IE47045B1 - Guanidine derivatives - Google Patents

Description

This invention relates to guanidine derivatives which are intermediates for histamine H-2 antagonists.

It is postulated that the physiologically-active compound histamine, which occurs naturally within the animal hody, is able to combine, in the course of exerting its activity, with certain specific receptors of which there are at least two distinct and separate types. The first has been named the H-l receptor (Ash and Schild, Brit.J Pharmae., 1966, 27, 427) and the action of histamine at this receptor is blocked (antagonised) by classical antihistamine drugs such as mepyramine. The second histamine receptor has been named the H-2 receptor (Black et al., Nature, 1972, 236, 385) and the action- of histamine at this receptor is blocked by drugs such as cimetidine.

It is known that one of the results of the blockade of the action of histamine at the H-2 receptor is the inhibition of the secretion of gastric acid and a compound which possesses this ability is therefore useful in the treatment of peptic ulcers and other conditions caused or exacerbated by gastric acidity.

In Patent Specification Nos 36050 and 38353 described histamine H-2 receptor antagonists which are imidazole and thiazole derivatives having a side chain in the 4-position, to the end of which is attached, for example, a urea, thiourea, guanidine or N-cyanoguanidine.

In Patent Specification No. /Ύ8 there are described histamine H-2 receptor antagonists which are guanidine derivatives of the formula I:- (CH2)m-Y-(CH2)n-NH-A-B I 4704S - 3 in which X is a sulphur atom or an NH radical; Y is an oxygen or sulphur atom, a direct bond, a methylene orsulphinyl radical or a 'cis or trans vinylene radical; m is 0 to 4 and n is 1 to 4, provided that when Y is a sulphur or oxygen atom or a sulphinyl radical, m is 1 to 4 and wheh Y is an oxygen atom or a sulphinyl radical n is 2 to 4; R1 is a hydrogen or halogen atom or an alkyl radical of to 6 carbon atoms; .

R is a hydrogen atom, an alkyl radical of 1 to 10 carbon atoms, an alkanoyl radical of 1 to 6 carbon atoms or an aroyl radical of 7 to 11 carbon atoms; A is a 3>4-dicxocyclobuten-l,2-diyl radical or a radical of the formula C=Z in which Z is an oxygen or sulphur atom or a radical of the formula NCN, NNO2, CHN02, NCONH2, C(CN)2, NCOR3, NCO2R3, NSO2R3 or NR*1 in which R3 is an alkyl radical of 1 to 6 carbon atoms or an aryl radical of 6 to 12 carbon atoms and R1* is a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms; B is an alkoxy or alkylthio radical of 1 to 6 carbon atoms or a radical of the formula NR3R^ in which R3 and ?$ which may be the same or different, aro- hydrogen atoms, alkyl radicals of 1 to 10 carbon atoms, alkenyl radicals of 3 to 10 carbon atoms in which the double bond is separated from the nitrogen atom of NR^R^ by at least one carbon atom, eycloalkyl radicals of 3 to 8 carbon atoms, (primary hydroxy)alkyl radicals of 2 to 6 carbon atoms in which the oxygen atem is separated from the nitrogen atom of Nr5r6 by at least two carbon atoms, alkoxyaikyl radicals of 3 to 10 carbon atoms in which the oxygen atom is separated from the nitrogen atom of NR3R^ by at least two carbon atoms, alkylaminoalkyl radicals of 3 to 10 carbon atoms in which the nitrogen atom is separated from the nitrogen atom of NR3R^ by at least two carbon atoms; or tfialkylaminoalkyl radicals of 4 to 10 carbon atoms in which the nitrogen atom is separated from the 5 6 nitrogen atom of NRR by at least two carbon atoms; and the pharmaceutically-acceptable acid-addition salts thereof.

The guanidine derivatives of the formula I may be prepared using an intermediate of the formula II :- (CH^-Y-CCHg^-NHg XI 2 in which X, m, n, R and R have the meanings stated above, and the acid-addition salts thereof.

It is to 'be understood that, in the above formula II and throughout this specification, although the double bond in one side chain has been inserted in a particular position, other tautomeric forms are possible, and this invention includes such tautomeric forms within its scope.

A particular value for when it is a halogen atom . or an alkyl radical is a bromine atom or a methyl radical, p A particular value for R when it is an alkyl, alkanoyl or aroyl radical is a methyl, n-butyl, acetyl, propionyl or benzoyl radical.

The following are 4 preferred features of the guanidine derivative of the formula II. When any one of these 4 features is taken, either singly or in combination, with tne other general features of the guanidine derivative of the formula II listed above, there are obtained preferred sub-groups of compounds within the above general definition. 1. X is a sulphur atom. 2. R1 is a hydrogen atom. 3. R2 is a hydrogen atom or an alkyl radical. 4. Y is a sulphur atom and m is 1 and n is 2, or Y is a direct bond and m is 2 and n is 2.

A suitable acid-addition salt of the guanidine derivative of the formula II is, for example, a salt formed with hydrochloric, hydrobromic, phosphoric, sulphuric, 4704S acetic, citric or maleic acid.

Particularly preferred compounds are those cf the formula II in which X is a sulphur atom or NH radical, • · 1 9 Y is a sulphur atom, m is 1, n is 2 and R and R are hydrogen atoms and X is a sulphur atom or NH radical, Y is a direct bond, m is.2 and n is 2 and R and R are hydrogen atoms, and the acid-addition salts thereof.

When Y is a sulphur or oxygen atom the compound of the formula II may be prepared by reaction of a dichloroketone of the formula ClCHR1C0(CH2)mCl with a compound of the formula III:R2NH NH \=N-C^ / \ III NH, followed by reaction of the product, the compound of the formula IV:„1 X IV -(CH2)m-Cl R2NH / h2n Λ Nwith a compound of the formula HD-(CH2)n-NH2 in which D is an oxygen or sulphur atom, for example as set out in Examples 1, 2 or 3· When Y is a direct bond, a methylene radical or a cis or trans vinylene radical, the compound of the formula II may be prepared by reaction of a bromoketone of the formula V:BrCHR1CO(CH2)m-Y-(CH2)n-Η with a compound of the formula III given above followed by hydrolysis of the phthalimido residue, for example as set out in Examples 4, 5 or 8.

When Y Is a cis or trans vinylene radical, the compound of the formula II may be prepared by a Wittig reaction, for example by reaction of a compound of the formula BrCHR’''CO(CH2)mCH=P(Ph)-j with an aldehyde of the for example as set out in Examples 10 or 11, followed if necessary by isomerisation of the double bond.

The starting material of the formula II in which is a halogen atom may be prepared by halogenation of the compound of the formula II in which R^ is a hydrogen atom, for example as set out in Example 9.

The invention is illustrated, but not limited, by the following Examples:47045 - 7 Example 1 A suspension of 2-guanidino-4-[(2-aminoethyl )thiomethyl]thiazole hydrochloride (9.12 g.) in methanol (300 ml.) was treated with triethylamine (6.06 g.) to give a clear pale yellow solution. Dimethyl (cyanoimido)dithiocarbonate (4.38 g.) was added and the solution stirred overnight at room temperature. The mixture was poured into water and extracted with ethyl acetate to give a yellow gum. Trituration with acetone gave 2-guanidino-4-[2-(3~ cyano-2-methylisothioureido)ethylthiomethyl]thiazole (7.3 g.) as a pink solid, m.p. 146-148°C.

The 2-guanidino-4-[(2-aminoethyl)thiomethyl] thiazole hydrochloride used as starting material may be prepared as follows :A suspension of amidinothiourea (16.8 g.) in acetone (75 ml.) was treated with 1,3-dichloroacetone (18 g.) in acetone (60 ml.). There was a slight exotherm and the crystalline suspension gradually changed to a fine white solid. After stirring overnight at room temperature the solid was filtered off and washed with acetone. Crystallisation from ethanol gave 2-guanidino-4-chloromethylthiazole hydrochloride, m.p. 191-193°C.

A solution of 2-aminoethanethiol hydrochloride (4.52 g.) in ethanol (40tml.) was added portionwise at 0°C. to a solution of sodium ethoxide (prepared from 2 g. of sodium) in ethanol (60 ml.) under a nitrogen atmosphere. After stirring at O°C for 2 hours, a solution of 2-guan±dino-4chlorcmethylthiazole hydrochloride (4.54 g.) in ethanol (35 ml.) was added dropwise over 15 minutes while the temperature was maintained at 0-2°C.

After the addition was complete the reaction mixture was stirred at room temperature for 16 hours, filtered, and the filtrate acidified with concent10 rated hydrochloric acid. On standing 2-guanidino-4Q2-aminoethyl)thiomethyl]thiazole hydrochloride precipitated as a white crystalline solid (4.56 g,), m.p. 268-270°C, (decomp,).

Example 2 A solution of 2-guanidino-4-{j(3-aminopropyl) thiomethyl]thiazole hydrochloride (1.64 g.) and triethylamine (-1.01 g.) In cold methanol (20 ml.) was treated with dimethyl (cyanoimido)dithiocarbonate (0.73 g.) and the solution stirred for 16 hours at room temperature. 33% w/v Ethanolic methylamine - 9 (12 ml.) was added and the mixture stirred at room temperature for 18 hours. The solution was evaporated to give a brown gum which was applied to Merck 60 F-254 preparative plates and eluted with ethyl acetate/ ammonia (s.g. 0.880)/ethanol 6:1:1 v/v/v. The pale yellow oil was converted to the hydrogen maleate salt and the product recrystallised from methanol to give 2-guanidino-4-[3-(2-cyano-3-methylguanidino)prop.ylthiomethyl]thiazole hydrogen maleate, m.p. 175-177°C.

The starting material may be prepared as follows :j-Aminopropanethiol hydrochloride (2.54 g.) in ethanol (20 ml.) was added to a solution of sodium ethoxide (1 g. Na in 25 ml.), in ethanol at 0°C. under a nitrogen atmosphere. The suspension was stirred at 0°C, for 2 hours and a solution of 2-guanidino-4chloromethylthiazole hydrochloride (2.27 g.) in ethanol (25 ml.) was then added. The suspension was allowed to reach room temperature and stirred for 16 hours. Filtration of the suspension and acidification of the filtrate with concentrated hydrochloric acid gave a precipitate of 2-guanidino-4-[(3-aminopropyl)thiomethyl]thiazole hydrochloride, m.p. ^350^. 470 45 - 10 Example 3· A-mixture of 2-(2-n-hutylguanidino)-4-(2aminoethyl)thiomethylthiazole hydrochloride (1.10 g.), methylisothiocyanate (0.70 g.), triethylamine (0.90 g.) and methanol (5 ml.) was stirred at room temperature for four hours, It was then diluted with water (25 ml.) extracted with ethyl acetate (2 x 25 ml.) and the combined extracts washed with water (50 ml.). The organic layer was then extracted with N hydrochloric acid (2 x 25 ml.), the combined aqueous layers washed with ethyl acetate (25 ml.) and then basified by addition of aqueous ammonia. The resulting emulsion was extracted with ethyl acetate and the extract was washed with water and dried over magnesium sulphate.

It was filtered and evaporated to dryness to give 2-(2-n-butylguanidino)-4-[2-(3-methylthioureido)ethylthiomethyl] thiazole as a brown gum. The n.m.r. spectrum in dg dimethyl sulphoxide using tetramethyl47045 - 11 silane as internal standard had the following resonances (S):- 0.6-1.5 (7H, multiplet); 2.5 (2H, multiplet); 2.75 (3H, triplet); 3“3.5 (4H, multiplet); 3.55 (2H, singlet); 6.45 (IH, singlet); 6.7-7.6 (broad multiplet).

The 2-(2-n-butylguanidino)-4-(2-aminoethyl)thiomethylthiazole hydrochloride used as starting material may be prepared as follows :A solution of 1,3-dichloroacetone (3.02 g.) in acetone (10 ml.) was added to a stirred suspension of (N-n-butylamidino)thiourea (4.04 g.) in acetone (25 ml.) at room temperature. The resulting clear pale yellow solution was stirred for three days, then cooled in ice, and the precipitated solid filtered off and washed with acetone to give 2-(2-nbutylguanidino)-4-chloromethylthiazole hydrochloride.

A solution of 2-aminoethanethiol hydrochloride (I.85 g.) in ethanol (30 ml.) was added .to a stirred solution of sodium (0.90 g.) in ethanol (50 ml.) under a nitrogen atmosphere. A solution of 2-(2-n-butylguanidino)-4-chloromethylthiazole hydrochloride (2.20 g.) in ethanol (50 ml.) was added dropwise to the mixture, which was then stirred Tor 3 hours while warming to room temperature. A mixture of concentrated hydrochloric acid (5 ml.) and water (15 ml.) was then added, and the mixture evaporated to dryness. The residual gummy solid was extracted with boiling ethanol (3 χ 20 ml.) and the residual white solid discarded The combined ethanolic extracts were filtered and the filtrate evaporated to dryness to give 2-(2-nbutyIguanidino)-4-(2-aminoethyl)thiomethylthiazole hydrochloride as a thick gum which was used without further purification. - 13 Example 4 To a stirred mixture of 2-guanidino-4(4-aminobutyl)thiazole hydrochloride hydrobromide (0.4 g.) in ethanol (25 ml.) at ambient temperature was added triethylamine (0.3 ml.) and then dimethyl (cyanoimido)dithiocarbonate (0.18 g.) and the whole mixture stirred at room temperature for 5 hours. Λ solution of 33% w/v methylamine in ethanol (30 ml.) was then added nd the mixture allowed to stand for 16 hours. A small amount of charcoal was added, the mixture stirred for a few minutes, and then filtered and the filtrate evaporated to dryness. The residual ‘ gum was purified by column chromatography on silica gel using chloroform/methanol/ammonia (s.g. 0.880) 80:20:0.5 v/v/v as eluant. The purified product (0.25 g.) was recrystallised from acetonitrile to give 2-guanidino-4-[4-(2-cyano-3-methylguanidino)butyl]thiazole, m.p. 165-167.5¾.

The 2-guanidino-4-(4-aminobutyl)thiazole hydrochloride hydrobromide used as starting material may be prepared as follows :A mixture of N-(6-bromo-5-oxohexyl)phthalimide (4.5 g.) and amidinothiourea (1.65 g.) in ethanol (300 ml.) was heated under reflux for 1 hour. The reaction mixture as allowed to cool and the product, 2-guanidino-4-(4-phthalimidobuty1) thiazole hydrobromide (4.3 g.), m.p. 218-221 °C., was filtered off. - 14 A mixture of 2-guanidino-4-(4-phthalimidobutyl)thiazole hydrobromide (3-43 g.) and potassium hydroxide (1.68 g.) in water (50 ml.) was heated at 100 °C. for 15 minutes. The reaction mixture was then acidified to pH2 with 2N HCl, and the mixture heated at 100 °C. for 1 hour. The cooled reaction mixture was extracted three times with ethyl acetate, the aqueous layer was evaporated to dryness and to'the residue was added toluene which was evaporated fco dryness. The resulting gummy solid was dissolved in methanol, the insoluble material filtered off and the filtrate evaporated to dryness to give 2-guanidino-4-(4-aminobutyl)thiazole hydrobromide hydrochloride. The free base (1.2 g.·) was obtained by passage down an ion-exchange column [Amberlite IRA-400 (OH)] in 50% v/v methanol/water. Ealnple 5 A solution of 2-(2-methylguanidino)-4-(4nhthalimidobutyl)thiazole hydrobromide (0.65 g.) in ethanol/water 3:1 v/v (50 ml.) containing' sufficient sodium hydroxide to maintain the pH above 12 was 7 0 4 5 - 15 heated under reflux for 15 minutes. The pH was then adjusted to 3 with concentrated hydrochloric acid and the solution heated under reflux for a further 15 minutes. The solution was then made strongly alkaline by addition of dilute sodium hydroxide and evaporated to dryness. The residue was dissolved in water (30 ml.) and the solution extracted with ethyl acetate (2 x 40 ml.). The combined ethyl acetate extracts were evaporated co dryness and the residue (0.27 g.) dissolved in ethanol (10 ml.) and treated with dimethyl (cyanoimido)dithiocarbonate (0.l8 g.). The mixture was allowed to stand overnight to give a solution of 2-(2-methyIguanidino)-4-[4-(3-cyano-2-methylisothioureido)butyl]thiazole in ethanol.

The 2-(2-methyIguanidino)-4-(4-phthalimidobutyl)thiazole hydrobromide used as starting material may be prepared as follows:To a solution of (N-methylamidino)thiourea (0.4 g.) in hot ethanol (20 ml.) was added N-(6-bromo5-oxohexyl)phthalimide (1.5 g.). The mixture was heated under reflux for 1 hour, cooled and evaporated to dryness. The residue was triturated with acetonitrile and the resulting solid was filtered and dried to give 2-(2-methylguanidino)-4-(4-phthalimidobutyl)thiazole hydrobromide, m.p. 210-12°C. - 16 Example 6 A mixture of 2-guanidino-4~(4-aminobutyl)imidazole (0.15 S·) and methylisothiocyanate (0.1 g.) in ethanol (10 ml.) was stirred overnight and then evaporated to dryness. The residue was purified by chromatography on a silica gel column using chloroform/methanol/ammonia (s.g. 0.880) 80:20:0.3 v/v/v.

The appropriate fractions on evaporation gave a gum which crystallised on triturating in petroleum ether (b.p. 40-60°C.) to give 2-guanidino-4-[4-(3-methylthio ureido)butyl]imidazole, m.p. 179-l84°C.

The 2-guanidino-4-(4-aminobutyl)imidazole used as starting material may he obtained as follows:Biguanide (1.01 g.) was stirred in dry dimethylformamide (15 ml.) and N-(6-bromo-5-oxohexyl)phthalimide (1.5 g.) added. The mixture as stirred for 3 hours, acetic acid (5 ml.) was then added and the total reaction mixture evaporated to dryness.

The residue was dissolved in water (10 ml.) and extracted with ethyl acetate (5 x 20 ml.). The combined ethyl acetate extracts were evaporated to give a brown foam which was purified by column chromatography on silica gel using chloroform/methanol/ ammonia (s.g. 0.880) 80:20:0.5 v/v/v. The appropriate fractions were evaporated to give 2-guanidino-4-(44704S - 17 phthalimidobutyl)imidazole as a brown foam (0.3 β·)· To a solution of 2-guanidino-4-(4-phthalimidobutyl)imidazole (0.25 g.) in water/ethanol 1:1 v/v (20 ml.) was added sufficient dilute sodium hydroxide solution to give a pH of 12. The mixture was heated under reflux for 30 minutes, the pH adjusted to 3 with concentrated hydrochloric acid, the mixture heated under reflux a further 30 minutes and then cooled. 'The pH was readjusted to 12 with sodium hydroxide solution and then the total mixture evaporated to dryness to give crude 2-guanidino-4(4-aminobutyl)Imidazole which was used without further purification.

Example 7 A mixture of 2-guanidino-4-(6-aminohexyl)thiazole (1.0 g.; obtained from the dihydrochioride salt) and methyl isothiocyanate (0.45 g.) in ethanol (10 ml.) was stirred at room temperature for 16 hours and then evaporated to dryness. The residue was recrystallised from ethanol and the product dried over refluxing toluene for 2.5 hours to give 2-guanidino4-[6-(3~methylthioureido)hexylJthiazole, m.p. 162-4 °C.

The 2-guanidino-4-(6-aminohexyl)thiazole dihydrochioride used as starting material may be prepared as follows: - Λ mixture of phthalic anhydride (5.3 g.) and 7-aminohcptanoic acid (5.8 g.) was heated at - 18 l85-19O°C. for 40 minutes and then cooled. The' cooled partially-solidified product was dissolved in ethyl acetate and the solution washed several times with dilute HCl. The organic layer was dried (MgSOjj), filtered and evaporated to dryness and the residue recrystallised from acetic acid to give 7-phthalimidoheptanoic acid (5 g.), m.p. 112-5¾.

A mixture of 7-phthalimidoheptanoic acid (5 g.) and thionyl chloride (4.3 g.) was stirred at room temperature for 2 hours. Toluene was added to the resulting solution and the mixture evaporated to dryness in vacuo. More toluene was added to the residue and the evaporation repeated. There was thus obtained the acid chloride (4.6 g.) as an oil which · solidified on standing and was used without further purification.

To diazomethane (3 g.) in dry ether at -60¾. was added triethylamine (1.6 g.) followed by a solution of the above acid chloride (4.6 g.) in dry ether. The yellow solution rapidly became cloudy and was allowed to warm up to room temperature. The suspension was then filtered and the filtrate evaporated in vacuo at room temperature to a small volume and allowed to stand. The solid which crystallised out was filtered off, washed with a minimum amount of ether and dried to give the diazoketone (3.8 g.), m.p. 59-61 °C.

A solution of the above diazoketone (3.8 g.) - 19 in acetone (15 ml.) was treated dropwise with 48? w/v aqueous HBr at room temperature with stirring until no further gas evolution was noted. The solution v?as stirred at room temperature for a further 15 minutes then diluted with water (15 ml.) and the resulting precipitate filtered, washed with water and dried to give N-(8-bromo-7~oxooetyl)phthalimide (4.2 g.), m.p. 83-86°C.

A mixture of amidinothiourea (1.4 g.) and ethanol (75 ml.) was heated to reflux and the suspension filtered to remove undissolved solids. The filtrate was reduced in volume to 25 ml. and this hot solution was added to a hot solution of N-(8-bromo7-oxooctyl)phthalimide (4.2 g.) in ethanol (10 ml.). The mixture was heated under reflux for 45 minutes, evaporated to a small volume and allowed to stand at room temperature. The resulting solid precipitate was filtered off, washed with a minimum quantity of ethanol, then ether, and dried to give 2-guanidino4-(6-phthalimidohexyl)thiazole hydrobromide (4.2 g.) which was used without further purification.

A suspension of 2-guanidino-4-(6-phthalimidohexyDthiazole (4.2 g.) in methhnol (30 ml.) and 10? w/v aqueous NaOH (10 ml.) was heated under reflux for 15 minutes. The pH of the mixture was then adjusted to 1 with concentrated HCl and the mixture heated under reflux for 30 minutes. The pH - 20 of the mixture was then adjusted to 12 with 10% w/v aqueous NaOH and the mixture heated under reflux for 15 minutes. The pH of the mixture was then adjusted to pH 1 with concentrated HCl and the mixture was heated under reflux for 30 minutes and then stirred at room temperature for 16 hours. The mixture was then evaporated to dryness in vacuo and the residue suspended in water-and filtered to remove solids which were further washed with water. The combined aqueous filtrates were extracted several times with ethyl acetate, then with ether. The aqueous layer was evaporated to dryness and the residue extracted several times with ethanol. . The combined ethanol extracts were evaporated to dryness, reextracted with ethanol and this extract filtered and evaporated to dryness to give 2-guanidino-4-(6-aminohexyl)thiazole dihydrochloride as a yellow foam which was used without further purification.

Example 8 A number of amines of the formula II were reacted with methyl isothiocyanate in ethanol at ambient temperature for 2 hours and the following compounds were thus obtained:- 21 Table I 470 45 h2n H2N 'n_ (CH2)mNHCNHCH3 m R Footnotes 2 K 1, 2> 3 3 H 4, 5, 6 4 Me 1, 2,5,7 5 H 1, 4, 8,9 5 Me 1, 4, 9, 10 Footnotes 1. Free base of amine starting material prepared in situ from hydrohalide salt by addition of one equivalent of triethylamine. 2. Product purified by column chromatography on silica gel using chloroform/methanol/ammonia (s.g. 0.880) 8:2:0.4 v/v/v as solvent. 3. M.p. 184-6°C. 4. Product purified by preparative thin layer chromatography on Merck 60 F-254 plates using chloroform/methanol/ammonia (s.g. 0.880) 7:3:0.5 v/v/v as solvent.

. The product was characterised by its n.m.r. - 22 spectrum in dg dimethyl sulphoxide using tetramethylsilane as an internal standard (5=0). 6. n.m.r. Spectrum (&):- 1.8 (2H, broad triplet); 2.5 (triplet, obscured by DMSO); 2.8 (3H, doublet); 3-3 (multiplet, obscured by HgO); 6.3 (IH, singlet); 6.9 (4H, broad singlet); 7.4. (2H, multiplet). 7. n.m.r. Spectrum (5):- 1.65 (4H, multiplet); 2.3 (3H, singlet); 2.6 (multiplet, obscured by DMSO); 3.0 (3H, doublet); 3.6 (multiplet, obscured by H^O); 6.9 (4h,‘broad singlet); 7·5 (2H, multiplet). 8. n.m.r. Spectrum (S)·’- 1.5 S(6H, broad multiplet); 2.5 (2H, obscured by DMSO); 2.8 (3H, doublet); 3·3 (triplet, obscured by H^O): 6.25 (IH, singlet); 6.8 (4h, broad singlet); 7.35 (2H, broad multiplet). 9. Product purified by preparative thin layer chromatography on Merck 60 F-254 plates using chloroform/methanol/ammonia (s.g. 0.880) 80:20:0.6 v/v/v as solvent. . n.m.r. Spectrum (8) of sample containing 0.8 mole of ethanol:- 1.1 (triplet, ethanol); 1.5 δ (6H, multinlet); 2.1 G(3H, singlet);' 2.4 (multiplet, obscured by DMSO and ethanol); 2.8 5(3H, doublet); 3·5 {[(multiplet, obscured by H^O); 6.7 (411, broad singlet); 7.3 (2H, multiplet).

The starting materials for use in the above 7 0 J 5 - 23 process may be obtained as follows :A solution of 5~phthalimidopentanoyl chloride (1.8 g.) in dry toluene (30 ml.) was added to an ethereal solution of diazoethane at -78 °C. and the mixture was allowed to warm to room temperature and stand for 15 hours. The solvent was evaporated off in vacuo, the residual oil dissolved in acetone, and to this solution was added concentrated hydrochloric acid until nitrogen ceased to be liberated.

The mixture was then evaporated to dryness and azeotroped with toluene. Purification of the crude material by dry column chromatography on silica GF 254 and using 20% v/v ethyl acetate/toluene as solvent yielded N-(6--chloro-5-oxoheptyl)phthalimide (0.70 g.), m.p. 61-3°C.

A solution of 6-phthalimidohexanoyl chloride (2 g.) in dry toluene was added to an ethereal solution of diazoethane at -78°C. and the mixture was allowed to warm to room temperature and stand for 15 hours. On standing a solid crystallised out of solution. The reaction mixture was filtered and the filtrate evaporated to dryness giving 1.43 g. of yellow-green oil.

This oil was then dissolved in acetone and concentrated hydrochloric acid added until effervescence ceased.

The resulting yellow-brown solution was then evaporated to dryness and azeotroped three times with toluene to give N-(7-ehloro-6-oxooctyl)phthaliraide (1.4 g.) 7 0 4 5 - 24 which was used without' further purification.

The second' and third parts of Example 4 were then repeated using the appropriate starting materials in place of N-(6-bromo-5-oxohexyl)phthal~ imide and the compounds in the following Tables II and III were thus obtained:Table II ΪΡ R X m.p. °C. 2 H Br 285-7 3 H Br 206-12 4 Me Cl 201-3 5 H Cl 5 Me Cl * * In this instance an d the product purified by preparative thin layer chromatography on Merck 60 F-254 plates using chloroform/methanol/ammonia (s.g. 0.880) 8:2:0.3 v/v/v as developing solvent. - 25 Table III h2n \ C=N h2k -¾)-ra2 m R Footnotes 2 H 1 3 H 2 4 Me 3 5 H 3 5 Me 3 Footnotes 1. Isolated as the hydrochloride hydrobromide salt. 2. The product was converted to the free base which was purified by preparative thin layer chromatography on Merck 60 F-254 plates using chloroform/ methanol/ammonia (s.g. 0.880) 8:2:0.3 v/v/v as solvent. 3· Isolated as dihydroehloride salt. 7 0 4 5 - 26 Example 9 A mixture of 2-guanidino-4-(4-aminobutyl)~ -bromothiazole (0.50 g.) and methylisothiocyanate (0.14 g.) in ethanol (20 ml.) was stirred for 1 hour at room temperature. The mixture was evaporated to dryness, and residual gum was purified by preparative thin layer chromatography on Merck 60 F-254 plates using chloroform/methanol/ammonia (s.g. 0.880) 8:2:0.2 v/v/v as solvent to give 2-guanidino-5~bromo-4-[410 (3-methylthioureido)butyl]thiazole, m.p. 128-131 °C.

The 2-guanidino-4-(4-aminobutyl)-5-bromothiazole used as starting material may be prepared as follows:A mixture of 2-guanidino-4-(4-aminobutyl)15 thiazole (0.5 g.) and 10% v/v bromine in concentrated hydrochloric acid (1.5 ml.) in concentrated hydrochloric aeid (10 ml.) was stirred at room temperature for 0.75 hours. The whole mixture was evaporated to dryness and azeotroped twice with toluene. The residue was 2o dissolved in water (5 ml.) and excess 3N sodium hydroxide added quickly with stirring. The product, 2-guanidino-4-(4-aminobutyl)-5-bromothiazole (0.5 g.) was filtered off, washed with a little water, and - 27 dried, m.p. 125-6 °C.

Example 10 A solution of 2-guanidino-4-(3~aminopropl-trans-enypthiazole (0.066 g.) in ethanol at 40°c. was t^ated with dimethyl (cyanimido)dithiocarbonate (Ο.Ο38 g.) and the solution kept at room temperature for 1 hour. The pale yellow solid which crystallised from the solution was collected to give 2-guanidino4-(3-(3-cyano-2-methylisothioureido)prop-l-trans10 enyllthiazole, m.p. 223-225°C. (vigorous decomp.).

The 2-guanidino-4-(3-aminoprop-l-trans. enypthiazole used as strating material may be prepared :as follows :A solution of (3-chloroacetonylidene)tri15 phenyIphosphine (3.0 g.) and 2-phthalimidoac.etaldehyde (1.62 g.) in chloroform (50 ml.) was heated under reflux for 48 hours, then evaporated to dryness under reduced pressure. . The residue was crystallised from ethanol to give N-(5-chloro-4-oxopent-2rtrans-enyl)20 phthalimide (1.29 g.), m.p. 124-126°C.

A mixture of N-(5-chloro-4-oxopent-2-transenypphthalimide (1.29 g.), amidinothiourea (0.59 g.) and ethanol (20 ml.) was heated unde'r reflux for one hour. The resulting solution was cooled, then filtered to give 2-guanidino-4-(3-phthalimidoprop-ltrans-enyl)thiazole hydrochloride (0.97 g·), m.p. 238-240 °C. (decomp.). 4-7045 - 28 A mixture of 2-guanidino-4-(3-phthalimidoprop-l-trans-enyl)thiazole hydrochloride (0.97 g.), hydrazine hydrate (0.27 g.) and methanol (20 ml.) was heated under reflux for 2 hours then evaporated to dryness. The solid residue was stirred for 5 minutes with 2N HCl (20 ml.) then filtered, and the filtrate evaporated to dryness. The residue was dissolved in water (10 ml.) and the solution adjusted to pH12 with 2N NaOH, saturated with sodium chloride and extracted five times with ethyl acetate. The combined ethyl acetate extracts were dried and evaporated to dryness to give 2-guanidino-4-(3-aminoprop-l-trans-enyl)thiazole (0.35 g.), characterised as the dihydrochloride, m.p. 249-251 °C. (after crystallisation from aqueous ethanol).

Example 11 A mixture of 2-guanidino-4-(4-phthalimidobut-l-trans-enyflthiazole hydrochloride (0.5 g.), - 29 hydrazine hydrate (0.2 g.) and methanol (15 ml.) was heated under reflux for 1.5 hours. The solution was cooled, treated with Ν,Ν,Ν',N'-tetramethylguanidine (0.3 g.), and evaporated to dryness, then the residue twice suspended in toluene (20 ml.) and evaporated to dryness.

A solution of the residue in ethanol (10 ml.) at 4o°C. was treated with dimethyl (cyanoimido)dithiocarbonate (0.175 g.) and the solution kept at room temperature for 2 hours then evaporated to dryness.

The residue was stirred with water (10 ml.) for 5 minutes, then the aqueous phase decanted and the residue washed with a further 10 ml. of water.

The residue was dissolved in 33% w/v methylamine in ethanol (5 ml.) and the solution kept at room temperature for 4 hours then evaporated to dryness. The residue was purified by preparative thin layer chromatography on Merck 60 F-254 plates using ethyl acetate/ethanol/ammonia (s.g. 0.880) 12:1:1 v/v/v as solvent and the band having Rf 0.3 was eluted with methanol to give 2-guanidino-4-[4-(2-cyano-3-methylguaunidino)but-l-trans-enyllthiazole (0.08 g.), characterised as its hydrogen maleate, m.p. l63-l65°C. (decomp.) (after crystallisation from methanol/ acetonitrile).

The 2-guanidino-4-(4-phthalimidobut-ltrans-enyl) thiazole hydrochloride used as starting - 30 material may be obtained as follows:A solution of (3~chloroacetonylidine)triphenylpbosphine (8.68 g.) and 3-phthalimidopropionaldehyde (5 g.) in chloroform (80 ml.) was heated under reflux for 24 hours. The solution was evaporated to dryness and the residue triturated with ethanol then filtered to give N-(6-chloro~5oxohex-3-trans-enyl)phthalimide (3.4 g.), m.p. 132135°C. (after reerystallisation from ethanol).

A mixture of N-(6-chloro-5-oxohex-3-transenyDphthalimide (0.554 g.), amidinothiourea (0.236 g.) and ethanol (30 ml.) was heated under reflux for 3.5 hours. The mixture was allowed to cool, then filtered to give 2-guanidino-4-(4-phthalimidobut-1-trans-enyl)15 thiazole hydrochloride, m.p. 226°C. (decomp.).

Claims (3)

CLAIMS:

1. A guanidine derivative of the formula XI :„1 CCH 2 ) m »Y-(CH 2 )n-NH 2 II in which X is a sulphur atom or NH radical; Y is an oxygen or sulphur atom, a direct bond,a methylene or sulphinyl radical or a cin or trans vinylene radical; m is 0 to 4 and n is 1 to 4, nrovided that when Y is a sulphur or oxygen atom or a sulphinyl radical m is 1 to 4 and when Y is an oxygen atom or a sulphinyl radical n is 2 to 4; R 1 is a hydrogen or halogen atom or an alkyl radical of 1 to 6 carbon atoms; R is a hydrogen atom, an alkyl radical of 1 to 10 carbon atoms, an alkanoyl radical of 1 to 6 carbon atoms or an -Λ aroyl radical of 7 to 11 carbon atoms; and the acidaddition salts thereof.

2. A guanidine derivative as claimed in claim 1 in . . . i ? winch Y is a sulphur atom, m is 1, n is 2 and R and R are hydrogen atoms.

3. A guanidine derivative as claimed in claim 1 in which Y is a direct bond, m is 2, n is 2 and R 1 · and are hydrogen atoms.