FI58121C - PROCEDURE FOR THE PRODUCTION OF PHARMACOLOGICAL ACTIVITIES - Google Patents

Description

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England-England (GB) 52210/72 Proven-Styrkt (71) Allen & Hanburys Limited, Three Colts Lane, Bethnal Green, London E.2., England-England (GB) (72) David Jack, London, Ernest Edvard Glover The present invention relates to an improvement or modification of the invention described in Finnish Patent 56,179, and Yarm, Yorkshire, England-England (GB) (7U) Leitzinger Oy (5U) A process for the preparation of pharmacologically active compounds which deals with the preparation of new imidazolium salts having neuromuscular blocking activity.

Said patent 56 179 describes novel compounds of general formula I.

R? JR1 R1 R2 I N-N = N —f

© / K,> \, © 2X 0 ID

R 1, R 3, R 2 and R 2, wherein R 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 and R together together with the carbon and nitrogen atoms to which they are attached form a pyridinium or tetrahydropyridinium group and X may be a physiologically acceptable anion such as bromide, chloride, acetate, phosphate, perchlorate or picrate.

2,581 21

New compounds belonging to the class described in the above-mentioned patent have now been prepared which have been found to have particularly valuable properties when a very short-term neuromuscular blockade is required. Table 1 shows the paralyzing activity of the 1,1'-azobis / 3-methyl-2-phenylbenzimidazolium / dibromide (AH 10407) of Example 1 in a mouse and the neuromuscular blocking activity measured in an anesthetized cat and anesthetized monkey in the anterior tibia.

Table 1 Neuromuscular blocking activity of AH 10407 (Example 1)

Animal Measured activity Mean duration observed with AH 10407 ED5Q dose

Mouse Paralyzing activity 0.49 EDgQ (mg / kg) I.V.

(95% confidence limits) (0.45-0.77)

Cat Neuromuscular blocking ak- 0.6 22 seconds (anestheticity »anterior weathered) squamous muscle ED5q (mg / kg) I.V.

Monkey Neuromuscular blocking ak- (anesthetic, anterior weather- 1.0 20 seconds played) skeletal muscle ED ^ irng / kg) I.V.

The compounds according to the invention have a short-lasting curare-like neuromuscular blocking effect. The desirability of a muscle relaxant for a short time is well known. For long surgeries, a sufficient level of relaxation can be achieved by continuous intravenous instillation, allowing the anesthetist to more precisely control the degree of relaxation and also making it possible to quickly return to spontaneous movement when the infusion is stopped. The short-acting muscle tension triggers currently in use are of the depolarizing type and have several disadvantages. Preoperative pain is one of the major disadvantages of using a succinyl line. Its occurrence is associated with depolarization and may be the result of muscle attacks that occur during initiation. Other disadvantages include the lack of a suitable antibody and the possibility of prolonged painlessness.

According to the invention, compounds of general formula II are prepared

- p η.

| N-N-N-N I 2X ^ (JX) Θ N = <) = N © r3 r3. 3 wherein R is phenyl optionally substituted with a lower μl alkyl or lower alkoxy group, R is an alkyl group containing 1 to 4 carbon atoms and X is a physiologically acceptable anion.

3

A particularly preferred group of compounds is that in which R represents a phenyl group, a 4-alkoxyphenyl group or a 4-alkylphenyl group in which the alkoxy and alkyl groups have 1 to 3 carbon atoms.

Examples of physiologically acceptable anions are bromide, chloride, acetate, phosphate, nitrate, aryl or aralkyl sulfonate, e.g. benzenesulfonate, or p-toluenesulfonate (tosylate) ^ and alkyl sulfonate, e.g. methanesulfonate.

The preparation of particularly preferred compounds is described in the Examples.

The novel compounds can be prepared by the method generally described in the aforementioned patent 56,179. Suitable oxidants are, for example, bromine or chlorine. The reaction is best carried out in water and at an elevated temperature, preferably at a temperature of about 60 ° C.

Thus, in principle, the N-amine- * 58121 compound of formula III, as defined below, is oxidized to couple the two molecules to form tetrazine.

The invention is characterized in that (a) a compound of formula III nh2 n V Ή x ® Θ N — x (III) 3 μ wherein R, R 3a X have the same meaning as above, is oxidized to couple two molecules of a compound of formula III together to form a sine, and if desired converting anion x ”to another anion X of the above meaning, or (b) converting a compound of formula II wherein X is bromide to a compound wherein X is a pharmaceutically acceptable anion other than bromide.

When oxidized with bromide, the starting product is perbromide in which two bromine molecules are loosely attached to each molecule of the compound of formula II, X s Br ”. This bromine can be easily removed by treating the perbromide with a ketone, e.g. acetone or cyclohexanol, to give compounds of formula II wherein X = Br ”.

When X = Br ”, the new compounds can be converted to chlorides X ~ Cl by treatment with excess concentrated hydrochloric acid. Such chlorides are then isolated by adding acetone to the resulting solution and recovering the solid. The bromides, X = Br, can also be converted to other salts by treatment with the silver salt of the corresponding acid in a suitable solvent, e.g. acetonitrile. Thus, e.g., nitrate, X = NO 2, benzenesulfonate, X = C 1 H 2 SO 2, and tosylate, X = CH 2 -C 6 H 2 SO 2, can be prepared from bromide, X = Br, and silver nitrate, silver benzenesulfonate, and silver, respectively. p-toluene sulfonate. A particularly useful reaction is the use of silver methane 1 phonate to give compounds of formula II in which X = CH 2 SO 4, which has the particular advantage of their high solubility in water.

Benzimidazolium salts of formula III, i. the starting amines can be prepared by known methods, including but not limited to the reactions shown schematically below: NHNH_'li UN K. CO R 3a,

IV V

uh2

^ NH.NHCOR3 ^) T

• -a, - co ~.

VI

VII

NH0 12 r14x (s n \

HV

Vili

Ilyrazide V is prepared from o-nitrophenylhydrazine and the acylating agent κ COY, which may be an ester, an acyl halide or an acid hydride. The reagent R COY may conveniently be an acid chloride (Y = Cl), where R is as defined above, and the reaction may be carried out, for example, in pyridine, optionally at elevated temperature.

Nitrohydrazide V can be reduced to aminohydrazide VI with hydrogen in the presence of a catalyst, for example palladium on carbon, at temperatures of 20 to * + 0 ° C and a pressure of 1 to 4 atm. Aminobenzimidazoles of formula VII are obtained from aminohydrazides VI by heating in aqueous solution with a strong acid, for example m-nitrobenzenesulphonic acid.

They are known compounds or can be obtained by standard methods described by Abramovitch and Schofield (J. Chem. Soc., 1955, 2326) and as shown in the scheme above.

The 1-aminobenzimidazolium salts of formula III can be obtained from 1-aminobenzimidazoles VII by conventional quaternization methods,. . . ,. 4 for example by heating with an alkyl halide R X, optionally 4 in a solvent, for example an alcohol R OH. The quaternary iodides of formula III, X = I, can be converted to bromides III, X = Br ~, using a bromide ion exchange resin such as Amberlite IRA40 (Br ~) or by heating with hydrobromic acid.

The novel compounds are used in combination with a pharmaceutically acceptable carrier in pharmaceutical preparations. Preparations suitable for parenteral use are preferred. These may be in the form of sterile aqueous solutions for injection or in the form of sterile solids which are dissolved in sterile water before use.

A suitable dose for a single injection is 2 to 100 mg, but continuous infusions or repeated injections may be required for long surgeries.

The following examples illustrate the invention: 7 58121

Example 1 (1) 1,1 * -Azobis / 3-methyl-2-phenylbenzimidazolium / dibromide (ci) 1-Amino-3-methyl-2-phenylbenzimidazolium iodide 1-Amino-2-phenylbenzimidazole (Abramovitch and Schofield, J. Chem. Soc., 1955, 2326) (0.2 g) in methyl iodide (10 ml) and methanol (5 ml) were heated at reflux for 24 hours. The solution was evaporated and the residue was crystallized from a mixture of ethanol and ether as colorless prisms, m.p. 209 ° C.

~ (b) 1-Amino-3-methyl-2-phenylbenzimidazolium bromide

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, mp 25-5 ° C.

(c) 1,1'-azobis-3-methyl-2-phenylbenzimidazolium / dibromide 1-amino-3-methyl-2-phenylbenzimidazolium bromide (0.3 g) dissolved in as little water as possible at 60 ° C, treated with saturated aqueous bromine (30 ml), 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, mp 218 ° C.

A number of other salts were prepared from this dibromide as described below.

(1) 1,1,1-Azobis / 3-methyl-2-phenylbenzimidazolium / dichloride 1,1'-Azobis / 3-methyl-2-phenylbenzimidazolium / dibromide was dissolved in as little concentrated hydrochloric acid as possible. Acetone was added and the solid was crystallized from a mixture of concentrated hydrochloric acid and acetone s 58121 to the dichloride, m.p. 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 equivalents) in ethanol and the solid was collected and crystallized. from a mixture of nitromethane and ether. The melting point of the product was 237-239 ° C.

(3) 1,1'-Azobis / 3-methyl-2-phenylbenzimidazolium / dimethanesulfonate-1,1'-azobis / 3-methyl-2-phenylbenzimidazolium / dibromide (13 g) in methanol (50 ml) was added dropwise to the stirred mixture. to a solution of silver methane sulfonate (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. Its melting point was 231-233 ° C.

The following salts were prepared in a similar manner: (4) 1,1 * -azobis / 3-methyl-2-phenylbenzimidazolium / dinitrate, melting point 192-194 ° C, from dibromide and silver nitrate.

(5) 1,1'-Azobis [3-methyl-2-phenylbenzimidazolium / dibenzenesulfonate], melting point 164-166 ° C, from dibromide and silver benzenesulfonate. 1 1,1'-Azobis [3-methyl-2-phenylbenzimidazolium] di-p-toluenesulfonate melting point 231-233 ° C, from dibromide and silver p-toluenesulfonate.

Example 2 1,1'-Azobis [2- (p-methoxyphenyl) -3-methylbenzimidazolium / dibromide (a) 1- (p-methoxybenzoyl) -2- (o-nitrophenyl) hydrazine o-nitrophenylhydrazine (1 g) and p-methoxybenzoyl chloride (1.1 g) in pyridine (25 ml) was heated at reflux for 30 minutes.

9,581 21

The pyridine was distilled off under reduced pressure and the residue was treated with cold 2N hydrochloric acid. The orange-yellow solid was crystallized from ethanol. Its melting point was 178-180 ° C.

(b) 1- (o-Aminophenyl) -2- (p-methoxybenzoyl) hydrazine 1- (p-Methoxybenzoyl) -2- (o-nitrophenyl) hydrazine (0.5 g) and palladium on carbon (0.2 g) in warm (60 g). ° C) in ethanol (100 ml) was shaken with hydrogen for 45 minutes at 2.75 kg / cm 3. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from ethyl acetate. Melting point 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 Congo. Red-indicator. It was then heated at reflux for 1.5 hours, cooled and neutralized with 4N sodium hydroxide. The solid was collected and crystallized from benzene, mp 187-188 ° C.

(d) 1-Amino-2- (p-methoxyphenyl) -3-methylbenzimidazolium iodide 1-Amino-2- (methoxyphenyl) benzimidazole (0.16 g) and methyl iodide (1 ml) in methanol (1 ml) were heated at reflux for 18 hours. . The solid was collected and crystallized from a mixture of methanol and ether. Melting point 205-207 ° C (decomposes).

(e) 1-Amino-2- (p-methoxyphenyl) -3-methylbenzimidazolium bromide, 1-amino-2- (p-methoxyphenyl) -3-methylbenzimidazolium iodide monohydrate in water was passed through an Amberlite 400 (Br -) ion exchange resin column and the eluent was evaporated. The residue was crystallized from a mixture of methanol and ether to give a solid, m.p. 24-226 ° C.

10,581 21 (f) 1,1'-Azobis [2- (p-methoxyphenyl) -3-methylbenzimidazolium / dibromide] -1-amino-2- (p-methoxyphenyl) -3-methylbenzimidazolium bromide (0.2 g) dissolved as much as possible to a small amount of water, was treated with saturated aqueous bromine (20 mL). The desired product 1,1,1-azobis [2- (p-methoxyphenyl) -3-methylbenzimidazolium / dibromide was obtained as a solid and collected and heated with acetone. The bromide was crystallized from a mixture of methanol and ether. The melting point of the product was 2U4 ° C.

1,1'-Azobis [2- (p-methoxyphenyl) -3-methylbenzimidazolium / dipicrate, m.p. 190-192 ° C, was obtained by treating a solution of dibromide in ethanol with ethanolic solution of picric acid and crystallizing the 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 O-Nitrophenylhydrazine (2 g) and p-toluyl chloride (2.3 g) in pyridine (25 mL) was heated at reflux for 30 minutes. The solution was evaporated under reduced pressure and the residue was treated with ice-cold 2N hydrochloric acid. An orange-yellow solid was crystallized from ethanol, m.p. 187 ° C.

(b) 1- (o-Aminophenyl) -2- (p-toluyl) hydrazine 1- (o-Nitrophenyl) -2- (p-toluyl) hydrazine (2 g) and palladium on carbon (0.8 g, 5%) in ethanol (200 ml) was shaken with hydrogen at 2 room temperature and 2.75 kg / cm. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated to a solid. This was crystallized from a mixture of ethyl acetate and ether, m.p. 172 ° C.

(c) 1-Amino-2- (p-tolyl) benzimidazole 2N Hydrochloric acid was added to 1- (o-aminophenyl) -2- (p-toluyl) hydrazine 581 21 11 (3.7 g) and sodium m-nitrobenzenesulfonate (7, * + g) in water (150 ml) until the mixture was acidic Congo Red indicator liquor. The mixture was heated at reflux for 2 hours, cooled and basified with UN sodium hydroxide. The solid was collected, dried and crystallized from benzene. The melting point of the product was 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 to reflux. 18 hours. The solution was evaporated and the residue triturated with ether. The solid was crystallized from a mixture of methanol and ether, m.p. -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 an Aberlite IRA U0 (Br) ion exchange resin column. The solution from the column was collected and evaporated. The residue was crystallized from a mixture of methanol and ether to give a white solid, m.p. 239 ° C.

(f) 1,1'-Azo [3-methyl-2- (p-tolyl) benzimidazolium / dibromide, trihydrate-1-amino-3-methyl-2- (p-tolyl) benzimidazolium bromide (0.2 g) dissolved in as little water as possible with heating to 60 ° C. To the hot solution was added saturated aqueous solution (20 mL). The mixture was stirred and allowed to cool. The red solid was collected and added to boiling in acetone. The desired product 1,1'-azobis- [3-methyl-2- (p-tolyl) benzimidazolium / dibromide, trihydrate was obtained as a yellow solid which was separated by filtration and crystallized from a mixture of methanol and ether, mp 222 ° C.

Claims (2)

58121 12 A process for the preparation of pharmacologically active compounds of general formula II 0 Q 1 ν-ν = ν-, Γ | R 2 is phenyl optionally substituted by 4 lower alkyl or lower alkoxy groups, R is an alkyl group containing 1 to 4 carbon atoms and X is a physiologically acceptable anion, characterized in that that (a) a compound of formula III (nh 2 ®) C jQ 3 4 wherein R, R 1 a X have the same meaning as above, is oxidized to link two molecules of a compound of formula III together to form tetrazine, and optionally converting anion X to another anion of the above meaning X-, or (b) converting a compound of formula II wherein X- is bromide to a compound wherein X is a pharmaceutically acceptable anion other than bromide.