analysis: calculated for ^ 27 ^ 24 ^ 2 ^ C 7 ^, 37; H, 5.92; N, 6.86.

Found: C, 79.84; H, 6.05; N, 6.93.

c) Ν, Ν'-bis (diphenylmethyl) thiourea (1.21 g, 0.005 mol) and phenacyl chloride (0.8g, 0.005 mol, Aldrich Chem. Co.) in 11 ml of absolute ethanol were heated to reflux temperature under nitrogen for three hours. hours.

After cooling, the reaction mixture was evaporated to dryness, the resulting oil was mixed with ca. 40 ml of diethyl ether. The solid was filtered, cooled with diethyl ether and vacuum dried over phosphorus pentoxide to give 4-phenyl-2-diphenylmethylaminothiazole hydrobromide, m.p. 166-168 ° C.

Example 10 a) N-Phenylethylenediamine (25 g, 0.184 mol, Aldrich Chem. Co.) was dissolved in diethyl ether, cooled to 0 ° C and the solution was bubbled with dry hydrogen chloride gas until no further precipitation appeared. The filtered solid was dried over phosphorus pentoxide to give 31.2 g (98%) of N-phenylethylenediamine hydrochloride.

B) N-phenylethylenediamine hydrochloride (31.2 g 0.149 mol) and ammonium thiocyanate (11.3 g, 0.149 mol) in 31 ml of bromobenzene were heated to reflux temperature under hydrogen for 2 hours. After cooling, the resulting solid was filtered off and the bromobenzene was removed from the filtrate under vacuum. The resulting solid was stirred in 250 ml of water, filtered and dissolved in hot isopropyl alcohol. After cooling, the solid dust was filtered and dried over phosphorus pentoxide to give 2.8 g (8%) of N- (2'-anilinoethyl) thiourea, m.p. 137-35 140 ° C.

Analysis: Calculated for cg H13 N3 S: C, 55.35; H, 6.71; N, 21.52.

Found: C, 55.64; H, 6.75; N 21.03 14 150068 c) N- (2'-anilinoethyl) thiourea (0.90 g, 0.0046 mol) and α-bromoacetophenone (0.92 g, 0.0046 mol, Aldrich Chem. Co.) in 6 ml of absolute ethanol was heated to reflux under nitrogen for 2 hours. After cooling the reaction mixture, the solvent was removed under vacuum. The resulting oil was dissolved in hot isopropyl alcohol, filtered and cooled. The solid was filtered and dried over phosphorus pentoxide to give 1.25 g (73.5%) of 2- (2'-anilinoethylamino) -4-phenyl-thiazole, m.p. 161-165 ° C.

Analysis: Calculated for C ^ CH NN₂SHBr: C, 54.24; H, 4.82; N, 11.16.

Found: C, 54.51; H, 4.59; N, 11.02.

Example 11

By the methods of Example 10, the hydrohalide salt was prepared from the following compound: r 2 20 R 3 - m-CH 2 -CH 2 -NH-

Salt mp ° C

HBr phenyl methyl 133-136

Biological testing 1

The immunoregulatory effect of the aminothiazoles described in Examples 2, 3, 5,8,9, 3 ° 10 and 11 was assessed by determining their ability to stimulate in vitro the lymphocyte formation of mouse typhoid cells cultured in the presence of Conca navalin. A (Con A) using VJMerluzzi et. et al., as essentially described in "Journal of Clinical and Experimental Immunology" Volume 22, page 486 (1975). The cells were derived from male C57B1 / 6 mice of 6-8 weeks of age from Jackson Laboratories in Bar Harbor, Maine, OSA, and Con A was from Sigma Chemi- 150068 cals in St. Louis, Missouri, USA. Each tissue culture (consisting of 0.10 ml of thymus cell solution, 0.05 ml of Con A standard solution and 0.05 ml of drug solution) was quadrupled and cell formation was measured after 48 5 hours of incubation at 37 ° C by adding each culture 3 H-thymidine (0 , 01 ml of specific activity; 1.9 C / mM from Schwarz-Mann, Inc. of Orangeburg, NY, USA) and then 3 determine the H-thymidine uptake in cellular deoxyribonucleic acid (DNA) by a radioactivity assessment at - * -0 using a liquid scintillation counter. The results thus obtained are expressed quantitatively by the mean number of counts per per minute (cpm) of H-thymidine taken up at the drug concentration with maximum activity in the quadruple tissue cultures. These four-fold assays are performed at eight different drug concentrations in the range of 0.02 to 50 µg / ml. The highest cpm value is used in the declaration system.

On this basis, four different activity levels were established by the present lymphocyte stimulation assay 20 (LSA) and these are defined in the following manner, namely those levels equal to Con A alone (6,000 - 300 cpn) were assigned one negative value or indicated by 0, the which had greater activity than Con A, but less than levamisole (10,000 - 700 cpm) is indicated as +, while those who had activity equal to levamisole (22,000 -900 cpm) are indicated san ++ and those who had an activity greater than levamisole (27,000 - 1,000 cpm) indicated by +++. For the compounds described in the above examples, the LSA activity in each case was +++.

o Π

A similar test of the known related compound 2-phenethylaminothiazole showed that this compound had no immunoregulatory effect.

Biological testing 2

The anti-inflammatory effect of aminothiazoles prepared according to the invention as well as the known compound 2-benzylamino-4-phenyl-thiazole were determined using standard carrageenin-induced rat foot

Claims (4)

150068 edema test according to the method substantially described by C.A. Winter et al., And cited in "Proceedings of the Society for Experimental Biology and Medicine, Vol. 111, page 544 (1962). The compounds were administered orally in the form of their previously mentioned hydrohalide salts at a dose level of 10, 33 or 100 mg / day. The results thus obtained are given in the table below in the form of the percent inhibition of edema obtained by each test compound in comparison with the non-drug-treated control (i.e., aqueous compound without compound): R2 NH-R1 13%% inhibition of edema R_ IT R_ HZ (33 mg / kg, po) 2-thenyl 4-fluorophenyl hydrogen HBr 49 20 2-phenethyl phenyl hydrogen HBr 47 4-methoxy-4-fluoro-hydrogen HBr 29 phenethyl phenyl benzyl phenyl hydrogen HBr 15 * * P y (10 mg / kg, po) 2-phenethyl phenyl hydrogen HBr 23 benzyl phenyl hydrogen HBr 6 * (100 mg / kg, po) 2-phenethyl phenyl hydrogen HBr 51 benzyl phenyl hydrogen HBr 18 * K 2 -benzylamino-4-phenyl-thiazole (known) 1. Analogous Process for the Preparation of Aminothiazoles of General Formula 2 35 R ^ w R3 - ^ -NH-R1 I S