DE1288591B - Process for the preparation of benzylguanidines - Google Patents

Description

The invention relates to a method of manufacture of benzylguanidines of the general formula

CH, -N = G

, Ν — R ²

_R 4

(I)

IO

in which either Z ^{1 is} in the 2- or 3-position and is a halogen atom, an alkyl or alkoxy group each having 1 to 4 carbon atoms or a nitro group, Z ^{2 is} a hydrogen atom or in the 4-, 5- or 6-position standing substituent denotes a halogen atom, an alkyl or alkoxy group with 1 to 4 carbon atoms or a nitro group and RVR ² , R ³ and K ^{A are} identical or different and each represent a hydrogen atom or an alkyl substituent with ί to 4 carbon atoms or Z ¹ is a hydrogen atom and Z ^{2 is} a hydrogen atom or, as a substituent in the 4-position, is a halogen atom, an alkyl or alkoxy group each having 1 to 4 carbon atoms or a nitro group and R ¹ , R ² , R ³ and R ^{l are} identical or different and each represent a hydrogen atom or an alkyl substituent having 1 to 4 carbon atoms and at least two of the radicals Z ² , R ^1,. R ³ , R ³ "and R ^{1 are} substituents of the type indicated, or their salts with pharmacologically acceptable acids. The process is characterized in that one is carried out in a manner known per se

a) a guanidine derivative of the general formula '

R ⁵ -N = C "

, N-R ⁷

_R ,

35

40

or a salt thereof with a compound of the general formula R ^{10 X known to be suitable for introducing the radical R 10} with cleavage of the radical X, where R ³ , R ″, R ⁷ , R ⁸ , R ″ and R ¹ ″ are each suitably used represents a benzyl group, the radicals R ¹ , R ^a , R ³ and R 'and a hydrogen atom, or

b) an S-substituted one, correspondingly N-substituted one Isothiourea or its salt with ammonia or an amine or a salt thereof or

c) if at least R ¹ and R ^{2 are} hydrogen, an appropriately substituted cyanamide with ammonia or an amine or a salt thereof.

implements and, if necessary, the compounds obtained converted in a manner known per se into salts of pharmacologically usable acids.

The products of the process selectively dampen the sympathetic nerve function and exercise on the parasympathetic or central nervous functions have little or no effect. You are therefore useful in treating hypertension.

The activity of the benzylguanidines of the formula (I) and the acid addition salts thereof is based on Base. The acid used is irrelevant for the salts, but it must be pharmacological and be pharmaceutically acceptable; For example, it can be hydrogen chloride, hydrogen bromide, sulfur, Milk, lemon, wine, amber, oxal, p-toluene sulfone or maleic acid.

Benzylguanidines or their acid addition salts are preferably prepared in which R ^{1 is} hydrogen, R ² and R ^{3 are} identical or different and each is a hydrogen atom or a methyl group and R ^{1 is} a hydrogen atom or a methyl or ethyl group, in particular N - Benzyl - Ν ', Ν "- dimethylguanidine, N - (2 - bromo- and N- (2,4-dichlorobenzyl) -guanidine, N- (2-chlorobenzyl) -N'-methylguanidine, N- (2-bromine -, N- (2-chloro-, N- (2-methyl- and N- (3-methylbenzyl) -N ', N "-dimethylguanidine and N- (2-methylbenzyl) -N'-methyl-N" - ethylguanidine or their acid addition salts.

The acid addition salts according to the invention Benzylguanidines made by either process can be reacted twice during or converted into other salts after the reactions. For example, you can use hydrochloride from hydroiodides by reaction with silver chloride or by heating with methanolic Hydrogen chloride. Are produced,

To demonstrate the excellent effects of the compounds of the method according to the invention • The following tests were carried out:

The compounds to be tested in each case were injected subcutaneously into cats and then considered active, provided-they on the nictitating membrane (that's that third eyelid) without causing pupillary dilation, had a relaxing effect. The relaxation was determined on the basis of the visible part of this membrane along the eyelid gap. Each compound was initially tested at 10 mg / kg. If it turned out to be inactive, another attempt was made with 30 mg / kg and, if so, she was active at 3 mg / kg and sometimes at 1 mg / kg. Those obtained in these experiments Results are shown in the table below. The table contains the results obtained for the in The present invention claimed compounds .wurden achieved, the · indicated dose the The minimum dose is at which the compounds were active.

example -. Dose in mg / kg 1 10 4th 1 6th 10 • 7. 3 8th 10 9 10 ti i0 12th 3 14th 3 15th 1 17th 10 18th 3 19th 22nd 10

The relaxation of the nictitating membrane by the process products occurs without dilation of the pupil or other signs of parasympathetic block, which is otherwise known to all, ganglion-blocking Means appears. The selective relaxation of the nictitating membrane in the conscious one Cat is characteristic of connections that dampen the sympathetic tone and the sympathetic Selectively block the nervous system and are therefore suitable for treating hypertension.

Compared to the [2- (octahydro-l-azocinyl) ethyl] guanidine known as an antihypertensive agent ("Guanethidine") has the l-benzyl-2,3-dimethylguanidine ("Betanidine") which can be prepared according to the invention the following advantages: ■

1. Period of action: Guanethidine does work over a longer period of time when administered orally as betanidin; Depending on the dosage, the duration of action seems to be about 2 to 3 days longer to be. · ■

In contrast, however, the antihypertensive effect is essential when betanidine is administered faster, often already 2 hours after administration. The effect also ends earlier.

Therefore, in the case of severe hypertension, where it matters, the blood pressure is raised as quickly as possible to influence betanidine over guanethidine. Even if only small doses of betanidin are administered, this dose is insufficient administration of a further dose should be possible without further ado. With the delayed onset of action Such a procedure is practically impossible for guanethidine.

Betanidin can also be used, for. B. be used when only a short-term antihypertensive Effect, for example before an operation, is desired. If the drug is then discontinued the blood pressure rises to the original level again within a day, for example, while with guanethidine you have to wait about 2 to 3 days.

2. Compared to betanidine, guanethidine has the disadvantage of considerable side effects. Guanethidine, for example, causes severe diarrhea that is proportional to the dose of guanethidine administered ^! so that a high dose or long-term guanethidine administration is not possible. ^;

The following examples illustrate the invention Procedure. The temperatures are given in degrees Celsius.

example 1

a) 2-bromobenzylamine (12.5 g), S-methylisothjouronium sulfate (10.0 g) and water (20 ml) were placed in a 100 ml Erlenmeyer flask. That Mixture was heated for 1 1/2 hours on a steam bath under a hood, during which time methyl mercaptan escaped (evidenced by foul smell). The reaction mixture was then cooled and with Alcohol (100 ml) diluted. A colorless solid was excreted, collected and washed with alcohol washed. The solid melted at 230 to 232; it was recrystallized in water and then melted at 247 to 248. He had the exact composition of N- (2-bromobenzyl) guanidine sulfate.

b) A mixture of 2-bromobenzylamine (14.0 g), S-methylthiouronium sulfate (10.0 g) and water (30 ml) were heated on the steam bath for about an hour, during which time methyl mercaptan was evolved. A white solid, 'which consisted of 2-bromobenzylguanidine suIfate eliminated; it was collected, washed with alcohol and ether, and recrystallized from water and had a melting point of 244 to 246.

B e i s ρ i e 1 2

N - ethyl - S - methylisothiourea - hydroiodide, melting point 83 to 85 (5.29 g), 2-chlorobenzylamine (3.2 g) and water (3 ml) were refluxed at 100 for 2 hours, whereby Methyl mercaptan was developed. The mixture was evaporated to dryness in vacuo and the remaining UI was made basic in excess with a strong hydroxide solution. The fixed one The precipitated base was extracted with ether and the extracts evaporated. Of the The residue was dissolved in ethanol and a slight excess of succinic acid was added. After adding of ether was N- (2-chlorobenzyl) -N'-äthylguanidin-hydrogen succinate obtained, which once from Water and once crystallized from ethanol to give crystals with a melting point from 152 to 153.

B e i s ρ i e 1 3

A solution of 2,4-dichlorobenzylamine (4.2 g) in ethanol (10 ml) and a solution of NIS-dimethylisothiourea sulfate (5.5 g) in water (10 ml) were mixed and heated to 100 for 3 hours. The product was evaporated to dryness and the remaining resin is converted into the base by adding sodium hydroxide solution. It was extracted with ether. After removing the ether, the oily base was in a light Dissolved excess hydrochloric acid. The hydrochloride solution was evaporated to dryness, and the residue, recrystallized from ethanol-ether, gave N- (2,4-dichlorobenzyl) -N'-methylguanidine hydrochloride; Melting point 177-184.

Examples 4 to

example No. ¹ H H R ¹ R ² R ³ R ⁴ 4th 2-Cl H CIh H CHs H 5 2-HO ₂ H . H- H H H 6th 2-Cl 4-C! H H H H 7th 2-Br H Ή H H-. H 8th CHi ,H H H

salt

Hydroiodide

sulfate

sulfate

sulfate

Hydroiodide solvent
for crystallization

Ethanol — ether.
hot water
Ethanol — water
Ethanol — water
Methanol — water.

Melting point

191 to 196.
237 to 240.
225 to 228 ■
219 to 220
138-brs 14h

1 2B8 591

continuation

example : ■ ζ ¹ - "■ · '■' ■ ■ ζ ² · R ¹ R ² R ³ R ⁴ . salt solvent
* for crystallization : Melting point 9. ' 2-Cl H CH ₃ H H H Hydroiodide Ether — propanol 112 to 115 ' 10 . .2-CH ₃ H .CH ₃ H H H Hydrqiodide Ethanol — ether 157 to 160-; ■ -ii .2-Br H . -CH ₃ H CH ₃ H Hydroiodide Ethanol — ether 178 to 181 " 12 ■ 3-Cl. H CH ₃ • Ή CH ₃ . H Hydroiodide Methanol 216 to 218- 13th 3-Np ₂ H CH ₃ H CH ₃ H Hydroiodide Methanol — ether 227 ° 14th 3-CHa H CH ₃ H CH ₃ H Hydroiodide Methanol-ethanol . 233 to 234 °

-.-.-.-. Example 15 -

A solution of 2-chlorobenzylamine (23 g) in Ether (100 ml) became a solution of methyl isothiocyanate (11.5g) in ether (50 ml) under gentle Stir added. Some heat developed and after 5 minutes N-2r-chlorobenzyl-N'-methylthiourea separated as white crystals with a melting point of 118 to 123. The crystals were collected, dissolved in methanol (60 ml) and treated with methyl iodide (20 ml). After refluxing for half an hour (initially if the mixture warmed up by itself) the mixture was evaporated and that of methanol-ether The residue which crystallized out gave N-2-chlorobenzyl-N \ N-dimethylisothiourea-hydroiodide; Melting point 173-176. Part of this hydroiodide (31g) was added with stirring to excess sodium carbonate (30g) in water (75ml) in the base converted and extracted into ether at the same time. The essential extract was dried and evaporated and gave a colorless syrup, which in dilute sulfuric acid to a solution of approximately 5, OpH was resolved again. This solution was made up to a volume of approximately 50 ml concentrated by evaporation in vacuo, with 35 ° / (iigem aqueous methylamine (100 ml) and sufficient Treated methanol to form a homogeneous solution, which is then 6 hours under light Reflux conditions were maintained. This solution was evaporated to dryness and the white solid Residue, recrystallized from methanol-acetone, gave N- (2-chlorobenzyl) -N "~ dimethylguanidine sulfate; Melting point 276-278.

Example 16

2-Bromobenzyl isothiocyanate (9g) was added to a mixture of 0.880 ammonia solution (100 ml) and ethanol (35 ml) and the solution was heated on the steam bath for ^{1 hour.} The excess of ammonia was removed to dryness by evaporation in vacuo. The residue, crystallized from aqueous ethanol, gave 2-bromobenzylthiourea; Melting point 127 to 128. A portion of this 2-bromobenzylthiourea (5.05 g) was suspended in ethanol (5 ml) and methyl iodide (4.26 g) and the mixture refluxed for 20 minutes. The resulting solution was concentrated slightly to remove excess methyl iodide. After the addition of ether, N - (2 - bromobenzyl) - S - methylisothiourea hydroiodide with a melting point of 126 to 127.5 crystallized out; A portion of this material (3.5 g) was dissolved in aqueous ethanol (5 NC ⁽⁾ / o, 5 ml) with a Lqsung of dimethyl; -amine (5O ° / o in methanol, 0.9 ml) '2 ^ai _A Held under reflux conditions for hours. After standing at room temperature overnight, a

V _{5 a} further amount of 50% strength methanolic dimethylamine (0.5 ml) was added and the mixture was refluxed for 2½ hours. The mixture was evaporated to dryness in vacuo, and the residue, crystallized from n-propanol-ether, gave N- (2-bromobenzyl) -N ', N'-dimethylguanidine hydroiodide; Melting point 162 to 163.5 ".

Example 17

N- (2-chlorobenzyl) -N ', S-dimethylisothiourea hydroiodide (Example 15) (3.6 g) in ethanol (10 ml) dissolved, was treated with 33% aqueous ethylamine (5 ml) and the mixture under for 6 hours Held at reflux. After evaporation in vacuo, a resin was obtained which was composed of acetone-ether N- (2-chlorobenzyl) -N'-ethyl-N "-methylguanidine hydroiodide crystallizes out revealed; Melting point 102-105.

Example 18

To a solution of 2-methylbenzylamine (12 g) in ether (100 ml) a solution of methyl isothiocyanate (7.3 g) in ether was added. After about 15 minutes, N-methyl-N '- (2-methylbenzyl) thiourea separated as a crystalline solid. It melted at 130 to 135.

This thiourea (12 g) in methanol (100 ml) was treated with methyl iodide (7.2 ml) which Mixture refluxed for 1 hour and: then cooled. After adding ether, a white crystalline precipitate which melted at 121 to 123 and consists of N, S-dimethyl-N'-2-methylbenzylisothiourea-hydroiodide duration.

A solution of this hydroiodide (7.9 g) in warm water (30 ml) was mixed with 28% aqueous methylamine (6 ml) and methanol. (30 ml) treated and gave a clear solution. The mixture was refluxed gently for 12 hours held, evaporated to dryness in vacuo. The residue, crystallized from methanol-ether, gave N, N'-dimethyl-N "- (2-methylbenzyl) -guanidine-hydroiodide, which melted at 187-189.

Example 19

NS - dimethyl - N '- (2 - methylbenzyl) - isothiourea hydroiodide (Example 18) (8 g), dissolved in warm water (40 ml), was ^{treated with 35 n} / o aqueous ethylamine (5 ml) and sufficient ethanol and a clear solution (approximately 30 ml).

The mixture was taken for about 12 hours Held reflux, evaporated in vacuo and gave a syrup, which recrystallized from methanol ether

■ lisierl. 'N - Ethyl -K': - methyli- N "- (2 - methylbenzyl) -

guanidine hydroiodide, which melted at 142 to 146 °.

B e i s ρ i e 1 20

2-bromobenzyl isothiocyanate (9.2 g) was added to a solution of ethylamine in water (6.8 ml of 33% W / v) and the mixture heated on the steam bath for 5 minutes. Ethanol (10 ml) was added added to dissolve the oil. The mixture was refluxed for 30 minutes and then im Vacuum evaporated until an oil was excreted. The mixture was cooled and inoculated to give N - (2 - bromobenzyl) - N '- ethyl thiourea; Melting point 110.5 to 111.5 °. Part of that stuff (10.95 g) was suspended in ethanol (20 ml) and methyl iodide (7.1 g) was added. The mixture warmed and was refluxed for 15 minutes. Another amount of methyl iodide (2.3 g) was added and the mixture was heated for 5 minutes. The excess of methyl iodide was distilled off. After cooling and adding ether, N- (2-bromobenzyl) -N'-ethyl-S-methylisothiourea-hydroiodide was obtained; Melting point 145 to 146 °. A portion of this material (2.0 g) was with Ethanol (10 ml) and aqueous methylamine (7.5 ml, 40%) refluxed for 4½ hours. Methyl mercaptan was developed. The solution was evaporated to dryness in vacuo, and the residue, crystallized from n-propanol and ether, yielded N - (2 - bromobenzyl) - N '- ethyl - N "- methylguanidine hydroiodide; Melting point 137.5 to 138.5 °.

Example 21

2-chlorobenzyl isothiocyanate (6.62 g) became a Solution of aqueous methylamine (10 ml, 35%) and ethanol (10 ml) were added. It developed Heat, and when the reaction subsided, the mixture was heated on the steam bath for 5 minutes. It was then concentrated in vacuo until crystallization occurred, when the mixture was cooled and the solid filtered off and washed with aqueous ethanol. The N- (2-chlorobenzyl) -N'-methylthiourea thus obtained melted at 118 to 12Γ. Part of this material (7.55 g) became too N - (2 - chlorobenzyl) - N ', S - dimethylisothiourea hydroiodide (as described in Example 20) converted, some of it (3.56 g) was refluxed with a solution of dimethylamine in methanol (10 ml, 50%) for 8 hours. Methyl mercaptan was developed. The solution was evaporated to dryness in vacuo, the residue with Made sodium hydroxide solution basic and the oil obtained extracted with benzene and ether. to an excess of succinic acid in ethanol was added to this extract, with slow Crystallization occurred. Several crystallizations from n-propanol and ether resulted in pure N- (2-chlorobenzyl) - Ν ', Ν "- trimethylguanidine - hydrogen succinate with a melting point of 112 to 114 °.

Example 22

N-Benzyl-N'-ethylthiourea (21.6 g) was added to Ethanol (10 ml) suspended and methyl iodide (25 ml) added, the heat evolving a caused slight reflux. After standing at room temperature for 25 minutes, the solution became concentrated in vacuo, and N-benzyl-N'-ethyl-S-methylisothiourea-hydroiodide crystallized; Melting point 123 to 124 °. The free base was made from part of this material and converted to the hydrogen oxalate; Melting point 97 to 99 °. Some of this salt (2.98 g) was treated with a solution of methylamine in methanol (25 ml, 40% w / v) and water (15 ml) for 5 hours held under reflux. The solution was evaporated to dryness in vacuo and the residue dissolved in dilute hydrochloric acid, with

ίο ether washed to small amounts non-basic To remove impurities. The acid solution was made basic with sodium hydroxide solution and the oil obtained is extracted with ether. The ether extracts were evaporated to dryness and a Solution of oxalic acid in n-propanol and then ether added. N-benzyl-N'-ethyl-N " - methylguanidine - hydrogen oxalate crystallized out; Melting point 162 to 163 °.

Example 23

Benzyl isothiocyanate (14.9 g) was slowly added to a solution of n-propylamine (15 ml) in n-propanol (20 ml) with cooling in water to moderate the exothermic reaction. The resulting solution, after standing for 20 minutes at room temperature, was evaporated to dryness in vacuo and the residue, crystallized from benzene-light petroleum (boiling point 60 to 80 °), gave N-benzyl-N'-η-propylthiourea; Melting point 93 to 94 °. A portion of this material (16.5 g) was added to methyl iodide (20 ml), which caused solution to occur with gentle warming. After standing for hours at room temperature, the solution was evaporated to dryness in vacuo and the residue was slowly crystallized out in ether while standing. Crude N - benzyl - S - methyl - N '- η - propylisothiourea hydroiodide, melting point 71 to 76 °, was obtained. A portion of this hydroiodide (3.5 g) was maintained without further purification with a solution of methylamine in methanol (20 ml, 40%) 5 ¹ ^ hours under reflux. The resulting solution was evaporated to dryness in vacuo; the residue was dissolved in dilute hydrochloric acid, the solution washed with ether and then made basic with sodium hydroxide solution and the oil extracted with ether. The extracts were evaporated to dryness in vacuo and a solution of oxalic acid in n-propanol, then ethyl acetate and ether were added. N-Benzyl-N'-methyl-N "-n-propylguanidine hydrogenoxatate crystallized out; melting point 158 to 159.5 °.

Claims (1)

Claim: Process for the preparation of benzylguanidines of the general formula 60 V: in which either Z ^{1 is} in the 2- or 3-position and a halogen atom, an alkyl or alkoxy group with in each case \ to 4 carbon atoms or a nitro group, Z ^{2 is} a hydrogen 909 506/1541 atom or as a substituent in the 4-, 5th or 6-position is a halogen atom, an alkyl or alkoxy group each having 1 to 4 carbon atoms, or a nitro group and R ¹ , R ² , R ³ and R ^{4 are the} same or are different and each represent a hydrogen atom or an alkyl substituent having 1 to 4 carbon atoms or Z ^{1 is} a hydrogen atom and Z ^{2 is} a hydrogen atom or as a sub in the 4-position? substituent is a halogen atom, an alkyl or alkoxy group each having 1 to 4 carbon atoms 10. ίο or denotes a nitro group and R ¹ , R ² , R ³ and R ^{4 are} identical or different and each represent a hydrogen atom or an alkyl substituent having 1 to 4 carbon atoms and at least two of the radicals Z ² , R ¹ , R ² , R ³ - and R ^{4 are} substituents of the type indicated, or their salts with pharmacologically usable acids, characterized in that one is carried out in a manner known per se a) a guanidine derivative of the general formula or a salt thereof with a compound of the general formula R ^{10 X known to be suitable for introducing the radical R 10} with cleavage of the radical X, where R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ^{10 are} each suitably used represents a benzyl group, the radicals R ¹ , R ² , R ³ and R ⁴ and a hydrogen atom, or b) an S-substituted one, correspondingly N-substituted one Isothiourea or its salt with ammonia, or an amine or a salt thereof, or if at least R ¹ and R ^{2 are} hydrogen, an appropriately substituted cyanamide with ammonia or an amine or a salt thereof converts and optionally the compounds obtained in a manner known per se into salts pharmacologically usable acids transferred.