NO122372B - - Google Patents

Description

Analogy method in manufacturing

of therapeutically active esters of substituted 3-indolyl-lower aliphatic acids.

The present invention relates to an analogous method for the production of a new group of therapeutically active esters of substituted α-(3-indolyl)-lower aliphatic 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, benzyl-oxy, benzoyl, amino, mono- or di -lower alkylamino, lower alkanoylamido, aminomethyl, N ,N-di-(lower alkyl)-carboxamido, nitro, 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,

R is hydrogen, lower alkyl or lower alkenyl,

R 1 is benzyl or lower alkyl except t-butyl, and

R,, is hydrogen, lower alkyl, lower alkenyl, lower alkoxy, di-lower alkylamino, lower alkanoylamido, N-lower alkyl-lower alkanoylamido, di-lower alkylaminomethyl, halogen, polyhalomethyl, nitro, cyano, mercapto, benzylthio, dimethylsulfamoyl, morpholinyl, N-methyl-piperazinyl, N-pyrrolidyl or N-azacyclopropyl.

A very important feature of these new compounds is the presence of one of the indicated aroyl groups bound to the nitrogen atom in the 1-styl ring in the indole. These aroyl groups can further be substituted in the aromatic ring as indicated above.

In the preferred starting materials, R 2 is hydrogen or a lower alkyl, lower alkoxy, preferably methoxy, nitro, amino or di-lower alkylamino, preferably dimethylamino group.

The α-(3-indolyl)-lower aliphatic acids are e.g. α-(3-indolyl) derivatives of acetic acid, propionic acid, butyric acid, valerian acid and similar acids.

The aforementioned new therapeutically active compounds 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.

The preferred process compounds are the benzyl ester and

the lower alkyl esters, except the t-butyl ester, of l-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolyl-acetic acid and l-(p-chlorobenzoyl)-2-methyl-5-dimethylamino-3-indolyl -acetic acid.

According to the present invention, the therapeutically active compounds of formula I are prepared by a compound of formula:

where R2, R^, R^ and R^ are as above, and M is an alkali metal, is acylated by reaction with a halide, anhydride, azide or a nitrophenyl ester of an acid of the formula R^-COOH, where R^ is as above indicated.

The preferred compounds according to the invention are prepared by an N-alkali metal salt of the benzyl ester or a lower alkyl ester, excluding the t-butyl ester, of 2-methyl-5-methoxy-3-indolyl-acetic acid, respectively 2-methyl-5-dimethylamino-3- indolyl-acetic acid, is reacted with a halide, anhydride, azide or a nitrophenyl ester of p-chlorobenzoic acid.

The following compounds are representative of the process products according to the invention and can be prepared by the above-mentioned process: Methyl-α-(1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl)-acetate, methyl-α-(1 -p-chlorobenzoyl-2,5-dimethyl-3-indolyl)-acetate, methyl-a-(1-p-methylthio-benzoyl-2-methyl-5-methoxy-3-indolyl)-acetate, ethyl-a-(1 -p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl)-propionate, ethyl-α-[1-(2,4-dichlorobenzoyl)-2-methyl-5-methoxy-3-indolyl]-propionate and benzyl α-[1-(naphthoyl)-2-methyl-5-methoxy-3-indolyl]-acetate.

The starting materials used in the present method are preferably prepared by treating a compound of the formula II where M is hydrogen with an alkali metal hydride, for example sodium hydride to form, for example, a sodium salt, which is then, according to the invention, brought into intimate contact with an acylating agent, as indicated above, in an anhydrous solvent. It is preferred to use solvents such as dimethylformamide, dimethylformamide-benzene, benzene, toluene or xylene. It is preferable to carry out the acylation at room temperature, although lower temperatures can be used if there is a risk that the special reactants may undergo decomposition.

An alternative method for acylation in the 1-position is to use a nitrophenyl ester of the acylating acid, such as e.g. the p-nitrophenyl ester. The latter is prepared by mixing the acid and p-nitrophenol in tetrahydrofuran and slowly adding dicyclohexylcarbodiimide in tetrahydrofuran. The dicyclohexyl urea that is formed is removed by filtration, and the nitrophenyl ester is recovered from the filtrate. Alternatively, the anhydride or azide of the acylating acid can be used.

In all cases, the acylation of the compound of formula II is carried out by forming a metal salt, in particular the sodium salt, of the acid with the metal hydride in an anhydrous solvent and adding the nitrophenyl ester.

The indolyl-carboxylic acid compounds which are used as starting material in the reaction described above, and which have the formula II, can be synthesized in different ways. These compounds are preferably prepared by reacting a suitably substituted phenylhydrazine (III) with a compound of the formula IV to form a phenylhydrazone which is cyclized under the reaction conditions to the indole compound:

where R^, Rg, R, and R^ are as indicated above. The reaction is normally carried out in a lower alkanol such as e.g. methanol, ethanol, isopropanol or butanol, containing an acid such as hydrochloric acid, hydrogen bromide, sulfuric acid or acetic acid, or in an aqueous mineral acid,

such as concentrated hydrochloric acid, hydrogen bromide, sulfuric acid or acetic acid, or other Lewis acids, such as ZnCl2» BF3> SnCl^ and the like. The acid serves as a catalyst in condensation and ring-closing reactions

the ions leading to the indole compound II. To avoid the possibility of transesterification, the solvent is preferably the same alcohol as in the ester. When R 2 is hydrogen, it is convenient to use the aldehyde in the form of an acetal, for example methyl-y.Y-dimethoxybutyrate. An acid addition salt of the phenylhydrazine reactant, e.g. the hydrochloride, is usually preferred to the free base for practical reasons, although such salts and the base are equivalent in the reaction itself.

Formation of the compound of formula II is carried out at an elevated temperature, and good results are obtained when the reaction mixture is heated under reflux for at least 15 minutes. A longer reaction time is not harmful and can be used if desired. The desired compound is recovered from the reaction mixture and purified, e.g. by solvent extraction, chromatography and/or distillation. As the esters of formula II are low-melting solids, they can be conveniently purified by distillation under reduced pressure.

The benzyl ester is obtained by preparing the free α-(1-unsubstituted-3-indolyl)-carboxylic acid and esterifying this with benzyl alcohol in an inert solvent with an acidic catalyst (sulfuric acid, arylsulfonyl acids, etc.). Alternatively, these benzyl esters of formula II are synthesized directly by using the benzyl ester of the suitable levulinic acid in the original synthesis of the indole ring, or it is prepared from other esters by base-catalyzed ester exchange.

Alternatively, it is possible to first prepare an indole with the formula:

where R 2 and R 1 are as indicated above, and then introduce the carboxylic acid residue in the 3-position. This is carried out by treating the indole of formula V with formaldehyde-dialkylamine under Mannich reaction conditions, whereby a substituted gramine is formed, and then reacting this compound with an alkali metal cyanide in a lower alkanol and finally hydrolysing with a strong base such as f .ex. sodium or potassium hydroxide.

While this method for introducing the carboxylic acid residue in the 3-position after formation of the indole ring is of course generally applicable to compounds with the above structure, it is particularly suitable for the preparation of compounds in which R2 is an alkyl radical other than methyl, e.g. a 2-ethyl, 2-propyl, 2-allyl and the like. Compounds with the formula V can be easily prepared according to methods described in the literature.

Products with a halogen, cyano, alkyl, aryl, aralkyl, nitro or hydrocarbonoxy group are produced via a synthesis starting from a substituted 2-nitrobenzaldehyde or 2-nitrotoluene.

The synthesis of various compounds where the indole ring system has a 5-substituent which has a nitrogen atom attached to the homocyclic ring of the indole is generally based on the 5-nitro compound. This is converted to the desired 5-substituent. Such conversion can take place before or after acylation of the 1-position, depending on the extent to which the desired 5-substituent can affect the acylation. If such an effect is possible, the 1-acylation should be carried out on the 5-nitroindole and the nitro group later converted to the desired 5-substituent. Such conversion can be carried out in several ways. Reduction of the 5-nitro group gives a 5-amino group which is transferred with alkyl halides to dialkylamino groups. If the alkyl halide is an α,u»-dihaloalkane (e.g. 1,4-dibromobutane), a heterocyclic ring (e.g. pyrrolidine ring) is formed. Similarly, bis-(p-chloroethyl) ether will give an N-morpholine compound. Alkylation can also be carried out simultaneously with reduction, e.g. with formaldehyde and Raney nickel and hydrogen. Acylation can likewise be carried out with the 5-amino compounds or with the 5-nitro compounds (and simultaneous reduction) to form 5-acylamido compounds.

The anti-inflammatory effect of the process compounds is evident from a granuloma-inhibiting test which is carried out as follows: The test is a modification of the one described by Meier et al. (Experientia 6 1950, 469). It mainly consists in implanting sterilized cotton pellets in rats, removing the pellets after 7 days (system test) or 5 days (local test), and determining the increase in 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 introduced 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 systemic tests, the average granulomatous weight of the two samples in each animal constituted the individual result. The test compounds were given orally once a day by introduction 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 - 4 with the following meaning:

1 about as good as acetylsalicylic acid

2 about as good as phenylbutazone

3 lo - 25 times as good as phenylbutazone

4 50 - lOO times as good as phenylbutazone

The compounds used and their activity appear in table 1.

Example 1

Ethyl α-(1-p-methylthiobenzoyl-2-methyl-5-methoxy-3-indolyl)-propionate

A suspension of 2.3 g (0.046 mol) of 50% sodium hydride/mineral oil in 250 ml of dimethylformamide is stirred for 20 minutes under nitrogen and cooling with ice. 8,6,4 9 (0.035 mol) ethyl-α-(2-methyl-5-methoxy-3-indolyl)-propionate is then added, and the mixture is stirred for 20 minutes. 8.6 g (0.046 mol) of p-methylthiobenzoyl chloride in 50 ml of dimethylformamide are added dropwise over 30 minutes. The mixture is stirred in an ice bath under nitrogen for 5 hours. It is then poured into a mixture of 500 ml of ether, 5 ml of acetic acid and 1 liter of ice water. The organic products are extracted with 3 x 300 ml of ether. The ether solutions are mixed and washed with a large amount of water and dried over sodium sulfate. The solution is filtered, evaporated almost to dryness, and the residue is passed through a column containing 300 g of aluminum oxide. The ethyl α-(1-p-methylthiobenzoyl-2-methyl-5-methoxy-3-indolyl)-propionate is eluted with 10% ether in petroleum ether. It is obtained as a yellow oil when the eluates are evaporated to dryness.

The starting material of p-methylthiobenzoyl chloride is obtained by

that a mixture of 27 g (0.15 mol) p-methylthiobenzoic acid and 21.4 g (0.18 mol) thionyl chloride is heated on a water bath for 1 hour.

About. 20 ml of benzene are then added and evaporated. The remaining solution is centrifuged and diluted with petroleum ether. On cooling, the acid chloride is separated, m.p. 40 - 44°C.

When using methyl-(2-methyl-5-methoxy-3-indolyl)-acetate and ethyl-α-(2-methyl-5-methoxy-3-indolyl)-butyrate as starting material in the process described above, respectively methyl-(1-p-methylthiobenzoyl-2-methyl-5-methoxy-3-indolyl)-acetate and ethyl α-[1-(p-methylthiobenzoyl)-2-methyl-5-methoxy-3-indolyl]-butyrate.

Example 2

Methyl g-(1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl)-acetate

To 3.9 g (0.078 mol) of 51% sodium hydride/mineral oil suspended in 150 ml of distilled dimethylformamide in a 1 liter 3-necked flask is added with stirring at 0°C 9.5 g (0.040 mol) of methyl-(2-methyl- 5-methoxy-3-indolyl)-acetate in 150 ml of dimethylformamide. The mixture is stirred for 1 hour, after which 9.1 g (0.052 mol) of p-chlorobenzoyl chloride in 50 ml of dimethylformamide are added dropwise over 30 minutes. The reaction mixture is stirred for a further 30 minutes at 0°C and is then allowed to stand for 12 hours under cooling.

The reaction mixture is filtered, and the solids are washed with ether. The ether is added to the filtrate, which is then washed with water and dried over sodium sulphate. After filtering off the sodium sulphate, add approx. 75 g of acid-washed aluminum oxide to the ether solution, and this mixture is evaporated to dryness. The indole-coated alumina is then packed into a column containing 400 g of alumina in advance. Elute with petroleum ether containing increasing amounts of ethyl ether. Methyl-α-(1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl)-acetate is eluted with 15% ether-petroleum ether. These latter eluates are combined and evaporated to dryness. Recrystallization of the residue from benzene-petroleum ether gives essentially pure methyl α-(1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl)-acetate, m.p. 99 - 100°C.

When the method described above is carried out with ethyl-α-(2-methyl-5-methoxy-3-indolyl)-propionate or benzyl-α-(2,5-dimethyl-3-indolyl)-propionate, respectively. ethyl α-(1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl)-propionate and benzyl α-(1-p-chlorobenzoyl-2,5-dimethyl-3-indolyl)-propionate.

Example 3

Ethyl α-[l-(o-methyl-p-methylthiobenzoyl)-2-methyl-5-methoxy-3-indolyl]-propionate

A mixture of 100 ml of dimethylformamide, 5.2 g (0.02 mol) of ethyl α-(2-methyl-5-methoxy-3-indolyl)-propionate and 1.2 g (0.025 mol) of sodium hydride in mineral oil (50 % dispersion) is stirred in an ice bath under nitrogen for 1 hour. A solution of 4.0 g (0.2 mol) of 2-methyl-4-methylthiobenzoyl chloride (obtained from the acid, m.p. 159 - 162°C, and thionyl chloride) and 25 ml of dimethylformamide is then added over a period of half hour, and stirring is continued at room temperature for 16 hours. The mixture is poured into 350 ml of water, extracted with ether, and the ether solution is washed with water, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. The remaining oil is dissolved in petroleum ether (60 - 70°C) and chromatographed on 250 g of acid-washed aluminum oxide. The ethyl α-[1-(o-methyl-p-methylthiobenzoyl)-2-methyl-5-methoxy-3-indolyl]-propionate is eluted with 15% ether in petroleum ether and isolated as an oil.

I-R-AmaS<l>3 5.77 (CO); 5.94 (CO); 6.21; 6.73-

Example 4

Ethyl- g-( 1- benzoyl- 2- methyl- 5- methoxy- 3- indolyl)- propionate

To a solution of 5.22 g of ethyl-g<->(2-methyl-5-methoxy-3-indolyl)-propionate in 20 ml of dimethylformamide is added a suspension of 1.2 g of 51% sodium hydride in mineral oil in 40 ml of dimethylformamide . After stirring for 1 hour at room temperature, a solution forms

2.88 ml of benzoyl chloride in 10 ml of dimethylformamide added to initiate a moderately exothermic reaction with precipitation of sodium chloride. The reaction mixture is stirred for 6 hours, after which it is allowed to stand overnight. The mixture is poured over for approx. 200 g of ice and extracted three times with ether. The ether solution is washed with water, sodium bicarbonate and dried over potassium carbonate. After filtration, the solution is evaporated to a syrup and chromatographed in a column containing loo and acid-washed aluminum oxide, using as eluent mixtures of benzene and petroleum ether in a volume ratio of 2:1 to 3:1. A total of 1.06 g of ethyl-a-(l-

benzoyl-2-methyl-5-methoxy-3-indolyl)-propionate in the form of a thick yellow oil. The infrared spectrum showed no N-H absorption near the range 2.8-3 microns, but showed strong C=0 absorption at 5.8 and 5.95 microns, which is characteristic of resp. functional ester and amide groups.

Example 5

Ethyl-g-(1- p- chlorobenzoyl- 2- methyl- 5- methoxy- 3- indolyl)- propionate

o

13 g of ethyl-(2-methyl-5-methoxy-3-indolyl)-propionate is added to an emulsion of 2.5 g of 51% sodium hydride in mineral oil in 240 ml of dimethylformamide. The resulting mixture is stirred at room temperature for 30 minutes, and then a solution of 8.75 g of p-chlorobenzoyl chloride in 50 ml of dimethylformamide is added over 40 minutes. The mixture is then stirred in an ice bath for 4 hours under nitrogen. It is then poured into a mixture of ether, acetic acid and water as described in example 1. After working up using 200 g of aluminum oxide in the chromatography column and an elution mixture consisting of benzene and petroleum ether in the ratio 1:1, ethyl-a-( 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl)-propionate as a yellow oil.

Example 6

Benzyl -( 1- benzoyl- 2- methyl- 5- methoxy- 3- indolyl)- acetate

A. A solution of 15 g of methyl-(2-methyl-5-methoxy-3-indolyl)-acetate and 0.2 g of sodium in 60 ml of benzyl alcohol is slowly fractionated over a period of 4.5 hours in a Vigreux column, during which methanol is removed. The excess of benzyl alcohol is then removed by distillation at 6o°C (2.5 mm), whereby a residue of 18.6 g of benzyl-(2-methyl-5-methoxy-3-indolyl)-acetate was obtained.

B. 10 g of the benzyl ester obtained above is added to 3.3 g

51% sodium hydride mineral oil emulsified in 260 ml of dimethylformamide according to the method in example 1. This mixture is treated as described in example 1 in 7.7 ml of benzoyl chloride, and the reaction mixture is worked up according to the method described above using 340 g of aluminum oxide in the chromatography column and elution with 20 - 30% ether in petroleum ether. From these eluates, benzyl-(1-benzoyl-2-methyl-5-methoxy-3-indolyl)-acetate is obtained,

sm.p. 91 - 92°C. When, in step A of this example, instead of methyl-(2-methyl-5-methoxy-3-indolyl)-acetate, an equivalent amount of methyl-(2-methyl-5-dimethylamino-3-indolyl)-acetate is used and

proceeds exactly as indicated in steps A and B, benzyl-(1-benzoyl-2-methyl-5-dimethylamino-3-indolyl)-acetate is obtained.

Example 7

Ethyl-a-(l-p-fluorobenzoy1-2-methyl-5-methoxy-3-indolyl)- propionate

10.5 g of ethyl-g<->(2-methyl-5-methoxy-3-indolyl)-propionate is added to a suspension of 2.2 g of 51% sodium hydride mineral oil suspended in 240 ml of dimethylformamide. After stirring for 25 minutes, 7.5 g of p-fluorobenzoyl chloride is added slowly over 40 minutes, and the resulting mixture is stirred for 40 minutes at 10 - 15°C. The reaction mixture is then poured into 400 ml of water, and the product is isolated as described in example 4, whereby essentially pure ethyl-α-(1-p-fluorobenzoyl-2-methyl-5-methoxy-3-indolyl)-propionate is obtained.

When the process described above is carried out by reacting the sodium salt of methyl-n,-(2-methyl-5-methoxy-3-indolyl)-propionate with p-trifluoromethylbenzoyl chloride, methyl-a-(1-p-trifluoro- methylbenzoyl-2-methyl-5-methoxy-3-indolyl)-propionate.

Example 8

Methyl-[1-(p-chlorobenzoyl)-2-methyl-5-(1'-pyrrolidino)-3-indolyl]-acetate

In a dry 125 ml flask, place 1.2 g of methyl-[2-methyl-5-(1'-pyrrolidino)-3-indolyl]-acetate in 60 ml of dry dimethylformamide. This solution is cooled to 0°C, and 0.23 g of 50% sodium hydride in mineral oil is added there. This mixture is stirred for 30 minutes. A solution of 0.8 g of p-chlorobenzoyl chloride diluted with 5 ml of dry dimethylformamide is then added dropwise. The mixture is stirred for 4 hours at 0°C under a nitrogen atmosphere and then overnight at room temperature under a nitrogen atmosphere. The reaction mixture is then poured into an ice-water-ether mixture containing a few milliliters of acetic acid.

The ether layer is separated, and the aqueous layer is washed with ether. The combined ether layers are washed once with sodium carbonate and twice with water, dried over anhydrous sodium sulfate and evaporated to an oil in vacuo. The product is absorbed on 10 g silica gel and chromatographed on 60 g silica gel. The product is isolated using ether-petroleum ether in the volume ratio 1:3 to 1:1. The whole material is crystallized from ether, m.p. 62 - 64°C.

Example 9

Methyl-[1-( p- chlorobenzoyl)- 2- methy1- 5- nitro- 3- indolyl]- acetate

In a dry 250 ml flask, place 3.9 g of methyl-(2-methyl-5-nitro-3-indolyl)-acetate in 125 ml of dry dimethylformamide. This solution is cooled to 0°C, and 0.8 g of 50% sodium hydride in mineral oil is added there. The mixture is stirred under nitrogen for 30 minutes. 2.75 Q of p-chlorobenzoyl chloride in 15 ml of dry dimethylformamide are added dropwise over the course of 5 minutes. The reaction mixture is stirred for 4 hours at 0°C under nitrogen and then overnight at room temperature under nitrogen. It is then poured into an ice-water-benzene solution containing a few milliliters of acetic acid. The benzene layer is separated, and the aqueous layer is washed with benzene. The combined benzene layers are washed with sodium bicarbonate and then with water and dried over anhydrous sodium sulfate, after which they are evaporated to dryness in vacuo, the product is crystallized from benzene "Skellysolve B", m.p. 170 - 171°C.

Microanalysis: Calculated C 59.OO - H 3.91 - N 7.24.

Found: C 59.24 - H 4.00 - N 7.39-

The corresponding propionate is formed when an equivalent amount of the corresponding methyl-α-(2-methyl-5-nitro-3-indolyl)-propionate is used as starting material.

Example 10

Benzyl-[1-(p-chlorobenzoyl)-2-methyl-5-nitro-3-indolyl]-acetate

In a dry 125 ml flask, place 3.0 g of benzyl-(2-methyl-5-nitro-3-indolyl)-acetate in 60 ml of dry dimethylformamide. The solution is cooled to 0°C in a nitrogen atmosphere and 0.475 g of 50% sodium hydride in mineral oil is added. The whole thing is stirred for 30 minutes. Then 1.65 g of p-chlorobenzoyl in 10 ml of dry dimethylformamide are added dropwise over the course of 5 minutes. The reaction mixture is stirred at 0°C for 4 hours under a nitrogen atmosphere and then at room temperature under nitrogen overnight. It is then poured into a mixture of ice water and benzene. The benzene layer is separated, and the aqueous layer is washed with benzene. The combined benzene extracts are washed with sodium bicarbonate and then with water, dried with anhydrous sodium sulfate and evaporated to dryness in vacuo. The product is crystallized from benzene "Skellysolve B", m.p. 166 - 167°c.

Microanalysis: Calculated C 64.86 - H 4.14 - N 6.05-

Found: C 64.78 - H 4.22 - N 5.91.

Example 11

Methyl-[1-(p-chlorobenzoyl)-2-methyl-5-(N-methylacetamido)-3-indolyl]-acetate

Methyl-[1-(p-chlorobenzoyl)-2-methyl-5-acetamido-3-indolyl]-acetate is added to a suspension of sodium hydride in dimethylformamide with stirring and ice-cooling. After 1 hour, methyl iodide is added, and the mixture is stirred overnight. The reaction mixture is poured into ice water and extracted with ether. Evaporation of the ether solution and chromatography of the remaining oil on aluminum oxide using 15 - 25% by volume of ether in petroleum ether as eluent gives methyl-|1-(p-chlorobenzoyl)-2-methyl-5-(N-methylacetamido)-3- indolyl] acetate.

Example 12

Methyl -[ 1-(p-chlorobenzoyl)-2-methyl-5-cyano-3-indolyl]-acetate

Acylation of methyl1-(2-methyl1-5-cyano-3-indolyl)-acetate in dimethylformamide with sodium hydride and p-chlorobenzoyl chloride according to the procedure in example 1 gives methyl-[1-(p-chlorobenzoyl)-2-methyl-5- cyano-3-indolyl]-acetate .

Example 13

Ethyl-g-(l-benzoyl-2-methyl-5-methoxy-3-indolyl)-acrylate

In a 250 ml round flask (flame-dried apparatus) 100 ml of dry dimethylformamide and 12.4 g of ethyl-α-(2-methyl-5-methoxy-3-indolyl)-acrylate are added at 0°C under nitrogen. 2.5 g of 50% sodium hydride in mineral oil is added. The mixture is stirred for 30 minutes, after which a solution of 11 g of p-nitrophenylbenzoate in 50 ml of dry dimethylformamide is added over the course of 15 minutes. The reaction mixture is stirred for 4 hours at 0°C under nitrogen and then at room temperature under nitrogen overnight. The reaction mixture is then poured into an ice-water-ether solution containing a few milliliters of acetic acid, and the layers are separated. The aqueous phase is washed with ether, and the ether extracts are combined. A saturated solution of hydrogen chloride gas in dry ether is added to the ether layers. The ether is decanted, whereby a heavy oil remains. The oil is washed with ether, after which aqueous sodium bicarbonate solution is added. The product is then extracted with ether. The ether layer is dried over anhydrous sodium sulfate and evaporated to dryness. The ethyl α-(1-benzoyl-2-methyl-5-methoxy-3-indolyl)-acrylate obtained is crystallized from dry ether.

Example 14

When benzyl-α-(2-methyl-5-methoxy-3-indolyl)-propionate, benzyl-(2-methyl-5-methoxy-3-indolyl)-acetate and benzyl-(2-methyl-5-nitro- 3-indolyl)-acetate is reacted by the method in example 13 with the p-nitrophenyl ester of p-difluoromethoxybenzoic acid, respectively. benzyl-α-[l-(p-difluoromethoxybenzoyl)-2-methyl-5-methoxy-3-indolyl]-propionate , benzyl-[l-(p-difluoromethoxybenzoyl)-2-methyl-5-methoxy-3-indolyl ]-acetate and benzyl-[1-(p-difluoromethoxybenzoyl)-2-methyl-5-nitro-3-indolyl]-acetate.

Example 15

The acylation procedures in example 2 are followed using different aromatic acyl chlorides in equivalent amounts instead of p-chlorobenzoyl chloride, as well as esters of 2-methyl-5-methoxy-3-indolyl-acetic acid or of a-(2-methyl-5-methoxy-3- indolyl)-propionic acid. The products obtained in these experiments are: methyl-[1-(p-bromobenzoyl)-2-methyl-5-methoxy-3-indolyl]-acetite, m.p. 106 - 107.5°C, methyl-[1-(p-nitrobenzoyl)-2-methyl-5-methoxy-3-indolyl]-acetate, m.p. 130 - 132°C, methyl-[1-(o-chlorobenzoyl)-2-methyl-5-methoxy-3-indolyl]-acetate, m.p. 91 - 93°C, methyl-[1-(m-chlorobenzoyl)-2-methyl-5-methoxy-3-indolyl]-acetate, m.p. 51 - 52°C, methyl-[1-(p-phenylbenzoyl)-2-methyl-5-methoxy-3-indolyl]-acetate, m.p. 101.5 - 103°C, methyl-[1-(p-acetoxybenzoyl)-2-methyl-5-methoxy-3-indolyl]-acetate, m.p. 99 - 101°C, t-butyl-α-[1-(p-bromobenzoyl)-2-methyl-5-methoxy-3-indolyl]-propionate, m.p. 103 - 105°C, methyl-[l~(α-naphthoyl)-2-methyl-5-methoxy-3-indolyl]-acetate (oil), methyl-[l-(p-benzyloxybenzoyl)-2-methyl- 5-methoxy-3-indolyl]-acetate,

sm.p. 116 - 118°C, methyl-[1-(p-hydroxybenzoyl)-2-methyl-5-methoxy-3-indolyl]-acetate, m.p. 155 - 158°C (prepared from the p-benzyloxy-benzoyl compound by catalytic hydrogenation in the presence of palladium) , methyl-[l-(o-benzyloxybenzoyl)-2-methyl-5-methoxy-3-indolyl]-acetate (not isolated - used for the preparation of the next compound by catalytic hydrogenation in the presence of palladium), methyl-[l-(o-hydroxybenzoyl)-2-methyl-5-methoxy-3-indolyl]-acetate (oil), methyl-[l -(o-fluorobenzoyl)-2-methyl-5-methoxy-3-indolyl]-acetate, m.p. 98 - 99°C, methyl-[1-(O-naphthoyl)-2-methyl-5-methoxy-3-indolyl]-acetate, m.p. 120 - 124°C, methyl-[1-(2,6-dimethoxybenzoyl)-

2-methyl-5-methoxy-3-indolyl]-acetate, m.p. 139.5 - 141°C, methyl-[1-(o,p-dichlorobenzoyl)-2-methyl-5-methoxy-3-indolyl]-acetate (oil).

Example 1°

Methyl-(1-p-chlorobenzoyl-2-methyl-1-5-dimethylamino-3-indolyl)-acetate

To a solution of 0.387 g of methyl-α-(1-p-chlorobenzoyl-2-methyl-5-nitro-3-indolyl)-acetate in 20 ml of distilled dimethoxyethane is added 1.5 ml of glacial acetic acid and. 0.5 ml of a 37% aqueous formaldehyde solution. This mixture is reduced with Raney nickel at 2.8 kg/cm and room temperature. After the theoretical amount of hydrogen has reacted, the mixture is filtered, evaporated in vacuum to a small volume and diluted with ether. The ether solution is washed with sodium bicarbonate and then with water and dried with anhydrous sodium sulfate, after which it is evaporated in vacuo and methyl-(1-p-chlorobenzoyl-2-methyl-5-dimethylamino-3-indolyl)-acetate remains as an oil. Micro-analysis: Calculated C 65.50 - H 5.50 - N 7.28.

Found: C 65.66 - H 5.91 - N 7.46.

Example 17

Methyl-(l-p-chlorobenzoyl-2-methyl-5-acetamide p-3-indolyl)-acetate

To 0.388 g of methyl-(1-p-chlorobenzoyl-2-methyl-5-nitro-3-indolyl)-acetate in 30 ml of anhydrous ethyl acetate, 0.306 g of acetic anhydride is added. The mixture is reduced with Raney nickel at room temperature and 2.8 kg/cm . After the theoretical amount of hydrogen has been absorbed, the catalyst is removed by filtration. The solution is evaporated in vacuum to a small volume and poured into a water-ether mixture. The ether layer is separated, and the aqueous layer is washed with ether. The combined ether extracts are washed with sodium bicarbonate and then with water, dried with anhydrous sodium sulfate and evaporated to dryness in vacuo. The methyl-(1-p-chlorobenzoyl-2-methyl-5-acetamido-3-indolyl)-acetate obtained is crystallized from benzene and ether, m.p. 176 - 177°C.

Microanalysis: Calculated C 63.25 - H 4.8o - N 7.02.

Found: c 63.4o - H 4.82 - N 6.89.

Claims (1)

1. Analogous method for the preparation of therapeutically active esters of substituted 3-indolyl-lower aliphatic 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, benzyl-oxy, benzoyl, amino, mono- or di -lower alkylamino, lower alkanoylamido, aminomethyl, N,N-di-(lower alkyl)-carboxamido, nitro, 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, R2 is hydrogen or lower alkyl, R^ is hydrogen, lower alkyl or lower alkenyl, R^ is benzyl or lower alkyl except t-butyl, and Rj- is hydrogen, lower alkyl, lower alkenyl, lower alkoxy, di-lower alkylamino, lower alkanoylamido, N-lower alkyl-lower alkanoylamido, di-lower alkylaminomethyl, halogen, polyhalomethyl, nitro, cyano, mercapto, benzylthio, dimethylsulfamoyl, morpholinyl, N-methylpiperazinyl, N-pyrrolidyl or N-azacyclopropyl, characterized by that a compound of the general formula: where R2, Rg, R^ and R^ are as indicated above, and M is an alkali metal, is acylated in a manner known per se with a halide, anhydride, azide or a nitrophenyl ester of an acid with the general formula: