NO159490B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BETA-CARBOLIN-3-CARBOXYLIC ACID DERIVATIVES. - Google Patents

Description

The invention relates to the production of new P-carboline-3-carboxylic acid derivatives. These new compounds have valuable pharmacological properties. They act particularly on the central nervous system and are suitable for use in psychopharmaceutical preparations.

The compounds produced according to the invention are P-carboline-3-carboxylic acid derivatives with the general formula I:

in which

R<1> means alkoxy with up to 6 carbon atoms,

rA means H, F, Cl, Br, I, NO2, CN, CH3, SCH3, SO2N(CH3)2 or

NR<4>R<5> where R<4> and R<5> each means hydrogen, alkyl with up to 6 carbon atoms, benzyl or 62_6~alkenyl or C2_6~alkynyi where the alkyl groups may be substituted with a halogen atom, COOR<6> or CHOR<6>OR<7>, in which R<6> and R<7> here can mean hydrogen or alkyl with up to 3 carbon atoms, and in which R<4> and R<5 >together with the nitrogen atom can mean pyrrolidine, pyrrol , pyrazole, piperidine, hexamethylamino, piperidone: , 1,1-dioxothiazolidine,

wherein R<6> and R<7> have the above

meaning, CHR<6->OR<10>, in which R<6> has the meaning given above and R<10> means hydrogen, alkyl of up to 3 carbon atoms or the group C(=0)R<6> in which R<6 > has the above meaning,

or OR<11> which means methoxy, phenoxy or benzyloxy, or C=CR<12>, where R<12> means hydrogen, alkyl with up to 3 carbon atoms, phenyl, CHR<6>R13, where R<6> and R13 together form =0

or R<6> has the meaning given above, and R<13> means OR<1>4, NR15R1<6> a halogen atom or P(=0)OR<6>(OR<7>), where R<6 > and R<7> have the meaning given above, and R<14> means hydrogen, alkyl of up to 3 carbon atoms or the tetrahydropyranyl residue, and in which R<15> and R<16> each means hydrogen alkyl of up to 6 carbon atoms or together with the neighboring nitrogen atom forms a piperidinyl ring, the A ring can contain up to two of the above-mentioned substituents or R<c> means hydrogen, alkyl with up to 6 carbon atoms or (C<H>2)nOCH3 or (CH2)nOC2H5 and n has the values 1 or 2, provided that R<c> cannot be hydrogen, alkyl of up to 6 carbon atoms, when RA means H, F, Cl, Br, I, NO2, CN, SCH3, SO2N(<C>H3) 2 or NR4R<5> in which R<4> and R<5> have the previously stated meaning.

Unless otherwise stated, the terms "alkyl", "aryl", "aralkyl", "alkoxy", "aryloxy" and "araloxy" group are used to define saturated or unsaturated unbranched or branched groups or ring systems.

The substituents in the A ring can be in the 5-, 6-, 7- or 8-position. The A-ring can be mono- or di-substituted with the substituents RA. The 5 and 6 positions are preferred.

The description in Canadian patent no. 786,351 mentions P-carboline-3-carboxylic acid amides, which are substituted in the 1-position with an alkyl group of up to 5 carbon atoms, a trifluoromethyl, a phenyl or a benzyl group, as well as two compounds, which have no substituent in the 1-position, namely β-carboline-3-carbohydrazide and β-carboline-3-carboxylic acid amide.

In the description in Danish patent no. 98,436, a method for the production of P-carboline-3-carboxylic acid methyl ester is mentioned.

From Danish application no. 3703/80, P-carboline-3-carboxylic acid derivatives are known in the form of esters, amides and amidines as well as thio analogues thereof.

It has now surprisingly been shown that the new P-carboline-3-carboxylic acid derivatives according to the invention have

The invention relates to the production of new P-carboline-3-carboxylic acid derivatives. These new compounds have valuable pharmacological properties. They act particularly on the central nervous system and are suitable for use in psychopharmaceutical preparations.

The compounds produced according to the invention are P-carboline-3-carboxylic acid derivatives with the general formula I:

in which

R<1> means alkoxy with up to 6 carbon atoms,

RA means H, F, Cl, Br, I, N02, CN, CH3, SCH3, SO2N(CH3)2 or

NR<4>R<5> in which R<4> and R<5> each means hydrogen, alkyl with up to 6 carbon atoms, benzyl or 62^6-alkenyl or C2_6~alkynyl, the alkyl groups may be substituted with a halogen atom, COOR <6> or CH0R<6>0R<7>, in which R<6> and R<7> here can mean hydrogen or alkyl with up to 3 carbon atoms, and in which R<4> and R<5 >together with the nitrogen atom can mean pyrrolidine, pyroi, pyrazole, piperidine, hexamethylamino, piperidone: , 1,1-dioxothiazolidine,

wherein R<6> and R<7> have the above

meaning, CHR<6->OR<10>, in which R<6> has the meaning given above and R<10> means hydrogen, alkyl of up to 3 carbon atoms or the group C(=0)R<6> in which R<6 > has the above meaning,

or OR<11> which means methoxy, phenoxy or benzyloxy, or CSCR<12>, where R<12> means hydrogen, alkyl with up to 3 carbon atoms, phenyl, CHR6R1<3>, where R<6> and R1<3> together form =0

or R<6> has the above meaning, and R<13> means OR14, NR15R1<6> a halogen atom or P(=0)OR6(OR7), wherein R<6> and R<7> have the above meaning meaning, and R<14> means hydrogen, alkyl of up to 3 carbon atoms or the tetrahydropyranyl residue, and in which R<15> and R<16> each means hydrogen alkyl of up to 6 carbon atoms or together with the neighboring nitrogen atom forms a piperidinyl ring as The A-ring may contain up to two of the above-mentioned substituents or R<c> means hydrogen, alkyl with up to 6 carbon atoms or (CH2)n0CH3 or (CH2)n0C2H5 and n has the values 1 or 2, provided that R<c> does not can mean hydrogen, alkyl of up to 6 carbon atoms, when RA means H, F, Cl, Br, I, N02, CN, SCH3, SO2N(C<H>3)2 or NR<4>R<5> wherein R< 4> and R<5> have the previously stated meaning.

Unless otherwise stated, the terms "alkyl", "aryl", "aralkyl", "alkoxy", "aryloxy" and "araloxy" group are used to define saturated or unsaturated unbranched or branched groups or ring systems.

The substituents in the A ring can be in the 5-, 6-, 7- or 8-position. The A-ring can be mono- or di-substituted with the substituents RA. The 5 and 6 positions are preferred.

The description in Canadian patent no. 786,351 mentions P-carboline-3-carboxylic acid amides, which are substituted in the 1-position with an alkyl group of up to 5 carbon atoms, a trifluoromethyl, a phenyl or a benzyl group, as well as two compounds, which have no substituent in the 1-position, namely β-carboline-3-carbohydrazide and β-carboline-3-carboxylic acid amide.

In the description in Danish patent no. 98,436, a method for the production of P-carboline-3-carboxylic acid methyl ester is mentioned.

From Danish application no. 3703/80, P-carboline-3-carboxylic acid derivatives are known in the form of esters, amides and amidines as well as thio analogues thereof.

It has now surprisingly been shown that the new P-carboline-3-carboxylic acid derivatives according to the invention have 3

better psychotropic properties in pharmacological investigations than known compounds.

The process for preparing the specified 3-substituted P-carbolines with the general formula I is characterized by

a) an indole derivative of the general formula III

in which

R<c> means (CH2)nOCH3, where n has the meaning stated above,

R<18> means alkoxy with 1-6 carbon atoms, and

RA means hydrogen, a group of the formula CHR<6->OR<10>, wherein R<6> and R10 have the meaning indicated above, OR<11>, wherein R<11> has the meaning indicated above, F, Cl . 2 whereby compounds are obtained where RA is -SO2N(CH3)2 when

RA is hydrogen,

2) or compounds where RA is hydrogen are halogenated to compounds where RA is halogen" after which the halogenation product thus formed is possibly converted to

compounds where RA is nitrile, or

3) compounds where RA is hydrogen, are nitrated to compound

see where RA is nitro, after which the nitro compound thus obtained is reduced to a compound where RA is amino compound, or

4) compounds where R<c> is (CH2)OCH3 are converted to compounds where R<c> is (CH2)nOC2H5 over compounds where R<c> is

halogen or

5) transesterified in the 3 position or

b) that a P-carboline-3-carboxylic acid alkyl ester of the general formula IV

in which R<c> has the meaning given above, and R<21> means alkoxy with up to 6 carbon atoms and Hal means chlorine, bromine or iodine, is reacted with a dialkyl phosphite of the formula in which R<6> and R<7> have the above stated meaning, to obtain a compound of the formula I, wherein RA means a group of the formula

or

c) a P-carboline-3-carboxylic acid alkyl ester of the general formula IV is reacted with a compound of the formula R<12>C=CH,

in which R<12> has the above meaning, or means a protecting group and that the treatment is carried out with dilute mineral acid when R<12> means a protecting group, after which the free 3-hydroxy-1-propynyl compound thus obtained is oxidized to 3-oxo-1 -propynyl compound or is chlorinated with thionyl chloride until the propynyl compound is optionally reacted with a trialkyl phosphite of the formula POR<6>(OR<7>)2, where R<6> and R<7> have the meaning stated above to obtain the corresponding 3-dialkoxyphosphoryl -1-propynyl compound or with piperidine in the presence of strong base to obtain the corresponding 3-piperidino-1-propynyl compound, or

d) that a compound of the general formula V

in which R<22> means alkoxy with up to 3 carbon atoms, and R<c> has the meaning given above, is reacted with an alkyl halide of the formula (R<5>)R<4>Hal, in which Hal means chlorine, bromine or iodine, wherein R<4> and R<5> have the above meaning, to obtain a compound of formula I, wherein RA means NR<4>R<5>, wherein R<4> and R<5> have the above stated meaning.

A preferred embodiment of process alternative a) is characterized in that the compound of formula III is cyclized with formaldehyde to form the corresponding 1,2,3,4-tetrahydrocarboline, and that this compound is then dehydrogenated. The starting material can be dissolved either in water in the presence of an acid or a base and heated with formaldehyde or in an inert water-immiscible solvent such as benzene, toluene, xylene, chlorobenzene, anisole, mesitylene, and heated with paraformaldehyde. This produces a 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]-indole derivative, which is dehydrogenated without further processing.

In another preferred embodiment of alternative a), the compound of formula III is treated with formic acid to form the corresponding formyl compound, and this compound is cyclized with phosphorus oxychloride or polyphosphoric acid to form the corresponding dihydrocarboline which is then dehydrogenated.

The dehydrogenation of the compound obtained by cyclization can be carried out using a method known per se. Such a method consists in the starting material being dissolved, or suspended in an inert solvent. Suitable solvents are all aprotic solvents, whose boiling point is above 100°C, and which are inert to the starting material. Examples include xylene, mesitylene, anisole, toluene, chlorobenzene and diphenyl ether. Elemental sulfur is then added in such a quantity that per double binding is used approx. 1 mole-equivalent sulfur. A small surplus is not only harmless, but appropriate. The reaction mixture is boiled under reflux for several hours, during which the course of the reaction is followed by thin-layer chromatography.

Another method is dehydrogenation with DDQ (dichloro-dicyanobenzoquinone) or chloranil in benzene, toluene, xylene, dioxane, tetrahydrofuran, methylene chloride or dimethoxyethane at a temperature between 0 and 60°C and in a reaction time of from 0.5 to 4 hours.

A further method is dehydrogenation with noble metal catalysts, such as platinum in finely divided form, finely divided palladium or palladium charcoal in xylene, mesitylene or cumol at 120-180°C and a reaction time of from 2 to 16 hours.

The production of sulfonic acid derivatives can take place in a manner known per se. Thus, the starting material can be dissolved in an inert solvent such as methylene chloride or chloroform, and chlorosulfonic acid is added while cooling.

To prepare corresponding alkylsulphamoyl derivatives, the previously obtained product is reacted with an alkylamine.

The halogenation can take place in a manner known per se. Thus, the starting material can be dissolved in an inert solvent and reacted with the corresponding halogen,

such as chlorine or bromine, optionally in the presence of a base catalyst at temperatures below room temperature. Inert solvents are, for example, chlorinated hydrocarbons such as methylene chloride, chloroform, dichloroethylene, etc. Suitable basic catalysts are pyridine and substituted pyridine, such as dimethylaminopyridine. A basic catalyst can be dispensed with during the chlorination.

For the introduction of iodine, not only elemental iodine is suitably used, but a mixture of iodine and iodine chloride, whereby the reaction can be carried out at room temperature in the presence of

a basic catalyst, such as pyridine.

The nitration can take place in a manner known per se. Thus, the starting material can be reacted with concentrated nitric acid at a temperature below room temperature. Concentrated nitric acid means the commercially available nitric acid, which may also be enriched with fuming nitric acid. During the nitration, the acid is a reaction agent as well as a solvent.

Any subsequent reduction of the obtained nitro compound to the corresponding amino compound likewise takes place according to methods known per se.

A preferred method is the reduction with hydrogen in the presence of metal catalysts, such as Raney nickel, platinum in finely divided form or palladium on a suitable carrier, such as coal or lime, at normal pressure and room temperature. But it is also possible to use hydrogen in statu nascendi, e.g. when using zinc/hydrochloric acid.

An optionally desired etherification of the 4-alkoxy group in the compound of formula I can take place in a manner known per se. Thus, the starting material can be dissolved in a polar solvent, such as acetonitrile, dimethylformamide or 1-methyl-2-pyrrolidone, and reacted with sodium iodide and trimethylchlorosilane at a temperature above room temperature.

The thus obtained 4-iodoalkyl compound with the formula is subjected to a nucleophilic substitution, which again takes place by methods known per se. Thus, the starting material is preferably heated to the boiling point of the reaction mixture with a corresponding alkali or tetraalkylammonium alcoholate, such as sodium ethylate or potassium methylate, possibly with the addition of a crown ether, such as 18-crown-6-, dicyclohexyl-18-crown-6-, dibenzo-18-crown- 6-ether in an inert solvent such as tetrahydrofuran, dioxane, methanol, ethanol, etc.

Any desired transesterification of the ester group

in position 3, can take place in a manner known per se. Thus, the starting material can be reacted with an alcohol ROH in the presence of catalytic amounts of RONa for 3-6 hours at temperatures between 80 and 120°C. The transesterification can optionally be carried out with the alcohol ROH in the presence of an acidic catalyst, such as paratoluenesulfonic acid, HC1 or CuCl2.

For the preparation of compounds of formula I according to alternative b), corresponding |3-carboline-3-carboxylic acid alkyl esters, which are substituted in the A ring with halogen, especially with chlorine, bromine or iodine, are phosphorylated by methods known per se.

For this, the starting material is dissolved in an aprotic solvent, such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone or hexamethylphosphoric triamide, and reacted hot,

i.e. at temperatures in the range from 50 to 140°C in the presence of a complex noble metal catalyst from the triarylphosphine class,

like for example. palladium-tetrakis-triphenylphosphine, and a strong organic base, such as triethylamine, pyridine or dimethylaminepyridine, with a dialkyl phosphite, such as e.g. dimethyl, diethyl or dipropyl phosphite.

3-carboline-3-carboxylic acid alkyl esters which are substituted with halogen in the A ring are also used as starting material for the preparation of compounds of formula I according to alternative c). To this end, the starting material is dissolved or suspended in an aprotic solvent, such as N-methyl-2-pyrrolidone or hexamethylphosphoric triamide and alkynylated in the presence of a base, such as di- or tri-alkylamine, e.g. diethylamine, methylethylamine, trimethylamine or triethylamine, as well as in the presence of a complex noble metal catalyst, such as e.g. palladium bis-(tri-o-tolylphosphine) dichloride or palladium bis-(triphenylphosphine) dichloride or a mixture of triphenylphosphine

and palladium(II) acetate with a compound of formula R<12>C=CH at temperatures above room temperature, preferably from 4 0

to 150°C.

It is appropriate to add copper I salts, such as e.g. copper I iodide.

The entire reaction is carried out appropriately

under the exclusion of humidity.

12

If R is a protecting group, the thus obtained compound of formula I can be hydrolyzed in heat with a dilute mineral acid, such as sulfuric acid, hydrochloric acid or perchloric acid, thereby forming the corresponding hydroxy compound, i.e. the propargyl compound.

The propargyl compound thus obtained can

if desired oxidized to aldehyde, respectively the 3-oxo-1-propynyl compound. Suitable oxidizing agents are e.g. manganese dioxide or chromic acid using a suitable solvent. For oxidation with manganese dioxide, all halogenated hydrocarbons such as chloroform or methylene chloride can be used, as well as ketones, such as acetone or methyl isobutyl ketone,

as well as pyridine, as well as mixtures thereof. The oxidation with pyridine dichromate is carried out in halogenated hydrocarbons or optionally in N-methyl-2-pyrrolidone. In the case of oxidation with chromic acid, acetic acid is further added.

The previously obtained propargyl compound can

also chlorinated with thionyl chloride at room temperature, in which method a solvent is not required,

as the thionyl chloride acts as a solvent. The 3-chloro-1-propynyl compound thus obtained can, if desired, then be reacted with a trialkyl phosphite by the previously mentioned method for producing a corresponding 3-dialkoxyphosphoryl-1-propynyl compound.

The previously obtained 3-chloro-1-propynyl compound can also, if desired, be reacted with piperidine in the presence of a strong base at temperatures above room temperature, to produce corresponding 3-piperidino-1-propynyl compounds. Examples of strong bases include 1,5-diazabicyclo-[5,4,0]undec-5-ene, ethyldiisopropylamine, diazabicyclononene, diazabicyclooctane, but also potassium tert-butylate, potassium carbonate, powdered potassium hydroxide.

For the preparation of compounds of formula I

according to alternative d) corresponding Ø-carboline-3-carboxylic acid alkyl esters, which in the A ring are substituted with an amino group with an alkyl halide, -tosylate or -mesylate, are reacted by methods known per se in a suitable solvent

►

in the presence of a base at temperatures in the range from room temperature to the boiling point of the reaction mixture.

Suitable solvents are all protic and aprotic solvents, insofar as they are inert towards the reaction participants. Examples include aliphatic alcohols such as methanol, ethanol and propanol, ketones such as acetone and methyl isobutyl ketone, ethers such as glycol dimethyl ether and diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane, as well as solvents such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone.

Suitable bases are all strong organic bases, such as triethylamine, dimethylaminopyridine, ethyldiisopropylamine, diaza-bicycloundecene, -nonene and -octene. But it is also possible to use an alkali metal carbonate such as sodium or potassium carbonate, as well as alcoholates such as potassium tert-butylate. The alkyl halide may optionally be substituted as indicated previously. In the case of the ring-closed compounds, it is only decisive that it is a non-geminal dihaloalkane or -alkene. Halogens include chlorine, bromine or iodine, as when chlorine is involved it is appropriate to add a copper (I) halide, such as copper (I) iodide.

The processing of the thus produced compounds is carried out using methods known per se, such as by e.g. extraction, crystallization, chromatography, etc.

The compounds according to the invention can be used

for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance with known galenic methods.

Suitable excipients for formulating pharmaceutical preparations are such physiologically tolerable organic or inorganic carriers for enteral and parenteral administration, which are inert to the compounds according to the invention.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycol, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and/or mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, buffers and dyes.

For parenteral use, injectable solutions or suspensions, especially aqueous solutions with the active compound dissolved in polyhydroxyethoxylated castor oil, are particularly suitable.

For oral use, tablets, dragées or capsules are particularly suitable, which have talc and/or a carbohydrate carrier or binder such as e.g. lactose, corn or potato starch. The application can also take place in liquid form, e.g. as juice, to which a sweetener is optionally added.

The compounds according to the invention are administered in a dosage unit of from 0.05 to 10 mg of active substance in a physiologically tolerable carrier.

The compounds according to the invention are used in a dose of from 0.1 to 300 mg/day, preferably from 1-30 mg/day.

Example 1

20.3 g of 3-methoxymethyltryptophan ethyl ester was dissolved in 350 ml of benzene, mixed with 2.48 g of paraformaldehyde and heated for three and a half hours in a water separator. After cooling, the benzene was distilled off, the distillate residue dissolved in 350 ml of toluene and heated for 20 hours under reflux after the addition of 4.5 g of 10% palladium charcoal. The cooled solution was filtered and concentrated. The resulting residue was chromatographed on silica gel with hexane/acetic acid ester. Crystallization of the main fraction from acetic acid ester/diisopropyl ether gave 6.4 g of 4-methoxymethyl-b-carboline-3-carboxylic acid ethyl ester with a melting point of 118-119°C.

Production of the starting material.

a) 191.0 ml of isopropylamine is mixed dropwise under ice-cooling during 2 hours with 165.3 g of methoxy-acetaldehyde, so that the temperature in the mixture does not exceed 10°C. It was then stirred for a further 30 minutes at 5°C and solids were added in portions

potassium hydroxide, until 2 phases appeared, after which the upper phase was separated and again mixed with potassium hydroxide and left for 12 hours at 5°C. The solution was then filtered and the filtrate distilled over approx. 2 g of barium oxide in a water jet vacuum. 110.9 g of isopropylimine of methoxyacetaldehyde, boiling point 35-39°C (40-30 mm Hg) were obtained.

b) To a solution of 96.5 g of indole in 510 ml of glacial acetic acid, it was added dropwise under ice cooling

110.9 g of the previously obtained imine in 230 ml of benzene, so that the temperature in the mixture did not exceed 10°C. It was then stirred for 12 hours at 5°C, after which the reaction mixture was slowly stirred for approx. 1.7 liters of ice water, the organic phase was separated, and the aqueous phase extracted twice, each time with 180 ml of benzene. Then the pH value of the aqueous phase was adjusted by dropwise addition of 6N caustic soda under ice-

cooling and extracted with benzene and ether. The extracts of the alkaline phase were dried over sodium sulfate and concentrated. 183.9 g of light yellow oil was obtained, which was used in the following step without further purification.

c) A solution of 92.0 g of the previously obtained product in 1.3 liters of toluene was mixed with 55.2 g

nitroacetic acid ethyl ester and stirred under argon for 16 hours at 80°C. After cooling, it was washed

twice, each time with 400 ml IN hydrochloric acid, then with saturated sodium chloride solution, followed by drying over sodium sulfate and concentration. 155.9 g of adduct was obtained as an oily isomer mixture, which was used in the following reaction without further treatment.

d) 24.9 g of the adduct obtained above was dissolved in 600 ml of ethanol and hydrogenated after the addition of

about. 32 g of Raney nickel at room temperature under normal pressure. After taking in 5650 ml of hydrogen

the catalyst was filtered off and it was concentrated. 203 g of 3-methoxymethyltryptophanethyl ester were obtained as an oily isomer mixture.

Example 2

In a similar way as in Ex. 1, the following p-carbolines were prepared: 5-methoxy-4-methoxymethyl-3-carboline-3-carboxylic acid ethyl ester, m.p. 16 8-17 0°C,

6-Methoxy-4-methoxymethyl-(3-carboline-3-carboxylic acid ethyl ester, m.p. 175-177°C,

7-Methoxy-4-methoxy acid ethyl -|3-carboline-3-carboxylic acid ethyl ester, m.p. 161-163°C,

5-benzyloxy-4-methoxymethyl-(3-carboline-3-carboxylic acid ethyl ester, m.p. 185-188°C,

6-chloro-4-methoxymethyl-3-carboline-3-carboxylic acid ethyl ester, m.p. 206-208°C,

5-Fluoro-4-methoxymethyl-&-carboline-3-carboxylic acid ethyl ester, m.p. 182-184°C,

6,7-dimethoxy-4-methoxymethyl-3-carboline-3-carboxylic acid ethyl ester, m.p. 163-164°C,

6,7-dichloro-4-methoxymethyl-3-carboline-3-carboxylic acid ethyl ester, m.p. 199-203°C.

Example 3

In the same way as in Ex. lc) 2.5 g of α-nitro-3_(2-methoxyethyl)-indolyl-(3)-propionic acid ethyl ester were prepared, which was hydrogenated analogously to 1 d) and the resulting compound was reacted with paraformaldehyde and dehydrogenated with palladium charcoal and chromatographed. After crystallization of the main fraction from acetic acid ester, 600 mg of 4-(2-methoxyethyl)-3-carboline-3-carboxylic acid ethyl ester with m.p. 181-183°C.

Production of the starting material.

a) From 16.1 ml of isopropylamine and 16.6 g of 3-methoxy-propionaldehyde (prepared according to Angew.Chem. 62,

115 (1950)) appeared under those in ex. 1 a) stated conditions 22.9 g of isopropylimine of 3-methoxy-propionaldehyde as an E,Z isomer mixture.

b) A solution of 20.7 g of indole in 104 ml of glacial acetic acid was reacted under those in ex. 1 b) stated conditions with

22.9 g of the imine obtained above in 54 ml of benzene. 19.2 g of condensation product appeared as a brownish oil.

c) 19.2 g of the above product was reacted with 10.4 g of nitroacetic acid ethyl ester under those in ex. lc)

stated conditions. After chromatography on silica gel with hexane/acetic acid ester, 8.5 g of α-nitro-3-(2-methoxy)-indolyl-(3)-propionic acid ethyl ester appeared as a yellow oil.

Example 4

Analog e.g. 3 and using known, substituted indoles, the following 3-carbolines were prepared: 6,7-dimethoxy-4-(2-methoxyethyl)-p-carboline-3-carboxylic acid ethyl ester, m.p. 206-208°C,

6-Methoxy-4-(2-methoxyethyl)-p-carboline-3-carboxylic acid ethyl ester, m.p. 189-191°C,

6-chloro-4-(2-methyloxyethyl)-β-carboline-3-carboxylic acid ethyl ester, m.p. 232-234°C,

5-Benzyloxy-4-(2-methoxyethyl)-&-carboline-3-carboxylic acid ethyl ester, m.p. 174-176°C,

6-benzyloxy-4-methoxymethyl-f3-carboline-3-carboxylic acid ethyl ester, m.p. 165-166°C

Example 5

A solution of 300 mg of 4-methoxymethyl-1-3-carboline carboxylic acid ethyl ester in 15 ml of methylene chloride was mixed dropwise with 0.6 ml of chlorosulfonic acid under ice-cooling. It was then stirred for 2 hours at 25°C, after which it was cooled to 5°C and 6 ml of a 40% aqueous dimethylamine solution was added dropwise. For further processing, it was diluted with acetic acid ester, it was washed with water and saturated sodium chloride solution, after which it was dried over sodium sulfate and concentrated. The crystallization of the crude product from acetic acid ester/ethanol gave 130 mg of 6-dimethylaminosulfonyl-4-methoxymethyl-3-carboline-3-carboxylic acid ethyl ester with a melting point of 191-193°C.

Example 6

A solution of 284 mg of 4-methoxymethyl-3-carboline-3-carboxylic acid ethyl ester in 13 ml of chloroform was cooled to

-30°C and mixed dropwise with 0.05 ml of bromine in 1 ml of chloroform. The solution was stirred for 2 hours at from -20 to -10°C, after which it was poured into ice-cold 10% sodium bisulfite solution

and extracted with methylene chloride. Crystallization from acetic acid ester gave 240 mg of 6-bromo-4-methoxymethyl-B-carboline-3-carboxylic acid ethyl ester with a melting point of 207-209°C.

Example 7

To a solution of 250 mg of 4-methoxymethyl-B-carboline-3-carboxylic acid ethyl ester in 12 ml of chloroform, 0.5 ml of bromine in 3 ml of chloroform was added dropwise at room temperature, and the solution was stirred for 2 hours at room temperature. After further processing as indicated in ex. 3 and crystallization from hexane/acetic acid ester yielded 250 mg of 6,8-dibromo-4-methoxymethyl-|3-carboline-3-carboxylic acid ethyl ester with a melting point of 98-99°C.

Example 8

To a mixture of 19.3 ml of 65% nitric acid and 9.65 ml of fuming nitric acid, 2.0 g of 4-methoxymethyl-B-carboline-3-carboxylic acid ethyl ester was added in portions under ice-cooling. The reaction mixture was stirred for 3 hours at 5°C, added dropwise to ice water and the mixture was then basified with concentrated aqueous ammonia solution and filtered. The precipitate was washed with water, dried, suspended in 30 ml of acetic acid ester and heated for 15 minutes under reflux. After cooling, filtration yielded 1.85 g of 4-methoxymethyl-6-nitro-p-carboline-3-carboxylic acid ethyl ester with a melting point of 274-276°C.

In a similar way, nitration of 2 g of 4-(2-methoxyethyl)-β-carboline-3-carboxylic acid ethyl ester produced the corresponding nitro compound 6-nitro-4-(2-methoxyethyl)-β-carboline-3-carboxylic acid ethyl ester in an amount of 1.80 g and with a melting point of 283-286°C.

Example 9

1.7 g of each of the two 6-nitro derivatives that appeared in ex. 8 was hydrogenated at room temperature and normal pressure in 70 ml tetrahydrofuran and 70 ml methanol after addition

of 300 mg of 10% palladium charcoal. After absorption of 4 20 ml of hydrogen, it was filtered and concentrated. Crystallization from acetic acid ester gave 1.2 g of 6-amino-4-methoxymethyl-B-carboline-3-carboxylic acid ethyl ester with a melting point of 199-201°C, respectively 1.1 g of 6-amino-4-(2-methoxyethyl)-B -carboline-3-carboxylic acid ester with a melting point of 238-242°C.

Example 10

A solution of 1.0 g of 4-methoxymethyl-B-carboline-3-carboxylic acid ethyl ester in 20 ml of methylene chloride and 1.5 ml of pyridine was mixed dropwise with 1.5 ml of iodine chloride at room temperature. After 60 min. 1.5 ml of iodine chloride and 200 mg of iodine were again added, the reaction mixture was stirred for a further 2 hours at room temperature, after which it was poured into ice-cold, saturated sodium thiosulphate solution and extracted with methylene chloride. Crystallization from acetic acid ester gave 520 mg of 6-iodo-4-methoxymethyl-B-carboline~3-carboxylic acid ethyl ester with a melting point of 204-206°C.

Example 11

A suspension of 300 mg of it in ex. 10 prepared 6-iodo derivative, 5 ml of dimethylformamide and 105 mg of copper cyanide were stirred for 2 hours at 160°C under argon. After cooling, the reaction mixture was poured into an aqueous ammonia solution and extracted with methylene chloride. Crystallization from acetic acid ester/ethanol gave 160 mg of 6-cyano-4-methoxymethyl-3-carboline-3-carboxylic acid ethyl ester with a melting point of 252-255°C.

Example 12

A suspension of 1.5 g of 4-methoxymethyl-B-carboline-3-carboxylic acid ethyl ester, 20 ml of acetonitrile, 3.1 g of sodium iodide and 2.7 ml of trimethylchlorosilane was stirred for 2 hours at 60°C. After cooling, the reaction mixture was poured into ice water and extracted with acetic acid ester. The extract was washed with saturated sodium thiosulfate solution, dried and concentrated. 1.65 g of 4-iodomethyl-B-carboline-3-carboxylic acid ethyl ester with

melting point of 280-286°C.

To a freshly prepared solution of 1.5 g of sodium ethylate in 20 ml of ethanol and 20 ml of tetrahydrofuran from sodium and absolute ethanol was added 1.65 g of the 4-iodomethyl derivative obtained above, and the reaction mixture was heated for 2 hours under reflux . After cooling, the reaction mixture was poured into a 10% sodium dihydrogen phosphate solution and extracted with acetic acid ester. Chromatography on silica gel with hexane/acetone and crystallization of the main fraction from acetic acid ester gave 720 mg of 4-ethoxymethyl-3-carboline-3-carboxylic acid ethyl ester with a melting point of 125-127°C.

Example 13

30 mg of sodium was dissolved in 15 ml of absolute methanol. Then 300 mg of 4-methoxymethyl-B-carboline-3-carboxylic acid ethyl ester was added and the reaction mixture was heated for 2 hours under reflux. The cooled solution was poured into a sodium dihydrogen phosphate solution and extracted with acetic acid ester. Crystallization from hexane/methylene chloride gave 270 mg of 4-methoxymethyl-B-carboline-3-carboxylic acid>methyl ester with a melting point of 134-135°C.

Example 14

In the same way as in ex. 13 is prepared from the present B-carboline-3-carboxylic acid ethyl ester and the corresponding alcohol the following compounds: 6,7-dimethoxy-4-methoxymethyl-B-carboline-3-carboxylic acid methyl ester, m.p. 163-164°C,

in

6,7-dimethoxy-4-methoxymethyl-B-carboline-3-carboxylic acid n-propyl ester, m.p. 172-174°C

6,7-dimethoxy-4-methoxymethyl-0-carboline-3-carboxylic acid isopropyl ester, m.p. 166-168°C,

in

4-methoxy s<y>met<y>1-B-carboline-3-carboxylic acid n-propyl ester, m.p. 154-157°C.

Example 15

1.46 g of 6-iodo-B-carboline-3-carboxylic acid ethyl ester was added to a mixture of 608 mg of diethyl phosphite, 448 mg of triethylamine, 240 mg of palladium tetrakis(triphenylphosphine) dichloride and 60 ml of N-methyl -2-pyrrolidone, and the reaction mixture was stirred for 12 hours at 90°C. After concentration, the resulting residue was chromatographed on 75 g of silica gel with methylene/acetone (1:1) as eluent. The corresponding combined fractions were chromatographed on 25 g of silica gel with methylene chloride/ethanol (10:2) as eluent, and 4 21 mg of 6-diethoxyphosphoryl-3-carboline-3-carboxylic acid ethyl ester emerged as an oil.

Example 16

In a similar manner, the corresponding iodine compounds were prepared: 6-diisopropoxyphosphoryl-B-carboline-3-carboxylic acid ethyl ester,

6-diethoxyphosphoryl-4-methyl-B-carboline-3-carboxylic acid ethyl ester,

6-diethoxyphosphoryl-4-methoxymethyl-B-carboline-3-carboxylic acid ethyl ester,

5- diethoxyphosphoryl-3-carboline-3-carboxylic acid ethyl ester,

6-diethoxyphosphoryl-B-carboline-3-carboxylic acid methyl ester,

all like oil.

Example 17

347 mg 6-bromo-4-ethyl-B-carboline-3-carboxylic acid ethyl ester, 32 mg palladium bis-(tri-o-tolylphosphine) dichloride, 32 mg copper (I) iodide, 5 ml diethylamine, 5 ml N -methyl-2-pyrrolidone and 250 mg of 3-dimethylamino-1-propyne were heated under nitrogen and exclusion of moisture for seven and a half hours at 80-90°C. After concentration, the resulting residue was chromatographed on 30 g of silica gel with methylene chloride/methanol (10:2) as eluent. The corresponding combined fractions were separated by preparative chromatography and 170 mg of 6-(3-dimethylamino-1-propynyl)-4-ethyl-B-carboline-3-carboxylic acid ethyl ester (as an oil) was formed.

Example 18

In a similar manner was prepared: 6-(3-dimethylamino-1-propynyl)-B-carboline-3-carboxylic acid ethyl ester (m.p. 253-258°C from ethanol),

6-(3-diethylamino-1-propynyl)-B-carboline-3-carboxylic acid ethyl ester (m.p. 270-275°C),

5-(3-Dimethylamino-1-propynyl)-B-carboline-3-carboxylic acid ethyl ester (m.p. 228-229°C, decomposition).

Example 19

1.6 g of 6-bromo-B-carboline-3-carboxylic acid ethyl ester was added together with 30 ml of diethylamine under nitrogen and exclusion of moisture to a mixture of 70 mg of copper(I) iodide, 50 mg of palladium(bis[tri-o -tolyl]phosphine) dichloride,

1 ml of tetrahydropyran-2-yl-propargyl ether in 50 ml of N-methyl-2-pyrrolidone. After 4 hours at 100-120°C, 1 ml of tetrahydropyran-2-yl-propargyl ether and 70 mg of copper (I) iodide, as well as 70 mg of palladium (bis[tri-o-tolyl]-phosphine) were added once more -dichloride, and the reaction mixture was kept for a further 3 hours at 100-120°C. It was then concentrated using an oil pump vacuum. The residue was treated with ethanol and filtered off. A small sample of the crystals was recrystallized from ethanol/diisopropyl ether. 40 mg of 6-(3-tetrahydropyran-2-yl-oxy-1-propynyl)-B-carboline-3-carboxylic acid ethyl ester (m.p. 265-268°C) was obtained. The rest of the crystals, which are still contaminated with the 6-bromo compound, were worked up according to ex. 21.

Example 20

In an analogous manner was prepared: 6-(3-methoxy-1-propynyl)-B-carboline-3-carboxylic acid ethyl ester,

6-(phenylethynyl)-B-carboline-3-carboxylic acid ethyl ester,

m.p. 281-287°C.

Example 21

1100 mg of it in ex. 19 prepared mixture of 6-bromo-B-carboline-3-carboxylic acid ethyl ester and 6-(3-tetrahydro-pyran-2-yl-oxy-1-propynyl)-B-carbolin-3-carboxylic acid ethyl ester was heated together with 50 ml of ethanol and 10 ml of semi-concentrated sulfuric acid for 10 minutes on a steam bath. After dilution with water, the mixture was made alkaline with 2N NaOH

and extracted twice with 50 ml of chloroform. The combined organic phases were dried, filtered and concentrated. The material obtained was separated on 65 g of silica gel with chloroform/ethanol (10:2) as eluent. By collecting corresponding fractions and recrystallizing from ethanol, 400 mg of 6-(3-hydroxy-1-propynyl)-3-carboline-3-carboxylic acid ethyl ester with m.p. 270-275°C.

Example 22

In a similar way, 6' became. c prepared: 5-(3-hydroxy-1-propynyl)-B-carboline-3-carboxylic acid ethyl ester, m.p. 268-270°C (during decomposition)

6-(3-hydroxy-1-propynyl)-4-methyl-3-carboline-3-carboxylic acid ethyl ester, m.p. 211-212°C (alcohol/petroleum ether).

Example <23>

78 mg of 6-(3-hydroxy-1-propynyl)-B-carboline-3-carboxylic acid ethyl ester was stirred in 2 ml of thionyl chloride for 3 hours at room temperature. After evaporation to dryness, it was heated in ethanol and the resulting product was filtered off. By recrystallization from glacial acetic acid/cyclohexane, 40 mg of 6-(3-chloro-1-propynyl)-p-carboline-3-carboxylic acid ethyl ester (m.p. 298°C/under decomposition) was obtained.

Example 24

156 mg of 6-(3-chloro-1-propynyl)-B-carboline-3-carboxylic acid ethyl ester was stirred for one and a half hours at 60°C with 85 mg of piperidine and 76 mg of 1,5-diazacyclo[5,4,p ]undec-5-en i

10 ml of absolute ethanol under nitrogen and exclusion of moisture. After evaporation, the remaining material was chromatographed on 25 g silica gel with methylene chloride/methanol (10:2)

as eluent. 51 mg of 6-[3-(1-piperidinyl)-1-propynyl]-B-carboline-3-carboxylic acid ethyl ester (m.p. 215-217°C) was obtained.

Example 25

4 60 mg of 6-(3-chloro-1-propynyl)-B-carboline-3-carboxylic acid ethyl ester was stirred for 3 hours at 120-130°C

in 4 ml of triethyl phosphite. After cooling, it was stirred with ether and the ether-soluble part chromatographed after evaporation on 50 g of silica gel with methylene chloride:ethanol (10:2).

105 mg of 6-[3-diethoxyphosphoryl-1-propynyl]-B-carboline-3-carboxylic acid ethyl ester was obtained as an oil.

Example 26

38 3 mg of 6-amino-B-carboline-3-carboxylic acid ethyl ester is heated in 15 ml of ethanol with 0.58 ml of ethyldiisopropylamine and 0.18 ml of 1,4-dibromobutane for 6 hours under nitrogen and with reflux. 0.4 ml of 1,4-dibromobutane was then added several times and refluxed for 3 hours. After evaporation, it was washed with water and boiled off with ethanol. 128 mg of 6-(1-pyrrolidinyl)-B-carboline-3-carboxylic acid ethyl ester with m.p. 259-261°C.

Example 27

In a similar manner was prepared: 4-methyl-6-(1-pyrrolidinyl)-B-carboline-3-carboxylic acid ethyl ester, m.p. 244-251°C,

4-Methoxymethyl-6-(1-pyrrolidinyl)-B-carboline-3-carboxylic acid ethyl ester, m.p. 212-214°C,

4-ethyl-6-(1-pyrrolidinyl)-B-carboline-3-carboxylic acid ethyl ester, m.p. 205-218°C.

Example 28

3.25 g of 6-amino-4-methyl-B-carboline-3-carboxylic acid ethyl ester was heated in 70 ml of ethanol with 1.7 ml of 1,4-dichloro-2-cis-butene and 4.5 g of ethyldiisopropylamine in 10 hours at 50°C. When stirring in 250 ml of ice water, the precipitated mate-

rial filtered, washed and dried in vacuum. The raw product

(3.4 g of a mixture of dihydropyrrole and pyrrole derivative)

was dissolved in 600 ml of methylene chloride and, after adding 17 g of the rut, stirred for 2 hours at room temperature. After filtering and distilling off the solvent, 2.75 g of crude product appeared which was crystallized from acetone. 2.13 g of 4-methyl-6-(1-pyrrolyl)-3-carboline-3-carboxylic acid ethyl ester with a melting point of 214-217°C were thus obtained.

Example 29

446 mg of 6-amino-B-carboline-3-carboxylic acid ethyl ester is heated in 17.5 ml of absolute ethanol with 410 mg of 1,5-dibromopentane and 500 mg of ethyldiisopropylamine under nitrogen for 4 hours and under reflux. After addition of a further 74 mg of 1,5-dibromopentane, it was stirred for a further 2 hours under reflux. After evaporation, it was dissolved in methylene chloride and it was washed with saturated bicarbonate solution, as well as saturated sodium chloride solution, then dried, filtered and concentrated. After recrystallization from alcohol, acetic acid ester and a little ether, 255 mg of 6-(1-piperidinyl)-3-carboline-3-carboxylic acid ethyl ester appeared, m.p. 255-256°C.

Example 30

In an analogous manner was prepared: 4-methyl-6-(1-piperidinyl)-3-carboline-3-carboxylic acid ethyl ester, m.p. 215-224°C,

4-Methoxymethyl-6-(1-piperidinyl)-3-carboline-3-carboxylic acid ethyl ester, m.p. 163-166°C,

5-(1-piperidinyl)-3-carboline-3-carboxylic acid ethyl ester,

m.p. 274-276°C,

6- hexamethyleneimino-3-carboline-3-carboxylic acid ethyl ester,

m.p. 220°C,

6-hexamethyleneimino-4-methyl-B-carboline-3-carboxylic acid ester,

m.p. 179°C.

Example 31

510 mg of 6-amino-B-carboline-3-carboxylic acid ethyl ester was heated in 7 ml of absolute tetrahydrofuran with 0.3 ml of 1,5-diaza[5,4,0]-bicyclo-undec-5-ene and 240 mg allyl bromide for 0.5 hours under nitrogen at 60°C. It was then evaporated and extracted with acetic acid ester and water. The organic phase was dried, filtered and concentrated. The remaining material was chromatographed on 60 g of silica gel with methylene chloride/ethanol (10:2) as eluent. The most polar compound of the two products formed was separated by another chromatography on 60 g of silica gel with methylene chloride/ethanol (9:1) as eluent. 200 mg of 6-N-allylamino-B-carboline-3-carboxylic acid ethyl ester, m.p. 190-194°C.

Example 32

In an analogous manner, the following was prepared: 5-allylamino-B-carboline-3-carboxylic acid ethyl ester, m.p. 199-20 2°C,

6- benzylamino-B-carboline-3-carboxylic acid ethyl ester, m.p. 2 37-2 39°C,

6-N-allyl-amino-4-methoxymethyl-3-carboxylic acid ethyl ester, m.p. 220-223°C.

Example 33

93 mg of 6-(N-ethylamine)-B-carboline-3-carboxylic acid ethyl ester was heated in 8 ml of absolute ethanol with 49 mg of 1,5-diaza-[5,4,0]bicyclo-undec-5-ene and 50 mg of allyl bromide under nitrogen for 2 hours at 70°C. After evaporation, it was extracted with acetic acid ester and saturated sodium bicarbonate solution. The organic phase was dried, filtered and concentrated. The remaining material was chromatographed on 80 g of silica gel with methylene chloride/ethanol (12:1) as eluent, and after recrystallization from acetic acid ester/ether, 56 mg of 6-(N-allyl-N-ethylamino-B-carboline-3-carboxylic acid ethyl ester) was obtained (m.p. 190-192°C).

Example 34

In an analogous manner was prepared: 6-(N-allyl-N-benzylamino)-p-carboline-3-carboxylic acid ethyl ester, m.p. 181-185°C,

6-(N-allyl-N-methylenecarboxyethylamino)-B-carboline-3-carboxylic acid ethyl ester, m.p. 156-158°C,

6-[N-allyl-N(2,2-diethoxyethyl)amino]-B-carboline-3-carboxylic acid ethyl ester, m.p. 166-167°C.

Example 35

5.5 g of 6-amino-B-carboline-3-carboxylic acid ethyl ester was stirred in 150 ml of absolute ethanol with 4.68 ml of allyl bromide and 6 ml of diazabicyclo[5,4,0]undec-5-ene under nitrogen and exclusion of moisture for two and a half hours at 70°C. After addition of 0.5 ml of allyl bromide, it was heated for a further 30 minutes at 70°C. After distilling off the ethanol, it was extracted with acetic acid ester/saturated bicarbonate solution. The organic phase was washed with saturated sodium chloride solution, dried, filtered and concentrated. After recrystallization from acetic acid ester, 3.45 g of 6-(N,N-diallylamino)-B-carboline-3-carboxylic acid ethyl ester appeared, m.p. 194-196°C.

Example 36

In an analogous manner was prepared: 6-(N,N-diallylamino)-4-methyl-B-carboline-3-carboxylic acid ethyl ester, m.p. 158-159°C (acetic acid ester), 6-(N,N-diallylamino)-4-ethyl-B-carboline-3-carboxylic acid ethyl ester, 6-(N,N-diallylamino)-4-methoxymethyl-3-carboline -3-carboxylic acid ethyl ester (oil),

6-[N,N-di-(2-buten-1-yl)-amino]-p-carboline-3-carboxylic acid ethyl ester, m.p. 145°C (acetic acid ester/ether),

6-[N,N-di-(2-methyl-2-propen-1-yl)-amino]-β-carboline-3-carboxylic acid ethyl ester, m.p. 211-212°C (EtOH/petroleum ether),

6-(N,N-dipropargylamino-B-carboline-3-carboxylic acid ethyl ester, m.p. 229-230°C,

6-(N,N-dibenzylamino)-B-carboline-3-carboxylic acid ethyl ester, m.p. 200-202°C,

6-(N,N-diallylamino)-4-methyl-B-carobline-3-carboxylic acid propyl ester, m.p. 190-192oC,

6-(N,N-diallylamino)-4-methyl-3-carboline-3-carboxylic acid methyl ester, m.p. 146-148°C.

Example 37

255 mg of 6-amino-B-carboline-3-carboxylic acid ethyl ester was stirred with 183 mg of 2-bromoacetic acid ethyl ester and 76 mg of potassium carbonate in a mixture of 2 ml of absolute dimethylformamide and 5 ml of absolute tetrahydrofuran for 2 hours at 40-50°C. The precipitated material was poured onto ice and filtered off. The remaining material was washed well with water. 6-(N-carbethoxymethyleneamino)-B-carboline-3-carboxylic acid ethyl ester was obtained in a yield of 60% and with a melting point of 157-158°C.

Example 38

150 mg of 6-N(5-bromopentane.arbohoyl)amino-3-carboline-3-carboxylic acid ethyl ester in 3 ml of N-methyl-2-pyrrolidone was mixed with 10 mg of 80% sodium hydride and stirred overnight. After evaporation, it was neutralized with glacial acetic acid, treated

lightly with water. After drying, the remaining material was chromatographed on 30 g of silica gel with toluene:glacial acetic acid:water (10:10:1). 50 mg of 6-[2-piperidon-1-yl]-B-carboline-3-carboxylic acid ethyl ester was obtained.

Example 39

500 mg of 6-amino-B-carboline-3-carboxylic acid ethyl ester was heated in 15 ml of ethanol with 0.92 ml of isopropyl bromide and 0.63 ml of 1,5-diaza-bicyclo-[5,4,0]-undec- 5 for 8 hours at 80°C. After evaporation, it was extracted into acetic acid ester/saturated sodium bicarbonate solution. The organic phase was separated, dried, filtered and concentrated. The remaining material was chromatographed on 120 g of silica gel with methylene chloride/ethanol (12:1) as eluent. After recrystallization from ethanol/ether, 6-N-isopropylamine-B-carboline-3-carboxylic acid ethyl ester with a m.p. at 230-232°C.

Example 4 0

Analogous to example 38, the following was prepared: 6-(N-[2-chloroethylamino])-B-carboline-3-carboxylic acid ethyl ester, m.p. 165-166°C (acetic acid/petroleum ether),

6-(N-[2,2-diethoxyethylamino])-B-carboline-3-carboxylic acid ethyl ester, m.p. 150-151^-C (EtOH/petroleum ether) .

Example 41

1 step

A solution of 21 g of indole-4-carboxylic acid methyl ester in 100 ml of methylene chloride, 24.9 ml of triethylamine and 7.34 g of 4-dimethylaminopyridine was mixed in portions with 34.2 g of p-toluenesulfonic acid chloride at 0°C. After 16 hours at 0°C

it was diluted with methylene chloride, washed to neutrality with saturated sodium bicarbonate solution and sodium bicarbonate solution, and the solvent was distilled off under vacuum. 35.57 g of 1-tosylindole-4-carboxylic acid methyl ester with et

m.p. of 145-147°C (diisopropyl ether).

2nd step

A cooled to 0°C suspension of 1.9 g of lithium aluminum hydride in 165 ml of tetrahydrofuran was mixed portionwise with 16.45 g of 1-tosylindole-4-carboxylic acid methyl ester.

After 30 minutes, 1.9 ml of water was carefully added dropwise, then 1.9 ml of 15% caustic soda and 5.7 ml of water. After 20 min. the precipitate was filtered off and washed with acetic acid ethyl ester, and the filtrate concentrated. The crude product (15.97 g) was crystallized from diisopropyl ether. 13.15 g of 4-hydroxymethyl-1-tosylindole with a m.p. at 125-126°C.

3rd step

To a solution of 13.5 g of 4-hydroxymethyl-1-tosylindole in 400 ml of methylene chloride, 27 g of powdered potassium hydroxide, 27 ml of methyl iodide and 2.7 g of tetrabutylammonium hydrogen sulfate were added in order. It was stirred vigorously for 24 hours. Then potassium hydroxide was filtered off, it was washed to neutrality with water, and the solvent was distilled off. The crude product (16.46 g) was crystallized from diisopropyl ether. 12.2 g of 4-methoxymethyl-1-tosylindole with m.p. 85.5-89°C.

4. steps

A solution of 2.84 g of sodium in 155 ml of ethanol was added dropwise over 10 minutes to a solution of 15.57 g of 4-methoxymethyl-l-tosylindole in 155 ml of ethanol, then heated for 1.5 hours under reflux, after which it was cooled and 1.5 liters of half-saturated, ice-cold sodium dihydrogen phosphate solution was added, then extracted with acetic acid ester and the acetic acid ester extract was washed to neutrality with water. After distilling off the solvent, the crude product was chromatographed on silica gel with hexane-acetic acid ester (0-20%). 6.2 g of 4-methoxymethyl-indole was obtained as a colorless oil.

5th and 6th steps

To a solution of 6.2 g of 4-methoxymethylindole

in 31 ml of glacial acetic acid was added dropwise at 10°C over 30 min.

a solution of 4.25 g of acetaldehyde isopropylimine in 8.5 ml of toluene. After 36 hours at 0-5°C, 50 ml of ice water was added with stirring, it was extracted with toluene, and the water phase was made alkaline with 5 ml of caustic soda until pH 12

under intense flash cooling, after which it was extracted with ether and washed with half-saturated sodium chloride solution, and the solvent was distilled off under vacuum. The crude product (8.52 g) was used directly for the next step.

The solution of 8.52 g of amine product from step 5

in 425 ml of toluene and 3.84 ml of nitroacetic acid methyl ester were heated for 4 hours at 80°C under a weak stream of nitrogen. After cooling, it was washed with 0.1 ml of hydrochloric acid and water until neutrality, the solvent was distilled off and the crude product (9.33 g) was chromatographed on silica gel with hexane-acetic acid ester (0-20%). 7.89 g of 4-methoxymethylindole-3-[2-nitro-3-methyl]-propionic acid ethyl ester appeared as a hard foam.

7th step

8.08 g of 4-methoxymethylindole-3-[2-nitro-3-methyl]-propionic acid ethyl ester was hydrogenated in 320 ml of ethanol with 10 g of Raney nock at 20 bar and room temperature. After 60 min.

the hydrogen uptake has ended. The catalyst was filtered off and the solvent distilled off in vacuum at a bath temperature of 30°C. 6.4 g of 4-methoxymethylindole-3-[2-amino-3-methyl]propionic acid ethyl ester appeared as a colorless oil.

8th step

6.4 g of crude 4-methoxymethylindole-3-(2-amino-3-methyl)-propionic acid ethyl ester was boiled with 0.66 g of paraformaldehyde in 140 ml of toluene for 16 hours in a water separator. After cooling to 0°C, it was diluted with 140 ml of toluene, and 11 g of dichlorodicyanobenzoquinone was added, after which it was stirred for 40 min. It was diluted with 500 ml of acetic acid ester, after which it

was washed several times with dilute ammonia solution and then with water, then dried, filtered, and the solution was distilled off under vacuum. Raw product 4.81 g. Chromatography on silica gel with hexane-acetic acid ester (50-100%) yielded 1.78 g of 5-methoxymethyl-4-methyl-B-carboline-3-carboxylic acid ethyl ester with m.p. 133-135°C (from acetic acid residues).

Example 42

In a similar way as discussed under steps 5-8

was prepared from the corresponding indole: 5-ethoxymethyl-4-methyl-B-carboline-3-carboxylic acid ethyl ester, m.p. 134-136°C (acetic acid ester)

5-Ethoxymethyl-4-methyl-B-carboline-3-carboxylic acid ethyl ester, m.p. 167-170°C (acetic acid ester),

5-benzyloxy-4-ethyl-B-carboline-3-carboxylic acid ethyl ester, m.p. 192-193°C (acetic acid ester)

5-benzyloxy-4-methyl-3-carboline-3-carboxylic acid ethyl ester m.p. 190-192°C (acetic acid ester)

5-Phenyloxy-4-methyl-B-carboline-3-carboxylic acid ethyl ester, m.p. 183-187°C,

5-acetoxymethyl-4-methyl-3-carboline-3-carboxylic acid ethyl ester, m.p. 161-165°C

Claims (1)

Analogous process for the preparation of therapeutically active 3-substituted 3-carbolines of the general formula I wherein R<1> means alkoxy of up to 6 carbon atoms, RA means H, F, Cl, Br, I, NO2, CN, CH3, SCH3, SO2N( CH3)2 orNR<4>R<5> in which R<4> and R<5> each means hydrogen, alkyl with up to 6 carbon atoms, benzyl or 62_g-alkenyl or C2_5~alkynyl in that the alkyl groups may be substituted with a halogen atom, COOR <6> or CHOR<6>OR<7>, in which R<6> and R<7> here can mean hydrogen or alkyl with up to 3 carbon atoms, and in which R<4> and R<5 >together with the nitrogen atom can mean pyrrolidine, pyrrole, pyrazole, piperidine, hexamethylamino, piperidone, 1,1-dioxothiazolidine, in which R<6> and R<7> have the meaning given above, CHR<6->OR<10>, in which R<6> has the meaning given above and R<10> means hydrogen, alkyl with up to 3 carbon atoms or the group C(=0)R<6> in which R<6> has the above meaning, or OR<11> which means methoxy, phenoxy or benzyloxy, or CSCR<12>, where R<12> means hydrogen, alkyl with up to 3 carbon atoms, phenyl, CHR6R1<3>, in which R<6> and R1<3> together form =0 or R<6> has the above meaning, and R<13> means OR14, NR15R16 a halogen atom or P( =0)OR6(OR7), in which R<6> and R<7> have the above meaning, and R<14> means hydrogen, alkyl with up to 3 carbon atoms or the tetrahydropyranyl residue, and in which R<15> and R <16> each means hydrogen alkyl with up to 6 carbon atoms or together with the neighboring nitrogen atom forms a piperidinyl ring, the A ring can contain up to two of the above-mentioned substituents or R<c> means hydrogen, alkyl with up to 6 carbon atoms or (C <H>2)nOCH3 or (CH2)nO C2H5 and n have the values 1 or 2, provided that R<c> cannot be hydrogen, alkyl of up to 6 carbon atoms, when RA means H, F, Cl, Br, I, NO2, CN, SCH3, SO2N(C<H >3)2 or NR<4>R<5> in which R<4> and R<5> have the previously stated meaning, characterized in that a) an indole derivative of the general formula III in which R<c> means (CH2)nOCH3, where n has the meaning stated above, R<18> means alkoxy with 1-6 carbon atoms, and RA means hydrogen, a group of the formula CHR<6->OR10, wherein R<6> and R1<0> have the meaning indicated above, OR<11>, wherein R11 has the meaning indicated above, F, Cl, Br, I, N02, CH3, CF3, SCH3 or SO2N(CH3)2 is cyclized with formaldehyde and that the resulting compound is dehydrogenated and optionally 1) the compound where RA is hydrogen is chlorosulfonated, after which the thus obtained sulfonyl chloride is reacted with N(CH3)2 whereby the compounds are obtained where RA is -S02N(CH3)2 when RA is hydrogen, 2) or compounds where RA is hydrogen are halogenated to compounds where RA is halogen' after which the halogenation product thus formed is optionally converted to compounds where RA is nitrile, or 3) compounds where RA is hydrogen, is nitrated to a compound where RA is nitro, after which the nitro compound thus obtained is reduced to a compound where RA is an amino compound, or 4) compounds where R<c> is (CH2)OCH3 are converted into compounds where R<c> is (CH2)nOC2H5 over compound r where R<c> is halogen or 5) is transesterified in the 3 position or b) that a p<->carboline-3-carboxylic acid alkyl ester with the general formula IV in which R<c> has the meaning given above, and R<21> means alkoxy with up to 6 carbon atoms and Hal means chlorine, bromine or iodine, is reacted with a dialkyl phosphite of the formula in which R<6> and R<7> has the above meaning, to obtain a compound of the formula I, in which RA means a group of the formula or c) a P-carboline-3-carboxylic acid alkyl ester of the general formula IV is reacted with a compound of the formula R<12>C= CH, in which R12 has the above meaning, or means a protecting group and that the treatment is carried out with dilute mineral acid when R<12> means a protecting group, after which the free 3-hydroxy-l-propynyl compound thus obtained is oxidized to 3-oxo-l- the propynyl compound or is chlorinated with thionyl chloride until the propynyl compound is optionally reacted with a trialkyl phosphite of the formula POR<6>(OR<7>)2, where R<6> and R<7> have the meaning stated above to obtain the corresponding 3-dialkoxyphosphoryl- l-propynylphorbin part or with piperidine in the presence of a strong base to obtain the corresponding 3-piperidino-1-propynyl compound, or d) that a compound of the general formula V in which R<22> means alkoxy with up to 3 carbon atoms, and R<c> has the meaning given above, is reacted with an alkyl halide of the formula (R<5>)R<4>Hal, in which Hal means chlorine, bromine or iodine, wherein R<4> and R<5> have the meaning stated above, to obtain a compound of formula I, wherein RA means NR<4>R<5>, wherein R4 and R<5> have the meaning stated above. R<6> and R<7> have the meaning stated above for obtaining the corresponding 3-dialkoxyphosphoryl-l-propynyl compound or with piperidine in the presence of a strong base for obtaining the corresponding 3-piperidino-l-propynyl compound, or d) that a compound of the general formula V in which R<22> means alkoxy with up to 3 carbon atoms, and R<c> has the meaning given above, is reacted with an alkyl halide of the formula (R<5>)R<4>Hal, in which Hal means chlorine, bromine or iodine, wherein R<4> and R<5> have the meaning stated above, to obtain a compound of formula I, wherein RA means NR<4>R<5>, wherein R4 and R<5> have the meaning stated above.