DK170504B1 - Analogy process for preparing beta-carboline-3-carboxylic acid derivatives - Google Patents

Description

in DK 170504 B1

The invention relates to an analogue and process for the preparation of novel β-carboline-3-carboxylic acid derivatives. These novel compounds have valuable pharmacological properties. In particular, they act on the central nervous system and are suitable for use in psychopharmaceuticals.

In the specification of Canadian Patent No. 786,351, β-carbolin-3-carboxylic acid amides are substituted, which in one style is substituted with an alkyl group of up to 5 carbon atoms, a trifluoromethyl, a phenyl or a benzyl group, as well as two compounds having no substituent in 1-step 11, namely β-carboline-3-carbohydride and β-carboline-3-carboxylic acid amide.

In the specification of Danish Patent No. 98,436, a process for producing E-carboline-3-carboxylic acid methyl ester for use as starting material in the preparation of corresponding 3-hydroxy-methanol compounds.

Furthermore, Danish Patent Application No. 3703/80 discloses / J-carboline-20 3-carboxylic acid derivatives in the form of esters, amides and amidines and thio analogs thereof which have affinity for benzodiazepine receptors.

It has now surprisingly been found to produce novel 25 β-carboline-3-carboxylic acid derivatives that exhibit psychotropic properties in pharmacological studies and greater affinity for benzodiazepine receptors than the known compounds, see subsequent table.

The compounds prepared by the process of the invention are /) - carboline-3-carboxylic acid derivatives of the general formula (I)

RC

35 cor1 RA A B C (1)

Η H

DK 170504 B1 2 where: A. R 1 represents an alkoxy group containing up to 6 carbon atoms; RA represents H; F; Cl; br; J; N02; SCH 3; S02N (CH3) 2; 4 5 4 5 * NR R, wherein R and R each represent a hydrogen atom;

10 O

"OR6 \ 7 OR7 ic c 7 where R and R represent _3-alkyl; CHR4 -OR4, where R3 represents an alkyl group of up to 3 carbon atoms; OR2, where R4 represents an alkyl group of up to 6 carbon atoms , an aryl group or an unbranched or branched aralkyl group having up to 12 carbon atoms; or C = CR12 where R12 represents CHR6R3, where R6 represents jc13 14 L0 C1-6 alkyl, and R represents a halogen atom or OR, 14 wherein R represents a hydrogen atom or an alkyl group of up to 3 carbon atoms, wherein the A ring optionally contains more than one of the above substituents; and 30 represents (CH 2) NO 17 where n is 1 or 2 and R 7 represents an alkyl group having up to 6 carbon atoms; or B. R * represents an alkoxy group containing up to 6 carbon-y atoms; A * R represents 35 OR 170 5 OR7 6 7 wherein R and R represent C ; or

CsCR12, where R12 represents CHR6R13, where R6 represents * 0 C · ,alkyl, and R13 represents a halogen atom or OR ^, 14 wherein R represents a hydrogen atom or an alkyl group having up to 3 carbon atoms, the A ring optionally containing more than one of the above substituents; and R 1 represents a hydrogen atom; an alkyl group having up to 6 carbon atoms; (CH2) nOR17, where n is 1 or 2, and R17 represents an alkyl group of up to 6 carbon atoms; or C. R * represents an alkoxy group containing up to 3 carbon atoms; RA represents H; F; Cl; br; J; N02; SCH 3; $ 02N (CH3) 2; NR 5 where R and R each represent a hydrogen atom, a 23 alkyl group of up to 6 carbon atoms, a C 1-6 alkynyl group, or wherein R and R together with the neighboring nitrogen atom form a piperidine or pyrrolidine ring ;

ISLAND

30 '' OR6 P <^ OR7 S7 where R and R represent C1-6 alkyl; 35 CH2-OR3, where R4 represents an alkyl group of up to 3 carbon atoms; OR ^ where R 'represents an alkyl group of up to to 6 DK 170504 B1 4 carbon atoms, an aryl group or an unbranched or branched aralkyl group having up to 12 carbon atoms; or

CsCR ^, where R ^ represents CHR ^R ^, where R® represents ioii 5 C C ,alkalkyl, and RJ et represents a halogen atom or OR, * -1 "0 14 where R represents a hydrogen atom or an alkyl group having up to to 3 carbon atoms, wherein the A ring optionally contains more than one of the above substituents; R 10 represents a hydrogen atom; an alkyl group having up to 6 carbon atoms; (CH 2) nOR17 where n is 1 or 2 and R17 represents an alkyl group having up to 6 carbon atoms, r provided that R does not represent a hydrogen atom or an alkyl group having up to 6 carbon atoms when RA represents H; F; Cl; Br; J; NO2; SCH3; SO2N (CH3) 2 or NR4R5 wherein R 4 and R 2 have the meanings given above, or D. R * represents a methoxy, ethoxy or propoxy group, 2 ° RA represents NrV, where R 1 and R 2 represent a hydrogen atom; or an ethyl, ally! -, 2-methyl-2-propen-1-yl, 2-buten-1-yl or 3-propargyl group, and r R represents a hydrogen atom, a methoxy, methyl or ethyl group, or E. R * represents an ethoxy group, R A represents a benzylthio group and 30 R represents a hydrogen atom; or F. R1 represents an ethoxy group, RA represents a 6-N-isopropylamino group, and * Γ R represents a hydrogen atom,

Unless otherwise defined, the terms "alkyl", "aryl", - - '. DK 170504 B1 "aralkyl", "alkoxy", "aryloxy" and "aralkoxy" group for the definition of saturated or unsaturated unbranched or branched groups or ring systems.

5 The substituent in the A-ring can be in the 5-, 6-, 7- or 8-position. The A-ring may be mono- or disubstituted with substituent a or R. 5- and 6-way11 are preferred.

The invention thus relates to an analogue and process for the preparation of the subject β-carboline-3-carboxylic acid derivatives of formula (I), which process is characterized by: a) an indole derivative of general formula III

RC

λ »“ f ^^^^ coR1 RA - A B 1 (ΙΠ) 20 'NH2

H

where 25 RC represents (CH 2) NOR 4, where and n have the meanings given above (A), R represents an alkoxy group having 1 to 6 carbon atoms, and 30 A '10

R represents a group of the formula ChL-OR, wherein R

£ 11 has the meanings given above (A); OR, wherein R 11 has the meanings given above (A); H; F;

Cl; br; J; Ν0 £; Nl · ^; SCH3 or SO2N (CH3) 2> 35 cycles with formaldehyde, thereby obtaining 1,2,3,4-tetrahydro-β-carbol in compound to be dehydrogenated to form a β-carboline-3 carboxylic acid derivatives of formula (I) wherein R 1, R 2 and R 2 have the meanings given above for RA, R 18 and R 6, respectively, and if necessary i) chlorosulfonated, and the sulfonyl chloride thus obtained is reacted with an amine of formula N (CH 2) 5 to form the dimethylsulfamoyl derivative, or if necessary ii) halogenated or, if necessary, iii) nitrated, then the nitro compound thus obtained is reduced to an amino compound or, if necessary, iv) re-etherified 4-way n or, if necessary, 15 v) re-esterified at 3-way n; rb) that an indole derivative of the general formula III wherein R represents 17 17 (CH 2) n ° R 'where R ° 9 n has the 20 meanings specified above (A), 18 R represents an alkoxy group having 1 to 5 carbon atoms, and k1 10 10

R represents a group of the formula CHg-OR, where and R

25 has the meanings given above under A; OR 1, where R 2 has the meanings given above under A; F; Cl; br; IN; N02; NH 2; SCH3 or SO2N (CH3) 2 is treated with formic acid to give the corresponding formyl compound, after which this compound is cyclized with phosphorus oxychloride or polyphosphoric acid to form the corresponding dihydrocarboline which is then dehydrogenated to form a β-carboline. -3-carboxylic acid derivative of formula (I) wherein R, R and R are as above

-r Λ / Q JO

R, R and R are indicated and, if necessary, i) chlorosulfonated, and the sulfonyl chloride thus obtained is reacted with an amine of formula N (CH3) 2 to form the dimethylsulfamoyl derivative, or DK 170504 B1 7 ii) halogenated, or iii) is nitrated, after which the nitro compound thus obtained is reduced to an amino compound, or 5 iv) is re-etherised at the 4-position, or v) is re-esterified at 3-step 11 in the nene;

c) that an E-carboline-3-carboxylic acid cool ester of the general formula IV

RC

15 21

S 'Nf ^ N-COR

Hal abc n (IV)

Η H

20 where C 21

R has the meanings given above (B) and R

represents an alkoxy group of up to 6 carbon atoms, Hal 25 represents chlorine, bromine or iodine, is reacted with a d in all cooling phosphorus in the formula

H

In OR6 O = V, 6 7 where R and R have the meanings given above (B), 3 pfl to form a compound of formula I wherein · R represents the group DK 170504 B1 8 0 "^ OR6 - K.

OR ^ 5 fi 7 Γ where R and R have the above meanings, R has the above meanings, and R * represents an alkoxy group of up to 5 carbon atoms; d) a β-carboline-3-carboxylic acid alkyl ester of the general formula C 21 IV wherein R and R have the meanings given above under c) is reacted with a compound of the formula R CsCH wherein R has the for R above referred to in (B) or denotes a protecting group for the preparation of β-carboline compounds of formula (I) wherein RA represents -k = C-R 12 and R1 and R means, which compounds if necessary 12 'i) if R is a protecting group, the protecting group is diluted with dilute mineral acid to give a free 3-hydroxy-1-propynyl compound which is then optionally ii) chlorinated with thionyl chloride to 3-chloro-1 propynyl compound;

e) a compound of general formula V

RC

3 ° C -rV cor22 H2N B N (V)

35 I I

Η H

22 where R represents an alkyl group of up to 3 carbon atoms, r and R represents a hydrogen atom, an alkyl group of up to 6 carbon atoms or (CH 2) nOR17 where n is 1, 2 or 3, and R 17 represents an alkyl group having up to 6 carbon atoms, 5 4 is reacted with a halide of formula (R) R Hal, where Hal is s chlorine, bromine or iodine and where R and R together with the adjacent nitrogen atom form a piperidine. or pyrrolidine ring, Λ to form a compound of formula I wherein R represents

i n 4 5 4 5 1 C

IU NR R, where R and R have the same meanings and R and R have

22 C

the same meanings as those above for R and R respectively; f) a compound of the general formula V 15

RC

cor2 2 h2n abc 20 f (V)

Η H

pc 22 "where R represents an alkyloxy group of up to 3 carbon atoms and R 1 represents (CH 2) nOR * 7, where n is 1, 2 or 3 and R * 7 represents an alkyl group of up to 6 carbon atoms, 5 4 is reacted with an alkyl halide of formula (R) R Hal wherein Hal 1 is chlorine, bromine or iodine and wherein R 4 represents a hydrogen atom, an alkyl group having up to 6 carbon atoms or a C 2 -C 5 alkynyl group, Λ to form a compound of formula I wherein R represents 35 NR 4 R 5, wherein R 4 and R 5 have the same meanings and R1 and RC 22 have the same meanings as indicated above for R and RC respectively; r g) a compound of the general formula (V) wherein R represents hydrogen, methoxy, methyl or ethyl, and R represents methoxy, ethoxy or propoxy, 9 8 8 9

is reacted with a compound of formula (R) R Br, wherein R and R

5 represents a hydrogen atom, an ethyl, allyl, 2-methyl-2-propen-8,9 l-yl-2-buten-1-yl or propargyl group, although R and R do not both simultaneously represent a hydrogen atom , to form an E-carbolic acid derivative of formula (I) wherein C 1 R represents hydrogen, methoxy, methyl or ethyl, R 1 represents A 8 9 8 methoxy, ethoxy or propoxy, and R represents NR R where R and g R represents ethyl, allyl, 2-methyl-2-propen-1-yl, 2-buten-1-yl, 3-propargyl or hydrogen;

(h) a compound of general formula VI

FC

^ COOR23 20 -—— 24 rA ——. A B rc00R (VI) U. I k-cko

N S * K

H

25

A C

wherein R and R have the meanings given above (C) and 23 24 R and R each represent an alkyl group of up to 3 carbon atoms, cyclized with phosphorus oxychloride to give the corresponding 1,2,3,4 tetrahydrocarboline, that this compound is decarbalkoxylated to form the corresponding dihydrocarboline and that it is dehydrogenated to prepare compounds of formula (I) wherein R 1 and R 2 have the above meanings.

i) that a β-carboline-3-carboxylic acid derivative of formula (I) wherein 1C A * R represents ethoxy, R represents hydrogen, and R represents NO 2 are reacted with benzyl mercaptan to form a β-carboline-3 - carboxylic acid derivative of formula (I) wherein R 1 represents ethoxy,

R1 represents a hydrogen atom and RA represents benzyl thi o; DK 170504 B1 11 j) reacting dimethyl amine and formaldehyde with benzylthioindole to form benzyl thiogramine, which is then reacted with formylaminomalon ester to form 2-formylamino-2- (benzylthioindolylmethyl) malonic acid diethyl ester which is reacted with phosphorus oxychloride, after which the reaction product formed is reacted with sodium cyanide to give a / 1-carboline-3-carboxylic acid.

1 C

is a vat of formula (I) wherein R represents ethoxy, R represents Λ hydrogen, and R represents a benzylthio group; or k) reacting 6-amino- / J-carboline-3-carboxylic acid ethyl ester with isopropyl bromide to form 6-N-isopropylamino / I-carboclin-3-carboxylic acid ethyl ester.

In a preferred embodiment of method (a), a compound of formula III is formalized with formaldehyde to give the corresponding 1,2,3,4-tetrahydrocarboline and 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 2 ° 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 a preferred embodiment of method (b), a compound of formula III is treated with formic acid to form the corresponding formula, and this compound is cyclized with phosphorus oxychloride or polyphosphoric acid to form the corresponding dihydrocarboline which is then dehydrogenated.

30

The dehydrogenation of the compound obtained by cyclization can be carried out by a method known per se. One such method consists in dissolving or suspending the starting material 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. For example, xylene, mesitylene, anisole, toluene, chlorobenzene and diphenyl ether may be mentioned. Next, elemental sulfur is added in such an amount that per double bond is used approx. 1 mole equivalent of sulfur. A small surplus is not only harmless, but appropriate. The reaction mixture is refluxed for several hours, during which the reaction is followed by thin chromatography.

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

A further method is dehydrogenation with precious metal catalysts such as finely divided platinum, finely divided palladium or palladium carbon in xylene, mesitylene or cumole at 120-180 ° C and a reaction time of from 2 to 15 hours.

* 5 The preparation of sulfonic acid derivatives can be carried out 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 under cooling.

To prepare similar methyl sulfamoylderates, the previously obtained product is reacted with a methylamine.

Halogenation can occur in a manner known per se. Thus, the starting material can be dissolved in an inert solvent and reacted with the appropriate halogen such as chlorine or bromine, optionally in the presence of a basic catalyst at temperatures below room temperature. For example, inert solvents are chlorinated hydrocarbons such as methylene chloride, chloroform, dichloroethyl, etc. Suitable basic catalysts are pyridine and substituted pyridine, such as dimethylaminopyridine. A basic catalyst can be avoided by the chlorination.

Conveniently, for the introduction of iodine, not only elemental iodine is 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.

Nitration can be done in a manner known per se. Thus, the starting material can be reacted with concentrated nitric acid at a temperature below 170 ° C. Concentrated nitric acid means the commercially available nitric acid, which may also be enriched with fuming nitric acid. The acid is, by nitration, the reactant as well as the solvent.

5

Any subsequent reduction of the obtained nitro compound to the corresponding amino compound also follows methods known per se.

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

15

An optionally desired re-etherization of a 4-alkoxy group in the compound of formula I can be carried out in a manner known per se. Thus, the starting material can be dissolved in a polar solvent, such as acetonitrile 1, dimethyl formamide or 1-methyl-2-pyrrolidone, and reacted with sodium sulfide in d and trimethylchlorosilane at a temperature above room temperature.

The 4-iodine-cooled compound thus obtained of the formula is subjected to a nucleophilic substitution which again takes place by methods known per se. Thus, the starting material, preferably to the boiling point of the reaction mixture, is heated with a corresponding alkali or tetraalkyl ammonium alcohol, such as sodium ethylate or potassium methylate, optionally 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 re-esterification of the ester group at the 3-position can be done 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 35 for 3-6 hours at temperatures between 80 and 120 ° C. Optionally, the re-esterification may be carried out with the alcohol ROH in the presence of an acidic catalyst such as paratoluene sulfonic acid, HCl or CuCl2.

For the preparation of compounds of formula I according to method (c) DK 170504 B1 14, the corresponding β-1-carboline-3-carboxylic acid coolers which are substituted in the A-ring with halogen, especially with chlorine, bromine or iodine, are even known methods.

For this, the starting material is dissolved in an aprotic solvent such as dimethyl formamide, dimethylacetamide, N-methylpyrrole in don or hexa-methylphosphorotriamide, and is reacted hot, i.e. at temperatures ranging from 50 to 140 ° C, in the presence of a complex noble metal catalyst of the triarylphosphine class, such as e.g. palladium-tetrakis-triphenylphosphine, and a strong organic base, such as triethylamine, pyridine or dimethylamine pyridine, with a dialkylphosphite such as e.g. dimethyl, diethyl or dipropyl phosphite.

Also used as starting material for the preparation of compounds of formula I according to method (d) is β-carboline-3-carboxylic acid alkyl esters which are substituted with halogen in the A-ring. 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-20-amylamine, e.g. di ethyl ami η, methyl ethyl ami η, trimethylamine or triethylamine, and 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> C 12 formula R CsCH at temperatures above room temperature, preferably from 40 to 150 ° C.

It is advisable to add copper-I salts, e.g.

copper-I-iodide.

30

The entire reaction is conveniently carried out with the exclusion of air and moisture.

12

If R is a protecting group, the compound thus obtained can see the formula I hydrolyzed heated with a dilute mineral acid such as sulfuric acid, hydrochloric acid or perchloric acid to form the corresponding hydroxy compound, i.e. propargylforbinde! late.

DK 170504 B1 15

A previously obtained propargyl compound can be chlorinated with thionyl chloride at room temperature, by which process a solvent is not required since the thionyl chloride acts as a solvent.

5

For the preparation of compounds of formula I according to method (e), corresponding β-carbol in-3-carboxylic acid alkyl esters substituted in the A-ring with an amino group with an alkyl halide, tosylate or mesylate are reacted by themselves. known methods in a suitable solvent in the presence of a base at temperatures ranging from room temperature to the boiling point of the reaction mixture.

Suitable solvents are all protic and aprotic solvents insofar as they are inert to the reactants. For example, mention may be made of 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, and solvents such as dimethyl formamide, dimethylacetamide and N -methylpyrrole in don.

20

Suitable bases are all strong organic bases such as triethylamine, di methyl ami nopyri di η, ethyl di in sopropylamine, di azabi cyclo-undecene, none and octene. But it is also possible to use an all potassium carbonate such as sodium or potassium carbonate, as well as alcoholates, such as potassium tert-butylate. All of the cooling halide may optionally be substituted as previously stated. In the case of the cyclized compounds, it is only essential that it is a non-alkaline di halo-alkane or alkene. As halogen, chlorine, bromine or iodine comes into play, as when it is chlorine it is appropriate to add 3 ° a copper (I) halide such as copper (I) iodide.

The work-up of the compounds thus prepared is carried out according to methods known per se, e.g. by extraction, crystallization, chromatography, etc.

35

The compounds of the invention can be used to formulate pharmaceutical compositions, e.g. for oral and parenteral administration in mammals including humans, in accordance with known galenic methods.

DK 170504 B1 16

Suitable adjuvants for formulating pharmaceutical compositions are such physiologically acceptable organic or inorganic carriers for enteral and parenteral administration which are inert to the compounds of the invention.

5

Examples of such carriers are water, saline, alcohols, polyethylene glycol, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid ethyl esters, hydroxyl acetic acid esters, hydroxy fatty acid esters,

The pharmaceutical compositions may be sterilized and / or mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, buffers and dyes.

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

20

For oral use, tablets, dragees or capsules having talc and / or a carbohydrate carrier or binder such as e.g. lactose, corn or potato starch, especially suitable. The use may also be in liquid form, e.g. as a juice optionally added to a sweetener.

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

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

35 DK 170504 B1 17

Table

Pharmacological Properties of / 5-Carboline-3-Carboxylic Acid Derivatives of Formula I.

RC

i. Affinity for benzodiazepine I \ I '^ pcoR1 receptor (inhibition of -' j ^ gel 3 LI Jl N H-flunitrazeo binding) 10 m μ in vitro in vivo IC50 '/ g / ml ED50, mg / kg \ ---; - Η H OEt *) 1.4 60 Η HN (C2H5) 2 * ^ 4300 82 20 ----- 6-Me2N-02S- CH20Me OEt 0.2 10 6 -N02 CH20Me OEt 0.2 > 200 25 6.7 (OMe) g CH20Me OMe 16.0 10.0 6-PO (OEt) 2 Me OEt 1.4 45 6-CsC-CH2-0Me H OEt 1.1 18.0 3Q 6-OC .CH2OH H OEt 0.5 43 5- (= C-CH 2 OH H OEt 0.2 79 · 6- (C = C-CH 2 Cl) H OEt 7.0 41 6-NH OEt 39 31 35 6-NH OEt 14 8 , 0 6-NH OEt 23 54 DK 170504 B1 18

Table (continued) 6-SMe CH2OMe OEt 0.6 14.0 5 6-OMe CH20Me OEt 0.8 10.0 6-N () 2 H OEt 0.4 35-5-CH20Et Me OMe 0.6 3, 8 5-OCH2Ph CH2 Ome 0.6 0.6 5 5-S-benzyl H OEt 4.3 13 10 5- O- CH3 OEt 2.0 2.8 6- NH2 CH2OMe OEt 12.0 9 6-NH- <H OEt 6.7 12 15 H CH2OCH3 OEt 1.2 4.6 6-C1 CH2CH20CH3 OEt 1.4 33 6-Br CH2OCH3 1.75 15 ^ According to DK Patent Application No. 3703/80 20

Example 1 20.3 g / 3-Methoxymethyltryptophanethyl ester was dissolved in 350 ml of benzene, pi mixed with 2.48 g of paraformaldehyde and heated for 3.5 hours in a water purifier. After cooling, benzene was distilled off, the residue was dissolved in 350 ml of toluene and heated for 20 hours under reflux after addition of 4.5 g of 10% palladium coal. The cooled solution was filtered and concentrated. The resulting residue 30 w 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-β-carboline-3-carboxylic acid ethyl ester, m.p. 118-119 ° C.

35

Preparation of the starting material.

a) 191.0 ml of Isopropylamine was mixed dropwise under ice-cooling over 2 hours with 165.3 g of methoxyacetaldehyde so that the temperature of the mixture did not exceed 10 ° C. Thereafter, DK 170504 B1 19 was stirred for another 30 minutes at 5 ° C and portions of solid potassium hydroxide were added until 2 phases occurred, after which the upper phase was separated and again mixed with potassium liquor and allowed to stand for 12 hours at 5 ° C. The solution was then filtered and the filtrate 5 distilled over ca. 2 g of barium oxide in 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 indo! in 510 ml of glacial acetic acid 110.9 g of the previously obtained imine was added dropwise in 230 ml of benzene dropwise in such a way that the temperature of the mixture did not exceed 10 ° C. Then, stirred for 12 hours at 5 ° C, then the reaction mixture was stirred slowly for approx. 1.7 liters of ice water, the organic phase was separated and the aqueous phase 1 was extracted twice, each time with 180 ml of benzene. Then, the pH of the aqueous phase was adjusted by dropwise addition of 6 N sodium hydroxide solution under ice-cooling and extracted with benzene and ether. The extracts of the alkaline phase were dried over sodium sulfate and concentrated.

203.9 g of pale yellow oil were obtained which was used without further purification in the subsequent step.

c) A solution of 92.0 g of the previously obtained product in 1.3 liters of toluene was mixed with 55.2 g of nitric acid ethyl ester and "stirred under argon for 16 hours at 80 C. After cooling, wash twice, each time with 400 ml of 1N hydrochloric acid, then with saturated brine, followed by drying over sodium sulfate and concentration. 155.9 g of adduct was obtained as an oily isomeric mixture which was used without further treatment in the subsequent reaction.

d) 24.9 g of the adduct obtained above were dissolved in 600 ml of ethanol and hydrogenated after the addition of ca. 32 g Raney nickel at room temperature under normal pressure. After uptake of 5650 ml of hydrogen, the catalyst was filtered off and concentrated.

20.3 g of β-methoxymethyltryptophan ethyl ester were obtained as an oily isomeric mixture.

5 DK 170504 B1 20

Example 2 In a similar manner to Example 1, the following β-carbolines were prepared: 5- methoxy-4-methoxymethyl- / 5-carboline-3-carboxylic acid ethyl ester, m.p. 168-170 ° C, 6- methoxy-4-methoxymethyl- 3-carboli n-3-carboxylic acid ethyl ester, m.p. 175-177 ° C, 7-methoxy-4-methoxymethyl-3-carboline-3-carboxylic acid ethyl ester, mp 161-163 ° C, 5-benzyloxy-4-methoxymethyl-1 -carboli n-3-carboxylic acid ethyl ester, m.p. 185-188 ° C, 6- chloro-4-methoxymethyl- / 5-carboli n-3-carboxylic acid ethyl ester, m.p. 206-208 ° C, 5-fluoro-4-methoxymethyl - / 3-carbolic in-3-carboxylic acid ethyl ester, m.p. 182-184 ° C, 6,7-dimethoxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, mp 163-164 ° C, and 6,7-dichloroacetic acid. 4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, m.p. 199-203 ° C.

Example 3 In the same manner as in Example 1c), 2.5 g of α-nitro-β- (2-methoxyethyl) -indolyl- (3) -propionic acid ethyl ester was prepared analogously to hydro (1d) 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) - / 5-carboline-3-carboxylic acid ethyl ester was obtained, mp 181-183 ° C.

Preparation of the starting material.

35 a) From 16.1 ml of isopropylamine and 16.6 g of methoxypropionaldehyde (prepared according to Angew. Chem. 62, 115 (1950)), 22.9 g of isopropyl imine of -methoxypropionaldehyde as an E, Z-isomer blend.

B) A solution of 20.7 g of indole in 104 ml of glacial acetic acid is reacted under the conditions specified in Example 1 b) with 22.9 g of the above-obtained imine in 54 ml of benzene. 19.2 g of condensation product was obtained as a brownish oil.

C) 19.2 g of the product obtained above were reacted with 10.4 g of nitric acid ethyl ester under the conditions given in Example 1 (c). After chromatography on silica gel with hexane / acetic acid ester, 8.5 g of c-nitro- (S- (2-methoxy) -indolyl- (3) -propionic acid ethyl ester was obtained as a yellow oil.

Example 4

Analogously to Example 3 and using known substituted indoles, the following β-carbolines were prepared: 6,7-dimethoxy-4- (2-methoxyethyl) -β-carbol in-3-carboxylic acid ethyl ester, m.p. 206-208 ° C , 6-methoxy-4- (2-methoxyethyl) -6-carboline-3-carboxylic acid ethyl ester, 2 ° mp 189-191 ° C, 6-chloro-4- (2-methyloxyethyl) -O-carboline-3-carboxylic acid ethyl ester, m.p. 232-234 ° C, 5-benzyloxy-4- (2-methoxyethyl) -β-carboline-3-carboxylic acid ethyl ester, m.p. 174-176 ° C, 6-benzyloxy-4-methoxymethyl-β-carboline. 3-carboxylic acid ethyl ester, m.p. 165-166 ° C,

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

DK 170504 B1 22

Example 6

A solution of 284 mg of 4-methoxymethyl / J-carboline-3-carboxylic acid ethyl ester in 13 ml of chloroform was cooled to -30 ° C and mixed 5 drops with 0.05 ml of bromine in 1 ml of chloroform. The solution was stirred for 2 hours at -20 to -10 ° C, then poured into ice-cold 10% sodium hydrogen sulfide top solution and extracted with methylene chloride. Crystallization from acetic acid ester gave 240 mg of 6-bromo-4-methoxy-methyl-β-carboline-3-carboxylic acid ethyl ester, mp 10 207-209 ° C.

Example 7

To a solution of 250 mg of 4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester in 12 ml of chloroform was added dropwise 0.5 ml of bromine in 3 ml of chloroform at room temperature and the solution was stirred for 2 hours at room temperature. After further processing as described in Example 3 and crystallization from hexane / acetic acid ester, 250 mg of 6,8-dibromo-4-methoxymethyl- / J-carboline-3-carboxylic acid ethyl-2® ester were obtained, mp 98-99 ° C.

Example 8

To a mixture of 19.3 ml of 65% nitric acid and 9.65 ml of smoking 25 nitric acid was added portionwise 2.0 g of 4-methoxy-methyl / J-carboline-3-carboxylic acid ethyl ester. The reaction mixture was then stirred for 3 hours at 5 ° C, added dropwise to ice water, and then the mixture was basified with concentrated aqueous ammonia solution and filtered. The precipitate was washed with water, dried, resuspended in 30 ml of acetic acid ester and heated at reflux for 15 minutes. After cooling, 1.85 g of 4-methoxymethyl-6-nitro-O-carboline-3-carboxylic acid ethyl ester, yielding a melting point of 274-276 ° C, were obtained.

o C

Similarly, by nitration of 2 g of 4- (2-methoxyethyl) -O-carboline-3-carboxylic acid ethyl ester, the corresponding nitro compound 6-nitro-4- (2-methoxyethyl) -β-carboline-3-carboxylic acid ethyl ester was obtained in an amount of 1.80 g and m.p. 283-286 ° C.

Example 9 DK 170504 B1 23 1.7 g Of each of the two 6-nitro derivatives obtained in Example 8 was hydrogenated at room temperature and normal pressure in 70 ml of tetrahydrofuran and 70 ml of methanol after the addition of 300 mg of 10% palla -diumkul. After uptake of 420 ml of hydrogen, filtered and concentrated. Crystallization from acetic acid ester gave 1.2 g of 6-amino-4-methoxymethyl-β-carboli n-3-carboxylic acid ethyl ester having a melting point of 199-201 ° C and 1.1 g of 6-amino-4- (2-methoxy) ethyl) -β-carboline-3-carboxylic acid ethyl ester having a melting point of 238-242 ° C.

Example 10 A solution of 1.0 g of 4-methoxymethyl-3-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 minutes, 1.5 ml of iodine chloride and 200 mg of iodine were added again, the reaction mixture was stirred for an additional 2 hours at room temperature, then 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-β-carboline-3-carboxylic acid ethyl ester, mp 204-206 ° C.

Example 11

A suspension of 1.5 g of 4-methoxymethyl-3-carbol in-3-carboxylic acid ethyl ester, 20 ml of acetonitrile, 3.1 g of sodium iodide and 2.7 ml of trimethyl chlorosilane 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 / 3-carboline-3-carboxylic acid ethyl ester were obtained, mp 280-286 ° C.

To a freshly prepared solution of 1.5 g of sodium ethyl sodium and absolute ethanol, in 20 ml of ethanol and 20 ml of tetrahydrofuran was added 1.65 g of the above-obtained 4-iodomethyl derivative and the reaction mixture was heated at reflux for 2 hours. 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 acetic acid ester fraction gave 720 mg of 4-ethoxymethyl - $ - carboline-3-carboxylic acid ethyl ester with a melting point of 125-127 ° C.

Example 12 30 mg of sodium was dissolved in 15 ml of absolute methanol. Then 10 300 mg of 4-methoxymethyl / 3-carboline-3-carboxylic acid ethyl ester was added and the reaction mixture was heated at reflux for 2 hours. 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- / J-carboline-3-carboxylic acid methyl ester, mp 134-135 ° C.

Example 13 In the same way as in Example 13, the following compounds were prepared from the existing β-carboline-3-carboxylic acid ethyl ester and the corresponding alcohol: 6.7-dimethoxy-4-methoxymethyl-5-carboline-3-carboxylic acid methyl ester, mp: 153-164 ° C, 23 6,7-dimethoxy-4-methoxymethyl- / J-carbolin-3-carboxylic acid n-propyl ester, mp: 172-174 ° C, 6.7-dimethoxy-4-methoxymethyl - β-carbolin-3-carboxylic acid isopropyl ester, m.p .: 166-168 ° C, 4-methoxymethyl-β-carboli n-3-carboxylic acid n-propyl ester, mp: 154-157 ° C.

Example 14 1.46 g of 6-Iodo / J-carboline-3-carboxylic acid ethyl ester were added, with the exclusion of moisture, to a mixture of 608 mg of diethyl phosphite, 448 mg of triethylamine, 240 mg of palladium-tetrakis (triphenylphosphine) dichloride and 60 ml N-methyl-2-pyrrolidone and the reaction mixture was stirred for 12 hours at 90 ° C. After concentration, the obtained residue was chromatographed on 75 g of silica gel with methylene / acetone (1: 1) as eluent. The corresponding total fractions were chromatographed on 25 g of silica gel with methylene chloride / ethanol (10: 2) as the eluent and 421 mg of 6-diethoxyphosphoryl-O-carboline-3-carboxylic acid ethyl ester was obtained as an oil.

5

Example 15 Similarly, from the corresponding iodine compounds were prepared: 6-di in sopropoxyphosphoryl / 1-carbolin-3-carboxylic acid ethyl ester, 5-diethoxyphosphoryl-4-methyl, 8-carboline-3-carboxylic acid ethyl ester, 6-diethoxyphosphoryl-4 -methoxymethyl-β-carbolin-3-carboxylic acid ethyl ester, 5-diethoxyphosphoryl-β-carboline-3-carboxylic acid ethyl ester, 6-diethoxyphosphoryl-β-carboline-3-carboxylic acid methyl ester, all as oil.

Example 16 (Analogous Example) 20 1.6 g of 6-bromo-β-carboline-3-carboxylic acid ethyl ester were added together with 30 ml of diethyl amine under nitrogen and the exclusion of moisture to a mixture of 70 mg of copper (I) in od. 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) in odi d as well as 70 mg of palladium (bis [tri-o-tolyl] phosphine) was added again. dichloride, and the reaction mixture was kept at 100-120 ° C for another 3 hours. Then, concentrated by means of 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) -α-carboline-3-carboxylic acid ethyl ester (mp 265-268 ° C) was obtained. The rest of the crystals still contaminated with the 6-bromine compound were worked up according to Example 21.

Example 17 Prepared by analog: 6- (3-methoxy-1-propynyl) - [beta] carboli n-3-carboxylic acid ethyl ester,

EXAMPLE 18 Of the mixture of 6-bromo-3-carboline-3-carboxylic acid ethyl ester and 6- (3-tetrahydropyran-2-yl-oxy-1-propynyl) -5-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 obtained material was separated on 65 g of silica gel with chloroform / ethanol (10: 2) as eluent. By collecting the corresponding fractions and recrystallisers from ethanol, 400 mg of 6- (3-hydroxy-1-propynyl) -β-carboline-3-carboxylic acid ethyl ester having a melting point of 270-275 ° C were obtained.

Example 19 was similarly prepared: 5- (3-hydroxy-1-propynyl) - / 5-carboli n-3-carboxylic acid ethyl ester, m.p. 268-270 ° C. (Decomposition).

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

Example 20 78 mg of 6- (3-Hydroxy-1-propynyl) - / 3-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 obtained product was filtered off. Recrystallization from glacial acetic acid / cyclohexane yielded 40 mg of 6- (3-chloro-1-propynyl) -8-carboline-3-carboxylic acid ethyl ester (m.p. 298 ° C, dec.).

35

Example 21 156 mg of 6- (3-Chloro-1-propynyl) -β-carboline-3-carboxylic acid ethyl ester was stirred for 1.5 hours at 60 ° C with 85 mg of piperidine and 76 mg of 1.5-diazacyclo [ 5,4,0] undec-5-en in 10 ml of absolute ethanol under nitrogen and moisture exclusion. After evaporation, the remaining material was chromatographed on 25 g of silica gel with methylene chloride / methanol (10: 2) as eluent. 51 mg of 6- [3- (1-5 pi peryldinyl) -1-propynyl] -1S-carbolin-3-carboxylic acid ethyl ester (mp 215-217 ° C) were obtained.

Example 22 1 ° 383 mg of 6-Amino-β-carboline-3-carboxylic acid ethyl ester was heated in 15 ml of ethanol with 0.58 ml of ethyl di in sopropylamine and 0.18 ml of 1,4-dibromo-butane for 6 hours under nitrogen and with reflux. Then 0.4 ml of 1,4-dibromobutane was repeatedly added and refluxed for 3 hours. After evaporation, wash with water and boil with ethanol. 128 mg of 6- (1-pyrrole in diyl) - 3-carbol in-3-carboxylic acid ethyl ester were obtained, mp 259-261 ° C.

Example 23 20 Similarly prepared: 4-methyl-6- (1-pyrrolidinyl) -? -Carboline-3-carboxylic acid ethyl ester, m.p. 244-251 ° C, 4-methoxymethyl-6- (1-pyrrolidinyl) -α-carboline -3-carboxylic acid ethyl ester, m.p. 212-214 ° C, 4-ethyl-6- (1-pyrrolidinyl) -8-carboline-3-carboxylic acid ethyl ester, mp 205-218 ° C.

Example 24 446 mg of 6-Amino / J-carboline-3-carboxylic acid ethyl ester were heated in 17.5 ml of absolute ethanol with 410 mg of 1,5-dibromopentane and 500 mg of ethyl di in sopropyl amine under nitrogen for 4 hours and at reflux. After adding an additional 74 mg of 1,5-dibromopentane, the mixture was stirred for a further 33 hours under reflux. After evaporation, dissolved in methylene chloride and washed with saturated bicarbonate solution as well as saturated brine, 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, m.p. 255-256 ° C) were obtained.

Example 25 5 Analogously prepared: 4-methyl-6- (1-piperidinyl) - S-carboline-3-carboxylic acid ethyl ester, m.p. 215-224 ° C, 4-methoxymethyl-6- (1-piperidinyl) ) -S-carboli n-3-carboxylic acid ethyl ester, m.p. 163-166 ° C, 5- (1-piperidinyl) -5-carboline-3-carboxylic acid ethyl ester, mp 274-276 ° C,

Example 26 510 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-di aza [5,4,0] bi cyclo-undec-5-ene and 240 mg al 1yl bromide for 0.5 hours under nitrogen at 60 ° C. Then it was evaporated and extracted with acetic acid ester 20 and water. The organic phase was dried, filtered and concentrated. The residue 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 of 60 g of silica gel with methylene chloride / ethanol (9: 1) as eluent. Thereby, 200 mg of 6-N-allylamino-19-carboline-3-carboxylic acid ethyl ester, m.p. 190-194 ° C, was isolated.

Example 27 3 ^ In analogous manner: 5-allylamino-β-carboline-3-carboxylic acid ethyl ester, m.p. 199-202 ° C, 6- N-allyl-4-methoxymethyl-3-carboxylic acid ethyl ester, 220-223 ° C.

Example 28 93 mg of 6- (N-ethylamine) -O-carboline-3-carboxylic acid ethyl ester was heated in 8 ml of absolute ethanol with 49 mg of 1,5-diaza- [5,4,0] bicycloundec-5-ene and 50 mg. allyl bromide under nitrogen for 2 hours at 70 ° C. After DK 170504 B1 29 evaporation was extracted with acetic acid ester and saturated sodium hydrogen carbonate solution. The organic phase was dried, filtered and concentrated. The residue was chromatographed on 80 g of silica gel with methylene chloride / ethanol (12: 1) as eluent, and after recrystallization 1 from acetic acid ester / ether, 56 mg of 6- (N-allyl-N-ethylamino-) was obtained. 8-carboline-3-carboxylic acid ethyl ester (mp 190-192 ° C).

EXAMPLE 29 5.5 g of 6-Amino / J-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 moisture exclusion for 2.5 hours at 70 ° C. After the addition of 0.5 ml of all 1yl bromide was heated for another 30 minutes at 70 ° C. After distillation 11, the ethanol was extracted with acetic acid ester / saturated bicarbonate solution. The organic phase was washed with saturated brine, dried, filtered and concentrated. After recrystallization from acetic acid ester, 3.45 g of 6- (N, N-diallylamino) - / J-carbol in-3-carboxylic acid ethyl ester 20 (m.p. 194-196 ° C) were obtained.

Example 30 Analogously prepared: 6- (N, N-di-allylamino) -4-methyl- / 3-carboline-3-carboxylic acid ethyl ester, mp 158-159 ° C (acetic acid ester), 6- (N, N -di-allylamino-4-ethyl-β-carboline-3-carboxylic acid ethyl ester, 6- (N, N-di-allylamino) -4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester (oil), 6- [N, N, -di- (2-buten-1-yl) -amino] -β-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 carboline-3-carboxylic acid ethyl ester, m.p. 229-230 ° C, 6- (N, N-diallylamino) -4-methyl- / 3-carbol in n-3-carboxylic acid propyl ester, mp 190-192 ° C, 6- (N, N-di-allylamino) -4-methyl-β-carboli n-3-carboxylic acid methyl ester,

Example 31 DK 170504 B1 mp 146-148 ° C, 5,500 mg of 6-Amino-3-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-ene for 8 hours at 80 ° C. After evaporation, the acetic acid ester / saturated sodium bicarbonate solution was extracted. The organic phase was separated, dried, filtered and concentrated. The residue was chromatographed on 120 g of silica gel with methylene chloride / ethanol (12: 1) as eluent. After recrystallization from ethanol / ether, 6-N-1-sopropylamino-β-carboline-3-carboxylic acid ethyl ester in 20% yield was obtained, mp 230-232 ° C.

15

Example 32 Step 1 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, methylene chloride was washed, washed to neutrality with saturated sodium bicarbonate solution and brine, and the solvent was distilled off under vacuum. 35.57 g of 1-tosylindole-4-carboxylic acid methyl ester were obtained, mp 145-147 ° C (diisopropyl ether).

Step 2

A suspension cooled to 0 ° C with 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 gently dropped, then 1.9 ml of 15% sodium hydroxide solution 35 and 5.7 ml of water. After 20 minutes, the precipitate which was washed with acetic acid ethyl ester was filtered off and the filtrate was concentrated. The crude product (15.97 g) was crystallized from di isopropyl ether. 13.15 g of 4-hydroxymethyl-1-tosylindole were obtained, mp 125-126 ° C.

DK 170504 B1 31 3rd stage

To a solution of 13.5 g of 4-hydroxyl methyl-1-tosyl in ndole in 400 ml of methylene chloride was successively added 27 g of powdered potassium hydroxide, 27 ml of methyl iodide and 2.7 g of tetrabutylammonium hydrogen sulfate. Stir vigorously for 24 hours. Then potassium hydroxide which was washed to neutral with water was filtered off and the solvent was distilled off. The crude product (16.46 g) was crystallized from di isopropyl ether. 12.2 g of 4-methoxymethyl-1-tosyl in ndole was obtained, mp 85.5-89 ° C.

Step 4

A solution of 2.84 g of sodium in 155 ml of ethanol was added dropwise 15 within 10 minutes to a solution of 15.57 g of 4-methoxymethyl-1-tosylindole in 155 ml of ethanol, then heated at reflux, then refluxed. was cooled and 1.5 liters of semi-saturated, ice-cold sodium dihydrogen phosphate solution were then extracted with acetic acid ester and the acetic acid ester extract 20 was washed to neutral 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 were obtained as a colorless oil.

5th and 6th step

To a solution of 6.2 g of 4-methoxymethyl indole in 31 ml of glacial acetic acid was added dropwise at 10 ° C over 30 minutes 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 extracted with toluene was added with stirring and the aqueous phase was made alkaline with 5 ml of sodium hydroxide solution until pH 12 under intense ice-cooling, then extracted with ether and washed with semi-saturated brine and the solvent. distilled off under vacuum. The crude product (8.52 g) was used directly

OC

to 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 nitric acetic acid methyl ester was heated for 4 hours at 80 ° C under the influence of a low nitrogen flow. After cooling, 0.1 ml hydrochloric acid and water were washed with DK 170504 B1 32 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 was obtained as a hard foam.

Step 7, 8.08 g of 4-methoxymethylindole-3-82-nitro-3-methyl] propionic acid ethyl ester was hydrogenated in 320 ml of ethanol with 10 g of Raney nickel at 20 bar and room temperature. After 60 minutes, hydrogen uptake is complete. The catalyst was filtered off and the solvent was distilled off in vacuo at a bath temperature of 30 ° C. 6.4 g of 4-methoxymethylindole-3- [2-amino-3-methyl] propionic acid ethyl ester 15 was obtained as a colorless oil.

Step 8 6.4 g of crude 4-methoxymethylindole-3- (2-amino-3-methyl) -propionic acid ethyl-2 ° 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, dilute with 140 ml of toluene and add 11 g of dichlorodicyanobenzoquinone and stir for 40 minutes. It was diluted with 500 ml of acetic acid ester, then washed several times with dilute 2 µm ammonia solution and then with water, then dried, filtered and the solvent was distilled off under vacuum. Crude product 4.81 g. Chromatography on silica gel with hexane-acetic acid ester (50-100%) yielded 1.78 g of 5-methoxymethyl-4-methyl- / 8-carboline-3-carboxylic acid ethyl ester, m.p. 133-135 ° C (from vinegar-30 acid residues).

Example 33 In a similar manner as described in steps 5-8, the corresponding indole was prepared: 5- ethoxymethyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester, mp 134-136 ° C (acetic acid ester), 5-ethoxymethyl 4-methyl-E-carboli n-3-carboxylic acid methyl ester, DK 170504 B1 33 m.p. 167-170 ° C (acetic acid ester), 5-benzyloxy-4-ethyl-) S-carboline-3-carboxylic acid ethyl ester, mp 192-193 ° C (acetic acid ester), 5-benzyloxy-4-methyl-β-carboli n-3-carboxylic acid ethyl ester, m.p. 190-192 ° C (acetic acid ester), 5-phenyloxy-4-methyl / J-carboli n-3-carboxylic acid ethyl ester, mp 183-187 ° C, 5-acetoxymethyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester, mp 161-165 ° C.

10

Example 34 476 mg of 6-amino-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester in 4.4 ml of dimethyl disulfide was mixed with 0.32 ml of isoamyl nitrite at room temperature and under nitrogen, and then heated for 20 minutes at 80 ° C. After evaporation, the mixture was mixed with acetone and the product was filtered off. The filtrate was chromatographed on 180 g of silica gel with toluene: glacial acetic acid: water (10: 10: 1) as eluent. After crystallization of the corresponding fractions from ethanol / petroleum ether, 47 mg of 4-methoxymethyl-6-thiomethyl- / J-carboline-3-carboxylic acid ethyl ester was obtained, mp 138-139 ° C.

Example 35 23 390 mg of 5-Chloro-6-amino-β-carboline-3-carboxylic acid ethyl ester were heated to boiling in 15 ml of ethanol with 230 mg of 1,5-dibrompentane and 310 mg of 1,8-diazabicyclo-5.4.0 ] undec-7-en for 1.5 hours. After evaporation, the residue was chromatographed on silica gel with methylene chloride ethanol (10: 1). 270 mg of 5-chloro-6- (1-piperidino) -β-carboline-3-carboxylic acid ethyl ester were obtained, m.p. 245 ° C (dec.).

Analogously, with all alkyl bromo d 140 mg of 5-chloro-6- (diallyl-amino) -b-carboline-3-carboxylic acid ethyl ester having a melting point of 210 DEG-210 DEG C. (decomposition) was obtained.

DK 170504 B1

Example 35 34 420 mg of 5-chloro-6-nitro-β-carboline-3-carboxylic acid ethyl ester, 40 mg of copper (I) in odi d and 130 mg of potassium benzylate were heated in 8 ml of 5 N-methylpyrrolidone for 7 hours at 70 ° C. After distilling off the solvent, the residue was chromatographed on silica gel with toluene: glacial acetic acid: water (10: 10: 1). 280 mg of 5-benzyloxy-6-nitro-β-carboline-3-carboxylic acid ethyl ester was obtained, m.p. 254 ° C (dec.).

10

Example 37 420 mg of 5-chloro-6-nitro- / S-carboline-3-carboxylic acid ethyl ester and 100 mg of piperidine were heated in 10 ml of hexamethylphosphoric triamide for 2 hours at ^ 80 ° C. After distilling off the solvent, the residue was chromatographed on methylene chloride ethanol on silica gel. 350 mg of 5-piperidino-6-nitro-β-carboline-3-carboxylic acid ethyl ester were obtained, m.p. 307 ° C (dec.).

Example 38 140 mg of 5-piperidino-6-nitro- / J-carboline-3-carboxylic acid ethyl ester in 10 ml of tetrahydrofuran was mixed with the 4-fold molar amount of titanium (III) chloride in water. After 6 minutes, neutralize, filter and evaporate. The remaining material was extracted with methylene chloride, the extract concentrated and recrystallized from glacial acetic acid. 102 mg of 5-piperidino-6-amino-β-carboline-3-carboxylic acid ethyl ester were obtained, mp 188-190 ° C.

30

Example 39 1.0 g of ethyl 6-amino-4-methyl-3-carboline-3-carboxylate, 50 ml of 99% ethanol, 800 µl allyl bromide and 1 ml of triethylamine were heated at 80 ° C for 20 hours under low Ng flow. Another 800 µ! Allyl bromide and 1 ml of triethylamine were added and heating continued for 5 hours. Evaporation of the reaction mixture and addition of 25 ml of water gave 1.2 g of ethyl 6-diallylamino-4-methyl- / J-carboline-3-carboxylate.

DK 170504 B1 TLC: RF - 0.44 CHCl 3: CH 3 CN: CH 3 OH: Et 3 N = 18: 4: 2: 1.

1.2 g of ethyl 6-diallylamino-4-methyl-3-carboline-3-carboxylate, 1.5 ml of H 2 O, 0.5 g of potassium hydroxide and 16 ml of 96% ethanol were refluxed for 1 hour on a steam bath. 0.5 ml of glacial acetic acid was added. Evaporation and addition of water gave 0.9 g of 6-diallylamino-4-methyl- / J-carboline-3-carboxylic acid.

TLC: Rp = 0. The substance was dried for 4 hours at 80 ° C in a drying cabinet.

Example 40

An ice-cooled mixture of 60% dimethylamine (1.4 ml) acetic acid (3 ml) and 40% formalin (1.7 ml) was added to 4-benzylthioindole (5.3 g). After stirring at room temperature for 20 hours, the reaction mixture was dripped to a solution of sodium hydroxide (3g in 25ml water), the mixture extracted with ethyl acetate (3x150ml). Then, the combined ethyl acetate phase was dried (NagSO4) and evaporated in vacuo and recrystallized from toluene. The yield was 280 mg of 4-benzylthiogramine. A mixture of toluene (2 ml), powdered NaOH 2 ° (10 mg), 4-benzylthiogramine (280 mg) and formylaminomalon ester (210 mg) was refluxed under nitrogen for one hour, after cooling, the crystalline product was filtered off, washed with water and dried. Yield was 290 mg of diethyl 2-formylamino-2- (4-benzylthioindol-3-yl-methyl) -malate. Diethyl 2-formyl amino-2- (4-benzylthioindol-3-yl-methyl) malonate (184 mg) was dissolved in phosphorus oxychloride (4 ml) and stirred, protected from light, for 24 hours. After evaporation in vacuo and neutralization with saturated sodium bicarbonate, the mixture was extracted with ethyl acetate (3 x 30 ml). The ethyl acetate phase was dried (sodium sulfate) and evaporated in vacuo. The evaporation residue 5 ° was dissolved in dimethyl sulfoxide (3 ml) and then sodium cyanide (39 mg) was added. This mixture was heated to 160 ° C for 5 hours. After cooling the reaction mixture, 10% acetic acid (10 ml) was added and the crystalline product was filtered off, dried and recrystallized from ethyl acetate. The yield was 18.1 mg of 55 ethyl 5-benzylthio-β-carboline-3-carboxylate, IR (KBr): 3340-3140 (m, wide signal) 3130 (w), 2980 (w), 2930 (w), 1725 (s), 1620 (m), 1590 (m), 1565 (w), 1555 (w), 1500 (w) cm -1. Rp = 0.53.

Example 41 DK 170504 B1 36

The sodium salt of benzyl mercaptan (150 mg) was mixed with ethyl 6-nitro-β-carboline-3-carboxylate and HMPA (5 ml) and stirred for 5 quarters at room temperature. Then, the reaction mixture was heated to 110 ° C for 24 hours, poured on ice and filtered. The filtered product was recrystallized from EtOH. The yield was 120 mg of ethyl 6-benzylthio-β-carboline-3-carboxyl.

10 15 20 25 30 35

Claims (11)

10. N Η H where: A. R 1 represents an alkoxy group containing up to 6 carbon atoms; RA represents H; F; Cl; br; J; ΝΟγ SCh3; S02N (CH3) 2; NR 4 R 5, wherein R 1 and R 6 each represent a hydrogen atom; O "/ OR6 P \ 25 \ R7 C7 where R and R represent C13 alkyl; CH - OR10 where R4 represents an alkyl group of up to 377 carbon atoms; OR11 where R11 represents an alkyl group of up to 6 carbon atoms, an aryl group or an unbranched or branched aralkyl group having up to 12 carbon atoms; or 35 ChCR12, where R12 represents CHR6R13, where R6 represents η λ · m C1-6 alkyl, and Ril5 represents a halogen atom or OR, 4 1 fl where R represents a hydrogen atom or an alkyl group of up to 3 carbon atoms, wherein the A ring optionally contains more than one of the above substituents; and RC represents {CH 2 OR 17 where n is 1 or 2 and R 17 represents an alkyl group having up to 6 carbon atoms; or 5 B. R * represents an alkoxy group containing up to 6 carbon atoms; Δ R represents 10O "OR6 p (\ R7 15 6 7 where R and R represent C1-6 alkyl; or C = CR12, where R12 represents CHR3, R6, where R6 represents 13 14 C1-6 alkyl, and R represents a halogen atom or OR, where R 1 represents a hydrogen atom or an alkyl group having up to 3 carbon atoms, wherein the A ring optionally contains more than one of the above substituents; and R R represents a hydrogen atom; an alkyl group having up to 6 (CH 2) NO 17, where n is 1 or 2, and R 17 represents an alkyl group having up to 6 carbon atoms, or C. R * represents an alkoxy group containing up to 3 carbon atoms; 30 RA represents H; F; Cl; Br; J; NO2; SCH3; SO2N (CH3) 2; 4 5 4 5 NR R, wherein R and R each represent a hydrogen atom, an alkyl group of up to 6 carbon atoms, a C9 K alkynyl group. or 4 5 33 group, or wherein R and R together with the neighboring nitrogen form a piperidine or pyrrole derivative; DK 170504 B1 39 0 "OR6 5. OR7 6 7 wherein R and R are C1-6 alkyl; CHg-OR ^, wherein R ^ represents an alkyl group of up to 310 carbon atoms; OR ** wherein R ** represents an alkyl group of up to 6 carbon atoms, an aryl group, or an unbranched or branched aralkyl group of up to 12 carbon atoms; or R ChCH *, wherein R * represents CHR ^R *, where R® represents 1 o *C, alkyl, and R bet represents a halogen atom or OR14,, 14 wherein Reg represents a hydrogen atom or an alkyl group having up to to 3 carbon atoms, wherein the A ring optionally contains more than one of the above substituents; R represents a hydrogen atom; an alkyl group of up to 6 carbon atoms; (CH 2 + OR 2, where n is 1 or 2 and R 4 represents an alkyl group of up to 6 carbon atoms, no Γ 60, provided that R is not a hydrogen atom or an alkyl group of up to 6 carbon atoms when R H; F; Cl; Br; J; NO ^; SCH ^; SO ^ N (CH ^) ^ or NR ^ R5, wherein R ^ and R ^ have the above meanings; or D. R * represents a methoxy, ethoxy or propoxy group, A 8 9 8 9 R represents NR R, wherein R and R represent a hydrogen atom; or an ethyl, allyl, 2-methyl-2-propen-1-yl, 2-buten-1-yl or 3-propargyl group, and R 5 represents a hydrogen atom, a methoxy, methyl or ethyl group; or E. R * represents an ethoxy group, DK 170504 B1 40 Λ R represents a benzylthio group, and R R represents a hydrogen atom; or 5 F. R1 represents an ethoxy group, Λ R represents a 6-N-isopropylamino group, and r R represents a hydrogen atom, characterized in that a) a ndolderi vat of the general formula III f, r ^ Nf ^ VcoR18 RAB ^ NH. (III) 20 N 'H where 25 R 1 represents (CH 2) NO R 4, where and n have the meanings given above (A), 18 R represents an alkoxy group having 1 to 6 carbon atoms and 30 A' 10 10 R represents a group with the formula CH? -0R, wherein R 11 has the meanings given above (A); OR, wherein R 1 has the meanings given above (A); H; F; Cl; br; J; N02; NH ^; SCH3 or SO2N (CH3) 2.25 cycles with formaldehyde, thereby obtaining 1,2,3,4-tetrahydro-β-carboline compound to be dehydrogenated to form a β-carboline-3-carboxylic acid derivative of formula (I) wherein R 1, R 2 and R * have the meanings given above for R 1, R 2 and R 1, respectively, and if necessary i) chlorosulfonate and then the sulfonyl chloride thus obtained is reacted with a amine of formula N (CH 3) 2 to form the di methyl sulfamoyl derivative, or if necessary ii) halogenated or, if necessary, 10. ii) nitrated and the nitro compound thus obtained reduced to an amino compound or, if necessary, iv) is re-etherised at the 4-position or, if necessary, 15 v) re-esterified at the 3-position; rb) that an indole derivative of the general formula III wherein R represents 17 17 (CH 2) nOR, wherein R and n have the 20 meanings given above (A), 18 R represents an alkoxy group having 1 to 6 carbon atoms, and A ' R 10 represents a group of formula CH 2 -O R wherein R 25 has the meanings given above under A; OR11, wherein R11 has the meanings given above under A; F; Cl; br; IN; N02; NH 2; SCH3 or SO2N (CH3) 2, is treated with formic acid to give the corresponding formyl compound, after which this compound is cyclized with phosphorus oxychloride or polyphosphoric acid to form the corresponding dihydrocarboline, which is then dehydrogenated to form a 3 -carboline-3-carboxylic acid derivative AC 1 of formula (I) wherein R, R and R 35 A, C 18 R, R and R are indicated and, if necessary, 1 chlorosulfonated, and the sulfonyl chloride thus obtained is reacted with an amine of formula N (CH 2) 2 to form the dimethylsulfamoyl derivative, or DK 170504 B1 42 ii) halogenated, or iii) nitrated, then the nitro compound thus obtained is reduced to an amino compound, or 5 r iv) is re-etherized at the 4-position, or * 7 · v) is re-esterified at the 3-position; C) that a β-carboxy-3-carboxylic acid cool ester of the general formula IV RC 15 Hal ABC n C ™) Η H 20 where C 01 R has the meanings given above (B) and R represents an alkoxy group having up to 6 carbon atoms, Hal 23 represents chlorine, bromine or iodine, reacted with a dialkyl phosphite of formula H Wherein R 2 and R 7 have the meanings given above under (B), 35 A to form a compound of formula I wherein R * represents the group DK 170504 B1 43 0 "OR6 ^ 7 OR7 5 g 7 c wherein R and R have the above meanings, R has the above meanings, and R * represents a d) that a / 5-carboline-3-carboxylic acid chimeric ester of the general formula IV wherein R and R have the meanings given above under c) is reacted with a compound having the formula R is CsCH, wherein R has 12 the meanings given to R above under (B) or represents a protecting group for the preparation of β-carboline compounds of formula (I) wherein R R represents -CsC-R12 and R R and RC has the meanings given above (B), which compounds if necessary 12 'i) if R is a protecting group, the diluted mineral acid protecting group is decomposed to give a free 3-hydroxy-1-propynyl compound, which optionally ii) chlorinated with thionyl chloride to 3-chloro-1-propynyl compound-2 l sen; e) that a compound of the general formula V «RC 30 cor2 2 ^ B ΑΛ n (v) 35 in Η H 22 wherein R represents an alkyloxy group of up to 3 carbon atoms, C and R represents a hydrogen atom, an alkyl group of up to Wherein: n is 1, 2 or 3 and R17 represents an alkyl group of up to 6 carbon atoms is reacted with a halide of formula (R4) R4 Hal where Hal is chlorine, bromine or odor and where R 2 and R 2 together with the adjacent nitrogen atom form a piperidine or pyrrolidine ring, r to form a compound of formula I wherein R ^ and R ^ have the same meanings and R * and R ^ have the same meanings as those set forth above for R22 and RC respectively; f) a compound of the general formula V 15 RC - COR2 2 2 ° ^ B JL C N (v). II Η H 25 22 where R represents an alkyloxy group of up to 3 carbon atoms and RC represents (CH 2) nOR17 where n is 1, 2 or 3 and R17 represents an alkyl group of up to 6 carbon atoms is reacted with an al is halo, chloro, bromo or od, and R 2 and R 2 represent a hydrogen atom, an alkyl group having up to 6 carbon atoms or a C 2 -C 5 -alkyl group. alkynyl group, A · to form a compound of formula I wherein R represents NR 1 R 2, wherein R 2 and R 2 have the same meanings and R 2 and R 2 have the same meanings as given above for R and Rc respectively; pg) that a compound of the general formula (V) wherein R represents hydrogen, methoxy, methyl or ethyl and R represents methoxy, ethoxy or propoxy, go 8 9 is reacted with a compound of formula (R) R Br, wherein R and R 5 represent a hydrogen atom, an ethyl allyl, 2-methyl-2-propen-8,9 1-yl-j 2-buten-1-yl or propargyl group, although R and R are not both simultaneously represents a hydrogen atom to form an β-carbolic acid derivative of formula (I) wherein Γ 1 Ru represents hydrogen, methoxy, methyl or ethyl, R 1 represents A 8 9 8 methoxy, ethoxy or propoxy, and R represents NR R where R and □ R represent ethyl, allyl, 2-methyl-2-propen-1-yl, 2-buten-1-yl, 3-propargyl or hydrogen; H) that a compound of the general formula VI RC ^ COCR23 20. f jxCOOR2 (VI) ra I a B in L N-CHO W / HH 25 AC where R and R have the meanings given above (C), and 23 24 R and R each represent an alkyl group of up to 3 carbon atoms, cyclized with phosphorus oxychloride to give the corresponding 1,2,3,4-tetrahydrocarboline, this compound is decarbalkoxylated to form the corresponding dihydrocarboline, and this is dehydrogenated to produce compounds of formula (I) wherein R and R have the above meanings. I) that an β-carboline-3-carboxylic acid derivative of formula (I) wherein R represents ethoxy, R represents hydrogen, and R represents NO 2 are reacted with benzyl mercaptan to form an β-carbol in-3-carboxylic acid derivative of formula (I) wherein R * represents ethoxy, CAR represents a hydrogen atom, and R represents benzylthio; 46 DK 170504 B1 (j) reacting dimethylamine and formaldehyde with benzyl thioindole to form benzylthiogramine, which is then reacted with formyl-aminomalon ester to form 2-formylamino-2- (benzylthioindolylmethyl) malonic acid diethyl ester which is reacted with phosphorus oxychloride , after which the reaction product formed is reacted with sodium cyanide to form an? -carboline-3-carboxylic acid. 1 C is hydrogen of formula (I) wherein R represents ethoxy, R represents> Λ hydrogen, and R represents a benzyl thi group; or k) reacting 6-amino-β-carboline-3-carboxylic acid ethyl ester with isopropyl bromide to give 6-N-isopropylamino-β-carboline-3-carboxylic acid ethyl ester. 15 20 25 30 -i 35