DE2453082A1 - SUBSTITUTED THIAZOLYLURA OR THIAZOLYLTHIOURA DERIVATIVES AND THEIR SALTS, AS WELL AS THEIR USE AND METHOD OF MANUFACTURING THE SAME - Google Patents

Description

DR. STEPHAN G. BESZEDES PATENT ADVOCATE

306 DAChAU near MUNICH

BOX 1168

HEIDEWEG 2

TELEPHONE: DACHAU 43 71

Postal checking account Munich 136B 71 Bank account no. 9D 637 at the Kreis- und Stadtsparkasse Dachau-Indersdorf

P 752

description

for patent application

EGYT GYOGYSZSRVEGYisZETI GYAR

Budap e s t, Hungary

concerning

Substituted-thiazolylurea- respectively Thiazolylthiourea derivatives and their salts as well as their use and processes for the preparation

the same

The invention relates to new thiazolylurea or thiazolylthiourea derivatives, their use as Medicines, in particular as agents for inhibiting gastric secretion and against gastric ulcers and as anti-inflammatory agents Means, as well as a method for producing the same.

It is known that many substituted -urea- and

509821/1044

Thiourea derivatives are pharmaceutically valuable. Have so for example according to the German Offenlegungsschrift 2,132,431 and 2,144,683 differ from 4-phenyl-2-aminothiazole derivative substituted urea and thiourea derivatives have a viricidal effect or effect against viruses.

Numerous processes for the production of urea and thiourea derivatives are known (Chem. Rev. Jjj ^ [19553, ¹⁸¹ > Houben-Weyl, Volume VIII [1952], 149 to 166, Georg Thieme Verlag, Stuttgart; Houben-Weyl [1955J , Volume IX, 884 to 889, Georg Thieme Verlag, Stuttgart). Moreover, it is known that in the reaction of ω-thiobiuret Broinacetophenon with 1- (4'-phenylthiazol-2 ^1-yl) urea is produced (Chem. Ber. 22 [1966 ^, 2 937).

It has now been found, surprisingly, that substituted thiazolylurea or thiazolylthiourea derivatives, in which in the 2-position of the thiazole ring a carbamide or thiocarbamide group and at the same time in the 4-position of the thiazole ring is a pyridyl radical and optionally the 5-position of the thiazole ring by a lower alkyl radical is substituted, pharmaceutically, especially in relation to the inhibition of gastric secretion and against Stomach ulcers, as well as anti-inflammatory, are superior compounds.

The invention therefore relates to substituted thiazolylurea or thiazolylthiourea derivatives the general formula

509821/1044 - 3 -

' ^ S ' ^Λ 4

5 Y

in which -

R _x , for a pyridyl radical,

1-2 are independently hydrogen or lower alkyl radicals,

Represents oxygen or sulfur and

and Rc independently of one another for hydrogen,

lower alkyl radicals, allyl radicals, cycloalkyl radicals with 3 to 6 members. or, optionally phenyl radicals substituted by halogen. or

and R ₁ - together with the nitrogen atom of the carbamide or thiocarbamide group to which they are attached, heterocyclic rings of the general formulas

509821/1044

- N (CH ^) _n X

"respectively

- N Z XI,

in which latter

η is a number from 4 "to 7 and

Z is oxygen or a group of the formulas ^ N-H, ^ N-CH, or

^ means to represent,
as well as their acid addition salts.

509821/1044

It is preferred according to the invention that the lower alkyl radicals, for which Rp, R ₅ ,, R ₄ , and / or Rr can or can stand, have 1 or 2 carbon atoms.

Furthermore, the cycloalkyl radicals for which R ^, and / or Rj- may or may be, preferably Cyclopropyl, cyclopentyl or cyclohexyl radicals.

Furthermore, it is preferred that the halogen, through which the phenyl radical or the phenyl radicals, for the or the R ^ and / or Rr- can be or may, may or may be substituted, is chlorine or bromine.

It is also preferred that η 5 to 7> in particular 5>.

Furthermore, according to the invention, medicaments which 1 or more of the above compounds as active ingredient or active ingredients, advantageously together with common pharmaceutical carriers and / or auxiliaries, included, provided.

As already mentioned, the compounds of the formula I according to the invention have valuable pharmacological properties. As has been demonstrated by experiments on rats, they inhibit the production of kagenic acid to a high degree or secretion and also act on various Strongly inhibitory to experimentally induced ulcers. One of the main advantages of the invention Compounds to the gastric acid secretion inhibiting agents previously used in therapy consists in that the compounds according to the invention do not have their effect via the parasympathetic or cholinergic system exercise. So since they are not paralyzing the parasympathetic nervous system, respectively Act parasymp'atholytic, they do not have that either

- 6 509821/1044

numerous undesirable side effects of atropine derivatives (such as dry mouth, dilated pupils and disorders of the ability to accommodate), so that for the invention Connections are not contraindicated.

Gastric acid secretion and inhibition of Shay ulcers were determined by the method of H. Sh.ay et al (G-astroenterology, jj_ Pl94-5J »^ 3) j the inhibition of on immobilization and insulin-related ulcers according to the method of Borsy and coworkers (Acta Pharm. Hung. 3,8 pl968J, 151) and the pupil dilation respectively mydriatic effect, on the basis of which it can be decided whether the compound has an anticholinergic effect or not determined by the method of P. Pulewka (Arch. f. exp. Path, and Pharm. 168 [1932], 507).

The pharmacological data obtained by these investigations are summarized in Table 1 below. Xanthene-9-carboxylic acid (diethylmethylammoniumeth ~ 2-yl) ester bromide / diethyl (2- -hydroxyethyl) methylammonium bromide xanthene-9-carboxylate | [Methanthelini.

- 7 509821/1044

- 7 - table

Examined Inhibition of Inhibition of ulcers at in at Anticholinergic effect after acute toxicity intra- link Gastric acid Peroral ED ^ Q value Shay mg / kg insulin ED ^ Q value Pulewka LD [.Q value peri- secretion - ulcers at ulcer in the in in t one al Peroral Immobilisa intestine ■ mg / kg mg / kg ED ^ value > 40 tion throes 30th drawing perorally 510 in > 40 20th way 150 mg / kg > 40 > 40 35 Ileum > 100 310
i 28 30th 18th in > 100 23O Connection No. 1
(Example 1) 19th > 40 > 40 20th > 1 > 100 1,700 560 Connection No. 2
(Example 2) 12 ■ > 40 • 30 > 40 M. > 100 27O 1,000 Connection No. 3
(Example 2) 16 > 40 > 40 40 > 100 390 310 Connection No. 4
(Example 2) 22nd > 40 > 100 460 Compound No. 6
(Example 2) 40 40 » > 100 1,500 Compound No. 8
(Example 2) 40 2,000 Compound No. 10
(Example 3) 15th > 1 580

Continuation of the table

Examined Inhibition of Inhibition of ulcers at mg / kg at Anti-cholinergic effect after acute toxicity intra- link Stomach acid Peroral ED, Q value Shay at insulin ED ₅₀ - ¥ ert Pulewka LD ₅₀ value peri- secretion in - ulcers Immobilisa ulcer in the crooked in in toneal Peroral tion ulcers intestine mg / kg . mg / kg ED ^ value \ 40 5 drawing perorally 300 in > 40 way mg / kg / * 40 > 40 Ileum '> 100 470 > 40 in Compound No. 11 18th > 40 40 > 1 > 100 520 800 (Example 4) > 40 Compound No. 12 20th > 40 > 1 > 100 1,800 45O (Example 5) > 40 Compound No. 13 30th > 1 > 100 1,500 (Example 5) Compound No. 14 15th 15.2 11.5 > 1 570 76 (Example 5) 20.7 Xanthene-9-carbon 17th acid (diethyl) methylammonium ether 20th 3.1O ~ ⁵ 320 -2-yl) ester bromide J methantheline]

From Table 1 above, it can be seen that the toxicity of the compounds according to the invention significantly lower when used intraperitoneally and when used perorally generally less than

that of the xanthene-9-carboxylic acid (diethylmethylammoniumeth-2-yl) ester bromide used as a reference substance is. In the case of some compounds, the difference is almost 1 order of magnitude in favor of the compounds according to the invention. Furthermore the therapeutic indices of the compounds according to the invention are more favorable than that of the comparison substance Xanthene ^ -carboxylic acid diethylmethylammoniumeth ^ -yl) - -ester bromide.

. In summary, it can be stated that the advantages of the compounds according to the invention over the currently disclosed in Secretion and ulcer-inhibiting substances used in therapy in the absence of anticholinergic effects, in the minor ones Toxicities and in the superior therapeutic indices exist.

Some of the compounds according to the invention also show the inhibitory effect exerted on the secretion and ulcers still have important anti-inflammatory properties. Regarding the anti-inflammatory effect, it is extremely beneficial that at the same time an inhibitory effect in relation to ulcers exists because, as is well known, the anti-inflammatory drugs that have been tried and tested in pharmacy Agents cause stomach ulcers as a side effect.

The anti-inflammatory action of compounds according to the invention was investigated by means of the carraghenin test on rats (method according to Winter [Proc. Soc. Exp. Med. 111. [1962], 544}). The rats were ^{injected with 0.1 car 5 of} a 1% orraghenin solution into the sole of the hind paw, and the increase in volume of the paw was measured after 3 hours. The compounds were used in a dose of.

- 10 509821/1044

100 mg / kg administered orally. The test results are compiled in the following table 2.

- 11 509821 / 10A4

-H table 2
Inhibitory effect of the compounds on carraghenin edema in rats

Examined
link Peroral dose
in
mg / kg inhibition
in
% Connection No. 1
(Example 1) 100 37 Connection No. 2
(Example 2) 100 40 Connection No. 3
(Example 2) 100 61 Connection No. 4-
(Example 2) 100 58 Compound No. 6
(Example 2) 100 37

- 12 -

Table 2 continued

σ
co
oo
ro

Examined
link Peroral dose
in
mg / kg inhibition
in
% Connection ITr. 9
(Example 2) 100 32 Compound No. 10
(Example 3) 100 40 Compound No. 11
(Example 4) 100 18th Compound No. 13
(Example 5) 100 50

CO O CX)

The "two substances, which had proved most effective (Compound Nos. 3 and 4) were further examined, it was found _n that in the carragheenin edema test the ED ₁ -Q-We ^ Tt of compound no.. 3 when administered intraperitoneally is 110 mg / kg. Under the same conditions, the EDcQ value of compound No. 4 is 70 mg / kg. The investigations were carried out by the method of Winter and coworkers (Proc. Soc. Exp. Med. 111 [ 1962 J, 544) The EDcQ value of 4-n-butyl-1,2-diphenylpyrazolidine-3,5-dione (phenylbutazone) is 40 mg / kg.

Compound no. 4 was further investigated by the cotton granuloma test according to Winter (J. Pharm. Exp. Ther. 141 fi963j, 369). With intraperitoneal administration for 1 week, the EDc-Q value found was 45 mg / kg.day. The 4-n-butyl-1,2-diphenylpyrazolidine-3,5-d.ione used as comparison substance showed the following ED values in the same experiment (according to T. Komatsu and colleagues, Arzneimittelforschung 22 [1972], 2 099):

at 25 mg / kg day 15% at 50 mg / kg day 19% at 100 mg / kg day 23%

EDj-Q values for 4-n-butyl-1,2-diphenylpyrazolidine-3 _i 5-dione could not be determined because the test animals died after treatment with 100 mg / kg daily for 1 week.

The compounds according to the invention can be in the form of conventional pharmaceutical preparations, for example pills, Tablets, capsules, granules, solutions or emulsions. They can be used in the pharmaceutical industry

- 14 5 0.9821 / 1044

customary carriers and / or auxiliaries are used by means of processes customary in pharmacy. The daily dose of the compounds according to the invention is expedient
10 to 500 mg.

The invention also relates to a process for the preparation of the compounds of the formula I according to the invention,
which is characterized in that

a) Haloacylpyridine hydrohalides of the general

formula

H-

I.
E - C - C --- Ep. HX ■ Il,

Il I

O X

wherein R ^ and Rp are as defined above and X stands for halogen, with thiobiurets or dithiobiurets of the general formula

III

wherein R,, R ^,, R ₁ - and X as defined above

are to be implemented or

b) 2-aminothiazoles of the general formula

509821/1044

N - H 3

IV,

wherein E ^, R ₂ and E ^ are defined as above, with isocyanates "and isothiocyanates of the general formula

X C «N -

wherein R ^, R, - and Y are as defined above, reacted be or

c) 2-aminothiazoles of the general formula

N- H

509821/1044

E ^, E2 and R-, as stated above, in the presence of strong inorganic or organic acids with alkali metal cyanates or alkali metal thiocyanates implemented or

d) thiazol-2-ylcarbamic acid ester, respectively Thiazol-2-ylthiocarbamic acid esters of the general formula

H-C

I Il -7 i-

—-Ο — Ε

YI,

■ 6

wherein

R2 and

as specified above

and E ^ - for a lower alkyl radical or a Phenyl radical, with amines or ammonia of the general formula

H-N

711

- 17 -

509821/1044

wherein R ^ and R, - are as defined above, implemented be or

e)! Thiazole-2-carboxylic acid azides of the general formula

y "

VIII,

G-N,

wherein R. and Rp are as defined above and Y denotes oxygen by heat treatment to give thiazol-2-yl isocyanates of the general formula

IX,

- 18 -

509821/10 A4

wherein R ,, and E2 are as defined above and Y oxygen "means to be reacted and the latter without isolation of the same with amines or ammonia of the general formula

H-N "VII

wherein R ₄ and R ₁ - are as defined above, are reacted or

f) 2-aminothiazoles of the general formula

R ₁ —η r— R.

N-H

where R ^ and R _{2 are} as defined above and R ^ is hydrogen, with carbon disulfide and dicyclohexylcarbodiimide to give thiazol-2-yl isothiocyanates of the general formula

- 19 - "

509821/1044

• Ε,

where R _x and Rp are as defined above and Y is sulfur, are reacted and the latter with amines or ammonia of the general formula

H-ii

VII,

in what will

and R ₁ - as defined above, implemented

or

g) li-thiazol-2-ylcarbamoylchloride, respectively N-thiazol-2-ylthiocarbamoyl chlorides of the general formula

XII

N-O-Cl

- 20 -

509821 / "10

worm E ^, H ^ »S ^ and Y are defined as above, with amines or ammonia of the general formula

H-N

VII,

B _r

where B ^ and Et- are as defined above, are implemented ₍ or

h) 2-aminothiazoles of the general formula

E.

IV,

N-H

where E ^, Ep and E ^ are defined as above, with carbamoyl chlorides or thiocarbamoyl chlorides the general formula

, R /

Cl-C-N

Ii

XIII

509821/1044

- 21 -

wherein R ₁ , and E _n - are as defined above, are reacted,

whereupon, if necessary, in a manner known per se, the obtained Bases of the formula I are converted into acid addition salts with inorganic or organic acids or the acid addition salts of the bases of the formula I obtained by reacting with basic substances to give the free ones Bases of the formula I or can be converted into other acid addition salts by reaction with other acids.

The method according to the invention is expediently described in Carried out in the presence of inert solvents or diluents. As a solvent or diluent can for example water, lower alcohols such as methanol, ethanol or propanols, ethers respectively ethereal compounds such as diisopropyl ether, di-n-butyl ether, ethylene glycol dimethyl ether, dioxane or [Tetrahydrofuran, acid amides such as methylformamide, dimethylformamide, Methylacetamide, dimethylacetamide, N-methylpyrrolid- -2-one or hexamethylphosphoric triamide, aromatic Hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons, such as methylene chloride, ethylene chloride, chloroform or chlorobenzene, or dimethyl sulfoxide respectively Mixtures of these can be used.

As Eeaktionstemperaturen be applied advantageously -20 to +200 ⁰ C.

To achieve optimal yields, it is advantageous to carry out the reaction according to variant a) of the invention Process close to the boiling point of the solvent used (water or a mixture of water / water

- 22 -

509821/1044

and a lower alcohol). With the variants b) and f) of the process according to the invention, if as Solvent ethers are used, preferably "at the boiling point the solvent worked; if dimethyl sulfoxide is used as the solvent, a reaction temperature of 90 to 100 C favorable. In variants b) and f) of the invention Process, it is appropriate to the reaction by adding 5 to 10 wt .-% triethylamine, based on the Amount of reactants to accelerate as a catalyst. The implementation according to variant c) of the invention Process can for example be carried out in the presence of strong acids in an aqueous medium, there are However, cases in which it is more advantageous to work in the presence of trifluoroacetic acid in benzene or toluene. the Implementation according to variant d) of the process according to the invention can, for example, be carried out at room temperature in dimethyl sulfoxide in the presence of alkali metals (such as sodium or lithium) or alkali hydrides (such as sodium hydride or lithium hydride) can be carried out, but as another possibility it is also possible to work without a solvent be by the thiazol-2-ylcarbamic acid ester respectively ü? hiazol ~ 2-yl thiocarbamic acid ester of the formula VI with an excess of the corresponding amine or can be made to react by ammonia. In the latter case it is when using low boiling points Amines or ammonia expediently to carry out the reaction in a closed container under pressure. The reaction according to variant e) of the process according to the invention is preferably carried out in the presence of aromatic hydrocarbons carried out as solvents or diluents, the reaction temperature being the boiling point of the solvent or a temperature close to this is selected. In variants g) and h) of the invention In the process, chlorinated hydrocarbons are preferably used as the solvent and an Aain is used as the acid acceptor

- 23 9821/1044

used in excess, "in variant h) of the process according to the invention expediently tertiary organic bases, for example pyridine, o (-picoline or triethylamine) are used. The temperature of the reaction mixture is initially kept at a low value by external cooling and then the reaction is completed by warming to room temperature, optionally up to 10O ⁰ C.

In the process of the invention, the reactants become generally brought to reaction in stoichiometric amounts. However, in some cases it can turn out to be Prove expedient to use the more accessible reactant in a slight excess.

In variant a) of the process according to the invention, the products fall as an acid addition salt with a hydrogen halide acid. In some cases it may be necessary to liberate the base from the salt obtained. To this Purpose can be as basic substances the alkali and alkaline earth hydroxides, carbonates and bicarbonates and also aqueous ammonia solutions can be used. The usage the latter is particularly advantageous.

If the product is obtained in the form of the free base, can these are converted into salts in a manner known per se.

The acid addition salts are those with inorganic acids, primarily hydrogen chloride, hydrogen bromide, Sulfuric acid and phosphoric acid, and those with organic acids, especially maleic acid, fumaric acid and D-tartaric acid, into consideration.

The invention is not considered a limitation on the basis of the following, Examples to be understood are explained in more detail.

- 24 · 509821/1044

example 1

N- | V- (3'-pyridyl) -thiazol-2-yl] »urea (Connection no.1)

a) Variant a) of the process according to the invention

A mixture of 5-7 g of 3-bromoacetylpyridine hydrobromide, 3.6 g of thiobiuret and 50% of water was heated to 95 ° C. for 2 hours. The solution was filtered hot, heated again to 95 ° C. and made alkaline with a 25% aqueous ammonia solution with vigorous stirring or shaking. The solution was then cooled with ice water and the precipitated product was isolated. Thus, 3.9 g (91% of theory) of N-fl · - (3'-pyridyl) - thiazole-2-yij-urea having a melting point 318-319 ⁰ C obtained.

b) Variant c) of the process according to the invention

It was a suspension of 4-, 4-5 g of 2-amino-4- (3'-pyridyl) -thiazole (J. Heterocyclic Chem. £ 97Ojf, 1,139) and 3.25 g of sodium cyanate in 75 cnr anhydrous toluene with vigorous stirring or shaking at 4-5 to 50 ^° C. for 2 hours, a solution of 5> 7 g

7th

Trifluoroacetic acid in 25 cnr anhydrous toluene was added dropwise. The mixture was then for 2 hours to Boiling heated. After cooling, the toluene was through

Decant away. The residue was 150 cnr one Treated 4% hydrochloric acid, the resulting solution was filtered and the pH of the filtrate was adjusted to 9 with an 8% aqueous ammonia solution. The precipitation was separated off, dried and converted from acetone

- 25 509821 / 10U

crystallized. 3A5 S (63% of theory)

N- [4- (3'-pyridyl) -thiazol-2-yl] -urea with an enamel

receive point 316-318 ⁰ G.

Example 2

i-Isopropyl-3- \ K '- (3'-pyridyl) -thiazol-2 -ylj -

-urea

(Compound No. 2) Variant b) of the process according to the invention

A mixture of 5.32 g of 2-amino-4 ~ (3'-pyridyl) - thiazole, 13 om ^ anhydrous dimethyl sulfoxide, 0.5 cnr anhydrous triethylamine and 3 g of isopropyl isocyanate was obtained for 2 hours

ο -5

heated to 100 C for a long time and then poured into 50 cnr cold water. The precipitated product was filtered off, washed with water and dried at 100 ⁰ C. 6.4 g (81% of theory) of i-isopropyl-3- | 4 '- (3 "- pyridyl) -thiazol- -2'-yIj -urea, which after recrystallization from methyl ethyl ketone had a melting point of 297 to 301G.

When using methyl isocyanate, ethyl isocyanate, n-propyl isocyanate, n-butyl isocyanate, cyclohexyl isocyanate, Phenyl isocyanate or p-chlorophenyl isocyanate Instead of the isopropyl isocyanate, those listed in Table 3 below were compiled in the manner described above Get connections.

509821/1044

r- 26 -

Tabel

CD CO OO

Ϊ »...
; "Verbii
No. idung
Description . Melting point
in
⁰ C 3 1-methyl-3- [V- (3 "-pyridyl) -thiazol-2'-yl] -urea 310 to 313 4- 1-ethyl-3- [4 ^u - (3 "- pyridyl) -thiazol-2'-yl] -urea 312 to 314 5 1- (n-Propyl) -3 - [^ '- (3 ¹ ' -pyridyl) -thiazol-2'-yl] -
-urea 172 to 174 6th 1- (n-Butyl) -3-f4 '- (3 ·' -pyridyl) -thiazol-2'-yl] -
-urea 182 to 188 7th 1-Cyclohexyl-3- [ft- ^l - (3 ' ¹ ' -pyridyl) -thiazol-2 '-ylj-
-urea 226 to 228 8th 1-Phenyl-3- [ ^z »- ¹ - (3" -pyridyl) -thiazol-2 '-yl] -urea 314 to 3I6 9 1- (p-Chlorophenyl) -3 - &'-(3''-pyridyl)-thiazol-2' -ylj -
-urea 303 to 3O6

Example $

1-ethyl-3-methyl-3- (V - (3 ¹ '-pyridyl) -thiazol-2'-yl] -

-urea

(Compound No. 10) Variant b) of the process according to the invention

3.83 g of 2-methylamino-4 ~ (3'-pyridyl) -thiazole, 0.5 cnr of anhydrous triethylamine, 40 cur of anhydrous ethylene glycol dimethyl ether (1,2-dimethoxyethane) and 2.2 g of ethyl isocyanate were refluxed for 6 hours heated to boiling. The solvent was then evaporated under reduced pressure and the residue was recrystallized from a mixture of isopropanol and petroleum ether. 3.9 g (74% of theory) 1-ethyl-3-methyl-3-J4 · - (3 "-pyridyl) -thiazol-2 · -yl] -.-urea with a melting point of 142 to 14-5 ⁰ C obtained.

example

1-Isopropyl-3-methyl-3- [4 '- (3 ¹ ' -pyridyl) - -thiazol-2 · -yl] -urea

(Compound No. 11) Variant b) of the process according to the invention

The procedure described in Example 3 was followed, with the difference that 2.55 S isopropyl isocyanate were used instead of ethyl isocyanate. Thus, 4.68 g (83% of theory) 1-isopropyl-3-methyl-3- - (V - (3 · '-pyridyl) -thiazol-2'-yl] -urea, which after recrystallization from benzene had a melting point of 105 to 108 ⁰ O was obtained.

- 28 509821/1044

Example 5

1-Oyclopropyl-3-methyl-3- [V- (3 "-pyridyl) - -thiazol-2'-yl | -thiourea

(Compound No. 12) Variant b) of the process according to the invention

A mixture of 11.5 g of 2-methylainino-4- (3'- pyridyl) thiazole, 30 cnr of anhydrous ethylene glycol dimethyl ether (1,2-dimethoxyethane), 1.5 cm of anhydrous triethylamine and 8.4 g of cyclopropyl isothiocyanate was obtained Heated to boiling under reflux for 5 hours and then kept in a refrigerator overnight. The precipitated crystals were separated. So were 12.56 g (72% of theory) 1-cyclopropyl-3-methyl-3- [4 ^? - (3 '' - pyridyl) ~ thiazol-2'-YLJ thiourea, the (1,2-dimethoxyethane) had a melting point 136-139 ⁰ C after recrystallization from ethylene glycol dimethyl ether was obtained.

When working in the manner described above, but using 2-amino-4 ~ (3'-pyridyl) -5- -methylthiazole in place of the 2 »methylamino-4- (3'-pyridyl) - thiazoles or methyl isothiocyanate, allyl isothiocyanate and benzyl isothiocyanate instead of cyclopropyl isothiocyanate were those in the following Table 4 obtained compounds compiled.

- 29 509821/1044

CD CO CO

- 29 - Table

■ - verb
No. indung
description Melting point
in
⁰ C 13th 1-Cyclopropyl-3-C ⁴ " ¹ -C3" -pyridyl) -5-methyltniazole ~ 2 '-
-ylj-thiourea 258 to 261 14th 1,3-I> imethyl-3- [4 '- (3 "-pyridyl) -thiazol-2 ¹ -yl] -
-thiourea 168 to 169 15th 1-Benzyl-3-methyl-3- [4 '- (3 ¹ ' -pyridyl) -thiazol-2'-
-ylj -thiourea 181 to 182 16 1-Allyl-3-methyl-3 - ['4' - (3 ^t '-pyridyl) -thiazol-2' -yl] -
-thiourea 105 to 110

- 30 -

The cyclopropyl isotiocyanate used as starting material above has been obtained as follows. "

There were added to a solution of 4 to 3.2 g of sodium hydroxide 100 m cur water 66 cnr carbon disulfide added and then the Eeaktionsgemisch was' cooled with ice water to ⁰ +10 G Then, with stirring or shaking for 25 minutes 61.6 g of cyclopropylamine is added . It was still - stirred ^ hour or shaken and then heated to 80 ⁰ C. The mixture was stirred or shaken for 2 hours at this temperature.

The reaction mixture cooled to room temperature

1 ⁷ y

105 cnr of ethyl chloroformate were added dropwise over a period of 4 hours. The mixture was stirred or shaken for a further −π hour at room temperature. The oily upper phase was then removed, the aqueous phase was extracted by shaking with ether, the ethereal solution was added to the separated oily phase, this was dried and finally the ether was evaporated off under reduced pressure. Yield j 63.2 g (58.5% of theory) of cyclopropyl isothiocyanate; Boiling point: 105 "to 107 ° C / 16O Torr.

Example 6

1-phenyl-3- [4- ^l - (3 ^l '-pyridyl) -thiaζol- -2 · -yl] -urea

(Compound No. 17) Variant e) of the process according to the invention

There was added 0.5 g of 4- (3'-pyridyl) -thiazol-2-ylcarbonsäureazid in 5 cnr anhydrous benzene at 80 ⁰ C heated. After the evolution of gas had ceased, 0.4 g of freshly distilled aniline and 0.1 cnr of anhydrous triethylamine were added to the mixture

- 31 509821/1044

added and the reaction mixture was ^{held at 80 °} C. for a further 30 minutes. After cooling, the product was isolated by filtration. So was 0.28 g (46% of theory) 1-phenyl-3- [4 '- (3 "-pyridyl) -thiazol-2'-yl] -urea, which after recrystallization from a mixture of dimethylformamide and Ethanol had a melting point of 298 to 306 ⁰ C obtained. With the product 1-phenyl-3- [4 '- (3''-pyridyl)-thiaζol-2'-yl] - prepared from 2-amino-4- (3'-pyridyl) -thiazole and phenyl isocyanate according to Example 2 urea (compound no. 8), the compound has a melting point ^296-0

The 4- (3'-pyridyl) -thiazο1- used as starting material -2-ylcarboxylic acid azide has been obtained as follows:

There were added to a solution of 14.2 g of 4- (3 * -pyridyl) -thiaζol- -2-carboxylic acid ethyl ester in 60 cnr methanol 15 cnr 72% hydrazine hydrate. After a few minutes, crystals separated out from the red solution and separated off. Thus were 12.25 g (93% of theory) of 4- (3'-pyridyl) -thiazol- -2-carboxylic acid, which had after recrystallization from isopropanol, melting point 176-180 ⁰ C, was obtained.

2.2 g of the 4- (3'-pyridyl) -thiazole-2-carboxylic acid hydrazide obtained as described above were suspended in 25% of water. The suspension was cnr 1 a 37% ^en -ig added hydrochloric acid. Then 0.7 S sodium nitrite in 5 cnr v / water was added dropwise with stirring or shaking and ice-water cooling. A yellow suspension was formed from which the product was filtered off after 15 minutes. It was dried at 30 ⁰ C. 2.15 g (93% of theory) of 4- (3'-pyridyl) -thiazol-2-ylcarboxylic acid azide with a melting point of 113 Ms 119 ° C. were obtained.

- 32 509821/104 / *

2A53082

Example 7

1- (n-Butyl) -3- [4 '- (3 ·' -pyridyl) -thiazole- -2'-ylj-urea

(Compound No. 18) Variant e) of the process according to the invention

The procedure described in Example 6 was repeated, with the difference that n-butylamine was used instead of the aniline. Thus, 0.24 g (4-3% of theory) of 1- (n-butyl) -3- [4 '- (3 ^! ' -Pyridyl) -thiazol-2'-yl] -urea was obtained as a product with a melting point obtained from 180 to 185 ° C.

Example 8

1-methyl-3 - & - ^l - (3 ' ^f -pyridyl) -thiazol- -2 · -yl] -urea

(Compound Rr. 19) Variant a) of the process according to the invention

A mixture of 5-7 g of 3-bromoacetylpyridine hydrobromide, 4.0 g of 1-methyl-4-thiobiuret (Ber. 2 £ [1892J, 750) and 40 cnr of water was stirred or shaken at 95 ° C. for 1 hour. The solution was filtered hot and its pH was adjusted to 8.5 with an 8% strength aqueous ammonia solution. The product was filtered off, washed with water and finally dried at 60 ⁰ C. 3.8 g (81% of theory) 1-methyl-3- [4 '- (3 "- -pyridyl) -thiazol-2'-yIJ-urea with a melting point of 309 to 313 ° C. were obtained.

- 33 509821/1044

Example 9

1-ethyl-3- [V- (3 "-pyridyl) -thiaζol- -2'-yl] urea

(Compound no.20)
Variant a) of the process according to the invention

The procedure described in Example 8 was followed, but with the difference that 1-ethyl-4-thiobiuret (Ber. 2 £ [750) was used in place of 1-methyl-4-thiobiuret. Yield: 3 »67 g (.7 ¹ week of theory) 1-ethyl-3- & ■ · - (3" -pyridyl) -thiazol-2 · -yl] -urea with a melting point of 311 to 315 ° C.

Example 10

1-phenyl-3- [4 -'- (3 "-pyridyl) -tliiazole- -2'-yl] urea

(Compound No. 21) Variant a) of the process according to the invention

The procedure described in Example 8 was repeated, with the difference that 1-phenyl-4-thiobiuret (JACS $ 1 [1929J ₅ 2 223) was used as the starting substance instead of 1-methyl-4-thiobiuret. Thus, 1-phenyl-3- [V- (3 X '-pyridyl) -thiazol-2'-yl] -urea was obtained with a melting point of 310-316 ⁰ C in 80% yield.

Claims 509821/1044

Claims (6)

Claims "I.) Substituted thiazoly! Urea or Thiazolylthiourea derivatives of the general formula N-G-N R, ^X 4- * 5 wherein stands for an iyridyl radical, and R ^ independently of one another hydrogen or mean lower alkyl radicals, Represents oxygen or sulfur 509821/104 k ^, iind Rc independently of one another for hydrogen, lower alkyl radicals, allyl radicals, cycloalkyl radicals with 3 to 6 members or, optionally substituted by halogen, phenyl radicals or ^, and Ec together with the nitrogen atom of Carbamide or thiocarbamide group to which it is attached are, heterocyclic elements of the general formulas respectively - 36 - 509821/1044 in which latter η is a number from 4- Ms 7 and Z oxygen or a group of the formulas ^ W - H, ^ N - CH, means to represent
as well as their acid addition salts. 2.) Thiazolylurea or thiazolylthiourea derivatives according to claim 1, characterized in that the lower alkyl radicals for which Ro> R *> R ^ and / or R ₁ - can or can have 1 or 2 carbon atoms. 3.) Thiazolylurea or thiazolylthiourea derivatives according to claim 1 or 2, characterized characterized in that the cycloalkyl radicals for which R ^, and / or R, - can stand or can, Cyclopropyl, cyclopentyl or cyclohexyl radicals are. 4-.) Thiazolylurea or thiazolylthiourea derivatives according to claim 1 or 2, characterized in that the halogen by which the phenyl radical or the phenyl radicals, for which R 1 and / or R ₁ - can or can be, can or can be substituted can be chlorine or bromine. - 37 - 509821/1044 5 ·) Thiazoly / urea- '"or thiazolylthiourea derivatives according to claim 1 or 2, characterized in that η 5 "to 7> in particular 5 »is. 6.) Medicines, characterized by a content to 1 or more compounds according to claims 1 to 5 as active ingredient or ingredients, expediently together with customary pharmaceutical carriers and / or auxiliaries. 7 ·) Process for the preparation of the compounds according to claim 1 to 5 »characterized in that one a) Haloacylpyridine hydrohalides of the general J formula H
I.
IL, - C - C - Rv .HX II, 0 X wherein E _x and Eo are as defined in claim 1 or 2 and X is halogen, with thiobiuretene or dithiobiuretene of the general formula Ill, Ö XW X Sr _x ο wherein R,, R ^, E ₁ - and. 1 as defined in claims .1 to 5, implements or - 38 509821/1044 b) 2-aminothiazoles of the general formula TS- N-H IV, wherein Ε, -, IL ^ ^and R * ^w ^ ^e ^ ^m claim 1 or 2 are defined, with isocyanates or isothiocyanates of the general formula Y = C-N-R wherein R ^,, R, - and Y are as defined in claim Λ , 3 »4 or 5, converts or c) 2-aminothiazoles of the general formula - 39 - 509821/1044 IV, IT-H wherein ^and Claim 1 or . , Rg ^and R *
2 are set, in the presence of strong inorganic or organic acids with alkali metal cyanates or alkali metal thiocyanates or d) thiazol-2-ylcarbamic acid ester, respectively Thiazol-2-ylthiocarbamic acid esters of the general formula 509821/1044 R, • Ε, σ - 0 - E, VI, wherein Ry,, Rp and R ^ as in claim. 1 or 2 and Rg is a lower alkyl radical or a phenyl radical stands, with amines or ammonia of the general formula R. H-N VII wherein R ^ and R ₁ - are as defined in claim 1, 3, 4 · or 5, reacts or 'Thiazole-2-carboxylic acid azides of the general formula 509821 / 1OAA E. ir C-N, VIII, wherein R. and Rp as defined in claim 1 or 2 are and 'Y is oxygen, by heat treatment to thiazol-2-yl isocyanates of the general a formula wherein R ^ and R ^ as defined in claim 1 or 2 and Y is oxygen, and the latter without isolating the same with amines, respectively Ammonia of the general formula H-N VII 509821/1044 wherein R. and R ₁ - as in claim. 1, 3 »4- or 5
are set, implements or f) 2-aminothiazoles of the general formula -R, IV, N-H wherein R. and Rp are as defined in claim 1 or 2 and R ^ is hydrogen, with carbon disulfide and dicyclohexylcarbodiimide
Thiazol-2-yl isothiocyanates of the general formula 509821/1044 wherein R ^ and Rp as in claim. 1 or 2 set and Y is sulfur, and the latter with amines or ammonia of the general formula R / i H-U VII wherein R ^ and R ₁ - are as defined in claim 1, J, 4 or 5, reacts or g) N-Thiazol-2-ylcarbamoylchloride "respectively N-Thiazol ^ -ylthiocarbamoylchloride of the general formula U-O-GL R ₅ r XII 509821/1044 wherein and T as in claim. 1 or 2 are set, with amines or ammonia of the general formula H - Έ ' * 4 VII wherein R ₇ , and R ₁ - are as defined in claim 1, 3, 4 or 5, converts or h) 2-aminothiazoles of the general formula IV, N-H wherein R ^, R ₂ and R ^ are as defined in claim 1 or 2, with garbamoyl chlorides or thiocarbamoyl chlorides of the general formula -R / Cl-G-N Il ' XIII, 5 0 9 8 2 1/1 over 4 hours wherein E ^, and R, - as in claim 1, 3, 4 or 5 are established, implements, whereupon, if necessary, in a "known manner." the bases of the formula I obtained are converted into acid addition salts with inorganic or organic acids or the acid addition salts of the bases of the formula I obtained by reaction with basic substances decübcrnel I into the free bases or by reacting converted into other acid addition salts with other acids . 509821/1044