CH646964A5 - 2-GUANIDINOTHIAZOLE DERIVATIVES. - Google Patents

Description

The present invention relates to 2-guanidino-thiazole derivatives of the formula hn = c-nh i 2 nh ch0x (ch0) nh-co-r d. 2 Tea spoons

wherein n represents an integer from 2 to 4;

R is hydrogen, optionally substituted by hydroxy, cyano, amino or phenoxy Ci-Có-alkyl, C3-C & cycloalkyl, optionally substituted by phenyl or C2-C7-alkoxy-carbonyl C2-C6-alkenyl, C4-C7-alkadienyl, optionally by 1-3 substituents from the group halogen, cyano, nitro, amino, C2-Cio-dialkylamino, tetra-zolyl, hydroxy, Ci-Cò-alkoxy, benzoyloxy, C2-C7-alkoxy-carbonyl, sulfamoyl, Ci-Cö- Alkylsulfonyl, Ci-Có-Alkansul-fonamido or Ci-Cc-Alkanoyl substituted Có-Ci2-aryl, or a 5- or 6-membered heterocycle optionally substituted by halogen, Ci-Cä-alkyl or phenyl; and in what

X represents a single bond or a sulfur atom, and pharmaceutically acceptable acid addition salts thereof, which are useful as agents for treating gastric ulcers or as histamine H2-receptor antagonists.

Examples of the group names given in connection with the above formula I are given below:

Ci-C6-alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl or hexyl;

C3-C6-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

C2-C6-alkenyl is, for example, vinyl, allyl, butenyl, pentenyl or hexenyl;

C4-C7 alkadienyl is, for example, butadienyl, pentadienyl, hexadienyl or heptadienyl;

Ci-Co alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy or hexyloxy; C2-C7-alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl or hexyloxycarbonyl;

Ci-Có-alkanoyl is, for example, formyl, acetyl, propionyl, butyryl, pentanoyl or hexanoyl;

Ci-C6-alkanesulfonamido is, for example, methanesulfonamido, ethanesulfonamido, propanesulfonamido, isopropanesulfonamido, butanesulfonamido, isobutanesulfonamido, pentanesulfonamido or hexanesulfonamido; Ci-C6-alkylsulfonyl is, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl or hexylsulfonyl;

C2-Cio-dialkylamino is, for example, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, methylethylamino, methylpropylamino, ethylbutylamino or methylbutylamino;

C6-Ci2-aryl is, for example, phenyl, tolyl, xylyl, naphthyl, methylnaphthyl or ethylnaphthyl;

the 5-membered heterocycle is, for example, thienyl, furyl, isoxazolyl or isothiazolyl;

the 6-membered heterocycle is, for example, pyridyl and

2nd

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

3rd

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Halogen is, for example, chlorine, bromine or iodine.

Such 2-guanidinothiazole-H2 receptor antagonists are described in US Pat. No. 4,165,377 (1979) thiotidine, which carries the N-methylcyanoguanidino group, which can be converted into the carcinogenically active nitroso N-methylcyanoguanidino group in the mammalian organism [Pool, et al., Toxycology, 15, 69 (1979)]. Furthermore, the unexamined Ja-PS 141 271/1978 comprises N- [2 - ((2-pyridyl) methylthio) ethyl] acetamide, which has no activity as a histamine-Hj-receptor antagonist.

The first preferred compounds of formula I are those in which n is an integer of 2 or 3, R optionally by 1-3 groups such as halogen, cyano, nitro,

Amino, C2-Cio-dialkylamino, tetrazolyl, hydroxy, Ci-Ce-alkoxy, benzoyloxy, C2-C7-alkoxycarbonyl, sulfamoyl, Ci-Ce-alkylsulfonyl, Ci-Cs-alkanesulfonamido or Ci-Có-alkanoyl substituted phenyl and X a Represent sulfur atom.

The second preferred compounds of formula I are those in which n is an integer of 2 or 3, R2 is a 5-membered heterocyclic ring optionally substituted by halogen, Ci-Cs-alkyl or phenyl and s X is a sulfur atom.

Third preferred compounds of the formula I are those in which n is an integer of 2 or 3, R is a 6-membered heterocyclic ring which is optionally substituted by halogen, Ci-Ce-alkyl or phenyl and io X is a sulfur atom.

Finally, compounds of the formula I are preferred in fourth place, in which n is an integer of 2 or 3, R is hydrogen, optionally substituted by cyano, amino or phenoxy-Ci-Cö-alkyl, C3-Có-cycloalkyl, if present by phenyl or C2-C7-alkoxycarbonyl substituted C2-C7-alkenyl or C4-C7-alkadienyl and X represent a sulfur atom.

The 2-guanidinothiazole derivatives (I) can be prepared according to the following reaction scheme:

hn = c-nh_ I 2 nh s ^ n di)

RCOOH (III)

(WegA)

CH2X (CH2) nNH2

hn = c-nh_ .1 2 nh

S ^ N

hn = c-nh_ l 2 nh

HS (CH2) nNHCOR (V) (route B) (X = S)

• n

ch-b 2

(iv)

(I)

ch x (ch_) nhcor 2 x 2'n

HN = C-NH2

I.

NH

I.

S = C-NH2

(VI)

A-CH2COCH2S (CH2) nNHCOR (VII)

(Path C) (X = S)

wherein A and B represent a reactive group such as halogen or the residue of an active ester (e.g. tosyloxy) and n, R and X have the meaning given above.

WegA

The desired compounds of formula I can be prepared by reacting the amine (II) with the carboxylic acid (III) or its reactive derivative (e.g. halide, mixed acid anhydride, or active ester such as tosylate) in an inert solvent, if necessary in the presence of a base or a condensing agent (eg DCC, triphenylphosphine / 2,2'-dipyridyl disulfide). This acylation takes place in a conventional manner with mixed acid anhydride, acid halide, according to the DCC or the triphenylphosphine method as follows:

(1) with mixed acid anhydride:

60 The amine (II) is reacted with a mixed acid anhydride containing the acyl radical (RCO) of the carboxylic acid (III), which was previously prepared. The reaction can be carried out at a temperature of from -20 ° C to 60 ° C. The mixed acid anhydride is prepared by reacting the carboxylic acid (III) with an alkyl chlorocarbonate such as methyl chlorocarbonate, ethyl chlorocarbonate or the like in the presence of a base such as triethylamine, pyridine or the like in an inert

646964

Solvents at a temperature of - 30 ° C to 0 ° C.

Examples of solvents are tetrahydrofuran, methylene chloride, dioxane, dimethyl sulfoxide, dimethylformamide, acetonitrile, hexamethylphosphoric triamide or the like.

(2) with acid halide:

The amine (II) is reacted with an acid halide of the carboxylic acid (III) in the presence of a base such as triethylamine,

Implemented pyridine or the like. This reaction can be carried out in a suitable solvent such as dimethylformamide, acetonitrile, hexamethylphosphoric triamide, tetrahydrofuran or the like at a temperature of from -20 ° C to 60 ° C.

(3) DCC method:

The amine (II) is reacted with the carboxylic acid (III) in the presence of DCC (dicyclohexylcarbodiimide) in a suitable solvent such as chloroform, dimethylformamide, dimethyl sulfoxide or the like. This reaction can take place at a temperature of - 20 ° C to 60 ° C.

(4) Triphenylphosphine method:

The amine (II) is reacted with the carboxylic acid (III) in the presence of triphenylphosphine and 2,2'-dipyridil disulfide in a suitable solvent such as dimethylformamide or the like at a temperature of from -20 ° C to 60 ° C.

The amine (II) used as the starting product is prepared according to the process described in US Pat. No. 4,165,377.

WegB

The desired compounds (I) can be prepared by reacting the 2-guanidino-4- (activated) methylthiazole (IV) with mercaptan (V) in the presence of a base. The reaction takes place in an inert solvent (e.g. methanol, ethanol, diethyl ether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetone, chloroform) at a temperature of 0 ° C to 60 ° C. Examples of the base are alkali metal hydroxides (e.g. sodium hydroxide), alkali metal carbonates (e.g. potassium carbonate, sodium carbonate) and alkali metal alkoxides (e.g. sodium methoxide, potassium ethoxide).

The thiazole (IV) used as the starting product is e.g. prepared by treating guanylthiourea with 1,2-dichloroacetone in an inert solvent such as acetone. (U.S. Patent 4,165,377).

The mercaptan (V) is prepared by treating a disulfide (VIII) with the carboxylic acid (III) or its reactive derivative according to acylation and reducing the acylaminoalkyl disulfide (IX) obtained with sodium borohydride in an inert solvent (e.g. ethanol or methanol) as follows :

-fS (CH2) nNH2] 2 RCOOH (III) {S (CH2) nNHCOR] 2

(Vili) (IX)

NaBH4 HS (CH2) "NHCOR (V)

WegC

The desired compound can also be prepared by reacting guanylthiourea (VI) with the ketone derivative (VII) in the presence of a base such as triethylamine, pyridine or the like. The reaction takes place in an inert solvent such as ethanol, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, chloroform or the like, at a temperature from 0 ° C. to the boiling point of the solvent.

The ketone derivative (VII) used is prepared by reacting 1,2-di (activated) ketone (X) with the mercaptan (V) in the presence of a base such as triethylamine,

Pyridine or an ion exchange resin (OH type), preferably an ion exchange resin (OH type) in an inert solvent such as ethanol, acetone, dimethyl-lo sulfoxide or the like at a temperature of - 20 ° C to 30 ° C.

A-CH2COCH2-A + HS (CH2) "NHCOR

, 5 (X) (V) ^ ACH2COCH2S (CHz) nNHCOR (VII)

If necessary, the nitro group in the benzene ring of compound (I) (R-aryl) can be reduced to the corresponding amino group with a mild reducing agent such as titanium trichloride or the like in aqueous acetic acid at room temperature. Any amino protective groups, such as carbobenzoxy or trityl, which were introduced into the product (I) when the 2s reactions mentioned above were carried out, can subsequently be removed therefrom in a conventional manner.

The product (I) can be converted into pharmaceutically acceptable acid addition salts thereof. Such acid addition salts are those with inorganic acids (e.g. hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid) or those with organic acids (e.g. acetic acid, succinic acid, oxalic acid, maleic acid, malic acid, phthalic acid, methanesulfonic acid). Acid addition salts can be formed to improve crystallizability, solubility, stability or handling.

2-Guanidinothiazole derivatives (I) obtained in this way and their pharmaceutically acceptable acid 4-addition salts are useful as agents for the treatment of gastric ulcers or histamine H2-receptor antagonists. For example, 2-Guanidino-4- [2- (formamido) ethylthio-methyljthiazole maleate has the following pharmacological effects:

45

a) Histamine Ha antagonism in vitro using extracted guinea pig atrium after pretreatment with the test compound:

50 pA2 = 7.05

[Ariens, Molecular Pharmacology, vol. 1, Academic Press, New York, 1964];

55 b) Inhibition of peptic secretion, caused by histamine, in vivo when using male rats from the Donryu strain:

ED50 0.25 mg / kg (i.v.)

60

[Gosh, et al. Brit. J. Pharmacol., (1958), 13.54];

c) Lethal dose in mice:

65 LD50148 mg / kg (IV); 7691 mg / kg (p.o.)

[Bliss; Ann. Appi, biol., 22, 134-307 (1935); Qant. J. Pharmacol., 11, 192 (1938)].

5

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The other compounds showed similar pharmacological effects.

The 2-guanidinothiazole derivatives (I) and their pharmaceutically usable addition salts can be used alone or in combination with pharmaceutically suitable carriers such as wheat starch, corn starch, potato starch, gelatin, etc. The choice of suitable carriers is given by the preferred mode of administration, the solubility of the substance and the usual pharmaceutical practice. Examples of pharmaceutical compositions are tablets, capsules, pills, suspensions, syrups,

Powders and solutions. These compositions can be prepared in a conventional manner. A suitable daily dose of the 2-guanidinothiazole derivatives (I) or their pharmaceutically usable acid addition salts in adult humans is 1.0-40.0 mg / kg, preferably 1.0-15.0 mg / kg in a single dose or several times.

Histamine H2 receptor antagonism has been described by Black et al. [Black et al., Nature, 236, 385, (1972)].

example 1

A mixture of 201 mg of p-sulfamoylbenzoic acid, 262 mg of triphenylphosphine and 220 mg of 2,2'-dipyridyl disulfide in 4 ml of dry dimethylformamide was stirred at room temperature for one hour. 304 mg of 2-guanidino-4 - (- aminoaethylthio-methyl) thiazole dihydrochloride (US Pat. No. 4,165,377) and 0.4 ml of triethylamine were added to the solution obtained. After stirring at room temperature for 20 hours, the solvent was removed in vacuo and the residue was placed on a silica gel column (50 g) and eluted with ethyl acetate / methanol (20/5 v / v), giving 274 mg (67% yield) 2- Guanidino-4- [2- (4-sulfamoylbenzamido) ethylthiomethyl] thiazole was obtained. Treatment of the product with 300 mg of maleic acid in acetone gave 297 mg of the monomaleate as crystals of mp. 215-217 ° C. (decomposition) from methanol.

Anal, for C18H22O7N6S3:

Example 2

When using p- (N) -tetrazolylbenzoic acid instead of p-sulfamoylbenzoic acid and carrying out the reaction as described in Example 1, 2-guanodino-4-2- (4- (N) -tetrazolylbenzamido) ethylthiomethylthiazole was obtained in 28% yield. Monomaleate, mp. 211 ° C (decomposition) from methanol.

Anal, for C19H21O5N9S2:

10th

Calculated: C 43.92; Found: C 43.85;

H 4.07 (%); H 4.15 (%).

15

Example 3

0.24 ml of triethylamine and 191 mg of ethyl chlorocarbonate were added at 0 ° C. with stirring to a solution of 352 mg of p- (methylsulfonyl) benzoic acid in 10 ml of dry tetrahydrofuran. After stirring at this temperature for 20 min, the resulting suspension was treated with 500 mg of 2-guanidino-4- (amino-ethylthiomethyl) thiazole-dihydrochloride and 0.5 ml of triethylamine and allowed to cool to room temperature overnight with stirring. The precipitated solid was filtered off and then the filtrate was evaporated in vacuo to an oil which was chromatographed on a silica gel column (40 g) using ethyl acetate / methanol (20: 5) as eluent and 154 mg (82 % Yield) 2-guanidino-4- [2- (4-methylsulfonylbenzamido) ethylthiomethyl] thiazole 30 gave. Treatment of this product with 500 mg of maleic acid in acetone gave 600 mg of monomaleate in the form of crystals of mp. 192-194 ° C. (decomposition) from methanol.

35 Anal, for C19H23O7S3N5:

Calculated: C 43.08; Found: C 42.81;

H 4.38. H 4.20;

N 13.33 (4).

Calculated: C 40.74; Found: C 40.63;

H 4.18; H 4.08;

N 15.84 (%). N 15.74 (%).

Monohydrochloride, mp. 220 ° C (decomposition).

40 Examples 4-22

When using the carboxylic acid (III), the reaction was carried out as described in Example 3, the product (I) according to Table 1 being obtained.

hn = c-nh nh a

i-l

RCOOH (III)

ch2s (ch2) 2kh2

(II)

hn = c-nh I

nh

"> S ^ N

1 = 1 ^ ii xh2s (ch2) nhcr

(I)

Table 1

Example No.

salt

Mp (° C)

Yield (%)

Maleate

Maleate

175-176

161-163

80.2

87.4

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Table 1 continued

Example No.

salt

Mp (° C)

Yield (%)

10th

11

12

13

14

15

16

17th

18th

19th

20th

21st

-CH = C (CH3) 2

now

CHs

-CH = CH2

ov- ° ch3

^ och3

-CH = CH-CH = CHCH3

-CH = CH-COOBu

Oxalate V2H2O

Maleate

Maleate

Maleate

Maleate

Maleate

175-176d.

91

Maleate

Maleate

Maleate

Maleate V2H2O

Maleate V2H2O

Maleate V4H2O

Maleate

V2U2O

Maleate

Maleate I / 2H2O

212-214d. 43.3

197-198

183-185

175-177

173-175

181-183

207-209 134-136

95-98d. 154-156d.

168-170d. 99-101d.

35

63

71

76

55

34 62.5

30.5 58.5

179-180d. 81.6

181-182d. 72.8

66.3

54.4

1.25 maleate 0.75 H2O

141-145d. 11.1

7

Table 1 continued

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Example No.

salt

Mp (° C)

Yield (%)

22

Maleate

179-181

39

nh,

Example 23

300 mg of p-nitrobenzoyl chloride and 0.74 ml of triethylamine were stirred at 0 ° C. into a suspension of 500 mg of 2-guanidino-4- [2- (amino) ethylthiomethyl] thiazole dihydrochloride in 5 ml of dry dimethylformamide added, the suspension obtained was stirred further and allowed to warm to room temperature overnight. The solvent was removed in vacuo and the residue was applied to a silica gel column (40 g) and chromatographed using ethyl acetate / methanol (20: 5 v / v) as eluent to give 614 mg

2-guanidino-4- [2- (4-nitrobenzamido) ethylthio-

methyl] thiazole in 98% yield. Monomaleate, mp. 180-181 ° C (sintering at 170 ° C) from methanol.

Anal, for C18H20O7N6S2:

15 calc .: C 43.43; H 4.06; N 16.92 (%).

Found: C 43.08; H 4.14; N 16.76 (%).

Example 24-34

20 Using the carboxylic acid chloride (III), the reaction was carried out as described in Example 23, the product (I) being obtained in accordance with Table 2 below:

Table 2

Example I

No. -

salt

Mp (° C)

Yield (%)

24th

25th

26

27th

28

29

30th

31

32

33

34

cooch,

<1

ß-naphthyl

-ch20_ <O)

oh

-CH = CH-Ph

Maleate

Maleate Maleate

Maleate Maleate Maleate Maleate

Maleate

Maleate H2O

Maleate

Maleate

189-190

188-189

175-177d.

151-152d. (Sintering at 145 ° C)

200-202d.

182-184d. 177-178

191-192d.

141-145d.

183-185d.

188-190

22

73.8 89

95 69.8 77.8 48.4

62.1

60.4

55.5

21st

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8th

Example 35

To a mixture of 800 mg of 2-guanidino-4- [2- (amino) ethythiomethyl] thiazole, 132 mg of formic acid and 590 mg of DCC in 15 ml of dry dimethylformamide was added 0.8 ml of triethylamine with stirring. After stirring the resulting mixture at room temperature for 16 h, the precipitate formed was filtered off and the filtrate was concentrated in vacuo to an oily residue, which was placed on a silica gel column (70 g) using ethyl acetate-methanol (20: 5 v / v) was chromatographed as eluent and gave a mixture of 706 mg of the free base and carbonate of 2-guanidino-4- [2- (formamido) ethylthiomethyl] thiazole. This was dissolved in methanol and carbon dioxide gas was passed through the solution. After evaporation of the solvent, 720 mg of the carbonate were obtained in 85% yield as crystals of mp. 138-140 ° C.

Anal, for C <> H 15O4N5S2 • 1 -5 KhCOa- V2H2O:

Chromatographies. The eluate was concentrated and gave 196 mg of 2-guanidino-4- [2- (acetamido) ethylthio-methyljthiazole, identical to the product from Example 14. The yield was 25%.

s Preparation of l-chloro-3- [2- (acetamido) ethylthio] -2-pro-panon:

2 g of Amberlite IR4B (OH-10 type) were added to a solution of 667 mg of 2-acetamidoethanethiol in 25 ml of absolute ethanol. The resulting mixture was cooled to 0 ° C, mixed with 908 mg of 1,3-dichloroacetone, stirred at 0 ° C for 1 h, and then left to stand at 3-5 ° C overnight. The resin was filtered off and the filtrate was evaporated in vacuo at a temperature below 35 ° C. The oily residue was chromatographed on a silica gel column using ethyl acetate-methanol (20: 5 v / v) as the eluent. The eluate was concentrated in vacuo to give 607 mg of l-chloro-3- [2- (acetamido) ethyl-thio] -2-propanone in the form of an oil. Yield: 52%.

20th

Ber: C 30.41; Found: C 30.55;

H 4.82 (%). H 4.66 (%).

Example 36

A solution of 268 mg of N-benzoylcysteamine in 5 ml of ethanol was added dropwise to a solution of about 70 mg of metallic sodium in 25 ml of ethanol at 0 ° C. with stirring, and the resulting mixture was stirred at 0 ° C. for a further 2 hours . A solution of 239 mg of 2-guanidino-4-chloromethylthiazole in 5 ml of ethanol was added dropwise to the mixture, which was stirred at room temperature for 15 hours. The reaction mixture was then concentrated in vacuo and mixed with acetone, whereupon the insoluble material was filtered off and the filtrate was mixed with maleic acid acetone, 414 mg of 2-guanidino-4- [2- (benzamido) ethylthiomethyl] thiazole maleatin 91. 4% yield as crystals of mp. 200-292 ° C (decomposition) were obtained.

Example 37 40

When using 273 mg of N-nicotinoylcysteamine, the reaction was carried out as in Example 36, whereby 0.35 g of 2-guanidino-4- [2- (nicotinamido) ethylthio-methyl] thiazole maleate was obtained in 77.4% yield.

Example 38

Using 3,4,5-trimethoxybenzoic acid, the reaction was carried out as in Example 3, whereby 2-guanidino-4- [2- (3,4,5-trimethoxybenzamido) ethylthio-methyl] thiazole maleate in the form of crystals of Mp 163-165 ° C (decomposition) was obtained in 66% yield.

Example 39

Using p-methylsulfonylbenzoic acid, the reaction was carried out as in Example 3, whereby crystals of 2-guanidino-4- [2- (4-methylsulfonylbenzamido) ethylthiomethyl] thiazoI hydrochloride of mp 196-198 ° C. were obtained .

Example 40 60

320 mg of guanylthiourea were added to a solution of 607 mg of l-chloro-3- [2- (acetamido) ethylthio] -2-propanone in 25 ml of absolute ethanol and the resulting mixture was refluxed with stirring for 3 hours. After cooling, the reaction mixture was mixed with 1.5 ml of 65 triethylamine and concentrated in vacuo. The residue was on a silica gel column (25 g) using ethyl acetate-methanol (20: 5 v / v) as the eluent

NMR, 8CDCl3: 1.98 (3Hs), 2.65 (2Ht, J = 7 Hz),

3.45 (2Hs), 4.28 (2Hs), 6.22 (1H brs).

Example 41

To a suspension of 30 g of 2-guanidino-4- [2- (amino) ethylthiomethyl] thiazole dihydrochloride and 13 gN, N-dimethylformamide dimethylacetal in 550 ml of dry tetrahydrofuran was added 30 g of triethylamine. The resulting mixture was refluxed with stirring for 5 h and then concentrated in vacuo. The residue was mixed with 300 ml of 10% aqueous potassium carbonate solution and stirred at room temperature for 3 days. The reaction mixture was then brought to about Ph 7 with dilute hydrochloric acid and chromatographed on a column with Amberlite IRC-50 (H + type), the elution being carried out with 10% aqueous ammonia solution. The eluate was concentrated in vacuo and gave 11.6 g of 2-guanidino-4- [2- (form-amido) ethylthiomethyl] thiazole as a viscous oil. The oil was dissolved in acetone and reacted with a solution of 11 g of maleic acid in acetone to give 15.3 g of crude maleate in the form of crystals, which after recrystallization from ethanol gave 11.8 g of monomaleate. M.p. 146-148 ° C. Yield: 32%.

45 Anal, for CsHi3NsOS2-C4H4O4:

Calc .: C 38.39; Found: C 38.58;

H 4.56; H 4.47;

N 18.66; N 18.45;

S 17.08 (%). S 16.74 (%).

Example 42

To a solution of 7.2 g of 2-guanidino-4- [2 - (- nitrobenzamido) ethylthiomethyl] thiazole monomaleate in 200 ml of 50% acetic acid was added 89 ml of 20% aqueous titanium trichloride solution at room temperature and the resulting mixture was stirred at room temperature for 45 min. The reaction mixture was then basified with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate. The precipitated resinous material was dissolved in methanol and the solution was combined with the ethyl acetate phase. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate-methanol (20: 5 v / v) as the eluent. The eluate was concentrated to an oil which was treated with a solution of 4.6 g of maleic acid in acetone. The crude maleate obtained was recrystallized from ethanol to give 3.1 g of 2-guanidino-4-

[2- (4-aminobenzamido) ethyl tiomethyl] thiazole monomeat with mp. 171-172 ° C (decomposition). The yield was 46%.

Anal, for C14H18N6OS2:

Calculated: C 46.34; H 4.75; N 18.02; S 13.75 (%).

Found: C 46.35; H 4.82; N 17.63; S 13.55 (%).

Example 43

To a solution of 7.8 g of N-carbobenzoxy-y-amino-butyric acid in 200 ml of dry tetrahydrofuran was added 3.4 triethylamine and 3.1 g of methyl chlorocarbonate at -10 ° C. and the resulting mixture was kept at this temperature for 30 minutes touched. 7.0 g of triethylamine and 10 g of 2-guanidino-4- [2- (amino) ethylthiomethyl] thiazole dihydrochloride were added to the mixture, which was then stirred at room temperature overnight. The precipitate formed was filtered off and washed exhaustively with tetrahydrofuran. The filtrate was combined with the washing solutions and concentrated in vacuo. The residue was mixed with 50 ml of 30% hydrobromic acid-acetic acid and stirred at room temperature for 12 hours. The reaction mixture was then diluted with 11 dry ether, the resulting hygroscopic precipitate was quickly filtered off, dissolved in 50 ml of water and neutralized with solid sodium carbonate. The solution was evaporated to dryness in vacuo, the residue obtained was extracted with ethanol and the extract was concentrated to 3.0 g of a viscous oil. This oil was treated with a solution of 3.0 g maleic acid in ethanol to give 1.5 g 2-guanidino-4- [4-aminobutyramido) ethylthio-methyl] thiazole monomaleate. Mp 87-89 ° C (recrystallized from 95% ethanol).

Anal, for Ci 1H20N6OS2 • 2C4H4O4 • Vi H2O:

Ber. C 49.92; H 5.24; N 15.07; S 11.50 (%).

Found: C 40.30; H 5.19; N 15.22; S 11.86 (%).

Example 44

To a solution of 472 mg of 2-guanidino-4- (3-aminopropyl) thiazole (U.S. Patent No. 4,165,377) and 0.8 ml of triethylamine in 8 ml of dry dimethylformamide was added 500 mg of nicotinyl chloride hydrochloride at -20 ° C given. The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was mixed with 3 ml of water and made basic with 5% aqueous sodium hydrogen carbonate solution. The precipitate obtained was filtered off, washed exhaustively with water and dried to the crude product. This Rohpro646964

The product was treated with a solution of 300 mg of maleic acid in methanol and diluted with acetone to give 300 mg of 2-guanidino-4- [3- (nicotinamido) propyl] thiazole monomealeate. Mp 176 ° C (decomposition) from ethanol.

Anal, for CnHióNsOS • C4H4O4:

Calculated: C 48.56; H 4.79; N 19.99; S 7.63 (%),

Found: C 48.31; H 4.59; N 19.73; S 7.80 (%).

Example 45

To a solution of sodium hydride (50% suspension in mineral oil, 590 mg) in 20 ml of absolute ethanol was added dropwise a solution of 733 mg of 2-acetamidoethanethiol in 3 ml of absolute ethanol at -20 ° C and the resulting mixture was at -20 ° C stirred for 10 min. Then 1.88 g of solid 2-guanidino-4-chloromethyl-thiazole hydrochloride (US Pat. No. 4,165,377) were added, which was stirred at room temperature overnight. The precipitate obtained was filtered off, washed with ethanol and the filtrate was combined with the washing solutions and concentrated to dryness in vacuo. The residue obtained was placed on a silica gel column which was eluted with ethyl acetate-methanol (20: 5 v / v). The eluate was concentrated in vacuo to 1.5 g of 2-guanidino-4- [2- (acetamido) ethylthio-methyl] thiazole in the form of an oil. The yield was 89%.

Examples 46-50 The following compounds were obtained according to route B as in Example 3:

Table 3

Example No.

n

R

salt

Mp (° C)

Yield (%)

47

3rd

Monomaleate

176-179d.

65.1

48

3rd

n

-CH3

Monomaleate

158-159

74.4

49

3rd

H

Monomaleate

127-129

39.8

50

4th

- <p>

Monomaleate

135-137

33.3

51

4th

CHj

Monomaleate

160-162

55.8

9

s

10th

15

20th

25th

30th

35

40

45

50

B

Claims (10)

646964 1. Compound of the formula hn = c-nh 1 2 nh ■ —k ^ ch2x (ch2) nnh-co-r where n represents an integer from 2 to 4; R is hydrogen, optionally substituted by hydroxy, cyano, amino or phenoxy Ci-Có-alkyl, Cz-Cô-cycloalkyl, optionally substituted by phenyl or C2-C7-alkoxy-carbonyl C2-C6-alkenyl, C4-C7-alkadienyl, optionally by 1-3 substituents from the group halogen, cyano, nitro, amino, C2-Cio-dialkylamino, tetra-zolyl, hydroxy, Ci-Có-alkoxy, benzoyloxy, C2-C7-alkoxy-carbonyl, sulfamoyl, Ci-Ca Represents alkylsulfonyl, Ci-Cö-alkansulfonamido or Ci-Có-alkanoyl substituted C6-Ci2-aryl, or a 5- or 6-membered heterocycle optionally substituted by halogen, Ci-Có-alkyl or phenyl; and in what X represents a single bond or a sulfur atom, and pharmaceutically usable acid addition salts thereof. 2. A compound according to claim 1, wherein n is an integer of 2 or 3, R optionally by 1-3 substituents from the group halogen, cyano, nitro, amino, C2-Cio-dialkylamino, tetra-zolyl, hydroxy, Ci-Cö-alkoxy, benzoyloxy, C2-C7-alkoxy-carbonyl, sulfamoyl, Ci Cs-Alkylsulfonyl, Ci-Ce-Alkansul-fonamido or Ci-Có-Alkanoyl substituted phenyl and X represent a sulfur atom. 3. A compound according to claim 1, wherein n is an integer of 2 or 3, R represents a 5-membered heterocycle optionally substituted by halogen, Ci-C6-alkyl or phenyl and X represents a sulfur atom. 4. A compound according to claim 1, wherein n is an integer of 2 or 3, R represents a 6-membered heterocycle optionally substituted by halogen, Ci-Cs-alkyl or phenyl and X represents a sulfur atom. 5. A compound according to claim 1, wherein n is an integer of 2 or 3, R represents hydrogen, optionally substituted by cyano, amino or phenoxy Ci-Có-alkyl, C3-C6-cycloalkyl, optionally substituted by phenyl or C2-C7-alkoxycarbonyl-substituted C2-C7-alkenyl or C4-C7-alkadienyl and X represents a sulfur atom . 6. 2-guanidino-4- [2- (formamido) ethylthiomethyl] thiazole according to claim 5. 7. 2-guanidino-4- [2- (acetamido) ethylthiomethyl] thiazole according to claim 5. 8. 2-guanidino-4- [2- (nicotinamido) ethylthio-methyljthiazole according to claim 4. 9. 2-guanidino-4- [3 - (formamido) propylthio-methyl] thiazole according to claim 5. 10. 2-guanidino-4- [3- (acetamido) propylthio-methyljthiazole according to claim 5.