IL31452A - 1-amino-3-hydroxy-guanidine derivatives,their preparation and pharmaceutical compositions containing them - Google Patents

Description

Hunt* D» *:3»n mnpn 'T am l-A IH0-3-HYDROXY~GUANIDIie DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM SANDOZ A.G 64 Case 6O-6193 7/YO/HD IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS This invention relates to benzylideneamino guanidine derivatives.

The present invention provides compounds of formula I, in which ^ and R^ , which may be the same or different, each represents a hydrogen, chlorine or fluorine atom, with the proviso that the benzene ring is at least monosubstituted. processes' The invention also provides/a-me^kod- for the preparation compounds of formula I, characterised by reacting a substituted benzaldehyde of formula II, in which R^ and ^ are as defined above, with l-amino-5-hydroxyguanidine in the presence of a solvent which is inert under the reaction conditions, or b) reacting a substituted benzaldehyde S-alkylisothio-semicarbazone of formula III, - 2 - 60-6193 in which R^ and are as defined above, and R, represents an alkyl radical of 1 to k carbon atoms, with hydroxylamine in the presence of a solvent for both reactants which is inert under the reaction conditions.

In process a) the l-amino-3-hydroxyguanidine may if desired be used in the form of an acid addition salt. Suitable solvents include alkanols of 1 to k carbon atoms, e.g. methanol, ethanol or isopropanol. The reaction is suitably conducted at a temperature of from about 20° to 70°C, preferably 25° to V?°C.

In process b) the hydroxylamine is preferably used in the form of an acid addition salt, e.g. the hydrochloride. Suitable solvents include water in admixture with an alcohol of 1 to h carbon atoms, e.g. methanol or ethanol, and tetrahydrofuran-water mixtures. The reaction is suitably carried out at a temperature from about 10°C to the reflux temperature, preferably at about 20°C to ^0°C .

The particular solvent and temperature used are not critical in obtaining compounds of formula I.

The resulting compounds of formula I may be recovered and purified by conventional techniques, e.g. recrystallisation and filtration. -.5. - 60-6193 When the l-amino-3-hydroxyguanidine, or the hydroxylamine, is utilised in the form of an acid addition salt, the compound of formula I is obtained in the form of the corresponding salt. The free base form may be obtained therefrom by conventional techniques. Similarly, an acid addition salt form of the compound of formula I may be obtained by salifying a free base form.

Certain aldehydes of formula II used as starting materials in process a) are known and may be prepared by methods disclosed in the literature. Those which have not been specifically disclosed may be prepared by analogous methods from known materials. l-amino-3-hydroxyguanidine i-O" new~acHii- - - f»d- ;fe&-pr p- may be prepared by reacting an isothiosemicarbazide of formula IV, in which signifies an alkyl radical of 1 to k carbon atoms or a benzyl radical, in the form of an acid addition salt with hydroxylamine, in the form of an acid addition salt, in the presence of a base and a solvent which is inert under the reaction conditions.

As the isothiosemicarbazide of formula IV, there is preferably used S-methyl-isothiosemicarbazide. Suitable acid addition salts - k 60-6193 for use in the process include strong mineral acid salts, e.g. hydrochlorides and hydriodides, and alkyl sulphates, e.g. methyl sulphates. Suitable bases include the alkali metal and alkaline earth metal hydroxides, e.g. sodium and potassium hydroxide. For good yields there is preferably employed about 1 molar equivalent of the base. The reaction is. suitably conducted at a temperature of about 20-60°C, preferably 25-35°C. The solvent is desirably aqueous, e.g. water alone or water in admixture with an alkanol such as ethanol or isopropanol.

The resulting l-amino- .-hydroxyguanidine may be isolated and purified by conventional techniques. The free base and acid addition salt forms may be obtained from each other by conventional techniques.

Certain of the compounds of formula TV are known compounds and may be prepared by methods disclosed in the literature. Those not specifically disclosed may be prepared by analogous methods from known materials.

The S-alkylisothiosemicarbazones of formula III, used as starting materials in process b) , may be obtained by. treating a substituted benzaldehydethiosemicarbazone of formula V, in which R and R are as defined above, - ς - 60-6193 with an alkyl halide containing 1 to carbon atoms in the presence of a solvent which is an excess of alkyl halide or which is inert under the reaction conditions.

The alkyl halide is preferably a bromide or iodide, e.g. methyl iodide or bromide, or ethyl iodide. Suitable solvents include methylene chloride, tetrahydrofuran, benzene, alcohols, e.g. alkanols such as methanol, ethanol and isopropanol, and mixtures of such solvents. The reaction is suitably carried out at from about room temperature (approximately 20°C) to the reflux temperature, preferably 50° to 80°C. However, neither the particular solvent nor reaction temperature is critical.

The resulting compound of formula III may be recovered and isolated, in the form of an acid addition salt corresponding to the alkyl halide used, by conventional techniques. The free base form may be obtained in conventional manner, e.g. by treatment with sodium carbonate in a solvent for the carbonate and salt, e.g. water or a water-alkanol mixture, at a temperature of from about 0° to about 50°CJ conveniently at room temperature. The particular temperature and solvent are not, however, critical.

Some of the compounds of formula V are known and may be prepared by methods disclosed in the literature. Those not specifically disclosed may be prepared by treating an appropriate substituted benzaldehyde with thiosemicarbazide in solvent such as ethanol at reflux temperature.

The compounds of formula III may also be obtained by treating an aldehyde of formula II in a solvent which is inert under - 6 - 60-6195 the reaction conditions with a compound of formula VI, in which represents an alkyl radical of 1 to k carbon atoms, the compound of formula VI being in the form of an acid addition salt , e.g. a hydrohalide, a sulphate or a nitrate. The reaction may be carried out at a temperature of from 20° - 100°C, preferably at a temperature of from 50° - 70°C. Suitable solvents include alcohols, for example a lower alkanol, e.g. methanol, ethanol or isopropanol.

The compounds of formula I may also be represented by their tautomeric equivalents indicated in formula It' and It", in which and F?2 are as defined above.

While herein reference is made only to compounds of formula I, such equivalents are within the scope of the invention. - 7 - 60-6193 The compounds of formula I have pharmacological activity. In particular they have hypotensive activity as indicated by their effect v/hen administered to anesthetized dogs and the blood pressure . is measured using a mercury manometer or transducer via a catheter inserted in the carotid or femoral artery, and are indicated for use as hypotensives. Λ suitable indicated daily dosage is from about θνΐ- loo milligrams to about milligrams, preferably given in divided 1.5 150 dosages of from about θτθ¾- milligrams to about ·£■©- milligrams 2 to / times a day or in sustained release form.

The compounds may be used mixed with a pharmaceutically acceptable carrier and such conventional other adjuvants as may be desired and administered orally in such forms as tablets, capsules, elixirs, suspensions or solutions, or parenterally in such forms as injectable solutions, suspensions or emulsions. The compounds may be administered in the form of their pharmaceutically acceptable acid addition salts, which possess the same order of activity as the free . bases. Suitable pharmaceutically acceptable acid addition salts, which may be prepared in conventional manner, include mineral acid salts, such as the hydrochloride, hydrobromide, sulfate and phosphate, and organic acid, salts, such as the succinate, benzoate, acetate, p-toluenesulfonate and benzene-sulfonate.

A representative formulation suitable for oral administration is a tablet., prepared by standard tabletting techniques, which contains the following: - 8 - 60-6193 Ingredient Parts by Weight Compound of formula I, e.g. l-(2, 6-dichlorobenzylideneamino)- 10 3-hydroxyguanidine hydrochloride tragacanth lactose 79-5 corn starch 5 talcum magnesium stearate 0.5 Preferred compounds of formula I are those which are substituted in the 2 and 6 positions of the benzene ring, especially l-(2,6-dichlorobenzylidene-amino)-j5-hydroxyguanidine .

The compounds of formula I also have antifungal and herbicidal activity.

The following'Examples further illustrate the invention. - 9 - 60-6193 EXAMPLE 1; l-(2,6-dichlorobenzylideneamino)-3-hydroxyguanidlne hydrochloride 22i sodium hydroxide solution (5 ml) is added to a stirred suspension of S-methy'lisothiosemicarbazide hydriodide (2.33-g) and hydroxylamine hydrochloride (0.70 g) in water (6 ml) and stirred for k hours. The solution is evaporated in vacuo to provide l-amino-3- hydroxyguanidine . One third of the residue is dissolved. n 16 ml of ethanol and 2,6-dichlorobenzaldehyde (0.6 g) is added to this solution. T e reaction mixture is then stirred for hours. The solution is then evaporated i vacuo and the residue dissolved in ether (30 ml) and in hydrochloric acid (30 ml). The aqueous phase is rendered al'caline with 2N sodium carbonate solution and extracted with ether. The ether layer is dried with sodium sulfate and evaporated. The residue is dissolved in ether and excess dry hydrogen chloride is passed into the solution. The resultant mixture is evaporated in vacuo and the residue triturated with methylene chloride to afford a crude product. Eecrystallization from ethanol-ether (1:3) provides l-(2, 6-dichloro-benzylideneaaino)-3-hydroxyguanidine hydrochloride; m.p. 173°-175°C.

When the above process is carried t and S-benzylisothiosemicarbazide hydriodide- is used in place of S-methylisothiosemicarbazide hydriodide,: the identical product is again obtained. | EXAMPLE 2; I- (2,6-dichlorobenzylideneamino) -3-hydroxyguanidine hydrochloride (Alternate Procedure) A mixture of 2,6-dichlorobenzaldehyde (37.5 g)> thiose i-carbazide (^5. g) a ethanol (hOO ml) is heated under reflux with stirring for 2 hours. The reaction mixture is cooled and crystalline 2,6-dichlorobenzaldehyde thiosemicarba oae is collected by filtration; : - 10- 60-6193 · A mixture of 2,6-dichlorobenzaldehyde thiosemicarbazone (II8.5 g), methyliodide (70 g) and ethanol (500 ml) is heated under* · reflux vith stirring for 3 hours. The reaction mixture is cooled and the product collected "by filtration to afford 2,6-dichlorobenzaldehyde methyiisothiose icarbazone hydriodide; m. .. 09°-211° dec.

Alternate procedure for 2,6-dichlorobenzaldehyde methyliso-thiosemicarbazone hydriodide: A mixture of 2,6-dichlorobenzaldehyde ( .O ε) and S-methylisothiosemicarbazide hydriodide I.6 g) in ethanol (50 ml) is refluxed for 3 hours. After cooling to room temperature 2,6-dichlorobenzaldehyde methylisothiosemicarbazone hydriodide is collected by filtration; m.p. 209° - 211°C.

A siixture of 2,6-dichlorobenzaldchyde methylisothiosemi- carbazone hydriodide " (21k g) and 2N sodium carbonate solution (1000 ml) is stirred for 1 hour. The resultant solid is collected by filtration and washed vith 800 ml/vater to provide 2,6-dichlorobenzaldehyde nethylisothioseaicarbazone; m.p, 77-79°· ' Solid 2,6-dichlorobenzaldehyde methylisothiosenicarbazone (119 g) is added to a solution of hydroxylaaine hydrochloride (62.8 g) in vater (150 ml) and ethanol (lOOO ml) and stirred for 18 hours.

The clear solution is evaporated in vacuo and the residue taken up of of in a nixture of 1500 ml/vater, 200 ml/2i.T hydrochloric acid and 1500 ml of ether. The aqueous phase is separated and made basic vith 200 ml of concentrated ammonium hydroxide. After stirring for 1/2 hour , the resultant solid is collected by filtration, vashed vith vater, and dried to afford the free base, vhich is suspended in methanol (800 ml) · and treated vith hydrogen chloride gas to form the salt. The resultant solution is evaporated in vacuo and the residue crystallized from 12 - 31452/2

Claims (20)

1. · l-Amino-3-hydroxyguanidine compounds of the formula in which TH^ and R2> which ma be the same or different, are each a hydrogen, chlorine or fluorine atom, with the proviso that the benzene ring is at least monosubstituted.

2. Compounds of formula I in Claim 1, in which R1 and 2, which may be the same or different, represent each a chlorine of fluorine atom.

3. Compounds according to Claim 2, in which the sub-stituents ^ and 2 are in the 2 and 6 positions of the benzene ring..

4. l-( 2,6-dichlorobenzylideneamino)-3-hydroxyguanidine.

5. 1-(2-chlorobenzylideneamino)-3-hydroxyguanidine .

6. · l-(2,4-dichlorobenzylideneamino)-3-hydroxyguanidine.

7. · Compounds according to any of Claims 1 to 6 in the form of an acid addition salt thereof.

8. A process for the preparation of compounds of formula I in Claim 1 which comprises reacting a substituted benzaldehyde of the formula - 13 - 31452/2 In which R^ and ≥ have the same meaning as in Claim 1, with l-amino-3-hydroxyguanidine in the presence of a solvent which is inert under the reaction conditions.

9. A process according to Claim 8, wherein the solvent is an alkanol of 1 to 4 carbon atoms.

10. A process according to Claim 9, wherein the solvent is methanol, ethanol or isopropanol.

11. A process according to any of Claims 8, 9 or 10, wherein the reaction is carried out at a temperature of from 20° to 70°C.

12. A process according to Claim 11, wherein the reaction is carried out at a temperature of from 25° to 45°C

13. A process for the preparation of compounds of formula I in Claim 1 which comprises reacting a substituted benzaldehyde S-alkylisothio-semicarbazone of the formula · in which R-^ and R2 have the same meaning as in Claim 1 and R-j represents an alkyl radical of 1 to 4 carbon atoms, with hydroxylamine in the presence of a solvent for,both reactants which is inert under the reaction conditions.

14. A process according to Claim 13, wherein the solvent is water in admixture with either an alcohol of from 1 to 4 carbon atoms or tetrahydrofuran. - 14 - 31452/2

15. A process according to Claim 14, wherein the alcohol is methanol or ethanol.

16. A process according to any of Claims 13» 14 or 15 wherein the reaction is carried out at a temperature from about 10°C to the reflux temperature of the reaction mixture.

17. A process according to Claim 16, wherein the reaction is carried out at a temperature of fz-om 20° to 50°C.

18. Processes for the production of compounds of formula I in Claim 1 substantially as hereinbefore described with reference to the Examples.

19. Pharmaceutical compositions comprising a compound of formula I in Claim 1 in the form of the free base or a pharmaceutically acceptable acid addition salt, in association with a pharmaceutically acceptable carrier or diluent.

20. Pharmaceutical compositions according to Claim 19 substantially as hereinbefore described. PC/rb