NO119274B - - Google Patents

Description

Process for the production of therapeutically active,

hitherto unknown substituted 6,7-benzomorphans-

The present invention relates to a process for the production of hitherto unknown benzomorphan derivatives with value

full pharmacological properties.

It was surprisingly found that compounds of the general formula I, where means hydrogen, the hydroxyl group or a lower alkanoyloxy acid residue,

1*2 a lower alkyl or P-methoxyethyl residue or a phenyl residue,

R 3 hydrogen or a lower alkyl residue and

R 4 a lower alkyl or a phenyl radical,

has valuable pharmacological properties, in particular analgesic effect.

Many of these compounds are in contrast to morphine and

other known benzomorphans, surprisingly free of disease-causing properties. Furthermore, the new benzomorphans show an antitussive effect, and some of them are antagonists of morphine.

The compounds can be used parenterally or orally in a

usual pharmaceutical form of administration, i.e. in the form of

tablets, capsules, powders, suspensions, solutions, syrups, etc. Of particular advantage are forms with delayed active substance release, which can be prepared according to one or another known method.

In the compounds of the general formula I, in addition to hydrogen, the hydroxyl group is acetoxy, propionoxy or butyroic acid. R2 is a lower alkyl residue, which in particular is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl-, tert. butyl, n-pentyl residue, p-methoxyethyl residue or a

phenyl residue. R^ is, in addition to hydrogen, a lower alkyl residue, such as ;

in particular the methyl, further ethyl, n-propyl or isopropyl residue. In addition to the phenyl residue, R^ is a lower alkyl residue, such as e.g. methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, iso~.-- . •

butyl-, sec. butyl-, tert. the butyl or n-amyl residue.

The preparation of compounds of the general formula I takes place by reacting a compound of the general formula II,

where means hydrogen or a lower alkyl residue, and R^, R» and R.j have the meanings given under formula I, with a carboxylic acid derivative of the general formula III,

where Hal means a halogen atom and

R^ has the meanings given under formula I,

and, if desired, if R 1 represents an alkanoyloxy group, hydrolyzes in a manner known per se. . Compounds with the general formula II are obtained, e.g. in the cyclization of a compound of the general formula IV,

in

where R5' has the meaning of Rj- with the exception of hydrogen and

R^, R^ and R^ have the meanings given under formula I, in the presence of a Lewis acid to a compound of the general formula IIa:

These compounds are, if desired, transferable with the bromine-cyanide decomposition reaction according to Braun to compounds of the general formula IIb,

where R^, R£ and R^ have the meanings given under formula I. As carboxylic acid derivatives with the general formula III are e.g. the following are suitable: chlorocarbonic acid methyl-, -ethyl-, -propyl-, -butyl-, -amyl-, as well as -phenyl ester, as well as the corresponding bromine derivatives.

As alkylating agents, i.e. for the conversion of the 2'-hydroxyl group to a lower alkoxy group, in particular diazoalkanes, such as e.g. diazomethane, speaking.

Reactive functional derivatives of lower alkane carboxylic acids, such as e.g. anhydrides and halides, such as acetic anhydrides, propionic anhydrides, acetyl chloride, acetyl bromide, propionyl chloride as well as propionyl bromide.

If R 1 denotes a lower alkanoyloxy group, such a group can be hydrolysed in a manner known per se, e.g. by the action of an aqueous mineral acid or a lye.

; It is advantageous to carry out the reaction according to the invention in a suitable inert organic solvent, which in particular; toluene or anhydrous benzene, whereby work is usually done at an elevated temperature, such as e.g. at the boiling temperature of the reaction mixture. The reaction can also be carried out in an inert atmosphere, for example under nitrogen.

As can be seen from formula I, the compounds according to the invention can exist in optically isomeric forms. Thus, the presence of an asymmetric carbon atom in the morphan ring leads to the formation of d- and l-forms. If R in formula I is an alkyl residue, then stereoisomers are possible, whereby the alkyl group can be bound cis or trans to the residue R_ in the 5-position.

The geometric or stereoisomeric forms can be distinguished,

if desired, in a manner known per se, e.g. by fractionated crystallization or by distillation.

If one wants to separate enantiomorphic forms, then the diastereoisomeric salts are formed in the usual way using an optically active acid. All these isomeric forms are likewise subject to the invention.

The following examples illustrate the implementation of the method according to the invention. The temperatures are indicated in degrees Celsius.

EXAMPLE I

2- carbethoxy- 5-( P- methoxyethyl)- 6, 7- benzomorphan- hydrochloride

a) 4-(P-Methoxyethyl)-pyridine- methyl iodide

Methyl iodide (313 g, 137 ml, 2.20 mol) is added dropwise

stir into a solution of 274 g (2.00 mol) 4-(P-methoxyethylpyridine) in 400 ml acetone and 200 ml benzene at such a rate that reflux is maintained. It is then stirred further for 3 hours, whereby the reaction mixture is cooled to room temperature. The mixture is cooled overnight, the product is separated, recrystallized from acetone and dried, melting point 75 - 78(|<>>.

in

b) 1-methyl-4-(P-methoxyethyl)-1,2,5,6-tetrahydropyridine A solution of 223 g (0.80 mol) 4-(P-methoxyethyl)-pyridine-

methyl iodide in 320 ml of water and 320 ml of methanol are added dropwise

stir at such a rate to a solution of 50 g (1.2 mol) of sodium borohydride in 240 ml of water that the temperature is kept at 50 - 60°. Further solid sodium boron hydride (44 g) is then added, and the mixture is stirred overnight at room temperature. The solution is then filtered, concentrated..i

vacuum to approx. one-third of its volume and extracted several times with ether. The ethereal extracts are washed with saturated aqueous sodium sulfate, dried over sodium sulfate and evaporated. The residue gives, after distillation, the product with a boiling point of 90 - 92°/12 torr.

c) 1-Benzy1-1-methyl-4-(P-methoxyethyl)-1,2,5,6-tetrahydro-pvridinium chloride

By adding a 10% molar excess of benzyl chloride to a solution of 7.8 g of 1-methyl-4-(3-methoxyethyl)-1,2,5,6-tetrahydropyridine in 30 ml of acetone, the quaternary salt is prepared. The reaction mixture is allowed to stand at room temperature,

the crystallized product is separated and recrystallized from acetone, melting point 134.5 - 137.5°.

d) 2- benzyl- 4-( P- methoxyethyl)- 1- methyl- 1, 2, 5, 6- tetrahydro-pyridine

A solution of 2.0 mol of phenyllithium in ether (71.5 mL, 0.143 mol)

1 is added dropwise with stirring to a suspension of dry 1-benzyl-1-methyl-4-(P-methoxyethyl)-1,2,5,6-tetrahydropyridinium chloride (35.8 g, 0.127 mol) in 225 ml of anhydrous ether with such speed that a light backlash is maintained. The mixture is kept under reflux for a further 2 hours, cooled and set to acid with 100

ml 2-n hydrochloric acid. The aqueous phase is separated and made alkaline again under cooling with ice and concentrated ammonium hydroxide. The product is extracted with ether, the extract is dried over sodium sulphate and evaporated. The product is then distilled, boiling point 128 - 135°/0.5 torr. The picrate is obtained by adding

In the setting of a solution of 20.8 g (0.091 mol) picric acid

in

in 200 ml of ethanol to a solution of 27.2 g (0.111 mol) of the

crude base in 30 ml of ethanol. As an oil forms, acetone is added

to maintain the information. The reaction mixture is allowed to stand for a few days in a refrigerator, then the product is isolated and recrystallized from ethanol-acetone, melting point 100.5 - 102.5° (after three hours of soaking at 60°/0.1 torr).

2-Benzyl-4-(P-methoxyethyl)-1-methyl-1,2,5,6,-tetrahydro-pyridine can then be prepared by the following procedure: A solution of 30.0 ml of benzyl chloride in 100 ml ether is added over the course of one hour to a suspension of 8.0 g of magnesium shavings and 8.0 g of magnesium powder in 250 ml of ether. The mixture is kept under stirring and under reflux for a further two hours and the solution is then filtered through glass wool in an extractor and added over 10 minutes to a suspension of 56.0 g of 4-(3-methoxy-ethyl)-pyridine- methyl iodide in 100 ml of ether. This mixture is stirred for a further 2 hours and heated under reflux, whereupon 150 ml of a cold saturated solution of ammonium chloride, containing 20 ml of concentrated

aqueous ammonia.

in

The ether solution is separated and extracted with a cold aqueous solution of 20 ml of concentrated hydrochloric acid. The aqueous extracts are made alkaline with ammonia and extracted with ether. The ether solution is dried over sodium sulfate and evaporated. Crude 2-benzyl-4-(P-methoxyethyl)-1-methyl-1,2-dihydro-pyridine is obtained in the form of an oil. The oil is dissolved in 70 ml of methanol, and 6.0 g of sodium borohydride are added while cooling and stirring. The mixture is heated under reflux for 1 1/4 hours and allowed to stand overnight at room temperature. The methanol is removed in vacuo, the residue is shaken with water and ether, the ether solution is dried over sodium sulphate, evaporated and the residue is distilled in vacuum. One obtains a first fraction with a boiling point of 125°/1 torr and another with a boiling point of 150°/4 torr. The first fraction is distilled again and the distillate is used for the cyclization reaction described below. e) 2- methyl- 5-( P- methoxyethyl)- 6, 7- benzomorphan hydrochloride A solution of the soluble portion of 12.0 g of aluminum tribromide in 20 ml of carbon disulfide is added over the course of 10 minutes with stirring and cooling with ice, a solution of 3.0 g of freshly distilled 2-benzyl-4-(p-methyl)-1,2,5,6-tetrahydropyridine in 20 ml of carbon disulfide. After 5 minutes, the cooling bath is removed, the mixture is heated to reflux temperature and kept under reflux for 30 minutes. The mixture is then cooled, the solution is decanted and the residue is washed with carbon disulfide.

After the viscous residue has completely cooled over ice, add 20

ml of concentrated aqueous ammonia. Chloroform is then added and the mixture is heated with stirring to bring the ice to melt and the mixture to heat. The solid is filtered off and washed well with chloroform, the chloroform layer is separated, dried over anhydrous sodium sulfate and evaporated. The remaining oil obtained is distilled at 130°/0.05 torr and the distillate is converted with ether-acetone to the hydrochloride.

This salt is recrystallized twice from acetone and gives 2-methyl-5-(3-methoxyethyl)-6,7-benzomorphan hydrochloride, melting point 163 - 165°.

f) 2- carbetox- 5-( P- methoxyethyl)- 6, 7- benzomorphan A solution of 5 ml of ethyl chloroformate in 35 ml of toluene is used

under nitrogen a solution of 10.35 g of 2-methyl-5-(@-methoxy-ethyl)-6,7-benzomorphan in 35 ml of toluene. The solution is kept under reflux for 6 hours, cooled, filtered and the filtrate evaporated. The residue is dissolved in dichloromethane, washed with 1-1 hydrochloric acid, dried over sodium sulphate and evaporated. 2-Carbethoxy-5-(P-methoxyethyl)-6,7-benzomorphan is obtained, melting point

84.5 - 86° (after recrystallization of oil from aqueous ethanol).

EXAMPLE 2

2'- acetoxy- 2- carbethoxy- 5- phenyl- 6, 7- benzomorphan A solution of 1.5 g of 2'-acetoxy-2-methyl-5-phenyl-6,7-benzo-morphan in 50 ml anhydrous benzene is added over the course of 45 minutes to a solution of 1.5 g of ethyl chloroformate in 25 ml of anhydrous benzene. The mixture is kept at reflux for 2 hours and stirred for 15 hours. The solution is then filtered, washed with l-n

hydrochloric acid, dried over magnesium sulphate and evaporated. One obtains, 2<1->acetoxy-2-carbethoxy-5-phenyl-6,7-benzomorphan, melting point 105 - 107°.

Prepared in an analogous manner: 2'-acetoxy-2-carbethoxy-5-methyl-9p-ethyl-6,7-benzomorphan from 2'-acetoxy-2,5-dimethyl-9p-ethyl-6,7-benzomorphan, melting point 122 - 124°.

EXAMPLE 3

2'-hydroxy-2-carbethoxy-5-phenyl-6,7-benzomorphan A mixture of 0.8 g of 2'-acetoxy-2-carbethoxy-5-phenyl-6,7-benzomorphan and 40 ml of 2-n, hydrochloric acid is heated for 17 hours under reflux, cooled and extracted with chloroform. The extracts are evaporated in vacuo and the residue recrystallized from benzene-petroleum ether. 2<1->hydroxy-2-carbethoxy-5-phenyl-6,7-benzomorph an is obtained, melting point 207 - 208°. By acetylation with acetate

, hydride in pyridine, the 2'-hydroxy compound is transferred to the 2'-acetoxide derivative. Temp. 105 - 107°.

EXAMPLE 4

2'- hydroxy- 2- carbophenoxy- 5- phenyl- 6, 7- benzomorphan- hemihydrate 5.0 g 2'-hydroxy-5-phenyl-6,7-benzomorphan and 75 ml benzene

is brought into a 200 ml capacious, with magnetic rib work, dresses,

wooden-necked flask equipped with thermometer and dropping funnel. While the

formed slurry is removed, 8.9 g of phenylchloroformate in 50 ml of benzene are added dropwise over 30 minutes. The slurry is heated for 4 hours under reflux, then cooled and filtered. The benzene solution is dried over sodium sulphate and evaporated to dryness, the white residue is dissolved in 150 ml of acetic acid, concentrated to approx. 100 ml and decant. One obtains 2'-hydroxy-2-carbophenoxy-5-phenyl-6,7-benzomorphan hemihydrate, melting point

219 - 220°. The product is recrystallized from n-butanol.

Melting point 2 23 - 2 25°.

Claims (1)

Process for the production of therapeutically active, , j hitherto unknown substituted 6,7-benzomorphans with the general: formula I, ; t where means hydrogen, the hydroxyl group, a lower alkoxy or alkanoyloxy residue, R2 a lower alkyl or (3-methoxyethyl residue, phenyl, halophenyl or hydroxyphenyl, R^ hydrogen or a lower alkyl residue and R^ a lower alkyl or a phenyl residue, characterized by reacting a compound with the general formula II, where R 1 means hydrogen or a lower alkyl residue and R 1' R 2 OQ; R3 ^ar ^e un(^er formula 1 given meanings, with a carboxylic acid derivative of the general formula III, where Hal means a halogen atom and R^ has the meanings given under formula I, and, if desired, alkanoylates a compound of the general formula I, where means the hydroxyl group, in a manner known per se, or, if R^ means an alkoxy - or alkanoyloxy group, hydrolyzes in a manner known per se.