FI70890B - PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICAL PROPERTIES OF GUARANIDINOTIAZOLFOERENINGAR - Google Patents

Description

ΓΤ ~ ττ——] ANNOUNCEMENT

Β (11 UTLÄGGNINGSSKRIFT 70 8 90 5¾) ¾ C (45) P-tr..tti tty (51) K ».ik. * / Int.ci. * C 07 D 277Λ2 FINLAND —FINLAND (21) Patent application - Patentansöknlng 800591 (22) Date of application - Ansökningsdag 27-02.80 (Fl) (23) Date of commencement— Glltighetsdag 27-02.80 (41) Has become public - Bllvit offentllg 07-09-80

National Board of Patents and Registration Date of date of publication and publication.

Patent- och registrstyrelsen '' Ansökan utlagd oeh utl.skrlften publicerad lo.u / .oo (86) Kv. application - Int. ansökan (32) (33) (31) Privilege claimed - Begärd priority 06.03-79, 23-06.79, 02.08.79 Japan-Japan (jp) 257 ^ 5/79, 79508/79, 98906/79 (71) Yamanouchi Pharmaceutical Co., Ltd., 5 ~ 1, Nihonbashi-Honcho, 2-chome, Chuo-ku, Tokyo, Japan-Japan (JP) (72) Yasufumi Hirata, Omiya-shi, Saitämä, Isao Yanagisawa, Nerima-ku, Tokyo , Yoshio Ishii, Omiya-shi, Saitama, Shinichi Tsukamoto, ltabashi-ku, Tokyo, Noriki Ito, Iwatsuki-shi, Saitama, Yasuo Isomura, Yokohama-shi, Kanagawa, Masaaki Takeda, Urawa-shi, Saitama, Japan-Japan ( JP) (7 * 0 Leitzinger Oy (5 * 0 Method for the preparation of pharmacologically valuable gyanidothiazole compounds - Förfarande för framstä11 Ning av pharmacologiskt värdefulla guani-d i not iazolfören i ngar

The present invention relates to a process for the preparation of pharmacologically valuable gyanidinotiazole compounds of the formula

R-NH / V ^ <CH2> „rY- <CH2> n-A

V C = N-f if (I) H 2 wherein R is a hydrogen atom or a lower alkyl group, Y is a sulfur atom or a methylene group, m and n are each an integer from 1 to 3, A is a group 2 70890 - N-R 1 or -CONH-R 4,

S

NH-R2 where R1 is a hydrogen atom, a syrano group, a carbamoyl group, a ureido group, a hydroxyl group, a lower alkoxy group, a lower alkanoyl group, a lower alkanoylamino group, a benzoyl or naphthyloxy group, a haloalkyl group, a , a phenyl or naphthyl group which may be substituted by an amino group, a halogen atom, a hydroxyl group or a lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, a phenyl or naphthylamino group, a C 5-7 cycloalkylamino group or a lower allyl, an alkynyl group, a cyano group or a lower alkanoyl group, and R 4 is a hydrogen atom, a lower alkyl group, a hydroxyl group or a sulfoyl group.

The compounds of the above-mentioned general formula I readily form acid addition salts and also exist as tautomers in the position / N-R1

-C

\ nh-r2 which acid addition salts can be used for medical purposes. These salts include salts of guanidinothiazole compounds with inorganic acids or organic acids. Examples of inorganic acid salts include hydrochlorides, hydrobromides and sulfates, etc. Particularly useful salts of organic acids include salts with aliphatic carboxylic acids such as acetic acid, maleic acid, fumaric acid, etc.

A first feature of the present invention is / that the compounds provided by the present invention have gastric acid inhibitory activity that is not caused by anticholinergic activity. Because conventional commercially available subjects for inhibiting gastric acid secretion are mostly based on anticholinergic activity, and because anticholinergic activity has been claimed to have undesirable side effects, the compounds of this invention are useful as novel types of gastric acid secretion inhibitors.

Another feature of this invention is that some of the compounds of this invention have activity that inhibits gastric acid secretion via the histamine β receptor. Ash and Schild, "Brit.

J. of Pharmacol. Chemother ", 2J, 427 (1966) and Black et al .;" Nature ", 236, 385 (1972) have proposed that histamine receptors be classified as β-receptors and non-H1-receptors, i.e. H2-receptors. The H2-receptor mediates histamine effect on gastric acid secretion and heart rate in the isolated guinea pig atrium Conventional anti-histamines such as mepyramine do not inhibit these histamine effects, but H2-receptor blockers such as methamide act against them.

Since histamine H2 ~ receptor antagonists, an activity to which inhibits gastric acid secretion and gastrin peruserittymistä or food-induced gastric acid secretion in March, can be used as gastric ulcer and duodenal gastric acid hypersecretion, ulcers caused by misen.

Belgian patent numbers 804,145 are known to date as substances having the characteristics of the compounds of this invention; 866.156; 867.105; 867.594; and compounds of U.S. Patent No. 3,950,333, etc. However, the compounds of the present invention are all novel compounds having different structures and improved pharmacological effects compared to these known compounds.

The compounds of this invention may be administered orally or parenterally, but most preferably orally. The 70890 compounds of the invention are used as the free bases or their pharmacologically acceptable salts. They are generally used in the form of medicaments or pharmaceutical mixtures with carriers or diluents which can generally be used for the preparation of medicaments. For oral administration, it is most convenient to use the pharmaceutical compositions of this invention as capsules or tablets, but they may also be used as long-acting preparations. The mixtures can also be used as sugar-coated preparations or syrups. Their doses for oral administration are 50 to 800 mg per day, suitably administered in 1 to 4 separate doses.

The compounds of general formula I of this invention inhibit histamine-induced gastric acid secretion, as demonstrated by the following tests.

(i) Gastric acid excretion in anesthetized dogs:

Mixed breed dogs weighing 8-15 kg were fasted for 24 hours and anesthetized intravenously with pentobarbital (30 mg / kg). After ligation of the pylorus and esophagus, a stainless steel cannula was inserted through the abdominal wall of the stomach (Okabe, S. et al .: Japan J. Pharmacol. 2T_, 17-22, 1977). Gastric fluid was drained by gravity through a gastric cannula every fifteen minutes. Test compounds were administered intravenously after gastric acid secretion induced by continuous intravenous infusion of histamine (160 pg / kg-h) reached steady state. Gastric acidity was measured by automatic titration (Kyoto Electronics Manufacturing Co., AT-107) by titration with 0.05 N sodium hydroxide. The difference between the pre-drug acid output and the minimum acid output, usually achieved within 45 minutes after drug administration, was used to calculate the percentage inhibition of gastric acid secretion at each dose. The 50% inhibition of acid production was obtained from a dose-response curve in which inhibition was plotted semi-logarithmically against dose. The results are shown in Table I in column (A).

(ii) Gastric acid secretion in rats with pylorus ligated:

Male Wistar rats weighing approximately 200 g and housed 5,70890 in their own cages were fasted for 24 hours but were given free access to water before the experiments. Pylorus was ligated under ether anesthesia under the procedure of Shay et al. method (Gastroenterol. 5, 43-61, 1945). Test compounds were administered intraduodenally immediately after ligation of the pylorus. Animals were sacrificed 4 hours after drug administration and gastric contents were collected. Gastric acidity was measured by automatic titration (Kyoto Electronics Manufacturing Co., AT-107) by titration with 0.05 N sodium hydroxide. For each dose, the percentage inhibition of gastric acid secretion from the acid production of the control group and the treated group was calculated. ED5Q values were determined by the probit method. The results are shown in Table I in column (B).

(iii) Acute toxicity in mice: Drugs were injected intravenously into ICR male mice weighing approximately 35 g, 0.0 ml / 10 mg / 10 seconds, and the animals were observed for 7 days. LD50 values were determined by the up and down method using 10 animals. The results are shown in Table 1 in column (C).

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3 -Ö H H H H Ό-H T3 (0 x! M ui in n n ie n h cn E-i> 1 W W W W> 1— | x M * 7 70890 The guanidinothiazole compounds of the general formula I of the present invention can be prepared by the following methods.

Manufacturing method 1: »X V1„ ν '\' / r2-nh2 \ / R1-nh2 in, \ / ma «

R-NHN //V(CU2,.-Y-<CH2)n-CCN"ni I

In the above formulas, R * is a lower alkyl group, and R, R 1, R 2, Y, m and n have the same meaning as above.

This process is carried out either by reacting a starting compound of formula IIj and a reactive amount of an amine of formula IIIj, or by reacting a starting compound of formula II2 and a reactive amount of an amine of formula III2. The amines represented by the formulas ΙΙΙχ or III2 used in this process are amines which are capable of producing the desired product Ιχ by reacting with the starting compound IIj or II2.

Examples of amines of formula IIIi are ammonia (ammonium chloride); lower alkylamine such as methylamine, dimethylamine, ethylamine, isopropylamine, etc .; lower alkenylamine such as allylamine, 2-butenylamine, etc .; lower alkynylamine such as propargylamine, pentynylamine, etc .; and the like. Examples of amines of formula III2 are ammonia (ammonium chloride); cyanamide; urea, hydroxyl-8,70890 amine; o-lower alkylhydroxyamine such as o-methylhydroxylamine, o-butylhydroxylamine, etc .; lower acylamine such as acetamide, etc .; acylhydrazine such as acetylhydrazine, benzoylhydrazine, etc .; bentseenisulfonyylihydratsiini; semi-carbazide; aralkylamine such as benzylamine, phenethylamine, etc .; lower alkylsulfonamide such as methanesulfonamide, ethanesulfonamide, etc .; halogen lower alkylsulfonamide such as trifluoromethanesulfonamide, etc .; substituted or unsubstituted arylsulfonamide such as benzenesulfonamide, p-chlorobenzenesulfonamide, p-aminobenzenesulfonamide, etc .; sulfamide; lower alkyl sulfamide such as methyl sulfamide, diethyl sulfamide, etc .; aryl sulfamide such as phenyl sulfamide, naphthyl sulfamide, etc .; aralkyl sulfamide such as benzyl sulfamide, etc .; glycine: and the like.

The reaction is usually carried out in a solvent. Suitable solvents are, for example, organic solvents such as methanol, ethanol, isopropanol, chloroform, ether, tetrahydrofuran, benzene, etc. It is preferable that the solvents do not contain water. The reaction temperature is not particularly limited, but the reaction is best carried out at room temperature or under heating. It is also recommended that the reaction system be neutral-basic.

Preparation 2: r-niix - (en.,) -Y- (CIU -ci0 »4-» h2 m, Ψ R-WH \ 70890 9

In the above formulas, R, R ', R 1, Y, m and n have the same meaning as above.

This process is carried out by reacting a starting compound of formula II2 with a reactive amount of an amine of formula III2. The starting compound of formula II1 is obtained by hydrolyzing a starting compound of formula 111 or II2 in which R1 or R1 is a hydrogen atom by a conventional method. Examples of amines of formula III are ammonia; 3. lower alkylamine such as methylamine, ethylamine, isopropylamine, etc .; hydroxyl amine; and the like. Reaction conditions such as solvent, reaction temperature, etc. are the same as in Production Method 1.

In addition, the product of the present invention can be prepared by other methods, such as a method in which the R 1 or R 2 groups of the desired product I are converted into each other, and the like. The following are example methods.

"N-R 1 (i) The desired product of formula I (when A is a group -C), N nh-r 2 having a carbamoyl group, is obtained by passing dry hydrogen chloride gas through an alcohol containing a compound of formula I having a cyano group, while cooling or treating this compound with concentrated hydrochloric acid.

* N-R 1, (ii) The desired product of formula I (wherein A is -C 1-4), wherein R 1 and R 2 represent the same lower acyl group, is obtained by reacting a lower acyl halide with a compound of formula I, wherein both R 1 and R 2 represent a hydrogen atom.

(iii) The desired product of formula I (wherein A is a group -CN), nh-r4 where R 4 is -SC> 2NH 2, is obtained by hydrolysis of a compound of formula I in case A is a group -C 1 N -R 1 in which R is a sulfamoyl- x NH-R2 group and R2 is a hydrogen atom.

The methods of this invention are further illustrated by the following examples. In the following examples, the abbreviations m.p. Anal., NMR and mass., mean the melting point, the results of the elemental analysis, the magnetic resonance spectrum of the nucleus and the mass spectrum, respectively.

70890

Example 1 h2n. / N ^ noh

^ J CH „SCH_ CH_C

H2N X ™ 2 4.72 g of methyl 3 - / (2-guanidinothiazol-4-yl) methylthio / propionimidate were dissolved in 35 parts of methanol, and then 25 ml of a methanolic solution of free hydroxylamine prepared by treating 1.2 g of hydroxylamine hydrochloride 0.93 g of sodium methoxide. The mixture was stirred for 2 hours at room temperature, after which the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using a mixture of chloroform and methanol as a developing solvent. The product was recrystallized from methanol-acetone to give 1.3 g of 3 - [(2-guanidinothiazol-4-yl) methylthio] propionamidoxime. The product has the following physicochemical properties: (i) Melting point: 177-179 ° C (decomposes) (ii) Elemental analysis Cg Hi4N60S2.1 / 4H2O:

C H N

Calculated: 34.46% 5.24% 30.14%

Found: 34.78% 5.23% 30.06% Methyl 3 - [(2-guanidino-thiazol-4-yl) methylthio] -propionimidate used as a raw material in this example was prepared by the following method.

M CH_SCH „CH„ CN

N 2 2 2 (a) H, N - ά l |

xs ^

To a mixture of 490 ml of water and 320 ml of ethanol was dissolved in a stream of nitrogen 98.1 g of S- (2-aminothiazol-4-ylmethyl) isothiourea 2-hydrochloride (see 11 J. Amer. Chem. Soc. ", 6-8, 2155- 2159 (1946)).

70890 11

37.0 g of chloropropionitrile was added thereto, after which the mixture was cooled to 0-10 ° C, and a solution of 45.1 g of sodium hydroxide in 450 ml of water was added dropwise to the mixture. The mixture was then stirred for 1 hour at 0-10 ° C: and another 1 hour at room temperature. The resulting product was extracted four times with 600 ml of chloroform.

The obtained chloroform layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give 47.2 g of 3- (2-aminothiazol-4-ylmethylthio) propionitrile, m.p. 104-106 ° C.

(B)

s N 2 x, CH 2 SCH 2 CH 2 CN

jT ~ \ _ 11 / i!

^ ^ -CONHCNH —I

50 g of S- (2-aminothiazol-4-ylmethylthio) propionitrile was dissolved in 500 ml of acetone. To the solution was added 45 g of benzoyl isocyanate, followed by refluxing for 5 hours. The solvent was then concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give 79.4 g of 3- [2- (3-benzoylthioureido) thiazol-4-ylmethylthio / propionitrile as needle-like crystals, m.p. 158-160 ° C.

(c) s N ch2sch2ch2cn "- / '7"

h2ncnh —C I

80 g of 3- [2- (3-benzoylthioureido) -thiazol-4-ylmethylthio] -propionitrile was dissolved in a mixture of 1400 ml of acetone and 350 ml of methanol. A second solution containing 20 g of potassium carbonate in 300 ml of water was added to the solution. The mixture was stirred for 5 hours at 50 ° C. The solvents were then concentrated under reduced pressure, and the resulting residue was added to 2000 ml of ice water, followed by stirring for 24 hours. The precipitated crystals were collected by filtration to give 53.3 g of 3- (2-thioureidothiazol-4-ylmethylthio) propionitrile, m.p. 135-137 ° C.

(d) sch3 n ch2sch2ch2cn

1 _ / 'll -HI

HN = C-NH -C

15 g of 3- (2-thioureidothiazol-4-ylmethylthio) propionitrile were dissolved in 200 ethanol and 12.4 g of iodomethyl were added to the solution. The mixture was then refluxed with heating for 1 hour. The solvent was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give 20.9 g of 3- [2- (S-methylisothioureido) thiazol-4-ylmethylthio] -p-opionitrile hydroiodide, m.p. 148-149 ° C. (decomposes).

N CH SCH CH CN

h2nn _r il H-N \

S

20 g (0.05 mol) of 3- [2- (S-methylisothioureido) thiazol-4-ylmethylthio] propionitrile hydroiodide and 2.68 g (0.05 mol) of ammonium chloride were dissolved in 200 parts of methanol, containing 17.0 g (1.0 mol) of ammonia. The solution was heated in a sealed tube for 15 hours at 80-90 ° C.

After cooling the reaction mixture, the solvent was distilled off under reduced pressure. To the obtained residue was added 200 ml of water, and the mixture was made alkaline by adding saturated aqueous potassium carbonate solution. The resulting brown precipitate was collected by filtration, air-dried and recrystallized from acetone to give 6.2 g of 3- (2-guanidinothiazol-4-ylmethylthio) propionitrile, m.p. 132 ° C.

13 70890 (f) s

H2N \ / ΪΓ NH

10 g of 3- (2-guanidinothiazol-4-ylmethylthio) propionitrile was dissolved in a mixture of 60 ml of anhydrous methanol and 120 ml of anhydrous chloroform. The solution was cooled to 0-10 ° C under a stream of nitrogen and dry hydrogen chloride gas was bubbled through it for 3 hours. The solution was then allowed to stand in a sealed vessel for 20 inches at 0 -4 ° C.

The solvents were distilled off under reduced pressure, and the concentrated residue was poured into 200 ml of ice water containing 30 g of potassium carbonate. The mixture was extracted three times with 150 ml of chloroform containing 20% methyl alcohol.

The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 10.3 g of methyl 3 - [(2-guanidinothiazol-4-yl) methyl] propionimidate.

Example 2

Following the reaction procedure of Example 1, the following compound was prepared:

S

2 ^ C = N - ^ I NOCH

H N ^ \ λ>

n2w N CH0SCH_CH_C

2 2 2 \ nh2

CHCOOH 1 1/4 II

CHCOOH

o-methyl 3 - [(2-guanidinothiazol-4-yl) methylthio] propionamidoxime maleate.

s 14 70890

Amine used in the reaction: H2NOCH3

Physicochemical properties of the product: (i) Melting point: 161-164 ° C.

(ii) Elemental analysis C, .H..0-N, S „1 / 2H_0: 14 z 1 o 6 * *

C H N

Calculated: 38.00% 5.01% 18.99%

Found: 38.04% 4.94% 19.31%

Example 3 / NH2

N CH, SCH9CH C

H2 S

10 ml of an ethanol solution containing 0.28 g of cyanamide was added to 1.9 g of ethyl 3 - [(2-guanidinothiazol-4-yl) methylthio] -propionimidate, and the mixture was allowed to stand overnight at room temperature.

The solvent was then distilled off from the reaction mixture under reduced pressure, and the resulting residue was purified by silica gel column chromatography using a mixture of chloroform and methanol as a developing solvent to give 1.35 g of N-cyano-3 - [(2-guanidinothiazol-4-yl) methylthio / propionamide. The product has the following physicochemical properties: 1

Melting point: 102.5-104 ° C (recrystallization from methanol-ether).

(ii) Elemental analysis, C9H13N7S2:

C H N

Calculated: 38.15% 4.62% 34.60%

Found: 37.84% 4.59% 34.26%

Examples 4-8

Following the reaction procedure of Example 3, the following compounds were prepared: 70890

Example 4: NH_ / 2

N CH_SCH_CH C

/ 2 2 2%

H_N x // I NCH C = CH

1 C = N- [11- (2-propynyl) -3 - [(2-guanidinothiazol-4-yl) methylthio] -propionamide.

Amine used in the reaction: H2NCH2ChCH Physicochemical properties of the product: (i) Mass spectrum: m / e 296 (M +) (ii) NMR spectrum (DMSO-d 6 + CD 2 OD) δ: 2.30 (2H, tl 2.70 ( 2H, t) SCH 2 CH 2), 2.83 (1H, t, CH 2 CH 2), 3.60 (2H, S,)> - CH 2 S "), 3.70 (2H, d, NC (CH 2 CH 2)), 6.48 (1H, S, A)

S H

Example 5: / NH2 N ch2Sch2ch2C y-λ N-benzyl-3 - [(2-guanidinothiazol-4-yl) methylthio] propionamide. Amine used in the reaction: H2NCH2

Physicochemical properties of the product: (i) Mass spectrum: m / e 241 (M-NH 2 CH 2 Cl 2)

Z ZOO

70890 (ii) NMR spectrum (DMSO-d 6): δ: 2.38 (2H, O SCH CH) f 3.60 (2H, S,> -CH 2 s "),

2.75 (2H, tJ

4.17 (2H, S, NCH 2 V 1), 6.45 (1H, S 2),

H H H

7.30 (5H, S, -O-H} *

H H

Example 6: / NH 2 N 2 CHOCHCHCH »C. HCl H N /," r 1 2 2%

2 'C = N _ / I NH

.

(ii) Elemental analysis, CgH2NgS ^ Cl:

C H N

Calculated: 32.59% 5.13% 28.51%

Found: 32.33% 5.01% 28.28%

Example 7: ^ NH2 N CH0SCH0CH C, - / '"v" 2 2 2 ^ / \\ HN // I xN-NHCO0 - \ _ / ^ C = N -C' X- '^ \ / H2N s N -benzoyl-3 - [(2-guanidinothiazol-4-yl) methylthio] propionamidazrazone.

70890 17

Amine used in the reaction: H nnhCO - '^ y

Physicochemical properties of the product: (i) Melting point: 103 - 106 ° C.

(ii) Elemental analysis, ci5Hi9N7OS2:

C H N

Calculated: 47.73% 5.01% 25.97%

Found: 47.43% 5.00% 25.72%

Example 8: NH0 / 2

M CH2SCH2CH2C

H-N, N-NHCOOCH-C = N-C 1-3 N, N-N-acetyl-3 - [(2-guanidinothiazol-4-yl) methylthio] propionamide hydrazone.

Amine used in the reaction: H 2 NHCOCH 2.

Physicochemical properties of the product: (i) Melting point: 163 - 166 ° C.

(ii) Elemental analysis, cioHi7N7OS2:

C H N

Calculated: 38.08% 5.43% 31.09%

Found: 37.86% 5.62% 30.73%

Example 9 NH2 -9ΡΠ

N CH SCH-CH.C

0.5 g of N-cyano-3 - [(2-guanidinothiazol-4-yl) methylthio] -propionamidine was dissolved in a mixture of 15 ml of ethanol and 10 g of ml of chloroform. Dry hydrogen chloride gas was bubbled through the solution for 1.5 hours while cooling with ice water, and then the reaction mixture was concentrated under reduced pressure. To the residue was added 10 ml of ethanol, and the mixture was reconcentrated under reduced pressure. The precipitate formed was dissolved in a small amount of ethanol, then ether was added thereto, and the mixture was allowed to stand overnight. The precipitated crystals were collected by filtration to give 0.55 g of N-carbamoyl-3 - [(2-guanidino-thiazol-4-yl) methylthio] -propionamidine.di-hydrochloride. Product 1-Ia has the following physicochemical properties: (i) Melting point: 171-173 ° C.

(ii) Elemental analysis, C 9 H 8 N 2 S 2 O 2 Cl 2 J

C H N

Calculated: 28.88% 4.58% 26.19%

Found: 28.73% 4.64% 25.78%

Example 10

S

CH NH / \ ^ ON -, »«

2 N nCH_SCH CH9C

nh2 6.4 g of methyl 3- (2-methylguanidinothiazol-4-ylmethylthio) propionimidate was dissolved in 30 ml of ethanol, 0.9 g of cyanamide was added to the solution, and the mixture was stirred for 2 hours at room temperature.

The solvent was then distilled off under reduced pressure. The obtained residue was then purified by column chromatography using a mixture of chloroform and methanol as a developing solvent. Recrystallization from ethanol gave 2.0 g of N-cyano-3- (2-methylguanidinothiazol-4-ylmethylthio) propionamidine, m.p. 144-145 ° C.

Elemental analysis,

C H N

Calculated: 40.39% 5.08% 32.97%

Found: 40.13% 5.00% 32.68% 70890 19

Example 11 ch .. m, ✓ JC = N-fi NH '\ A - ^ NCONH2 2 XN CH0SCHOCH „C. -amidine was dissolved in a mixture of 20 ml of ethanol, 30 ml of chloroform and 10 ml of methanol. The solution was cooled to 0-5 ° C and hydrogen chloride gas was bubbled through it for 1 hour, after which the solvents were distilled off under reduced pressure. The resulting residue was recrystallized from ethanol to give 1.2 g of N-carbamoyl-3- (2-methylguanidinothiazol-4-ylmethylthio) -propionamidine di-hydrochloride, m.p. 180-182 ° C.

Elemental analysis, cioh; 19N7OS2C12.1 / 2H2O:

C H N

Calculated: 30.23% 5.07% 24.68%

Found: 30.52% 5.06% 24.41% -

Example 12

S

c = n ^ 1 x. mHs ° 2 N CH-SCH-CH-C '-f Δ z * NNH2 2.0 g of methyl 3- (2-guanidinotiazol-4-ylmethylthio) propionimidate and 1.21 g of benzenesulfonylhydrazine were dissolved in 49 ml of methanol. The solution was stirred at room temperature for 24 hours, after which the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using a mixture of chloroform and methanol as a developing solution to give 1.2 g of N-benzenesulfonyl-3- (2-guanidinothiazol-4-ylmethylthio) -propionamide hydrazone, m.p. 159.5-161 ° C.

70890 20

Elemental analysis, c ^ 4H ^ gN70 S3:

C H N

Calculated: 40.66% 4.63% 23.71%

Found: 40.30% 4.54% 23.46%

Example 13 S ._ H 2 N. /

^ C = N-6 I NCH2COOH

H2 N N CH ~ SCH0CH_C

2 2 2 \

N NH

2 2 g of methyl 3- (2-guanidinothiazol-4-ylmethylthio) propionimidate were suspended in 20 ml of methanol, and then a solution of 0.5 g of glycine in 5 ml of water was added to the suspension. The mixture was stirred for 2 hours at room temperature, and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from a mixture of water and acetone to give 1.0 g of 3- (2-guanidinothiazol-4-ylmethylthio) propionamidoglycine, m.p. 140-141 ° C (dec).

Elemental analysis, c10H16N6 ° 2S2 · 21/41 ^ 0:

C H N

Calculated: 33.65% 5.79% 23.55%

Found: 33.82% 5.43% 23.65%

Example 14 S \ H2N \ />

C = N - (I

H2N ^ ^ NCN

CH „SCH CH, C

^ NHCN

70890 5/1 g of methyl 3- (2-guanidinothiazole-4-methylthio) propionimidate were dissolved in 35 ml of methanol, and 0.9 g of cyanamide was added to the solution. The mixture was then stirred at room temperature for 24 hours, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using a mixture of chloroform and methanol as a developing solvent to give 4.8 g of N-cyano-3- (2-guanidinothiazol-4-ylmethylthio) propionamidine and 0.3 g of N, N1-dicyano3- (2-guanidinothiazole). 4-yl) methylthiopropionamidine, mp 223-224 ° C (dec).

Mass spectrum: (FD method); m / e 309 (M + + 1) NMR (d 6 DMSO): δ 2.5-2.8 (4H, m, --CH 2 CH 2 -), 3.75 (2H, s, -CH 2 S-) 7.10 (1H, s, ~ TÖ), 8.10 (4H, lev.s, S2N'c = N-) NN 52n ^

Example 15 H N S \ 'C-N - ^ | «H .N · 'N JL NNC0NHo 2 N N ^ 2 CH-SCH_CH C 2 2 2 \ nh2

To a solution of 246.6 mg of potassium tert-butoxide in 10 ml of anhydrous metal was added 245.3 mg of semicarbazide hydrochloride under ice-cooling. The mixture was stirred for 10 minutes at room temperature, after which 540 mg of methyl 3 - [(2-guanidino-thiazol-4-yl) -thiomethyl] -propionimidate was added thereto. The mixture was stirred for 2 days at room temperature, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography using a mixture of chloroform and methanol to give 0.4 g of N-carbamoylamino-3- (2-guanidinothiazol-4-yl) methyllithio / propionamidine. The product was dissolved in 5 lanes of methanol, and 0.4 g of maleic acid was added to the solution. The mixture was stirred for 10 minutes, after which the solvent was distilled off. To the residue was added 20 ml of acetone, and the insoluble matter was separated by filtration to give 0.3 g of N-carbamoylamino-3 - [(2-guanidinothiazol-4-yl) methylthio] -propionamidine dimaleate monohydrate, m.p. 109-111 ° C.

V: · »70890

Elemental analysis, NQS O: -L / 26 ö z

C H N S

Calculated: 36.04% 4.59% 19.79% 11.30%

Found: 36.01% 4.53% 19.55% 11.37%

Example 16 H2N. ^ / S "·· C = N— / |

h2N- ^ NCN

N CH2SCH2CH2C2

NHCH

To 5.2 g of methyl N-cyano-3 - [(2-guanidinothiazol-4-yl) methylthio] propionimidate was added 50 ml of a 40% methanol solution of methylamine, and the mixture was allowed to stand for 20 hours at room temperature. The solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using a mixture of chloroform and methanol as a developing solvent. The product thus purified was converted to the maleate in acetone and recrystallized from methanol to give 1.0 g of N-cyano-N'-3- (2-guanidinothiazol-4-ylmethylthio) propionamidine, m.p. 159-161 ° C.

Elemental analysis, c 16 H 21 N 2 O 2 S 2 · 1 / 2H 2 O:

C H N

Calculated: 39.99% 4.61% 20.40%

Found: 39.89% 4.69% 20.24%

The methyl (1N-cyano-3 - [(2-guanidino-thiazol-4-yl) methylthio]} propionimidate used as a starting material in the example is obtained by the following method.

7.5 g of 3- (2-guanidinothiazol-4-ylmethylthio) propionitrile was dissolved in a mixture of 90 ml of dried chloroform and 40 ml of dried methanol. The solution was cooled to 0-10 ° C under a stream of nitrogen and 25 g of hydrogen chloride gas was passed through it. The solution was then allowed to stand for 48 hours at 0-10 ° C. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 50 ml of dried 23,70890 methanol. 1.3 g of cyanamide was added to the solution, followed by stirring for 3.5 hours at room temperature. The solvent was then concentrated under reduced pressure, and 50 ml of ice water in which 12 g of potassium carbonate had been dissolved was added to the resulting residue. The product was extracted three times with 50 ml of chloroform. The obtained extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

Example 17

h2n ^ c = n_ / N

η / '\ A' nhcoch3. 1 CHCOOH

CH2SCH CH2C x 2 l |

1 Δ ^ NCOCHj CHCOOH

1.2 g of 3- [2-guanidinothiazol-4-ylmethylthio] propionamidine was dissolved in 10 ml of dimethylformamide. To the solution was added 0.4 g of triethylamine, and the mixture was cooled below 15 ° C. A solution of 1.4 g of acetyl chloride in 3 ml of chloroform was added dropwise to the mixture.

The mixture was then stirred for 30 minutes at room temperature, and the solvent was distilled off. To the resulting residue was added a solution of 0.8 g of potassium carbonate in 2 ml of water. The water was distilled off, and the residue was subjected to silica gel column chromatography. The product was developed with a mixture of chloroform and methanol. The eluent was distilled off to give 0.3 g of N, N · -diacetyl-3- (2-guanidinothiazol-4-ylmethylthio) propionamidine. The product was added to a solution of 0.2 g of maleic acid in 10 ml of acetone, followed by stirring for 30 minutes at room temperature. The precipitate formed was collected by filtration to give 0.2 g of N, N1-diacetyl-3- (2-guanidino-thiazol-4-ylmethylthio) propionamidine.1 / 2-maleate.H0, m.p. 180-181 ° C.

Elemental analysis, ci4H22N6S2 ° 5:

C H N S

Calculated: 40.19% 4.52% 20.00% 15.30%

Found: 39.91% 4.53% 20.01% 15.27% 70890 24

Example 18

S

3 g of methyl 3- (2-guanidinothiazol-4-ylmethylthio) propionate were dissolved in 30 ml of a 40% solution of H, N, N, N, N, N,. The solution was allowed to stand for 24 hours at room temperature, whereupon the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography using a mixture of chloroform and methanol as a developing solvent. 5 g of N-methyl-3- (2-guanidinothiazol-4-ylmethylthio) -propionamide hydrochloride, m.p. 126-127 ° C.

Elemental analysis, C ^ H ^ N ^ OS ^ 1 C (%) H (%) N (%)

Calculated: 34.89 5.20 22.60

Found: 34.51 5.19 22.55

The methyl 3- (2-guanidinothiazol-4-ylmethylthio) propionate used as a starting material in the example was prepared by the following method.

10 g of 3- (2-guanidinothiazol-4-ylmethylthio) propionitrile was dissolved in a mixture of 60 ml of methanol and 120 ml of chloroform.

The solution was cooled to 0-10 ° C and 30 g of hydrogen chloride gas was passed through it. The solution was allowed to stand for 20 hours at 0-10 ° C. To the reaction mixture was added 0.7 ml of water, and the mixture was allowed to stand for several 20 hours at room temperature. The reaction mixture was then added to 250 ml of ice water containing 120 g of potassium carbonate. The mixture was extracted four times with 100 ml of chloroform containing 20% methanol. The obtained extract was concentrated under reduced pressure, and the residue was purified by column chromatography using a mixture of chloroform and methanol as a developing solvent to give 5.0 g of methyl 3- (2-guanidino-thiazol-4-ylmethylthio) propionate, m.p. 106-107 ° C.

25 70890

Example 19 «2«. / s \ -C = N Λ A /

2 \. CH0SCH0CH0C

N 2 2 2 v

NHO

Following the procedure of Example 18 but substituting hydroxylamine for methylamine gave 3- (2-guanidino-thiazol-4-ylmethylthio) -propionhydroxamic acid.

The product has the following physicochemical properties: (i) Melting point: 155 - 156 ° C.

(ii) NMR (DMSO-d 6) δ: 2.24 (2H, t, -CH 2 -C) 2.66 (2H, t, -SCH 2 CH 2 -) 3.58 (2H, s, -CH 2 S-) δ, 48 (1H, s, (iii) Mass spectrum (FD method) m / e 276 (M + +1)

Example 20 h2n \ ys 7> c = n —e 'h7n ^ v A. o

N S

CH SCH CH-C

1 1 X NH 2 5.0 g of methyl 3- (2-guanidinothiazol-4-ylmethylthio) propionimidate was dissolved in a mixture of 30 ml of ethanol and 30 ml of water. The solution was allowed to stand for 20 hours at 40 ° C, after which the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using a mixture of chloroform and methanol. Recrystallization from methanol gave 3.2 g of 3- (2-guanidinothiazol-4-ylmethylthio) propionamide, m.p. 193-194 ° C (dec).

26 70890

Elemental analysis, C8H13N50S2:

C H N

Calculated: 37.05% 5.05% 27.00%

Found: 36.97% 5.06% 26.84%

Example 21 H2N \

C = N - (. M

HCl * N CH-SCH-CH-C * w * x nhso2nh2 2.5 g of N-sulfamoyl-3- (2-guanidinothiazol-4-ylmethylthio) propionamide was dissolved in 50 ml of 1N hydrochloric acid. The solution was stirred. After 2 hours at 40 ° C, the precipitated crystals were collected by filtration and recrystallized from a mixture of methanol and ethyl acetate to give 1.65 g of 3- (2-guanidinothiazol-4-ylmethylthio) propionylsulfamide hydrochloride, m.p. 166-167 ° C.

Elemental analysis, CgH ^ NgO SgCl.HjO:

C H N

Calculated: 24.46% 4.36% 21.39%

Received: 24.78% 4.23% 21.61%

Example 22

S

H_N / |

2 ^ ON - <I

H N \ & NS0 NH

2 N 2 CH 2 SCH 2 CH 2 C

4.09 g of methyl 3 - [(2-guanidinothiazol-4-yl) methylthio] propionimidate was dissolved in 30 ml of methanol. To the refluxing solution was then added 15 ml of a methanol solution containing 2.88 g of sulfamide. The mixture was refluxed for about 3 hours, after which the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using a mixture of chloroform and methanol (20: 1 to 10: 1) as the developing solvent. There was thus obtained 3.26 g of N-sulfamoyl-3 - [(2-guanidinothiazol-4-yl) methylthio] propionamidine. The product has the following physicochemical properties: i) Melting point: 163 - 164 ° C.

(ii) Elemental analysis, COH5N7 ° 2S3:

C H N

Calculated: 28.48% 4.48% 29.06%

Found: 28.37% 4.48% 28.97% iii) NMR Spectrum (DMSO-d 6) δ: 2.50 (2H, m, -SCH 2 CH 2 -), 2.65 (2H, m, -SCH 2 CH 2 -). ), 3.60 (2H, s, 1), ch 2s- 6.45 (1H, s,) V * iv) Mass metering: (FD method), m / e 338

Example 23

S

H_N ^ NS0oCHo HCCOOH

„N-C = N ^ I li li

2 N XCH2SCH2CH2C-NH2. HCCOOH

a) 1.27 g of methyl 3 - [(2-guanidinothiazol-4-yl) methylthio] propionimidate and 0.86 g of methanesulfonamide were dissolved in 10.2 ml of methanol. The solution was allowed to react for 48 hours at room temperature, after which the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography using a mixture of chloroform and methanol (20: 1 → 10: 1) to give 1.44 g of amorphous N-methanesulfonyl-3 - [(2-guanidinothiazol-4-yl) methylthio] propionamidine. The product has the following physicochemical properties: i) NMR spectrum (CD 2 OD) δ: ('r -V' 70890 28 2.58 (2H, d, -SCH 2 CH 2 -), 2.78 (2H, d, -SCH 2 CH 2 -) ), 2.91 (3H, s, -CH 2), 3.67 (2H, s, I), "s H 2 CH 2 S- 6.50 (1H, s, - / V").

cH2s ~ ii) Mass spectrum (EI method): m / e 336.

b) The N-methanesulfonyl-3 - [(2-guanidinothiazol-4-yl) -methylthio] -propionamidine thus obtained was dissolved in acetone, and then an acetone solution containing 0.5 g of maleic acid was added dropwise to the solution. Crystals then precipitated which were collected by filtration to give N-methanesulfonyl-3 - [(2-guanidino-thiazol-4-yl) -methylthio] -propionamide maleate. The product has the following physicochemical properties: i) Melting point: 195 - 197 ° C.

(ii) Elemental analysis, c 13 H 20 N 6 O 6 S 3:

C H N

Calculated: 34.51% 4.45% 18.57%

Found: 34.64% 4.49% 18.12%

Example 24 (C 2 N 2 N 2 O 2 - (Q) H 2 N NN 2 CH, SCH, CH 9 Cl 2 N 2 NH 2 800 mg methyl 3 - [(2-guanidinothiazol-4-yl) methylthio) propionidide and 590 mg benzenesulfonamide was dissolved in 8 ml of methanol. The solution was allowed to react for 24 hours at room temperature, after which the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography using a mixture of chloroform and methanol (20: 1 → 10: 1) to give 855 mg of amorphous N-benzenesulfonyl-3- (2-guanidinothiazol-4-yl) methylthiopropionamidine. The product has the following physicochemical properties: 70890 29 i) NMR spectrum (DMSO-d 6) δ: 2.60 (4H, m, -S-CH 2 CH 2 v), 3.55 (2H, s, s_> »

S H

6.40 (1H, s, If), 7.50 (3H, m, SO 2);

B

B

7.80 (2H, m, SO 2 -p * *

B

ii) Mass spectrum (FD method): m / e 398 Example 25

S

H2 CH 2 SCH 2 CH-C

1 N NH 2 1 g of methyl 3 - [(2-guanidinothiazol-4-yl) methylthio] propionimidate and 0.38 g of methanesulfonamide were dissolved in 10 ml of methanol and the solution was allowed to react for 48 hours at room temperature. The solvent was distilled off under reduced pressure. The resulting residue was dissolved in 3 ml of ethanol, and the solution was allowed to cool, whereupon white crystals precipitated. The crystals were collected by filtration and dried to give 0.7 g of N-methanesulfonyl-3 - [(2-guanidinothiazol-4-yl) methylthio] propionamidine. The product has the following physicochemical properties: i) Melting point 117-118 ° C.

ii) NMR spectrum (CD 3 OD) δ: 2.60 (2H, m, -SCH 2 CH 2 C), 70890 2.80 (2H, m, -SCH 2 CH 2 C), 2.92 (3H, s, SO 2 CH 3), 3.66 (2H, s, K),

S-CH

Δ - 6.50 (1H, s,).

N ^

Example 26

S

H2N - C = N / il / V NH

H2N "\ S NSO2 Y_ / 2 N CH <jSCH ~ CH_C '- 2' nh2 1 g of methyl 3 - [(2-guanidinothiazol-4-yl) methylthio] propionimidate and 0.69 g of p-aminobenzenesulfonamide was dissolved in 10 ml of ethanol, and the solution was allowed to react for 48 hours at room temperature, after which the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography using a mixture of chloroform and methanol (20: 1-> 10: 1) to give 1.2 g of N - (p-Aminobenzenesulfonyl) -2- (2-guanidinothiazol-4-yl) -methylthiopropionamidine as an amorphous solid The product has the following physicochemical properties.

NMR Spectrum (DMSO-d 6) δ: 2.50 (2H, m, -SCH 2 CH 2 C), 2.64 (2H, m, -SCH 2 CH 2 C), 3.56 (2H, s, A), 5.68 (2H , s O NH2),

S S

6.40 (1H, s, If), 70890 31

B

6.54 (2H, d, NH 2),

B

6.80 (4H, s, N "2 \), nh2- c = n"

B

7.44 (2H, d, 1 H / NH 2), N • NSO - 7.74, 8.38 (2H, s, -C) N nh 2

Examples 27 to 28

Following the procedures of Example 26, the following compounds were prepared.

Example 27: ch3hn s-n h2n- ^ NSO2NH2 Δ nch »sch ch9c * 1 NH2 N-sulfamoyl-3 - [(2-methylguanidinothiazol-4-yl) methylthio] propionamidine.

Amine used in the reaction: H2NS02m2 Physicochemical properties of the product: i) Melting point: 163-164 ° C (recrystallized from methanol).

(ii) Elemental analysis, CgH17N702S3:

C H N

Calculated: 30.76% 4.88% 27.90%

Found: 30.47% 4.84% 27.60% 70890 32

Example 28:

Η2Ν> = Ν '^ (1 ^ NS02NH2 H N N ^ NcH0SCH2CH2CH2C

1 2 l Δ \ NH4N-sulfamoyl-4 - [(2-guanidinothiazol-4-yl) methylthio] butyramidine. Amine used in the reaction: N, NSC

Physico-chemical properties of the product: (i) Melting point: 159 to 161 ° C (recrystallization from ethanol).

ii) Elemental analysis, C 9 H 8 N 2 S 2 O 2

C H N

Calculated: 30.76% 4.88% 27.90%

Found: 30.39% 4.86% 27.01%

Examples 29 to 32

Following the procedure of Example 23, the following compounds were prepared:

Example 29:

a) S

H 2 N>. / ^ / ΓΛ ✓ C = N \ A ^ NS02NHCH2-A /

H-N N CH0SCH_CH0C

2 2 2 2 N 2 H -N-benzylsulfamoyl-3 - [(2-guanidinothiazol-4-yl) methylthio] -propionamidine.

b) The previous maleate.

70890 33

Amine used in the reaction: N, NSC, NHCl2

Physicochemical properties of the products: a) i) NMR spectrum (DMSO-d 6): δ: 2.50 (2H, m, SCH 2 CH 2 C), 2.64 (2H, m, SCH_ 2 CH 2 C), 3.60 (2H, s, X ), ch2s- 4.02 (2H, d, CH2 -O-

S H

6.46 (1H, s, -ζ X ~) / N '' 'CH2S- 6.82 (4H, s, --2N \ c = n_>' h2n '7.18 (1H, q, SO2NHCH2 - ( / V \),

H v_ H

7.24 (5H, s, / h) *

H XH

7.50, 8.30 (2H, s, -C.).

nh2 b) i) Melting point: 160-162 ° C.

ii) Elemental analysis, C, QH ~ cN 0 S_: ± y 2. b / o 3

C H N

Calculated: 41.98% 4.64% 18.04%

Found: 41.79% 4.64% 17.90% 70890 34

Example 30: a) S.

H N / - CH3

/ V '. UFO N N

H N '/' N 'f 2 N CH

2 N CH 2 SCH_CH C U 3 2 2 2 N Nh 2 N-dimethylsulfamoyl-3 - [(2-guanidinothiazol-4-yl) methylthio] -propionamidine.

b) The previous maleate.

CH T

Amine used in the reaction: H7NS0 „N v 2 nch3

Physicochemical properties of the products: (a) (i) NMR spectrum (DMSO-d 6): δ: 259 (6H, d, 'C-3) f "c» 3 2.5-2.8 (4H, m, SCH 2 CH 2), 3.64 (2H, s, Achs> S Ph 6.50 (1H, s, _ / "ip), λ 6.84 (4H, s, H2N.

h2n ^ C N ''

7.70, 8.36 (2H, s, -C

b) i) Melting point: 183-186 ° C.

(ii) Elemental analysis, C .H _N 0CS:

JL 4 2. j / 6 J

C H N

Calculated: 34.92% 4.81% 20.30%

Found: 34.82% 4.76% 19.96% 70890 35

Example 31: H2N v /> 3s ^ NS02CF3

2 N 2 CH, SCHOCH_C CHCOOH

Δ ^ 2 "* NH 2 I1

NH2 CHCOOH

N-trifluoromethanesulfonyl-3 - / (2-guanidinothiazole-4-yl) methyl-thio / propionamidine dimaleate.

Amine used in the reaction: H2NSO2CF2 i) Melting point: 168-170 ° C (recrystallization from methyl ethyl ketone) ii) Elemental analysis, C 17 H 21 N 6 O 10 S 3 F 3:

C H N

Calculated: 32.80% 3.40% 13.50%

Found: 32.70% 3.46% 14.00%

Example 32: a) ® H0N \ / ~~ Ί C = N ('^ NSO-NHCH-, H n "V ^ 23

2 CH-SCH-CH C

* * Z N NH 2 N-methylsulfamyl-3 - [(2-guanidinothiazol-4-yl) methylthio] -propionamidine.

b) The previous maleate.

Amine used in the reaction: H2NSO2NHCH2 Physicochemical properties of the products: a) i) NMR spectrum (DMSO-d 6): δ: 2.45 (2H, d, NHCH 2), δ f: ..- 36 2.55 (2Η, nf SCH 3 CH 9 -CH 2) 70890 2.70 (2H, m, SCH 9 CH 9 -Ct), 3.60 (2H, s, -

ΤΪ ^ * CH2S

6.46 (1H, s, Oc! 6.46 (1H, q, SO 2 NHCH 3));

H 2 N

6.80 (4H, s, C = N-), /

H 2 N

nso2 7.48, 8.26 (2H, s, -C

b) i) Melting point: 181-184 ° C

(ii) Elemental analysis, C13H21N7O5S3:

C H N

Calculated: 33.40% 4.53 «20.97%

Found: 33.36% 4.43% 20.68%

Example 33

^ NCN

i * NH H, NV / V (C ,, 2> 4CX

! H2NN * (CU2i4C _ 2 C = N - f J XNH2 j C-M - / jf \ OCH - * - Vs>

I H2n '* J! H2N S

0.6 g of cyanamide was added to 10 ml of a methanol solution containing 2.5 g of methyl 5- (2-guanidinothiazol-4-yl) pentanoimidate, and the solution was stirred at room temperature for 1.5 hours. The solvent tis-1 was discarded and 10 ml of acetone was added to the residue. The precipitated crystals were separated by filtration and the product was purified using dimethylforamide-water. The purified product was dissolved in a mixture of 0.7 ml of acetic acid, 8 ml of ethanol and 16 ml of water, and 11.6 ml of N-NaOH solution was added to the solution. The precipitated crystals were collected by filtration to give 1.9 g of N-cyano-5- (2-guanidinothiazol-4-yl) pentanoamidine.

i) Melting point: 195-196 ° C

ii) Elemental analysis, C10H15N7S

C H N

Calculated: 45.27% 5.70% 36.95%

Found: 45.13% 5.82% 36.62% The methyl 5- (2-guanidinothiazol-4-yl) pentanoimidate used in this example was prepared by the following method.

37 7 0 8 9 0 (a) ckch2) 4coci - ^ ckch2) 4coch2ci 30 ml of an ether solution containing 8 g of 5-chlorovaleryl chloride were added dropwise with stirring at -5 to 0 ° C to 300 ml of an ethereal solution of diazomethane which was prepared from 43 g of p-tosyl-N-methyl-N-nitrosoacetamide. The solution was allowed to stand at the same temperature for 2 hours. Hydrogen chloride gas was passed through the reaction solution at 0 ° C, and the solution was allowed to stand at the same temperature for 0.5 hours. To the solution was added 100 ml of water, and the ether layer was separated. The aqueous layer was extracted twice with 100 mL of ether. The ether layers were combined and the resulting ether solution was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was distilled off under reduced pressure to give 8.2 g of 1,6-dichloro-2-hexanone, b.p. 120-125 ° C (14 mmHg).

<b> N ^ yiCH2 \ C1 H2 * K // Y -HCl

C1CH2CO (CH2) 4Cl -> ^ C = N - ^ M

H2N s Y

16.4 g of guanylthiourea was added to 200 ml of an acetone solution containing 23.5 g of 1,6-dichloro-2-hexanone, and the solution was stirred for 2 days. The solvent was distilled off, and the residue was purified by silica gel column chromatography using a mixture of chloroform and methanol as a developing solvent to give 2-guanidino-4- (4-chlorobutyl) thiazole hydrochloride; . This hydrochloride was dissolved in 300 ml of water, and 100 ml of an aqueous solution containing 17.4 g of potassium carbonate was added to the solution. The resulting solution was extracted with 500 ml, 200 ml and 200 ml of chloroform. The extracts were combined and dried over anhydrous potassium carbonate, and the solvent was distilled off. The obtained crystals were recrystallized from a mixture of ether and n-hexane to give 20 g of 2-guanidino-4- (4-chlorobutyl) thiazole, m.p. 83-84 ° C.

38 70890 (e) N 2 - (CH 2> 4Cl 1 H 2 N 2 S 2 H 2 N * 4.9 g of sodium cyanide was added to 24 ml of dimethyl sulfoxide and the resulting mixture was heated at 70 ° C. To the solution was added at 70-75 ° C with stirring. , 5 g of 2-guanidino-4- (4-chlorobutyl) thiazole and the solution were stirred at the same temperature for 3 hours, the reaction solution was cooled and 100 ml of chloroform was added, the insoluble matter was separated by filtration, and the residue was purified by silica gel column chromatography using to give 15 g of 2-guanidino-4- (4-cyanobutyl) thiazole, the melting point of which is 104-105 ° C after recrystallization from a mixture of ethyl acetate and n-hexane.

(d) NH

N (CH) C

V \ // 0CH3

C = N - \ I

10 g of 2-guanidino-4- (4-cyanobutyl) thiazole were suspended in a mixture of 60 ml of methanol and 110 ml of chloroform. Hydrogen chloride gas was bubbled through the solution at -5 to + 5 ° C for 2 hours with stirring. The resulting solution was allowed to stand for 2 days at 5 ° C, and the solvent was distilled off. The residue was suspended in a mixture of chloroform and methanol, and the suspension was poured into ice water containing 60 g of potassium carbonate. The chloroform layer was separated and the aqueous layer was extracted three times with 150 ml of chloroform. The extracts were combined and dried over anhydrous potassium carbonate. The solvent was distilled off to give 11 g of methyl 5- (2-guanidinothiazol-4-yl) pentanoimidate, m.p. 143-145 ° C.

Example 34; 39 70890

^ NCN

N (CH2,4C n H2N χ / NH2

,, ^ - - \ J

^ NCONH

N. (CH) 4C

H2N \ /, "T ^ 2 NNH2. 2HCl C = N - <1 H N X \

* S

1 g of N-cyano-5- (2-guanidinothiazol-4-yl) pentanoamidine was suspended in a mixture of 20 ml of methanol and 30 ml of chloroform. Hydrogen chloride gas was bubbled through the suspension for 1.5 hours at -5 to + 5 ° C and the solution was concentrated in vacuo, the oily residue was recrystallized from a mixture of methanol and ether containing a small amount of water. There was thus obtained 1.1 g of N-carbamoyl-5- (2-guanidinothiazol-4-yl) -pentanoamidine dihydrochloride monohydrate, m.p. 148-150 ° C.

Elemental analysis, C ^ QH ^^ N ^ 0S.2HCl.H2O

C H N

Calculated: 32.09 5.65 26.20

Found: 32.10 5.65 26.06

Example 35 ^ .NS05NH9 N \ ^ (CH ~). C A Δ N NHL · 2 ^ C = N - <I 2 H2N '\> 1.3 g of methyl 5- (2-guanidinothiazol-4-yl) pentanoimidate and 1.1 g of sulfamide were dissolved in 4.3 ml of methanol. The solution was allowed to stand overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using a mixture of acetone and methanol as a developing solvent. The obtained crystals 40 70890 were dissolved in a mixture of 0.4 ml of acetic acid, 4 ml of ethanol and 8 ml of water. The solution was treated with activated carbon. 6.6 ml of N-NaOH was added to the filtrate, and the precipitated crystals were collected by filtration to give 0.70 g of N-sulfamoyl-5- (2-guanidinothiazol-4-yl) pentanoamidine, m.p. 156-157 ° C.

Elemental analysis, CQH N o s „y i / / 22

C H N

Calculated: 33.84 5.36 30.70

Found: 33.55 5.45 30.24

Following the reaction procedure set forth in the previous example, N-propylsulfamyl-5- (2-guanidinothiazol-4-yl) pentanoamidine was obtained, m.p. 173-175 ° C (reaction component: H 2 N 2 O 2 NH (Cl 2) 2 CH 3 .5 hours).

^ NSO ^ NHCH CH, CH?

H N N (CH -) .C

H2NX /, V 2 4 \ C = N ~ ('|| ™ 2 \ s /'

Elemental analysis, ci2H23N7 ° 2S2

C H N

Calculated: 39.87 6.41 27.12

Found: 40.09 6.48 26.87

Example 36

M ^ NH

, 'V- (CH2) 4C

H ~ N // TT \ NH ~ .HCl

^ C = N - \ I

0.02 g of ammonium chloride was added to 5 ml of a methanol solution containing 0.64 g of methyl 5- (2-guanidinothiazol-4-yl) pentanoimidate, and the solution was stirred at room temperature overnight. To the reaction solution was added 5 ml of acetone, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from aqueous ethanol to give 0.37 g of 5- (2-guanidinothiazol-4-yl) pentanoamidine hydrochloride.

4i 70890

Elemental analysis, C.H N S.HC1 y 16 6

Calculated 39.06 6.19 30.36

Found: 39.16 6.30 30.17

Example 37 N 2 O 2 - N 2 V 2 H 2 N (CH 2) 4 C n '-'

hNNv // NH2 CH-C00H

2 XC = N- <»I '1

H2N2 CH-COOH

0.64 g of methyl 5- (2-guanidinothiazol-4-yl) pentanoimidate and 0.27 g of p-aminobenzenesulfonamide were added to 5 ml of ethanol, and the solution was refluxed under heating for 5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using chloroform-methanol as a developing solvent. The obtained product was dissolved in acetone, and an acetone solution containing 0.4 g of maleic acid was added to the resulting solution. The precipitated crystals were recrystallized from methanol-ether to give 0.51 g of N- (4-aminobenzenesulfonyl) -5- (2-guanidinothiazol-4-yl) pentanoamidine maleate, m.p. 143-146 ° C.

Elemental analysis, C19H25N7 ° 6S2 C H N

Calculated: 44.61 4.93 19.17

Found: 44.89 4.96 18.67

Following the reaction procedure given in the above example (reaction component: O-SO 2 NH 4 '), N-phenyl' sulfonyl-5- (2-guanidinothiazol-4-yl) pentanoamidine maleic acid salt, m.p. 162-164 ° C, was obtained.

42 7 0 8 9 0 Λ-ö /, "Y (CH 2 NH 2 H 2 N I,

CH-COOH,

Elemental analysis, C, nH_.N 0 S ~: 19 24 g 6 2

C H N

Calculated: 45.96 4.87 16.92

Found: 45.67 4.92 16.81

Following the above reaction procedure (reaction component: H 2 N 2 O 2 NH 4 H 2), N-cyclohexylsulfamyl-5- (2-guanidinothiazol-4-yl) pentanoamidine maleic acid salt was obtained, m.p. 130-131 ° C.

N 2 N 2 O 2 NH-O HNN / V 2 CH-J.C.

2 \ // 2 4 S MU

C = N - (I '2 CH-COOH

R2N "'Il

CH-COOH,

Elemental analysis, C2.9H3iN7 ° 6S2 ’

C H N

Calculated: 44.09 6.04 18.94

Found: 44.05 6.00 18.66

Example 38

- NCH „C-CH

M * 2

um / (CHt) * C CH-COOH

H2N \ / '\ 24 XNH. . 2 l |

C = N \ 11 2 CH-COOH

H 2 N 2 - 0.64 g of methyl 5- (2-guanidinothiazol-4-yl) pentanoimidate was dissolved in 5 ml of methanol, and 0.09 g of propargylamine was added to the solution, followed by standing overnight at room temperature. The solvent was distilled off, and the residue was purified by chromatography on a 43,70890 silica gel column using chloroform-methanol-triethylamine as a developing solvent. The obtained oily product was dissolved in acetone, and an acetone solution containing 0.4 g of maleic acid was added to the solution. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 0.14 g of N-propargyl-5- (2-guanidinothiazol-4-yl) pentanoamidine dimaleate.

Elemental analysis, C20H26N6 ° 8S:

C H N

Calculated: 47.05 5.13 16.46

Found: 46.75 5.20 16.34

Following the reaction procedure given in the above example (reaction component: -O »·, N-benzyl-5- (2-guanidinothiazol-4-yl) pentanone amine dihaleate was obtained, m.p. 92-94 ° C.

N / “2-0 H0N. /, 2l A CH-COOH

C = N— <I 2. 2

HjN ^ '___ "CH-COOH

Elemental analysis, c24H30N6 ° 8S:

C H N

Calculated: 51.24 5.37 14.94

Found: 50.76 5.35 14.82

Example 39 NS0oC-, Hc N ^ 225 H2N, '' y- "4C \ X C = N— / 'I ™ 2

v "ΛJ

0.17 g of ethanesulfonamide and 0.64 g of methyl 5- (2-guanidinothiazol-4-yl) pentanoimidate were added to 5 ml of methanol, and the solution was refluxed under heating for 5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography 70890 44 using chloroform-methanol as a developing solvent to give 0.36 g of N-ethylsulfonyl-5- (2-guanidinothiazol-4-yl) pentnoamidine, m.p. 115-116 ° C.

Elemental analysis, cnH20N6 ° 2S2 C H N

Calculated: 39.74 6.06 25.28

Found: 39.70 6.07 25.12

Example 40 “NNHCOCH-, # 3

N (CH) C

0.64 g of methyl 5- (2-guanidinothiazol-4-yl) pentanoimidate was dissolved in 5 ml of methanol, and 0.27 g of acetylhydrazine was added to the solution. The reaction solution was stirred at room temperature overnight, and the precipitated crystals were collected by filtration. The obtained product was washed with ethanol-ether to give 0.27 g of N-acetyl-5- (2-guanidino-thiazol-4-yl) pentanoamidrazone, m.p. 157-159 ° C.

Elemental analysis, C ^ jH ^ gN ^ OS:

C H N

Calculated: 44.43 6.44 32.97

Found: 44.06 6.37 32.60

Following the reaction procedure given in the above example (reaction component: H 2 NNHSO 2 -o), N-benzenesulfonyl-5- (2-guanidinothiazol-4-yl) pentanoamidrazone was obtained, m.p. 206-207 ° C.

45 jr \ 70890 * NNHSO <> H N “> v ^ (CH,) .C i> - = -, 24 \ Nh2 H2N ^

Elemental analysis, ci5H2iN7 ° 2S2:

C H N

Calculated: 43.55 5.35 24.79

Found: 45.33 5.38 24.79

Example 41 N (CH 2 O / NHCHo / 2 4 3

H2N ^ / 'I

1 = 1 ml of a 40% methanol solution of methylamine was added to 0.27 g of ethyl 5- (2-guanidinothiazol-4-yl) propionic acid, and the solution was allowed to stand at room temperature for 2 days. The precipitated crystals were collected by filtration. and washed with methanol followed by ether to give 0.21 g of N-methyl 5- (2-guanidinothiazol-4-yl) pentanoic acid amide This product was recrystallized from aqueous methanol to give the purified product, mp 22-232 ° C.

Elemental analysis, cioH17N5OS:

C H N

Calculated: 47.04 6.71 27.43

Found: 46.86 6.54 27.68 The 5- (2-guanidinothiazol-4-yl) -pentanoic acid ethyl ester used as a starting material in this example was prepared by the following method.

* · V '46 (a) HN, N (CH2) 4Cx C = n7 /' OCH2CH3 H2N2 / 2 g of 2-guanidino-4- (4-cyanobutyl) thiazole was suspended in a mixture of 15 ml of ethanol and 25 ml of chloroform, and hydrogen chloride gas was passed through the solution for 2 hours at -5 to + 5 ° C with stirring. The resulting solution was allowed to stand for 4 days at 5 ° C, and the solvent was distilled off under reduced pressure. The residue was suspended in ethanol and the suspension was poured into ice water / containing 15 g of potassium carbonate. The precipitated crystals were collected by filtration, washed with water and ether to give 2.1 g of ethyl 5- (2-guanidinothiazol-4-yl) pentanoimidate, m.p. 138-139 ° C.

<B)

N (CH) C

H2N \ Y OCH2CH3 N. ^ (CH0) .COOCH-CH-,

**> · .- ( 'T

H N \ I

2 s 30 ml of ethanol and 3 ml of water were added to 1.2 g of ethyl 5- (2-guanidino-thiazol-4-yl) pentanoimidate. The resulting solution was strongly acidified with ethanolic hydrochloric acid and heated at 50 ° C for 10 minutes. After cooling, 30 ml of chloroform and 30 ml of water were added to the reaction solution. The solution was made alkaline with potassium carbonate and the chloroform layer was separated. The aqueous layer was further extracted twice with 20 ml of chloroform. The chloroform layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography using chloroform-methanol as a developing solvent to give 2.0 g of 5- (2-guanidinothiazol-4-yl) pentanoic acid ethyl ester. This product was recrystallized from ethanol to give the purified product, mp 109- HO ° C.

70890 47

Example 42

. NOH

0.13 g of hydroxylamine hydrochloride and 0.117 g of sodium hydroxide were dissolved in 5 ml of methyl alcohol. To the solution was added 0.64 g of methyl 5- (2-guanidinothiazol-4-yl) pentanoimidate, after which the reaction mixture was allowed to stand for 3 days at room temperature. The solvent of the reaction mixture was distilled off, and the residue was crystallized by adding ethyl alcohol and water. The obtained crystals were dissolved in a mixture of 0.4 ml of acetic acid, 4 ml of ethyl alcohol and 8 ml of water, and the solution was treated with activated carbon. 6.6 ml of 1N sodium hydroxide was added to the filtrate, and the precipitated crystals were collected by filtration to give 0.24 g of 5- (2-guanidinothiazol-4-yl) pentanoamidoxime, m.p. 167-168 ° C.

Elemental analysis, CnH., N OS: y 6 6

C H N

Calculated: 42.17 6.29 32.79

Found: 42.24 6.39 32.47.

Claims (1)

A process for the preparation of pharmacologically valuable gyanidinotiazole compounds of the formula R-NH 4 N 2 N 2 S (CH 2) in -Y- (CH 2) n A C = N- / J H 2 N 2 in which R is a hydrogen atom or a lower alkyl group, Y is a sulfur atom or a methylene group, m and n are each an integer from 1 to 3, A is a group N-R 1 or -CONH-R 4, -c 1-4 nh-r 2 wherein R x is a hydrogen atom, a cyano group, a carbamoyl group, a ureido group, a hydroxyl group, a lower alkoxy group, a lower alkanoyl group, a lower alkanoylamino group, a benzoyl or naphthoylamino group, a phenyl or naphthylsulfamoyl group, an aralkyl group, a carboxymethyl group or a group -SO 2 -R 3 in which R 3 is a substituent having a lower alkyl group, a halogenoxy group, a halogen-lower alkyl group a group or a lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, a phenyl or naphthylamino group, a C5-7 cycloalkylamino group or an aralkylamino group, R2 is a hydrogen atom, a lower alkyl group , a lower alkenyl group, a lower alkynyl group, a cyano group or a lower alkanoyl group, and R 4 is a hydrogen atom, a lower alkyl group, a hydroxyl group or a sulfamoyl group, characterized in that a compound of the formula X R-NB // ύ (CH 2) ro-Y- (CH 2) is reacted ) nC C = N — A | T O-R 'H2N2 wherein R' is a lower alkyl group, X is an oxygen atom, N-Rx or N-R2 and R, R1, R2, Y, m and n have the same meaning as in the above formula , and an amine of the formula R 1 -NH 2, R 2 -NH 2 or R 4 -NH 2 »wherein R 1, R 2 and R 4 are as defined above. 70890 * · \ 49 For the preparation of pharmacologically active substances in guan-dinothiazole derivatives with the formula R "NH \ / Ν \ γ ^ Η2 (CH2) nA c = N- (J h2n ^ där R is a hydrogen atom or an alkyl group, Y is en svavel-atom atom or methyl group, m ooh n är bägge ett heltal 1-3 »A är en grupp NR., eller -CONH-R. nnh-r2 där R ^ är en väteatom, en cyano group, en carbamoyl group, en ureido group , en hydroxyl group, en alkoxy group, en alkanoylamino group, en alkanoylamino group, benzoyl or naphthoylamino group, phenyl or naphthylsulfamoyl group, en aralkyl group, carboxymethyl group or en group -SC ^ Rj » haloalkylalkyl, phenyl or naphthyl, which may be substituted by amino, halogen, hydroxyl or alkoxy, amino, mono- or di-lasalalkylamino, phenyl or naphthylamino, C 1-6 cycloalkylamino group or aralkylamino group, R2 is not an atom, not an alkyl group , en alkenyl group, en alkynyl group, cyano group or alkanoyl group group, ooh R ^ är en väteatom, en alkyl group, en hydroxyl group or sulfamoyl group, kännetecknat därav, att bringaa att reagera in the form of a mixture. f V0-R · «2» \ ε ^