SU843746A3 - Method of preparing aminothiazoles or their acid-additive salts - Google Patents

Abstract

A series of 2-aryl aminothiazoles and the pharmaceutically acceptable acid addition salts thereof having anti- antiflammatory and immune regulant activity are disclosed. Preferred compounds include 2- phenethylamino-4-phenyl-thiazole, 2- phenethylamino-4,5-diphenyl- thiazole, 5-methyl-2-phenethylamino- 4-phenyl-thiazole, 2-thenylamino-4- phenyl-thiazole and 2-thenylamino-4- (p-fluorophenyl)thiazole.

Description

(54) METHOD OF OBTAINING AMINOTHIAZOLES

OR THEIR ACID-ADDITIVE SALTS are reacted with haloacetaldehyde or a compound that forms haloacetaldehyde in the presence of a solvent and an acid acceptor at 20–80 ° С2. . Derivatives of substituted 2-phenylimothiazoline have biologically active properties. The purpose of the invention is to obtain new compounds expanding the arsenal of means of influencing a living organism. The goal is achieved by the fact that in the process for the preparation of compounds of formula 1 or their acid addition salts the cil-halo-carbonyl compound of the formula UI RCOCH (Z) 2 b where Z is a halogen atom, and R and R have the above values, is reacted with N-aralkylthiourea Formulas (III) fi R —NH — C — NH, where R is - (CH, i) riX, —CH ,; CHrLNHX or - (CHj) Y, where X, Y and m have the above values, or with a disubstituted N-aralkylthiourea of the formula (IV) II IR-NH-C.-NH-R where R is the CH group "where X is the above values, in an environment of an innocent organic solvent at elevated temperature and the target product is selected in free form or in the form of an acid additive salt. The n-alkanol with 1-6 carbon atoms is preferably used as an inert organic solvent and heated to 50175CC. . Ethanol is preferably used as the n-alkanol. Preferably, this reaction should be carried out in an inert atmosphere, for example, in a stream of nitrogen or another inert gas. Typically, such a reaction is almost completely completed within about 1-15 hours, depending on the temperature created, for example, about 1-4 when ethanol is used as the solvent and the process is carried out at its boiling point using a reflux condenser. The compound is obtained in the form of a hydrbhalide salt, and the free base can be further obtained from this salt using appropriate means, for example, by bringing this salt into contact with an excess amount of base, in particular an alkali metal oxide or alkali carbonate, followed by extraction basic aminothiazole acceptable organic solvent, for example a simple ether, similar to diethyl ether. The acid addition salts of the aminothiazoles of the formula I can be easily obtained by bringing the free base into contact with the corresponding mineral or organic acid either in an aqueous solution or in an appropriate organic solvent. Then the solid salt can be obtained by precipitation or evaporation of the solvent. Example 1. 479 g of phenethylamine (3.96 mol) are dissolved in 3500 ml of diethyl ether and the solution is cooled to. Then, a dry gaseous hydrogen chloride is passed through a stirred solution for 10 minutes by bubbling, and the precipitated solid material is filtered off. The filtrate is then cooled and hydrogen chloride is bubbled through the solution again for 10 minutes and the solid material collected is collected. This process is then repeated until acidification of the filtrate with dry hydrogen chloride ceases to cause any precipitate to form. The collected solid material is dried in air and then over phosphorus pentoxide in vacuum to obtain 514 g (82%) of phenethylamine hydrochloride with mp. 216-218 ° C. 257 g (1.63 mol) of phenethylamine hydrochloride and 123.6 g (1.63 mol) of ammonium thiocyanate are heated to 160 s in 340 ml of bromobenzene in a stream of nitrogen. After holding at this temperature for 90 minutes, the mixture is cooled to room temperature and then to 5-C. This procedure is repeated using another portion of 257 g of phenethylamine hydrochloride. The combined solid material obtained as a result of the reaction is stirred in 1.5 liters of water and the mass is filtered. By recrystallization from isopropyl alcohol, 261.5 g (45%) of N-phenethyl urea with m.p. 132-134 ° C. Example 2. 225 g (1.25 mol) of N-phenethyl thiourea and 250 g (1.25 mol) of ct -bromoacetophenone in 1500 ml of absolute ethanol are subjected to aging at reflux for 2.5 h in a stream of nitrogen. After reducing the volume of the solvent by 10%, the reaction mixture is cooled to room temperature, and then 0 ° C in an ice bath. The solid material is filtered off, re-dissolved in 2500 ml of absolute alcohol and heated to temperature. The mixture is heated under reflux. Then the volume of solvent is reduced to 2000 ml. and the reaction mixture is cooled to. This process is then repeated, and after the second recrystallization, the solid material is collected and dried under vacuum over phosphorus pentoxide to obtain 365 g (81%) of 2-phenethylamino-4-phenylthiazole Hydrobromide with mp. 169-1720С.

Found,%: C 57.35; H 5.04;

7.83.

N С, - Н, .HBr. Calculated®,%: C 56.50 H 7.68}

4.74.

N

Example 3. 140 g of N.-phenethyl thiourea (0.779 mol) and 225 g of j (0.82 mol) of desyl bromide in 833 ml of absolute ethanol are subjected to a boiling temperature using the back of the fridge for 2 hours in a stream of nitrogen, and during the course of 2 hours. for this reaction, an additional 300 ml of absolute alcohol is added. Next, the reaction mixture is cooled to, the precipitated solid material is filtered off, recrystallized from absolute alcohol and dried ngsch

Found,%: C 62.62; H 4.82; N 6.48.

Sdz H oN S-HBr

Calculated,%: C.63,14; H 4.82; N 6.40.

Example 4. 2.0 g (0.011 mol) of N-phenethyl thiourea and 2.34 g (0.011 mol) of d-bromopropiophenone in 10 ml of absolute alcohol are kept at the boiling point using a reflux condenser in

0 for 90 minutes in a stream of nitrogen. The ethanol is then removed in vacuo, an excess of ethyl acetate is added, the solid material is filtered and dried over phosphorus pentoxide. 5, by recrystallization from absolute alcohol, 2.86 g (70%) of 5-methyl-2-phenethylamino-4-phenylthiazole hydrobromide with mp. 1721750c.

Found,%: C 57.67; H 5.11;

0 N, 7.39.

CiaH eNiSrHBr

Calculated,% C 57.59; H 5, N 7.46.

For example, 5. In a similar manner to Examples 1 and 2, a guide is obtained) the 1-halgen salts of the following compounds

Also

Hydrochloride Example 6. 90 g (0.6 mol) of benzylamine hydrochloride and 50 g of 1 (0.66 mol) of ammonium thiocyanate in 130 ml of bromobenzene were subjected (kept for 20 min to obtain a yellow-white suspension. After cooling, the filtered solid the material is washed three times with water and three times with isopropyl alcohol. As a result of recrystallization from isopropyl alcohol and drying over pentoxide of phosphorus, 38.26 g are obtained.

149-150,5

Methyl

201-205 Phenyl

156-158 Hydrogen atom (38%) H-benzylthiouchenins with m.p. 160-1630С. Example 7. 2.0 g of N-benzylthiomochevine (0.012 mol) and 2.07 g (0.012 mol) of o-chloro-p-fluoroacetophenone in 15 ml of absolute ethanol are refluxed for 2 hours in a stream of nitrogen. After cooling, the filtered solid was washed with diethyl ether and dried with phosphorus pentoxide to obtain 3.47 g

(91%) 2-benzylamino-4- (p-fluorophenyl) -thiaEOLH hydrochloride with m.p. 1921950s.

Found,%: C 59.64; H 4.38; N 8.62.

C.fc H ,,, NnSF. HCI

Calculated,%: C 59.90; H 4.40; N 8.73.

Example 9. 30 g (0.265 mol) of 2-tyenylamine are dissolved in 400 ml of diethyl ether and cooled to OC in an ice bath. Dry hydrogen chloride gas is bubbled through this solution for 5 minutes. The resulting solid material is filtered and dried over phosphorus pentoxide to give 26.7 g (61%) of 2-thienylaminendndrochloride, m.p. 186-190®С.

13.35 g (0.089 mol) of 2-thienylamine hydrochloride and 7.4 g (0.089 mol of ammonium thiocyanate in 20 ml of bromobenzene are kept at boiling temperature d under reflux for 90 minutes. Then the reaction mixture is cooled and the filtered solid is washed three times with water As a result of recrystallization of chloroform 3 and drying over phosphorus pentaoxide, 5.0 g (33%) of M-thienylsporustine are obtained with mp 99-101 ° C

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

CHI 1S

Calculated,%: C, 41.83; H 4.68;

16.26.

N

Example 10. 2.0 g (0,0116 mol) of M-thienylthiourea and

Example 8 Analogously to Examples 6 and 7, the hydrohalide salts of the following compounds are prepared.

P

L

J NH-CHj-X

syphenyl

2.3 g (0.0166 mol) of cvi -bromoacetophenone in 15 ml of absolute ethanol is maintained at reflux for 90 minutes under a stream of nitrogen. The reaction mixture is cooled and ethanol is removed in vacuo. After the residue is dissolved in hot isopropyl alcohol and the solution is diluted with diethyl ether, an oil-like product is formed. Then the diethyl ether is decanted, the oil is dissolved in a small amount of ethanol and cooled. The solid that forms is filtered and dried over phosphorus pentoxide to give 3.20 g (78%) of 2-thienylamino-4-phenylthiazole hydrobromide, mp. 115-118s.

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

 eleven

Calculated,%: C, 47.58; H 3.71;

7.93.

N

Example 11: 0.80 g (0.0046 mol) of N-thienyl thiourea and O, 80 g (0.0046 mol) of CX- - lor-p-fluoroacetophenone - in 11 ml of absolute ethanol is kept at the boiling point under reflux in a stream of nitrogen for 90 minutes After

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

Naatseno,%: C 51.41; H 3.63; N 8.39,

WITH,. H, NASgF-.HCI

 , In isleno,%: C, 51.45; H 3.70; N 8.57. Example 13.25.0 g (0.257 mol) Furfurylamine is dissolved in 1300 ml of diethyl ether and the solution is cooled to an ice bath. Through this solution, gaseous dry hydrogen chloride is bubbled through until this rtop, the precipitate is completely stopped. The mothers solid is filtered off and dried in vacuum over phosphorus pentoxide to obtain 33.46 g (97%) of furfurylamine hydrochloride with mp. 147-149 with 33.46 g (0.250 mol) of furfurilamine hydrochloride and 38.14 g (0.501 mol) of ammonium thiocyanate in 71 ml of bromobenzene are maintained at reflux in a stream of nitrogen for 20 minutes and then cooled to room temperature . This reaction mixture is mixed with a solution of 125 ml of water and 100 ml of ethyl acetate and left at room temperature overnight. The mixture is then diluted to give 500 ml of ethyl acetate and 350 ml of water and the aqueous layer is separated. The organic layer is washed with water and dried over sodium sulfate. After filtration, the organic layer is evaporated to dryness, and the benzene is removed in vacuo. The resulting solid material is crushed in a mortar, then tblJ: and fine particles are mixed in diethyl ether to remove residual bromobenzene. Next, the solid material is filtered off, washed with diethyl ether and dried in vacuum over phosphorus pentoxide to obtain 12.06 g (30%) of N-furfuri thiourea with m.p. 80-91 C. Found,%: C 46, 91; H 4.90; N 17.57. Calculated,%: C 46.14; H 5.16; .N 17.93. Example 14. 0.82 g (p, 005 mol) N -furfurylthiourea and Example 12. Analogously to Examples 10 and 11, hydrohalgenic salts of the following compounds are obtained

DG5-mn-sngo

For example, from 1.07 g (0.005 mol) of oL-bromopropiophenone in 11 ml of absolute ethanol Vg are kept at reflux temperature in a stream of nitrogen for 3 hours. After cooling to room temperature, the solvent is removed in vacuo to obtain a thick brown oil, which is triturated using five portions of 35 ml of ethyl acetate to be heated under reflux. The volume of ethyl acetate is then reduced to approximately 25 ml and the mixture is cooled to room temperature. The precipitated solid material is filtered off, washed with ethyl acetate and dried under vacuum over phosphorus pentoxide to give 0.585 g (33%) of 2-furfurylamino-5-methyl-4-phenylthiazole hydrobromide, m.p. 150-15З C. Found,%: C 51.97; H 4.47; N 8.42. C, 5 H, /, Calculated,%: C 51.29, H 4.30; N7.97. Example 15. Analogously to Examples 13 and 14, the hydrohalide salts of the following compounds 192-194 are prepared. Hydro-phenyl bromide Example 16. 25.0 g (0.136 mol) of diphenylmethylsmina is dissolved in 660 ml of diethyl ether and the solution is cooled to. Then, for 10 minutes, dry hydrogen chloride gas was bubbled through this solution, and during this period an additional 30 ml of diethyl ether was added to the mixture. The precipitate formed is filtered off, washed with DETHYLETHYL ETHER and UHT CONNECTION in vacuum over phosphorus pentoxide to give 28.3 g (95%) of diphenylmethyl amine hydrochloride, m.pl. ZOZ-ZYu S (with decomposition). 28.3 g (0.129 mol) of diphenylmethyl amine hydrochloride and 9.81 g (0.129 mol) of ammonium thiocyanate in 37 ml of bromobenzene are maintained at reflux in a stream of nitrogen for 3.5 hours and then cooled to room temperature. The solid material is filtered and triturated twice with 200 ml portions of water. The solid material is then dissolved in 850 ml of ethanol, the solution is filtered and evaporated in vacuo to a volume of approximately 350 ml. After cooling, the solid material is filtered off, washed with ethanol and evaporated in vacuo over phosphorus pentoxide to obtain 14.72 g (56%) of N, M-bis (diphenylmethyl) -thiourea with m.p. 216-217, Found,%: C 79.84, H 6.05; M 6.93. Cg7 NfjS: Calculated,%: C 79.37; H 5.92; N 6.86. PRI me R I 17. 1.21 g (0.05 mol) of N, K-bis- (diphenylmethyl) thiourea and 1.21 g (0.005 mol) of desyl chloride in 11 ml of absolute ethanol are maintained at boiling points Reverse cold water in a stream of nitrogen for 3 hours. After cooling, the reaction mixture is evaporated to dryness, and the resulting oil is mixed with approximately 40 ml of diethyl ether. The solid material is filtered, cooled with diethyl ether and dried under vacuum over phosphorus pentoxide with a yield of 1.01 g (75%) of 4,5-diphenyl-2-diphenylmethylaminothiazole hydrochloride with mp. 195-198 p. Found,%: C 73,12; H 5.28; N. HciieHO,%: C 73.91; H 5.09; N 6.16. Example 18. Similarly, when frames 16 and 17, 4-phenyl-2-diphenylmethylaminothiazole hydrobromide is obtained with m.p. 166-168C. Example 19. 25 g (0.184 mo of N-phenylethylenediamine is dissolved in diethyl ether, the solution is cooled to and barried through dry hydrogen chloride gas until the precipitate forms. The filtered dry material is dried over phosphorus pentoxide to obtain 31.2 g (98%) of N-phenylethylene diamine hydrochloride, 31.2 g (0.149 mol) of N-phenylethylene diamine hydrochloride and 11.3 g (0.149 mol) of ammonium thiocyanate in 31 ml of bromobenzene are kept at the boiling point under reflux in a stream of nitrogen in for 2 hours after oh The solid formed is filtered off and the bromobenzene is removed from the filtrate in vacuo. Then the solid is stirred in 250 ml of water, filtered and dissolved in hot isopropyl alcohol. After cooling, the solid material precipitated is filtered, washed and dried over tioxidum phosphorus to obtain 2.8 g (8%) of N- (2-anilinoethyl) thiourea with a melting point of 137140 ° C. Found: C 55.64; H 6.75; 21.03. 1 NO, S Calc.,%: C 55.35; H 6.71; 21.52. Example 20: 0.90 g (0.0046 mol) of N- (2-anilinoethyl) thiourea and 0.92 g (0.0046 mol) of l-bromoacetoacetate in 6 ml of absolute ethanol are kept at reflux temperature nitrogen for 2 hours. After cooling the reaction mixture, the solvent is removed in vacuo. The resulting oil is dissolved in hot isopropyl alcohol, the solution is filtered and cooled. The solid material is filtered and dried over phosphorus pentoxide to give 1.25 g (73.5%) of 2- (2-anilinoethylamino) -4-phenylthiazole, mp. 161-165p. Found,%: C 54.51; H 4.59; 11.02. With „N-S. NVG Calculated,%: C 54.24; H 4.82; 11.16. Example 21. Analogously to Examples 19 and 20, the hydrohalide salts of the following compounds V — N are prepared. CHj-CHj-NH Hydrochloride-Phenyl Phenyl 139-143 Hydrobro-Phenyl Methyl 133-136, Example 22, Immunoregulatory activity of the aminothiazoles described in examples 2-5.7 / 8,11,12,14 15, 17,18,20 and 21, are assessed by determining their ability to stimulate in vitro lymphocyte proliferation of the thymus cells of mice cultured in the presence of Concanavalin A (Kon.A), by carrying out the procedure of V.J. Merlu qi and others. These cells were taken from a male C57B1 / 6 adult mouse aged 6-8 weeks. Each cell culture, consisting of 0.10 ml of an initial solution of thymus gland cells, 0.05 ml of an initial solution of Kon.A and 0.05 ml of a medicinal solution, was quadrupled, and cell proliferation was measured after 48 h of the incubation period by means of pulsation of the culture using Dyne 10,01ml specific activity. 1.9 C / tM). The insertion of H-thymidine into the cellular deoxyribonucleic acid (DNA) is then determined by evaluating radioactivity using a liquid scintillation counter. The results thus obtained are quantitatively expressed as the average number of units per minute (EV) of H-thymidine introduced at a given level of a drug with maximal activity by quadrupling the cell cultures. These determinations are carried out by quadrupling at eight different concentrations of drugs in the range of 0.0250 µg / ml. The maximum values obtained are used in the evaluation system. Based on this, in this test, lymphocyte stimulation (sludge) receives four different levels of activity, with each H-type last determined according to the following, namely, those levels that correspond to the level of only one Con. A (6000 t300 evm), denoted as negative or zero, which are superior in activity (10,000 i +, 700 evm) Kon.A, but inferior to levamisole, denoted as +, which correspond to the activity of levamisole (22000 i 900 evm), denoted ++ , while those levels that are superior d t activity of levamisole are denoted +++. The activity of ILS for the compounds described in the above examples, in each case, corresponds to a score of +++. Example 23. The anti-inflammatory activity of the aminothiazoles of formula 1 was determined using a standard test with carrageenin-induced rat paw edema. These compounds are administered to animals through the mouth in the form of their above-described hydrohalide salts at a dosage of 33 mg / kg. The results obtained in this case are expressed as the degree of inhibition, in percent, of the process of formation of edema, achieved using each of the test compounds, in comparison with the edema that occurs in the control individual that did not receive the drug, i.e. received an aqueous solution that does not contain any of these compounds. The table shows the anti-inflammatory activity of aminothiazoles of formula 1 U:

The aminothiaols of formula 1 and their acid addition salts can thus be used as anti-inflammatory agents and with the help of regulating the immune response in the body of warm-blooded animals. The combination of anti-inflammatory activity and immunoregulatory activity is especially valuable in the treatment of diseases such as rheumatoid arthritis, as well as other diseases associated with immune deficiency and accompanied by inflammation.

Compounds 1 can be administered to a patient in need of treatment in the usual way, in particular through the mouth or paratheral, with acceptable dosages being in the range of about 0.10-50 mg / kg of the patient's live weight, preferably about 0.1515 mg / kg of live weight per day. However, the optimal dosage for the individual patient being treated is determined by the person responsible for the treatment, and usually to determine the most acceptable dose, start with reduced dosages which are then gradually increased. The dose itself will vary depending on the compound used and on the patient being treated.

The compounds of formula I can be used in pharmaceutical formulations containing these compounds or their acid addition salts in combination with a pharmaceutically acceptable excipient or diluent. The class of pharmaceutically acceptable excipients includes solid e inert fillers or diluents and sterile aqueous or organic solutions. The active compound is included in such pharmaceutical compositions in amounts sufficient to achieve a dosage that is within the above ranges. For example, for oral administration, compounds of the formula I can be used in combination with an appropriate solid or liquid filler or diluent in the manufacture of capsules f tablets, powders, syrups, solutions, suspensions, and the like. Pharmaceutical compositions may include IB se, also additional components, in particular flavoring agents, sweeteners, bases for the preparation of drugs, and the like. For parenteral administration, the compounds of the formula I can be used in combination with sterile aqueous or organic media, allowing you to prepare solutions or suspensions for injection. So, for example, with this

Sesame and peanut butter, propylene glycol aqueous solution, etc. can be used as a target. as well as: aqueous solutions of water-soluble acid addition salts of the compounds of formula I. Injection solutions prepared in this way can be administered intravenously, intraperitoneally, subcutaneously or intravenously / mashechno, moreover, they should be administered intravenously and intraperitoneally. For the treatment of local inflammations: 1n the compounds of formula I can be used by applying to the site of inflammation in the form of ointments, pastes creams, etc. in accordance with usually pharmaceutical practice.

The activity of the proposed compounds as anti-inflammatory agents can be determined by pharmacological tests, for example, a standard test by administering carrageenin, which causes swelling of rat paws, in accordance with the usual procedure described by K.A., Winter et al. During this test, the anti-inflammatory activity is determined according to the degree of inhibition, in percent, of the formation of edema on the hind paw of male white rats (usually weighing about 150-190 g), caused by the foot of carrageenin injection. Carrageenin is injected using a 1% aqueous suspension 1 hour after oral administration to the animals ;. drug, which is usually given to animals in the form of an aqueous solution or suspension. The degree of swelling is then determined after 3 h after injection of carragenin by comparing the initial volume of the foot into which carrageumine is injected with its volume after 3 hours. An increase in the volume of the foot after 3 hours after injection of carragenin constitutes an individual reaction . A particular compound is active if the difference is between the responses of the animals given the drug (6 animals per group) and the animals of the control group, i.e. animals whose input: only one basis | for the preparation of a drug is significant compared with the results achieved using standard compounds similar to acetylsalicylic acid at a dosage of 100 mg / kg or phenylbutazone at a dosage of 33 mg / kg (dosage for Both compounds are indicated for oral administration).

The immunoregulatory activity of the proposed compounds can be determined using such pharmacological tests as stimulating the in vitro lymphocytic proliferation of cells of the myochene thymus gland cultured in the presence of Koncanavalin A (Kon. A) with the usual evaluation procedure described by VJ Merluzzi and others. The process of such a study is carried out by testing at four different levels of lymphocyte stimulation (sludge) to determine the activity of the compounds of formula 1, more specifically setting Compounds whose activity is equal to the activity of only Kon.A alone exceeds the activity of Kon.A, but less than the activity of levamisole, on the activity of levamieol, as well as those compounds whose activity exceeds that of levamisole. Those compounds whose activity exceeds the activity of Concanavalin A are considered active for this purpose (Example 22).

Claims (3)

1. A process for the preparation of aminothiazoles of the general formula (I). “. Tj2gi X Jun-r „9g de R - -CH - (CH2) 2X, X : sn. NHX or CHj CH (j but de X is phenyl or mono () alkoxyphenyl; thienyl or furyl, Y is an integer equal to 1 or 2 m R is phenyl, thienyl, or monosubstituted phenyl, wherein said substituent is alkyl with 13 carbon atoms, hydroxy group, alkoxy group with 1-3 carbon atoms, chlorine, bromine or fluorine atom; Rb is a hydrogen atom, alkyl with 13 carbon atoms or phenyl. 25 where fC is the -CH group where X is as defined above, in an inert organic solvent at elevated temperature and the desired product is isolated in free form or in the form of an acid addition salt. . 2. Method POP1, characterized in that, as 5 Inert organic solvent using n-alkanol with 1-6 carbon atoms and heating lead to 501750s. 3. A method according to claim 2, characterized in that ethanol is used as the n-alkanol. Sources of information taken into account in the examination 1. Heterocyclic compounds. Ed. P. Elderfilda.M., Inost5 ranna literature, 1961, v.5, with. 456-457. 2.Patent UK  1505020, class C 07 D 277/42, published 03/22/78. 0 or their acid addition salts, characterized in that the 6-halocarboiyl compound of formula (II) (Z) R where Z is a halogen atom, and R and R have the above values, are reacted with an N-aralkyl thiourea of formula (III) B - NH-C-11H | where R is - (CU „X, -CHqCH-NHX or (CHa) Y, where X, Y and m are as defined above, or with a disubstituted N-aralkylthiourea of the formula (IV) S R - 8H-C-HH-R lV