NO131593B - - Google Patents

Description

Analogy methods for the production of

therapeutically active d-2-(6-substituted-2-naphthyl)propanals.

The present invention relates to a method for the production of therapeutically effective d-2-(6-substituted-2-naphthyl)propanals with the general formula:

where R is a methoxy or methylthio group.

Compounds of formula III have anti-inflammatory analgesic and anti-pyretic properties and, accordingly, they can

used for the treatment of inflammation, pain and fever in mammals.

The compounds of formula III are particularly useful in the treatment of inflammations, such as inflammatory conditions in the muscular system, in the leg joints or in other tissues. The compounds can therefore be used in the treatment of conditions characterized by inflammation, such as rheumatism, injuries, lacerations, arthritis, broken bones, post-traumatic conditions and gout in general. In cases where, in the above-mentioned conditions, pain and fever are associated with inflammation, the compounds produced can be used to alleviate these conditions as well as the inflammation.

By measuring the anti-inflammatory activity using Carrageenin-induced edema according to Winter et. al., "The Proceedings of The Society for Experimehtal Biology and Medicine", Volume III, 5^4 (1962), it has been demonstrated that d-2-(6-methoxy-2-naphthyl)pro-. panal has eight times higher activity than phenylbutazone. d-2-(6-methylthio-2-naphthyl)-propanal has the following physical properties: m.p. 98-100°C, (a)j= + 199° (chloroform) and has four times higher activity than phenylbutazone.

The preferred method of administration is oral administration, whereby daily doses can be provided in an appropriate manner depending on the nature of the disorder. Usually, one will use daily doses from 0.1 to 60 mg of the active compound per kg body weight. Most conditions will be affected by a dose of 0.5 to 5 mg per kg body weight. For such oral administration, pharmaceutically acceptable non-toxic preparations can be used by using known pharmaceutical diluents.

The compounds of formula III are prepared by a method which can be illustrated as follows:

In the above formulas, R has the same meaning as

indicated above.

The compounds of formula III are prepared from the corresponding d-2-(6-substituted-2-naphthyl)propionic acids indicated by formula I by the following method. The latter compounds are first converted into the corresponding acid chlorides by a reaction with thionyl chloride in benzene under reflux conditions, after which the solvent is evaporated. The remaining acid chloride is then reduced with 2 equivalents of lithium aluminum tritertiary butoxyhydride in an ether solvent such as tetrahydrofuran, tetrahydropyran, dimethoxyethane, etc., at temperatures from -80 to 0°C for a period of 30 minutes to 12 hours, whereby compounds are obtained with formula III, which can then be isolated by commonly known methods. Thus, the reaction mixture can be mixed with water and then extracted with benzene. The benzene phase can then be evaporated in vacuo to dryness and the residue recrystallized from dichloromethanehexane.

Another method for producing compounds of formula III consists in oxidizing the 1-form of propanols of formula II to the respective d-2-(6-substituted-2-naphthyl)propanals with chromium trioxide pyridine complex, and where the molar ratio between the complex and compounds of formula II' should be in the range between, 0.8:1 to 10:1, preferably approx. 5:1- Reactions are carried out in an inert organic solvent, such as a halogenated hydrocarbon, e.g. dichloromethane, chloroform or carbon tetrachloride, hydrocarbons such as hexane, heptane, benzene and toluene, amines such as dimethylaniline, pyridine, collidine, quinoline and lutidine, besides ethers such as tetrahydrofuran, tetrahydropyran, dimethoxyethane and diethyl ether. The reaction is carried out at temperatures from 0 to 60°C,

and the time period used is dependent on the reaction temperature. Time periods from 1 to 48 hours are usually sufficient. The compounds of formula II can then be isolated from the reaction mixture by conventional techniques. E.g. the reaction mixture can be chromatographed on silica gel, eluted with dichloromethane, which gives . the compounds of formula III which can then be crystallized from dichloromethane-hexane.

Compounds of formula I can be prepared by several known methods. Thus, a $-substituted naphthalene can be reacted with acetyl chloride in nitrobenzene in the presence of at least 3 molar equivalents of aluminum chloride, whereby the corresponding '6-substituted 2-acetylnaphthalene derivative is produced. The resulting derivative is heated with morpholine in the presence of sulfur to approx. 150°C, the resulting product is refluxed with concentrated hydrochloric acid, whereby the corresponding 2-(6-substituted 2-na-phyl)acetic acid derivative is produced. The addition of a methyl group in the C-2 position is carried out by esterifying the 2-(6-substituted 2-naphthyl)acetic acid derivative by usual methods, e.g. by a treatment with diazoalkane, e.g. diazomethane, in ether -or- with an alkane, such as methanol, in the presence of boron trifluoride"y whereby the corresponding alkyl ester is obtained. The ester product is then treated with sodium hydride in an ether solvent, such as- i,2-dimethoxymethane to become treated with a methyl halide, e.g. methyl iodide, so that the corresponding 2-(6-substituted-2-naphthyl) propionic acid alkyl ester is produced, which is then hydrolysed to racemic compounds of formula I.

The d-isomers of formula I can be obtained by selective biological degradation, or by: preparing diastereoisomer salts of 2-(6-substituted 2-naphthyl)propionic acid derivatives with dissolved, optically active amine bases, such as cinchonidine, whereby the formed diastereoisomers are separated by fractional crystallization. The separated diastereoisomeric salts can then be acid-cleaved, whereby the respective d-2-(6-substituted-2-naphthyl)propionic acid derivatives are produced.

Compounds of formula II can e.g. produced by

reducing compounds of formula I with lithium aluminum hydride in an inert organic ether solvent. The compounds of formula I are treated with at least 0.75 molar equivalents of lithium aluminum hydride, preferably with from 1 to 2.5 molar equivalents. Suitable inert organic ethers are diethyl ethers, dipropyl ethers, diisopropyl ethers, dibutyl ethers, tetrahydrofuran, tetrahydropyran and dimethoxyethane. The reaction is carried out at a temperature between 0°C and the boiling point

for the solvent used, preferably between 15 and M5°C.

The compounds of formula II can then be isolated by destroying any excess of lithium aluminum hydride by adding an excess of ethyl acetate. The mixture is then diluted with water, filtered and extracted with an inert organic solvent which is immiscible with water. The organic phase can then be evaporated to dryness, and the compounds of formula II are then obtained by recrystallization from acetone-hexane. Alternatively, the compounds of formula I' can be reduced by treating them with diborane in tetrahydrofuran at temperatures between 0 and 65°C.

Production 1.

A mixture of 1.6 g of 2-methoxynaphthalene, 1.6 g of acetyl chloride and 20 ml of nitrobenzene was added to 4.0 g of aluminum chloride.

The resulting mixture was stirred for 48 hours at 25°C and then washed with water until the mixture was free of chloride ions. The mixture was dried over sodium sulfate and evaporated under reduced pressure. The residue, 2-acetyl-6-methoxynaphthalene, was refluxed in 2 ml of morpholine containing 0.5 g of sulfur for 2 hours, after which the reaction mixture was filtered and evaporated. The resulting reaction derivative was extracted with diethyl ether, after which the extracts were combined and evaporated. The residue was refluxed in 10 ml of concentrated hydrochloric acid for two hours, cooled to 25°C and then neutralized with aqueous sodium hydroxide. The mixture was then extracted with ether, and the extracts combined, washed with water to neutrality, and dried and evaporated to give 2-(6-methoxy-2-naphthyl)acetic acid.

forward position 2-

A mixture of 22 g of methyl 2-(6-methoxy-2-naphthyl)acetate (prepared by treating 20.5 g of 2-(6-methoxy-2-naphthyl)acetic acid with 4.5 g of diazomethane in ether), and 2 .5 g sodium hydride in 150 ml 1,2-dimethoxyethane, added 25 g methyl iodide. The reaction mixture was allowed to stand for several hours, then diluted with ethanol and water and extracted with methyl chloride. The extracts were combined, washed with water until neutral, dried over sodium sulfate, filtered and evaporated, whereby methyl 2-(6-methoxy-2-naphthyl)-propionate was produced.

To the resulting product was added a mixture of 15 g of sodium carbonate, 200 ml of methanol and 25 ml of water. The reaction mixture was allowed to stand for 24 hours, after which the mixture was acidified with 200 ml of 2-normal hydrochloric acid. The acidified mixture was extracted with methylene chloride, the extracts combined, washed with water, dried over sodium sulfate and evaporated, whereby 2-(6-methoxy-2-naphthyl)propionic acid was produced.

Manufacturing 3.

230 g of dl-2-(6-methoxy-2-naphthyl)propionic acid in methanol

was dissolved in 4.6 1 of hot methanol. The resulting solution was boiled until it became turbid, then sufficient methanol was added to make the solution clear again. To the hot solution was added a solution of 296 g of cinchonidine in 7.4 l of methanol heated to approx. 60°C. The solutions were combined with stirring and left at room temperature for 2 hours. After the reaction mixture had reached room temperature, it was stirred for an additional 2 hours and then filtered. The filtered solids were washed with several portions of cold methanol and then dried.

100 g of cinchonidine salt crystals were added to a stirred mixture of 600 ml of ethyl acetate and 450 ml of 2-N aqueous hydrochloric acid. After the mixture was stirred for 2 hours, the ethyl acetate layer was removed and washed with water to neutrality, dried over sodium sulfate and evaporated to give d-2-(6-methoxy-2-naphthyl)propionic acid.

Manufacturing 4.

A mixture of 0.4 g of lithium aluminum hydride and 100 ml of ethyl ether was added to a mixture of 2.3 g of d-2-(6-methoxy-2-naphthyl) propionic acid and 100 ml of ethyl ether. The mixture was stirred at 0°C for 30 minutes, after which 10 ml of ethyl acetate was added. After 1 hour, 4 ml of water was added to the mixture. The resulting mixture was filtered and evaporated under reduced pressure to give 1-2-(6-methoxy-2-naphthyl)-1-propanol.

By repeating the above procedure with the d-isomers

of compounds from preparation 2, the corresponding optical isomers of 2-(6-substituted-2-naphthyl)-1-propanols can be prepared.

The following examples illustrate the invention.

Example 1

A solution of 23 g of d-2-(6-methoxy-2-naphthyl)propionic acid in 100 ml of benzene and 20 ml of thionyl chloride was heated under reflux for 2 hours. The reaction mixture was then evaporated in vacuo, so that the corresponding acid chloride was produced. A solution of this residue in 300 ml of tetrahydrofuran was cooled to -80°C and treated with 47 g of lithium aluminum tritertiary butoxyhydride (2 molar equivalents). The reaction mixture was stirred for one hour at -80°C and then allowed to warm to room temperature and then poured into water. The mixture was then extracted with benzene, and the organic phase evaporated in vacuo, whereby d-2-(6-methoxy-2-naphthyl)-propanal was obtained, which was recrystallized from dichloromethane-hexane.

Example 2

A solution of 580 mg of 1-2-(6-methoxy-2-naphthyl)-1-propanol in 25 ml of dichloromethane is treated with 2.9 g of chromium trioxide-p-yridine complex and stirred at room temperature for 5 hours. The mixture was then completely onto a column of silica gel. Elution with dichloromethane gives 260 mg of d-(2-6-methoxy-2-naphthyl)propanal which was recrystallized from dichloromethane-hexane. (Melting point 70-?2oC,

/ a7~ + 151° in dioxane.

Claims (1)

Analogous process for the preparation of therapeutically active d-2-(6-substituted-2-naphthyl)-propanals with the general formula: o where R is a 'methoxy- or methylthio group,' characterized in that a) the corresponding 1-2-(6-substituted-2-naphthyl)-propanol is oxidized, or b) the corresponding d-2-(6-substituted-2 -naphthyl)propionic acid is subjected to reduction.