KR820000848B1 - Pocess for preparing amino-thiazole derivatives - Google Patents

Abstract

The thiazoles I ≮R1 = -CH(X)X1, -(CH2)n-X, -CH2-CH2-NH-X,-(CH2)mY; X = Ph, C1-3 alkyl, OH, C1, Br, substituted phenyl; Y = thienyl, furyl; n,m = 1, 2; R2 = Ph, p-fluorophenyl; R3 =H, Ph≉and their salts were prepd. for use as antiinflammatory agents and immunoregulators. Thus, 1.25 mol N-phenethyl thiourea and 1.25 mol α-bromoacetophenone were refluxed in 1500 m1 anhydrous EtOH for 2.5 hr to give 81% 2-phenethylamino-4-phenylthiazoleHBr(m.p. 169-172≰C).

Description

Manufacturing method of amino thiazoles

The present invention relates to substituted amino thiazole derivatives of the following structural formula (I) useful as anti-inflammatory agents and immunomodulators, and to methods for preparing pharmaceutically harmless acid addition salts thereof.

In the above structural formula

, ―(CH₂)n―X, ―CH₂―CH₂――NH―X, ―(CH₂)mY로부터 선택된 그룹이고, X는 페닐 또는 탄소수 1 내지 3의 알킬, 하이드록시, 탄소수 1 내지 3의 알콕시, 클로로, 브로모, 플루오로에 의해 치환된 페닐이며, Y는 티에닐, 1치환된 티에닐, 푸릴, 1치환된 푸틸이며 (여기서 치환체는 탄소수 1 내지 3의 알킬, 염소, 브롬, 불소이다), n 및 m 은 각각 1 내지 2의 정수이고, R₂는 페닐, 티에닐, 또는 탄소수 1 내지 3의 알킬, 하이도록시, 탄소수 1 내지 3의 알콜시 염소, 브롬, 불소에 의해 1치환된 페닐이고, R₃는 수소, 탄소수 1 내지 3의 알킬, 페닐 또는 탄소수 1 내지 3의 알킬, 탄소수 1 내지 3의 알콕시, 브롬, 염소 및 불소에 의해 1치환된 페닐로부터 선택된 그룹이며, 단 X와 R₂가 페닐이고, R₃가 수소일때는 n은 1이 아니다.R ₁ is

, — (CH ₂ ) n —X, —CH ₂ —CH ₂ ——NH—X, — (CH ₂ ) mY, and X is phenyl or alkyl having 1 to 3 carbon atoms, hydroxy, and having 1 to 3 carbon atoms. Phenyl substituted by alkoxy, chloro, bromo, fluoro of 3, Y is thienyl, monosubstituted thienyl, furyl, monosubstituted putyl (wherein the substituents are alkyl having 1 to 3 carbon atoms, chlorine, bromine N and m are each an integer of 1 to 2, and R ₂ is phenyl, thienyl, or alkyl having 1 to 3 carbon atoms, hygiene, alcohol having 1 to 3 carbon atoms, chlorine, bromine and fluorine. Is phenyl monosubstituted by R ₃ is a group selected from hydrogen, alkyl of 1 to 3 carbon atoms, phenyl or alkyl of 1 to 3 carbon atoms, phenyl monosubstituted by alkoxy, bromine, chlorine and fluorine of 1 to 3 carbon atoms. Provided that when X and R ₂ are phenyl and R ₃ is hydrogen, n is not 1.

As R _2, phenyl and p-fluorophenyl are preferable, and R ₃ is preferably hydrogen and phenyl.

Many compounds that are useful as anti-inflammatory agents are known. For example, corticosteroids, phenylbutazone, indomethacin, various kinds of 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-4carboxamide-1, 1-dioxides (US Pat. No. 3,591,584). Therefore, these compounds are useful for the treatment of arthritis and other inflammatory diseases such as rheumatoid arthritis. These symptoms can also be treated with the use of immunomodulators such as levamissole. Arthritis Rheumatism, 20 , 1445 (1977) and Lancet, 1,393 (1976).

As a result of efforts to obtain newer and more effective compounds for the treatment of these diseases, the present invention has found novel aminothiazoles having anti-inflammatory and modulating immune responses.

Several methods of synthesizing 2-aralkyl-animothiazoles have been introduced in the literature, for example 2-phenethylamino thiazole is disclosed in Chem, Abs, 59 , 1613 (1963); 2-benzylaminothiazole is disclosed in JACS, 74 , 2272 (1952); 2-benzylamino-4-phenyl-thiazole is described in J. Ind. Chem. Soc. 44 , 57 (1967). However, the pharmacological effects of these compounds have not been published.

Preferred are compounds wherein R ₁ is — (CH ₂ ) n —X, in particular n = 2, in particular X is phenyl or p-methoxyphenyl, R ₂ is phenyl, p-fluorophenyl, R ₃ is phenyl, methyl 2-phenethyl amino-4-phenyl-thiazole, 2-phenethyl amino-4.5-diphenyl-thiazole and 2-phenethyl amino-5-methyl-4-phenyl-thiazole which are hydrogen, and the like.

More preferred groups are compounds in which R ₁ is — (CH ₂ ) mY, in particular m = 1. Suitable groups for Y are thienyl, furyl, in particular R ₂ is phenyl or p-fluorophenyl, R ₃ is hydrogen, Methyl and phenyl.

이고, X는 페닐, R₂는 페닐, R₃는 수소 또는 페닐인 화합물이다.Even more preferred group is R ₁

And X is phenyl, R ₂ is phenyl, R ₃ is hydrogen or phenyl.

Another preferred group is a compound wherein R ₁ is -CH ₂ -CH ₂ -NH-X, in particular X is phenyl, R ₂ is phenyl, and R ₃ is hydrogen.

The present invention also encompasses pharmaceutical compositions comprising novel substituted aminothiazoles or acid addition salts thereof together with pharmaceutically toxic carriers and diluents. The pharmaceutical composition preferably contains the abovementioned preferred compounds, in particular 2-phenethylamino-4-phenyl, thiazole, 2-phenylamino-4- (p-fluorophenyl) -thiazole, 2- ( p-methoxyphenethyl amino) -4- (p-fluorophenyl) -thiazole or pharmaceutically harmless acid addition salt. A method of treating rheumatoid arthritis in a host is to administer to the host an effective amount of the novel amino thiazole according to the invention. Particularly the abovementioned preferred compounds, 2-phenethyl amino-4-phenyl-thiazole, 2- (p-methoxyphenethylamino) -4- (p-fluorophenyl) -thiazole or 2-phenylamino- 4- (p-fluorophenyl) -thiazole or their pharmaceutically toxic acid addition salts are administered.

(R₁은 상기 정의와 같다)의 치환된 N-아릴티오우레아로부터 제조하는데,

는 R₁NH₂의 아민으로부터 쉽게 제조할 수 있다. 예를 들어 R₁이 -(CH₂)m-X인 경우에는 비치환되거나 적당히 치환된 벤질아민(n-1) 및 페네틸아민(n=2)가 사용된다. 이들 아민의 상응하는 테닐 또는 푸릴 유도체는 R₁이-(CH₂)m-Y인 화합물 제조에 사용된다.The novel aminothiazoles according to the present invention have a structural formula

Prepared from substituted N-arylthioureas (R ₁ is as defined above),

Can be easily prepared from the amine of R ₁ NH ₂ . For example, when R ₁ is-(CH ₂ ) mX, unsubstituted or appropriately substituted benzylamine (n-1) and phenethylamine (n = 2) are used. The corresponding tenyl or furyl derivatives of these amines are used to prepare compounds wherein R ₁ is- (CH ₂ ) mY.

인 경우에는 비치환되거나 치환된 디페닐메틸아민이 출발물질로 적합하나, R₁이 -CH₂-NH-Y 인 경우에는 비치환되거나 치환된 n-페네틸렌 디아민이 사용된다.R ₁ is

In the case of, unsubstituted or substituted diphenylmethylamine is suitable as starting material, but when R ₁ is -CH ₂ -NH-Y, unsubstituted or substituted n-phenethylylene diamine is used.

X, Y, n and m are as described above.

Starting material amines are first converted into hydrochloride or other halogenated hydrochloride salts by reacting hydrogen chloride or other hydrogen halides in an amine solution dissolved in an inert solvent (e.g., ether such as diethyl ether) at a temperature of -10 ° C to 10 ° C. Switch. The amine halide hydrochloride is then reacted with an alkali metal thiocyanate such as ammonium thiocyanate and potassium thiocyanate in an inert organic solvent (e.g. bromobenzene, chlorobenzene, xylene, etc.) to the desired N-aralkylthiourea. Get

The reaction is carried out in bromobenzene in which nitrogen or the like is in a inert atmosphere at a temperature of 110 ° to 250 ° C., in particular 150 ° to 200 ° C. (eg reflux temperature). The reaction is completed in 30 minutes to 6 hours depending on the reaction temperature used. For example, the reaction is completed in 1 to 3 hours at 150 to 200 ° C.

When the N-aralkyl thiourea is prepared as above, it can be seen that some bis-aralkyl substituted thiourea is formed, which can be easily separated from the desired monosubstituted product by methods such as recrystallization.

However, in the present invention, even if a smaller amount of monosubstituted compound is obtained and separated and used as a reactant of the novel aminothiazole of the present invention, the substituted or unsubstituted diphenylmethylamine hydrochloride and ammonium thiocyanate The reaction result is mainly produced by bis-substituted thiourea.

However, when forming the desired diphenylmethyl-amino thiazole of the present invention, bis-substituted thiourea is used as a starting material and bis-substituted thiourea decomposes itself to release monosubstituted compounds.

A suitable N-aralkyl thiourea is converted to the desired aminothiazole by reaction with a suitably substituted α-halo ketone or aldehyde of the structure R ₂ COCH (Z) R ₃ . Provided that R ₂ and R ₃ are as described above and Z is halogen, in particular chlorine or bromine.

For example, α-bromo acetophenone is used when R ₂ is phenyl and R ₃ is hydrogen, whereas decyl such as 2-chloro-2-phenyl-acetophenone when R ₂ and R ₃ are both phenyl Halides are suitable.

Other suitable α-haloketones or aldehydes are readily selected to introduce the desired R ₂ and R ₃ substituents into the thiazole ring. This reaction is carried out with n-alkanes having 1 to 6 carbon atoms, particularly in an inert organic solvent such as anhydrous ethanol. The reaction temperature is from 50 ° to 175 ° C., especially the reflux temperature of the solvent is used.

The reaction is carried out in nitrogen or another inert atmosphere and the reaction is complete in 1 to 15 hours depending on the reaction temperature used. For example, running at reflux with ethanol takes 1 to 4 hours.

The desired compound is obtained in the form of a hydrochloride, which can be contacted with an excess of base such as an alkali metal hydroxide or carbonate to extract the free base amino thiazole with a suitable organic solvent (e.g. diethyl ether) to obtain an organic base. .

Pharmaceutically toxic acid addition salts are obtained by contacting the free base with an appropriate inorganic or organic acid in aqueous solution or other suitable solvent. It is precipitated or the solvent is evaporated to give a solid salt.

Hydrochloride, hydrobromide, iodide hydrochloride, sulfate, sulfite, nitrate, phosphate, acetate lactate, maleate, fumarate, oxalate, citrate, tartrate, succinate Ate, gluconate, methanesulfonate, and the like.

The novel amino thiazoles of the present invention and their pharmaceutically harmless acid addition salts are used as anti-inflammatory agents and modulators of immune responses in warm-blooded animals. The combination of anti-inflammatory and immunomodulatory effects is particularly effective in treating diseases involving inflammation associated with rheumatoid arthritis and immunodeficiency. Therefore, the compound according to the present invention reduces pain and edema and at the same time relieves immune disease by regulating the immune response of the treated animal to release immunity.

The compounds according to the invention are administered orally or parenterally to a subject in need thereof in an amount of 0.10 to 50 mg / kg / dey, in particular an amount of 0.15 to 15 mg / kg / day. However, the optimal dose varies depending on the individual subject, and in general, a small dose is initially administered and gradually increased to obtain an optimal dose. This varies depending on the particular drug used and the subject to be treated.

The present compounds can be prepared by mixing the present compounds or their pharmaceutically toxic acid addition salts with pharmaceutically toxic carriers or diluents. Suitable pharmaceutical carriers include inert solid weights, diluents, sterile water, organic solutions and the like. The active compounds are present in this composition in effective doses in the above-mentioned ranges.

Therefore, for oral administration, it is mixed with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical composition may contain additives such as perfumes, sweeteners, excipients and the like. For parenteral administration, the compound is dissolved in sterile water or an organic solvent to form an injectable solution or suspension. For example, there is not only an amino thiazole solution dissolved in sesame oil, peanut oil, aqueous propylene glycol, etc., but also an aqueous solution of a water-soluble nontoxic salt of the present compound. The injection solution thus prepared is intravenous, intraperitoneal injection. It can be used for subcutaneous injection and intramuscular injection. It is good for intravenous injection and intraperitoneal injection. For the purpose of topical treatment, the compound is used topically in the form of ointments, creams, paspa, etc.

The effect of the compound as an anti-inflammatory agent can be demonstrated by the following reference, "Carrageenan-induced edema test of rats." [See CA Winter et . al ., see Proceedings fo the Soicty of Experimental Biology in Medicine, Volme 111 page 544 (1962)]

In this test, the anti-inflammatory effect was measured in% of the degree of inhibition of edema formed by injection of carrageenin into the back of the albino male's hind paw. (Rat: 150-190 g).

One hour after oral administration of the drug in the form of an aqueous solution or suspension, a 1% suspension of carrageenin is injected.

The formation of edema is analyzed by comparing the size of the first plantar injection 3 hours after carrageenan injection and the size after 3 hours. It depends on the individual response of the increase in edema after 3 hours. If the reaction between drug-treated animals (6 per group) and the control group (excipients only) was compared with oral administration of 100 mg / 1 kg of acetyl salicylic acid or 33 mg / kg of phenylbutazone If you think you are excellent, you think you are active.

The immunomodulatory action of the compounds can also be determined through pharmacological tests that stimulate lymphocytic division of thymic cells in rats cultured in the presence of Concanvalin A. [Reference: V.J. Merluzzi et. al., see Journal of Clinical and Experimental Immunology, Volume 22, page 486 (1975)].

In this study, the following evaluation criteria were used. Equivalent to a single Con A activity; Better than Con A activity but less than revamisol; Standard active compound in this region: Equivalent to levamisol activity: Better than levamisol activity.

If the effects of these compounds were superior to Concanavalin A, they were considered to be active.

The following examples illustrate the invention in more detail.

Example 1

Phenylethylamine (479 g, 3.96 mol, Eastman Scintillaion Gr.) Is dissolved in 3500 ml of diethyl ether and the solution is cooled to 0 ° C. The solid obtained is filtered through dry hydrogen chloride gas while stirring the solution for 10 minutes. Cool the filtrate, run the hydrogen chloride gas through this solution again for 10 minutes, and collect the solid. This operation is repeated until no more precipitate is produced by dry hydrogen chloride gas. The solids are collected, dried in air and then dried over phosphorus pentoxide in vacuo to yield 514 g (82%) of phenethylamine hydrochloride. Melting point: 216-218 degreeC.

Phenylamine hydrochloride (257 g, 1,63 moles) and ammonium thiocyanate (123,6 g, 1.63 moles) are heated to 160 ° C. in 340 ml bromobenzene under nitrogen atmosphere. After heating for 90 minutes, the mixture is cooled to room temperature and cooled to 5 ° C. This process is repeated until more 257 g of phenethylamine hydrochloride are obtained. The obtained solid was collected, stirred in 1.5 L of water, filtered, and recrystallized from isopropyl alcohol to yield 261.5 g (45%) of N-phenethyl thiourea. Melting point: 132-134 degreeC.

Example 2

1500 ml of anhydrous ethanol solution containing N-phenethyl thiourea (225 g, 1.25 mol) and α-bromoacetophenone (250 g, 1.25 mol Adrich Chem Co.) was heated to reflux for 2.5 hours under nitrogen atmosphere. . After reducing the solvent by 10%, the reaction mixture is cooled to room temperature and then cooled to 0 ° C. in an ice bath. The solid is 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. Repeating this process and then collecting the secondary recrystallized solid and drying over phosphorus pentoxide under vacuum yielded 365 g (81%) of 2-phenethylamino-4-phenylthiazole hydrobromide. Melting point: 169 to 172 ° C.

Analysis: C ₁₇ H ₁₆ N ₂ S · HBr.

Calculated Value: C, 56,50 H, 4.74 N, 7.68.

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

Example 3

833 ml of anhydrous ethanol solution containing N-phenethyl thiourea (140 g, 0.779 mol) and decyl bromide (250 g, 0.82 mol Eastman Chem Co.) was heated at reflux temperature under nitrogen gas for 2 hours, and 300 ml More anhydrous ethanol is added. After cooling the reaction mixture to 10 ° C., the solid was filtered, recrystallized from anhydrous ethanol and dried over phosphorus pentoxide to give 281.0 g (83%) of 2-phenethylamino-4,5-diphenyl-thiazole brominated Hydrochloride is obtained. Melting point: 171 to 174 캜.

Analysis of C ₂₃ H ₂₀ N ₂ S · HBr

Calculated Value: C, 63, 14 H, 4.84 N, 6.40.

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

Example 4

10 ml of anhydrous ethanol solution containing N-phenethyl thiourea (2.0 g, 0.011 mole) and α-bromopropiophenone (2.34 g, 0.011 mole Aldrich Chem Co.) at 90 ° C. under reflux for 90 minutes Heat. Ethanol is removed under vacuum, excess ethyl acetate is added and the solid is filtered and dried over phosphorus pentoxide. Recrystallization from anhydrous ethanol yields 2.86 g (70%) of 5-methyl-2-phenethylamino-4-phenethylamino-4-phenylthiazole hydrobromide. Melting point: 172 to 175 ° C.

Analysis of C ₁₈ H ₁₈ N ₂ SHBr

Calculated Value: C, 57,59 H, 5.10 N, 7.46.

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

Example 5

The halide hydrochloride salts of the following compounds were prepared according to the processes of Examples 1 and 2.

Example 6

An orange-white suspension is obtained by heating a 130 ml bromovene solution containing benzylamine hydrochloride (90 g, 0.6 moles, Pfaltz & Bauer Co.) and ammonium thiocyanate (50 g, 0.06 moles) at 155 ° C. for 20 minutes. . After cooling, the solid is filtered, washed three times with water and three times with isopropyl.

Recrystallization from isopropyl alcohol and drying over phosphorus pentoxide yields 38.6 g (38%) of N-benzyl thiourea. Melting point: 160-163 degreeC.

Example 7

15 ml of anhydrous ethanol solution containing N-benzyl thiourea (2.0 g, 0.012 mol) and α-chloro-p-fluoroacetophenone (2.07 g, 0.012 mol Aldrich Chem Co.) was refluxed under nitrogen gas. Heat at for 2 hours. After cooling, the filtered solid was washed with diethyl ether and dried over phosphorus pentoxide to yield 3.47 g (91%) of 2 benzylamino-4- (p-fluorophenyl) -thiazole hydrochloride. Melting point: 192-195 degreeC.

Analysis of C ₁₆ H ₁₃ N ₂ SFHCI

Calculated Value: C, 59,90 H, 4.40 N, 8.73.

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

Example 8

According to the process of Examples 6 and 7, a halogenated hydrochloride salt of the following compound was prepared.

Example 9

2-tenylamine (30 g, 0.235 moles, Fairfield CHemical Co.) is dissolved in 400 ml of diethyl ether and cooled to 0 ° C. in an ice bath. The dried solid chloride was passed through this solution for 5 minutes, and the solid obtained was filtered and dried over phosphorus pentoxide to give 26.7 g (61%) of 2-tenylamine hydrochloride.

Melting point: 186 to 190 ° C.

20 ml of bromobenzene solution containing 2-tenylamine hydrochloride (13.35 g, 0.089 mole) and ammonium thiocyanate (7.4 g, 0.089 mole) is heated at reflux for 90 minutes. The reaction mixture is cooled and the solid is filtered and washed three times with water. Recrystallization from chloroform and drying over phosphorus pentoxide yields 5.0 g (33%) of N-tenyl thiourea. Melting point: 99-101 ° C.

Analysis for _{C 6 H 8 N 2 S 2} · HBr

Calculated Value: C, 41,83 H, 4.68 N, 16.26.

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

Example 10

Heat 15 ml of anhydrous ethanol solution containing N-tenyl thiourea (2.0 g, 0.0116 mole) and α-bromoacetophenone (2.3 g, 0.0116 mole, Aldrich Chem, C0.) At reflux temperature under nitrogen gas for 90 minutes. do. The reaction mixture is cooled down and the ethanol is removed under vacuum. The residue is dissolved in hot isopropyl alcohol and diluted with diethyl ether to form an oil. The diethyl ether layer is decanted to dissolve the oil in a small amount of ether and cool. The resulting solids were combined and dried over phosphorus pentoxide to yield 3.20 g (78%) of 2-tenylamino-4-phenyl-thiazole hydrobromic acid. Melting point: 115 to 118 ° C.

Analysis of the _{C 4 N 12 N 2 S 2} · HBr

Calculated Value: C, 47,58 H, 3.71 N, 7.93.

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

Example 11

11 mL of anhydrous ethanol solution containing N-tenyl thiourea (0.80 g, 0.0046 mol) and α-chloro-p-fluoroacetophenone (0.08 g, 0.0046 mol Aldrich Chem.) At reflux under nitrogen gas Heat 90 minutes. After cooling, the ethanol was removed in vacuo, the solid was treated with ethanol, filtered and dried in vacuo over phosphorus pentoxide to 0.846 g (56%) of 2-tenylamino-4- (p-fluorophenyl) -thiazole hydrochloride Is obtained.

Melting point: 184 to 187 캜.

Analysis of C ₁₄ H ₁₁ N ₂ S ₂ F · HCI

Calculated Value: C, 51,45 H, 3.70 N, 8.57.

Found: C, 51.41 H, 3.63, N, 8.39.

Example 12

The hydrochloride halides of the following compounds were prepared according to the procedures of Examples 10 and 11.

Example 13

Fulfurylamine (25.0 g, 0.257 mol, Pfaltz Bauer Co.) is dissolved in 1300 mL of diethyl ether and cooled to 0 ° C. in an ice bath. Dry hydrogen chloride gas is passed through the solution until no further precipitate is formed. Filtration of the solid and drying over phosphorus pentoxide yielded 33.46 g (97%) of furfuryl amine hydrochloride.

Melting point: 147-149 degreeC.

71 ml of bromobenzene solution containing fulfurylamine hydrochloride (33.46 g, 0.250 mole) and ammonium thiocyanate (38.14 g, 0.501 mole) is heated at reflux under nitrogen gas for 20 minutes and cooled to room temperature. The reaction mixture is mixed with 125 ml of water and 100 ml of ethyl acetate solution and stopped overnight at room temperature. The mixture is diluted with 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 bromobenzene is removed under reduced pressure. The obtained solid is pulverized in mortar and finely ground powder is stirred in diethyl ether to remove residual bromobenzene. The solid was filtered off, washed with diethyl ether and vacuum dried over phosphorus pentoxide to yield 12.6 g (30%) of N-yl thiourea. Melting point: 80-91 degreeC.

Analysis of C ₆ H ₈ N ₂ OS

Calculated Value: C, 46, 14 H, 5.16 N, 17.93.

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

Example 14

11 hours of anhydrous ethanol solution containing N-fulfuryl thiourea (0.82 g, 0.005 mol) and α-bromopropiophenone (1.07 g, 0.005 mol Aldrich Chem Co.) at reflux temperature under nitrogen gas for 3 hours. Heat during. After cooling at room temperature the solution was removed under vacuum to give a cloudy brown oil which was treated five times with 35 ml of refluxed ethyl acetate. Reduce the amount of ethyl acetate to 25 ml and cool to room temperature. The precipitate was filtered off, washed with ethyl acetate and dried over phosphorus pentoxide to yield 0.585 g (33%) of 2-fulfurylamino-5-methyl-4-phenyl-thiazole hydrobromide. Melting point: 150-153 degreeC.

Analysis of C ₁₅ H ₁₄ N ₂ OS · HBr

Calculated Value: C, 51,29 H, 4.30 N, 7.97.

Found: C, 51.97 H, 4.47, N, 8.42.

Example 15

According to Examples 13 and 14, hydrochloride hydrochloride of the following structure is prepared.

Example 16

Diphenylmethylamine (25.0 g, 0.136 mol, Matheson Coleman & Bed Co.) is dissolved in 660 mL diethyl ether and cooled to 0 ° C. Through this solution, dry hydrogen chloride gas was passed for 10 minutes, at which time 300 ml of diethyl ether was added. The precipitate is filtered off, washed with diethyl ether and then vacuum dried over phosphorus pentoxide.

28.3 g (95%) of diphenylmethylamine hydrochloride are obtained. Melting point: 303 to 310 캜 (decomposition).

37 ml of bromobenzene solution containing diphenylmethylamine hydrochloride (28.3 g, 0.129 mol) and ammonium thiocyanate (9.81 g, 0.129 mol) is heated at reflux under nitrogen gas for 3.5 hours and cooled to room temperature . This solid is filtered off and treated twice with 200 ml of water. The solid is dissolved in 850 ml of ethanol, filtered and evaporated to 350 ml. After cooling, the solid was filtered off, washed with ethanol and dried in vacuo over phosphorus pentoxide to afford 14.72 g (56%) of N, N'-bis- (diphenylmethyl) -thiourea. Melting point: 216 to 217.5 ° C.

Analyzes for C ₂₇ H ₂₄ N ₂ S

Calculated Value: C, 79.37 H, 5.92 N, 6.86.

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

Example 17

11 mL of anhydrous ethanol solution containing N, N′-bis- (daphenylmethyl) -thiourea (1.21 g, 0.005 mol) and decyl chloride (1.21 g, 0.005 mol Aldrich Chem Co.) was refluxed under nitrogen gas. Heat at temperature for 3 hours. After cooling, the reaction mixture is evaporated to dryness and the oil obtained is mixed with about 40 ml of diethyl ether. Filtration of the solid, cooling with diethyl ether, and vacuum drying over phosphorus pentoxide yielded 1.01 g (75%) of 4,5-diphenyl-2-diphenylmethylamino-thiazole hydrochloride. Melting point: 195-198 ° C.

Analysis of C ₂₈ H ₂₂ N ₂ SHCI

Calculated Value: C, 73,91 H, 5.09 N, 6.16.

Found: C, 73.12 H, 5.28, N, 6.06.

Example 18

4-phenyl-2-diphenylmethylamino-thiazole hydrobromide is obtained according to the processes of Examples 16 and 17.

Melting point: 166 to 168 ° C.

Example 19

N-phenylethylenediamine (25 g, 0.184 moles, Aldrich Chem. Co.) is dissolved in diethyl ether, cooled to 0 ° C. and passed through dry hydrogen chloride gas until no precipitate is produced. Drying the solid on phosphorus pentoxide yields 31.2 g (98%) of N-phenylethylenediamine hydrochloride.

31 ml of bromobenzene solution containing N-phenylethylene diamine hydrochloride (31.2 g, 0.149 mol) and ammonium thiocyanate (11.3 g, 0.149 mol) is heated at reflux under nitrogen gas for 2 hours. After cooling, the solid obtained is filtered and bromo benzene is removed under vacuum. The resulting solid is stirred in 250 ml of water, filtered and dissolved in hot isopropyl alcohol. After cooling, the solid was filtered and dried over phosphorus pentoxide to yield 2.8 g (8%) of N- (2'-anilinoethyl) -thiourea. Melting point: 137-140 degreeC.

Analysis of C ₉ H ₁₃ N ₃ S

Calculated Value: C, 55,35 H, 6.71 N, 21.52.

Found: C, 55.64 H, 6.75, N, 21.03.

Example 20

61 mL of anhydrous ethanol solution containing N- (2′-anilinoethyl) -thiourea (0.90 g, 0.0046 mol) and α-bromoacetophenone (0.92 g, 0.0046 mol) was added at reflux under nitrogen gas. Heat for 2 hours. Cooling of the reaction mixture removes the solvent under vacuum. The resulting oil is dissolved in hot isopropyl alcohol, filtered and cooled. Filtration of the solid and drying over phosphorus pentoxide yielded 1.25 g (73.5%) of 2- (2'-anilinoethylamino) -4-phenyl-thiazole. Melting point: 161-165 degreeC.

Analysis of C ₁₇ H ₁₇ N ₃ S · HBr

Calculated Value: C, 54.24 H, 4.82 N, 11.16.

Found: C, 54.21 H, 4.59, N, 11.02.

Example 21

According to the process of Examples 19 and 20 to prepare a hydrochloride hydrochloride of the following compound.

Example 22

The immunomodulatory effects of animothiazoles described in Examples 2,3,4,5,7,8,10,11,12,14,15,17,18,20,21 have been shown to have a large cannavaline A The ability to stimulate lymphocyte proliferation in rats and pleural cells cultured in the presence of is evaluated by evaluation. Merluzzi et. al., as as essentially described in the Journal of Clinical and Experimental Immunology, Vol. 22, p. 486 (1975).

These cells were obtained from 6 to 8 week old male C 57 B 1/6 and Con A was obtained from Missouri Cent. Louis Sigma Chemicals.

Individual cell cultures (consisting of 0.10 ml of thymic cell stock solution, 0.05 ml of Con A stock solution, and 0.05 ml of drug solution) were multiplied by 4 times, and the cells were cultured at 37 ° C. for 4 hours before being investigated. H ³ -thymidine is added to individual cultures (0.01 ml of specific activity 1.9 C / mM) and the extent to which H ³ -thymidine is introduced into intracellular DNA is measured using radioactivity.

The experimental results are expressed as the average amount (cpm) of H ³ -thymidine introduced per minute at the highest concentration of drug by the 4-fold cell culture method. This 4-fold assay was performed at 8 different concentrations within the range of 0.02 to 50 µg / ml.

The best cpm value obtained is used for the scoring system. Based on this point, four different active concentrations were obtained from this lymphocyte stimulation assay (LSA), which is expressed as follows.

That is, the concentration equivalent to Con A alone (6000 ± 300 cpm) was set to 0;

Superior to Con A activity and less active than levamisol (10,000 ± 700 cpm) +;

The concentration equivalent to levamisol (22,000 ± 900 cpm) was + +;

The concentration (27,000 ± 1,000 cpm) superior to the levamisole was made + + +.

Example 23

The anti-inflammatory effect of the aminothiazoles of the present invention is measured by carrageenan induced plantar edema standard test. [Reference: C.A. Winter et. al., and reported in the Proceedings of the Society for Experimental Biology and Medicine, Vol. 111, p. 544 (1962)]

The compound is orally administered 33 mg / kg in the form of the hydrohalide described above. The results of this experiment are shown in the table below comparing the percent edema inhibition by the individual test compounds with the control group (aqueous solution only).

Claims (1)

constitutional formula

Substituted N-aralkyl thiourea or R ₁ is

If is a structural formula

A phosphorus bis-substituted N-aralkyl thiourea is reacted with an α-halocarbonyl compound having the structure R ₂ COCH (Z) R ₃ , wherein the compound of formula (I) is pharmaceutically toxic and Method for preparing acid addition salts.

R ₁ in the above formula

_{- (CH 2) n -X,} -CH 2 --CH 2 -NH-X and - a (CH _{2) m} Y, wherein X is phenyl or phenyl substituted with 1 being, wherein said substituent is alkyl of 1 to 3 carbon atoms , Hydroxy, alkoxy of 1 to 3 carbon atoms, chloro, bromo or fluoro, Y is thienyl, monosubstituted thienyl, furyl or monosubstituted furyl, wherein the substituents are alkyl of 1 to 3 carbon atoms, chloro , Bromo or pullouro, m is an integer of 1 or 2, R ₂ is phenyl, thienyl or monosubstituted phenyl, wherein the substituent is alkyl of 1 to 3 carbon atoms, hydroxy, of 1 to 3 carbon atoms Alcohol, bromo, chloro, bromo or pullouro, R ₃ is hydrogen, alkyl of 1 to 3 carbon atoms, phenyl or monosubstituted phenyl, wherein the substituents are alkyl of 1 to 3 carbon atoms, 1 to 3 carbon atoms Is alkoxy, bromo, chloro, or pullouro, and Z is halogen.