NO126865B - - Google Patents

Description

Analogy method for the preparation of therapeutic

active l-acyl-3-indolylaliphatic acid derivs.

The present invention relates to a process for the production of new therapeutically effective l-acyl-3-indolylaliphatic acid derivatives with the general formula:

where R"1" is an alkyl group, halogen-substituted alkyl group or alkenyl group with up to 10 carbon atoms, R 2 is methyl, R 3 is a hydrogen atom or a lower alkyl group, R^ is a lower alkoxy group, lower -alkyl or lower alkylthio group, and n is 0, 1 or 2, provided that R 1 is a substituent in the 4-, 5- or 6-position of the indole nucleus.

These derivatives can be prepared using different methods and according to the present invention the desired acid derivatives are thus prepared by

a) that a compound with the general formula:

1 2 6

where R , R , R , R and n have the same meaning as stated above, and R 5 is an alkoxy, amino or benzyloxy group, is decomposed to the free acid in a manner known per se, or

b) that for the preparation of the compound of formula I where

in is 0, a 1-acyl-3-hydroxy-2,3-dihydro-3-indolylacetic acid derivative

with the general formula:

12 6 ^) ' where R , R and R .have the same meaning as stated above, and R is a hydroxy or alkoxy group, is dehydrated and possibly simultaneously hydrolysed, on i and. known manner, or

c) that for the preparation of compounds of formula I where

• n is 0, a l-acyl-2,3-dihydro-3-indolylaliphatic acid derivative with

the general formula:

where R 1 , R 2 , R-"5 3 and R 6 have the same meaning as stated above, is dehydrogenated in a manner known per se.

The alternative methods indicated above can be illustrated in more detail as follows:

A benzyl ester of a 3-indolylaliphatic acid derivative is hydrogenated, e.g. in the presence of a suitable metal catalyst, e.g. palladium, whereby the ester is decomposed into the free form. 3-indoly1-fatty acid derivative. The reaction follows the following scheme:

When e.g. a tertiary butyl ester of said acid is treated in the presence of an arylsulfonic acid, e.g. p-toluenesulfonic acid, then it is hydrolysed to the desired product. In certain cases, the desired product can be obtained by simply heating and melting the tertiary butyl ester.

The reaction goes e.g. according to the following form:

When a 3-indolyl fatty acid araid is further treated in an inert solvent in the presence of a suitable amount of nitric acid,* then in certain cases the desired, free 3-indolylaliphatic acid can be obtained. The 1-acyl-3-indolylacetic acid derivatives with formula I can, as mentioned, also be obtained by dehydration and possibly simultaneous hydrolysis of 1-acyl-3-hydroxy-2,3-dihydro-3-indolylacetic acid derivatives with the general formula: ;12 5 6 ; where R , R , R and R have the meaning stated above. The reaction usually proceeds readily by heating the compounds in an inert solvent with stirring. The reaction temperature should be in the range from 70° to 200°C. However, if the reaction should not proceed readily, the compound can either be refluxed azeotropically using benzene, toluene or xylene as a solvent together with water, or the compound can be heated in the presence of a suitable dehydrating agent, e.g. a suitable amount of anhydrous sodium sulphate, whereby a dehydration reaction takes place. ;If R-> is an alkyl group, such as e.g. t-butyl, the compound is treated in the presence of an arylsulphonic acid, whereby the compound is dealkylated to the desired free acid without N-substituents being affected. The 1-acyl-3-hydroxy-2,3-dihydro-3-indolylacetic acid derivative which was used as starting material in the above-mentioned method is prepared by adding a haloacetic acid ester to the corresponding 1-acyl-indoxyl derivative, after which the mixture is heated while stirring in a non-polar organic solvent in the presence of zinc grains, and, if necessary, in the presence of a little iodine. An example of the above-mentioned reaction is the following: When you then carry out dehydration and hydrolysis of the ester, you will obtain the desired 1-(2<1>,4'-hexadienoyl)-2-methyl-5-methoxy-3 -indolylacetic acid. ;The desired 1-acyl-3-indolylaliphatic acid compounds can, as mentioned, also be prepared by dehydrogenating 1-acyl-2,3-dihydro-3-indolylaliphatic acid derivatives with the general formula: ;where R 1 , R q , R-^ 7 and R CL has the above meaning. In this dehydrogenation reaction, non-polar solvents such as benzene, xylene and toluene can be used as well as other organic solvents such as acetone, acetic acid, chloroform, ethanol or methanol. Chloral, selenium dioxide, halogen and similar compounds can be used as oxidizing compounds. ;The 1-acyl-2,3-dihydro-3-indolylaliphatic acid derivative used is obtained in high yield by reacting the corresponding 2,3-dihydro-3-indolylaliphatic acid derivative with acyl chloride in the presence of an alkaline reagent. The l-acyl-3-indolylaliphatic acid derivatives produced by the present process are new and have significant anti-inflammatory, analgesic and antipyretic effects, besides having anti-arteriosclerotic and anti-hypercholesterolemic effects. In the table below, data obtained by comparison between compounds produced according to the present method and known compounds with regard to anti-inflammatory activity are indicated. Of existing non-steroidal anti-inflammatory drugs, indomethacin has the greatest activity, but has correspondingly high toxicity. It has even been observed that when 10 mg/kg of said drug was administered orally, occult bleeding occurred in rats. In addition, all common anti-inflammatory drugs tend to promote bleeding in the digestive organs and there are a number of examples of this type of bleeding leading to death. Phenylbutazone, which is currently the most widely used anti-inflammatory agent, has low activity in relation to its high toxicity and consequently has a low therapeutic ratio. In contrast to the above-mentioned properties, the compounds prepared according to the invention have a very low toxicity, and even when up to 1000 mg/kg of the prepared acids were orally administered to rats and mice, poisoning symptoms rarely occurred, and occult bleeding could not be detected in the excrement . Nevertheless, the activity of the acid is higher than that of phenylbutazone and oxyphenbutazone. The therapeutic ratio of the manufactured compounds is thus far "greater than for any other known drug with a similar effect. In addition to this, 1-(3',3'-diethylacryloyl)-2-methyl-5-methoxy-3-indolylacetic acid, 1-(5<1->chloro-3<1->pentenoyl)-2-methyl-5-methoxy-3-indolylacetic acid, 1-heptanoyl-2-methyl-5-methoxy-3-indolyl-acetic acid, 1-t-pentanoyl-2-methyl-5-methoxy-3-indolylacetic acid, y-[1-(2',4'-hexadienoyl)-2-methyl-5-methoxy-3-indolyl]-butyric acid and 1-(4 - methylpentanoyl)-2-methyl-5-methoxy-3-indolylacetic acid similar therapeutic effects. ;Most of these compounds have higher analgesic and antipyretic effects than aminopyrine and aspirin. These compounds also have preventive effects against experimental atherosclerosis besides that they has a significant lowering effect on the blood's cholesterol content. ;The following examples illustrate the invention. ;Example 1 ;4.7 g of t-butyl-1-(2,4,-hexadienoyl)-2-methyl-5-methoxy-3-indolyl acetate was added 45 ml of benzene to the mixture, p-toluenesulfonic acid was further added and the mixture was refluxed. After heating, the reaction mixture was washed with 30 ml of a 10% aqueous sodium bicarbonate solution, and then several times washed with water and then dried. The benzene was removed by distillation under reduced pressure, and the reaction mixture was purified by recrystallization from acetone to give 1-(2',4'-hexadienoyl)-2-methyl-5-methoxy-3-indolylacetic acid, mp 161° - 162°C. ;Analysis: ;;Using the method in example 1, the following compounds were prepared: ;Example 2 ;1-decanoyl-2-methyl-5-methoxy-3-indolylacetic acid. Melting point 126°C. ;Analysis: ;;Example 3 ;1-(4'-chlorobutyloyl)-2-methyl-5-methoxy-3-indolylacetic acid, melting point 149° - 150°C. ;Analysis: ;Example 4 ;1-f 4'-methylpentenoyl^-2-methyl-5-methoxy-3-indolylacetic acid, melting point 135°C. ;Analysis: ;;Example 5 ;3.7 g of 1-acetyl-2-methyl-5-methoxy-2,3-dihydro-3-iridolylacetic acid was added to 100 ml of benzene, after which 7*5 g of chloranil was added.

The reaction mixture was heated and refluxed for 3 hours. After the solvent was removed under reduced pressure, the residue dissolved in acetone, while insoluble substances were removed. The acetone was then removed, whereby crude crystalline 1-acetyl-2-methyl-5-methoxy-3-indolylacetic acid was obtained. The crystals were recrystallized from acetone-water, and a bright yellow, pure product with melting point I63<0> - 164°C was obtained.

According to the procedure in example 5, the following compound was synthesized:

Example 6

l-chloroacetyl-2-methyl-5-methoxy-3-indolylacetic acid, melting point 156° - 157°C

Example 7

To a solution of 5.2 g of 1-(2,4-hexadienoyl)-2-methyl-3-hydroxy-5-methoxy-2,3-dihydro-3-indolylacetic acid t-butyl ester in 120 ml of toluene, 0.2 g of p- toluenesulfonic acid added. The mixture was heated under reflux for 3 hours, allowed to cool and washed thoroughly with water. The resulting solution was concentrated under reduced pressure to a residue which was recrystallized from aqueous acetone to give 1-(2,4-hexadienoyl)-2-methyl-5-methoxy-3-indolylacetic acid, mp 162°-163°C

Claims (1)

Analogous process for the preparation of therapeutically effective l-acyl-3-indolylaliphatic acid derivatives with the general formula: where R is an alkyl group, halogen-substituted alkyl group or alkenyl group with up to 10 carbon atoms, R 2 is methyl, R 3 is a hydrogen atom or a lower alkyl group, R^ is a lower alkoxy, lower alkyl or lower alkylthio group, ' and n is 0 , 1 or 2, provided that R^ is a substituent in the 4-, 5- or 6-position of the indole nucleus, characterized by) that a compound with the general formula: where r\ R^, R^, R^ and n have the meaning given above, and R^ is an alkoxy, amino or benzyloxy group, is decomposed to the free acid of formula I in a manner known per se, or b ) that for the preparation of compounds of formula I where n is 0,. a l-acyl-3-hydroxy-2,3-dihydro-3-indolylacetic acid derivative of the general formula: where R , R and R have the meaning given above, and Br is a hydroxy or alkoxy group, is dehydrated pg possibly simultaneously hydrolyzed in a manner known per se, or c) that for the preparation of compounds of formula I where in n is 0 , a l-acyl-2,3-dihydro-3-indolylaliphatic acid derivative with the general formula: 1 0 ~K £\ where R , R , R and R have the meaning stated above, is dehydrogenated in a manner known per se.