DD144055A5 - PROCESS FOR PRODUCING NEW AMINOTHIAZOLE - Google Patents

Description

213371 -f-

Process for the preparation of new aminothiazoles

Invention:

The invention relates to novel substituted aminothiazoles which are useful in the repair or alleviation of inflammatory conditions and as immune regulators, and to medicaments containing such compounds.

Characteristic of the known technical, solutions.

c Of a number of connections is on the. Known art that sie'als anti-inflammatory agents are useful, ^'1, for example, the corticosteroids, phenylbutazone, indomethacin and various 3' 4-dihydro ~ 4-oxo "2H-l, 2-benaothiasin-4""Carboxymid-l, l dioxides, as disclosed in U.S. Patent No. 3,591,584, these compounds are of therapeutic value in the treatment of arthritic

or other inflammatory conditions, such as rheumatoid arthritis. Such conditions have also been treated by administration of immunoregulators, such as levamisole, described, for example, in arthritis Rheumatism 20, 1445 (1977) and Lancet 1, 393 (1976). In efforts to find new and improved therapeutic agents for the treatment of these conditions, it has now been found that the novel aminothiazoles of the invention possess a particularly desirable combination of pharmacological properties, namely that they are effective both as antiinflammatory agents and as regulators of the body's immunoreaction _o They are therefore of particular value in the treatment of rheumatoid arthritis and other conditions where relief or remedy of inflammation and regulation of the immune response of the body is desired.

The synthesis of a limited number of 2-aralkylaminothiazoles has been described in the art, for example, 2-phenethylaminothiazole, Chem. Abs. 9, Ibl3e (1963); 2-Benzylaminothiazole, J _e AC _o S ₀ j [I, 2272 (1952) and 2-benzylamino-4-phen: yl-thiazole, J ₀ Ind. Chem. Soc. ^ t 57 (1967) o However, these publications do not disclose any pharmacological activity of such compounds

Object of the invention?

The invention relates to substituted aminothiazoles which are useful as anti-inflammatory agents and as regulators of the immune response of the body, in particular the novel compounds of the invention are those of the formula

 N

9 biii -iq7 ^r -i * Sii!: «: IVi ο

and their pharmaceutically acceptable acid addition salts, wherein R-i is selected from

X is -CH ^, - (CH ₂ ) -X, -CH ₂ -GH ₂ -KH-X and - (CH ₂ ) _m Y, wherein X is

^x x

is selected from phenyl and monosubstituted phenyl, the substituent is selected from alkyl of 1 to 3 carbon atoms, hydroxy, alkoxy of 1 to 3 carbon atoms, chlorine, bromine and fluorine, Y is selected from thienyl, monosubstituted thienyl, furyl and monosubstituted furyl, the Substituent is selected from alkyl having 1 to 3 carbon atoms, chlorine, bromine and fluorine, η and m are each the integer 1 or 2, R _{2 is} selected from phenyl, thienyl and monosubstituted phenyl * the substituent is selected under alkyl with up to 1 to 3 carbon atoms, hydroxy, alkoxy of 1 to 3 carbon atoms, chlorine, bromine and fluorine, and Ro is selected from hydrogen, alkyl of 1 to 3 carbon atoms, phenyl and monosubstituted phenyl, the substituent is selected from alkyl of 1 to 3 carbon atoms, Alkoxy of 1 to 3 carbon atoms, chlorine, bromine and fluorine, provided that η is not 1 when both X and R ₂ 'are phenyl and d R ^ are hydrogen. Preferred substituents for R ₂ are phenyl and p-fluorophenyl and R-, hydrogen and phenyl.

A preferred group of compounds is that wherein Rn is - (CH ₂ ) -X, especially for η = 2 _O. Most preferred are those compounds wherein X is phenyl or p-methoxyphenyl, R _{2 is} phenyl or p-fluorophenyl , Ro is phenyl, methyl or hydrogen, including 2-phenethyl-amino-4-phenyl-thiaol, 2-phenethylamino-4,5-diphenylthiazole and 2-phenethylamino-5-methyl-4-phenyl-thiazole.

Another group of interests is that where R is -, - (CH ₂ ) -Y, especially for m = 1 "preferred groups

for Y are thienyl and furyl, in particular those Ver compounds in which R2 is phenyl or p-fluorophenyl and Ro is hydrogen, methyl and phenyl.

Another group of compounds is that in which -CH '.., preferred compounds being those

are those in which X is phenyl, B ^ phenyl and R ^ is hydrogen or phenyl.

Another group of interesting compounds is that wherein R is -CHp-CHp-NH-X, especially those compounds wherein X is phenyl, R is phenyl and R 1 is hydrogen.

The invention also includes pharmaceutical compositions comprising a novel, substituted aminothiazole of the invention as described above or its pharmaceutically acceptable acid addition salt together with a pharmaceutically acceptable carrier or diluent. Preferred pharmaceutical agents are those containing the preferred compounds described above, most preferably those containing Phenethylamino-4-phenylthiazole, 2-Thenyland.no-4- (p-fluorophenyl) thiazole or 2 ~ (p -methoxyphenethylamino) -4-Cp-fluorophenyl) thiazole or pharmaceutically acceptable acid addition salts of these compounds.

fiarlegung ^ of the, nature of the invention ι

The invention also includes a method of treating rheumatoid arthritis in a patient by administering to it an effective antiarthritic amount of a novel aminothiazole of the invention, especially those preferred compounds described above, and more particularly 2-phenethylamino-4-phenyl-thiazoi, 2- (2) p-

· »5 -

1 33 /

Methoxyphenethylamino) -4- (p-fluorophenol: yl) thiazole or 2-Then: ylainino-4- (p-fluorophenol: yl) thiazole or their pharmaceutically acceptable acid addition salts

The novel aminothiazoles according to the invention are prepared from a suitably substituted N-arylthiourea of the formula

Il

The latter compounds are readily prepared from known and readily available amines of the formula LMp. For example, the group R - ^ - (CH ₂ ) -X, are unsubstituted or suitably substituted benzylamines (n = 1) and phenethylamines (n = 2). Corresponding Thenyl or Fury1 analogs of these amines are used in the preparation of compounds in which R-,

) -Y is _f Is R ₁ -GH. , are unsubstituted _ ^{m λ} X

or substituted diphenyl methylamine suitable starting materials, while when R-, -OHpCH ₂ -UH-S, unsubstituted or substituted n-phenethyl ^ endiamines can be used. In the foregoing, X, Y, η and m are as defined above. The starting amine is first converted to the hydrochloride or other hydrohalide by reaction with hydrogen chloride or other hydrogen halide, generally by passing the gas into a solution of the amine in an inert organic solvent, typically an ether such as diethyl ether ^ is conducted at a temperature of about -10 ⁰ C to about 10 C ·. The amine hydrohalide is then treated with ammonium thiocyanate or an alkali metal thiocyanate such as potassium thiocyanate in an inert organic solvent, generally an aromatic

3371

Solvent, such as bromobenzene, chlorobenzene, xylene and the like, to ge ^ fünschten N-Aralkylthioharnstoff unconverted The reaction takes place preferably in an inert atmosphere, for example under nitrogen, at a temperature of about HO ⁰ C to about 250oC, preferably from 150 ⁰ C to 20O ⁰ C, for example at reflux temperature in bromobenzene. The reaction is generally min in about 30 to about 6 ⁰ C ₀ In the preparation of M-Aralky thioureas! H finished, depending on the temperature employed, generally in about 1 to 3 hours at I50 to 200, as described above, It is commonly found that some bis-aralkyl-substituted thiourea forms, but this can be readily separated from the desired monosubstituted product, for example by recrystallization. It has been found, however, that the reaction of substituted or unsubstituted diphenylmethylamine hydrohalides and ammonium thio-adeate predominantly although less amounts of the monosubstituted compounds can be obtained in this reaction and used after separation as the starting material for the novel aminothiazoles. However, it has also been found that the bis-substituted thioureas are used as the starting material for the formation of the desired dipheptides of this invention nylmethylaminothiazole can be used as the bissubstituierte thiourea sets in situ and provides the monosubstituted compound.

The appropriate H-aralkylthionate is converted to the desired aminothiazole by reaction with a suitably substituted, -4-halo ketone or aldehyde of the formula R ₂ COCH (Z) Rt, where Ro and R- are as previously defined and Z is halogen, preferably chloro or bromine, transferred for example, when R ₂ is phenyl and Y ro / is on Hydrogen, j ^ © bromoacetophenone used ground, while when R ₂ and R, are both phenyl sindj a suitable reagent is a Desy! halide, for

~ 7 -

Example 2-chloro-2-phen; ylacet] aopfrenone. Other suitable α-L-haloketones or aldehydes are readily selected to give the desired substituents R ₂ and R- in the thiazole ring. The reaction is carried out in an inert organic solvent, typically an n-alkanol having from 1 to 6 carbon atoms, preferably in absolute ethanol. Reaction temperatures between about and 175 ° C are employed, preferably the refluxing temperature of the solvent. The reaction is carried out in an inert atmosphere, for example under nitrogen or other inert gas. It is generally completed in about 1 to 15 hours, depending on the temperature used, for example in about 1 to 4 hours using ethanol Reflux temperature, »The. The desired compound is obtained as a hydrohalide, and the free base can then be prepared from the salt by conventional methods, for example, by contacting it with an excess of a base such as an alkali metal hydroxide or carbonate, followed by extraction of the desired free base aminothiazole with its own appropriate organic solvents, for example an ether, such as diethyl ether.

The pharmaceutically acceptable acid addition salts of the novel aminothiazoles are also within the scope of the invention and may be readily prepared by contacting the free base with the appropriate mineral or organic acid, either in aqueous solution or in a suitable organic solvent. The solid salt may then be precipitated or evaporated of the solvent erhalten'werden. The pharmaceutically acceptable acid addition salts of the invention include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acetate, lactate, maleate, pumarate, oxalate, citrate, tartrate, succinate, methanesulfonate, and the like.

- 8th

The novel aminothiazoles and their pharmaceutically acceptable acid addition salts of the present invention are useful as anti-inflammatory agents and as regulators of the immune response in warm-blooded animals. The combination of anti-inflammatory activity and immunoregulatory activity is particularly valuable for the treatment of conditions such as rheumatoid arthritis and other disorders associated with deficiency connected immune response and accompanied by inflammation _o So act compounds of the invention alleviates or depleting for Schwerzen and swelling associated with these conditions, also the patient's Immureaktion während.sie regulate and thereby correct the underlying immune disorder by maintaining immune ability · Therefore, the invention also includes a method of treating rheumatoid arthritis of rheumatoid arthritis by administering an effective antiarthritic amount of an aminothiazole of the invention or de Thereafter, the compounds of the present invention may be administered to the subject to be treated by conventional routes, for example, oral or parenteral, including doses in the range of from about 0.01 to about 50 mg / kg of body weight per day, preferably about 23.15 to about 15 mg / kg of body weight per day · However, the optimal dosage for the individual patient to be treated is determined by the person responsible for the treatment, generally initially administered lower doses and gradually increasing them »to determine the most appropriate dosage» This varies with the particular compound used and with the patient being treated.

The compounds can be used in medicaments containing the compound or a pharmaceutically acceptable acid addition thereof in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers are for example

inert solid fillers or diluents and sterile or organic solutions ₀ The active compound is present in such medicinal products in amounts sufficient, the desired dosage amount in the range described above to devoted Thus, for oral administration, the compounds with a suitable solid or liquid carrier or Diluent for the preparation of capsules, tablets, powders, syrups, solutions, suspensions and the like can be combined. The medicines may, if desired, additional components, such as flavorings or flavors _? Sweeteners, excipients and the like included. For parenteral administration, the compounds may be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions of the aminothiazoles in sesame or peanut oil, aqueous propylene glycol and the like may be used, as well as aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts of the compounds Solutions may then be administered intravenously, intraperitoneally, subcutaneously or intra-muscularly, with intravenous and intraperitoneal administration being preferred. For topical treatment of inflammation, the compounds may also be administered topically in the form of ointments, creams, pastes and the like in conventional pharmaceutical practice.

The activity of the compounds of the invention as antiinflammatory agents may be determined by pharmacological tests, for example, by the carrageenin-induced rat foot edema standard test using the general C ₈ A ₀ Winter et al., Proceedings of the Society of Experimental Biology in Medicine. Vol. 111, p. 544 (1962). In this test, the antiinflammatory activity is expressed as the percent inhibition of edema formation in the hind paw of male albino rats (generally weighing

10 -

213371

190 g) in response to a subplantar injection of carrageenan. The carrageenan is used as 1 follow aqueous suspension 1 h after oral administration of the active substance is injected, usually given in the form of an aqueous solution or suspension of the edema formation is then 3 hours after the carrageenin injection by comparing the Anfangsvοlumens the injected paw and the volume of a 3 h-period determined. The volume increase 3 hours after carrageenin injection represents the individual response. Compounds are considered active if the response between the drug-treated animals (6 rats per group) and the control group, that is the animals, is the vehicle alone were found to be significant when compared to those obtained by standard compounds such as acetylsalicylic acid at 100 mg / kg or phenylbutazone at 33 mg / kg, both administered orally.

The immunoregulatory activity of the compounds of the invention may be determined by such pharmacological assays as the in vitro stimulation of lymphocyte proliferation of mouse thymus cells grown in the presence of concanavalin A (Con A) using the general evaluation method of V. . J ₀ Merluzzi et al., Journal of Clinical and experimental Immunology, Volume 22, p 486 (1975) · In this study, four different values of lymphocyte stimulation test activity were (LSA) specified for the product to test compounds _o or those Con A alone were the same; those above the Con Α activity but below levamisole, the standard compound of choice in this field, those with the same activity as levamisoi and those with greater activity than levamisole. Compounds are considered active for the purposes of the invention when superior to concanavalin A »

11

Ausführunresbeispiele;

The invention is illustrated by the following examples. Of course, it is not limited to the specific details of these examples.

example 1

Phenethylamine (479 g, 3.9 ° M, Eastman Scintillation Grade) was dissolved in 3500 ml of diethyl ether and the solution was cooled to ⁰ ° C. To dry hydrogen chloride gas was passed through the stirred solution for 10 minutes and the resulting pests were filtered The filtrate was then cooled The reaction was repeated until further acidification of the filtrate with dry hydrogen chloride gave no further precipitation. The combined pesticides were dried in air and then over phosphorus pentoxide under vacuum to give 514 g (m.p. 82%) phenethylamine i-tydrochlorid, mp. 21b * to deliver to 218 ⁰ C,

Phenethylamine hydrochloride (257 g, 1.63 mol) and ammonium thiocyanate (123.6 g, 1.63 mol) were heated at ⁰ ° C in 340 mL bromobenzene under nitrogen. Stream was heated to room temperature for 90 min Cooled to 5 ° C. This procedure was repeated with a further batch of 257 g of phenethylamine hydrochloride. The combined pesticides from the above reaction were stirred in 1.5 l of water and filtered. Recrystallization from isopropyl alcohol provided 26.1 g (45 %). N-phenethylthiourea: ·, mp 132-134 °.

N-phenethyl thiourea (225 g, 1.25 mol) and bromoacetophenone (250 g _s, 1.25 mol) in 1500 ml of absolute ethanol were brought to reflux for 2.5 h under nitrogen.

- 12 -

133 71

hitzt. After lowering the volume of solvent by 10 % , the reaction mixture was cooled to room temperature and then to O ⁰ G in an ice bath. The solids were filtered off, redissolved in 2500 ml of absolute ethanol and heated to reflux. The volume of solvent was reduced to 200 ml and the reaction mixture cooled to ⁰ ° C. This procedure was repeated and after the second recrystallization the pellets were collected and placed under vacuum dried over phosphorus pentoxide, -um 365 g (81%) 2-phenethylamino-4-phenyl-thiazol-Hydrobormid, -Schmp I69 to 172 ⁰ C, to provide ·.

Analysis; above ₀ for G ₁₇ H ₁₆ N ₂ S ₀ HB ₁ , * 0 56.50, H 4.74, Ii 7.68

gef; C 57.3b, H 5.04, Έ 7.83.

Example 3

H-Phenethylthiurea (140 g, 0.799 mol) and desyl bromide (225 g, 0.82 mol) in 833 nil of absolute ethanol were heated under nitrogen at reflux for 2 h, during which further 300 ml of abs. Wurdeno ethanol added The reaction mixture was cooled to 10 ⁰ C, the solids are filtered, recrystallized from absolute ethanol and dried over PhosphorpeziJbxid to 281.0 g (83%) of 2 ~ phenethylamino-4,5-diphenyl ~ thiazole hydrobromide, mp. 171 to 174 ° C, to give ..

Analyzes about ₀ for C ₂₃ H ₂₀ N ₂ S-HBr: C 63.14, H 4.84, N 6.40

Fe _o : C 62.62, H 4.82, N 6.48.

Example _i §

IT-phenethylthiourea (2.0 g, 0.011 mol) and o-bromopropiophenone (2.34 g, 0.011 mol) in 10 ml of absolute ethanol were heated to reflux for 90 min under nitrogen. The ethanol was then removed under vacuum,

- 13 -

I O

Added ethyl acetate in excess and the pesticides were filtered and dried over phosphorus pentoxide. Recrystallization from absolute ethanol provided 2.86 g (70 %). 5 ~ methyl 2-phenethylamino-4-phenylthiazole hydrobromide, mp 172-175 ° C.

Analysis: above ₀ for

Found ,;

: G 57.59, H 5.10, N 7.4-6 C 57.67, H 5.11, Έ 7.39.

Example 5

Following the procedures of Examples 1 and 2, hydrohalides of the following compounds were prepared.

IiH-CH ₂ -CH ₂ -X

Salt X

HBr phenyl phenyl phenyl

HBr p-bromophenyl

HBr p-bromophenyl

HBr p-methoxyphenyl

HBr p-methoxyphenyl

HBr p-Met.hoxyphenyl

HCl p-methoxyphenyl

22 "

p-methoxyphenyl

p-Pluorophenyl Phenyl Phenyl Phenyl Phenyl P-ITuorphenyl

H H H

Mp.

135-139

163-165

171-174

150 to 151.5

169-171

149 to 150.5

CH-

Phenyl 201-205 H 156-158

Example b

Benzylamine hydrochloride (90 g, ₅ 0.6 mol) and ammonium thiocyanate (50 g, O, bb MoI) in 130 mL of bromobenaol were heated to 155 ° C for 20 min to give a yellow-white suspension. After cooling, the filtered pesticides were obtained

-

washed three times with water and three times with isopropyl alcohol. ,

Recrystallization from isopropyl alcohol and drying over phosphorus pentoxide yielded 38.26 g (38 %) of N-benzylthiourea, mp. 60 ° -63 °.

Example 7

H-Benzylthiourea (2.0 g, 0.012 mol) and 1-chloro-p-fluoro-acetophenone (2.07 g, 0.012 mol) in 15 ml abs. Ethanol was heated at reflux for 2 h under nitrogen. After cooling, the filtered pesticides were washed with diethyl ether and dried over phosphorus pentoxide, yield 3.47 g (91 %) of 2-benzyl-amino-4-p (fluorophenyl) -thiazole hydrochloride, m.p. 192-195 ° C ,

Analysis: Calcd. For O ₁₆ H ₁₃ N ₂ SS ^ HCl: G 59.90, H 4.40, N 8.73

gefo: C 59.64, H 4.38, Ii 8.62.

Example 8

Following the procedures of Examples 6 and 7, hydrohalides of the following compounds were prepared:

Salt XR ₀ τ, mp ⁰ O

C.

HBr phenyl phenyl phenyl 250-252 HBr phenyl p-methoxyphenyl H 155-157 HBr phenyl p-chlorophenyl H 211-212

- 15

Saia XR ₂

HBr Phenol Phenyl 7/8 HBr Phenyl 2,5-Dimethoxyphenyl HBr Phenyl p-Methylphenyl HBr Phenyl Thienyl 7/8 HBr p-Pluorophenyl Phenyl HBr p-Pluorophenyl Phenyl HGl p-Pluorophenyl p-Fluorophenyl HBr p-Chlorophenyl Phenyl HBr p-Chlorophenyl phenyl

CH ₃

H H H H

Phenyl HH CH ₃

Mp. °

157-160 159-161 155-159

100 84-85 225-227 154-158 176-180 148-151

Example 9

2-Thenylamine (30 g, 0.265 mol) was dissolved in 400 ml of diethyl ether and cooled to ⁰ ° C. in an ice-bath. Dry hydrogen chloride gas was bubbled through the solution for 5 minutes. The resulting pesticides were filtered and dried over phosphorus pentoxide to yield 26.7 g (6 L %) of 2-thenylamine hydrochloride, Schmpo 186 I90 C.

2-Thenylamine hydrochloride (13.35 g, 0.089 mol) and ammonium thiocyanate (7.4 g, 0.089 mol) in 20 mL bromobenzene were heated to reflux for 90 min. The reaction mixture was cooled and the filtered pest was washed three times with water. Recrystallize of chloroform and drying over phosphorus pentoxide gave 5.0 g (33%) H ~ Theny thiourea, mp "99 - 101 ⁰ C.

Analysis? about <

for C ₆ H ₈ I ₂ S ₂ JC 41.83, H 4.68, Έ 16.26 gef _e : C 41.56, H 4.58, N 16.07 «

H-Thenylthioharnstoff (2.0 g, 0.0116 mole) and "C -Bromacetophenori (2.3 g 0.0116 mol _s) in 15 ml abs" ethanol were heated at reflux for 90 min under nitrogen,

- 16 -

1337J

The reaction mixture was cooled and the ethanol removed under vacuum. When the residue was dissolved in hot isopropyl alcohol and diluted with diethyl ether, an oil was formed. The diethyl ether was decanted, the oil dissolved in a small amount of ethanol and cooled. The resulting solids were filtered and dried over phosphorus pentoxide to yield 3.20 g (78%) of 2-Then:. ~ Ylamino-4-phenylthiazole hydrobromide, mp 115-118 ⁰ C.

Analysis: for C ₁₄ H ₁₂ IT ₂ S ₂ THBr: C 47.58, H 3.71, N 7.93

f _o : C 47.75, _s H 3.74, N 7.90.

Example 11

I-thenyl thiourea (0.80 g, 0.0046 mol) and chloro-1-fluoro-acetophenone (0.80 g, 0.0046 mol) in 11 mL abs. Ethanol was heated to reflux for 90 minutes under nitrogen. After cooling, the ethanol was removed in vacuo and the precipitates were triturated with ethanol, filtered and dried in vacuo over phosphorus pentoxide, yield 0.848 g (56 %) of 2-Then: ylamino-4 - (p ~ fluorophenyl) thiazole hydrochloride, mp 184 -. 187 ⁰ C.

Analysis: Calculated for C ₁₄ H ₁₂ N ₂ S ₂ THBR. C 47.58, H 3.71, N 7.93

gefo: C 47.75, H 3.74, N 7.90.

Example _i 11

K-thenylthiourea (0.80 g, 0.0046 mol) and * 6 _T 'chloro-p-fluoro-acetophenone (0 _s, 80 g, 0.004b mol) in 11 mL abs. Ethanol was heated to reflux for 90 minutes under nitrogen. After cooling, the ethanol was removed under vacuum and the pesticides were triturated with ethanol, filtered and dried in vacuo over phosphorus pentoxide. Yield 0.848 g (56 %) of 2-thenylamino-4- (p -.fluorphenyl) -thiazol-

17 -

3371

Hydrochloride, mp 184 -. 187 ⁰ C

Analysis * 'ber. for C ₁₄ H ₁₁ H ₂ S ₂ E ¹ .HOl * C 51.45, H 3.70, Ή 8.57

gef. * 0 51.41, H 3.63, Ή 8.39.

Example 12

Following the procedures of Examples 10 and 11, hydrohalides of the following compounds were prepared;

IH-CH ₂

// W

Salt R ₉ ro mp. ⁰ C

154-158

HBr phenyl CH ₃ 179.5-181.5 Hol Thienyl H 137-142

p-methoxyphenyl beist H phenyl CH ₃ thienyl H USK-22nd

Furfurylamine (25.0 g ₉ 0.257 mol) was dissolved in 1300 ml of diethyl ether and cooled to ⁰ ° C. in an ice bath. Dry hydrochloric acid gas was bubbled through the solution until no further precipitation took place. The solids were filtered and evaporated in vacuo Phosphorus pentoxide to 33.46 g (97 %) of purfurylamine hydrochloride, mp ₀ 147-149 ^P <dried »

Purfurylamin hydrochloride (33 _S 46 g, O _$ 25O mole) and ammonium thiocyanate _(38? 14 g, 0.501 Hol) in 71 ml bromobenzene was 20 min under nitrogen at reflux for ER

- 18 -

heated 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 left overnight at room temperature. The mixture was then diluted to give 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 bromobenzene removed under vacuum. The resulting solids were ground in a mortar with pestle and the fine particles were stirred in diethyl ether to remove residual bromobenzene. The pesticides were then filtered, washed with diethyl ether and vacuum dried over phosphorus pentoxide, yield 12.06 g (30%) of N-furfuryl thiourea, mp 80-91 ⁰ ,

Analysis for C ₆ HgN ₂ OSj C 46.14, H 5.16, N 17.93

C 45.91, H 4.90, N 17.57.

Example 14

Ni-furfurylthiourea (0.82 g, 0.005 mol) and γ-bromopropiophenone (1.07 g, 0.005 mol) in 11 mL of absolute ethanol were heated at reflux for 3 h under nitrogen. After cooling 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. The ethyl acetate was reduced in volume to about 25 ml and cooled to room temperature. The precipitated solids were filtered, washed with ethyl acetate and vacuum dried over phosphorus pentoxide and yielded 0.585 g (33%) 2-Furfurylamino-5 ~ methyl-4-phenyl ~ thiazole ~ Hydrobo: πnid ₉ Schmpο ^150-0

Analysis; over * for C ₁₅ H ₁₄ N ₂ -OS ^ HBr? C 51.29, H 4.30, N 7.97

gef. j C 3.97, H 4.47, N 8.42 _e

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ί 3371

Example 15

Following the procedure of both Examples 13 and 14, hydrohalides of the following compounds were prepared:

M-GH,

t \

salt R ₂ ^R 3 C. C HBr phenyl H 123-126 HBr phenyl phenyl 192-194 Example 16

Diphenylmethylamine (25.0 g, 0.136 mol) was dissolved in 660 ml of diethyl ether and cooled to ⁰ ° C. Dry hydrogen chloride gas was bubbled through the solution for 10 minutes, to which additional 300 ml of diethyl ether were added. The precipitate was filtered, washed with diethyl ether and vacuum dried over phosphorus pentoxide, yield 28.3 g (95 %) of diphebylmethylamine hydrochloride mp 303-310 ⁰ C (decomposition) «

Diphenylmethylamine hydrochloride (28.3 g, 0.129 mol) and ammonium thiocyanate (9.81 g, 0.129 mol) in 37 ml of bromobenzene were heated under reflux for 3.5 h under nitrogen and then cooled to hem temperature. The pests were filtered and washed twice 200 ml of water were triturated. They were then dissolved in 850 ml of ethanol, filtered and concentrated to a volume of about 350 ml. After cooling, the pesticides were filtered, washed with ethanol

- 20 -

3371

and over phosphorus pentoxide to 14.72 g (56%) of N, N'-bis- (diphenylmethyl) thiourea, mp 216 -. 217.5 ⁰ G, dried "

Analysis? calc. for C ₂₇ H ₂₄ N ₂ S: ° ⁷⁹ » ³⁷ » ^{H 5} » ⁹² > ^{Έ 6} » ⁸⁶

gef.:O 79.84, H 6.05, N 6.93.

Example 17

N, H-bis (diphenylline thy I) thiourea (1.21 g, 0.005 mol) and desyl chloride (1.21 g, 0.005 mol) in 11 mL abs. Ethanol was heated to reflux under nitrogen. After cooling, the reaction mixture was concentrated to dryness, the resulting oil mixed with about 40 ml of diethyl ether. The Peststoffe were filtered, cooled with Diathyläther and vacuum dried over phosphorus pentoxide to yield 1.01 g (75%) of 4,5-diphenyl-2-diphenylmethylaminothiazol-Hydr0chlorid, mp 195 -. 198 ⁰ C.

Analysis: Calcd. For O ₂₈ H ₂₂ N ₂ S.HOl: C, 73.91, H, 5.09, N, 6.16

gef. : C 73 * 12, H 5.28, N 6.06.

Example _ι 18

Following the procedures of Examples 16 and 17 4-phenyl-2-diphenylmethylamino-thiazol-Hydrobo was ¹ £ mid Herge provides, mp. 166 -r 168 ⁰ O.

Be J ₁ S ₁ P ₁ Je _- ^ Ig ₁₁

N-phenylethylenediamine (25 g, 0.184 mol) was dissolved in diethyl ether, cooled to 0 C, and dry hydrogen chloride gas was bubbled through the solution until no further precipitation occurred. The filtered solids were

21 -

337?

dried over phosphorus pentoxide, yield 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) in 31 ml of bromobenzene were refluxed under nitrogen for 2 h. After cooling, the solids obtained were filtered off and the bromobenzene was filtered off The resulting solids were stirred in 250 ml of water, filtered and dissolved in hot isopropyl alcohol. After cooling, the solids were filtered and dried over phosphorus pentoxide, yield 2.8 g (8 %) of N- (m.p. 2'-Anilinoäthyl) thiourea, mp 137 -. 140 ⁰ C

Analyzes about ₀ for G ₉ H ₁₃ N ₃ Si G 55.35, H 6.71, N 21.52

gef. ; G 55.64, H 6.75, N 21.03.

Example 20

N- (2'-anilinoethyl) -thiourea (0.90 g, 0.0046 mol) and ^ -bromoacetophenone (0.92 g, 0.0046 mol) in 6 ml abs. Ethanol was heated at reflux for 2 h under nitrogen. After cooling the reaction mixture, the solvent was removed under vacuum. The resulting oil was dissolved in hot isopropyl alcohol, filtered and cooled. The solids were filtered and dried over phosphorus pentoxide, yield 1.25 g (73.5 %) of 2- (2 "-anilinoethylamino) -4-phenyl-thiazole" Schmp " 161-165 ⁰ G.

Analyzes about _c for C ₁₇ H ₁₇ N ₃ S ₈ HBRS G 54 _S 24, H 4.82, N 11.16 Found: ^C ,: 54.51 G * H 4.59, N ll _s 02 _c

Following the working grounds of Examples 19 and 20, hydrohalides of the following compounds were prepared.

- 22 -

Salt R ₂ R ^ mp. ⁰ C

HCl phenyl phenyl 139-143 HBr phenyl methyl 133-136

Example 22

The immunoregulator activity of the aminothiazoles described in Examples 2, 3, 4, 5, 7, 8, 10, 11, 12, 14, 15, 17, 18, 20 and 21 was determined by determining their ability to stimulate lymphocyte proliferation of mouse thymus cells cultured in vitro in the presence of concanavalin A (Con A) using the procedure of VJ Merluzzi et al., essentially as described in the Journal of Clinical and Experimental Immunology, Vol. 22, p. 486 (1972). The cells came from male C57BL / 6 mice at ages 6 to 8 Y / eeks Zerworben from Jackson Laboratories of Bar Harbor, Maine, and the Con A was from Sigma Chemicals of St ₀ Lous, Missouri). Each cell culture (consisting of 0.10 ml of thymus cell stock solution, 0.05 ml of Con ^ stock solution and 0.05 ml of drug solution) was set in quadruplicate and the cell proliferation after 48 h incubation at 37 ° C by the pulses of each culture with "Ή -Thymidine (O ₅ Ol ml specific activity 1.9 C / mlVI) and to ~

3 Finally, determine the incorporation of H-thymidine into the desoxyribonucleic acid (DNA) of the cell by measuring the radioactivity using a placental scintillation counter. The results obtained are quantified as average counts per

23 -

Minute of in-thymidine incorporated in drug amount with maximum activity expressed by quadruple cell cultures. · These quadruplicates are performed at eight different drug concentrations ranging from 0.02 to 50 / μg / ml. The next count / min value achieved is utilized in the scoring system On this basis, four different activity values were determined in the lymphocyte stimulation test (LSA), and these are defined in the following manner, namely those values corresponding to Con A alone (6 000 ~ 1 / min) were considered negative or zero, those over activity of Con A (10 000 ί 700 l / min), but below levamisole, were considered positive, whereas those corresponding to levamisole (22 000i 900 l / min) were rated ++ and those with an activity of 27 000 i l / min.) were assessed as +++ via levamisole. The LSA activity for the compounds described in the above examples was in each case +++.

The anti-inflammatory activity of aminothiazole oils according to the invention was determined using the carrageenin-induced rat foot edema standard test, as in the manner of essentially C ₀ A. Winter et al., Proceedings of the Society for Experimental Biology and Medicine, Vol. 111, p (I962). The compounds were administered orally in the form of their previously described hydrohalides at a dose of 33 mg / kg. The results thus obtained are shown in the following table, expressed as the percent inhibition of edema formation by each test compound, as compared with the non-drug-treated control (that is, an aqueous solution without a compound).

24 -

.H ₂ H ₃ HZ % Edema inhibition -R ₁ phenyl phenyl HOl (33 mg / kg, p.o.) benzyl phenyl H HBr 33 4 ~ fluorobenzyl 4-fluorophenyl H HBr , 41 2 ~ Ihenyl phenyl H HBr 49 2-phenethyl phenyl phenyl HBr 47 2-phenethyl 4-methoxyphenethyl 4-fluorophenyl 1 H HBr 48 29

Claims (5)

where!?,. is selected from the group comprising -CH, - (CH ₀ ) -X, -CH ₀ -CH ₀ -MX and - (CH ₀ VY ₅ wherein X is selected from the group comprising phenyl and monosubstituted phenyl, said substituent is selected from the group comprising alkyl having 1 to 3 carbon atoms, hydroxy j alkoxy having 1 to 3 carbon atoms, chlorine, bromine and fluorine; Y is selected from the group consisting of thienyl, monosubstituted thienyl, furyl and monosubstituted furyl, said substituent being selected from the group comprising alkyl having 1 to 3 carbon atoms. Chlorine, bromine and fluorine; η and m are each an integer from 1 to 2 ξ R ₀ is selected from the group consisting of phenyl, thienyl and monosubstituted phenyl, the abovementioned substituent is selected from the group comprising alkyl having 1 to 3 carbon atoms, hydroxy, alkoxy with i bis 3 carbon atoms, chlorine, bromine and fluorine? and R-3 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, phenyl and monosubstituted phenyl, said substituent being selected from the group consisting of alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms. Bromine, chlorine and fluorine, with the proviso that η is not 1 when X and K _{0 are} together Phenyl and R ~ is hydrogen, characterized in that a suitable * N-aralkyl substituted thiourea of the formula R. NH C ₁ HHp, or if desired when Rv CET [V is a K-aralkyl bisubstituted thiourea of the formula R 1 H 2 H (JKER 4) in which R 1 and X are as previously defined S-.
are reacted with a cC-halocarbonyl compound of the formula RpCOCH (Z) R-, wherein Rp and R ~ are as previously defined and Z is carbon, and, if desired, converting the compound of formula (I) into a pharmaceutically acceptable acid addition salt. 2. The method according to item 1, characterized in that the reaction is carried out in an n-alkanol having 1 to 6 carbon atoms at a temperature between 50 and 175 ° C. 3. The method according to item 2, characterized in that the n-alkanol Äthan © l is. 4. Method according to point 3 », characterized in that R ^ - (clip) -X means. 5 · Method according to item 4-, characterized in that η 2, X is phenyl and R _{3 is} hydrogen.