CS227049B2 - Method of preparing 2,4-di-substituted thiazol derivatives - Google Patents

Description

The present invention relates to certain novel thiazole derivatives which have been found to be potent antagonists of the H 2 -receptors of histamine and are therefore useful in the treatment of peptic ulcers.

The most successful H2-receptor antagonist developed so far is the imidazole derivative cimetidine, i.e. N-cyano-N'-methyl-N '- {2 - [(5-methyl-1H-imidazol-4-ylmethyl) thio] methyl } guanidine, which may be represented by a structural formula

N-CN

II

H (Y-c-CH 2 S-C 4 NH-C-NH-CN), see, for example, Brit. J. Pharmacol. 53, 435p (1975)]. This compound has achieved great success in the treatment of peptic ulcers in human medicine.

In accordance with the invention, it has now been found that the thiazole derivatives of general formula I

IZ7

T

CHRISTINE

R ¹ and R ² are each independently hydrogen, C 1 -C 4 alkyl, benzyl, or benzoyl, or both together with an adjacent nitrogen atom form a saturated 5- to 7-membered heterocyclic ring containing optionally another heteroatom selected from the group consisting of oxygen and nitrogen,

R ³ represents a hydrogen atom or a C 1 -C 4 alkyl group,

Z is oxygen, sulfur or CH2, n is 2 or 3 when Z is oxygen or sulfur and 1, 2 or 3 when Z is CH2,

R ⁵ represents a hydrogen atom or a C 1 -C 4 alkyl group, m is 1, 2 or 3,

Q represents the remainder of the formula and o * c-c = o where

A is N-CN, N-NO 2, CH-NO 2, S, O, NH, N-SO 2 -aryl, N-SO 2 -alkyl, N-CO-NH 2, N-CO-alkyl, N-CO 2 - alkyl, CH-SO 2 -aryl or CH-SO 2 -alkyl, wherein the alkyl contains 1 to 4 carbon atoms and the aryl is a phenyl group, a halophenyl group, an alkylphenyl group having 1 to 4 carbon atoms in the alkyl moiety or an alkoxyphenyl group having 1 to 4 atoms carbon in the alkoxy moiety, and

B is a radical of the formula -NRR ⁶ wherein

R @ ⁶ and R @ ⁶ are each independently hydrogen, C1 -C5 alkyl, C3 -C6 cycloalkylmethyl, C2 -C5 hydroxyalkyl or C3 -C6 cycloalkyl. or a alkoxyalkyl or dialkylaminoalkyl group in which the total number of carbon atoms is less than 8 and wherein there is a chain of at least two carbons between the heteroatoms, and pharmaceutically acceptable salts thereof, are particularly potent H 2 -receptor antagonists or useful intermediates for preparing such compounds.

Preferred are those compounds of formula I wherein:

R ¹ and R ² independently represent hydrogen, or alkyl of 1-3 carbon atoms, or only one of ^R1 and ^R2 may represent benzyl or benzoyl, or R ¹ and R ² together with the adjacent nitrogen atom, form piperidino, pyrrolidino or morpholino, provided that only one of R ¹ and R ² can be hydrogen when Z is -CH 2,

R ⁵ represents a hydrogen atom or a C 1 -C 3 methyl group,

R ⁵ represents a hydrogen atom or a methyl group,

A is N-CN, N-NO2,

CH-NO2, S, O, NH, N-SO2-aryl, N-SO2-alkyl, N-CO-NH2, N-CO-alkyl, N-CO2-alkyl, CH-SO2-aryl or CH-SO2- CH3 in which the alkyl contains 1 to 3 carbon atoms and the aryl is a phenyl group, a halophenyl group, an alkylphenyl group having 1 to 3 carbon atoms in the alkyl moiety or an alkoxyphenyl group having 1 to 3 carbon atoms in the alkoxy moiety,

R ⁶ represents a hydrogen atom, and pharmaceutically acceptable, non-toxic acid addition salts thereof.

Further preferred meanings of the individual general symbols in the compounds of the invention are summarized in the following overview:

(a) Z is sulfur, (bj n is 2, (cj R ³ is hydrogen, (d) R ⁵ is hydrogen, (ej m is 1, (fj R ¹ and R ² are methyl, ( gj grouping

R ¹ - (CHR ⁵ _µm —N \

R ² is a dimethylaminomethyl group, (h) A is NCN or CHNO2, (B ij represents a radical of the formula NR ⁶ wherein

R is hydrogen and R ⁶ is C 1 -C 4 alkyl and (j) B is methylamino.

Preferred compounds of the invention are:

N-methyl-N - ([2- (dimethylaminomethyl) -4-thiazolyl] methylthioethyl-2-nitro-1,1-ethylenediamine,

N-methyl-N‘-2 - {[2- (dimethylaminomethyl] -4-thiazolyl] methylthio; ethyl-N'-cyanoguanidine and pharmaceutically acceptable salts thereof.

1-4C-Alkyl groups of formula I are methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like. and p-tolyl, O-, m- and p-ethylphenyl, and the like. Analogously, C 1 -C 4 alkoxyphenyl groups in the alkoxy moiety include O-, m- and p-anisyl, O-, m- and The term "halophenyl" refers to O-, m-, and p-chlorophenyl, -bromophenyl, -fluorophenyl, and iodophenyl.

C 1 -C 5 alkyl groups include all of the above alkyl groups

C 1-4 alkyl groups in addition to n-amyl, isoamyl, 2-methylbutyl, 2-methyl-2-butyl and the like.

C 3 -C 6 cycloalkyl groups include cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, methylcyclopentyl and the like.

Illustrative examples of alkoxyalkyl or dialkylaminoalkyl groups having a total of less than 8 carbon atoms and wherein the heteroatom is separated from the nitrogen atom to which it is attached by a chain of at least two carbon atoms include 2-methoxyethyl, isopropoxyethyl, 3-ethoxy- 2-methylpropyl, 2- (2-pentyloxy) ethyl, 2-dimethylaminoethyl, diethylaminoethyl, 2-methylpropylamino-2-propyl and the like.

Pharmaceutically acceptable salts of the compounds of the present invention include those derived from inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and the like. Also salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyaicanoic acids, and alkanedioic acids, from aromatic acids, aliphatic and aromatic sulfonic acids, and the like. , pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, ma lelates, salts with mandelic acid, butyne-1,4-dioates, hexin-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, benzenesulfonates, toluenesulfonates, chlorobenzenesulfonates, phenylenesopropionates, phenylenesopropionates , phenylbutyrates, citrates, lactates, β-hydroxybutyrates, propanesulfonates, 1-naphthalenesulfonates, 2-naphthalenesulfonates and the like salts.

The compounds of formula (I) above contain at least one basic center, namely an aminoalkyl group on the carbon atom at the 2-position of the thiazole ring, but may also contain a second or third basic salt-forming center. For example, a substituted amidine terminal moiety may also contain nitrogen atoms which, depending on the nature of the substitution, may be sufficiently basic to form salts with non-toxic acids.

The present invention is a process for preparing compounds of the formula I and their pharmaceutically acceptable salts, characterized in that a compound of formula VI ft ³ .CH _of Z- (CH _Z) -NH-L-Q ^Z

In / (villa in which

R ¹ , R ² , R ³ , R ⁵ , Z, Q, m and n are as defined above and

L ² is a leaving group, reacted with an amine of formula

HNRR ⁶ wherein

R and R ⁶ are as defined above, and the resulting product of formula I is optionally converted into a pharmaceutically acceptable salt thereof.

The leaving group in the meaning of the symbol L ² is preferably a radical of the formula -YR ⁴ in which

Y is oxygen or sulfur; and

R ⁴ represents a C 1 -C 5 alkyl group, a —CH 2 -alkenyl group wherein the alkenyl group contains 2 to 4 carbon atoms, or a benzyl group.

The reaction of the invention is preferably carried out at a temperature of 20 to 100 ° C in a polar solvent such as water or a C 1 -C 4 alkanol.

The basic precursors of the starting materials of the general formula (VI) are the amide derivatives of the general formula (V), the preparation of which is illustrated in Reaction Scheme A in which the sulfur compound Z is used as a non-limiting example.

Scheme A? with ^X N- (CHRfC6-NfyHX)

Br 1 CHR-CO-CO _from a.lk (II)

Rf = 1 - CO ₂ * 1k / R ¹ (CHR ⁵ ) 4 (III) ^X R

R-y = CH 2 OH

V ϊ (IV) (CHR 11) N ² R ²

HBr

RH R (Vi) (CHR ^S ) jr

R

HS- (CH _z) n NH _of

-CH 2 S-fCH 3 J 1 H 2 4

In the above Scheme, "alk" is suitably a methyl or ethyl group and R ¹ , R ² , R ³ , R ⁵ , m and n are as defined above. LiBEt3H represents lithium triethylborohydride.

In accordance with the above procedure, the acid addition salt of aminoalkylthioacetamide is reacted with the β-bromo-α-ketoester of formula II, such as ethyl bromopyruvate (R ³ = H ³ to form alkyl (methyl or ethyl) -2- (aminoalkyl) The reduction of this ester with a suitable hydride reducing agent such as lithium triethylborohydride, lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride and the like gives the corresponding hydroxymethyl derivative of formula IV. ω-thiopropylamine, in the presence of an acid, 2 - [(2-aminoalkyl-4-thiazolyl) methylthlojalkylamine of formula Va, optionally substituted at the 5-position of the thiazole ring by an alkyl group, is obtained directly.

In Scheme A, a compound of formula (IV) can be converted to a compound of formula (V) by treatment with a hydroxymethyl group such as thionyl chloride to form 4-chloromethylthiazole and then reacting with a sodium salt of the appropriate mercaptoalkylamine. In principle, any standard leaving group (nucleophilic substitution labile), including, for example, p-tosyloxy, mesyloxy (methanesulfonyloxy), bromine, iodine, and the like, may be used in place of chlorine in the chloromethyl side chain.

Alternatively, 4-chloromethylthiazole hydrochloride (or other suitable acid addition salt) can be melted with a mercaptoalkylamine salt such as the hydrochloride of the amine to provide the desired primary amine, i.e., a compound of formula Va wherein Z is sulfur.

If an analog of the compound of formula Va containing an oxygen (Z-O) side chain is to be prepared, a process in which 2-chloroethylamine or 3-chloropropylamine is reacted with 4-thiazolylmethanol under basic conditions as well as a procedure analogous to Williamson synthesis of ethers in which the hydroxyalkylamine sodium salt is reacted with 4-thiazolylmethyl halide.

A substituted aminothioacetamide hydrohalide of the formula

R ¹ X \ II

N - CH2 - C - NH2. HX in which

R ¹ and R ² are C 1 -C 4 alkyl groups shown in Reaction Scheme A, representing known compounds such as dimethylaminothioacetamide, diethylaminothioacetamide and the like in the form of hydrohalides. These compounds can be prepared as described in J. Org. Chem., (Russia, B 884 (1970)).

The precursors of formula (V) are converted into the starting materials of formula (VI) by treatment with suitable reagents, which are then reacted with the amines of formula (NHRR8 ⁾ to give compounds of formula (I).

This process is illustrated by the following Reaction Scheme B, in which Z, R ¹ to R ⁶ , m, are as defined above:

R2

Scheme B

R 1 .CH ₂ -Z- (CH ₂ ) 4 NH ₂ , R 1

V) ( ^{CHR) r N} ( _R) 2 (CH, S) _from CH 2 CH-NO ₂ ³ (VIIIb) (CH ₃ S) _from ON-CN (VIIIa)

RH (CHR ⁵⁾ ^

N-CN • CH _from Z- (CH ^ NH-CSC ^ (Via)

O, N-CH ² II

RCH 2 -Z-CH 2 NH-C-S

CH,

R '(VIb)

AND

NHz. R

N-CN

II

R CH ₂ Z- (CH ₂ ) 4 NH-C-NH-R (1) nh ₉ r

O-N-CH

R 1 -CH-Z-ICH 4 NH-C-NHR ^S 4 ^N 4

T (CHR ^X R ^Z (lb))

For example, dimethyl cyandithioimidocarbonate is reacted with a thiazolylmethylthioalkylamine or other amine of formula V containing a thiazolyl side chain to give N-2 - [(2-aminoalkyl-5-optionally substituted-4-thiazolyl) methylthio] ethyl (or propyl) -S-methyl-N'-cyanopseudothiourea (VIa; Z-S) Reaction of this compound with a primary amine of formula NH ² R ⁶ yields the desired product of formula Ia Those compounds in which A is CH-NO 2 and the like, as in of Formula VIb, are prepared similarly and similarly 1 reacted to form an analogous final product with an ethylenediamine terminal moiety as in Formula 1b.

In the reaction of a compound of formula V to form a compound of formula VIb, 1-methylsulfinyl-1-methylmercapto-2-nitroethylene can be used instead of 1,1-bis-methylmercapto-2-nitroethylene to give the same intermediate of formula VIb because the methylsulfinyl group is in the substitution reaction is preferred over methyl mercapto.

According to the above procedure, in some cases, a reagent corresponding to Formula VIIIa or VIIIb may be used in which the SCH3 moiety is replaced by the OCH3 moiety. This methoxy group is exchanged by reaction with an amine of the formula NH ² R ⁶ in the same manner as described above for the group SCH 3. For example, compounds of formula (CH3O) 2-C-A wherein A is N-CN may be used.

The process of Reaction Scheme B may be modified using the appropriate oxygen-containing side-chain starting materials to provide compounds of formula I wherein Z is oxygen.

The starting materials of formula V in which Z is CH 2 and n is 1, 2 or 3 can be prepared according to the following reaction scheme C.

## STR3 ## Br (XVI) @ +

N-CH3-CS-NH4 HCl

2 ^ lower alkanol heating

lower alkanol

NH2NH2. H2O

In the formulas shown in this scheme, R ¹ , R ² , R ³ , R ^{5 have the} meanings given above.

In accordance with Reaction Scheme C, ω- (phthalimino) alkyl halomethyl ketone of formula XVI is reacted with dimethylaminothioacetamide hydrochloride to give 2-aminoalkyl-5-optionally substituted-4- (γ- (phthalimidoyalkylthiazole (XVII)). alkali hydrolysis using an alkali metal hydroxide solution followed by dilute hydrochloric acid may be used, and the product of formula (Vc) obtained as a primary amine corresponds to the starting material of formula (Va). The reaction is carried out in accordance with Reaction Scheme A, and may be reacted to give the compounds of formula I wherein Z is CH 2.

In the above reaction schemes, the aminoalkyl group at the 2-position of the thiazole ring is presented in all reaction steps in the unaltered form as it was present in the starting material (starting material in Reaction Scheme AJ). when either or both R ¹ and R ² are hydrogen. for example, in the case where R ^J is hydrogen and R 2 an alkyl group, when a given reaction scheme to the preparation of the hydroxymethyl derivative IV can be to use a benzyl protecting a group which can then be cleaved from the protected compound of formula IV by catalytic hydrogenation to regenerate the secondary amine group NHR ^2. Similarly, an acyl protecting group, such as a benzoyl group, can be removed by reduction to lithium triethylborohydride alcohol. using By analogy, if a primary alkylamino group is to be present at the 2-position of the thiazole ring, a suitable protecting group, such as phthalimido, may be used. In this instance, such a starting material wherein R ¹ and R ² together with the nitrogen atom to which they are attached, form a phthalimido group. This grouping may be maintained throughout the synthetic process until it is desired to be removed by hydrolysis, for example hydrazine. The aforementioned protecting group is particularly preferred when 4-chloromethylthiazole is used as an intermediate.

It will be understood that the guanidines and ethenediamines of the invention may exist in a variety of tautomeric forms. It will be appreciated that in each such case, even if only one tautomeric form is described or drawn, the invention includes all other tautomeric forms.

The invention is illustrated by the following non-limiting examples.

Preparation 1

Morfolinothioacetamld

To a mixture of 203 ml of triethylamine and pyridine, each containing 63 g of morpholinoacetonitrile, hydrogen sulfide gas was introduced under stirring and heating for about 2.5 hours. Stirring was continued overnight and the next day hydrogen sulfide was added to the reaction mixture while heating. The solvents were removed in vacuo, the residue was triturated with ether, the ether discarded and the residue dissolved in ethanol. The precipitated rat 16 morpholinothioacetamide is filtered off and converted into morpholinothioacetamide hydrochloride by melting at 64-80 ° C with an alcoholic solution of hydrogen chloride (see also J. Am. Chem. Soc., 72, 2804 (1950)).

Using the procedure described above, piperidinothioacetamide hydrochloride was prepared by substituting piperidinoacetonitrile for morpholinoacetonitrile, melting after recrystallization from ethyl acetate at 166-168 ° C (see also Helv. Chim. Acta, 43, 659 (1960)).

Starting from 62 g of the starting piperidinoacetonitrile, 35 g of the above product is obtained.

Using the above procedure, 68.4 g of new pyrrolidinoacetamide hydrochloride melting at about 195 to 197 ° C are obtained using 100 g of pyrrolidinoacetonitrile.

Analysis:

calculated:

C 39.88%, H 7.25, N 15.50, S 17.74; found:

% C, 39.66;% H, 6.99;% N, 15.76.

Using the above procedure, a new N-methyl-N-ethylaminothioacetamide hydrochloride was prepared using 49 g of methylethylaminoacetonitrile, 200 ml of triethylamine and 200 ml of benzene, melting at 115-117 ° C.

Example 1

Preparation of ethyl 2- (dimethylaminomethyl) -4-thiazolecarboxylate

A mixture of 15.5 g of dimethylaminothioacetamide hydrochloride, 20.5 g of ethyl bromopyruvate and 100 ml of ethanol was heated at reflux for about 4 hours, after which time the solvent was removed by rotary evaporation in vacuo. The residue containing ethyl 2- (dimethylaminomethyl) -4-thiazolecarboxylate formed in the above reaction was dissolved in a mixture of ether and water. The aqueous layer was separated, the ether layer was extracted with an equal volume of water and discarded. The two aqueous layers were combined, washed with ether, the ether layer was discarded again, the aqueous layer was cooled to 0-5 ° C and solid potassium carbonate was added until basic reaction to litmus. An oily product consisting of ethyl 2- (dimethylaminomethyl) -4-thiazolecarboxylate as the free base is precipitated. The oily layer was extracted with ether, the ether extract was separated, dried and the ether evaporated in vacuo. The residue was purified by high pressure liquid chromatography on silica gel using increasingly polar mixtures of toluene and ethyl acetate as eluent. The ethyl 2- (dimethylaminomethyl) -4-thiazolecarboxylate thus obtained has the following physical characteristics:

Analysis:

calculated:

C 50.45, H 6.59, N 13.07, S 14.96; found ·

H, 50.13%, H, 6.39%, N, 12.89%, S 15.04%.

NMR (deuterochloroform, tetramethylsilane as internal standard, δ '):

1.43 (triplet, 3H);

2.40 (singlet, 6 H),

3.87 (singlet, 2 H),

4.47 (quartet, 2H),

8.20 (singlet, 1 H).

Analogously to the above, a solution of 20.4 g of ethyl bromopyruvate and 20.8 g of N-methyl-N-benzoylthioacetamide in 100 ml of ethanol is heated at reflux for about 4 hours. The solvent was evaporated in vacuo and the residue was dissolved in 65 ml of 4.5N aqueous hydrochloric acid. The acidic aqueous layer was extracted with ether, the ethereal extract was discarded and 11.5 g of sodium carbonate was added to the aqueous layer. The ethyl 2- (methylbenzoylaminomethyl) -4-thiazolecarboxylate formed in the above reaction, which is insoluble in solution, is separated and extracted with ether. The ether extract was separated, dried and the ether evaporated. 20.2 g of ethyl 2- (methylbenzoylaminomethyl) -4-thiazolecarboxylate melting after recrystallization from ethyl acetate at 151.5 to 153.5 ° C is obtained.

Analysis:

calculated:

% C, 59.19;% H, 5.30;

found *

% H, 5.25;% N, 8.90.

NMR (deuterochloroform, tetramethylsilane as internal standard, δ values):

1.42 (triplet, 3H);

3.07 (singlet, 3H);

4.41 (quartet, 2H),

4.98 (singlet, 2 H),

7.40 (apparent singlet, 5H),

8.16 (singlet, 1 H).

Example 2

Preparation of 2- (dimethylaminomethyl) -4-thiazolylmethanol

A solution of 12.5 g of ethyl 2- (dimethylaminomethyl) -4-thiazolecarboxylate in about 35 ml of anhydrous tetrahydrofuran is cooled to about 0 ° C under nitrogen and maintained at 0 to 5 ° C. 1M solution of lithium triethylborohydride in tetrahydrofuran. The reaction mixture was stirred for about 2 hours. 36 ml of 6N aqueous hydrochloric acid was added thereto while maintaining the temperature between -3 ° C and 0 ° C. The volatiles were evaporated in vacuo on a rotary evaporator, water was added to the residue and the volatiles were evaporated again. Water was again added to the residue and the aqueous mixture was extracted several times with ether. The ethereal extracts were separated and discarded, the aqueous solution was cooled and basified by the addition of solid potassium carbonate. The basic aqueous mixture was extracted with ethyl acetate to give 2- (dimethylaminomethyl) -4-thiazolylmethanol, which was insoluble in basic solution, and the ethyl acetate extracts were combined, washed with a saturated aqueous sodium chloride solution and dried to evaporate the ethyl acetate. 7.7 g of oil containing 2- (dimethylaminomethyl) -4-thiazolylmethanol formed in the above reaction, having the following physicochemical constants.

Analysis:

calculated:

H, 7.02; N, 15.26.

found:

H, 6.77; N, 15.85.

NMR (deuterochloroform, tetramethylsilane as internal standard, λ values):

2.33 (singlet, 6H);

3.74 (singlet, 211),

4.32 (singlet, 1Hj,

4.72 (singlet, 2Hj,

7.15 (singlet, 1 H),

The product boils at 102 ° C / 67 Pa.

In an analogous manner to the above, 22.5 g of ethyl N-methyl-N-benzoyl-2-aminomethyl-4-thiazolecarboxylate are dissolved under nitrogen in 125 ml of dry tetrahydrofuran and 320 ml of 1 M lithium triethylborohydride in tetrahydrofuran are added. used in the previous case is necessary because both the ethyl ester group needs to be reduced to the hydroxymethyl group and the benzoyl group (as the benzyl alcohol is recovered to regenerate the secondary amino group). The reaction mixture was quenched as before with 6N scientific hydrochloric acid and water. Removal of the volatiles left a thick oily residue which was taken up in a mixture of a small amount of water and 60 ml of ether. 1 ml of 12N aqueous hydrochloric acid was added to strongly acidify the aqueous phase, the ether layer was separated, the aqueous phase was extracted five more times with equal portions of ether, the ether extracts were discarded, the aqueous layer was separated and the water evaporated in vacuo. The acidic residue is strongly alkalized with cooling with 50% aqueous sodium hydroxide solution (6 g of sodium hydroxide in 6 ml of water). 2-Methylaminomethyl-4-thiazolylmethanol, formed by the above-described reaction series, is insoluble in the basic layer and precipitates. The residue was taken up in ethyl acetate in a continuous extractor and the solvent was evaporated to give a reddish brownish oily residue of 2-methylaminomethyl-4-thiazolylmethanol (10.7 g), which was converted to dihydroehloride by standard laboratory procedure.

Alternatively, a mixture of 2.14 g of ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate and 0.38 g of sodium borohydride in 20 ml of isopropanol is heated under reflux for about 14 hours. The reaction mixture was cooled, then 2 ml of water was added first, and then carefully treated with 4 ml of 5N aqueous hydrochloric acid. The volatiles were evaporated, 10 ml of methanol were added to the residue, and the mixture was heated under reflux for about 1 hour. The methanol was evaporated and the solid residue was digested with 10 ml of isopropanol on a steam bath. The isopropanol solution is decanted off and the solid residue is extracted again with 10 ml of isopropanol. The isopropanolic solution is combined with the extract and insoluble in hot filtration. The filtrate is cooled and the precipitated crystalline material is filtered off. Recrystallization of the filter cake from isopropanol gave 1.73 g of 2- (dimethylaminomethyl) -4-thlazolylmethanol hydrochloride, m.p. 153-154 ° C.

Analysis:

calculated:

C 40.28, H 6.28, Cl 16.99, N 13.42; found:

% C, 40.38;% H, 5.04;% Cl, 17.24;

The substituted 4-thiazolylmethanols prepared according to this example are readily converted to the corresponding thiazolylmethyl chlorides as described below.

1.05 g of 2- (dimethylaminomethyl) -4-thiazazolylmethanol hydrochloride was suspended in 15 ml of chloroform, 2.50 g of thionyl chloride were added and the resulting mixture was heated to reflux with stirring for about 2.75 hours. All volatiles, including excess thionyl chloride, were evaporated, the residue was suspended in chloroform and the chloroform was evaporated. The residue was recrystallized from methanol / ethyl acetate to give 2- (dimethyl aminomethyl) -4-thiazolylmethyl chloride hydrochloride, m.p. 136-138 ° C.

Analysis:

calculated:

37.01% C, 5.32% II, 31.21% Cl, 12.33% N;

found:

H, 5.08; H, 31.41; N, 12.36. Example 3

Preparation of 2- [2- (dimethylaminomethyl) -4-thiazolyl] methylthio; ethy laminu

18.8 g of 2-dimethylaminomethyl-4-thiazolytmethanol are mixed with 12.3 g of 2-aininoethanthiol hydrochloride (cyseamine hydrochloride) and 160 ml of 48% aqueous hydrobromic acid. The reaction mixture was stirred at about 100 ° C for about 11 hours, after which time the volatiles were evaporated in vacuo on a rotary evaporator. Water was added to the residue and the volatiles were evaporated again. The residue of 2 - ([2- (dimethylaminomethyl) -4-thiazolyl) methylthiomethylamine trihydrobromide formed by the above reaction was dissolved in ethanol, the ethanol was evaporated and the residue was redissolved in ethanol. Evaporation of the ethanol gave a hygroscopic residue which, after recrystallization from a mixture of methanol and ethyl acetate, gave 2-β- [2- (dimethylaminomethyl) -4-thiazolyl] methylthio ethy ethylamine trihydrobromide with the following constants. Analysis:

calculated:

% C, 22.80;% C, 4.25;% Br, 50.56;

13.53% S;

found:

% C, 23.02;% H, 4.31;% Br, 50.64;% M: 8.80;

NMR (perdeuterodimethylsulfoxide, tetramethylsilane as internal standard, δ values):

2.55-3.2 (m.ltipl.et, 4H),

2.84 (singlet, 6 H),

3.92 (singlet, 2H),

4.74 (singlet, 2 H),

7.2 to 7.7 (broad signal, 1H),

7.94 (singlet, 1 H),

7.9.2 (broad signal, 3H),

10.22 (broad signal, 1H1.

As described above, a mixture of 2- (methylaminomethyl) -4-thiazolylmethanol-dihydrochloride (10.1 mmol), cysteamine hydrochloride (1.15 g) and 48% aqueous hydrobromic acid (15 ml) was stirred at about 100 ° C for about 7.5 hours. Water and hydrobromic acid are evaporated on a rotary evaporator, the residue of 2 - ((2- (methylaminomethyl) -4-thiazolyl) methylthiolethylamine trihydrobromide) formed in the above reaction is dissolved in water and the water is evaporated. The water was evaporated again, the residue was dissolved in a small volume of water, and a solution of 5.5 g of potassium carbonate in 15 ml of water was added, and the resulting basic solution was evaporated to dryness. The thiazolyl] methylthio (ethylamine free base was stirred with ethanol and evaporated. The residue was stirred twice with isopropanol, the solid was extracted several times with boiling isopropanol, the combined isopropanol extracts were filtered, and the isopropanol was evaporated. The yellow oily residue was dissolved in chloroform. the chloroform solution was filtered and chloroform was evaporated from the filtrate to give 1.59 g of yellow oily 2 - ((2- (methylaminomethyl) - 4-thiazolyl] methylthio) ethylamine having the following physical characteristics.

NMR (deuterochloroform, tetramethylsilane as internal standard, δ values):

1.53 (overlapping singlets, 311),

2.53 (singlet, 3 H),

2.62 (triplet, 21%),

2.86 (triplet, 2 H),

3.81 (singlet, 2 H),

4.04 (singlet, 2 H),

7.04 (singlet, 1 H).

The above primary amine can be prepared by an alternative process of melting the acid addition salt of 2-dialkylaminoalkyl-4-isothiazolylmethyl chloride with the cysteamine (or homocysteamine) addition salt. This alternative procedure illustrates the following reactions.

2.92 g of 2- (dimethylaminomethyl) -4-thiazolylmethyl chloride hydrochloride are thoroughly mixed with 0.96 g of cysteamine hydrochloride and the mixture is slowly warmed to about 100 degrees Celsius under anhydrous conditions over one hour. The reaction mixture was then heated at 104-110 ° C for 6 hours, after which time the reaction was virtually complete by thin layer chromatography (ethanol-ammonia / density 0.88 / 95: 5). The reaction mixture was cooled and the cooled melt was dissolved in a minimum amount of water. The solution was transferred to a rotary evaporator and the water was evaporated. The residue solidified and the solid material was recrystallized from a mixture of methanol and ethyl acetate. The thus obtained hygroscopic crystals of 2 - {[2- (dimethylaminomethyl) -4-thiazolyl] methylthioethylamine trihydrochloride melt to release hydrogen chloride at about 165-173 ° C.

Analysis:

calculated:

31.72 O / o C, 5.91% H, 31.21% Cl, 12.33% N,

18.82% S;

found:

C, 31.63; H, 6.15; N, 31.34.

18.63% S.

Example 4

Preparation of N-methyl] -N‘-2-j [2- (dimethylaminomethyl) -4-thiazolyl] methylthioethyl-t-cyanguanidine

3.07 g of dimethyl cyandithioimidocarbonate are dissolved in 35 ml of ethanol and a solution of 4.62 g of 2 - {[2- (dimethylaminomethyl) -4-thiazolyl] methylthiojethylamine in 50 ml is added dropwise with stirring over about 1.5 hours. ethanol. The reaction mixture was stirred for a further 20 hours, after which time the volatiles were removed by rotary evaporation. Chromatography of the residue on silica gel using ethyl acetate containing increasing amounts of methanol as eluent to give fractions containing methyl N-2 - {[2- (dimethylamlnomethyl j -4-thiazolyl] methylthio-N kyankarbamidothioát ¹ formed in the above reaction. These fractions The residue (4.8 g) melts after recrystallization from carbon tetrachloride at 75 to 77 ° C.

calculated:

% C, 43.74;% H, 5.81;% N, 21.25; found:

% C, 43.46;% H, 5.71;% N, 20.98;

2.52 g of the thioester prepared above are dissolved in 12 ml of methanol and 30 ml of a 35% methylamine in ethanol solution (w / w) are added with stirring. After 5 hours, the solvent and excess amine were removed by rotary evaporation and the residue was purified by silica gel chromatography using ethyl acetate with increasing methanol as eluent. The fractions containing N-methyl-N‘-2 - {[2- (dimethylaminomethyl) -4-thiazolyl] methylthio} ethyl-N'-cyanoguanidine formed in the above reaction were combined and evaporated to give

1.86 g of the desired product as a glassy residue.

- Analysis: calculated:

46.13 ° C, 6.45% H, 26.90% N;

ΤΊΑΐΡ7ΡΤΊΓ) *

H, 6.39%, N 26.85%

NMR (deuterochloroform, tetramethylsilane as internal standard, δ values):

2.34 (singlet, 6H);

2.72 (triplet, 2H),

2.84 (doublet, 3H),

3.42 (multiplet, 2H);

3.74 (singlet, 2 H),

3.82 (singlet, 2 H),

6.08 (multiplet, 1 H),

6.22 (multiplet, IHj,

7.10 (singlet, 1 H).

The above procedure is repeated except that the reaction with N-2 - ([2- (Dimethylamino! J phosphonomethyl -4-thiazolyl] ^{methylthiolethyl-N} -kyankarbamidothioátem used instead of methylamine ethylamine. To give N-ethyl-N ' 2 - {[2- (dimethylaminomethyl) -4-thiazolyl] -methylthioethyl-N'-cyanoguanidine.

H, 6.79; N, 25.74; S, 19.64; found:

48.05 o / o C, 7.01 o / o H, N 25.51%, 19.33% S.

NMR (deuterochloroform, tetramethylsilane as internal standard, δ values):

1.22 (triplet, 3 H),

2.34 (singlet, 6H3,

2.72 (triplet, 2 H),

3.1 to 3.55 (unresolved multiplets, 4H),

3.74 (singlet, 2 H),

3.82 (singlet, 2 H),

5.7 (broad signal, 1H),

6.0 (broad signal, 1Hj,

7.08 (singlet, 1 H).

Example 5

Preparation of N-methyl-N‘-2 - {[2- (dimethylaminomethyl) -4-thiazolyl] methylthio'ethyl-N'-p-tolylsulfonylguanidine

1.35 g of dimethyl p-toluenesulfonylimidodithiocarbonate is suspended in 10 ml of ethanol and a solution of 1.16 g of 2 - {[2- (dimethylaminomethyl) -4-thiazolyl] methylthiolethylamine in 10 ml of ethanol is added to the suspension with stirring at room temperature over 15 minutes. After the addition was complete, the reaction mixture was stirred for 2.5 hours, then the solvent was evaporated in vacuo. The residue is stirred with 20 ml of a 35% (w / w) ethanolic methylamine solution. The resulting mixture was stirred for about 15 hours, after which time the solvent and other volatile components were evaporated in vacuo. The residue is chromatographed on silica gel using ethyl acetate with increasing methanol as eluent. The N-methyl-N met-2 - {[2- (dimethylaminomethyl) -4-thiazolyl-1-methylthio} ethyl] -N'-p-tolylsulfonylguanidine fractions formed as described above were combined and the solvent was evaporated. 1.9 g of a glassy residue are obtained.

Analysis:

calculated:

H, 6.16; N, 15.86; O, 7.75.

21.78% S;

found:

H, 6.27; N, 16.10; O, 7.45.

21.62% S.

NMR (deutero-chloroform, tetramethylsilane as internal standard, γ values:

2.34 (singlet, 6HJ)

2.38 (singlet, 3H);

2.62 (triplet, 2 H),

2.80 (doublet, 3H),

3.35 to 3.55 (multiplet, greater than 2H)

3.72 (singlet, 2 H),

3.74 (singlet, 2Hj,

7.06 (singlet, 1 H),

7.18 (doublet, 2H),

7.70 (doublet, 2H).

The above procedure was repeated using dimethyl methanesulfonylimidodithiocarbonate as the starting material. N-methyl-N methyl-2 - {[2- (dimethylaminomethyl) -4-thiazolyl] methylthioethyl-N'-methanesulfonylguanidine melting after recrystallization from ethyl acetate at 95-97 ° C is obtained.

Analysis:

calculated:

C 39.43, H 6.34, O 8.75;

found:

C 39.71, H 6.19, O 8.72%.

Example 6

Preparation of N-2 - {[2- (dimethylaminomethyl) -4-thiazolyl] methylthioethyl-N- (2-methoxyethyl) -2-nitro-1,1-ethylenediamine

A mixture of 2.31 g of 2 - {[2- (dimethylaminomethyl) -4-thiazolyl] methylthiojethylamine and 1.65 g of 1-nitro-2,2-bis (methylthio) ethylene in 30 ml of acetonitrile is heated at reflux for about 4 hours. The solvent was evaporated. The residue is chromatographed on silica gel using ethyl acetate as the eluent. Fractions containing the desired product by thin layer chromatography were combined and the solvent was evaporated. 2.39 g of 1- (2- (2- (dimethylaminomethyl) -4-thiazolylmethylthio) ethylamino-1-methylthio-2-nitroethylene, melting after recrystallization from ethyl acetate at 68.5 to 70.0 degrees Celsius, are obtained.

Analysis:

calculated:

C, 41.36; H, 5.78; N, 16.08; S, 27.60;

found:

% C, 41.54;% H, 5.61;% N, 16.14%.

A mixture of 1.25 g of 1- (2 - / (2- (dimethylaminomethyl) -4-thiazolyl) methylthio / ethylamino} -1-methylthio-2-nitroethylene, 0.27 g of 2-methoxyethylamine and 20 ml of ethanol is stirred for about 3 hours The solvent was evaporated and the residue was chromatographed using ethyl acetate with increasing amounts of methanol as the eluent to give the title compound, eluting with methanol / ethyl acetate (5: 95). After evaporation of the solvent, an oily N-2 - ( [2- (dimethylaminomethyl) -4-thiazolyl] methylthiomethyl-N '- (2-methoxyethyl) -2-nitro-1,1-ethylenediamine.

Analysis:

calculated:

C, 44.78; II, 6.71; N, 18.65; O, 12.78; found:

C, 44.65; H, 6.59; N, 18.32; O, 13.03%. NMR (CDCl3)?

2.36 (singlet, 6Hj,

2.76 (triplet, 2 H),

3.40 (singlet, 3Hj,

3.1 to 3.65 (multiplets, 6H)

3.75 (singlet, 2j,

3.83 (singlet, 2 H),

6.54 (singlet, 1 H),

6.75 (broad signal, 1H),

7.80 (singlet, 1 H),

10.35 (broad signal, 1H).

Using the procedure described above, 1-) 2- [2- (dimethylaminomethyl-4-thiazolyl) methylthio] ethylamino-1-methylthio-2-nitroethylene is reacted with 3-dimethylaminopropylamine, cyclopropylamine, 2-hydroxyethylamine, dimethylamine and ammonium. The following products are obtained.

N-2 - {[2- (Dimethylaminomethyl) -4-thiazolyl] methylthio (ethyl-N - (3-dimethylaminopropyl) -2-nitro-1,1-ethylenediamine as a glassy mass).

Analysis:

calculated:

47.74 o / o c, 7.51 θ / ο H, 20.88% N;

found:

H, 7.24; N, 21.16.

NMR (deutero-chloroform, γ values:

1.77 (quintet, 2Hj,

2.23 (singlet, 3H);

2.28 (singlet, 3H);

2.36 (singlet, 6H);

2.23 to 2.28 (overlapping signals, 2H),

2.72 (triplet, 2 H),

3.0 to 3.5 (multiplets, 4H)

3.75 (singlet, 2 H),

3.84 (singlet, 2 H),

6.50 and 6.53 (singlets, 1H total),

7.11 (singlet, 1 H),

8.6 (broad signal, 1H),

10.2 (broad signal, 1H).

N-2 - {[2- (Dimethylaminomethyl) -4-thiazolyl] methylthio (ethyl-N'-cyclopropyl-2-nitro-1,1-ethylenediamine) melting after recrystallization from methanol / ethyl acetate at 128.5 to 131.5 ° C.

Analysis:

calculated:

H, 6.49; N, 19.59. found:

% H, 6.12;% N, 19.35.

N-2 - {[2-Dimethylaminomethyl) -4-thiazolyl] methylthio (ethyl-N '- (2-hydroxyethyl) -2-nitro-1,1-ethylenediamine. Silica gel was eluted with a 94: 5: 1 mixture of ethyl acetate, methanol and ammonium hydroxide (density 0.88), and had a R _f value of 0.43 on silica gel in a mixture of ethanol and ammonium hydroxide (95: 5).

NMR (CDCl3):

2.37 (singlet, 6H),

2.80 (triplet, 2 H),

3.1 to 3.6 (multiplets, 4H)

3.74 (singlet, 2Hj,

3.85 (singlet, 1Hj, ca. 3.8 (uncleaved multiplet, 2Hj,

6.58 (singlet, 1H,

7.11 (singlet, 1H,

7.80 (broad signal, 1H),

10.36 (broad signal, 1H).

N-2 - {[2- (Dimethylaminomethyl) -4-thiazolyl] methylthio (ethyl-N ', N'-dimethyl-2-nitro-1,1-ethylenediamine) The product resulting in reversed form is purified by silica gel chromatography eluent of ethyl acetate-methanol (95: 5).

calculated:

45.19% C, 6.71% H, · 20.27% N;

γίλΙ ^ 'ζοτίο ’

% H, 6.71;% N, 20.54.

NMR (CDCl3):

2.36 (singlet, 6 H),

2.79 (triplet, 2 H),

2.91 (singlet, 6Hj,

3.44 (doublet of triplets, 2H),

3.74 (singlet, 2 H),

3.86 (singlet, 2 H),

6.48 (singlet, 1 H),

7.12 (singlet, 1 H),

9.46 (broad signal, 1H).

N - {[2- (Dimethylaminomethyl) -4-thiazolyl] methylthio (ethyl-2-nitro-1,1-ethylenediamine) melting after purification by silica gel chromatography using a mixture of ethyl acetate, methanol and ammonium hydroxide (density 0.88) in 94: 5: 1 ratio at 125-127 ° C.

Analysis:

calculated:

% C, 41.62;% H, 6.03;% N, 22.06;

found:

% H, 6.21;% N, 21.87.

Example 7

Preparation of 3- (2- / [2- (dimethylaminomethyl-4-thiazolyl) methylthio) ethyramino-4-methylamino-3-cyclobutene-1,2-dione

To a solution of 568 mg of 3,4-dimethoxy-3-cyclobuten-1,2-dione in 15 ml of methanol is added, over a period of 1.5 hours, a solution of 925 mg of 2 - ((2- (dimethylaminomethyl) -4-thiazoles)] After 3 hours, a small amount of solids was removed from the reaction mixture by filtration, the filtrate was evaporated to a volume of ca. 10 ml and 6 ml of a 35% solution of roethylamine in ethanol was added. After 25 hours of reaction, the precipitated solid product is filtered off and the filter cake is washed with methanol and recrystallized from ethanol to give 0.72 g of 3- (2 - [(2- (dimethylaminomethyl) -4-thiazolyl] methylthio) ethyl-amino-4. m.p. 163-167 ° C;

Analysis:

calculated:

% C, 49.39;% H, 5.92;% N, 16.46; found:

H, 6.01; N, 16.18; O, 9.59.

The compounds of formula (I) above are potent antagonists of the H 1 -receptors of histamine and thus anti-ulcer agents. The relationship of H 2 -receptors to gastric acid secretion in mammals is described in Black et al. in Nature, 236, 385 (1972).

Blocking activity at the H 2 -receptors was determined using the following assay. Female white rats are treated with estrone 24 hours before starting the experiment. The rats are sacrificed, their uterine horns are removed and placed at room temperature in an isolated organ bath containing De jalon solution. After equilibration, the uterine strips are exposed to a 50 mM aqueous potassium chloride solution which induces a sustained contraction. In the uterus with such contraction, histamine induces dose-dependent relaxation mediated by Hs-receptors. For each tissue, a control curve of response to the applied dose of histamine is plotted. After the histamine dose-response control curve is constructed, histamine is washed extensively and the test antagonist (compound of the invention) is added to the bath at a concentration of 10 ⁵ M for 30 minutes. The uterine strips are then brought to concentration in the presence of the antagonist by treatment with aqueous potassium chloride and a second histamine dose-response curve is constructed. In the presence of a competitive antagonist, the histamine dose response curve is shifted to the right parallel to the control curve without decreasing the maximum. For each antagonist concentration, the dose ratio (DR) is calculated by dividing the ED 50 value for histamine in the presence of a competitive antagonist by dividing the control ED 50 value for histamine. The dissociation constant (K _B ) of the antagonist is calculated from the dose ratios according to the following formula:

K _E = [antagonist] / (DR-1)

Cimetidine is used as internal standard.

The results of the above experiment with N-methyl-N ^: -2 '} [2- (dimathylaminomethyl) -4-thiazolyl] methylthioethyl-2-nitro-1,1-ethylenediamine show that this compound has approximately 11 times higher affinity for histamine H 2 -receptors than cimetidine. N-Methyl-N '- 2H - [2- (dimethylaminomethyl) -4-thiazolyl] methylthiomethyl-1'-cyanguanidine has an affinity of about 1.5-fold higher than cimetidine. The K _B value for the first compound (at nanomolar concentration) was found to be 87, while the K _n value for cimetidine is 871, which, according to the Schild relationship, indicates a relative affinity of about 10: 1.

In the second Ha-receptor blocking activity assay, the isolated gastric mucosa of the frog is used (see Warrick and Lin, Communications in Chem.). Pathology and Pharmacology, 13, 149 (1976)]. This test is performed as follows.

The gastric mucosa is separated from the musculature of the skipper (Rana catesbeiana), which is inserted between a pair of Ussing lucids made of lucite. The baths are filled with Ringer's frog solution and gastric secretion is stimulated by adding histamine to the serosal side of the mucosa (final concentration 10 ^-5 mol / liter). The secreted acid is automatically titrated to pH 4.5. Once the response to a histamine concentration of 10 ^-5 mol / liter has stabilized, an antagonist (a compound of the invention) is added to the bath on the serosal side and maximum inhibition is recorded for each concentration of the H 2 antagonist. The ED50 of the test substance is calculated from the dose-response curve. The relative potency of each unknown antagonist is calculated by dividing the ED 50 for cimetidine by the ED 50 for the test substance. N-Methyl-N'-2 - {[2- (dimethylaminomethyl) -4-thiazolyl] methylthioiethyl-2-nitro-1,1-ethylenediamine has a relative potency of 17.78 compared to 1.0 for cimetidine.

To test the antisecretory activity of the compounds of the invention for gastric acid secretion, dogs with gastric fistula, with preserved vagal innervation of the fistula and denervated Heidenhain pocket are used. This procedure induces a sustained gastric acid secretion by intravenous infusion of histamine. Test antisecretory agents are administered either by intravenous infusion for 30 minutes or orally 75 minutes before the stomach secretion is removed from the fistula. N-Methyl-N-2- [2- (dimethylaminomethyl) -4-thiazolyl] methylthiomethyl-2-nitro-1,1-ethylenediamine is approximately 6.5 times more potent than cimetidine and approximately 11 times more potent than oral when administered intravenously in this test.

These latter results show that N-methyl-N'-2 - ([2- (dimethylaminomethyl) -4-thiazolyl] methylthiomethyl-2-nitro-1,1-etendiamine and other compounds of the present invention are pancreatic absorption is better than cimetidine and other previously developed histamine II receptor antagonists, and their greater oral oral toxicity is evidenced by their relatively higher oral toxicity compared to intravenous toxicity. for the above-mentioned ethendiamine and for cimetidine.

For N-methyl-N‘-2-j [2- (dimethylaminomethyl) -4-thiazolyl] methylthiomethyl-2-nitro-1,1-ethylenediamine: mouse (intravenous administration)

265 mg / kg; mouse (oral administration) 1685 mg / / kg; rat (intravenous administration) above 300 mg / kg; rat (oral) 1680 mg / kg.

For cimetidine, the following corresponding values are reported in the literature: 150 mg / kg, 2600 mg / kg, 106 mg / kg, respectively. 5009 mg / kg. The relative decrease (relative to cimetidine) of the oral toxicity of the compounds of the invention is as surprising as their higher oral absorption.

The above-mentioned efficacy and toxicity values of the compounds of the invention are indicative of a favorable therapeutic index for these compounds. Preliminary tests also show that the compounds of the invention have a longer duration of action than cimetidine.

When the compounds of the invention are used as antisecretory agents, they may be administered either parenterally or orally.

The invention also provides a pharmaceutical composition comprising, as an active ingredient, a compound of formula (I) above wherein B is NRR ⁶ , or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers. Preferred dosage forms are oral compositions such as capsules or tablets.

For the preparation of dosage forms for oral administration, a suitable amount of the free base of the invention or a pharmaceutically acceptable salt thereof is admixed with one or more conventional carriers and / or excipients such as starch, and filled with pluggable gelatin capsules or compressed into tablets , each usually containing 100 to 400 mg of active ingredient. These tablets may be scored to allow for lower or partial doses. An isotonic saline solution is preferably used for parenteral administration by intravenous infusion, although isotonic preparations containing the free base may also be used.

It is believed that due to the high oral absorption and long duration of action of the compounds of the invention, in particular N-methyl-N'-2 - {[2- (dimethylaminomethyl) -4-thiazolyl] methylthio-ethyl-2-nitro-1,1 -ethendiamine, oral administration of about 50 to 80 mg of the active compound of the invention three to four times a day will suffice to control acid secretion in patients with ulcer disease and thus alleviate the symptoms thereof, but generally the compounds of the invention are administered orally in daily doses to humans. The preferred dosage range for oral administration is about 2 to 5 mg / kg mammal body weight / day, although doses in the range of 1 to 10 mg / kg may generally be used. /day.

Claims (3)

SUBJECT A process for the preparation of 2,4-disubstituted thiazole derivatives of the general formula I VYNALEZU A-O-C-C = O RCH-Z-CHCHNH-Q-B -C- or -c = ClII in which R ¹ and R ² are each independently hydrogen, C 1 -C 4 alkyl, benzyl or benzoyl, or both together with the adjacent nitrogen atom form a saturated 5- to 7-membered heterocyclic ring containing optionally further a heteroatom selected from the group consisting of oxygen and nitrogen, R ³ represents a hydrogen atom or a C 1 -C 4 alkyl group, Z is oxygen, sulfur or CH 2, n is 2 or 3 when Z is oxygen or sulfur and 1, 2 or 3 when Z is group CH ₂ , R ⁵ represents a hydrogen atom or a C 1 -C 4 alkyl group, m is 1, 2 or 3, Q represents a radical of the formula wherein A is N-CN, N-NO2, CH-NO2, S, O, NH, N-SO2-aryl, N-SO2-alkyl, N-CO-NH2, N-CO-alkyl, N-CO2-alkyl, CH-SO2-aryl or CH-SO2- alkyl wherein the alkyl contains 1 to 4 carbon atoms and the aryl is a phenyl group, a halophenyl group, an alkylphenyl group having 1 to 4 carbon atoms in the alkyl moiety or an alkoxyphenyl group having 1 to 4 carbon atoms in the alkoxy moiety, and B is a radical of the formula -NRR ⁶ wherein R @ ⁶ and R @ ^{6 each} independently represent a hydrogen atom, a C1 -C5 alkyl group, a C3 -C6 cycloalkylmethyl group, a C2 -C5 hydroxyalkyl group, a C3 -C6 cycloalkyl group. or an alkoxyalkyl or dialkylaminoalkyl group in which the total number of carbon atoms is less than 8 and wherein there is a chain of at least two carbons between the heteroatoms, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula VI Y ₍ 7 ICHR'V \ ₂ R ^x in which R ¹ , R ² , R ³ , R ⁵ , Z, Q, m and n are as defined above and L ² is a leaving group, reacted with an amine of formula HNRR ⁶ wherein R and R ⁶ are as defined above, and the resulting product of formula I is optionally converted into a pharmaceutically acceptable salt thereof. 2. A process according to claim 1, wherein the corresponding starting materials are used to form the thiazole derivatives of the above general formula (I) in which: R ¹ and R ² independently represent hydrogen or an alkyl group having 1 to 3 carbon atoms, or only one of ^R1 and ^R2 may represent benzyl or benzoyl, or R ¹ and R ² together with the adjacent nitrogen atom, form piperidino, pyrrolidino or a morpholino group with the proviso that only one of R ¹ and R ^Z can be hydrogen when Z represents CH, R ³ represents a hydrogen atom or a C 1 -C 3 alkyl group, R ⁴ represents an alkyl group having 1 to 5 carbon atoms, R ⁵ represents a hydrogen atom or a methyl group, A is N-CN, Ν-NO2, CH-NO2, S, O, NH, N-SO2-aryl, N-SO2-alkyl, N-CO-NH2, N-CO-alkyl, N-CO2-alkyl, CH-SO2-aryl or CH-SO2- CH3 in which the alkyl contains 1 to 3 carbon atoms and the aryl is a phenyl group, a halophenyl group, an alkylphenyl group having 1 to 3 carbon atoms in the alkyl moiety or an alkoxyphenyl group having 1 to 3 carbon atoms in the alkoxy moiety, R ⁶ represents a hydrogen atom and Q represents a group —C = A, and pharmaceutically acceptable acid addition salts thereof. 3. A process according to claim 1, which is based on compounds of the above formulas to give N-methyl-N '- {[2- (dimethylaminomethyl) -4-thiazolyl] methylthiomethyl-2-nitro-1,1 -ethendiamine and pharmaceutically acceptable salts thereof. Severography, n. p „závod?, Most Price 2,40 Kčs