NO163148B - PROCEDURE FOR PLANNING A SEALING SYSTEM ON A OFFSHOREBORE PLATFORM. - Google Patents

Description

Process for the production of substituted 3-indolyl acetic acids.

The present invention relates to a new process for the production of substituted 3-indolyl acetic acids with the general formula:

where

is phenyl, biphenylyl or naphthyl which may be substituted

with hydroxyl, lower alkyl, lower alkoxy, carbo-lower alkoxy, lower.alkanoyl, .lower alkanoyloxy, phenyl, phenoxy, benzyl, benzyloxy, benzoyl, amino, mcno- or di-lower alkylamino, lower alkanoylamido, N,N-di -(lower alkyl)-earboxamido, .aminomethyl,' cyano, halogen, halogen-lower alkyl, halogen-lower alkoxy, halogen-lower alkanoyl', mercapto, lower alkylthio, halogen-lower alkylthio, phenylthio, benzyl • thio, benzoylthio, lower alkylsulfonyl, lower alkylsulfinyl or di-(lower alkyl)sulfamoyl,

PL-, is hydrogen or lower alkyl, and

R,j is hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkoxy, amino, monolower-alkylamino, di-lower alkylsmino, bis-hydroxyethylamino, lower alkanoylamido, aminomethyl, N-lower alkyl-lower alkanoylamido, di-lower alkylaminomethyl, halogen, cyano, di-lower alkylsulfamoyl, morpholino, N-methylpiperazinyl, N-pyrrolidyl or N-azacyclbpropyl.,

A very important feature of the process compounds is the presence of one of the indicated aroyl groups bound to the nitrogen atom in the 1-position of the indole.

In the preferred process products are lower alkoxy, preferably methoxy, or lower alkylamino, preferably dimethylamino.

The salts of these 1-aroyl-3-indolyl-acetic acids can be obtained by treating the free acid with a base under mild conditions. In this way, one can prepare alkali metal salts such as sodium and potassium, aluminum or magnesium salts, or salts of alkaline earth metals, for example barium and calcium salts.

It is known from the Journal of Organic Chemistry 2Q, page 1177,

to catalytically reduce sodium 3-indolylglyoxylate to form 70% sodium 3-indolylglycolate and 10% 3-indolylacetic acid.

It is further known from Belgian patent no. 615-395 that 1-acyl-3-indolyl-acetic acid benzyl esters can be hydrogenolysed without attack on the 1-acyl group.

However, no conclusions can be drawn from these reactions regarding the reaction conditions that are necessary to carry out steps. 1 of the present method.

The method compounds discussed above have a high degree of anti-inflammatory activity and can be used to prevent and inhibit the formation of granuloma tissue. Some of them have this activity to a strong degree and are of value in the treatment of arthritis and dermatological diseases and similar conditions that respond to treatment with anti-inflammatory agents. In addition, the process products have antipyretic activity to a considerable extent. For these purposes, they are normally used orally in the form of tablets or capsules, and the optimal dose obviously depends on the particular compound used and on the nature and degree of the infection. Although the optimal amounts of these compounds will depend on the compound used,

and of the particular disease state to be treated, the preferred compounds can be orally used in amounts within the range of 1.0 - 200 mg per day in the case of arthritis, depending on the activity of the particular compound and the patient's responsiveness.

According to the invention, the compounds of formula I are prepared by hydrogenating a compound of the general formula: where R-^ and R^ are as indicated above, and R'^ is R^ or nitro, at a pressure of approx. lh kg/cm^, in the presence of a palladium catalyst in an inert solvent such as dioxane, and that it formed a compound of the general formula:

where R-p Rp and R ^ are as indicated above, is heated in an inert solvent in the presence of a catalytically effective amount of a strong acid, and that the acid thus formed, if desired, is transferred to a salt thereof in a manner known per se .

Preferred connections are obtained by starting from a connection

of formula II where R^ is p-chlorophenyl, R^ is methyl and R^ is methoxy or dimethylamino.

The 1-aroyl-3-indolyl acetic acids described herein are prepared by converting a t-butyl ester in the second step to the free acid under suitable reaction conditions. It has been observed that the 1-aroyl substituent is readily hydrolyzed under conditions commonly used in the saponification of an ester to the free acid. For this reason, care must be taken in the conversion of the 1-aroyl-3-indolyl-acetic acid ester to the corresponding free acids.

The anti-inflammatory effect of the process compounds is evident from a granuloma-inhibiting test which is carried out as follows:

The proof is one modification of the one described by Meier

and collaborators (Experientia 6 1950, *+69) • It consists mainly in the implantation of sterilized cotton pellets on rats, the removal of the pellets after 7 days (system sample) or 5 days (local sample), and determination of the oknirigen of dry weight of each pellet.

The: initial weight of the pellets varied from trial to trial, but within one and the same trial all were within a tolerance of + 1 mg. Two pellets were injected into each animal, one on each side of the abdominal cavity. When the local effect of a compound was to be studied, the compound was placed on a pellet in a medium containing a wetting agent, while the medium alone was used on the other pellet, so that each animal was its own control. In the case of systemic samples, the average granuloma dry weight of the two samples in each animal constituted the individual result. The test compounds were given orally once a day by insertion into the stomach with a probe.

In all experiments, male Holtzman rats over a body weight of approx. 125 - 175 g. The activity was expressed by the numbers 1 - h with the following meaning:

1 about as good as acetylsalicylic acid

2 " " " " phenylbutazone

3 10 - 25 times as good as phenylbutazone

h 50 -100 " " " " "

The compounds used and their activity are shown in the following table.

Example

Step 1

^-.38 g of t-butyl-1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl-glyoxylate are dissolved in 50 ml of dry dioxane and hydrogenated at 30°C under a pressure of lh kg/cm 2 under using 1.0 g of palladium p<å>o carbon catalyst with 10% palladium. The hydrogenation is complete after 8 hours.

The catalyst is then filtered off and the filtrate is evaporated, whereby an oily substance is obtained. This residue is recrystallized from 25 ml of hexane. t-Butyl-1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolyl-acetate is obtained.

Step 2

300 ml of p-toluenesulfonic acid monohydrate (1.0 g) is added to benzene containing t-butyl-1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolyl acetate (0.03 mol), and the resulting mixture heated under reflux and stirring in a nitrogen atmosphere for ^0 minutes. Below this, 665 ml of isobutylene is developed (theoretically 672 ml). The reaction mixture is diluted with 200 ml of benzene at a temperature of

55 - 60°C and washed with hot water at 60 - 65°C to a pH value

of k - 5. The hot solution in benzene (temperature 60 - 65°C) is freed from water with sodium sulfate and decolorized by adding 1.0 g of Darco G-60. The solution is then filtered while hot and evaporated to a volume of approx. 50 - 75 ml. The mixture is then cooled to 10°C, and left to stand for 1-5 hours. The impure 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid thus obtained is filtered off, washed twice with 5 ml of a mixture of benzene and petroleum ether (1:1), then twice with 10 ml petroleum ether and dried in vacuum at 25°C. The weight of the product is 9.7 g, (benzene solvate) m.p. 110 - 115°C.

9.7 g of this crude product are dissolved in 38.8 ml of t-butanol at 70°C. The solution obtained is filtered and 38.8 ml of cyclohexane are added in a warm state (60 - 70°C). The solution is cooled to 10°C, after which it is allowed to stand for 1 hour. The product is then filtered off, washed twice with 10 ml of a cold mixture of t-butanol and cyclohexane (1:1) and then twice with 10 ml of petroleum ether. It is then dried in a vacuum at 80°C in a nitrogen atmosphere. The product obtained is 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolyl-acetic acid with a melting point of 153 - 154°C.

Claims (1)

Procedure for the production of substituted 3-indolyl acetic acids with the general formula: where R-^ is phenyl, biphenylyl or naphthyl which may be substituted with hydroxyl, lower alkyl, lower alkoxy, carbo-lower alkoxy, lower alkanoyl, lower alkanoyloxy, ■phenyl, phenoxy, benzyl, benzyloxy, benzoyl, amino, mono- or di-lower alkylamino, lower alkanoylamido, N,N-di-(lower alkyl)-carboxamido, aminomethyl, cyano, halogen, halogen-lower alkyl, halogen-lower alkoxy, halogen-lower alkanoyl, mercapto, lower alkylthio, halogen-lower alkylthio, phenylthio, benzylthio, benzoylthio, lower alkylsulfonyl,. lower alkylsulfinyl or di-(lower alkyl)-sulfamoyl, R 2 is hydrogen or lower alkyl, and R 2 is hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkoxy, amino, monolower alkylamino, di-lower alkylamino, bis-hydroxyethy]ainino, lower alkanoylamido, aminomethyl, N-lower alkyl- lower alkanoylamido, di-lower alkylaminomethyl, halogen, cyano, di-lower alkylsulfamoyl, morpholino, N-methylpiperazinyl, N-pyrrolidyl or N-azacyclopropyl, as well as salts thereof, characterized in that a compound with the general formula: where R 1 and R 2 are as indicated above, and R 1 is R 2 or nitro, is hydrogenated at a pressure of approx. 1^ kg/cm^, in the presence of a palladium catalyst in an inert solvent such as dioxane, and that it formed a compound with the general formula: where R^, B.^ and R^ are as indicated above, is heated in an inert solvent in the presence of a catalytically effective amount of a strong acid, and that the acid thus formed is, if desired, transferred to a salt thereof of i and familiar way.