NO742601L - - Google Patents

Description

Schering Aktiengesellschaft, Berlin und Bergkamen,

MUllerstrasse 170-172, 1 Berlin 65, and

Waldstrasse 14, 4619, Bergkamen, Federal Republic of Germany

Inventors:

Helmut Biere, Zeltinger St r. 15, 1 Berlin 28, Germany Hanns Ahrens, Ernst-Ring-Str. 8, 1 Berlin 38, _ u Clemens Rufer, Westhofener Weg 14, 1 Berlin 38>., _ Eberhard SchrOder, Bergengruenstr. 44a, 1 Berlin 38, - - Henning Koch, Marienburger Allée 47, 1 Berlin 19, - " -

Attorney: Taridbergs Patentkontor A-S,

Uranienborg Terrasse 19, Oslo 3

Procedure for the production of carbazole derivatives

The present invention relates to a method for the production of new carbazole derivatives with the general formula:

where R^ is hydroxymethyl, alkanoyloxymethyl, tetrazolyl, cyano, oximinocarbonyl, aminocarbonyl, carboxyl, their salts with physiologically acceptable bases, their esters with physiologically objectionable alcohols or their amides with physiologically objectionable amines, R2, 3, R4 is hydro9enJhalogen, lower alkyl, trifluoromethyl or

lower alkoxy,

R^ and R^ have the same meaning as R2 to R^ or together form a group with a 5- or 6-membered isocyclic ring, and

R^ is a hydrocarbon group containing 3-8 carbon atoms or, when at least

one of the substituents R^ to Rg is different from hydrogen, also hydrogen, methyl or ethyl.

The new carbazole derivatives are pharmacologically active compounds which, especially when used locally, are distinguished by strong anti-inflammatory activity. As explained in more detail below, the new carbazole derivatives with regard to their activity differ advantageously from the known structurally analogous N-phenylanthranilic acid derivatives, which when applied topically have only a very small anti-inflammatory activity.

As the pharmacologic test results indicated below show, the new carbazole derivatives can have different substituents R^ to R^, without losing their anti-inflammatory activity when used locally.

As substituents R, besides hydroxymethyl, tetrazolyl, cyano, oximinocarbonyl and aminocarbonyl, especially carboxyl, its salts physiological bases, its esters with physiologically objectionable alcohols and its amides with physiologically objectionable amines come into consideration. As physiologically acceptable salts of the carboxyl group R^kan

for example, the alkali and alkaline earth metal salts are mentioned, such as the sodium salt or the calcium salt.

Physiologically unacceptable alcohols with which the carboxyl group can be esterified are, for example, straight-chain or branched or cyclic, saturated or unsaturated hydrocarbon groups, which may optionally be interrupted by an oxygen or nitrogen atom, or may be substituted with hydroxy, amino or carboxyl groups, which e.g. alkanols, alkenols, alkynols, cycloalkanols, cycloalkenols, cyclo-alkyl-alkanols, phenylalkanols, phenylalkenols, alkanediols, hydroxy-carboxylic acid-aminoalkanols or alkylaminoalkanols and dialkyl-aminoalkanols with 1-4 carbon atoms in the alkyl group.

Alcohols which are suitable for esterification of the carboxyl group in the 1-position are e.g. those having a methyl-, carboxymethyl-, ethyl-, 2-hydroxyethyl-, 2-methoxyethyl-, 2-aminoethyl-, 2-dimethyl-aminoethyl-, 2-carboxyethyl-, propyl-, allyl-, cyclopropylmethyl-, isopropyl -, 3-hydroxypropyl-, propynyl-, 3-aminopropyl-, butyl-, sec-butyl-, t-butyl-, butyl-(2)-, cyclobutyl-, pentyl-, isopentyl-, t-pentyl-, 2 -methylbutyl-, cyclopentyl-, hexyl-, cyclohexyl-, cyclohex-2-enyl-, cyclopentylmethyl-, heptyl-, benzyl-, 2-phenyl-ethyl-, octyl-, bornyl-, isobornyl-, raenthyl-, nonyl- , decyl-, 3-. phenylpropyl, 3-phenyl-prop-2-enyl, undecyl or dodecyl group.

Physiologically unacceptable amines with which the carboxyl group in the 1-position can be amidated are preferably alkylamine, dialkylamine, alkanolamine, dialkanolamine with 1-6 carbon atoms in

the alkyl or alkanol group or 5- or 6-membered N-heterocyclic groups in consideration. Examples of suitable amines can be mentioned: methylamine, ethylamine, isopropylamine, ethanolamine, dimethylamine, diethylamine, diethanolamine, pyrrolidine, piperidine, morpholine or N-methylpiperazine.

Furthermore, the substituent R 1 can also be an alkanoyloxymethyl group, whose alkanoyl group preferably has 1-8 carbon atoms. Examples of suitable alkanoyl groups include: the formyl group, the acetyl group, the propionyl group, the butyryl group and the hexanoyl group.

As lower alkyl groups R^ to R^, alkyl groups with 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl or t-butyl, can preferably be used.

A halogen atom R^ to R^ preferably means a fluorine, chlorine or bromine atom.

By a common substituent with a 5- or 6-membered isocyclic ring formed by the substituents R^ and R^ is meant a cyclopentene, cyclohexene or benzene group.

Suitable hydrocarbon groups Ry with 1-8 carbon atoms are, for example, straight-chain or branched alkyl groups, which may optionally be substituted with 3- to 6-membered cycloalkyl groups or with phenyl groups. Examples of the hydrocarbon group Ry can be mentioned: methyl, ethyl, propyl, isopropyl, butyl, hexyl, 3-cyclopropyl-propyl, cyclopentylmethyl or benzyl.

The present invention relates to a method for the production of the new carbazole derivatives with the general formula I, which method is characterized by dehydrating tetrahydrocarbazole derivatives with the general formula II or lii in a manner known per se:

where R to R^ are as stated above, optionally alkylates a secondary amino group in the 9-position, esterifies or etherifies free hydroxyl groups, saponifies ester groups, and transfers free carboxyl groups or reactive derivatives thereof to salts, esters, amides, cyano groups, oximinocarbonyl groups, hydroxymethyl groups or tetrazolyl groups.

The dehydration of the tetrahydrocarbazole derivatives of formula II

and III takes place by methods known per se. It is e.g. possible to dehydrate the compounds of formula II or ill with precious metal catalysts of the platinum group. As noble metal catalysts are e.g. platinum oxide catalysts or especially palladium-charcoal catalysts are suitable.

The reaction is preferably carried out in a high-boiling aromatic solvent such as e.g. toluene, xylene, cumene, anisole, chlorobenzene, dichlorobenzene or chlorotoluene. The reaction temperature is also determined by the choice of solvent, and is approx. lOO - 200°C, preferably 130 - 180°C. If the tetrahydrocarbazole derivatives of formula II

or III contains halogen atoms, these can be split off when a halogen-free solvent is used in the reaction. If the reaction is carried out in a halogen-containing solvent (which contains the same halogen atom as the compound to be dehydrated), the splitting off of the halogen atoms can be avoided.

Further oxidizing agents for the method are quinones, such as p-benzoquinone, chloranil, tetrachloro-o-benzoquinone, dichloro-dicyan-benzoquinone, etc., or inorganic oxidizing agents such as lead dioxide,

manganese dioxide, sulphur, etc. High-boiling solvents such as xylene, cumol, chlorobenzene, dichlorobenzene etc. are used as solvents. The reaction temperature is 100 - 200°C, preferably 130 - 160°C.

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The possibly subsequent alkylation of a secondary amino group present in the Q-position likewise takes place by known methods, which are usually used for N-alkylation of indole derivatives.

One can, for example, metallate the nitrogen atom in the carbazole ring by reaction with metal hydrides or metal amides, such as sodium hydride or sodium amide, and let the halides (chloride, bromide or iodide) in the ultimately desired hydrocarbon group act on the thus obtained reactive compounds. In this reaction, which is carried out at a reaction temperature of from approx. 0°C to 120°C, polar aprotic solvents such as dimethylformamide, N-methylpyrrolidone or hexamethylphosphoric acid triamide are preferably used.

The subsequent esterification of the free hydroxymethyl groups is also carried out by known methods for this purpose. As a possible esterification method, e.g. mention is made of the esterification of hydroxy compounds with acid anhydrides or acid chlorides in the presence of aromatic N-heterocyclic compounds such as pyridine, collidine or lutidine, or in the presence of aqueous solutions of basic alkali metal compounds such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, sodium hydroxide or potassium hydroxide.

Any subsequent saponification of the esters takes place by methods known per se. Examples include the fors. opening of the ester in water or aqueous alcohols in the presence of acidic catalysts, such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or with basic catalysts such as potassium hydrogen carbonate. potassium carbonate, sodium hydroxide or potassium hydroxide.

The possibly subsequent esterification of the free acids likewise takes place by methods known per se. Thus, for example, the acids can be reacted with diazomethane or diazoethane to obtain the corresponding methyl or ethyl esters. A generally applicable method is the reaction of the acids with the alcohols in the presence of carbonyldiimidazole or dicyclohexylcarbodiimide. Furthermore, there is e.g. possible to react the acids with alkyl halides in the presence of copper(I) oxide or silver oxide.

Another method consists in transferring the free acids to the corresponding acid alkyl ester with the corresponding dimethylformamide alkyl acetals. Furthermore, the acids can be reacted with the alcohols or the lower alkanecarboxylic acid esters of the alcohols in the presence of strongly acidic catalysts such as hydrogen chloride, sulfuric acid, perchloric acid, trifluoro-

methylsulfonic acid or p-toluenesulfonic acid...

However, it is also possible to transfer the carboxylic acids to the acid chlorides or mixed acid anhydrides and react these with the alcohols in the presence of basic catalysts such as pyridine, collidine, lutidine or 4-dimethylaminopyridine.

The salts of the carboxylic acids are formed, for example, by saponification of the esters using basic catalysts or by neutralization of the acids using alkali metal carbonates or alkali metal hydroxides, which e.g. sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, potassium hydrogen carbonate or potassium hydroxide.

Furthermore, it is possible to react esters of formula I with the ultimately desired alcohol in the presence of acidic or basic catalysts. Acid or basic catalysts are preferably hydrogen chloride, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, trifluoroacetic acid, for example alkali metal, alkaline earth metal or aluminum alcoholates.

Any subsequent amide formation or hydroxamic acid formation from the free carboxylic acids or their reactive derivatives also takes place by methods known per se. Thus, one can e.g. react the carboxylic acids under the known conditions with amines, or hydroxylamine in the presence of dicyclohexylcarbodiimide, and the corresponding aminocarbonyl compounds are obtained.

Furthermore, there is e.g. possible to transfer the acid chlorides, mixed anhydrides or esters corresponding to the carboxylic acids to the corresponding amides or hydroxamic acids under known conditions by treatment with ammonia, with amines or with hydroxylamine.

The eventual subsequent transfer of reactive carboxylic acid derivatives to nitriles also takes place by methods known per se, such as e.g. in such a way that one allows water-extracting means, such as e.g. dicyclohexylcarbodiimide, carbonyldiimidazole, polyphosphoric acid, thionyl chloride or phosphorus oxychloride under the known conditions, act on the corresponding aminocarbonyl-yl phosphoric compounds.

In order to prepare the hydroxymethyl compounds from the corresponding reactive derivatives of the carboxylic acids, known methods are also used. thus, for example, the carboxylic acid esters can be reduced to the corresponding hydroxymethyl compounds in an aprotic halogen-free solvent, as in ethers (such as diethyl ether, diisopropyl ether, tetrahydrofuran or glycol dimethyl ether) with complex metal hydrides such as lithium aluminum hydride, diisobutyl aluminum hydride or diethyl aluminum hydride.

Known methods can also be used to prepare the tetrazolyl compounds. Thus, for example, the nitriles can be converted in polar aprotic solvents such as dimethylformamide, N-methylacetamide, N-methylpyrrolidone or hexamethylphosphoric acid triamide, under known conditions with alkali metal azides, such as sodium azide, to the corresponding tetrazolyl compounds.

It has already been mentioned that the new carbazole derivatives are pharmacologically active compounds, which are particularly distinguished by a strong anti-inflammatory activity when applied locally.

The anti-inflammatory activity of the new carbazole derivatives when applied topically can be determined by Tonelli's method as follows: The compound to be tested is dissolved in an irritant, consisting of 4 parts of pyridine, 1 part of distilled water, 5 parts of ether and 10 parts of a 4 % essential croton oil solution. With this experimental solution, felt strips were attached to the inside of an object carrier forceps, soaked, and this was pressed under light pressure for 15 seconds on the right ear of male rats weighing 100 to 160 g. The left ear remained untreated and served as a comparison. 3 hours after application, the animals were euthanized, and 9 mm disks were punched out of their ears. The weight difference between the discs of the right and left ear is a measure of the edema formed.

The control animals were treated in the same way, but with the difference that the irritation solution used did not contain any test compound.

The anti-inflammatory activity was determined by dividing the average difference in ear weight of the treated group by the average difference in ear weight of the control group.

The following table shows the activity of the ca rbazol-der i vates compared to the known anti-inflammatory active compounds I and II.

It appears from the table that the new carbazole derivatives excel compared to the structurally analogous known N-phenylanthranilic acid derivatives by superior anti-inflammatory activity. The anti-inflammatory activity of the new carbazole derivatives is, when applied locally, approximately as strong as that of the known anti-inflammatory active corticoids.

Surprisingly, not only the new carbazole derivatives, but also already known carbazole derivatives which differ from those of formula I in that the substituents R^ to R^ are always hydrogen, show a pronounced local anti-inflammatory activity, as can be seen from the table . Consequently, these compounds are also suitable for the production of locally anti-inflammatory active pharmaceuticals.

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According to the present invention, non-steroidal compounds are therefore produced, which locally exhibit an excellent anti-inflammatory activity.

The corticoids used to date for the treatment of skin inflammations always have a systemic activity in addition to the local activity. Even with local application, as a result of resorption through the inflamed skin or as a result of skin damage, these corticoids can enter the bloodstream where, as hormone-active compounds, they affect the body's functions in many ways.

With the locally active carbazole derivatives produced according to the invention, this disadvantage does not exist.

In addition, the carbazole derivatives have the advantage that they are less toxic and have a certain antibacterial and antifungal activity, which is desirable in the local treatment of inflammation.

The new compounds are suitable in combination with the usual carriers in galenic pharmacy for the local treatment of allergies, contact dermatitis, eczema of various kinds, neurodermatitis, erythroderma, burns, Pruritis vulvae et ani, rosacea, Erythematodes cutaneus, psoriasis, Lichen ruber planus et verrucosus and similar skin diseases.

The preparation of the medicinal preparations takes place in the usual way, with the active substance being transferred with suitable additives in the desired application forms such as solutions, skin lotions, ointments, creams, inhalants or plasters. In the medicines formulated in this way, the concentration of the active substance depends on the form of application.

For skin lotions and ointments, an active substance concentration of 0.005% to 5% is preferably used.

The starting compounds for the present method are known or they can be easily prepared according to the following formula:

where R to R- are as above, and R is a lower alkyl-

2 / o

group, the components being heated to 50 - 200°C, for example, under inert gas in the presence of Lewis acids such as zinc chloride, and optionally with the addition of a lower alcohol such as ethanol or a lower carboxylic acid such as acetic acid, as a solvent.

With the esters thus obtained, under the conditions already described, a secondary amino group present in the 9-position may be alkylated, free hydroxyl groups can be esterified or etherified, the ester group can be saponified and free carboxyl groups or reactive derivatives thereof can be transferred into salts, esters, amides, oximinocarbonyl groups, cyano groups, hydroxymethyl groups or tetrazolyl groups.

In principle, these condensations can also be carried out using other α-halocyclohexanone derivatives, such as e.g. α-chloro or α-iodo-cyclohexanone derivatives. Furthermore, it is possible to carry out the reaction without the use of Lewis acids, and to use other catalysts such as boron trifluoride, phosphoric acid or hydrogen chloride.

If the reaction is carried out using substituted anilines, the substituted aniline is conveniently used in excess, preferably in a 2.2 to 2.5 molar excess. The reaction can be carried out with or without a solvent. Alcohols such as ethanol and butanol, or ethers such as dioxane, dimethoxyethane etc. are used as solvents. When working without solvents

the excess of the aniline component can serve as solvent. In both cases, a catalyst such as zinc chloride is added.

The reaction is preferably carried out under an atmosphere of protective gas, e.g. nitrogen or noble gas.

The reaction temperature is also determined by the choice of the solvent, and amounts to 80 - 200 PC, preferably, especially when working without a solvent or when using solid aniline components, at 140 - 150°C.

The turnover takes place under normal pressure or reduced pressure, preferably at 100 mm Hg.

If substituted phenylhydrazines (IV) are used as starting compounds, the reaction preferably takes place at temperatures between 50° and 150°C and can be carried out with or without solvent using the catalysts known from Fischer-indole synthesis such as f . e.g. zinc chloride, hydrogen chloride, sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, etc. The preferred solvents are acetic acid, glacial acetic acid and alcohols. However, the reaction can also be carried out without a solvent in molten zinc chloride or in polyphosphoric acid and phosphoric acid.

The previously unknown compounds with the general formula II and 5,6,7j8-tetrahydrocarbazole-1-carboxylic acid itself as well as its esters and amides are surprisingly also distinguished by a pronounced anti-inflammatory activity upon local application, and can be used in the same way as active pharmaceutical ingredient such as the carbazole derivatives.

The present invention thus also relates to the use of the unknown 5,6,7,8-tetrahydrocarbazole-1-carboxylic acid derivatives.

The following examples serve to illustrate the present method.

Example 1

a) 10 g of 3-bromo-2-oxo-cyclohexanecarboxylic acid ethyl ester is mixed with 10 g of 3-methoxyaniline and heated under light vacuum (approx. 100 torr)

and stirred for 7 hours at 140°C.

After cooling, the mixture is diluted with carbon tetrachloride, filtered, the organic phase is washed, evaporated in vacuo, and the residue is purified by chromatography on silica gel with cyclohexane-benzene as eluent, and 6-methoxy-1,2,3,4-tetrahydrocarbazole-1 is obtained -carboxylic acid ethyl ester. b) Dissolve 2.05 g of 6-methoxy-1,2,3,4-tetrahydro-carbazole-1-carboxylic acid ethyl ester in 20 ml of xylene, add 2 g of 10% palladium-charcoal catalyst and heat for 4 hours during reflux. After cooling the reaction mixture, the catalyst is filtered off, the solution is evaporated in vacuo, the residue is recrystallized from benzene, and 1.5 g of 6-methoxy-carbazole-1-carboxylic acid ethyl ester with a melting point of 107°C is obtained.

Example 2

a) Under the conditions in example 10, 10 g of 3-bromo-2-oxo-cyclohexane-carboxylic acid ethyl ester are reacted with 2-methpxyaniline to 8-methoxy-1>2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester. b) The 8-methoxy-1,2,3,4-tetrahydrocarbazol-1-carboxylic acid ethyl ester is dissolved in chlorobenzene, dehydrated as described in example 1b after the addition of 10% palladium charcoal, and after recrystallization from ethanol in 73 % yield of the 3-methoxy-carbazole-1-carboxylic acid ethyl ester with a melting point of 7<6>°C.

Example 3

a) Under the conditions in example 10, 10 g of 3-triomer-2-oxo-cyclohexane-carboxylic acid ethyl ester are reacted with 2-methylaniline to 8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester. b) The 8-methyl-1,2,3,4-t rahydrocarbazole-1-carboxylic acid ethyl ester is dissolved in cumol, dehydrated as described in example lb after adding 10% palladium charcoal, and after recrystallization from methanol in 75% yield of the 8-methyl-carbazole-l-carboxylic acid ethyl ester with melting point 68°C

Example 4

.a) Under the conditions in example la, 10 g of 3-bromo-2-oxo-cyclohexane-carboxylic acid ethyl ester are reacted with 3-fluoroaniline to 7-fluoro-1,2,3,4-tetrahydrocarbazole-1-ca rcarboxylic acid ethyl ester.

b). The tetrahydro-carbazole derivative thus prepared is dissolved in chlorobenzene, dehydrated as described in example 1b while adding

of 10% palladium charcoal, and the 7-fluoro-carbazole-1-carboxylic acid ethyl ester with melting point 132°C is obtained after recrystallization from isopropyl alcohol in 77% yield.

Example 5

a) Under the conditions in example la, 10 g of 3-bromo-2-oxa-cyclohexane-carboxylic acid ethyl ester are reacted with 4-fluoroaniline to 6-fluoro-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester. b) The thus prepared tetrahydro-carbazole derivative is dissolved in o-dichlorobenzene, dehydrated as described in example 1b with the addition of 10% palladium charcoal, and after recrystallization from isopropyl alcohol in 60% yield 6-fluorine is obtained -carbazole-1-carboxylic acid ethyl ester with melting point 130°C.

Example 6

a) Under the conditions in example la, 10 g of 3-bromo-2-oxo-cyclohexane-carboxylic acid ethyl ester are reacted with 3-trifluoromethylaniline to 7-trifluoromethyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.

b) The thus prepared tetrahydrocarbazole derivative is dissolved

in o-dichlorobenzene, is dehydrated as described in example 1b with 10%-ig

palladium coal, and after recrystallization from isopropyl alcohol, 7-trifluoromethyl-carbazole-1-carboxylic acid ethyl ester with a melting point of 80°C is obtained in 55% yield.

Example 7

a) Under the conditions in example la, but with the addition of 0.5 g of zinc chloride after 2 hours, 10 g of 3-bromo-2-oxo-cyclohexane-carboxylic acid ethyl ester is reacted with 5-chloro-2-methylaniline to 5-chloro- 8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester. b) The thus prepared tetrahydro-Tcarbazole derivative is dissolved in chlorobenzene, 10% palladium charcoal is added and dehydrated as described in example 1b, and after recrystallization from isopropyl alcohol-methanol, 5-chloro-8 is obtained in 85% yield ~methyl-carbazole-l-carboxylic acid ethyl ester with melting point 102°C.

Ex empe1 8

a) Under the conditions in example Yes, 10 g of 3-bromo-2-oxo-cyclohexane-carboxylic acid ethyl ester are reacted with 3-chloro-2-methylaniline to 7~

chloro-8-methyl-1,2,3,4-tetrahydrocarbazo1-1-carboxylic acid ethyl ester. b) The thus prepared tetrahydro-carbazole derivative is dissolved in chlorobenzene, 10% palladium charcoal is added and dehydrated as described in example 1b, and after recrystallization from isopropyl alcohol-methanol, 7-chloro-8 is obtained in 70% yield -methyl-carbazole-1-carboxylic acid ethyl ester with melting point 98°C.

Example 9

600 mg of 7-chloro-8-methyl-1,2,3,4-tetrahydro-carbazole-1-carboxyl-acid ethyl ester is added to 1 g of chloranil and 15 ml of xylene and heated for 25 hours under reflux. The solvent is then distilled off, sodium dithionite and diluted caustic soda are added to the residue and extracted several times with benzene. The organic phase is washed, evaporated, the residue is recrystallized from isopropyl alcohol-methanol, and 350 mg (61%) of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester with melting point 97°C is obtained.

Example 10

a) Under the conditions in example 7a, 10 g of 3-bromo-2-oxo-cyclohexane-carboxylic acid ethyl ester is reacted with 5-chloro-2-methoxyaniline to

5-Chloro-8-methoxy-1,2,3,4-tetrahydro-carbazole-1-carboxylic acid ethyl ester.

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b) The thus prepared tetrahydro-carbazole derivative is dissolved in chlorobenzene, 10% palladium charcoal is added and dehydrated as described in example 1b, and after recrystallization from isopropyl alcohol, 5-chloro-8-methoxy is obtained in 52% yield -carbazole-1-carboxylic acid ethyl ester with melting point 113°C.

Example 11

a) Under the conditions in example 7a, 10 g of 3-bromo-2-oxo-5-methyl-cyclohexane-carboxylic acid ethyl ester are reacted with 3-chloro-2-methylaniline

to 7-chloro-3,8-dimethyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid - ethyl ester. b) The thus prepared tetrahydro-carbazole derivative is dissolved in chlorobenzene, 10% palladium charcoal is added and dehydrated as described in example 1b, and after recrystallization from isopropyl alcohol, 7-chloro-3,8-dimethyl is obtained in 70% yield -carbazole-1-carboxylic acid ethyl ester with melting point 137°C.

Example 12

a) Under the conditions of example 7a, log 3-bromo-2-oxo-cyclohexane-carboxylic acid ethyl ester is reacted with 2,3-dichloroaniline to 7>8~

dichloro-1,2,3,4-tet rahydro-carbazole-1-carboxylic acid ethyl ester.

b) The thus prepared tetrahydro-carbazole derivative is dissolved in o-dichlorobenzene, 10% palladium charcoal is added and dehydrated as

described in example 1b, and 7,8-dichloro-carbazole-1-carboxylic acid ethyl ester with a melting point of 107°C is obtained after recrystallization from isopropyl alcohol in a 60% yield.

Example 13

a) Under the conditions in example la, 10 g of 3-bromo-2-oxo-cyclohexane-carboxylic acid isoamyl ester are reacted with 2,3-dichloroaniline to 7,8-dichloro-1,2,3,4~tetrahydro-carbazole-1- carboxylic acid isoamyl ester. b) The thus prepared tetrahydro-carbazole derivative is dissolved in o-dichlorobenzene, 10% palladium charcoal is added and dehydrated as

described in example 1b, and after recrystallization from methanol a 45% yield of 7,8-dichloro-carbazole-1-carboxylic acid iso-amyl ester with a melting point of 66°C is obtained.

Example 14

a) Under the conditions in example 7a, 10 g of 3-bromo-2-oxo-cyclohexane-carboxylic acid ethyl ester are reacted with 2,3-dimethylaniline to 7,8-

dimethyl-1,2,3,4-tetrahydro-carbazol-1-carboxylic acid ethyl ester.

b) The thus prepared tetrahydrocarbazole derivative is dissolved in xylene, 10% palladium charcoal is added and dehydrated as described in

example lb, and after recrystallization from isopropyl alcohol 1 66% yield of 7,8-diraethyl-carbazole-1-carboxylic acid ethyl ester with melting point 93°C is obtained

Example 15

Under the conditions of example 9, 7,8-dimethyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester is dehydrated with chloranil,

and after recrystallization from isopropyl alcohol, 7,8-dimethyl-carbazole-l-carboxylic acid ethyl ester with a melting point of 92°C is obtained in 50% yield.

Example 16

3.1 g of 5-chloro-8-methoxy-1,2,3,4-tetrahydro-carbazole-1-carboxylic acid ethyl ester is heated with 20 ml of xylene and 3910% palladium charcoal for 6 hours under reflux. The mixture is allowed to cool, the catalyst is filtered off, the solution is evaporated in vacuo, the residue is recrystallized from ethanol, and 2.0 g (66%) of 8-methoxy-carbazole-1-carboxylic acid ethyl ester with a melting point of 75°C is obtained.

Example 17

Under the conditions in example 16, 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester is dehydrated, and after recrystallization from methanol, 8-methyl-carbazole-1 is obtained in 60% yield -carboxylic acid ethyl ester with melting point 68°C.

Example 18

1.2 g of 6-methoxy-carbazole-1-carboxylic acid ethyl ester is added

2 ml ethanol and a solution of 2.5 Q potassium hydroxide in 10 ml water,

and heated for 4 hours while stirring and refluxing. The mixture is poured into water, filtered, the filtrate is acidified drop by drop with hydrochloric acid,

the separated crude product is recrystallized from acetone-ethyl acetate, and 0.8 g (80%) of 6-methoxy-carbazole-1-carboxylic acid with melting point 262°C is obtained.

Example 19

Under the conditions in example 18, 8-methoxy-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from methanol, 8-methoxy-carbazole-1-carboxylic acid is obtained in 65% yield with

melting point 252°C. '

Example 20

Under the conditions in example 18, 8-methyl-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from acetic acid, 8-methyl-carbazole-1-carboxylic acid with a melting point of 286°C is obtained in 70% yield.

Example 21

Under the conditions in example 18, 7-fluoro-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from dioxane-water, 7-fluoro-carbazole-1-carboxylic acid with a melting point of 26 s 0 OC is obtained in 70% yield. -

Example 22

2.2 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester is added to a solution of 4.2 g of potassium hydroxide, 50 ml of water and 5 ml of dimethylsulfoxide and heated for 6 hours under reflux. The mixture is then diluted with 50 ml of hot water, filtered, the filtrate is acidified dropwise with hydrochloric acid, the separated product is recrystallized from dioxane-water, and 1.5 g (77%) of 7-chloro-8-methyl-carbazole-l-carboxylic acid is obtained with melting point 249°C

Example 23

Under the conditions in example 22, 5-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from dioxane-water, 5-chloro-8-methyl-carbazole-1-carboxylic acid is obtained in 55% yield with melting point 303°C.

Example 24

Under the conditions in example 22, 7-chloro-3,8-dimethyl-carbazole-1-ca rcarboxylic acid is saponified, and after recrystallization from dioxane-water, 7-chloro-3,8-dimethyl is obtained in 85% yield -carbazole-1-carboxylic acid with melting point 294°C

Example 25

Under the conditions in example 22, 5-chloro-8-methoxy-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from dioxane, 5-chloro-8-methoxy-carbazole-1-carboxylic acid with a melting point of 70% is obtained 328°C.

Example 26

Under the conditions in example 22, 78-dichloro-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from dioxane-water, 7>8-dichloro-carbazole-1-carboxylic acid with a melting point of 290°C is obtained in 83% yield.

Example 27

Under the conditions in example 22, 7,8-dimethyl-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from dioxane, 7,8-dimethyl-carbazole-1-carboxylic acid with a melting point of 239° is obtained in 65% yield C.

Example 28

Under the conditions in example 22, 6-fluoro-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from dioxane-water, 6-fluoro-carbazole-1-carboxylic acid with a melting point of 254°C is obtained in 92% yield

Example 29

Under the conditions in example 22, J-trifluoromethyl-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from dioxane-water, 83-ig yield of 7-trifluoromethyl-carbazole-1-carboxylic acid with a melting point of 266°C is obtained.

Example 30

a). To a suspension of 0.39 lithium aluminum hydride in 5 ml of absolute tetrahydrofuran, 0.560 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester dissolved in 10 ml of absolute tetrahydrofuran is added dropwise, and the mixture is stirred for 1 hour at room temperature. heated for 1 hour under reflux, allowed to cool, diluted with 20 ml of acetic acid ester, the mixture is added dropwise hydrochloric acid while cooling, the organic phase is separated, washed and evaporated in vacuo. The residue is recrystallized from toluene, and 7-chloro-1-hydroxymethyl-8-methyl-carbazole with a melting point of 187°C is obtained in 95% yield b) The hydroxymethyl compound thus obtained is added to pyridine and acetic anhydride, left for 30 minutes at room temperature and

taken up in chloroform. The chloroform solution is washed, evaporated in vacuo, and 7-chloro-1-acetoxymethyl-8-methyl-carbazole-like glassy solidified mass is obtained in 85% yield.

c'->

Example 31

7.8 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid is added to 200 ml of diethyl ether and cooled to -10°C. 8.79 phosphorus pentachloride is introduced into the suspension while stirring, and the mixture is stirred for 2 hours at approx. 0°C. Dry ammonia is then introduced while stirring for 1 hour, and stirring is continued for 10 hours at room temperature.

The reaction mixture is then poured into water, extracted with acetic acid ester, the extract is washed and evaporated. The residue is recrystallized from dioxane, and 7.1 g (91%) of 7-chloro-8-methyl-carbazol-1-carboxylic acid amide with melting point 223°C is obtained.

Example 32

Under the conditions in example 31, but with the difference that instead of ammonia, an excess of morpholine is added to the reaction mixture, 7,8-dimethyl-carbazole-1-carboxylic acid is transferred to carboxylic acid morpholinide, and after recrystallization from dioxane-

water in 75% yield 7,8-dimethyl-carbazole-1-carboxylic acid morpholinide with melting point 183°C.

Example 33

1. To a solution of 200 mg of hydroxylamine in 15 ml of ethanol, a 1% sodium-containing sodium ethylate solution and 1.0 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester are added in portions while cooling. The mixture is stirred for 1 hour at 0°C and for a further 12 hours at room temperature and then evaporated in vacuo. The residue is taken up in water, acidified with hydrochloric acid to pH 1, extracted with acetic acid ester, the extract is washed and evaporated, the residue is recrystallized from ethanol-water, and 7-chloro-8-methyl-carbazol-l- carbohydroxamic acid with a melting point of 200°C. 2. 1.8 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid is poured into 13 g of thionyl chloride, 0.5 ml of dimethylformamide is added and stirred for 1 hour at room temperature. 10 ml of absolute chloroform is then added to the mixture, heated for 2 hours at 6o°C and evaporated in vacuo. To remove the thionyl chloride, the residue is taken up several times in chloroform,

and the solution obtained is evaporated in vacuo. The crude product obtained is recrystallized from petrol-chloroform and gives 7-chloro-8-methyl-carbazole-1-carboxylic acid chloride with a melting point of 130°C.

The acid chloride thus obtained is added to 15 ml of ether and 1.3 g of crystalline hydroxylamine and stirred for 16 hours at room temperature.

o

The precipitate is then suctioned off, washed with ether and dissolved in water.

The aqueous solution is acidified with 2 N hydrochloric acid to pH 1, extracted with acetic acid ester, the extract is evaporated, the residue is recrystallized from dioxane-water, and 0.72 g (40%) of 7-chloro-8-methyl-carbazole-l-carbohydroxamic acid is obtained with melting point 200°C.

Example 34

a) Under the conditions in example 7a, 10 g of 3-bromo-2-oxo-cyclohexane-carboxylic acid ethyl ester are reacted with 3-chloro-4-methylaniline to 7-chloro-6-methyl-1,2,3,4-tetrahydrocarbazole-1 -carboxylic acid ethyl ester and 5-chloro-6-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl-. ester, which is separated by chromatography. b) The 7-chloro-6-methyl-tetrahydro-carbazole derivative thus prepared is dissolved in chlorobenzene, 10% palladium charcoal is added and

is dehydrated as described in example 1b, and after recrystallization from isopropyl alcohol, 7-chloro-6-methyl-carbazole-1-carboxylic acid ethyl ester with a melting point of 155°C is obtained in 75% yield.

Example 35

Under the conditions in example 18, 7-chloro-6-methyl-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from ethanol-dioxane, 7-chloro-6-methyl-carbazole-1-carboxylic acid is obtained in 85% yield with melting point 310°C.

Example 36

The 5-chloro-tetrahydro-carbazole derivative prepared according to example 33a is dissolved in chlorobenzene, 10% palladium charcoal is added and dehydrated as described in example 1b, and after recrystallization from isopropyl alcohol an 80% yield of 5-chloro is obtained -6-methyl-carbazole-1-carboxylic acid ethyl ester with a melting point of 160°C

Example 37

Under the conditions in example 18, 5-chloro-6-methyl-carbazole-l-carboxylic acid ethyl ester is saponified, and after recrystallization from dioxane-water, 5-chloro-6-methyl-carbazole-l-carboxylic acid is obtained in a 70% yield with melting point 305°C.

Example 38

a) Under the conditions in example 7a, 10 g of 3-bromo-2-oxo- ■cyclohexanecarboxylic acid ethyl ester with 2-chloro-3-methylaniline to 8-chloro-7-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester. b) The thus prepared tetrahydro-carbazole derivative is dissolved in chlorobenzene, 10% palladium charcoal is added and dehydrated as described in example 1b, and after recrystallization from isopropyl alcohol a 60% yield of 8-chloro-7-methyl is obtained -carbazole-1-carboxylic acid ethyl ester with melting point 73°C.

Example 39

Under the conditions in example 18, 8-chloro-7-methyl-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from dioxane, 8-chloro-7-methyl-carbazole-1-carboxylic acid with a melting point of 75% is obtained 266°C.

Example thaw

a) Under the conditions in example 7a, 10 g of 3-bromo-2-oxo-cyclohexane-carboxylic acid ethyl ester are reacted with 3-chloro-2-ethylaniline to J-chloro-8-ethyl-1,2,3,4-tetrahydrocarbazole- 1-carboxylic acid ethyl ester. b) The thus prepared tetrahydro-carbazole derivative is dissolved in chlorobenzene, 10% palladium charcoal is added, and dehydrated as described in example 1b, and 7-chloro-8-ethyl-carbazole-l-carboxylic acid is obtained -ethyl ester.

Example 4l

Under the conditions in example 18, 7-chloro-8-ethyl-carbazole-1-carboxylic acid ethyl ester is saponified, and 7-chloro-8-ethyl-carbazole-1-carboxylic acid is obtained.

Example 42

a) Under the conditions in example 7a, 10 g of ,3-bromo-2-oxo-cyclohexane-carboxylic acid ethyl ester is reacted with a-naphthylamine to benzo-[a]-1,2,3,4-tetrahydro-carbazole-1-carboxylic acid ethyl ester. b) The thus prepared tetrahydrocarbazole derivative is dissolved in xylene, 10% palladium charcoal is added and dehydrated as described in

example lb, and one obtains after recrystallization from isopropyl alcohol in a 70% yield benzo-[a]-carbazole-1-carboxylic acid ethyl ester with a melting point of 93°C.

Example 43

Under the conditions in example 18, benzo-[a]-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from methanol-dioxane, benzo-[a]-carbazole-1-carboxylic acid with a melting point of 343° is obtained in 80% yield C.0

Example 44

1,397.8-dichloro-carbazole-1-carboxylic acid is dissolved in 30 ml of absolute dimethylglycol and 0.6 g of triethylamine is added. The mixture is cooled to -10°C, 0.63 g of chloroformate isobutyl ester is added and stirred for 20 minutes at -10°C. The precipitate formed is then rapidly suctioned off, the filtrate is added to 0.5 g of dimethylaminoethanol in 2 ml of dimethylglycol, stirred for 10 minutes at -10°C and allowed to stand for 16 hours at approx. 0°C.

The reaction mixture is then evaporated in vacuo, the residue is taken up in ether, filtered, and the filtrate is washed, dried and evaporated in vacuum. 1.6 g (99%) of 7,8-dichloro-carbazole-1-carboxylic acid-(2'-dimethylamino-ethyl)-ester is obtained as an oil.

Example 45

Under the conditions of example 31, but with the addition of 2-dimethylamino-ethanol instead of ammonia, the 7-chloro~8-methyl-carbazole-1-carboxylic acid (2'-dimethylamino-ethyl) ester with melting point 91°C (from cyclohexane) is reacted .

Example 46

1) 0 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester in 20 ml of dimethylformamide is added to 0.2 g approx. 50% sodium hydride suspension and stirred for 4 hours at room temperature. 0.8 g of methyl iodide is added to the mixture and stirred further for 12 hours. The solvent is distilled off in vacuo, the residue is taken up in chloroform, the chloroform phase is washed and evaporated. The residue is purified with cyclohexane-toluene over a silica gel column, and 0.74 g (70%) of 7-chloro-8,9-dimethyl-carbazole-1-carboxylic acid ethyl ester is obtained as an oil.

Example empe1 47

Under the conditions in example 18, 7-chloro-8,9-dimethyl-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from dioxane-water in a 75% yield, 7-chloro-8,9-dimethyl-carbazole is obtained -1-carboxylic acid with melting point 237°C.

Example 48

Under the conditions of Example 45, but using benzyl chloride instead of methyl iodide, 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester is transferred in 65% yield to 7-chloro-8-methyl-9-benzylcarbazole The -1-carboxylic acid ethyl ester with melting point 81°C (from methanol).

Example 49

Under the conditions in example 18, the 7-chloro-8-methyl-9-benzyl-carbazole-1-carboxylic acid ethyl ester is saponified, and after recrystallization from methanol in 75% yield 7-chloro-8-methyl-9 -benzyl-carbazole-1-carboxylic acid with melting point 190°C.

Example 50

In 15 ml phosphorus oxychloride is introduced in portions while stirring

3.9 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid amide. The mixture is slowly heated to 120°C and held for 2 hours at this temperature.

The reaction mixture is allowed to cool, it is poured with vigorous stirring into a solution of 100 ml of ice water and 25 ml of aqueous ammonia solution, the precipitate formed is filtered off with suction, recrystallized from isopropyl alcohol, and 2.7 g (75%) of 7-chloro- 8-methyl-carbazole-1-carbonitrile with melting point 267°C.

Example 51

2.1 g of 7-chloro-8-methyl-carbazole-1-carbonitrile are dissolved in 50 ml of hexamethylphosphoric triamide and 5.2 g of sodium azide are added while stirring. The mixture is stirred for 20 minutes and, while cooling, 6.1 ml of 98% formic acid is added dropwise, and the mixture is stirred for 3 days at 6o - 70°C. The mixture is then poured into a mixture of 50 g of ice and 200 ml of 0.5 N caustic soda, and further caustic soda is added until a pH value of 10 is reached.

The mixture is extracted with chloroform, the chloroform phase is discarded, the aqueous phase is acidified with hydrochloric acid to pH 3 and extracted with ether. The ether phase is dried and evaporated. The residue is recrystallized from isopropyl alcohol, and 2.5 g (98%) of 7-chloro-'8-methyl 1-1-(5-tetrazolyl)-carbazole with a melting point of 279°C are obtained.

Example 52

a) 4-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid is added to methanol containing hydrogen chloride and stored for 16 hours at room temperature.

It is then diluted with methanol, the solution is neutralized by shaking with "Amberlite IR 4B", evaporated in vacuo, the residue is recrystallized from isopropyl alcohol, and 4-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester is obtained.

- o

b) The tetrahydro-carbazole derivative thus prepared is dissolved in chlorobenzene, 10% palladium charcoal is added and dehydrated as described in example 1b, and after recrystallization from isopropyl alcohol in 65% yield 4-chloro-carbazole is obtained 1-carboxylic acid methyl ester with melting point 136°C.

Example 53

Under the conditions in example 18, 4-chloro-carbazole-1-carboxylic acid methyl ester is saponified, and after recrystallization from isopropyl alcohol in a 70% yield, 4-chloro-carbazole-1-carboxylic acid with a melting point of 280°C is obtained.

Example 54

a) Under the conditions in example la, 10 g of 5-chloro-anthranilic acid methyl ester is reacted with 2-bromo-cyclohexanone to 3-chloro-5, 6, 7, 8_"t et ra -

hydrocarbazole-1-carboxylic acid methyl ester.

b) The thus obtained tetrahydro-carbazole derivative is dissolved in chlorobenzene, 10% palladium charcoal is added and dehydrated as described in example 1b, and after recrystallization from isopropyl alcohol in 65% yield 3-chloro-carbazole is obtained 1-carboxylic acid methyl ester with melting point 169°C.

Example 55

Under the conditions in example 18, 3-chloro-carbazole-1-carboxylic acid methyl ester is saponified, and after recrystallization from acetic acid ester, 3-chloro-carbazole-1-carboxylic acid with a melting point of 245°C is obtained in 85% yield.

Example 56

a) Under the conditions in example 7a, 10 g of 4-methylanthranilic acid methyl ester is reacted with 2-bromo-cyclohexanone to 4-methyl-5,6,7,8-tetrahydro-carbazole-1-carboxylic acid methyl ester. b) The thus prepared tetrahydro-carbazole derivative is dissolved in xylene, 10% palladium charcoal is added, dehydrated as described in

example lb, and the 4-methyl-carbazole-1-carboxylic acid methyl ester is obtained.

Example 57

Under the conditions in example 18, the 4-methyl-carbazole-1-carboxylic acid methyl ester is saponified, and 4-methyl-carbazole-1-carboxylic acid is obtained.

Example 58

a) Under the conditions in example la, 10 g of 5-methylanthranilic acid methyl ester are reacted with 10 g of 2-bromo-cyclohexanone to 3-methyl-5>6,7,8-tetrahydro-carbazole-1-carboxylic acid methyl ester. b) The thus obtained tetrahydro-carbazole derivative is dissolved in xylene, 10% palladium charcoal is added, dehydrated as described in

example lb, and 3-methyl-carbazole-1-carboxylic acid methyl ester is obtained.

Example 59

Under the conditions in example 18, the 3-methyl-carbazole-1-carboxylic acid methyl ester is saponified, and 3-methyl-carbazole-1-carboxylic acid is obtained.

Example 6o

15,792-Amino-5-chloro-benzoic acid methyl ester is added to 0.5 g of zinc chloride and 7,192-bromocyclohexanone, and heated for 5 hours at 60°C.

The mixture is allowed to cool, diluted with toluene, the toluene phase is washed with dilute hydrochloric acid and water, dried and evaporated in vacuo. The residue is recrystallized from isopropyl alcohol-cyclohexanone, and 4.5 g (42%) of 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester is obtained.

Example 6l

1.2 g of 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester is stirred for 10 minutes in a mixture of 15 ml of isopropyl alcohol and 35% aqueous caustic soda in a bath heated to H0° C. The isopropyl alcohol is then distilled off slowly, the sodium salt of the 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid is filtered off, washed with ether and dried.

The salt is taken up in dilute hydrochloric acid and extracted with acetic acid ester, the extract is evaporated, the residue is recrystallized from acetic acid ester, and 0.9 g (80%) of 3-chloro-5,6,7,8-tetrahydro-carbazole-1-carboxylic acid is obtained with melting point 25l°C.

Example 62

Under the conditions in example 59, 2-bromo-cyclo-■hexanone is reacted with 2-amino-5-methyl-benzoic acid methyl ester, and after recrystallization from cyclohexane in 55% yield, 3-methyl-5,6,7, 8-tetrahydrocarbazole-1-carboxylic acid methyl ester rced melting point 111°C.

. Example 63

Under the conditions in example 60, 3-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester is saponified, and after recrystallization from isopropyl alcohol, 3-methyl-5,6,7,8 is obtained in 75% yield -tetrahydrocarbazole-1-carboxylic acid with a melting point of 225°C.

Example 64

1. Under the conditions in example 59, 2-bromo-cyclohexanone is reacted with N-methylanthranilic acid methyl ester, and after recrystallization from methanol, 9-methyl-5,6,7,8-tetrahydro-carbazole-1 is obtained in 15% yield -carboxylic acid methyl ester with melting point 56°C. 2. Under the conditions in example 45, 5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester is methylated, and 9-methyl-5,6,7,8-tetrahydrocarbazole-1 is obtained in 65% yield -carboxylic acid methyl ester.

Example 65

Under the conditions in example 6o, 9-methyl-5,6,7,8~ tetrahydrocarbazole-1-carboxylic acid methyl ester is saponified, and after recrystallization from ethanol, 9-methyl-5,6,7,8 is obtained in 75% yield -tet ra - hydrocarbazole-1-carboxylic acid with melting point 180°C.

Claims (1)

Analogous method for the preparation of therapeutically active carbazole derivatives with the general formula: where is hydroxymethyl, alkanoyloxymethyl, tetrazolyl, cyano, oximinocarbonyl, aminocarbonyl, carboxyl, their salts with physiologically acceptable bases, their esters with physiologically objectionable alcohols and their amides with physiologically objectionable amines, R 1 to R 2 are hydrogen, halogen, lower alkyl, trifluoromethyl or lower alkoxy, idec. R^ can occupy positions 3 or 4j R^ and Rg have the same meaning as R^ to R^ or-- together form a 5- or 6-membered isocyclic ring, and is a hydrocarbon group with 3 - 8 carbon atoms, or when at least one of the substituents R^ to R^ is different from hydrogen, R^ can also be hydrogen, methyl or ethyl, characterized in that tetrahydrocarbazole derivatives with the general formula II or III: where R^ to R^ is as indicated above, is dehydrated, a secondary amino group present in the 9-position is optionally alkylated, free hydroxyl groups are optionally esterified or etherified, ester groups are optionally saponified, and free carboxyl groups or reactive derivatives thereof are optionally transferred into a salt, ester , amide, oximinocarbonyl, cyano, hydroxymethyl or tetrazolyl.