NO139561B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE COMPOUNDS - Google Patents

Description

This invention relates to an improvement or modification

of the invention described in Norwegian patent 133,500 and concerns the production of new imidazolium salts with neuromuscular, blocking activity.

New compounds are described in the aforementioned patent 133,500

with the general formula I:

where R 1 and R 2 , which may be the same or different, mean hydrogen,

lower alkyl, halogen, phenyl, halogen-, hydroxy-, lower alkoxy-, trifluoromethyl- or nitro-substituted phenyl,

R 3 and R 4 together with the carbon and nitrogen atoms to which they are attached

to, forms pyridinium or tetrahydropyridinium, and X is a physiologically acceptable anion such as bromide, chloride,

acetate, phosphate, perchlorate or picrate.

We have now produced new connections that fall into place

under the class described in our above-mentioned patent, and these compounds have been found to have particularly valuable properties when neuromuscular blockade of very short duration is desired.

The paralytic activity in mice and the neuromuscular blocking activity in an anesthetized cat and an anesthetized monkey, measured on the tibialis anterior muscle, are e.g. for 1,1'-azobis[3-methyl-2-phenylbenzimidazolium] dibromide (AH 10407) according to example 1

shown in Table 1.

The compounds produced according to the invention have a short-term, curare-like neuromuscular blocking effect. The desirability of a short-acting muscle relaxant is well known. For long operations, a sufficient degree of relaxation can be achieved by continuous intravenous instillation, whereby the anesthetist gains better control over the relaxation and whereby one also

has a rapid return to spontaneous movement when the infusion is stopped. The short-acting muscle relaxants currently in use are of the depolarizing type and are fraught with several disadvantages. Post-operative pain represents one of the main disadvantages of using succinylcholine. The appearance of such pain is associated with depolarization and may be a consequence of the muscle fasciculations that occur at the beginning. Other disadvantages are the lack of a suitable antagonist and the possibility of prolonged apnea.

According to the invention, compounds with the general formula II are prepared:

where R 3 denotes phenyl which is optionally substituted with lower alkyl or lower alkoxy,

R 4 means an alkyl group containing from 1 to 4 carbon atoms, and

X means a physiologically acceptable anion.

A particularly preferred group of compounds are those where R 3 denotes a phenyl group, a 4-alkyl-phenyl group, or a 4-alkyl-phenyl group where the alkoxy and alkyl groups contain from 1 to 3 carbon atoms.

Examples of physiologically acceptable anions include

bromide, chloride, acetate, phosphate, nitrate, aryl or aralkyl sulphonate, e.g. benzenesulfonate or p-toluenesulfonate (tosylate) and alkylsulfonate, e.g. methanesulfonate..

Particular preferred compounds are those described

in the examples.

The new compounds can be prepared by the method generally described in the aforementioned patent 133,500. Suitable oxidising agents include e.g. bromine or chlorine. The reaction is preferably carried out in water and at an elevated temperature, preferably approx. 60°C.

In principle, an N-amino compound is thus submitted

with the below formula III oxidation to bind together two molecules thereof and thus form a tetrazine.

A method for the preparation of pharmacologically active compounds with the above general formula II is characterized by the fact that a compound of formula III:

where R 3 , R 4 and X - have the meanings given above, is subjected to oxidation to bind together 2 molecules of the compound of formula III to thus form a tetrazine, and optionally the anion X is converted into another anion X with the meaning given above . A compound of formula II where X is a bromide ion can be converted into a compound where X is a pharmaceutically acceptable anion other than bromide.

When oxidized with bromine, the first product is a perbromide where two bromine molecules are loosely linked to each molecule of the compound with formula II, X=Br. This bromine can conveniently be removed by treating the perbromide with a ketone, e.g. acetone or cyclohexanone, whereby compounds of formula II are obtained where X = Br~.

When X = Br, the new compounds can be converted into the chlorides, X = Cl, by treatment with an excess of concentrated hydrochloric acid. Such chlorides are then isolated by adding acetone to the resulting solution and collecting the solid. The bromides, X = Br, can also be converted into other salts by treatment with the silver salt of the corresponding acid in a suitable solvent, for example acetonitrile. Thus, for example, the nitrate, X = NO^ , the benzene sulphonate, X CgHj-SO^ , and the tosylate,

X = CH3-CgH4SO3 , is prepared from the bromide, X = Br , and respectively silver nitrate, silver benzene sulphonate and silver p-toluene sulphonate. A particularly suitable reaction consists in using silver methane sulphonate for the preparation of compounds of formula II where X = CH^SO^-/ which have special advantages due to their high solubility in water.

The benzimidazolium salts of formula III, i.e. the amines used as starting materials, can be prepared by known methods, which include but are not limited to the reactions shown schematically below:

The hydrazide V is prepared from o-nitrophenylhydrazine and an acylating agent R 3COY, which can be an ester, an acyl halide or an acid anhydride. The reaction component R 3 COY can conveniently be an acid chloride (Y = Cl) where R 3 has the meanings indicated above, and the reaction can be carried out, for example, in pyridine, possibly at an elevated temperature.

The nitrohydrazide V can be reduced to the aminohydrazide VI with hydrogen in the presence of a catalyst, for example palladium on charcoal, at temperatures of 20-40°C and at pressures of 1 to 4 atmospheres. Aminobenzimidazoles of formula VII are obtained from the aminohydrazides VI by heating in aqueous solution with a strong acid, for example m-nitrobenzenesulfonic acid. They are known compounds or can be obtained by standard methods such as described by Abramovich and Schofield (J. Chem. Soc, 1955, 2326)

and as shown in the above diagram.

1-Aminobenzimidazolium salts of formula III can be obtained from the 1-aminobenzimidazoles VII by usual quaternization methods, for example by heating with an alkyl halide R 4X, optionally in a solvent, for example an alcohol R 4OH. Quaternary iodides with formula III X = I , can be converted to the bromides III,

X = Br , using a bromide ion exchange resin such as "Amberlite IRA40" (Br ) or by heating with hydrobromic acid.

The new compounds are used together with a pharmaceutically acceptable carrier in pharmaceutical preparations. Preparations for parenteral use are particularly preferred. These can be in the form of sterile, aqueous solutions for injection or sterile, solid substances to be dissolved in sterile water before use.

A suitable injectable single dose ranges from 2 to 100 mg, but continuous infusion or repeated injections may be necessary for long periods of operation.

The following examples illustrate the invention:

Example 1

(1) 1, 1'- azobis[ 3- methyl- 2- phenylbenzimidazolium J dibromide (a) 1- amino- 3- methyl- 2- phenylbenzimidazolium iodide

1-amino-2-phenylbenzimidazole (Abramovich and Schofield,

J. Chem. Soc, 1955, 2326) (0.2 g) in methyl iodide (10 ml) and methanol (5 ml) was heated under reflux for 24 h. The solution was evaporated, and the residue was crystallized from a mixture of ethanol and ether to give colorless prisms of melting

point 209°C.

(b) 1-amino-3-methyl-2-phenylben2imidazolium bromide.

The iodide in water was treated with "Amberlite IRA/400"

(Br) ion exchange resin. The aqueous solution was evaporated and the residue was crystallized from a mixture of ethanol and ether to give colorless prisms of melting point 255°C. (c) 1,1'-azobis[3-methyl-2-phenylbenzimidazolium] dibromide.

1-amino-3-methyl-2-phenylbenzimidazolium bromide (0.3 g)

in the smallest amount of water necessary to give complete dissolution at 60°C, was treated with saturated aqueous bromine (30 ml) which was also heated to 60°C. The red solid was filtered off and heated in anhydrous acetone (30 mL) for 5 minutes. The solution was cooled and the yellow solid was collected and crystallized from a mixture of hydrobromic acid (48%) and acetone. The desired product 1,1'-azobis[3-methyl-2-phenylbenzimidazolium] dibromide was obtained as a yellow solid with a melting point of 218°C.

From this dibromide a number of other salts were prepared as described below. (1) 1,1'-azobis[3-methyl-2-phenylbenzimidazolium] dichloride.

1,1'-azobis[3-methyl-2-phenylbenzimidazolium] dibromide

was dissolved in the minimum amount of concentrated hydrochloric acid. Acetone was added and the solid was crystallized from a mixture of concentrated hydrochloric acid and acetone to give the dichloride, mp 131-132°C. (2) 1, 1'-azobis[3-methyl-2-phenylbenzimidazolium] dipicrate.

1,1'-azobis[3-methyl-2-phenylbenzimidazolium] dibromide

in ethanol was treated with picric acid (2 equiv.) in ethanol, and the solid was collected and crystallized from a mixture of nitromethane and ether. The product had a melting point of 2 37-239°C. (3) 1, 1'-azobis[3-methyl-2-phenylbenzimidazolium] dimethanesulfoant.

1,1'-azobis[3-methyl-2-phenylbenzimidazolium] dibromide

(13 g) in methanol (50 ml) was added dropwise to a stirred solution of silver methanesulfonate (8.2 g) in acetonitrile (50 ml). The silver bromide was filtered off, the filtrate was evaporated, and the residue was crystallized from a mixture of methanol and acetone. It had a melting point of 231-233°C.

The following salts were prepared in a similar manner:

(4) 1,1-azobis[3-methyl1-2-phenylbenzimidazolium] dinitrate, melting point 192-194°C, from the dibromide and silver nitrate. (5) 1,1'-azobis[3-methyl-2-phenylbenzimidazolium jdibenzenesulfonate, melting point 164-166°C, from the dibromide and silver benzenesulfonate. (6) 1, 1'-azobis[3-methyl-2-phenylbenzimidazolium] di-p-toluenesulfonate, melting point 231-233°C, from the dibromide and silver p-toluenesulfonate.

Example 2.

1, 1'-azobis[2(p-methoxyphenyl)-3-methylbenzimidazolium] dibromide.

(a) 1(p-Methoxybenzolyl)-2-(o-nitrophenyl)hydrazine. O-nitrophenylhydrazine (1g) and p-methoxybenzoyl chloride (1.1 g) in pyridine (25 ml) were heated under reflux for 30 minutes. The pyridine was distilled off under reduced pressure, and the residue was treated with cold 2N hydrochloric acid. The orange solid was crystallized from ethanol and had a melting point of 178-180°C. (b) 1(o-aminophenyl)-2(p-methoxybenzoyl)hydrazine.

1(p-Methoxybenzoyl)-2(o-nitrophenyl)hydrazine (0.5 g)

and palladium-charcoal (0.2 g) in hot (60°C) ethanol (100 ml) was shaken with hydrogen at 3.16 kg/cm 2 pressure for 45 minutes. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from ethyl acetate and had a melting point of 188-189°C.

(c) 1-amino-2(p-methoxyphenyl)benzimidazole.

A suspension of 1(o-aminophenyl-2(p-methoxybenzoyl)-hydrazine (0.4 g) and sodium m-nitrobenzenesulfonate (0.8 g) in water (25 ml) was treated with concentrated hydrochloric acid until the solution was acidic over Congo red. It was then heated under reflux for 1.5 hours, cooled and neutralized with 4N sodium hydroxide. The solid was collected and crystallized from benzene and had a melting point of 187-188°C. (d) l- amino- 2 (p-Methoxyphenyl)-3-methylbenzimidazolium iodide 1-Amino-2(p-methoxyphenyl)benzimidazole (0.16 g) and methyl iodide (1 mL) in methanol (1 mL) were heated under reflux for 18 h. solid was collected and crystallized from a mixture of ethanol and ether and had a melting point of 205-207°C (decomposition). (e) 1-amino-2(p-methoxyphenyl)-3-methylbenzimidazolium bromide,

monohydrate.

1-amino-2(p-methoxyphenyl)-3-methylbenzimidazolium iodide

in water was passed through a column of "Amberlite 400" (Br ) ion exchange resin and the eluent was evaporated. The residue was crystallized from a mixture of methanol and ether to give a solid, mp 224-226°C. (f) 1,1'-azobis[2(p-methoxyphenyl)-3-methylbenzimidazolium]dibromide.

1-amino-2(p-methoxyphenyl)-3-methylbenzimidazolium bromide

(0.2 g) in the smallest amount of water necessary to obtain complete dissolution was treated with a saturated aqueous solution of bromine (20 ml). The desired product 1,1'-azobis[2(p-methoxyphenyl)-3-methylbenzimidazolium]dibromide was obtained as a solid and was collected and heated with acetone, and the bromide was crystallized from a mixture of methanol and ether. The product had a melting point of 244°C.

1,1'-azobis[2(p-methoxyphenyl)-3-methylbenzimidazolium]-dipicrate, melting point 190-192°C, was obtained by treating a solution of the dibromide in ethanol with a solution of picric acid in ethanol and crystallizing it solid from a mixture of nitromethane and ether.

Example 3.

1,- 1' - azobis [ 3- methyl- 2-( p-tolyl) benzimidazolium] dibromide, trihydrate.

(a) 1-(o-nitrophenyl)-2(p-toluyl)hydrazine

0-nitrophenylhydrazine (2 g) and p-toluyl chloride (2.3 g)

in pyridine (25 mL) was heated under reflux for 30 min. The solution was evaporated under reduced pressure, and the residue was treated with ice-cold 2N hydrochloric acid. The orange,

solid was crystallized from ethanol and had a melting point of 187°C. (b) 1-(o-aminophenyl)-2(p-toluyl)hydrazine.

1-(o-nitrophenyl)-2(p-toluyl)hydrazine (2 g) and palladium on charcoal (0.8 g, 5%) in ethanol (200 ml) were shaken with hydrogen at room temperature and at a pressure of 3 .16 kg/cm2. When the uptake of hydrogen had ceased, the catalyst was filtered off and the filtrate was evaporated to give a solid. This was crystallized from a mixture of ethyl acetate and ether and had a melting point of 172°C.

(c) 1-amino-2(p-tolyl)benzimidazole.

2N hydrochloric acid was added to 1-(o-aminophenyl)-2(p-toluyl)hydrazine (3.7 g) and sodium m-nitrobenzenesulfonate (7.4 g)

in water (150 ml), until the mixture was acidic to Congo red. The mixture was heated under reflux for two hours, cooled and basified with 4N sodium hydroxide. The solid was collected and dried and crystallized from benzene. The product had a melting point of 205°C.

(d) 1-amino-3-methyl-2-(p-tolyl) benzimidazolium iodide. 1-Amino-2-(p-tolyl)benzimidazole (1.55 g) and methyl iodide (10 mL) in methanol (10 mL) were heated under reflux for 18 h. The solution was evaporated and the residue triturated with ether. The solid was crystallized from a mixture of methanol and ether and had a melting point of 216°C. (e) 1-amino-3-methyl-2-(p-tolyl) benzimidazolium bromide. 1-Amino-3-methyl-2-(p-tolyl)benzimidazolium iodide in ethanol was passed through a column of "Amberlite IRA 40" (Br) ion exchange resin. The solution from the column was collected and evaporated, and the residue was crystallized from a mixture of ethanol and ether to give a white solid, mp 239°C. (f) 1,1'-azobis[3-methyl-2-(p-tolyl)benzimidazolium] dibromide trihydrate.

1-amino-3-methyl-2-(p-tolyl)benzimidazolium bromide

(0.2 g) was dissolved in the minimum amount of water while heating to 60°C. Saturated aqueous bromine (20 mL) was added to the hot solution. The mixture was stirred and allowed to cool, and the red solid was collected and added to boiling acetone. The desired product 1,1'-azobis[3-methyl-2-(p-tolyl)benzimidazolium] dibromide trihydrate was obtained as a yellow solid which was separated, filtered off and crystallized from a mixture of ethanol and ether and had melting point 222°C.

Claims (1)

Analogous method for the preparation of pharmacologically active compounds with the general formula: where R 3 means phenyl which is optionally substituted with lower alkyl or lower alkoxy, R 4 means an alkyl group containing from 1 to 4 carbon atoms, and X means a physiologically acceptable anion, characterized in that (a) a compound of formula III: where R<3>, R4 and X~ have the meanings indicated above, is subjected to oxidation to bind together 2 molecules of the compound of formula III to thus form a tetrazine, and optionally the anion X is converted into another anion X with the above indicated meaning, or (b) a compound of formula II wherein X is a bromide ion is converted to a compound wherein X is a pharmaceutically acceptable anion other than bromide.