IE51151B1

IE51151B1 - 2-guanidinothiazole derivatives

Info

Publication number: IE51151B1
Application number: IE956/81A
Authority: IE
Original assignee: Shionogi & Co
Priority date: 1980-04-29
Filing date: 1981-04-29
Publication date: 1986-10-15
Also published as: AR231538A1; IL62747A; AU540239B2; DE3116890A1; FR2481280B1; SE452462B; IL62747A0; NL8102099A; NZ196923A; JPH027952B2; CH646964A5; SE8102683L; DK188881A; AU6996681A; JPS574977A; GB2076397A; IT1146750B; ES8206501A1; FR2481280A1; BE888602A

Abstract

Compounds of the general formula: (wherein n is an integer from 2 to 4; R is hydrogen, C1-C6 alkyl (optionally substituted by hydroxy, cyano, amino or phenoxy), C3-C6 cycloalkyl, C2-C6 alkenyl (optionally substituted by phenyl or C2-C7 alkoxy-carbonyl), C4-C7 alkadienyl, C6-C12 aryl (optionally substituted by one to three groups selected from halogen, cyano, nitro, amino, C2-C10 dialkylamino, tetrazolyl, hydroxy, C1-C6 alkoxy, benzoyloxy, C2-C7 alkoxycarbonyl, sulfamoyl, C1-C6 alkylsulfonyl, C1-C6 alkanesulfonamido or C1-C6 alkanoyl), or a heterocycle (optionally substituted by halogen, C1-C6 alkyl or phenyl); and X is a single bond or thia), their 5-halo and alkyl derivatives and salts thereof are anti-peptic ulcer agents and histamine H2 receptor antagonists. The preparation of 1-chloro-3-[2- acetamidoethylthio)-2-propanone is described.

Description

The present invention relates to certain 2—guanidino— thiazole derivatives useful as anti-peptic ulcer agents or histamine H2 receptor antagonists.

U.S. Patent Specification No. 4,165,377 discloses tio5 tidine as a 2-guanidinothiazole type H2 receptor antagonist.

This has a N-methylcyanoguanidino group which is potentially changeable into the carcinogenic nitroso N-methylcyanoguanidino group in the mammalian body /Pool, et al., Toxicology, 15, 69 (1979)/7- Japanese Unexamined Patent Publication No. 141,271/1978 discloses N-/2-(pyridyl)methylthio)ethy£7“ acetamide which has no activity as a histamine Hg receptor antagonist.

The present invention provides a compound of the formula: HN=C-NH 1 2 NH whereinn is an integer from 2 to 4; R is hydrogen, C^-Cg alkyl (optionally substituted by hydroxy, cyano, amino or phenoxy), Cg-Cg cycloalkyl, Cg-Cg alkenyl (optionally substituted by phenyl or Cg-C^ alkoxycarbonyl) , alkadienyl, Cg-Cg2 (optionally substituted by one to three substituents selected from halogen, S1151 cyano, nitro, amino, C2-Cjq dialkylamino, tetrazolyl, hydroxy, Cj-Cg alkoxy, benzoyloxy, C2-C? alkoxyearbonyl, sulfamoyl, Cj-Cg alkylsulfonyl» Cj-Cg alkanesulfonamido or Cj-Cg alkanoyl), or a 5- or 6-membered heterocycle (optionally substituted by halogen, Cj-Cg alkyl or phenyl)? and X is a single bond or thia. The invention includes acid addition salts, preferably pharmaceutically or veterinarily acceptable, of such compounds.

In the above formula (I), Cj-Cg alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyi, t-butyl, pentyl, isopentyl and hexyl? Cg-Cg cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl? “Cg-Cg alkenyl includes vinyl, allyl, butenyl, pentenyl and hexenyl? C^-C? alkadienyl includes butadienyl, pentadientyl, hexadienyl and heptadienyl? C1~C6 aIR°xyM includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy and hexyloxy? “Cg-C^ alkoxylcarbonyl includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl'and hexyloxycarbonyl? Cj-Cg alkanoyl includes formyl, acetyl, propionyl, butyryl, pentanoyl and hexanoyl? Cj-Cg alkanesulfonamido” includes methanesulfonamido, ethanesulfonamido, propanesulfonamido, isopropanesulfonamido. butanesulfonamido, Isobutanesulfonamide, pentanesulfonamido and hexanesulfonamido; Cl“C6 alliYlsul£onY1· includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentyl5 sulfonyl and hexylsulfonyl; Cj-C^q dialkylamino includes dimethylamino, diethylamino, dipropvlamino, dibutylamino, dipentylamino, methylethylamino, methylpropylamino, ethylpropylamino, ethylbutylamino and methylbutylamino; Cg-C12 aryl includes phenyl, tolyl,, xylyl, naphthyl, methylnaphthyl and ethylnaphthyl; -membered heterocycle” includes thienyl, furyl, isoxazolyl and isothiazolyl; 6-membered heterocycle includes pyridyl; and 15 halogen includes chlorine, bromine and iodine.

Preferred compounds of formula (I) are those in which n is 2 or 3, R is phenyl optionally substituted by one to three substituents selected from halogen, cyano, nitro, amino, C2~C^0 dialkylamino, tetrazolyl, hydroxy, C^-Cg alkoxy, benzoyloxy, alkoxycarbonyl, sulfamoyl, C^-Cg alkylsulfonyl, Cj-Cg alkanesulfonamido and C^-Cg alkanoyl, and X is thia.

Other preferred compounds of formula (I) are those in which n is 2 or 3, R is a 5-membered heterocycle optionally substituted by halogen, c^-Cg alkyl or phenyl, and X is thia.

Other preferred compounds of formula (I) are those in which n is 2 or 3, R is a 6-membered heterocycle optionally susbtituted by halogen, C^-Cg alkyl or phenyl, and X is thia.

Other preferred compounds of formula (I) are those in which n is 2 or 3, R is hydrogen, C^-Οθ alkyl (optionally substituted by cyano, amino or phenoxy,, C3-Cg cycloalkyl, C2-C7 alkenyl (optionally substituted by phenyl or C2~C7 alkoxyearbonyl) or C^-C.? alkadienyl, and X is thia.

Another class of compounds of the invention are those in which n is 2 and X is thia; provided that if R is substituted C^-Cg alkyl the substituent(s) is/are cyano, amino or phenoxy.

The 2-guanidinothiazole derivatives of formula (I, can be prepared in accordance with the following scheme: 5115 1 HN=C-NH_ I 2 NH HS(CH2)nNHCOR(v) CH -B 2 (Route B)(X=S) (iv) HN=C-NH„ ι 2 NH S=C-NH„ S N I=k (I) Λ-CH COCH S(CH ) NHCOR (VII) (Route C)(X=S) CH„X(CH„) NHCOR 2 ' 2'n (VI) wherein each of A and B is independently a reactive group such as, for example, halogen or a residue of an active ester (e.g. tosyloxy), and n, R and X are as defined above.

Route A Compounds (I) can be prepared by reacting amines (II) with carboxylic acids (III) or with reactive derivatives thereof, such as, for example, halides, mixed acid anhydrides or active esters such as tosylate esters, in an inert solvent, if necessary, in the presence of a base or a condensing agent, if desired, such as, for example, dicylcohexyi carbodiimide, termed hereinafter DCC, or triphenylphosphine/ 2,2'-dipyridyl disulfide. This acylation may be performed in a conventional manner such as, for example, by the mixed acid anhydride method, the acid halide method, the DCC method or the triphenylphosphine method, as follows: (1) Mixed acid anhydride method: An amine (II) may be reacted with a mixed acid anhydride containing the acyl moiety (RCO) of a carboxylic acid (III). The reaction may be generally performed at a temperature of from -20°C to 60°C. Preparation of the mixed acid anhydride can be achieved by reacting a carboxylic acid (III) with an alkyl chlorocarbonate, such as, for example, methyl chlorocarbonate or ethyl chlorocarbonate, in the presence of a base such as, for example, triethylamine or pyridine, preferably in an inert solvent at a temperature of from -3O°C to 0°C. Examples of the solvent are tetrahydrofuran, methylene chloride, dioxane, dimethylsulfoxide, dimethylformamide, acetonitrile and hexamethylphosphoric triamide. (2) Acid halide method: An amine (II) may be reacted with an acid halide derived from a carboxylic acid (III) preferably in the presence of a base such as, for example, triethylamine or pyridine. This reaction may be performed in an appropriate solvent such as, for example, dimethylformamide, acetonitrile, hexamethylphosphoric triamide or tetrahydrofuran, at a temperature of from -20°C to 60°C. (3) DCC method: An amine (II) is reacted with a carboxylic acid (III) in the presence of DCC in an appropriate solvent such as, for example, chloroform, dimethylformamide or dimethylsulfoxide. This reaction may be performed at a temperature of from -20°C to 60°C. (4) Triphenylphosphine method: An amine (II) is reacted with a carboxylic acid (III) in the presence of triphenylphosphine and 2,21-dipyridyl disulfide in an appropriate solvent such as, for example, dimethylformamide, preferably at a temperature of from -20°C to 60°C.

The starting amine (II, may be prepared in accordance with the method disclosed in U.S. Patent Specification No. 4,165,377.

Route B The objective compounds (I) can be prepared by reacting a 2-guanidino-4-(activated)methylthiazole (IV) with a mercaptan (V) in the presence of a base. The reaction may be carried out in an inert solvent such as, for example, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetone or chloroform, preferably at a temperature of from 0°C to 60°C. Examples of the base are alkali metal hydroxides (e.g. eodium hydroxide), alkali metal carbonates (e.g. potassium carbonate or sodium carbonate) and alkali metal alkoxides (e.g. sodium methoxide or potassium ethoxide).

The starting thiazoles (XV) may be prepared, for example, by treating guanylthiourea with 1,3-dichloroaoetcne in an inert solvent such as, for example, acetone /U.S. Patent Specification No. 4,165,3727· The mercaptans (V) may be prepared by treating 10 disulfides (VIII) (see the scheme below, with carboxylic acids (III) or with reactive derivatives thereof as in the acylation step as described above and reducing the resulting acylaminoalkyl disulfides (IX) with e.g. sodium borohydride in an inert solvent, (e.g. ethanol or methanol), as follows: -[•S(CH2)nNH2]2 RCOOH (III) ; _£s(CH2)nNHC0R], (VIII) (XX) h'aBHU ? HS(CH2)nNHCOR (V) wherein n and R are each as defined above.

Route C Compounds (I) can also be prepared by reacting guanylthioureas (VI) with ketone derivatives (VII) in the presence of a base such as, for example, triethylamine or pyridine. The reaction may be performed in an inert solvent such as, for example, ethanol, tetrahydrofuran, dimethylsulfoxide, dimethylformamide or chloroform, preferably at a temperature of from 0°C up to the boiling point of the solvent used.

The ketone derivatives (VII) may be prepared by reacting 1,3-di(activated)ketones (X) with mercaptans (V) in the presence of a base such as, for example, triethylamine or pyridine, or an ion exchange resin(preferably OH type), an ion exchange resin being used for preference, preferably in an inert solvent such as, for example, ethanol, acetone or dimethylsulfoxide at a temperature of from -20°C to 30°C.

A-CH COCfi,-A - HS(CH2)nNHC0R (X) (v) _ΑΟΗ2ΟΟΟΗ23(ΟΗ2)λΝΗΟΟΚ (VII) wherein A, n and R are each as defined above.

If necessary, the nitro group on the benzene ring of the compounds (I) (R=aryl) can be reduced to the corresponding amino group, with a mild reducing agent such as, for example, titanium trichloride in aqueous acetic acid at room temperature. Any amino-protecting group such as carbobenzoxy or trityl which has been necessarily introduced into the product (I) through the above routes may be . η removed therefrom by conventional means.

The products (I) can be converted into pharmaceutically acceptable or veterinarily acceptable acid addition salts, such as those with inorganic acids, such as, for example, hydrochloric acid, sulfuric acid, nitro acid, phosphoric acid or thiocyanic acid, or those with organic acids, such as, for example, acetic acid, succinic acid, oxalic acid, maleic acid, malic acid, phthalic acid or methanesulfonic acid for the purporses of preparation, crystallisation, solubilisation, or improvement of stability of the product.

The thus-obtained 2-guanidinothiazole derivatives (I, and their pharmaceutically or veterinarily' acceptable acid addition salts are useful as anti-peptic ulcer agents or histamine h2 receptor antagonists. For example, 2-guanidino 4-/2-(formamido)ethylthiomethyl/thiazole maleate showed the following pharmacological activities; a) Histamine H2 antagonism in vitro using extracted guinea pig atrium resulting from pretreatment with the test compound: pA2 » 7.05 /Ariens, Molecular Pharmacology, vol. 1, Academic Press, New York, 196 4/,fa, Inhibition of peptic secretion due to histamine in vivo using Donryu strain male rats: ED5o 0.25 mg/kg (i.v., /Ghosh, et al. Brit. J. Pharmacol., (1958), 13, 54}; c) Lethal dose In mice: LD5q 148 mg/kg (i.v.); 7691 mg/kg (p.o.) /Bliss; Ann. Appl. Biol., 22 , 134-307 (1935; Qant. J. Pharmacol., 11, 192 (1938/75 Other compounds (I) showed similar pharmacological activities.

The 2-guanidinothiazole derivatives (I) and their salts may be applied singly or in combination with appropriate carriers such as, for example, wheat starch, com starch, potato starch or gelatin. The choice of carriers is determined by the preferred route of administration, the solubility of the substance and standard pharmaceutical or veterinary practice. Examples of pharmaceutical preparation forms which may be used are tablets, capsules, pills, suspensions, syrups, powders and solutions. These compositions can be prepared by convention al methods. A suitable daily dosage of the 2-guanidinothiazole derivatives (I) or their pharmaceutically acceptable acid addition salts for human adults is of the order of 1.0 to 40.0 mg/kg, preferably 1.0 to 15.0 mg/kg, in single or divided doses.

Histamine H2 receptor antagonism was reported by Black et al. /Slack et al., Nature, 236, 385 (1972/7.

Another aspect of the present invention provides a compound of the formula: R' CH2S(CH2)2NH-C-R wherein R is hydrogen, Cj-Cg alkyl (optionally substituted by cyano, amino or phenoxy), C3-Cg cycloalkyl, C2-Cg alkenyl (option5 ally substituted by phenyl or C2~Cy alkoxyearbonyl), C4-Cy alkadienyl, Cg-C12arY1 (optionally substituted by one to three substituents selected from halogen, cyano, nitro, amino, C2-Cig dialkylamino, tetrazolyl, hydroxy, C^-Cg alkoxy, benzoyloxy, Cj-C? alkoxyearbonyl, sulfamoyl, Cj-Cg alkyl10 sulfonyl, C^-Cg alkanesulfonamide or C^-Cg alkanoyl), or a hetero-aromatic ring (optionally susbtituted by halogen, C^-Cg alkyl or phenyl); and R1 is hydrogen, halogen or alkyl. Such compounds may be made by preparative routes similar to those disclosed above, particularly Routes A and B.

Therapeutic formulations may be made using these compounds in accordance with the information given above.

The invention includes a pharmaceutical or veterinary formulation comprising a compound of the invention or a salt of the invention formulated for pharmaceutical or veterinary use, respectively. Such formulations may be in unit dosage form and/or may include acceptable diluents, carriers or excipients.

The invention also embraces a compound salt of the invention for use as an anti-peptic ulcer agent or a histamine H2 receptor antagonist, (i.e. when intended for, made for, sold for, disposed of for, or otherwise dealt with for such use).

The present invention will now be further described and illustrated by means of the following Examples.

Example 1, A mixture of p-sulfamoylbenzoic acid (201 mg), triphenylphosphine (262 mg) and 2,2’-dipyridyl disulfide (220 mg) in dry dimethylfomamide (4 ml) was stirred at room temperature for 1 hour. To the resulting solution were added 2-guanidino-4-(2-aminoethylthiomethyl)thiazole dihydrochloride (304 mg) (U.S. pat. U,165,377) and triethylamine (0.4 ml). After stirring was continued at room temperature for 20 hours, the solvent was evaporated in vacuum, and the residue was subjected to silica gel (50 g) column chromatography eluting with ethyl acetate/ methanol (20/5 v/v) to afford 2-guanidino-4-[2-(4-sulfamoylbenzamido)ethylthioraethyljthiazole (274 mg) in 67 $ yield. Treatment of the product with maleic acid (300 mg) in acetone yielded the monomaleate (297 mg) as crystals with a melting point range ef 215-217°C dec. (methanol).

Anal. Calcd. for cl8H2207N0S3! C, 40.74; H, 4.18; N, 15.84 («4). Found: C, 40.63; H, 4.08; N, 15.74 («4).

The monohydrochloride: mp. 220°C (dec,).

Example 2.

Using p-(N)-tetrazolylbenzoic acid in lieu of p-sulfamoylbenzoic acid, the reaction was carried out as in Example 1, whereby 2-guanidino-4-[2-(4-(N)-tetrazolylbenzamido)ethylthiomethyl]thiazole was obtained in 28 «4 yield. The monomaleate: m.p, 211°C (dec.) (methanol).

Anal. Calcd. for C19H21°3N9S2: c’ ^3-92: H, 4.07 (%). Found: C, 43-85; H, 4.15 (%)· Example 3· To a solution of p-(methylsulfonyl)benzoic acid 5 (352 mg) in dry tetrahydrofuran (10 ml) were added triethylamine (0.24 ml) and ethyl chlorocarbonate (191 mg) at 0’C with stirring. After stirring at that temperature for 30 minutes, the resulting suspension was treated with 2-guanidino· 4-(2-aminoethylthiomethyl)thiazole dihydrochloride (500 mg) TO and triethylamine (0-5 ml) and allowed to come to room temperature overnight with stirring. The precipitated solid was filtered off and the filtrate was evaporated in vacuum to leave an oil. which was purified by silica gel (40 g) chromatography eluting with ethyl acetate/methanol (20:5) to give 2-guanidino-4-[2-(4-methylsulfonylbenzamido)ethylthiomethylJthiazole (154 mg) in 82 % yield. Treatment of the product with maleic acid (500 mg) in acetone gave the monomaleate (600 ng) as crystals with a melting point range of 192-194¾ (dec.) (methanol) Anal. Calcd. for C^O^N ; C’ *3·°8; H, 4.38; N, 13-22 (%). Found: C, 42-31; H, 4.20; N, 13-33 (#) · Examples 4-22 Using the carboxylic acid (ill), the reaction was carried out as in Example 3, whereby the products (I) were obtained as shown in Table 1.

HN-C-XH^ NH A RCOOH(III) HJiaC-NH2 NH S^N ch2s(ch2)2nh2 (II) M, (I) , ν ll CH S(CH )NHCR Table 1.

Ex. No. I R Salt m.p.(*C) Yield (¢) 4 -CN maleate 175-176 80*2 5 -(g^OCH3 maleate 161-163 87-4 6 -ch=c(ch3)2 oxalate l/2H20- 175-1764. 91 7 maleate 212-2l4d. 43.3 TTLpu 8 maleate 197-198 35 9 / maleate 183-185 63 10 maleate 175-177 71 Ex. No . I R Salt m.p.(°C) Yield (%) 11 JCOOCH^ maleate 173-175 76 12 COOCH^ ^°2 maleate 131-183 55 13 O-CO~Ph maleate 207-209 34 IkCH3 maleate 134-136 62.5 15 -CH=CH2 maleate l/2H20 95-98d. 30.5 16 -^\-och3 maleate l/2H20 154-156d. 58.5 17 -CH=CH-CH=CHCH3 maleate l/4H20 179-l80d. 81.6 18 maleate 1/2H2O I8l-I32d. 72.8 Jl 11 19 maleate l68-l?Od. 66.3 Ex. No. I R Salt m.p.(°C) Yield (¢) 20 -CHaCH-COOBu maleate 1/2¾ 0 99-101d. 54.4 21 1.25male ate * O.75H2O l4l-l45d. 11.1 22 NH2 maleate 179-131 39 Note: The abbreviations have the following significance: Bu (butyl)ι Ph (phenyl)> d (decomposition).

Example 23· To a suspension of 2-guanidino-4-[2-(amino)ethylthiomethyljthiazole dihydrochloride (500 mg) in dry dimethylformamide (5 ml) were added p-nitrobenzoyl chloride (300 mg) and triethylamine (0./4 ml) at 0°C with stirring.

The resultant suspension was stirred and allowed to come to room temperature overnight. The solvent was evaporated in vacuum and the residue was subjected to chromatography on silica gel (4o g) column, eluting with ethyl acetate-methanol (20:5 v/v) to afford 2-guanidino-4-[2-(4-nitrobenzamido)ethylthiomethyljthiazole (ol4 mg) in 93 fi yield. The monomaleate: m.p. 13O-181*C (sintering at 1?O°C) (recrystallized from methanol). 5115 1 Anal. Calcd. for cl8H2oo7-V6S2: C’ H, 4.06; Ii, 16.92 {$). Found: C, 43-08; H, 4-14; N, 16.76 (#) .

Examples 24-34.

Using a carboxylic acid chloride (ill), reactions ware carried out as in Example 23, whereby the product (I) was obtained as shown in Table 2.

Table 2- Ex. No. I R Salt m.p.(’C) Yield (#) 2b ^o)-coOCh3 maleate 189-190 22 25 maleate 188-189 73-8 26 β-naphthyl maleate 175-177d. 89 27 -ch2o— maleate 15l-152d. (sintering at IdS’C) 95 28 -© maleate 200-202d. 69.8 29 maleate 182-I84d. 77-8 30 maleate 177-178 48-4 Ex- No. I R Salt m.p.(°C) Yield (fi) 31 maleate 191-192d. 62.1 32 -@h0CH3 maleate «2° · I4l-l45d. 60.4 33 -CH=CH-Ph maleate 183-I85d. 55-5 34 -<^-n(ch3)2 maleate 188-190 21 Example 3¾.

To a mixture of 2-guanidino-4-[2-(amino)ethylthiomethyl jthiazole (800 mg), formic acid (132 mg) and DCC (590 mg) in dry dimethylformamide (15 ml) was added triethylamine (0.8 ml) with stirring· After the resulting mixture was stirred at room temperature for 16 hours, the precipitated solid was filtered off and the filtrate was evaporated in vacuum to leave an oily residue, which was chromatographed on a column of silica gel (70 g) eluting with ethyl acetatemethanol 20:5 v/'v) to give a mixture (706 mg) of the free base and the carbonate of 2-guanidino~4-[2-(formawido)ethylthiomethyljthiazole. It was dissolved in methanol and carbon dioxide gas was passed through the solution, Evaporation of the solvent gave the carbonate (720 mg) in 85% yield as crystals with a melting point ranqe of 138-14O°C.

Anal. Calcd. for C^H^O^N.S,, . 1.5 I^COyi H20: C, .iti; H, 4.82 (%)· Found: C. 30-55: H, 4.66 (¢) .

Example 36· To a solution of metallic sodium (about 70 mg) ia ethanol (5 ml) uas added dropwise a solution of N-benzoylcysteamine (268 mg) in ethanol (5 ml) at 0°C with stirring, and the resultant mixture was stirred at 0°C for 2 hours.

A solution of 2-guanidino-4-chloromethylthiazole (239 mg) in ethanol (5 ml) was added dropwise to the mixture, which was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuum, and the mixture was mixed with acetone· The insoluble material was filtered off and the filtrate was mixed with maleic acid./acetone to give 2-guanidino· 4-[2-(benzamido)ethylthiomethyljthiazole maleate (4l4 mg) in 91.4% as crystals with a melting point range of.200-2C2°C (dec.).

Example 37· Using X-nicotinoylcysteamine (273 mg), the reaction was carried out as in Example 36, whereby 2-guanidino-4[2-(nicotinamido)ethylthiomethyljthiazole maleate (θ·35 g) was obtained in 77 >4 yield· Example 38· Using 3, 4, 5-trimethoxybenzoic acid, the reaction was carried out aa in Example 3, whereby 2-guanidino-4-[2(3> 4, 5-trimethoxybenzamido)ethylthiomethvlJthiazole maleate 51161 was obtained as crystals with a melting point range of 163-165 C (dec.) in 66% yield.

Example 39· Using p-methylsulfonylbenzoic acid, the reaction was carried out as in Example 3> whereby 2-guanidino-4-[2(4-methylsulfonylbenzamido)ethylthiomethyl]thiazole hydrochloride was obtained as crystals with a melting point range· of 196-198°C.

Example 4o.

To a solution of l-chloro-3-[2-(acetamido)ethylthio]2-propanone (607 nig) in absolute ethanol (25 ml) was added guanylthiourea (320 mg), and the resultant mixture was refluxed with stirring for 3 hours- After cooling, the reaction mixture was mixed with triethylamine (ΐ·5 ml) and concentrated in vacuum. The residue was chromatographed on a column of silica gel (25 g), which was eluted with ethyl acetate-methanol (20:5 v/v). The eluate was concentrated to give 2-guanidino-4-[2-(acetamido)ethylthiomethyljthiazole (ΐ9έ mg), which was identical with the product in Example 14. The yield was 25 #.

Production of l-chloro-3-[2-(acetamido)ethylthio]2-propanone: To a solution of 2-aeetamidoethanethiol (667 mg) in absolute ethanol (25 ml) was added Antoerlite (Anberlite is a Trade Mark) IR4B (OH type) (2 gj. Ihe resultant mixture was cooled to 0°C, mixed with 1»3—dichloroace tone (90S mg), stirred at 0*C for 1 hour, then allowed to stand overnight at 3-5°C. The resin was filtered off. and the filtrate was concentrated in vacuum at a temperature below 35’C. The oily residue was chromatographed on a rninmn of silica gel, which was eluted with ethyl acetate5 methanol (20:5 v/v). The eluate was concentrated in vacuum to give l-chloro-3-[2-(acetamido)ethylthio]-2-propanone (607 mg) as an oil. The yield was 52 NMR, 6CDC13: 1-98 (3Hs). 2.65 (2Ht. J=7 Hz), 3.45 (2Hs),-4.23 (2Hs), 6.22 (iHbrs).

Example 4l.

To a suspension of 2-guanidino-4-[2-(amino)ethylthiomethyl ]thiazole dihydrochloride (30 g) and Ν,Ν-dimethylformamide dimethyl acetal (l3 g) in dry tetrahydrofuran (550 ml was added triethylamine (30 g) . The resultant mixture was refluxed under stirring for 5 hours and concentrated in vacuum. The residue was mixed with 10 % aqueous potassium carbonate solution (300 ml) and stirred at room temperature for 3 days. The reaction mixture was neutralized with dilute hydrochloric acid to approximately pH 7 and chromatographed on a column of 20Amberlite IRC-50 (H type), which was eluted with 10 % aqueous ammonia solution. The eluate was concentrated in vacuum to give 2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole (11-6 g) as a viscous oil· The oil was dissolved in acetone and mixed with a solution of maleic acid (ll g) in acetone to give the crude maleate (15-3 g) as crystals, which were recrystallized from ethanol to give the monomaleate (11.8 g). m.p. l46-l48*C· The yield was 32 %· Anal. Calcd. for C8H13N5OS2'C4Hh°4: C* 38‘39: H, 4.56; N, 18-66; S, 17-08 (%). Found: C, 38.58; H, 4.47; N. 18-45; S, 16.74 (^).

Example 42· To a solution of 2-guanidino-4-[2-(4-nitrobenzamido)ethylthiomethyljthiazole monomaleate (7-2 g) in 50 % acetic acid (200 ml) was added 20 $ aqueous titanium tri10 chloride solution (89 ml) at room temperature and the resultant mixture was stirred at room temperature for 45 minutes. The reaction mixture was basified with 10 aqueous sodium hydroxide solution and extracted with ethyl acetate· The precipitated resinous material was dissolved 2_5 in methanol and the solution was combined with the ethyl acetate layer. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a column of silica gel, which was eluted with ethyl acetatemethanol (20:5 v/v). The eluate was concentrated to give an oil, which was treated with a solution of maleic acid (4.6 g) in acetone. The resultant crude maleate was crystallized from ethanol to give 2-guanidino-4-[2-(4-aminobenzamido)ethylthiomethyljthiazole monomaleate (3-1 g)· m.p. 1/1172*C (dec.)· The yield was 46 £.

Anal. Calcd. for C ,^Η : C, 46.34; H, 4.75; Ν. 18.02; S. 13-75 (¢)- Found: C, 40-35; H, 4.82; N, 17-63; S. 13-55 (¢)Example 43.

To a solution of N-carbobenzoxy-γ-aminobutyric acid (7.8 g) in dry tetrahydrofuran (200 ml) were added triathylaaine(3.4 g) and methyl chlorocarbonate (3-1 g) at -10'C and the resultant mixture was stirred for 30 minutes at the same temperature· Triethylamine (7-θ g) and 2-guanidino-^-[2(amino)ethylthiorcethylJ thiazole dihydrochloride (10 g) were added to the mixture, which was stirred at room temperature overnight- The precipitate was filtered and washed with tetrahydrofuran- The filtrate was combined with the washings and concentrated in vacuum- The residue was mixed with 3θ $ hydrobromic acid-acetic acid (50 ml) and stirred at room temperature for 12 hours. The reaction mixture was diluted with dry ether (l L). The resultant hygroscopic precipitate was rapidly filtered, dissolved in water (50 ml) and neutralized with solid sodium carbonate.

The solution was concentrated in vacuum to dryness- The residue was extracted with ethanol, and the extract was concentrated to give a viscous oil (3-0 g) - The oil was treated with a solution of maleic acid (3-0 g) in ethanol to give 2-guanidino-4-[2-(4-aminobutyramido)ethylthiomethyljthiazole monomaleate (1.5 g)- m-p- 37-39°C (recrystallized from 95 % ethanol).

Anal. Calcd. for 20^8^0^.1/2 «20: C, 40.92: H, 5.24; N, 15-07: S, 11.50 (%). Found: C, 40.30; H, 5-19; N, 15-22; S, 11-86 (fi).

Example 44.

To a solution of 2-guanidino-4-(3-aminopropyl)thiazole (U.S-pat- 4,165.377) (472 mg) and triethylamine (0.8 ml) in dry dimethylformamide (8 ml) was added liicotinyl chloride hydrochloride (5OO mg) at -20’C. The resultant mixture was stirred at room temperature overnight and concentrated ia vacuum. The residue was mixed with water (3 ml), and basified with 5 fi aqueous sodium hydrogen carbonate solution. The resultant precipitate was filtered, sufficiently washed with water and dried to give a crude product. The crude product was treated with a solution of maleic acid (3OO mg) in methanol and diluted with acetone to give 2guanjdino-4-[3-(nicotinamido)propyljthiazole monomaleate (300 mg), m.p. 176*C (dec·) (ethanol).

Anal. Calcd. for C^H^NgOS0^: C, 48.56; H, 4.79; N, 19-99; s. 7-63 (fi) Found: C, 48.31; H, 4-59; N, 19-73: S. 7-30.(^).

Example 45· To a solution of sodium hydride (50 fi suspension in mineral oil. 590 mg) in absolute ethanol (20 ml) was added dropwise a solution of 2-aeetamidoethanethiol (733 mg) in absolute ethanol (3 ml) at -20*C and the resultant mixture was stirred at -20°C for 10 minutes. Solid 2-guanidino-4chloromethylthiazole hydrochloride (U.S.pat. 4,165,377) (1.88 g) was added to the mixture, which was stirred, at room temperature overnight- The resultant precipitate was filtered and washed with ethanol. The filtrate was combined with the washings and concentrated in vacuum to dryness. The residue was chromatographed on a column of silica gel, which was eluted with ethyl acetate-methanol (20:5 v/v). The eluate was concentrated in vacuum to give 2-guanidino-4-[2-(acet10 amido)ethylthiomethyl]thiazole (l-5 g) as an oil. The yield was 89 %.

Examples 46-50-.

The following compounds were obtained in accordance with Route B as in Example 3: ExNo . n R Salt m.p.(°C) Yield(%) 47 3 -(5) N Monomaleate 176-179d. 65-1 48 3 -ch3 n 158-159 74.4 49 3 H 1» 127-129 39-8 SllSi Ex. No· n R Salt a.p.(“C) Yield(#) 50 4 Monomaleate 135-137 33-3 51 4 cn3 160-162 55-8 1C 1C

Claims

1. A compound of the formula: HN=C-NH A N 'CH 2 X(CH 2 ) n NH-C0-R wherein n is an integer from 2 to 4; R is hydrogen, Cj,-Cg alkyl (optionally substituted by hydroxy, cyano, amino or phenoxy), C^-Cg cycloalkyl, C 2 _C 6 alkenyl (optionally substituted by phenyl or C2-C? alkoxycarbonyl) , C^-C? alkadienyl, Cg-C12 aryl (optionally substituted by one to three substituents selected from halogen, cyano, nitro, amino, C 2 -C 1O dialkylamino, tetrazolyl, hydroxy, C^-Cg alkoxy, benzoyloxy, C 2 -Cy alkoxycarbor.yl, sulfamoyl, C-^-Cg alkylsulfonyl, C^-Cg alkanesulfonamido or C^-Cg alkanoyl), or a 5- or 6-membered heterocycle (optionally sustituted by halogen, C^-Cg alkyl or phenyl); and X is a single bond or thia.

2. A compound as claimed in claim 1, wherein n is 2 or 3, R is phenyl optionally substituted by one to three substituents selected from halogen, cyano, nitro, amino, C 2 - Cjq dialkylamino, tetrazolyl, hydroxy, C^-Cg alkoxy, benzoyloxy, C 2 -C 7 alkoxycarbonyl, sulfamoyl, Cg-Cg alkylsulfonyl, Cg-Cg alkanesulfonamido and Cg-C g alkanoyl, and X is thia.

3. A compound as claimed in claim 1, wherein n is 2 or 3, R is a 5-membered heterocycle optionally substituted 5 by halogen, Cg-C g alkyl or phenyl, and X is thia.

4. A compound as claimed in claim 1, wherein π is 2 or 3, R is a 6-membered heterocycle optionally substituted by halogen, Cg-Cg alkyl or phenyl, and X is thia.

5. A compound as claimed in claim 1, wherein n is 10 2 or 3, R is hydrogen, Cg-C g alkyl (optionally substituted by cyano, amino or phenoxy), Cg-Cg cycloalkyl, C 2 -Cy alkenyl (optionally substituted by phenyl or Cj-Cy alkoxycarbonyl) or C 4 - Cy alkadienyl, and X is thia.

6. A compound of the formula: hn=c-nh 2 NK CH 2 S(CH 2 ) 2 NH-C-R wherein R is hydrogen, Cg-Cg alkyl (optionally substituted by cyano, 53.151 amino or phenoxy), C.j-Cg cycloalkyl, Cj-Cg alkenyl (optionally substituted by phenyl or C 2 ~Cy alkoxyearbonyl), C^-Cy alkadienyl, C g -C 22 ar yl (optionally substituted by one to three groups selected from halogen, cyano, nitro, amino, 5 C 2 -C| 0 dialkylamino, tetrazolyl, hydroxy, C^-Cg alkoxy, benzoyloxy, Cy-Cy alkoxyearbonyl, sulfamoyl, C^-Cg alkylsulfonyl, C^-Cg alkanesulfonamido or C^-Cg alkanoyl), or a hetero-aromatic ring (optionally substituted by halogen, C^-Cg alkyl or phenyl); and 10 R 1 is hydrogen, halogen or alkyl.

7. A compound as claimed in claim 1, wherein n is 2 and X is thia; provided that if R is substituted C^-Cg alkyl the substituent(s) is/are cyano, amino or phenoxy.

8. 2-guanidino-4-/2-(formamido)ethylthiomethyl7 25 thiazole.

9. 2-guanidino-4-/2-(acetamido)ethylthiomethyl7 thiazole.

10. 2-guanidino-4-/2-(nicotinaraido)ethylthiomethyl7 thiazole.

11. 2-guanidino-4- < <3-(formamido)propylthiomethyl7 thiazole.

12. 2-guanidino-4-/3-(acetamido)propylthiomethy17“ thiazole.

13. 2-guanidino-4-/5-(nicotinamido)propylthiomethyl7 thiazole. 5

14. 2-guanidino-4-/S-(benzamide )ethylthiomethyl7~ thiazole.

15. '2-guanidino-4-/5-(4-sulfamoylbenzamido)ethylthiomethyl7thiazole.

16. 2-guanidino-4-/5-(4-aminobenzamido)ethylthiomethyl/thiazole.

17. 2-guanidino-4-/2-(3-aminobenzamido)ethylthiomethy thiazole.

18. 2-guanidino-/2-(2-thiophenecarboxamido)ethylthiomethy l/thiazole. 15

19. , 2-guanidino-4-/3-(2-furancarboxamido)ethylthiomethy l7thiazole.

20. 2-guanidino-4-/5-(4-(N)-tetrazolylbenzamido)ethylthiomethyl7thiazole. 51 458

21. A compound as claimed in claim 1 and specifically referred to hereinbefore.

22. An acid addition salt of a compound as claimed in any one of claims 1 to 21. 5

23. A salt as claimed in claim 22 which is pharmaceutically or veterinarily acceptable.

24. A process for preparing a compound as claimed in claim 1 which process comprises either a) reacting an amine of the formula: wherein n and X are as defined in claim 1, with a carboxylic acid of the formula: RCOOH, wherein R is as defined in claim 1, or with a reactive 15 derivative thereof, or b) reacting a 2-guanidino-4-(activated)methylthiazole of the formula: HN=C-NH NH S1151 wherein B is reactive group, with a mercaptan of the formula: HS(CH 2 ) n NHCOR wherein n and R are as defined in claim 1, 5 or c) reacting guanylthiourea of the formula: HN=C-NH ι 4 NH S=C-NH n « with a ketone derivative of the formula: A-CH.COCH-S(CH.) NHCCR, z z z n wherein A is a reactive group and n and R are as defined in l0 claim 1,

25. A process as claimed in claim 24(a), wherein the reaction is effected in an inert solvent.

26. A process as claimed in claim 24(a) or claim 25 wherein the reaction is effected in the presence of a base 15 or a condensing agent.

27. A process as claimed in any one of claims 24(a), 25 or 26, wherein the reaction is effected at a temperature of from -20°C to 60°C.

28. A process as claimed in claim 24(b), wherein the 2o reaction is effected in the presence of a base.

29. A process as claimed in claim 24(b) or claim 28, wherein the reaction is effected in an inert solvent.

30. A process as claimed in any one of claims 24(b), 28 or 29, wherein the reaction is effected at a temperature of from 0°C to 60°C. 5 31. A process as claimed in claim 24(c), wherein the reaction is effected in an inert solvent. 32. A process as claimed in claim 31, wherein the reaction is effected at a temperature of from 0°C up to the boiling point of the solvent. 10 33. A process as claimed in any one of claims 24(c),

31. Or 32, wherein the reaction is effected in the presence of a base.

32. 34. A process as claimed in claim 24 and substantially as hereinbefore described under any one of the headings 15 Route A, Route B or Route C.

33. 35. A process for preparing a compound as claimed in claim 1 and substantially as hereinbefore described in any one of the Examples.

34. 36. A pharmaceutical or veterinary formulation comprising a compound as claimed in any one of claims 1 to 21 or a salt as claimed in claim 23 formulated for pharmaceutical or veterinary use, respectively.

35. 37. A formulation, as claimed in claim 36 and in unit dosage form.

36. 38. A formulation as claimed in claim 36 or claim 37 also comprising a pharmaceutically acceptable or veterinarily acceptable, respectively, diluent, carrier or excipient.

37. 39. A compound as claimed in any one of claims 1 to 21 or a salt as claimed in claim 22 or claim 23 for use as an anti-peptic ulcer agent or a histamine H 2 receptor antagonist.