FI68617C - ANALOGIFICATION OF THERAPEUTIC ACTIVITIES FOR THERAPEUTIC ACTIVATION - Google Patents

Description

* 6861 7

An analogous method for the preparation of therapeutically active guanidine compounds

This invention relates to a process for the preparation of therapeutically axially active guanidine compounds by partition separated from application 791116 (patent 61308) -Avdelad frän tress 791116 (patent 61308).

It has long been assumed that several physiologically active substances are associated during their activity with certain characteristic sites in the body called receptors. Histamine is a compound that is thought to act in this way, but since the effects of histamine are more than one species, it is assumed that there is more than one type of histamine receptor. The effect of histamine, a species blocked by drugs commonly referred to as antihistamines (of which mepyramine is a typical example), is thought to comprise a receptor labeled H-1 by Ash and Schild (Brit. J. Pharmac. 1966, 27, 427). The products of the method of this invention are characterized in that they act on histamine receptors other than the H-1 receptor. Thus, they can be used to block certain effects of histamine that are not blocked by the above antihistamines. The products can also be used as inhibitors of certain effects of gastrin.

It is therefore an object of the present invention to provide an analogous process for the preparation of therapeutically active guanidines of the general formula xJ 1 -C - CH 2 S (CH 2) m NHH (I) in which A is a group such that imidazolyl, thiazolyl, isothiazolyl or 2 6861 7 a thiadiazolyl group, X is hydrogen, an alkyl group having 1 to 4 carbon atoms or a halogen atom; m is 2 or 3; is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; and R 2 is a hydrogen atom or a nitro or cyano group, and the invention is characterized in that the compound of general formula X - CH 2 Q (II)

A J

wherein A and X are as defined above and O is hydroxy, halogen or methoxy, is reacted with an aminomercaptan of the general formula HS (CH2) mNH2 (III) wherein m is as defined above and the resulting primary amine is formula X - C - CH 2 S (CH 2) m NH 2 (IV) wherein A, X and m are as defined above is reacted with an isothiol urea of general formula y NR 2 CH 2 SC (V) jossaι wherein R 1 and R 2 are same as above.

When Q is halogen, the reaction can be carried out under strongly basic conditions, e.g. in the presence of sodium methoxide or sodium hydroxide. Since the aminomercaptan is a primary amine, it may be necessary to protect the amino group, e.g. with a phthalimido group, which is subsequently removed by acid hydrolysis or hydrazinolysis. When Q is hydroxy or halogen, the reaction may be carried out under acidic conditions, e.g. in the presence of a halogen acid such as 48% hydrogen bromide or glacial acetic acid. Alternatively, a compound in which Q is methoxy instead of hydroxy may be used and the reaction performed in the presence of 48% hydrobromic acid. The compounds thus obtained may, of course, be in the form of acid addition salts.

The free base of formula (IV) may be prepared from the acid addition salt by treatment with a suitable base, e.g. an alkali metal alkoxide such as sodium methoxide or an inorganic base such as potassium carbonate.

The guanidines prepared by the method of the invention have been found to selectively inhibit the secretion of gastric acid due to histamine irritation in the stomachs of urethane-anesthetized rats. Similarly, the action of these compounds as antibodies to the effects of histamine can in many cases be demonstrated in other tissues which, according to Ash and Schild, cited above, are not H-1 receptors. Examples of such tissues are an overgudt, perfused isolated guinea pig heart, an isolated guinea pig heart right atrium, and an isolated rat uterus. Guanidines have also been found to inhibit the secretion of gastric acid caused by irritation of Penta-gastrin or food. Compounds that inhibit such effects of histamine are called histamine H2 receptor antagonists.

The level of activity achieved with preparations containing guanidine derivatives of formula I is illustrated by the dose range for anesthetized rats, which is between 0.5 and 256 micromoles per kilogram. Many guanidines provide 50% inhibition in this experiment at a dose of 1-10 micromoles per kilogram. Similar results have been obtained in dogs and humans.

6861 7

For therapeutic use, the pharmacologically active compounds of formula I are administered to a patient as a pharmaceutical preparation containing as active ingredient or substantially active ingredient at least one such compound in basic form or in the form of an addition salt with a pharmaceutically acceptable acid and in association with a pharmaceutical carrier.

Table 1 shows the histamine β-antagonist activities of the thiourea derivatives of the invention in terms of ED 2 (effective dose) values determined according to Black et al., Nature 236, (1972) 385-390.

table 1

Example ED 1 value (μmol) kg) 1 65 2 5 3 21 4 2.1 5 22 6 1.37 V 1.9 8 21 9 70 10 2.1 11 8.5 12 2.3 13 1, 9 14 1.6 15 88 16 5.0

The invention is described in more detail below by means of examples in which the temperatures are given in ° C. The preparation of some of the new primary amines used as starting materials is described in patents FI 60393 and 60394.

Example 1

A suspension of cysteamine hydrochloride (118-8 g) in ethanol (200 ml, dried over molecular sieves) was added portionwise at 0 ° C to a solution of sodium ethoxide (prepared from 48 g of sodium) in 1 liter of ethanol under a nitrogen atmosphere. After stirring for a further 2 hours at 0 ° C, a solution of 80 g of 4 (5) -chloromethylimidazole hydrochloride in 400 ml of ethanol was added dropwise over 45 minutes, maintaining the temperature at -1 ° + 2 ° C. After the addition, the mixture was stirred at room temperature overnight, the mixture was filtered, and the filtrate was acidified with concentrated hydrochloric acid. The solution was then evaporated to dryness, the residue was dissolved in 1 liter of ethanol, and an excess of picric acid in hot ethanol was added to the solution. The resulting crude picrate was dissolved in water (2.7 liters), and after decantation from the insoluble oil, the solution was allowed to cool to give 4 (5) - / (2-aminoethyl) thiomethyl] imidazolide picrate, m.p. 194-195 ° C. Treatment of this picrate with hydrobromic acid followed by extraction with toluene afforded the dihydrobromide, m.p. 178-179 ° C, after evaporation to dryness and recrystallization of the crude residue from ethanol.

A solution of 5.8 g of 4 - [(2-aminoethyl) thiomethyl] imidazole and 4.8 g of S-methylisothiouronium sulfate in 50 ml of water was heated under reflux for 3 hours. After the solution was concentrated to a small volume and acidified with dilute sulfuric acid, ethanol was added. The resulting product was recrystallized from aqueous methanol to give 5.2 g of 2 - [(4-imidazolyl) methylthio] ethylguanidine sulfate, mp 211-213 ° C.

Example 2 7.8 g of 4 - [(2-aminoethyl) thiomethyl] imidazole and 5.6 g of N-cyano-N ', S-dimethylisothiol urea dissolved in 500 ml of acetonitrile were refluxed for 24 hours. After concentration by evaporation, the residue was chromatographed on a silica gel column using acetonitrile as eluent, and the resulting product was recrystallized from acetonitrile to give N-cyano-N'-6,68617 methyl-N '' - [2- (4-imidazolylmethylanethyl) ethyl] thio) ethyl . 138-140 ° C.

Example 3 N- (2 - / (4-methyl-5-imidazolyl) methylthio / ethyl) -N'-nitroquanidine______

A solution of 30.0 g of 4-hydroxymethyl-5-methylimidazole hydrochloride and 23.0 g of cysteamine hydrochloride in 200 ml of acetic acid was heated under reflux for 10 hours. After cooling to 15-20 ° C, the crystallized solid was separated and washed with isopropyl alcohol to give 45.5 g of 4-methyl-5 - [(2-aminoethyl) thiomethyl] imidazole dihydrochloride, m.p. 189-192 ° C.

A solution of 30.0 g of 4-hydroxymethyl-5-methylimidazole hydrochloride and 23.0 g of cysteamine hydrochloride in 450 ml of concentrated hydrochloric acid was heated under reflux for 17 hours. Concentration after re-evaporation with water gave a residue which was dissolved in isopropyl alcohol, concentrated to a small volume and cooled to give 40.6 g of 4-methyl-5 - [(2-aminoethyl) thiomethyl] imidazole dihydrochloride melting point. 191 ° C.

A mixture of 15-0 g of 4-hydroxymethyl-5-methylimidazole hydrochloride, 11.5 g of cysteamine hydrochloride and a solution of hydrogen bromide in acetic acid (48%, 225 ml) was heated at reflux for 7 hours. After cooling, 21.6 g of 4-methyl-5 - [(2-aminoethyl) thiomethyl] imidazolide hydrobromide, m.p. 208-211 ° C, were obtained.

A solution of 1.7 g of 5-methyl-4- (2-aminoethylthiomethyl) imidazole and 1.45 g of S-methyl-N-nitroisothiourea in 35 ml of methanol was heated at 50-60 ° C for 2 1/2 hours, after which the solution was allowed to stand at room temperature for 48 hours. The crystalline product was filtered off and recrystallized from methanol to give N- (2- / 5-methyl-4-imidazolyl) methylthio / ethyl) -N'-nitroguanidine, m.p. 184-186 ° C.

Example 4 (i) 10.8 g of N, S-dimethylisothiurea methosulfate (prepared from N-: methylthiothiourea and dimethyl sulfate) were added over 0.5 hours to fuming sulfuric acid (15 ml) and concentrated sulfuric acid (45 ml). to the stirred mixture at -20 ° C. After the addition, the mixture was stirred for 5 minutes and poured onto crushed ice (500 ml) with stirring. After filtration and washing with water, the product was recrystallized from water to give N, S-dimethyl-N'-nitroisothiol urea, m.p. 149.5 to 150 ° C.

(ii) A solution of 1.6 g of N, S-dimethyl-N'-nitroisothiourea in warm methanol (20 ml) was added to a solution of 1.72 g of 5-methyl-4- / T2- aminoethyl) thiomethyl.imidazole in warm methanol (5 mL). The reaction mixture was kept at 60 ° C for 30 minutes and at 50 ° C for 20 hours. After evaporation to dryness, the oil obtained is chromatographed on silica gel using acetone as eluent. The product was crystallized from ether / methyl ethyl ketone to give 1.2 g of N-methyl-N '- [2 - ((5-methyl-4-imidazolyl) methylthio) ethyl] -N''-nitroguanidine, m.p. 112-114 ° C.

Example 5 8.5 g of the primary amine of Example 3 and 5.0 g of the N-cyano-S-methylisothiol urea were reacted according to the procedure of Example 2 by recrystallization from acetonitrile to give N-cyano-N '- / 2- ((5-methyl-4-imidazolyl) methylthio) ethyl / guanidine, m.p. 125-127 ° C.

Example 6 17.0 g of the primary amine of Example 3 and 11.2 g of the N-cyano-8,68617 N'-S-dimethylisothiol urea were reacted by the method of Example 2 by recrystallization from acetonitrile / ether to give the N-cyano N'-methyl-N '/ 2 - ((5-methyl-4-imidazolyl) methylthio) ethyl / guanidine (CIMETIDINE), m.p. 141-142 ° C.

Example 7 8.5 g of the primary amine of Example 3 and 6.2 g of the N-cyano-N'-ethyl-S-methyl-isothiol urea were reacted by the method of Example 2 by recrystallization from isopropyl alcohol / ether to give N-cyano-N ' -ethyl-N '' - [2 - ((5-methyl-4-imidazolyl) methylthio) ethyl] guanidine, m.p. 118-120 ° C.

Example 8 8.5 g of the primary amine of Example 3 and 6.8 g of the N-cyano-N'-propyl-S-methyl-isothiol urea were reacted by the method of Example 2 to recrystallize from an aqueous solution of isopropyl alcohol to give N-cyano-N'- [2 - ((5-methyl-4-imidazolyl) methylthio) ethyl] -N '' - propylguanidine, m.p. 108-110 ° C.

Example 9 (i) A solution of 22.0 g of homocysteamine hydrochloride and 25.6 g of 4-hydroxymethyl-5-methylimidazole hydrochloride in aqueous hydrobromic acid (500 ml) was refluxed under cooling for 1 hour. Concentration under reduced pressure followed by recrystallization from methanol / isopropyl alcohol gave 5-methyl-4 - [(3-aminopropyl) thiomethyl] imidazolidine hydrobromide (24.5 g), m.p. 200.5 to 202.5 ° C.

(ii) By reacting 20.0 g of 5-methyl-4 - [(3-aminopropyl) thiomethyl] imidazole (from dihydrobromide) with N-cyano-N1, S-dimethylisothiol urea according to the method of Example 2 and recrystallizing from isopropyl alcohol / ether gave 0.91 g of N-cyano-N'-methyl-N '' - [3 - ((5-methyl-4-imidazolyl) methylthio) propyl] guanidine, m.p. 156-158 ° C.

Example 10 15.6 g of 5-bromo-4 - [(2-aminoethyl) thiomethyl] imidazole and 5.6 g of N-cyano-N ', S-dimethylisothiol urea were reacted by the method of Example 2 by recrystallization from nitromethane to give N-cyano -N '- [2 - ((5-bromo-4-imidazolyl) methylthio) ethyl] -N' '- methylguanidine, m.p. 144-146 ° C.

Example 11 3.36 g of 2 - [(2-aminoethyl) thiomethyl] thiadiazolidihydrobromide was reacted as the free base by dissolving it in aqueous potassium carbonate solution and extracting with chloroform, and this free base was refluxed for 4 hours with 1.53 g of N, S-dimethyl isothiolytic acid. hemisulphate in water (25 ml). The mixture was concentrated and treated with sodium picrate and the precipitated solid was recrystallized from ethanol to give N-methyl-N '- / 2- (2-thiazolylmethylthio) ethyl / guanidine dipicrate, m.p. 137-138 ° C. The dipicrate is reacted to the dihydrochloride with an ion exchange resin IRA 400 (Cl ~ form).

Example 12 20.2 g of the primary amine (dihydrobromide) of Example 11 and 7.75 g of N-cyano-N ', S-dimethylisothiol urea were reacted by the method of Example 2 by recrystallization from isopropyl alcohol to give N-cyano-N'- n-ethyl-N '' - [2- (2-thiazolyl) methylthio) ethyl] guanidine, m.p. 120 to 122.5 ° C.

Example 13 3.36 g of the primary amine (dihydrobromide) of Example 11 and 1.43 g of N-cyano-N'-ethyl-S-methyl-isothiovea 1 ° 6861 7 were reacted by the method of Example 11, the residue was concentrated from the reaction mixture and recrystallized from isopropyl alcohol / ether to give N-cyano-N'-ethyl-N '' - [2 - ((2-thiazolyl) methylthio) ethyl] guanidine, m.p. 85-87 ° C.

Example 14 4.0 g of 3 - [(2-aminoethyl) -thiomethyl] isothiazole and 3.0 g of N-cyano-N ', S-dimethylisothiol urea were reacted by the method of Example 2 to recrystallize from isopropyl acetate to give N-cyano-N'-methyl-N '' - [2 - ((3-isothiazolyl) methylthio) ethyl] guanidine, m.p. 91-93 ° C.

Example 15 (a) 87 ml of phosphoryl chloride was added dropwise to a vigorously stirred mixture of 100 g of thiosemicarbazide, 100 g of methoxyacetic acid, of which 200 ml of petroleum ether, b.p. 90-100 ° C, 60-70 ° C. After the addition, the temperature was slowly raised to 95 ° C and held here until gas evolution ceased. The solvent was evaporated and the residual syrup was dissolved in 200 ml of water to give a yellow solution, the pH of which was adjusted to 7 by the addition of 10N sodium hydroxide. Filtration of the mixture gave 111 g of 5-amino-2-methoxymethyl- (1,3,4) -thiadiazole, m.p. 177-179 ° C after recrystallization from water.

(b) A dry well-stirred mixture of 34.8 g of the 5-amino compound and 75.9 g of sodium nitrite was added over 1 1/2 hours to a stirred mixture of 270 ml of a 48% aqueous solution of hydrobromic acid and 2 g of cupro bromide at -7 ° C. The mixture was stirred at -6 ° C for 1 hour and at ambient temperature for 1 1/2 hours, then neutralized with 10N sodium hydroxide, treated with sodium metabisulfite, heated at 60 ° C for 20 minutes, re-neutralized with 11,686,77 sodium hydroxide and filtered. The filtrate was extracted with cyclohexane for 13 hours and the cyclohexane extract was dried over calcium sulphate, filtered and evaporated to give 30.4 g of 5-bromo-2-methoxymethyl- (1,3,4) thiadiazole as an oil.

(c) 32.7 g of zinc dust was added to a stirred solution of 51 g of the 5-bromo compound in 200 ml of acetic acid at room temperature. The mixture was gently heated to give a vigorous reaction. The mixture was then refluxed for 1 1/2 hours, filtered and the residue was washed with 200 ml of boiling water. The combined filtrate and washings were neutralized and extracted continuously with ether for 8 hours. The ethereal extract was dried over magnesium sulfate and evaporated to give 17.6 g of 2-methoxymethyl- (1,3,4) thiadiazole, m.p. 30.5 to 32 ° C.

(d) Equimolar amounts of 2-methoxymethyl- (1,3,4) thiadiazole and cysteamine hydrochloride were refluxed under nitrogen for 42 hours with a 48% excess of hydrobromic acid, the mixture was evaporated to dryness and the residue was dissolved in water. The pH of the solution was adjusted to 11 by the addition of IRA 400 (OH) and chromatographed on a CG50 (H +) column eluting with dilute acetic acid. The eluate was evaporated to give 2- / 2- (1,3,4) thiadiazolylmethylthio / ethylamine as an oil, the compound was identified as a picrate which was recrystallised from ethanol, m.p. 110-112 ° C.

(e) 3.0 g of amine and 2.2 g of N-cyano-NS-dimethylisothiourea were reacted according to Example 2 by recrystallization from ethanol / ether to give N-cyano-N'-methyl-N1 ' - [2- (2- (1,3,4) thiadiazolylmethylthio) ethyl] guanidine, m.p. 118-120 ° C.

Example 16 (i) A mixture of 18.0 g of N-bromosuccinimide, 10.0 g of 6861 7 12 4-methyl-1,2,5-thiadiazole, 0.1 g of benzoyl peroxide and 250 ml of carbon tetrachloride was illuminated with a 350 watt electric lamp and boiled at reflux for 5 hours. The mixture was left overnight at ambient temperature, filtered and the filtrate evaporated and fractionally distilled to give 6.4 g of 3-bromomethyl-1,2,5-thiadiazole, b.p. 98-115 ° C (16 mm Hg), which was purified by preparative gas / liquid chromatography.

(ii) To a filtrate containing 0.46 g of sodium in 90 ml of ethanol at 0 ° C was added 1.1 g of nitrogen amine hydrochloride. After stirring for 2 hours, 1.81 g of 3-bromomethyl-1,2,5-thiadiazole was added over 5 minutes and stirring was continued at ambient temperature overnight. By evaporation to dryness and recrystallization of the residue from isopropyl alcohol, 1.0 g of 2- [3- (1,2,5-thiadiazolyl) methylthio / ethylamine dihydrochloride, m.p. 88-90 ° C.

(iii) A mixture of 0.95 g of dihydrochloride, N-cyano-N ', S-dimethylisothiol urea, 0.53 g of potassium carbonate, 50 ml of isopropyl alcohol and 5 ml of water was refluxed for 2 1/2 hours and evaporated then dry. By extraction and recrystallization from ethanol, N-cyano-N'-methyl-N "- [2 - ((1,2,5-thiadiazol-3-yl) methylthio) ethyl] guanidine was prepared, mp 92 ° C.

Claims (1)

An analogous process for the preparation of therapeutically active guanidines of the general formula ^ NR2 X - ^ C - CH2S (CH2) mNHC (I) A_J ^ NHR1 wherein A is a group such that imidazolyl, thiazolyl, an isothiazolyl or thiadiazolyl group, X is hydrogen, an alkyl group having 1 to 4 carbon atoms or a halogen atom, m is 2 or 3, is hydrogen or an alkyl group having 1 to 4 carbon atoms, and R 2 is hydrogen, a nitro or cyano group, characterized in that of the general formula X-C-CH 2 Q (II) in which A and X have the same meaning as above, and Q is hydroxy, halogen or methoxy, is reacted with an aminomercaptan of the general formula HSiCH 2 * mNH 2 (III) in which m is as defined above, and the resulting primary amine of formula X- CH2S (CH2) mNH2 (IV) AJ wherein A, X and m are as defined above is reacted with an isothiol urea of general formula CH s - (V) X NHR ^ where R ^ and R 2 have the same meaning as above.