CA1053682A - Carbazole derivatives and process for their manufacture - Google Patents
Carbazole derivatives and process for their manufactureInfo
- Publication number
- CA1053682A CA1053682A CA205,063A CA205063A CA1053682A CA 1053682 A CA1053682 A CA 1053682A CA 205063 A CA205063 A CA 205063A CA 1053682 A CA1053682 A CA 1053682A
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- carbazole
- carboxylic acid
- methyl
- chloro
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
New carbazole derivatives of the formula (I) which are topical anti-inflammatory agents, are produced by dehydrogenating a tetrahydrocarbazole derivative of the formula
New carbazole derivatives of the formula (I) which are topical anti-inflammatory agents, are produced by dehydrogenating a tetrahydrocarbazole derivative of the formula
Description
` 105368Z
This invention relates to new carbazole derivatives of the general formula I
4 = 1 2 (I) in which Rl represents a hydroxymethyl group, an alkanoyloxy-methyl group, with 1 to 8 carbon atoms in the alkanoyl group, a tetrazolyl group, a cyano group, an oximinocarbonyl group, an aminocarbonyl group, a carboxyl group, its salts with physio-logically tolerable bases, its esters of physiologically accep-i table alcohols or its amides of physiologically acceptable amines; R2 to R4 represent hydrogen atoms, halogen atoms, lower 1 alkyl groups, trifluoromethyl groups or lower alkoxy groups;
; R5 and R6 have the same meanings as R2 to R4 or together repre-' sent the residue of a five- or six- membered isocyclic ring;
and R7 represents a hydrocarbon radical containing 3 to 8 carbon ~ 20 atoms or, when at least one of the radicals R2 to R6 is a sub-j~ stituent different from hydrogen, a hydrogen atom, a methyl group 3 or an ethyl group.
; The new carbazole derivatives are pharmacologically ~- ~ctive substances, which are distinguished especially by their strong anti~inflammatory activity when used topically. As is explaàned more fully below, the new carbazole derivatives differ advantageously in their activity from the known structurally -~ analogous N~phenyl-anthranilic acid derivatives~ which when used ~` topically possess a very low anti~inflammatory activity.
As sfiown by the results of pharmacological tests given hereinafter, the new carbazole deri~vatives may contain various .,- ~
.:
, . ~ 1 --, . ~ .
.
lOS368Z
substituents Rl to R7 without losing their anti-inflammatory activity when used topically.
Rl substituents include, in addition to hydroxymethyl groups, tetrazolyl groups, cyano groups, oximinocarbonyl groups and aminocarbonyl groups, especially carboxyl groups, their salts with physiologically tolerable bases, their esters with physiologically acceptable alcohols and their amides with physiologically acceptable amines. Suitable physiologically tolerable salts of carboxyl groups include, for example, alkali or alkaline earth metal salts, such as the sodium salt or the calcium salt.
Physiologically acceptable alcohols, with which the carboxyl groups may be esterified, are, for example, straight-chained or branched or cyclic, saturated or unsaturated hydro-carbon radicals, which are optionally interrupted by an oxygen atom or a nitrogen atom or substituted by hydroxyl groups, amino ; groups or carboxyl groups, for example, alkanols, alkenols, alkinols, cycloalkanols, cycloalkenols, cycloalkyl-alkanols, phenylalkanols, phenylalkenols, alkandiols, hydroxy-carboxylic acids, aminoalkanols or alkylaminoalkanols and dialkylamino-alkanols containing 1 to 4 carbon atoms in the alkyl radical.
Alcohols suitable for esterifying the carboxyl group in the l-position are, for example, those containing a methyl, carboxymethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-amino-ethyl, 2-dimethylaminoethyl, 2-carboxyethyl, propyl, allyl, -cyclopropylmethyl, isopropyl, 3-hydroxypropyl, propinyl, 3-aminopropyl, butyl, sec.-butyl, t-butyl, butyl-t2), cyclobutyl, pentyl, isopentyl, t-pentyl, 2-methylbutyl, cyclopentyl, hexyl, cyclohexyl, cyclohex-2-enyl, cyclopentylmethyl, heptyl, benzyl,
This invention relates to new carbazole derivatives of the general formula I
4 = 1 2 (I) in which Rl represents a hydroxymethyl group, an alkanoyloxy-methyl group, with 1 to 8 carbon atoms in the alkanoyl group, a tetrazolyl group, a cyano group, an oximinocarbonyl group, an aminocarbonyl group, a carboxyl group, its salts with physio-logically tolerable bases, its esters of physiologically accep-i table alcohols or its amides of physiologically acceptable amines; R2 to R4 represent hydrogen atoms, halogen atoms, lower 1 alkyl groups, trifluoromethyl groups or lower alkoxy groups;
; R5 and R6 have the same meanings as R2 to R4 or together repre-' sent the residue of a five- or six- membered isocyclic ring;
and R7 represents a hydrocarbon radical containing 3 to 8 carbon ~ 20 atoms or, when at least one of the radicals R2 to R6 is a sub-j~ stituent different from hydrogen, a hydrogen atom, a methyl group 3 or an ethyl group.
; The new carbazole derivatives are pharmacologically ~- ~ctive substances, which are distinguished especially by their strong anti~inflammatory activity when used topically. As is explaàned more fully below, the new carbazole derivatives differ advantageously in their activity from the known structurally -~ analogous N~phenyl-anthranilic acid derivatives~ which when used ~` topically possess a very low anti~inflammatory activity.
As sfiown by the results of pharmacological tests given hereinafter, the new carbazole deri~vatives may contain various .,- ~
.:
, . ~ 1 --, . ~ .
.
lOS368Z
substituents Rl to R7 without losing their anti-inflammatory activity when used topically.
Rl substituents include, in addition to hydroxymethyl groups, tetrazolyl groups, cyano groups, oximinocarbonyl groups and aminocarbonyl groups, especially carboxyl groups, their salts with physiologically tolerable bases, their esters with physiologically acceptable alcohols and their amides with physiologically acceptable amines. Suitable physiologically tolerable salts of carboxyl groups include, for example, alkali or alkaline earth metal salts, such as the sodium salt or the calcium salt.
Physiologically acceptable alcohols, with which the carboxyl groups may be esterified, are, for example, straight-chained or branched or cyclic, saturated or unsaturated hydro-carbon radicals, which are optionally interrupted by an oxygen atom or a nitrogen atom or substituted by hydroxyl groups, amino ; groups or carboxyl groups, for example, alkanols, alkenols, alkinols, cycloalkanols, cycloalkenols, cycloalkyl-alkanols, phenylalkanols, phenylalkenols, alkandiols, hydroxy-carboxylic acids, aminoalkanols or alkylaminoalkanols and dialkylamino-alkanols containing 1 to 4 carbon atoms in the alkyl radical.
Alcohols suitable for esterifying the carboxyl group in the l-position are, for example, those containing a methyl, carboxymethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-amino-ethyl, 2-dimethylaminoethyl, 2-carboxyethyl, propyl, allyl, -cyclopropylmethyl, isopropyl, 3-hydroxypropyl, propinyl, 3-aminopropyl, butyl, sec.-butyl, t-butyl, butyl-t2), cyclobutyl, pentyl, isopentyl, t-pentyl, 2-methylbutyl, cyclopentyl, hexyl, cyclohexyl, cyclohex-2-enyl, cyclopentylmethyl, heptyl, benzyl,
2-phenylethyl, octyl, bornyl, isobornyl, menthyl, nonyl, decyl,
3-phenylpropyl, 3-phenyl-prop-2-enyl, undecyl or dodecyl radical.
l~S36B'~:
Physiologically acceptable amines, with which the carboxyl group in the l-position may be amidated, preferably include alkylamines, dialkylamines, alkanolamines, dialkanol~
amines containing 1 to 6 carbon atoms in the alkyl or alkanol residue, or five- or six-membered N-heterocycles. Suitable amines are, for example, methylamine, ethylamine, isopropyl-amine, ethanolamine, dimethylamine, diethylamine, diethanol-amlne, pyrrolidine, piperidine, morpholine and N-methyl- piper-azlne .
The substituent Rl may also be an alkanoyloxymethyl ~A~ group, of which the alkanoyl group prcferably contains 1 to 8carbon atoms. Suitable alkanoyl radicals include, for example, the formyl, acetyl, propionyl, butyryl and the hexanoyl radical.
As lower alkyl groups R2 to R6 there are preferably used alkyl groups containing 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl and t-butyl groups.
A halogen atom R2 to R6 is preferably a fluorine, chlo-rine or bromine atom.
The radical of a five- or six-membered isocyclic ring formed by the substituents R5 and R6 is cyclopentene, cyclo-hexene or benzene.
; Suitable hydrocarbon radicals R7 containing 1 to 8 carbon atoms are, for example, straight-chained or branched alkyl residues, which are optionally substituted by three- to six-membered cycloalkyl groups or by phenyl groups. As hydro-'` carbon radicals R7 there are mentioned, for example, the methyl, e~hyl, propyl, isopropyl, butyl, hexyl, 3-cyclopropyl-propyl, cyclopentyl-methyl and the benzyl radical.
The present invention also includes a process for pro-ducing the new carbazole derivatives of the general formula I,which is characterized in that tetrahydrocarbazole derivatives of the general formula II or III
.. . . . . . .
. .
~S36~Z
l~S36B'~:
Physiologically acceptable amines, with which the carboxyl group in the l-position may be amidated, preferably include alkylamines, dialkylamines, alkanolamines, dialkanol~
amines containing 1 to 6 carbon atoms in the alkyl or alkanol residue, or five- or six-membered N-heterocycles. Suitable amines are, for example, methylamine, ethylamine, isopropyl-amine, ethanolamine, dimethylamine, diethylamine, diethanol-amlne, pyrrolidine, piperidine, morpholine and N-methyl- piper-azlne .
The substituent Rl may also be an alkanoyloxymethyl ~A~ group, of which the alkanoyl group prcferably contains 1 to 8carbon atoms. Suitable alkanoyl radicals include, for example, the formyl, acetyl, propionyl, butyryl and the hexanoyl radical.
As lower alkyl groups R2 to R6 there are preferably used alkyl groups containing 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl and t-butyl groups.
A halogen atom R2 to R6 is preferably a fluorine, chlo-rine or bromine atom.
The radical of a five- or six-membered isocyclic ring formed by the substituents R5 and R6 is cyclopentene, cyclo-hexene or benzene.
; Suitable hydrocarbon radicals R7 containing 1 to 8 carbon atoms are, for example, straight-chained or branched alkyl residues, which are optionally substituted by three- to six-membered cycloalkyl groups or by phenyl groups. As hydro-'` carbon radicals R7 there are mentioned, for example, the methyl, e~hyl, propyl, isopropyl, butyl, hexyl, 3-cyclopropyl-propyl, cyclopentyl-methyl and the benzyl radical.
The present invention also includes a process for pro-ducing the new carbazole derivatives of the general formula I,which is characterized in that tetrahydrocarbazole derivatives of the general formula II or III
.. . . . . . .
. .
~S36~Z
4 ~ 4~
R6 R7 Rl R6 R7 Rl -in which Rl to R7 have the meanings given for formula I, are dehydrogenated in a known manner, and optionally a secondary amino group in the 9-position is alkyla~e-d~ free hydroxyl groups are esterified or etherified, ester groups are hydrolyzed, and free carboxyl groups or reactive derivatives thereof are converted into salts, esters, amides, cyano groups, oximino~
carbonyl groups, hydroxymethyl groups or tetrazolyl groups.
The dehydrogenation of the tetrahydrocarbazole deriva-tives of the general formulae II and III is carried out by known methods. Thus, for example, it is possible to dehydro-genate the compounds of the formula II or III with noble metal catalysts of the platinum group. Suitable noble metal catalysts include, for example, platinum oxide catalysts or especially -palladium-carbon catalysts.
The reaction is preferably carried out in a high boiling ` aromatic solvent, for example, toluene, xylene, cumene, anisole, ! chlorobenzene, dichlorobenzene or chlorotoluene. The reaction temperature is determined by the choice of the solvent and is approximately lO0 to 200C, and preferably 130 to 180C. ~1hen the tetrahydrocarbazole derivatives of the general formula II
or III contain halogen atoms, the latter can be split off if a halogen-free solvent is used for the reaction. If the reaction -is carried out in a halogen-containing solvent (which contains the same halogen atom as the compound to be dehydrogenated) the splitting off of halogen atoms can be avoided.
Additional oxidizing agents for use in the process :-. .. .
... . ~ , . .
.~
.:.~ : . . . .
1053,~8Z
include quinones, such as para-benzoquinone, chloranil, tetra-chlor-ortho-benzoquinone and dichloro-cicyano-benzoquinone, or inorganic oxidizing agents, such as lead dioxide, manganese dioxide and sulphur. The solvents are high-boiling solvents such as xylene, cumene, chlorobenzene and dichlorobenzene. The reaction temperature is 100 to 200C, and preferably 130 to The optional subse~uent alkylation of a secondary amino group in the 9-position is also carried out by known methods that are customarily used for the N-alkylation of indole deriva-tives.
Thus, for example, the nitrogen atom of the carbazole ring may be metallized by reaction with metal hydrides or metal amides such as sodium hydride or sodamide, and the reactive compounds thus obtained reacted with the halides (chlorides, bromides or iodides) of the finally desired hydrocarbon residue.
For this reaction, which is carried out at a reaction temperature of about 0 to 120C, there are preferably used polar aprotic solvents, such as dimethylformamide, N-methyl-pyrrolidone or hexamethylphosphoric acid triamide.
The subsequent esterification of the free hydroxymethyl group, as an optional measure, is also carried out by methods known for this purpose. A possible method of esterification is, for example, the esterification of the hydroxy compounds with acid anhydrides or acid chlorides in the presence of aromatic N-heterocycles 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.
The optional subsequent hydrolysis of the esters is carried out by known methods, for example, the hydrolysis of the esters in water or aqueous alcohol in the presence of acid catalysts, such as hydrochloric acid, sulphuric acid, para-toluene sulphonic acid, or of basic catalysts, such as potassium hydrogen carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
The optional subsequent esterification of the free acids is also carried out by known methods. The acids may be reacted, for example, with diazomethane or diazoethane, whereby the corresponding methyl or ethyl esters are obtained. A method lQ that is generally applicable is the reaction of the acids with the alcohols in the présence of carbonyl-diimidazole or dicyclo-hexyl-carbodiimide. It is possible to react the acids with alkyl halides in the presence of copper (I) chloride or silver oxide~
Another method consists of converting the free acids with the corresponding dimethylformamide-alkylacetals into the corresponding acid alkyl esters. Moreover, the acids may be reacted in the presence of strongly acid catalysts, such as hydr~gen chloride, sulphuric acid, perchloric acid, trifluoro-2a methyl sulphonic acid or para-toluene sulphonic acid, with the alcohols or lower-alkane carboxylic acid esters of the alcohols.
~ However, it is also possible to convert the carboxylic ,~ acids into the acid chlorides or mixed anhydrides, and to react~,~
~ ~ the 1-tter with the alcohols in the presence of basic catalytts I -.
~ 30 i~
~ ~ 6 -.. ... . . . .
.. . : . . . ~ .
~OS3682 such as pyridine, collidine, lutidine or 4-dimethylaminopyridine.
The salts of the carboxylic acids are formed, for example by hydrolyzing the esters with basic catalysts, or by neutralizin~ the acids with alkali carbonates or alkali hydrox-ides, for example, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, potassium hydrogen car-bonate or potassium hydroxide.
- 6a -.
105368;~ ~
It is also possible to react esters of the general formula I in the presence of acid or basic catalysts with the alcohol finally desired. For this purpose, there are preferably used, as acid or basic catalysts, hydrogen chloride, sulphuric acid, phosphoric acid, para-toluene sulphonic acid, trifluor-acetic acid or, for example, alkali, alkaline earth or alumin-ium alcoholates.
The optional subsequent amide formation of hydroxamic acid formation from the free carboxylic acids or their reactive derivatives is also carried out by methods known for this purpose. Thus, for example, the carboxylic acids are reacted under known conditions with the amines or hydroxylamine in the presence of dicyclohexyl-carbodiimide, and the corresponding ~-aminocarbonyl compounds are obtained.
It is also possible, for example, to convert the acid chlorides, mixed anhydrides or esters of the corresponding carboxylic acids under known conditions by treatment with ammonia, amines or hydroxylamine into the corresponding amides or hydroxamic acids.
The optional subsequent conversion of reactive carboxy-lic acid derivatives into nitriles is also carried out by methods known for such purpose, for example, by causing dehydrating agents, such as, for example, dicyclohexyl-carbodiimide, carbonyl-diimidazole, polyphosphoric acid, thionyl chloride or phosphorus oxychloride, to act on the corresponding aminocar-bonyl compounds under known conditions.
Known methods are also used to obtain from reactive derivatives of the carboxylic acids the corresponding hydroxy-methyl compounds. Thus, for example, the carboxylic acid ester in an aprotic halogen-free solvent, e.g., an ether (such as diethyl ether, diisopropyl ether, tetrahydrofurane or glycol .
~: ., .~ . , -~53682 dimethyl ether), may be reduced with a complex metal hydride such as lithium-aluminium hydride, diisobutyl-aluminium hydride or diethyl-aluminium hydride to form the corresponding hydroxy-methyl compound.
Known methods may also be used for preparing the tetra-zolyl compounds, for example, the nitriles in aprotic solvents such as dimethylformamide, N-methylacetamide, N-methylpyrro-lidone or hexamethyl-phosphoric acid triamide, may be reacted under known conditions with alkali azides, such as sodium azide, to form the corresponding tetrazolyl compounds.
It has already been mentioned that the new carbazole derivatives are pharmacologically active compounds, which are distinguished especially by a strong anti-inflammatory activity when applied topically. The inflammation-inhibiting activity of the new carbazole derivatives in local application can be de-termined by the method of Tonelli as follows:
The substance to be tested is dissolved in an irritant consisting of 4 parts of pyridine, 1 part of distilled water, ~ -
R6 R7 Rl R6 R7 Rl -in which Rl to R7 have the meanings given for formula I, are dehydrogenated in a known manner, and optionally a secondary amino group in the 9-position is alkyla~e-d~ free hydroxyl groups are esterified or etherified, ester groups are hydrolyzed, and free carboxyl groups or reactive derivatives thereof are converted into salts, esters, amides, cyano groups, oximino~
carbonyl groups, hydroxymethyl groups or tetrazolyl groups.
The dehydrogenation of the tetrahydrocarbazole deriva-tives of the general formulae II and III is carried out by known methods. Thus, for example, it is possible to dehydro-genate the compounds of the formula II or III with noble metal catalysts of the platinum group. Suitable noble metal catalysts include, for example, platinum oxide catalysts or especially -palladium-carbon catalysts.
The reaction is preferably carried out in a high boiling ` aromatic solvent, for example, toluene, xylene, cumene, anisole, ! chlorobenzene, dichlorobenzene or chlorotoluene. The reaction temperature is determined by the choice of the solvent and is approximately lO0 to 200C, and preferably 130 to 180C. ~1hen the tetrahydrocarbazole derivatives of the general formula II
or III contain halogen atoms, the latter can be split off if a halogen-free solvent is used for the reaction. If the reaction -is carried out in a halogen-containing solvent (which contains the same halogen atom as the compound to be dehydrogenated) the splitting off of halogen atoms can be avoided.
Additional oxidizing agents for use in the process :-. .. .
... . ~ , . .
.~
.:.~ : . . . .
1053,~8Z
include quinones, such as para-benzoquinone, chloranil, tetra-chlor-ortho-benzoquinone and dichloro-cicyano-benzoquinone, or inorganic oxidizing agents, such as lead dioxide, manganese dioxide and sulphur. The solvents are high-boiling solvents such as xylene, cumene, chlorobenzene and dichlorobenzene. The reaction temperature is 100 to 200C, and preferably 130 to The optional subse~uent alkylation of a secondary amino group in the 9-position is also carried out by known methods that are customarily used for the N-alkylation of indole deriva-tives.
Thus, for example, the nitrogen atom of the carbazole ring may be metallized by reaction with metal hydrides or metal amides such as sodium hydride or sodamide, and the reactive compounds thus obtained reacted with the halides (chlorides, bromides or iodides) of the finally desired hydrocarbon residue.
For this reaction, which is carried out at a reaction temperature of about 0 to 120C, there are preferably used polar aprotic solvents, such as dimethylformamide, N-methyl-pyrrolidone or hexamethylphosphoric acid triamide.
The subsequent esterification of the free hydroxymethyl group, as an optional measure, is also carried out by methods known for this purpose. A possible method of esterification is, for example, the esterification of the hydroxy compounds with acid anhydrides or acid chlorides in the presence of aromatic N-heterocycles 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.
The optional subsequent hydrolysis of the esters is carried out by known methods, for example, the hydrolysis of the esters in water or aqueous alcohol in the presence of acid catalysts, such as hydrochloric acid, sulphuric acid, para-toluene sulphonic acid, or of basic catalysts, such as potassium hydrogen carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
The optional subsequent esterification of the free acids is also carried out by known methods. The acids may be reacted, for example, with diazomethane or diazoethane, whereby the corresponding methyl or ethyl esters are obtained. A method lQ that is generally applicable is the reaction of the acids with the alcohols in the présence of carbonyl-diimidazole or dicyclo-hexyl-carbodiimide. It is possible to react the acids with alkyl halides in the presence of copper (I) chloride or silver oxide~
Another method consists of converting the free acids with the corresponding dimethylformamide-alkylacetals into the corresponding acid alkyl esters. Moreover, the acids may be reacted in the presence of strongly acid catalysts, such as hydr~gen chloride, sulphuric acid, perchloric acid, trifluoro-2a methyl sulphonic acid or para-toluene sulphonic acid, with the alcohols or lower-alkane carboxylic acid esters of the alcohols.
~ However, it is also possible to convert the carboxylic ,~ acids into the acid chlorides or mixed anhydrides, and to react~,~
~ ~ the 1-tter with the alcohols in the presence of basic catalytts I -.
~ 30 i~
~ ~ 6 -.. ... . . . .
.. . : . . . ~ .
~OS3682 such as pyridine, collidine, lutidine or 4-dimethylaminopyridine.
The salts of the carboxylic acids are formed, for example by hydrolyzing the esters with basic catalysts, or by neutralizin~ the acids with alkali carbonates or alkali hydrox-ides, for example, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, potassium hydrogen car-bonate or potassium hydroxide.
- 6a -.
105368;~ ~
It is also possible to react esters of the general formula I in the presence of acid or basic catalysts with the alcohol finally desired. For this purpose, there are preferably used, as acid or basic catalysts, hydrogen chloride, sulphuric acid, phosphoric acid, para-toluene sulphonic acid, trifluor-acetic acid or, for example, alkali, alkaline earth or alumin-ium alcoholates.
The optional subsequent amide formation of hydroxamic acid formation from the free carboxylic acids or their reactive derivatives is also carried out by methods known for this purpose. Thus, for example, the carboxylic acids are reacted under known conditions with the amines or hydroxylamine in the presence of dicyclohexyl-carbodiimide, and the corresponding ~-aminocarbonyl compounds are obtained.
It is also possible, for example, to convert the acid chlorides, mixed anhydrides or esters of the corresponding carboxylic acids under known conditions by treatment with ammonia, amines or hydroxylamine into the corresponding amides or hydroxamic acids.
The optional subsequent conversion of reactive carboxy-lic acid derivatives into nitriles is also carried out by methods known for such purpose, for example, by causing dehydrating agents, such as, for example, dicyclohexyl-carbodiimide, carbonyl-diimidazole, polyphosphoric acid, thionyl chloride or phosphorus oxychloride, to act on the corresponding aminocar-bonyl compounds under known conditions.
Known methods are also used to obtain from reactive derivatives of the carboxylic acids the corresponding hydroxy-methyl compounds. Thus, for example, the carboxylic acid ester in an aprotic halogen-free solvent, e.g., an ether (such as diethyl ether, diisopropyl ether, tetrahydrofurane or glycol .
~: ., .~ . , -~53682 dimethyl ether), may be reduced with a complex metal hydride such as lithium-aluminium hydride, diisobutyl-aluminium hydride or diethyl-aluminium hydride to form the corresponding hydroxy-methyl compound.
Known methods may also be used for preparing the tetra-zolyl compounds, for example, the nitriles in aprotic solvents such as dimethylformamide, N-methylacetamide, N-methylpyrro-lidone or hexamethyl-phosphoric acid triamide, may be reacted under known conditions with alkali azides, such as sodium azide, to form the corresponding tetrazolyl compounds.
It has already been mentioned that the new carbazole derivatives are pharmacologically active compounds, which are distinguished especially by a strong anti-inflammatory activity when applied topically. The inflammation-inhibiting activity of the new carbazole derivatives in local application can be de-termined by the method of Tonelli as follows:
The substance 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 an ethereal solution of 4%
strength of croton oil. Felt strips fixed to the inner sides of forceps, such as used for microscope slides, are impregnated with the test solution, and are pressed under light pressure for 15 seconds on the right ears of male rats weighing from 100 to 160 grams.
The left ears remain untreated and serve as controls.
Three hours after the application, the animals are killed and discs 9 mm in diameter are stamped out of their ears. The difference in weight between a disc from the right ear and a disc from the left ear is a measure of the oedema formed.
Control animals are treated in the same manner, except that the irritant solution used contains no test substance.
. - . ~
.: ... ...
The anti-inflammatory activity is determined by dividing the average difference in the ear weights of the treated group by the average difference in the ear weights of the control group.
The following table demonstrates the activity of the carbazole derivatives as compared with that of the known anti-inflammatory substances I and II.
Table .
No. Substance Concentration Anti-inflamm.
mg/ml activity in%
I N-(3-trifluoromethyl-phenyl)-3.75 0%
anthranilic acid 7.5 0%
15.0 20%
. _ II hydrocortisone acetate 7.5 19%
15.0 41%
III 9-methyl-carbazole-1- 7.5 33%
carboxylic acid _ _ .
IV 6-fluoro-carbazole-1- 7.5 24%
carboxylic acid 15.0 41%
V 7-trifluoromethyl-carbazole-1-7.5 40%
carboxylic acid 15.0 56%
_ VI 7,8-dichloro-carbazole-1- 7.5 37%
carboxylic acid (2'-dimethyl- 15.0 40%
aminoethyl) ester VII 7-chloro-8-methyl-carbazole-1- 3.75 42%
carboxylic acid 7.5 59%
15.0 85%
VIII 5-chloro-8-met`hyl-carbazole-1- 7.5 26%
carboxylic acid 15.0 52%
IX 8-chloro-7-carbazole-1- 3.75 38%
carboxylic acid 7.5 62%
15.0 83%
. . _ X 7-chloro-3,8-dimethyl-carbazole 7.5 2%
-l-carboxylic acid 15.0 56%
XI 7-chloro-8,9-dimethyl-carbazole 7.5 46 -l-carboxylic acid 15.0 69%
XII 7-chloro-8-methyl-carbazole-1- 7.5 31%
carboxylic acid amide 15.0 54%
g - -. : . .
: . . . , :. :
iO5368Z
No. Substance Concentration Anti-inflamm.
mg/ml activity in%
XIII 7-chloro-8-methyl-carbazole-1- 3.75 28%
carbo-hydroxamic acid 7.5 50%
15.0 70%
XIV 7-chloro-1-hydroxymethyl-8- 7.5 36%
methyl-carbaæole 15.0 41 XV 7,8-dimethyl-carbazole-1- 7.5 36%
carboxylic acid morpholide XVI benzo[a]-carbazole-l- 3.75 22%
carboxylic acid 7.5 46%
XVII carbazole-l-carboxylic acid 7.5 40%
15.0 50%
It can be seen from the table that the new carbazole de-rivatives, as compared with the structurally analogous known N-phenyl-anthranilic acid derivatives, are distinguished by a superior anti-inflammatory activity. The anti-inflammatory activity of the new carbazole derivatives when applied locally is approximately as strong as that of the known anti-inflamma-torily active corticoids.
Surprisingly, not only the new carbazole derivatives, bu~ also known carbazole derivatives that differ from those of the general f~rmula I in that the substituents R2 to R7 are all hydrogen atoms exhibit a pronounced topical anti-inflammatory activity, as can be seen from the above table. Accordingly these compounds are also suitable for the production of topical anti-inflammatorily active medicinal preparations.
Thus, within the scope of the present invention there have been prepared non-steroidal compounds that possess an excellent topical inflammation-inhibiting activity.
The corticoids hitherto used for the treatment of inflam- ~ -mation of the skin possess, in addition to the topical action, a systemic action. Such corticoids, even when topically applied, are able, because of absorption through the inflamed skin or because of skin lesions, to pass into the blood stream where, as hormone-active substances, they influence the body functions in various ways.
The topically active carbazole derivatives of the pre-sent invention do not have such a disadvantage.
Moreover, the carbazole derivatives have the advantage that they possess a low toxicity and display a certain anti-bacterial and antifungal activity, which is wholly desirable in the topical treatment of inflammations.
The new compounds are suitably used in conjunction with the carriers usual in galenical pharmacy for the local treat-ment of allergies, contact dermatitis, eczemas of very many types, neurodermatitis, erythrodermia, burns, Pruritis vulvae et ani, rosacea, Erythematodes cutaneus, psoriasis, Lichen ruber planus et verrucosus and like skin diseases.
The preparation of medicinal specialities is carried out in the usual manner by converting the active substances with suitable additives into the desired forms for application, for example, solutions, lotion, salves, creams, inhalant pre-parations or plasters. The concentration of active substance in the preparations thus formulated depends on the form of application. In the case of lotions and salves it is preferable to use a concentration of active substance of 0.005% to 5%.
The starting compounds for the process of the invention are known or can easily be prepared in accordance with the following scheme of the formulae .
4~0Br ~ R4 ~ ~î
R5HN ~ R5 ~ ~ N
(IV) (V) (III') R5\~ ~ 2 ~ R2 (VI) (VII) (II' ) R $o N2N~ R ' ~r ( IV ' ) (V) ( I I I
in which R2 to R7 have the above meanings, and R8 represents a lower alkyl group, by heating the components at 50 to 200C, ~
for example, under an inert gas in the presence of a Lewis .. :.
acid 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 solvent.
In the esters obtained, it is possible, under the con-ditions already described, optionally to alkylate a secondary amino group present in the 9-position, esterify or etherify free hydroxy groups,hydrolyze ester groups, and to convert free lOS3682 carboxyl groups or reactive derivatives thereof into salts, esters, amides, oximinocarbonyl groups, cyano groups, hydroxy-methyl groups or tetrazolyl groups.
In principle the condensation may also be carried out using other ~-halogen-cyclohexanone derivatives, for example, ~-chloro- or ~-iodo-cyclohexanone derivatives. It is also possible to carry out the reaction without using Lewis acids or to use other catalysts such as boron trifluoride, phosphoric acid or hydrogen chloride.
When the reaction is carried out using substituted anilines, the substituted aniline is advantageously used in excess preferably with a 2.2 to 2.5 molar excess. The reaction may be carried out with or without solvents. Preferred sol-vents are alcohols such as ethanol and butanol, or ethers such as dioxane and dimethoxy-ethane. In working without solvents, the excess of the aniline component may serve as solvent. In both cases a catalyst, for example, zinc chloride, may be added.
The reaction is preferably carried out under an atmos-phere of a protective gas, for example, nitrogen or an inert gas.
The reaction temperature, which is determined by the choice of the solvent, is 80 to 200C, and preferably, when working without solvents or when solid aniline components are used, 140 to 150C.
The reaction is carried out under atmospheric pressure or reduced pressure, preferably at 100 mm of mercury.
When substituted phenyl-hydrazines (IV) are used as starting materials,the reaction is preferably effected at a temperature of 50 to 150C, and may be carried out using cata-lysts known from the Fischer indole synthesis, for example,zinc chloride, hydrogen chloride, sulphuric acid, phosphoric lOS368Z
acid, polyphosphoric acid and boron trifluoride. Preferred solvents are acetic acid, glacial acetic acid and alcohols.
However, the reaction may also be carried out without solvents in molten zinc chloride or in polyphosphoric acid and phos-phoric acid.
The hitherto unknown compounds of the general formula II, 5,6,7,8-tetrahydrocarbazole-1-carboxylic acid itself, and esters and amides thereof are, surprisingly, also distinguished by a pronounced anti-inflammatory activity upon local applica-tion, and can be used as medicinally active substances in the same manner as the carbazole derivatives.
Accordingly, the invention also includes the unknown 5,6,7,8-tetrahydrocarbazole-1-carboxylic acid derivatives, and their preparation and use.
The following examples illustrate the process of the invention.
Example 1 -(a) 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are mixed with 10 g of 3-methoxyaniline, and the mixture is heated at 140C under a light vacuum (about 100 torr), while stirring, for 7 hours. After cooling, the mixture is diluted with carbon tetrachloride, filtered, the organic phase is washed, concentrated in vacuo, and the residue is purified by chromatography over silica gel with cyclohexane-benzene as eluent, and 6-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester is obtained.
(b) 2.05 g of 6-methoxy-1,2,3,4-tetrahydrocarbazole-l-carboxylic acid ethyl ester are dissolved in 20 ml of xylene, 2 g of 10% strength palladium-carbon catalyst are added, and the whole is heated for 4 hours under reflux. After cooling the reaction mixture, the catalyst is filtered, the solution ', , : ' : . ' ' l~S36t~Z
is concentrated in vacuo, the residue is recrystallized from benzene, and 1.5 g of 6-methoxy-carbazole-1-carboxylic acid ethyl ester melting at 107C are obtained.
Example 2 (a) Under the conditions given in Example l(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 2-methoxyaniline to form 3-methoxy-1,2,3,4-tetra-hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The 8-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester is dissolved in chlorobenzene, and, after the addition of 10% strength palladium-carbon, dehydro-genated as described in Example l(b), and, after recrystalliza-CR r~ z~k A tion from ethanol there is obtained a 73% yield of ~-methoxy-~
l-carboxylic acid ethyl ester melting at 76C.
Example 3 (a) Under the conditions given in Example l(a), 10 g of 3-bromo-2-oxo-cylcohexane carboxylic acid ethyl ester are reacted with 2-methyl-aniline to form 8-methyl-1,2,3,4-tetra-hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The 8-methyl-1,2,3,4-tetrahydrocarbazole-1-car-boxylic acid ethyl ester is dissolved in cumene, and, after the addition of 10% strength palladium-carbon, dehydrogenated as described in Example l(b), and, after recrystallization from methanol, a 75% yield of 8-methyl-carbazole-1-carboxylic acid ethyl ester melting at 68C is obtained.
Example 4 (a) Under the conditions given in Example l(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 3-fluoraniline to form 7-fluoro-1,2,3,4-tetra-hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10~ strength palladium-carbon is -added, and the derivative is dehydrogenated as in Example l(b), and, after recrystallization from isopropyl alcohol, a 77%
yield of 7-fluoro-carbazole-1-carboxylic acid ethyl ester melt-ing at 132C is obtained.
Example 5 (a) Under the conditions given in Example l(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 4-fluoraniline to form 6-fluoro-1,2,3,4-tetra-hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in ortho-dichlorobenzene, 10% strength palladium-carbon is added, and the derivative is dehydrogenated as des-cribed in Example l(b), and, after recrystallization from isopropyl alcohol, a 60% yield of 6-fluoro-carbazole-1-carboxy-lic acid ethyl ester melting at 130C is obtained.
Example 6 (a) Under the conditions given in Example l(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 3-trifluoromethyl-aniline to form 7-trifluoro-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in ortho-dichlorobenzene, 10% strength palladium-carbon is added, and the derivative is dehydrogenated as des-cribed in Example l(b), and, after recrystallization from isopropyl alcohol, a 55% yield of 7-trifluoromethyl-carbazole-l-carboxylic acid ethyl ester melting at 80C is obtained.
Example 7 (a) Under the conditions given in Example l(a), 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 are . :. . - : .
1()5368Z
reacted with 5-chloro-2-methyl-aniline to form 5-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, and the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol-methanol, an 85% yield of 5-chloro-8-methyl-carbazole-l-carboxylic acid ethyl ester melting at 102C is obtained.
Example 8 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 3-chloro-2-methyl-aniline to form 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, and the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol-methanol, a 70% yield of 7-chloro-8-methyl-carbazole-l-carboxylic acid ethyl ester melting at 98C is obtained.
Example 9 l g of chloranil and 15 ml of xylene are added to 600 mg of 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-l-carboxylic acid ethyl ester, and the whole is heated under reflux for 25 hours. The solvent is then distilled, sodium dithionite and a dilute solution of sodium hydroxide are added to the residue, and the mixture is extracted several times with benzene. The organic phase is washed and concentrated, and the residue is recrystallized from isopropyl alcohol-methanol to yield 350 mg (61%) of 7-chloro-8-methyl-carbazole-1~5368Z
l-carboxylic acid ethyl ester melti~ng at 97C.
Example 10 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 5-chloro-2-methoxy-aniline to form 5-chloro-8-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10~ strength palladium-carbon is added, and the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol, a 52% yield of 5-chloro-8-methoxy-carbazole-1-carboxylic acid ethyl ester melting at 113C is obtained.
Example 11 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-5-methyl-cyclohexane carboxylic acid ethyl ester are reacted with 3-chloro-2-methyl-aniline to form 7-chloro-3,8-dimethyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, and, the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol, a 70% yield of 7-chloro-3,8-dimethyl-carbazole-1-carboxylic acid ethyl ester melting at 137C is obtained.
Example 12 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 2,3-dichloro-aniline to form 7,8-dichloro-1,2,3,4-tetrahydro-carbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in ortho-dichlorobenzene, 10% strength palladium-105366~
carbon is added, and the derivative is dehydrogenated as de-scribed in Example l(b~, and, after recrystallization from isopropyl alcohol, a 60% yield of 7,8-dichloro-carbazole-1-carboxylic acid ethyl ester melting at 107C is obtained.
Example 13 - (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 2,3-dichloro-aniline to form 7,8-dichloro-1,2,3,4-tetrahydrocarbazole-l-carboxylic acid ethyl ester.
tb) The tetrahydrocarbazole derivative thus prepared is dissolved in ortho-dichlorobenzene, 10% strength palladium-carbon is added, and the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from methanol, a 45% yield of 7,8-dichloro-carbazole-1-carboxylic acid isoamyl ester melting at 66C is obtained.
Example 14 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 2,3-dimethyl-aniline to form 7,8-dimethyl-1,2,3,4-tetrahydro-carbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared i8 dissolved in xylene, 10% strength palladium-carbon is added, and the derivative is dehydrogenated as in Example l(b), and, after recrystallization from isopropyl alcohol, a 66% yield of 7,8-dimethyl-carbazole-1-carboxylic acid ethyl ester melting at 93C is obtained.
Example 15 Under the conditions given in Example 9, 7,8-dimethyl-1,2,3,4-tetrahydxocarbazole-1-carboxylic acid ethyl ester is lOS368Z
dehydrogenated with chloranil, and, after recrystallization from isopropyl alcohol, a 50% yield of 7,8-dimethyl-carbazole-l-carboxylic acid ethyl ester melting at 92C is obtained.
Example 16 3.1 g of 5-chloro-8-methoxy-1,2,3,4-tetrahydrocarbaz-ole-l-carboxylic acid ethyl ester are heated under reflux with 20 ml of xylene and 3 grams of 10% strength palladium-carbon for 6 hours. The mixture is allowed to cool, the catalyst is filtered, the solution is concentrated in vacuo and the resi-due is recrystallized from ethanol to yield 2.0 g ~66%) of 8-methoxy-carbazole-1-carboxylic acid ethyl ester melting at 75C.
Example 17 Under the conditions given in Example 16, 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester is dehydrogenated, and, after recrystallization from methanol, a 60% yield of 8-methyl-carbazole-1-carboxylic acid ethyl ester melting at 68C is obtained.
Example 18 2 ml of methanol and a solution of 2.5 g of potassium hydroxide in 10 ml of water are added to 1.2 g of 6-methoxy-carbazole-l-carboxylic acid ethyl ester, and the whole is heated under reflux for 4 hours, while stirring. The mixture is then poured into water, filtered, the filtrate is acidified drop-wise with hydrochloric acid and the crude product that separ-ates is recrystallized from acetone-ethyl acetate to yield 0.8 gram (80%) of 6-methoxy-carbazole-1-carboxylic acid melting at 262C.
Example 19 -Under the conditions given in Example 18, 8-methoxy-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, 105368~
after recrystallization from methanol, a 65% yield of 8-methoxy-carbazole-l-carboxylic acid melting at 252C is ob-tained.
Exa~le 20 Under the conditionsgiven in Example 18, 8-methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from acetic acid, a 70~ yield of 8-methyl-carbazole-l-carboxylic acid melting at 286C is obtained.
Example 21 Under the co~ditionsgiven in Example 18, 7-fluoro-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane-water, a 70% yield of 7-fluoro-carbazole-l-carboxylic acid melting at 260C is obtained.
Example 22 A solution of 4.2 grams of potassium hydroxide, 50 ml of water and 5 ml of dimethyl sulphoxide, is added to 212 grams of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester, and the whole is heated under reflux for 6 hours. Then the mixture is diluted with 50 ml of hot water, filtered, the fil-trate is acidified dropwise with hydrochloric acid and the product that separates is recrystallized from dioxane-water to yield 1.5 g (77%) of 7-chloro-8-methyl-carbazole-carboxylic acid melting at 249C.
xample 23 Under the conditionsgiven in Example 22, 5-chloro-8-methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane-water, a 55% yield of 5-chloro-8-methyl-carbazole-1-carboxylic acid melting at 303C is obtained.
Example 24 lOS368Z
Under the conditions given in Example 22, 7-chloro-3,8-dimethyl carbazole-l-carboxylic acid ethyl ester is hydro-lyzed, and, after recrystallization from dioxane-water, an 85%
yield of 7-chloro-3,8-dimethyl-carbazole-1-carboxylic acid melting at 294C is obtained.
Example 25 Under the conditio~ given in Example 22, 5-chloro-8-methoxy-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane, a yield of 70% of 5-chloro-8-methoxy-carbazole-1-carboxylic acid melting at 328C
is obtained.
Example 26 Under the conditionsgiven in Example 22, 7,8-dichlorD-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane-water, an 83% yield of 7,8-dichloro-carbazole-1-carboxylic acid melting at 290C is obtained.
Example 27 Under the conditionsgiven in Example 22, 7,8-dimethyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed,and, after recrystallization from dioxane, a 65~ yield of 7,8-dimethyl-carbazole-l-carboxylic acid melting at 239C is obtained.
Example 28 Under the co~ditionsgiven in Example 22, 6-fluoro-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane-water, a yield of 92% of
strength of croton oil. Felt strips fixed to the inner sides of forceps, such as used for microscope slides, are impregnated with the test solution, and are pressed under light pressure for 15 seconds on the right ears of male rats weighing from 100 to 160 grams.
The left ears remain untreated and serve as controls.
Three hours after the application, the animals are killed and discs 9 mm in diameter are stamped out of their ears. The difference in weight between a disc from the right ear and a disc from the left ear is a measure of the oedema formed.
Control animals are treated in the same manner, except that the irritant solution used contains no test substance.
. - . ~
.: ... ...
The anti-inflammatory activity is determined by dividing the average difference in the ear weights of the treated group by the average difference in the ear weights of the control group.
The following table demonstrates the activity of the carbazole derivatives as compared with that of the known anti-inflammatory substances I and II.
Table .
No. Substance Concentration Anti-inflamm.
mg/ml activity in%
I N-(3-trifluoromethyl-phenyl)-3.75 0%
anthranilic acid 7.5 0%
15.0 20%
. _ II hydrocortisone acetate 7.5 19%
15.0 41%
III 9-methyl-carbazole-1- 7.5 33%
carboxylic acid _ _ .
IV 6-fluoro-carbazole-1- 7.5 24%
carboxylic acid 15.0 41%
V 7-trifluoromethyl-carbazole-1-7.5 40%
carboxylic acid 15.0 56%
_ VI 7,8-dichloro-carbazole-1- 7.5 37%
carboxylic acid (2'-dimethyl- 15.0 40%
aminoethyl) ester VII 7-chloro-8-methyl-carbazole-1- 3.75 42%
carboxylic acid 7.5 59%
15.0 85%
VIII 5-chloro-8-met`hyl-carbazole-1- 7.5 26%
carboxylic acid 15.0 52%
IX 8-chloro-7-carbazole-1- 3.75 38%
carboxylic acid 7.5 62%
15.0 83%
. . _ X 7-chloro-3,8-dimethyl-carbazole 7.5 2%
-l-carboxylic acid 15.0 56%
XI 7-chloro-8,9-dimethyl-carbazole 7.5 46 -l-carboxylic acid 15.0 69%
XII 7-chloro-8-methyl-carbazole-1- 7.5 31%
carboxylic acid amide 15.0 54%
g - -. : . .
: . . . , :. :
iO5368Z
No. Substance Concentration Anti-inflamm.
mg/ml activity in%
XIII 7-chloro-8-methyl-carbazole-1- 3.75 28%
carbo-hydroxamic acid 7.5 50%
15.0 70%
XIV 7-chloro-1-hydroxymethyl-8- 7.5 36%
methyl-carbaæole 15.0 41 XV 7,8-dimethyl-carbazole-1- 7.5 36%
carboxylic acid morpholide XVI benzo[a]-carbazole-l- 3.75 22%
carboxylic acid 7.5 46%
XVII carbazole-l-carboxylic acid 7.5 40%
15.0 50%
It can be seen from the table that the new carbazole de-rivatives, as compared with the structurally analogous known N-phenyl-anthranilic acid derivatives, are distinguished by a superior anti-inflammatory activity. The anti-inflammatory activity of the new carbazole derivatives when applied locally is approximately as strong as that of the known anti-inflamma-torily active corticoids.
Surprisingly, not only the new carbazole derivatives, bu~ also known carbazole derivatives that differ from those of the general f~rmula I in that the substituents R2 to R7 are all hydrogen atoms exhibit a pronounced topical anti-inflammatory activity, as can be seen from the above table. Accordingly these compounds are also suitable for the production of topical anti-inflammatorily active medicinal preparations.
Thus, within the scope of the present invention there have been prepared non-steroidal compounds that possess an excellent topical inflammation-inhibiting activity.
The corticoids hitherto used for the treatment of inflam- ~ -mation of the skin possess, in addition to the topical action, a systemic action. Such corticoids, even when topically applied, are able, because of absorption through the inflamed skin or because of skin lesions, to pass into the blood stream where, as hormone-active substances, they influence the body functions in various ways.
The topically active carbazole derivatives of the pre-sent invention do not have such a disadvantage.
Moreover, the carbazole derivatives have the advantage that they possess a low toxicity and display a certain anti-bacterial and antifungal activity, which is wholly desirable in the topical treatment of inflammations.
The new compounds are suitably used in conjunction with the carriers usual in galenical pharmacy for the local treat-ment of allergies, contact dermatitis, eczemas of very many types, neurodermatitis, erythrodermia, burns, Pruritis vulvae et ani, rosacea, Erythematodes cutaneus, psoriasis, Lichen ruber planus et verrucosus and like skin diseases.
The preparation of medicinal specialities is carried out in the usual manner by converting the active substances with suitable additives into the desired forms for application, for example, solutions, lotion, salves, creams, inhalant pre-parations or plasters. The concentration of active substance in the preparations thus formulated depends on the form of application. In the case of lotions and salves it is preferable to use a concentration of active substance of 0.005% to 5%.
The starting compounds for the process of the invention are known or can easily be prepared in accordance with the following scheme of the formulae .
4~0Br ~ R4 ~ ~î
R5HN ~ R5 ~ ~ N
(IV) (V) (III') R5\~ ~ 2 ~ R2 (VI) (VII) (II' ) R $o N2N~ R ' ~r ( IV ' ) (V) ( I I I
in which R2 to R7 have the above meanings, and R8 represents a lower alkyl group, by heating the components at 50 to 200C, ~
for example, under an inert gas in the presence of a Lewis .. :.
acid 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 solvent.
In the esters obtained, it is possible, under the con-ditions already described, optionally to alkylate a secondary amino group present in the 9-position, esterify or etherify free hydroxy groups,hydrolyze ester groups, and to convert free lOS3682 carboxyl groups or reactive derivatives thereof into salts, esters, amides, oximinocarbonyl groups, cyano groups, hydroxy-methyl groups or tetrazolyl groups.
In principle the condensation may also be carried out using other ~-halogen-cyclohexanone derivatives, for example, ~-chloro- or ~-iodo-cyclohexanone derivatives. It is also possible to carry out the reaction without using Lewis acids or to use other catalysts such as boron trifluoride, phosphoric acid or hydrogen chloride.
When the reaction is carried out using substituted anilines, the substituted aniline is advantageously used in excess preferably with a 2.2 to 2.5 molar excess. The reaction may be carried out with or without solvents. Preferred sol-vents are alcohols such as ethanol and butanol, or ethers such as dioxane and dimethoxy-ethane. In working without solvents, the excess of the aniline component may serve as solvent. In both cases a catalyst, for example, zinc chloride, may be added.
The reaction is preferably carried out under an atmos-phere of a protective gas, for example, nitrogen or an inert gas.
The reaction temperature, which is determined by the choice of the solvent, is 80 to 200C, and preferably, when working without solvents or when solid aniline components are used, 140 to 150C.
The reaction is carried out under atmospheric pressure or reduced pressure, preferably at 100 mm of mercury.
When substituted phenyl-hydrazines (IV) are used as starting materials,the reaction is preferably effected at a temperature of 50 to 150C, and may be carried out using cata-lysts known from the Fischer indole synthesis, for example,zinc chloride, hydrogen chloride, sulphuric acid, phosphoric lOS368Z
acid, polyphosphoric acid and boron trifluoride. Preferred solvents are acetic acid, glacial acetic acid and alcohols.
However, the reaction may also be carried out without solvents in molten zinc chloride or in polyphosphoric acid and phos-phoric acid.
The hitherto unknown compounds of the general formula II, 5,6,7,8-tetrahydrocarbazole-1-carboxylic acid itself, and esters and amides thereof are, surprisingly, also distinguished by a pronounced anti-inflammatory activity upon local applica-tion, and can be used as medicinally active substances in the same manner as the carbazole derivatives.
Accordingly, the invention also includes the unknown 5,6,7,8-tetrahydrocarbazole-1-carboxylic acid derivatives, and their preparation and use.
The following examples illustrate the process of the invention.
Example 1 -(a) 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are mixed with 10 g of 3-methoxyaniline, and the mixture is heated at 140C under a light vacuum (about 100 torr), while stirring, for 7 hours. After cooling, the mixture is diluted with carbon tetrachloride, filtered, the organic phase is washed, concentrated in vacuo, and the residue is purified by chromatography over silica gel with cyclohexane-benzene as eluent, and 6-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester is obtained.
(b) 2.05 g of 6-methoxy-1,2,3,4-tetrahydrocarbazole-l-carboxylic acid ethyl ester are dissolved in 20 ml of xylene, 2 g of 10% strength palladium-carbon catalyst are added, and the whole is heated for 4 hours under reflux. After cooling the reaction mixture, the catalyst is filtered, the solution ', , : ' : . ' ' l~S36t~Z
is concentrated in vacuo, the residue is recrystallized from benzene, and 1.5 g of 6-methoxy-carbazole-1-carboxylic acid ethyl ester melting at 107C are obtained.
Example 2 (a) Under the conditions given in Example l(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 2-methoxyaniline to form 3-methoxy-1,2,3,4-tetra-hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The 8-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester is dissolved in chlorobenzene, and, after the addition of 10% strength palladium-carbon, dehydro-genated as described in Example l(b), and, after recrystalliza-CR r~ z~k A tion from ethanol there is obtained a 73% yield of ~-methoxy-~
l-carboxylic acid ethyl ester melting at 76C.
Example 3 (a) Under the conditions given in Example l(a), 10 g of 3-bromo-2-oxo-cylcohexane carboxylic acid ethyl ester are reacted with 2-methyl-aniline to form 8-methyl-1,2,3,4-tetra-hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The 8-methyl-1,2,3,4-tetrahydrocarbazole-1-car-boxylic acid ethyl ester is dissolved in cumene, and, after the addition of 10% strength palladium-carbon, dehydrogenated as described in Example l(b), and, after recrystallization from methanol, a 75% yield of 8-methyl-carbazole-1-carboxylic acid ethyl ester melting at 68C is obtained.
Example 4 (a) Under the conditions given in Example l(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 3-fluoraniline to form 7-fluoro-1,2,3,4-tetra-hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10~ strength palladium-carbon is -added, and the derivative is dehydrogenated as in Example l(b), and, after recrystallization from isopropyl alcohol, a 77%
yield of 7-fluoro-carbazole-1-carboxylic acid ethyl ester melt-ing at 132C is obtained.
Example 5 (a) Under the conditions given in Example l(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 4-fluoraniline to form 6-fluoro-1,2,3,4-tetra-hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in ortho-dichlorobenzene, 10% strength palladium-carbon is added, and the derivative is dehydrogenated as des-cribed in Example l(b), and, after recrystallization from isopropyl alcohol, a 60% yield of 6-fluoro-carbazole-1-carboxy-lic acid ethyl ester melting at 130C is obtained.
Example 6 (a) Under the conditions given in Example l(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 3-trifluoromethyl-aniline to form 7-trifluoro-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in ortho-dichlorobenzene, 10% strength palladium-carbon is added, and the derivative is dehydrogenated as des-cribed in Example l(b), and, after recrystallization from isopropyl alcohol, a 55% yield of 7-trifluoromethyl-carbazole-l-carboxylic acid ethyl ester melting at 80C is obtained.
Example 7 (a) Under the conditions given in Example l(a), 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 are . :. . - : .
1()5368Z
reacted with 5-chloro-2-methyl-aniline to form 5-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, and the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol-methanol, an 85% yield of 5-chloro-8-methyl-carbazole-l-carboxylic acid ethyl ester melting at 102C is obtained.
Example 8 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 3-chloro-2-methyl-aniline to form 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, and the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol-methanol, a 70% yield of 7-chloro-8-methyl-carbazole-l-carboxylic acid ethyl ester melting at 98C is obtained.
Example 9 l g of chloranil and 15 ml of xylene are added to 600 mg of 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-l-carboxylic acid ethyl ester, and the whole is heated under reflux for 25 hours. The solvent is then distilled, sodium dithionite and a dilute solution of sodium hydroxide are added to the residue, and the mixture is extracted several times with benzene. The organic phase is washed and concentrated, and the residue is recrystallized from isopropyl alcohol-methanol to yield 350 mg (61%) of 7-chloro-8-methyl-carbazole-1~5368Z
l-carboxylic acid ethyl ester melti~ng at 97C.
Example 10 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 5-chloro-2-methoxy-aniline to form 5-chloro-8-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10~ strength palladium-carbon is added, and the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol, a 52% yield of 5-chloro-8-methoxy-carbazole-1-carboxylic acid ethyl ester melting at 113C is obtained.
Example 11 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-5-methyl-cyclohexane carboxylic acid ethyl ester are reacted with 3-chloro-2-methyl-aniline to form 7-chloro-3,8-dimethyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, and, the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol, a 70% yield of 7-chloro-3,8-dimethyl-carbazole-1-carboxylic acid ethyl ester melting at 137C is obtained.
Example 12 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 2,3-dichloro-aniline to form 7,8-dichloro-1,2,3,4-tetrahydro-carbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in ortho-dichlorobenzene, 10% strength palladium-105366~
carbon is added, and the derivative is dehydrogenated as de-scribed in Example l(b~, and, after recrystallization from isopropyl alcohol, a 60% yield of 7,8-dichloro-carbazole-1-carboxylic acid ethyl ester melting at 107C is obtained.
Example 13 - (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 2,3-dichloro-aniline to form 7,8-dichloro-1,2,3,4-tetrahydrocarbazole-l-carboxylic acid ethyl ester.
tb) The tetrahydrocarbazole derivative thus prepared is dissolved in ortho-dichlorobenzene, 10% strength palladium-carbon is added, and the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from methanol, a 45% yield of 7,8-dichloro-carbazole-1-carboxylic acid isoamyl ester melting at 66C is obtained.
Example 14 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 2,3-dimethyl-aniline to form 7,8-dimethyl-1,2,3,4-tetrahydro-carbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared i8 dissolved in xylene, 10% strength palladium-carbon is added, and the derivative is dehydrogenated as in Example l(b), and, after recrystallization from isopropyl alcohol, a 66% yield of 7,8-dimethyl-carbazole-1-carboxylic acid ethyl ester melting at 93C is obtained.
Example 15 Under the conditions given in Example 9, 7,8-dimethyl-1,2,3,4-tetrahydxocarbazole-1-carboxylic acid ethyl ester is lOS368Z
dehydrogenated with chloranil, and, after recrystallization from isopropyl alcohol, a 50% yield of 7,8-dimethyl-carbazole-l-carboxylic acid ethyl ester melting at 92C is obtained.
Example 16 3.1 g of 5-chloro-8-methoxy-1,2,3,4-tetrahydrocarbaz-ole-l-carboxylic acid ethyl ester are heated under reflux with 20 ml of xylene and 3 grams of 10% strength palladium-carbon for 6 hours. The mixture is allowed to cool, the catalyst is filtered, the solution is concentrated in vacuo and the resi-due is recrystallized from ethanol to yield 2.0 g ~66%) of 8-methoxy-carbazole-1-carboxylic acid ethyl ester melting at 75C.
Example 17 Under the conditions given in Example 16, 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester is dehydrogenated, and, after recrystallization from methanol, a 60% yield of 8-methyl-carbazole-1-carboxylic acid ethyl ester melting at 68C is obtained.
Example 18 2 ml of methanol and a solution of 2.5 g of potassium hydroxide in 10 ml of water are added to 1.2 g of 6-methoxy-carbazole-l-carboxylic acid ethyl ester, and the whole is heated under reflux for 4 hours, while stirring. The mixture is then poured into water, filtered, the filtrate is acidified drop-wise with hydrochloric acid and the crude product that separ-ates is recrystallized from acetone-ethyl acetate to yield 0.8 gram (80%) of 6-methoxy-carbazole-1-carboxylic acid melting at 262C.
Example 19 -Under the conditions given in Example 18, 8-methoxy-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, 105368~
after recrystallization from methanol, a 65% yield of 8-methoxy-carbazole-l-carboxylic acid melting at 252C is ob-tained.
Exa~le 20 Under the conditionsgiven in Example 18, 8-methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from acetic acid, a 70~ yield of 8-methyl-carbazole-l-carboxylic acid melting at 286C is obtained.
Example 21 Under the co~ditionsgiven in Example 18, 7-fluoro-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane-water, a 70% yield of 7-fluoro-carbazole-l-carboxylic acid melting at 260C is obtained.
Example 22 A solution of 4.2 grams of potassium hydroxide, 50 ml of water and 5 ml of dimethyl sulphoxide, is added to 212 grams of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester, and the whole is heated under reflux for 6 hours. Then the mixture is diluted with 50 ml of hot water, filtered, the fil-trate is acidified dropwise with hydrochloric acid and the product that separates is recrystallized from dioxane-water to yield 1.5 g (77%) of 7-chloro-8-methyl-carbazole-carboxylic acid melting at 249C.
xample 23 Under the conditionsgiven in Example 22, 5-chloro-8-methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane-water, a 55% yield of 5-chloro-8-methyl-carbazole-1-carboxylic acid melting at 303C is obtained.
Example 24 lOS368Z
Under the conditions given in Example 22, 7-chloro-3,8-dimethyl carbazole-l-carboxylic acid ethyl ester is hydro-lyzed, and, after recrystallization from dioxane-water, an 85%
yield of 7-chloro-3,8-dimethyl-carbazole-1-carboxylic acid melting at 294C is obtained.
Example 25 Under the conditio~ given in Example 22, 5-chloro-8-methoxy-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane, a yield of 70% of 5-chloro-8-methoxy-carbazole-1-carboxylic acid melting at 328C
is obtained.
Example 26 Under the conditionsgiven in Example 22, 7,8-dichlorD-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane-water, an 83% yield of 7,8-dichloro-carbazole-1-carboxylic acid melting at 290C is obtained.
Example 27 Under the conditionsgiven in Example 22, 7,8-dimethyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed,and, after recrystallization from dioxane, a 65~ yield of 7,8-dimethyl-carbazole-l-carboxylic acid melting at 239C is obtained.
Example 28 Under the co~ditionsgiven in Example 22, 6-fluoro-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane-water, a yield of 92% of
6-fluoro-carbazole-1-carboxylic acid melting at 254C is obtained.
Example 29 Under the conditions given in Example 22, 7-trifluoro-., ~0~
methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and after recrystallization from dioxane-water, an 83% yield of 7-trifluoro-methyl-carbazole-l-carboxylic acid melting at 266C
- is obtained.
Example 30 (a) To a suspension of 0.3 g of lithium-aluminium hydride in 5 ml of absolute tetrahydrofurane is added dropwise 0.560 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester dissolved in lOml of absolute tetrahydrofurane, and the mixture is stirred for one hour at room temperature. The mixture is then heated under reflux for one hour, allowed to cool, diluted with 20 ml of ethyl acetate, hydrochloric acid is added dropwise to the mixture while cooling, and the organic phase is separated, washed and concentrated in vacuo. The residue is recrystallized from toluene, and a 95% yield of
Example 29 Under the conditions given in Example 22, 7-trifluoro-., ~0~
methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and after recrystallization from dioxane-water, an 83% yield of 7-trifluoro-methyl-carbazole-l-carboxylic acid melting at 266C
- is obtained.
Example 30 (a) To a suspension of 0.3 g of lithium-aluminium hydride in 5 ml of absolute tetrahydrofurane is added dropwise 0.560 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester dissolved in lOml of absolute tetrahydrofurane, and the mixture is stirred for one hour at room temperature. The mixture is then heated under reflux for one hour, allowed to cool, diluted with 20 ml of ethyl acetate, hydrochloric acid is added dropwise to the mixture while cooling, and the organic phase is separated, washed and concentrated in vacuo. The residue is recrystallized from toluene, and a 95% yield of
7-chloro-1-hydroxymethyl-8-methyl-carbazole melting at 187C is obtained.
(b) Pyridine and acetic anhydride are added to the hydroxymethyl compound thus obtained, the mixture is allowed to 9tand for 30 minutes at room temperature and is taken up in chloroform. The chloroform solution is washed, concentrated in vacuo, and an 85% yield of 7-chloro-1-acetoxymethyl-8-methyl-carbazole that solidifies as a glassy mass is obtained.
Example 31 7.8 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid are mixed with 200 ml of diethyl ether and cooled to -10C. 8.7 g of phosphorous pentachloride are introduced into the suspen-sion while stirring, and the mixture is stirred for 2 hours at about 0C. Dry ammonia is then introduced for one hour while stirring, and the mixture is further stirred for 10 hours at room temperature. The reaction mixture is then poured into water, extracted with ethyl acetate, and the extract is washed and , ~ , 1053~Z
concentrated. The residue is recrystallized from dioxane, and 7.1 g (91%) of 7-chloro-8-methyl-carbazole-1-carboxylic acid amide melting at 223C are obtained.
Example 32 Under the conditions given 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 converted into the carboxylic acid morpholide, and, after recrystallization from dioxane-water, a 75% yield of 7,8-dimethyl-carbazole-l-carboxylic acid morpholide melting at 183C is obtained.
Example 33 (1) To a solution of 200 mg of hydroxylamine in 15 ml of ethanol are added 10 ml of a sodium ethylate solution containing 1% of sodium and, in portions, 1.0 g of 7-chloro-8-methyl-carbazole-l-carboxylic acid ethyl ester, while cooling. The mixture is stirred for one hour at 0C and for a further 12 hours at room temperature, and is then concentrated ln vacuo. The re~idue is taken up in water, acidified to a pH of 1 with hydrochloric acid, extracted with ethyl acetate, the extract is washed and concentrated and the residue is recrystallized from ethanol-water to give a 20% yield of 7-chloro-8-methyl-carbazole-l-carbo-hydroxamic acid melting at 200C.
(2) 1.8 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid are introduced into 13 g of thionyl chloride, 0.5 ml of dimethylformamide is added, and the mixture is stirred for one hour at room temperature. 10 ml of absolute chloroform are then added to the mixture, which is heated for two hours at 60C and concentrated ln vacuo. In order to remove the thionyl chloride, the residue is taken up several times in chloroform, and the solution thus obtained is concentrated ln vacuo. The resulting crude product is recrystallized from benzine-chloroform to yield 7-chloro-8-methyl-carbazole-1-carboxylic acid chloride melting at 130C.
15 ml of ether and 1.3 g of crystalline hydroxylamine are added to the acid chloride thus obtained, and the whole is stirred for 16 hours at room temperature. The precipitate is filtered with suction, washed with ether and dissolved in water.
The aqueous solution is acidified with 2N hydrochloric acid to a pH of 1, extracted with ethyl acetate, the extract is concentrated, the residue is recrystallized from dioxane-water and 0.72 g (40%) of 7-chloro-8-methyl-carbazole-1-carbo-hydroxamic acid melting at 200C is obtained.
Example 34 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 3-chloro-4-methyl-aniline to form 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 are separated by chromatography.
(b) ~he 7-chloro-6-methyl-tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as in Example l(b), and, after recrystallization from isopropyl alcohol, a 75% yield of 7-chloro-6-methyl-carbazole-1-carboxylic acid ethyl ester melting at 155C is obtained.
Example 35 Under the conditions given in Example 18, 7-chloro-6-methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from ethanol-dioxane, and 85% yield of 7-chloro-6-methyl-carbazole-1-carboxylic acid melting at 310C is obtained.
Example 36 The 5-chloro-tetrahydrocarbazole derivative prepared .. . : . : . ' -:
105;~68Z
3~
A ~ according to Example ~(a) is dissolved in chlorobenzene, 10~
strength palladium-carbon is added, the derivative is dehydro-genated as described in Example l(b), and, after recrystalliz-ation from isopropyl alcohol, an 80% yield of S-chloro-6-methyl-carbazole-l-carboxylic acid ethyl ester melting at 160C
is obtained.
Example 37 Under the conditions given in Example 18, 5-chloro-6-methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane-water, a 70% yield of 5-chloro-6-methyl-carbazole-1-carboxylic acid melting at 305C is obtained.
Example 38 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 2-chloro-3-methyl-aniline to form 8-chloro-7-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol, a 60% yield of 8-chloro-7-methyl-carbazole-1-carboxylic acid ethyl ester melting at 73C is obtained.
Example 39 Under the conditions given in Example 18, 8-chloro-7- ~
methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, ;;
and, after recrystallization from dioxane, a 75% yield of 8-chloro-7-methyl-carbazole-1-carboxylic acid melting at 266C is obtained.
Example_40 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 3-chloro-2-aniline to form 7-chloro-8-ethyl-1,2,3,4-:, ' ' ' ' ' ~0s~6~z tetra hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as described in Example l(b), and 7-chloro-8-ethyl-carbazole-1-carboxylic acid ethyl ester is obtained.
Example 41 Under the conditions given in Example 18, 7-chloro-8-ethyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and 7-chloro-8-ethyl-carbazole-1-carboxylic acid is obtained.
Example 42 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester is reacted with -naphthylamine to form benzo[a]-1,2,3,4-tetrahydrocarbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in xylene, 10~ strength palladium-carbon is added, the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol, a 70 yield of benzo[a]-carbazole-l-carboxylic acid ethyl ester melting at 93C is obtained.
Example 43 Under the conditions given in Example 18, benzo[a]-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from methanol-dioxane, an 80% yield of benzo[a]-carbazole-l-carboxylic acid melting at 343C is obtained.
Example 44 1.3 g of 7,8-dichloro-carbazole-1-carboxylic acid are dissolved in 30 ml of absolute dimethyl glycol, and 0.6 g of triethylamine is added. The mixture is cooled to -10C, 0.63 g of isobutyl chloroformate is added, and the mixture is stirred for 20 minutes at -10C. The resulting precipitate is rapidly .. - , . : .
1~536~
filtered with suction, to the filtrate is added 0.5 g of dimethylamino-ethanol in 2 ml of dimethyl glycol, the mixture is stirred for 10 minutes at -10C and allowed to stand for about 16 hours at about 0C.
The reaction mixture is then concentrated ln vacuo, the residue is taken up in ether, filtered, and the filtrate is washed, dried and concentrated in vacuo. There are obtained 1.6 g (99%) of 7,8-dichloro-carbazole-1-carboxylic acid (2'-dimethyl-amino-ethyl) ester in the form of an oil.
Example 45 Under the conditions given in Example 31, the reaction is carried out with 2-dimethylamino-ethanol, instead of ammonia, to yield 7-chloro-8-methyl-carbazole-1-carboxylic acid (2'-dimethyl-amino-ethyl) ester melting at 91C (from cyclohexane).
Example 46 0.2 g of a sodium hydride suspension of about 50% strength is added to 1.0 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester in 20 ml of dimethylformamide, and the mixture is stirred for 4 hours at room temperature. Then 0.8 g of methyl iodide i8 added to the mixture, and the whole is stirred for a further 12 hours. The solvent is then distilled in vacuo, the residue is taken up in chloroform, and the chloroform phase is washed and concentrated. The residue is purified with cyclohexane-toluene over a column of silica gel, and there is obtained 0.74 g (70~) of 7-chloro-8,9-dimethyl-carbazole-1-carboxylic acid ethyl ester in the form of an oil.
Example 47 Under the conditions given in Example 18,7-chloro-8,9-dimethyl carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane-water, a 75% yield of 7-chloro-8,9-dimethyl-carbazole-1-carboxylic acid melting at 237C is obtained.
'~ ~0~3~Z
Example 48 4 Under the conditions given in Example ~, but using benzylchloride instead of methyl iodide, 7-chloro-8-methyl-carbazole-l-carboxylic acid ethyl ester is converted with a 65% yield into 7-chloro-8-methyl-9-benzyl-carbazole-1-caxboxylic acid ethyl ester melting at 81C (from methanol).
Example 49 Under the conditions given in Example 18, 7-chloro-8-methyl-9-benzyl-carbazole-1-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from methanol, a 75%
yield of 7-chloro-8-methyl-9-benzyl-carbazole-1-carboxylic acid melting at 190C is obtained.
Example 50 3.9 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid amide are introduced in portions into 15 ml of phosphorus oxychloride, while stirring. The mixture is then slowly heated to 120C and maintained for 2 hours at such temperature. The reaction mixture is allowed to cool and poured while stirring vigorously into a solution of 100 ml of ice-water and 25 ml of an aqueous solution of ammonia, and the precipitate formed is filtered with suction and recrystallized from isopropyl alcohol to yield 2.7 g (75%) of 7-chloro-8-methyl-carbazole-1-carbonitrile melting at 267C.
Example 51 2.1 g of 7-chloro-8-methyl-carbazole-1-carbonitrile are dissolved in 50 ml of hexamethyl-phosphoric acid triamide and 5.2 g of sodium azide are added while stirring. The mixture is stirred for 20 minutes and 6.1 ml of formic acid of 98%
strength are added dropwise while cooling, and the mixture is stirred for 3 days at 60 to 70C. The whole is then poured into a mixture of 50 g of ice and 200 ml of an 0.5N solution of sodium hydroxide and further quantities of sodium hydroxide 10536~
solution are added until a pH of 10 is reached.
The mixture is extracted with chloroform, the chloroform phase is discarded, and the aqueous phase is acidified with hydro-chloric acid to a pH of 3 and extracted with ether. The ether phase is dried and concentrated. The residue is recrystallized from isopropyl alcohol to yield 2.5 g (98~) of 7-chloro-8-methyl-l-(5-tetrazolyl)-carbazole melting at 279C.
Example 52 (a) Methanol-containing hydrogen chloride is added to 4-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid, and the mixture is maintained for 16 hours at room temperature. The mixture is diluted with methanol, the solution is neutralized by agitation with Amberlite IR 4B (trade mark), concentrated in vacuo, the residue is recrystallized from isopropyl alcohol, and 4-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester is obtained.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol, a 65% yield of 4-chloro-carbazole-1-carboxylic acid methyl ester melting at 136C is obtained.
Example 53 Under the conditions given in Example 18, 4-chloro-carbazole-l-carboxylic acid methyl ester is hydrolyzed, and, after recrystallization from isopropyl alcohol, a 70% yield of 4-chloro-carbazole-1-carboxylic acid melting at 280C is obtained.
Example 54 (a) Under the conditions given in Example l(a), 10 g of 5-chloro-anthranilic acid methyl ester are reacted with 2-bromo-cyclohexanone to form 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol, a 65%
yield of 3-chloro-carbazole-1-carboxylic acid methyl ester melting at 169C is obtained.
Example 55 Under the conditions given in Example 18, 3-chloro-carbazole-l-carboxylic acid methyl ester is hydrolyzed, and, after recrystallization from ethyl acetate, an 85% yield of 3-chloro-carbazole-l-carboxylic acid melting at 245C is obtained.
Example_56 (a) Under the conditions given in Example 7(a), 10 g of 4-methyl-anthranilic acid methyl ester are reacted with 2-bromo-cyclohexanone to form 4-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in xylene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as described in Example l(b), and 4-methyl-carbazole-1-carboxylic acid methyl ester is obtained.
Example 57 Under the conditions given in Example 18, 4-methyl-carbazole-l-carboxylic acid methyl ester is hydrolyzed, and 4-methyl-carbazole-1-carboxylic acid is obtained.
Example 58 (a) Under the conditions given in Example l(a), 10 g of 5-methyl-anthranilic acid methyl ester are reacted with 10 g of 2-bromo-cyclohexanone to form 3-methyl-5,6,7,8-tetrahydrocarbazole l-carboxylic acid methyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in xylene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as in Example l(b), and 3-methyl-.
- - . . ~, ~
~OS;~682 carbazole-l-carboxylic acid methyl ester is obtained.
Exam~le 59 Under the conditions given in Example 18, 3-methyl-carbazole-l-carboxylic acid methyl ester is hydrolyzed, and 3-methyl-carbazole-l-carboxylic acid is obtained.
Example 60 0.5 g of zinc chloride and 7.1 g of 2-bromo-cyclohexanone are added to 15.7 g of 2-amino-5-chloro-benzoic acid methyl ester, and the mixture is heated for 5 hours at 160C~ The mixture is then allowed to cool,is diluted with toluene, and the toluene phase is washed with dilute hydrochloric acid and water, dried and evaporated in vacuo. The residue is recrystallized from isopropyl alcohol-cyclohexanone to yield 4.5 g (42%) of 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester.
Example 61 ` 1.2 g of 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester are stirred for 10 minutes in a mixture of 15 ml of isopropyl alcohol and an aqueous sodium hydroxide solution of 35% strength in a hot ~110C) bath. The isopropyl alcohol is then slowly distilled, and the sodium salt of 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid is filtered, washed with ether and dried.
The salt is taken up in dilute hydrochloric acid and extracted with ethyl acetate, the extract is concentrated, the residue is recrystallized from ethyl acetate, and 0.9 g (80%) of 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid melting at 251C is obtained.
Example 62 Under the conditions given in Example 59, 2-bromo-cyclohexanone is reacted with 2-amino-5-methyl-benzoic acid methyl ester, and, after recrystallization from cyclohexane, a 55% yield of 3-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl .: - , : :
. , .. ~ --` 1053682 ester melting at 111C is obtained.
Example 63 Under the conditions given in Example 60, 3-methyl-5,6,7,
(b) Pyridine and acetic anhydride are added to the hydroxymethyl compound thus obtained, the mixture is allowed to 9tand for 30 minutes at room temperature and is taken up in chloroform. The chloroform solution is washed, concentrated in vacuo, and an 85% yield of 7-chloro-1-acetoxymethyl-8-methyl-carbazole that solidifies as a glassy mass is obtained.
Example 31 7.8 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid are mixed with 200 ml of diethyl ether and cooled to -10C. 8.7 g of phosphorous pentachloride are introduced into the suspen-sion while stirring, and the mixture is stirred for 2 hours at about 0C. Dry ammonia is then introduced for one hour while stirring, and the mixture is further stirred for 10 hours at room temperature. The reaction mixture is then poured into water, extracted with ethyl acetate, and the extract is washed and , ~ , 1053~Z
concentrated. The residue is recrystallized from dioxane, and 7.1 g (91%) of 7-chloro-8-methyl-carbazole-1-carboxylic acid amide melting at 223C are obtained.
Example 32 Under the conditions given 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 converted into the carboxylic acid morpholide, and, after recrystallization from dioxane-water, a 75% yield of 7,8-dimethyl-carbazole-l-carboxylic acid morpholide melting at 183C is obtained.
Example 33 (1) To a solution of 200 mg of hydroxylamine in 15 ml of ethanol are added 10 ml of a sodium ethylate solution containing 1% of sodium and, in portions, 1.0 g of 7-chloro-8-methyl-carbazole-l-carboxylic acid ethyl ester, while cooling. The mixture is stirred for one hour at 0C and for a further 12 hours at room temperature, and is then concentrated ln vacuo. The re~idue is taken up in water, acidified to a pH of 1 with hydrochloric acid, extracted with ethyl acetate, the extract is washed and concentrated and the residue is recrystallized from ethanol-water to give a 20% yield of 7-chloro-8-methyl-carbazole-l-carbo-hydroxamic acid melting at 200C.
(2) 1.8 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid are introduced into 13 g of thionyl chloride, 0.5 ml of dimethylformamide is added, and the mixture is stirred for one hour at room temperature. 10 ml of absolute chloroform are then added to the mixture, which is heated for two hours at 60C and concentrated ln vacuo. In order to remove the thionyl chloride, the residue is taken up several times in chloroform, and the solution thus obtained is concentrated ln vacuo. The resulting crude product is recrystallized from benzine-chloroform to yield 7-chloro-8-methyl-carbazole-1-carboxylic acid chloride melting at 130C.
15 ml of ether and 1.3 g of crystalline hydroxylamine are added to the acid chloride thus obtained, and the whole is stirred for 16 hours at room temperature. The precipitate is filtered with suction, washed with ether and dissolved in water.
The aqueous solution is acidified with 2N hydrochloric acid to a pH of 1, extracted with ethyl acetate, the extract is concentrated, the residue is recrystallized from dioxane-water and 0.72 g (40%) of 7-chloro-8-methyl-carbazole-1-carbo-hydroxamic acid melting at 200C is obtained.
Example 34 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 3-chloro-4-methyl-aniline to form 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 are separated by chromatography.
(b) ~he 7-chloro-6-methyl-tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as in Example l(b), and, after recrystallization from isopropyl alcohol, a 75% yield of 7-chloro-6-methyl-carbazole-1-carboxylic acid ethyl ester melting at 155C is obtained.
Example 35 Under the conditions given in Example 18, 7-chloro-6-methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from ethanol-dioxane, and 85% yield of 7-chloro-6-methyl-carbazole-1-carboxylic acid melting at 310C is obtained.
Example 36 The 5-chloro-tetrahydrocarbazole derivative prepared .. . : . : . ' -:
105;~68Z
3~
A ~ according to Example ~(a) is dissolved in chlorobenzene, 10~
strength palladium-carbon is added, the derivative is dehydro-genated as described in Example l(b), and, after recrystalliz-ation from isopropyl alcohol, an 80% yield of S-chloro-6-methyl-carbazole-l-carboxylic acid ethyl ester melting at 160C
is obtained.
Example 37 Under the conditions given in Example 18, 5-chloro-6-methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane-water, a 70% yield of 5-chloro-6-methyl-carbazole-1-carboxylic acid melting at 305C is obtained.
Example 38 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 2-chloro-3-methyl-aniline to form 8-chloro-7-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol, a 60% yield of 8-chloro-7-methyl-carbazole-1-carboxylic acid ethyl ester melting at 73C is obtained.
Example 39 Under the conditions given in Example 18, 8-chloro-7- ~
methyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, ;;
and, after recrystallization from dioxane, a 75% yield of 8-chloro-7-methyl-carbazole-1-carboxylic acid melting at 266C is obtained.
Example_40 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester are reacted with 3-chloro-2-aniline to form 7-chloro-8-ethyl-1,2,3,4-:, ' ' ' ' ' ~0s~6~z tetra hydrocarbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as described in Example l(b), and 7-chloro-8-ethyl-carbazole-1-carboxylic acid ethyl ester is obtained.
Example 41 Under the conditions given in Example 18, 7-chloro-8-ethyl-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and 7-chloro-8-ethyl-carbazole-1-carboxylic acid is obtained.
Example 42 (a) Under the conditions given in Example 7(a), 10 g of 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester is reacted with -naphthylamine to form benzo[a]-1,2,3,4-tetrahydrocarbazole-l-carboxylic acid ethyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in xylene, 10~ strength palladium-carbon is added, the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol, a 70 yield of benzo[a]-carbazole-l-carboxylic acid ethyl ester melting at 93C is obtained.
Example 43 Under the conditions given in Example 18, benzo[a]-carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from methanol-dioxane, an 80% yield of benzo[a]-carbazole-l-carboxylic acid melting at 343C is obtained.
Example 44 1.3 g of 7,8-dichloro-carbazole-1-carboxylic acid are dissolved in 30 ml of absolute dimethyl glycol, and 0.6 g of triethylamine is added. The mixture is cooled to -10C, 0.63 g of isobutyl chloroformate is added, and the mixture is stirred for 20 minutes at -10C. The resulting precipitate is rapidly .. - , . : .
1~536~
filtered with suction, to the filtrate is added 0.5 g of dimethylamino-ethanol in 2 ml of dimethyl glycol, the mixture is stirred for 10 minutes at -10C and allowed to stand for about 16 hours at about 0C.
The reaction mixture is then concentrated ln vacuo, the residue is taken up in ether, filtered, and the filtrate is washed, dried and concentrated in vacuo. There are obtained 1.6 g (99%) of 7,8-dichloro-carbazole-1-carboxylic acid (2'-dimethyl-amino-ethyl) ester in the form of an oil.
Example 45 Under the conditions given in Example 31, the reaction is carried out with 2-dimethylamino-ethanol, instead of ammonia, to yield 7-chloro-8-methyl-carbazole-1-carboxylic acid (2'-dimethyl-amino-ethyl) ester melting at 91C (from cyclohexane).
Example 46 0.2 g of a sodium hydride suspension of about 50% strength is added to 1.0 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester in 20 ml of dimethylformamide, and the mixture is stirred for 4 hours at room temperature. Then 0.8 g of methyl iodide i8 added to the mixture, and the whole is stirred for a further 12 hours. The solvent is then distilled in vacuo, the residue is taken up in chloroform, and the chloroform phase is washed and concentrated. The residue is purified with cyclohexane-toluene over a column of silica gel, and there is obtained 0.74 g (70~) of 7-chloro-8,9-dimethyl-carbazole-1-carboxylic acid ethyl ester in the form of an oil.
Example 47 Under the conditions given in Example 18,7-chloro-8,9-dimethyl carbazole-l-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from dioxane-water, a 75% yield of 7-chloro-8,9-dimethyl-carbazole-1-carboxylic acid melting at 237C is obtained.
'~ ~0~3~Z
Example 48 4 Under the conditions given in Example ~, but using benzylchloride instead of methyl iodide, 7-chloro-8-methyl-carbazole-l-carboxylic acid ethyl ester is converted with a 65% yield into 7-chloro-8-methyl-9-benzyl-carbazole-1-caxboxylic acid ethyl ester melting at 81C (from methanol).
Example 49 Under the conditions given in Example 18, 7-chloro-8-methyl-9-benzyl-carbazole-1-carboxylic acid ethyl ester is hydrolyzed, and, after recrystallization from methanol, a 75%
yield of 7-chloro-8-methyl-9-benzyl-carbazole-1-carboxylic acid melting at 190C is obtained.
Example 50 3.9 g of 7-chloro-8-methyl-carbazole-1-carboxylic acid amide are introduced in portions into 15 ml of phosphorus oxychloride, while stirring. The mixture is then slowly heated to 120C and maintained for 2 hours at such temperature. The reaction mixture is allowed to cool and poured while stirring vigorously into a solution of 100 ml of ice-water and 25 ml of an aqueous solution of ammonia, and the precipitate formed is filtered with suction and recrystallized from isopropyl alcohol to yield 2.7 g (75%) of 7-chloro-8-methyl-carbazole-1-carbonitrile melting at 267C.
Example 51 2.1 g of 7-chloro-8-methyl-carbazole-1-carbonitrile are dissolved in 50 ml of hexamethyl-phosphoric acid triamide and 5.2 g of sodium azide are added while stirring. The mixture is stirred for 20 minutes and 6.1 ml of formic acid of 98%
strength are added dropwise while cooling, and the mixture is stirred for 3 days at 60 to 70C. The whole is then poured into a mixture of 50 g of ice and 200 ml of an 0.5N solution of sodium hydroxide and further quantities of sodium hydroxide 10536~
solution are added until a pH of 10 is reached.
The mixture is extracted with chloroform, the chloroform phase is discarded, and the aqueous phase is acidified with hydro-chloric acid to a pH of 3 and extracted with ether. The ether phase is dried and concentrated. The residue is recrystallized from isopropyl alcohol to yield 2.5 g (98~) of 7-chloro-8-methyl-l-(5-tetrazolyl)-carbazole melting at 279C.
Example 52 (a) Methanol-containing hydrogen chloride is added to 4-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid, and the mixture is maintained for 16 hours at room temperature. The mixture is diluted with methanol, the solution is neutralized by agitation with Amberlite IR 4B (trade mark), concentrated in vacuo, the residue is recrystallized from isopropyl alcohol, and 4-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester is obtained.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol, a 65% yield of 4-chloro-carbazole-1-carboxylic acid methyl ester melting at 136C is obtained.
Example 53 Under the conditions given in Example 18, 4-chloro-carbazole-l-carboxylic acid methyl ester is hydrolyzed, and, after recrystallization from isopropyl alcohol, a 70% yield of 4-chloro-carbazole-1-carboxylic acid melting at 280C is obtained.
Example 54 (a) Under the conditions given in Example l(a), 10 g of 5-chloro-anthranilic acid methyl ester are reacted with 2-bromo-cyclohexanone to form 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in chlorobenzene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as described in Example l(b), and, after recrystallization from isopropyl alcohol, a 65%
yield of 3-chloro-carbazole-1-carboxylic acid methyl ester melting at 169C is obtained.
Example 55 Under the conditions given in Example 18, 3-chloro-carbazole-l-carboxylic acid methyl ester is hydrolyzed, and, after recrystallization from ethyl acetate, an 85% yield of 3-chloro-carbazole-l-carboxylic acid melting at 245C is obtained.
Example_56 (a) Under the conditions given in Example 7(a), 10 g of 4-methyl-anthranilic acid methyl ester are reacted with 2-bromo-cyclohexanone to form 4-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in xylene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as described in Example l(b), and 4-methyl-carbazole-1-carboxylic acid methyl ester is obtained.
Example 57 Under the conditions given in Example 18, 4-methyl-carbazole-l-carboxylic acid methyl ester is hydrolyzed, and 4-methyl-carbazole-1-carboxylic acid is obtained.
Example 58 (a) Under the conditions given in Example l(a), 10 g of 5-methyl-anthranilic acid methyl ester are reacted with 10 g of 2-bromo-cyclohexanone to form 3-methyl-5,6,7,8-tetrahydrocarbazole l-carboxylic acid methyl ester.
(b) The tetrahydrocarbazole derivative thus prepared is dissolved in xylene, 10% strength palladium-carbon is added, the derivative is dehydrogenated as in Example l(b), and 3-methyl-.
- - . . ~, ~
~OS;~682 carbazole-l-carboxylic acid methyl ester is obtained.
Exam~le 59 Under the conditions given in Example 18, 3-methyl-carbazole-l-carboxylic acid methyl ester is hydrolyzed, and 3-methyl-carbazole-l-carboxylic acid is obtained.
Example 60 0.5 g of zinc chloride and 7.1 g of 2-bromo-cyclohexanone are added to 15.7 g of 2-amino-5-chloro-benzoic acid methyl ester, and the mixture is heated for 5 hours at 160C~ The mixture is then allowed to cool,is diluted with toluene, and the toluene phase is washed with dilute hydrochloric acid and water, dried and evaporated in vacuo. The residue is recrystallized from isopropyl alcohol-cyclohexanone to yield 4.5 g (42%) of 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester.
Example 61 ` 1.2 g of 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester are stirred for 10 minutes in a mixture of 15 ml of isopropyl alcohol and an aqueous sodium hydroxide solution of 35% strength in a hot ~110C) bath. The isopropyl alcohol is then slowly distilled, and the sodium salt of 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid is filtered, washed with ether and dried.
The salt is taken up in dilute hydrochloric acid and extracted with ethyl acetate, the extract is concentrated, the residue is recrystallized from ethyl acetate, and 0.9 g (80%) of 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid melting at 251C is obtained.
Example 62 Under the conditions given in Example 59, 2-bromo-cyclohexanone is reacted with 2-amino-5-methyl-benzoic acid methyl ester, and, after recrystallization from cyclohexane, a 55% yield of 3-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl .: - , : :
. , .. ~ --` 1053682 ester melting at 111C is obtained.
Example 63 Under the conditions given in Example 60, 3-methyl-5,6,7,
8-tetrahydrocarbazole-1-carboxylic acid methyl ester is hydrolyzed, and, after recrystallization from isopropyl alcohol, a 75% yield of 3-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid melting at 225C is obtained.
Example 64 (1) Under the conditions given in Example 59, 2-bromo-cyclohexanone is reacted with N-methyl-anthranilic acid methyl ester, and, after recrystallization from methanol, a 15% yield of 9-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester melting at 56C is obtained.
(2) Under the conditions given in Example 45,5,6,7,8-tetrahydrocarbazole-l-carboxylic acid methyl ester is methylated, and a yield of 65% of 9-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester is obtained.
Example 65 Under the conditions given in Example 60, 9-methyl-5,6,7,8-tetrahydrocarbazole-l-carboxylic acid methyl ester is hydrolyzed, and, after recrystallization from ethanol, a 75% yield of 9-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid melting at 180C
is obtained.
Example 66 The composition for a salve:
0.05% of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester 2.50% of Allercur hexachlorophenate, micronized, particle size about 8 ~ (Allercur is a registered Trade Mark for l-para-chlorobenzyl-2-pyrrolidyl-methylbenzimidazole) 6.00% of ~ostapdat KW 340 (a registered trade mark for tertiary ester of 0-phosphoric acid and wax alcohol tetraglycol ether) lOS36~
0.10% of sorbic acid 10.00% of neutral oil (migloyol 812 - registered trade mark) 3.50% of stearyl alcohol 1.50~ of wool fat, anhydrous DAB 6 76.35~ of desalted water.
Example 67 The composition for a salve:
0.05 g of 8-chloro-7-methyl-carbazole-1-carboxylic acid ethyl ester 5.00 g of white wax DAB 6 5.00 g of wool fat DAB 6 20.00 g of white petroleum jelly DAB 6 25.00 g of Amphocerin K "Dehydag"
14.95 g of paraffin oil, liquid DAB 6 30.00 g of water, desalted 0.02 g of Crematest perfume oil No. 6580 "Dragee"
Example 68 1.000 g of micronized 7-chloro-8-methyl-carabazole-1-carboxylic acid ethyl ester (average particle size: smaller than 7 ~) and 39.000 g of ground lactose are mixed. Quantities of 40 mg of the mixture are charged into plug capsules. The inhalant preparation can be administered, after opening the capsule, by inhaling, preferably by sniffing, or a Spinhaler (trade mark) may be used for administering the inhalant preparation.
Example 64 (1) Under the conditions given in Example 59, 2-bromo-cyclohexanone is reacted with N-methyl-anthranilic acid methyl ester, and, after recrystallization from methanol, a 15% yield of 9-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester melting at 56C is obtained.
(2) Under the conditions given in Example 45,5,6,7,8-tetrahydrocarbazole-l-carboxylic acid methyl ester is methylated, and a yield of 65% of 9-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester is obtained.
Example 65 Under the conditions given in Example 60, 9-methyl-5,6,7,8-tetrahydrocarbazole-l-carboxylic acid methyl ester is hydrolyzed, and, after recrystallization from ethanol, a 75% yield of 9-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid melting at 180C
is obtained.
Example 66 The composition for a salve:
0.05% of 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester 2.50% of Allercur hexachlorophenate, micronized, particle size about 8 ~ (Allercur is a registered Trade Mark for l-para-chlorobenzyl-2-pyrrolidyl-methylbenzimidazole) 6.00% of ~ostapdat KW 340 (a registered trade mark for tertiary ester of 0-phosphoric acid and wax alcohol tetraglycol ether) lOS36~
0.10% of sorbic acid 10.00% of neutral oil (migloyol 812 - registered trade mark) 3.50% of stearyl alcohol 1.50~ of wool fat, anhydrous DAB 6 76.35~ of desalted water.
Example 67 The composition for a salve:
0.05 g of 8-chloro-7-methyl-carbazole-1-carboxylic acid ethyl ester 5.00 g of white wax DAB 6 5.00 g of wool fat DAB 6 20.00 g of white petroleum jelly DAB 6 25.00 g of Amphocerin K "Dehydag"
14.95 g of paraffin oil, liquid DAB 6 30.00 g of water, desalted 0.02 g of Crematest perfume oil No. 6580 "Dragee"
Example 68 1.000 g of micronized 7-chloro-8-methyl-carabazole-1-carboxylic acid ethyl ester (average particle size: smaller than 7 ~) and 39.000 g of ground lactose are mixed. Quantities of 40 mg of the mixture are charged into plug capsules. The inhalant preparation can be administered, after opening the capsule, by inhaling, preferably by sniffing, or a Spinhaler (trade mark) may be used for administering the inhalant preparation.
Claims (124)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a carbazole derivative of the general formula I
(I) in which R1 represents a hydroxymethyl group; a alkanoyloxymethyl having 1 to 8 carbon atoms in the alkanoyl group, tetrazolyl, cyano, oximinocarbonyl, aminocarbonyl or carboxyl group which may be free or in the form of a salt with a physiologically tolerable base, an ester with a physiologically unobjectionable alcohol or an amide with a physiologically unobjectionable amine; R2 to R4 each represents a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group or a lower alkoxy group, R2 being in the 3-position or the 4-position; R5 and R6 have the same meanings as R2 to R4 or together represent the residue of a five- or six-membered isocyclic ring; and R7 represents a hydrocarbon residue containing 3 to 8 carbon atoms provided that when at least one of the residues R2 to R6 is a substituent different from hydrogen, R7 may also be a hydrogen atom, a methyl group or an ethyl group which process comprises dehydrogenating a tetrahydrocarbazole derivative of the general formula II or III
(II) (III) in which R1 to R7 have the above meanings and when required in the product obtained, the secondary amino group in the 9-position is lower alkylated, a free hydroxyl group is esterified or etherified, an ester group is hydrolyzed and a free carboxyl group or an chloride or an hydride derivative thereof is converted into a salt,ester, amide, oximinocarbonyl group, cyano group, hydroxymethyl group or tetrazolyl group.
(I) in which R1 represents a hydroxymethyl group; a alkanoyloxymethyl having 1 to 8 carbon atoms in the alkanoyl group, tetrazolyl, cyano, oximinocarbonyl, aminocarbonyl or carboxyl group which may be free or in the form of a salt with a physiologically tolerable base, an ester with a physiologically unobjectionable alcohol or an amide with a physiologically unobjectionable amine; R2 to R4 each represents a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group or a lower alkoxy group, R2 being in the 3-position or the 4-position; R5 and R6 have the same meanings as R2 to R4 or together represent the residue of a five- or six-membered isocyclic ring; and R7 represents a hydrocarbon residue containing 3 to 8 carbon atoms provided that when at least one of the residues R2 to R6 is a substituent different from hydrogen, R7 may also be a hydrogen atom, a methyl group or an ethyl group which process comprises dehydrogenating a tetrahydrocarbazole derivative of the general formula II or III
(II) (III) in which R1 to R7 have the above meanings and when required in the product obtained, the secondary amino group in the 9-position is lower alkylated, a free hydroxyl group is esterified or etherified, an ester group is hydrolyzed and a free carboxyl group or an chloride or an hydride derivative thereof is converted into a salt,ester, amide, oximinocarbonyl group, cyano group, hydroxymethyl group or tetrazolyl group.
2. A process as claimed in claim 1 wherein the dehydrogenation is effected by means of a catalyst of the platinum group.
3. A process as claimed in claim 1 wherein the dehydroqenation is effected by means of a quinone.
4. A process as claimed in claim 1 wherein the dehydrogenation is effected by means of lead dioxide, manganese dioxide, or sulphur.
5. A carbazole derivative of the general formula I
(I) in which R1 represents a hydroxymethyl group, an alkanoyloxy-methyl having 1 to 8 carbon atoms in the alkanoyl group or alkoxymethyl group, a tetrazolyl group, a cyano group, an oximino carbonyl group, an amino-carbonyl group, or a carboxyl group which may be free or in the form of a salt with a physiologically tolerable base, an ester with a physiologically unobjectionable alcohol or an amide with a physiologically unobjectionable amine; R2 to R4 may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group or a lower alkoxy qroup, R2 being either in the 3-position or 4-position; R5 and R6 have the same meanings as R2 to R4 or together represent the residue of a five- or six-membered isocyclic ring; and R7 represents a hydrocarbon residue containing 3 to 8 carbon atoms, provided that, when at least one of the residues R2 to R6 is a substituent other than hydrogen, R7 may also be a hydrogen atom, a methyl group or an ethyl group whenever pre-pared or produced by the process as claimed in claim 1, 2 or 3 or an obvious chemical equivalent thereof.
(I) in which R1 represents a hydroxymethyl group, an alkanoyloxy-methyl having 1 to 8 carbon atoms in the alkanoyl group or alkoxymethyl group, a tetrazolyl group, a cyano group, an oximino carbonyl group, an amino-carbonyl group, or a carboxyl group which may be free or in the form of a salt with a physiologically tolerable base, an ester with a physiologically unobjectionable alcohol or an amide with a physiologically unobjectionable amine; R2 to R4 may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group or a lower alkoxy qroup, R2 being either in the 3-position or 4-position; R5 and R6 have the same meanings as R2 to R4 or together represent the residue of a five- or six-membered isocyclic ring; and R7 represents a hydrocarbon residue containing 3 to 8 carbon atoms, provided that, when at least one of the residues R2 to R6 is a substituent other than hydrogen, R7 may also be a hydrogen atom, a methyl group or an ethyl group whenever pre-pared or produced by the process as claimed in claim 1, 2 or 3 or an obvious chemical equivalent thereof.
6. A process as claimed in claim 1 in which in the reactants R1 is ethoxy carbonyl, methoxy carbonyl, isomethoxy carbonyl, hydroxy methyl, acetoxy methyl, tetrazolyl, oximino carbonyl, cyano amino carbonyl, carboxyl, amino carbonyl, morphorino carbonyl, 2-dimethylamino ethyl oxycarbonyl; R2 is hydrogen, methyl, chlorine, or methoxy; R3 is hydrogen or chlorine, R4 is hydrogen, methyl, fluorine or methoxy; R5 is hydrogen, fluorine, trifluoromethyl, chlorine, or methyl; R6 is hydrogen, methoxy, methyl, chlorine or ethyl or R5 and R6 together form a benzene ring and R7 is hydrogen methyl or benzyl.
7. A carbazole derivative of formula I given in claim 1 or a pharmaceutically acceptable salt, thereof whenever prepared or produced by the process as claimed in claim 6 or an ohvious chemical equivalent thereof.
8. A process as claimed in claim 1 which comprises refluxing 6-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in xylene in the presence of a palladium-carbon catalyst.
9, 1-Ethoxycarbonyl-6-methoxy-carbazole whenever prepared or produced by the process as claimed in claim 8 or an obvious chemical equivalent thereof.
10. A process as claimed in claim 1 which comprises refluxing 8-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in chlorobenzene in the presence of a pallad-ium-carbon catalyst.
11. A process as claimed in claim 1 which comprises refluxing 5-chloro-8-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in xylene in the presence of a palladium-carbon catalyst.
12. 1-Ethoxycarbonyl-8-methoxy-carbazole whenever prepared or produced by the process as claimed in claim 10 or 11 or an obvious chemical equivalent thereof.
13. A process as claimed in claim 1 which comprises refluxing 8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in cumene, in the presence of a palladium-carbon catalyst.
14. A process as claimed in claim 1 which comprises refluxing 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in xylene in the presence of a palladium-carbon catalyst.
15. 1-Ethoxycarbonyl-8-methyl-carbazole whenever prepared or produced by the process as claimed in claim 13 or 14 or an obvious chemical equivalent thereof.
16. A process as claimed in claim 1 which comprises refluxing 7-fluoro-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in chlorobenzene in the presence of a palladium-carbon catalyst.
17. 1-Ethoxycarbonyl-7-fluoro-carbazole whenever prepared or produced by the process as claimed in claim 16 or an obvious chemical equivalent thereof.
18. A process as claimed in claim 1 which comprises refluxing 6-fluoro-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in xylene in the presence of a palladium-carbon catalyst and ortho-dichlorobenzene.
19. 1-Ethoxycarbonyl-6-fluoro-carbazole whenever prepared or produced by the process as claimed in claim 18 or an obvious chemical equivalent thereof.
20. A process as claimed in claim 1 which comprises refluxing 7-trifluoro-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in xylene in the presence of a palladium-carbon catalyst and ortho-dichlorobenzene.
21. 1-Ethoxycarbonyl-7-trifluoromethyl-carbazole whenever prepared or produced by the process as claimed in claim 20 or an obvious chemical equivalent thereof.
22. A process as claimed in claim 1 which comprises refluxing 5-chloro 8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in chlorobenzene in the presence of a palladium-carbon catalyst.
23. 1-Ethoxycarbonyl-5-chloro-8-methyl-carbazole whenever prepared or produced by the process as claimed in claim 22 or an obvious chemical equivalent thereof.
24. A process as claimed in claim 1 which comprises refluxing 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in chlorobenzene in the presence of a palladium-carbon catalyst.
25. A process as claimed in claim 1 which comprises refluxing 7-chloro-8-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in xylene with chloranil.
26, 1-Ethoxycarbonyl-7-chloro-8-methyl-carbazole whenever prepared or produced by the process as claimed in claim 24 or 25 or an obvious chemical equivalent thereof.
27. A process as claimed in claim 1 which comprises refluxing 5-chloro-8-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in chlorobenzene in the presence of a palladium-carbon catalyst.
28. 1-Ethoxycarbonyl-5-chloro-8-methoxy-carbazole whenever prepared or produced by the process as claimed in claim 27 or an obvious chemical equivalent thereof,
29. A process as claimed in claim 1 which comprises refluxing 7-chloro-3,8-dimethyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in chlorobenzene in the presence of a palladium-carbon catalyst.
30. 1-Ethoxycarbonyl-7-chloro-3,8-dimethyl-carbazole whenever prepared or produced by the process as claimed in claim 29 or an obvious chemical equivalent thereof.
31. A process as claimed in claim 1 which comprises refluxing 7,8-dichloro-1,2,3,4-tetrahydro-carbazole-1-carboxylic acid ethyl ester in xylene in the presence of a palladium-carbon catalyst and ortho-dichlorobenzene.
32. 1-Ethoxycarbonyl-7,8-dichloro-carbazole whenever prepared or produced by the process as claimed in claim 31 or an obvious chemical equivalent thereof.
33. A process as claimed in claim 1 which comprises refluxing 7,8-dichloro-1,2,3,4-tetrahydrocarbazole-1-carhoxylic acid ethyl ester in xylene in the presence of a palladium-carbon catalyst and ortho-dichlorobenzene.
34. 1-Isoamyloxycarbonyl-7,8-dichloro-carbazole whenever prepared or produced by the process as claimed in claim 33 or an obvious chemical equivalent thereof.
35. A process as claimed in claim 1 which comprises refluxing 7,8-dimethyl-1,2,3,4-tetrahydro-carbazole-1-carboxylic acid ethyl ester in xylene in the presence of a palladium-carbon catalyst.
36. A process as claimed in claim 1 which comprises refluxing 7,8-dimethyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in xylene with chloranil.
37. 1-Ethoxycarbonyl-7,8-dimethyl-carbazole whenever prepared or produced by the process as claimed in claim 33 or 36 or an obvious chemical equivalent thereof.
38. A process as claimed in claim 8 which comprises reflux of the 6-methoxy-carbazole-1-carboxylic acid ethyl ester, so obtained in methanolic aqueous potassium hydroxide.
39. 6-Methoxy-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 38 or an obvious chemical equivalent thereof.
40. A process as claimed in claim 10 which comprises reflux of the 8-methoxy-carbazole-1 carboxylic acid ethyl ester so obtained in methanolic aqueous potassium hydroxide,
41. 8-Methoxy-carbazole-l-carboxylic acid whenever prepared or produced by the process as claimed in claim 40 or an obvious chemical equivalent thereof,
42. A process as claimed in claim 13 which comprises refluxing 8-methyl-carbazole-1-Carboxylic acid ethyl ester, so obtaincd in methanolic aqueous potassium hydroxide.
43. 8-Methyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 42 or an obvious chemical equivalent thereof.
44. A process as claimed in claim 16 which comprises refluxing 7-fluoro-carbazole-1-carboxylic acid ethyl ester so obtained in methanolic aqueous potassium hydroxide.
45. 7-Fluoro-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 44 or an obvious chemical equivalent thereof.
46, A process as claimed in claim 24 in which the 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester is refluxed with a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
47. 7-Chloro-8-methyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 46 or an obvious chemical equivalent thereof.
48. A process as claimed in claim 22 in which the 5-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester is refluxed with a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
49. 5-Chloro-8-methyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 48 or an ohvious chemical equivalent thereof.
50. A process as claimed in claim 29 in which the 7-chloro-3,8-dimethyl carbazole-1-carboxylic acid ethyl ester is refluxed with a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
51. 7-chloro-3,8-dimethyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 50 or an obvious chemical equivalent thereof.
52. A process as claimed in claim 27 in which the 5-chloro-8-methoxy-carbazole-1-carboxylic acid ethyl ester is refluxed with a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
53. 5-chloro-8-methoxy-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 52 or an obvious chemical equivalent thereof.
54. A process as claimed in claim 31 in which the 7,8-dichloro-carbazole-1-carboxylic acid ethyl ester is refluxed with a mixture of aqueous potassium hydroxide and dimethyl sul-phoxide.
55. 7,8-dichloro-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 54 or an obvious chemical equivalent thereof.
56, A process as claimed in claim 35 in which the 7,8-dimethyl-carbazole-1-carboxylic acid ethyl ester is refluxed with a mixture of agueous potassium hydroxide and dimethyl sul-phoxide.
57. 7,8-dimethyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 56 or an obvious chemical equivalent thereof.
58, A process as claimed in claim 18 in which the 6s fluoro-carbazole-l-carboxylic acid ethyl ester is refluxed with a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
59. 6-fluoro-carbazole-1-carboxylic acid whenever pre-pared or produced by the process as claimed in claim 58 or an obvious chemical equivalent thereof.
60. A process as claimed in claim 20 in which the 7-trifluoromethyl-carbazole-1-carboxylic acid ethyl ester is refluxed with a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
61. 7-trifluoromethyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 60 or an obvious chemical equivalent thereof.
62. A process as claimed in claim 24 in which the 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester so obtained in tetrahydrofurane is stirred with a suspension of lithium-aluminium hydride in absolute tetrahydrofurane and the mixture tRen refluxed.
63, 7-chloro-1-hydroxymethyl-8-methyl-carbazole when-ever prepared or produced by the process as claimed in claim 62 or an obvious chemical equivalent thereof.
64. A process as claimed in claim 46 in which the 7-chloro-8-methyl-carbazole-1-carboxylic acid so obtained is treated with phosphorous pentachloride in diethyl ether with cooling and the reaction mixture treated with gaseous ammonia.
65. 7-chloro-8-methyl-carbazole-1-carboxylic acid amide whenever prepared or produced by the process as claimed in claim 64 or an obvious chemical equivalent thereof.
66, A process as claimed in claim 56 in which the 7,8-dimethyl-carbazole-1-carboxylic acid so obtained is treated with phosphorous pentachloride in diethyl ether with cooling and the reaction mixture treated with excess morpholine.
67, 7,8-dimethyl-carbazole-1-carboxylic acid morpho-lide whenever prepared or produced by the process as claimed in claim 66 or an obvious chemical equivalent thereof.
68. A process as claimed in claim 46 in which the 7-chloro-8-methyl-carbazole-1-carboxylic acid so obtained is added with cooling to a solution of hydroxyl amine in ethanol and sodium ethylate containing sodium.
69. A process as claimed in claim 96 in which the 7-chloro-8-methyl-carbazole-1-carboxylic acid so obtained is treated with thionyl chloride and dimethylformamide and then the mixture heated in chloroform and the 7-chloro-8-methyl-carbazole-1-carboxylic acid chloride so obtained treated with hydroxyl amine.
70. 7-chloro-8-methyl-carbazole-1-carbohydroxamic acid whenever prepared or produced by theprocess as claimed in claim 68 or 69 or an obvious chemical equivalent thereof.
71. A process as claimed in claim 1 which comprises refluxing 7-chloro-6-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in chlorobenzene in the presence of a palladium-carbon catalyst.
72. 7-chloro-6-methyl-carbazole-1-carboxylic acid ethyl ester whenever prepared or produced by the process as claimed in claim 71 or an obvious chemical equivalent thereof.
73. A process as claimed in claim 71 in which the 7-chloro-6-methyl-carbazole-1-carboxylic acid ethyl ester so obtained is refluxed with a mixture of aqueous potassium hydrox-ide and dimethyl sulphoxide,
74, 7-chloro-6-methyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 73 or an obvious chemical equivalent thereof.
75. A process as claimed in claim 1 which comprises refluxing 5-chloro-6-methyl-1,2,3,4-tetrahydrocarbazole-1-car-boxylic acid ethyl ester in chlorobeznene in the presence of a palladium-carbon catalyst.
76. 5-chloro-6-methyl-carbazole-1-carboxylic acid ethyl ester whenever prepared or produced by the process as claimed in claim 75 or an obvious chemical equivalent thereof.
77. A process as claimed in claim 71 in which the 5-chloro-6-methyl-carbazole-1-carboxylic acid ethyl ester so obtained in refluxed with a mixture of aqueous potassium hydrox-ide and dimethyl sulphoxide.
78. 5-chloro-6-methyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 77 or an obvious chemical equivalent thereof.
79. A process as claimed in claim 1 which comprises refluxing 8-chloro-7-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in chlorobenzene in the presence of a palladium-carbon catalyst.
80. 8-chloro-7-methyl-carbazole-1-carboxylic acid ethyl ester whenever prepared or produced by the process as claimed in claim 79 or an obvious chemical equivalent thereof.
81. A process as claimed in claim 71 in which the 8-chloro-7-methyl-carbazole-1-carboxylic acid ethyl ester so obtained is refluxed with a mixture of aqueous potassium hydrox-ide and dimethyl sulphoxide.
82. 8-chloro-7-methyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 81 or an obvious chemical equivalent thereof.
83. A process as claimed in claim 1 which comprises refluxing 7-chloro-8-ethyl-1,2,3,4-tetrahydrocarbazole-1-carbox-ylic acid ethyl ester in chlorobenzene in the presence of a palladium-carbon catalyst.
84. 7-chloro-8-ethyl-carbazole-1-carboxylic acid ethyl ester whenever prepared or produced by the process as claimed in claim 83 or an obvious chemical equivalent thereof.
85. A process as claimed in claim 71 in which the 7-chloro-8-ethyl-carbazole-1-carboxylic acid ethyl ester so obtained is refluxed with a mixture of aqueous potassium hydrox-ide and dimethyl sulphoxide.
86. 7-chloro-8-ethyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 85 or an obvious chemical equivalent thereof.
87. A process as claimed in claim 1 which comprises refluxing benzo[a]-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid ethyl ester in xylene in the presence of a palladium-carbon catalyst.
88. Benzo[a]-carbazole carboxylic acid ethyl ester whenever prepared or produced by the process as claimed in claim 87 or an obvious chemical equivalent thereof.
89. A process as claimed in claim 71 in which the benzo[a]-carbazole-1-carboxylic acid ethyl ester so obtained is refluxed with a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
90. Benzo[a]-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 88 or an obvious chemical equivalent thereof.
91. A process as claimed in claim 54 in which the 7,8-dichloro-carbazole-1-carboxylic acid so obtained is treated with triethyl-amine in absolute dimethyl glycol with cooling and then isobutyl chloroformate and after removal of the precip-itate the filtrate treated with dimethylamine and ethanol in dimethyl glycol with cooling.
92. 7,8-Dichloro-carbazole-1-carboxylic acid (2'-dimethylaminoethyl) ester whenever prepared or produced by the process as claimed in claim 91 or an obvious chemical equivalent thereof.
93. A process as claimed in claim 46 in which the 7-chloro-8-methyl-carbazole-1-carboxylic acid is treated with phosphorous pentachloride in diethyl ether with cooling and the reaction mixture treated with 2-dimethylamino ethanol.
94. 7-Chloro-8-methyl-carbazole-1-carboxylic acid (2'-dimethylaminoethyl) ester whenever prepared or produced by the process as claimed in claim 93 or an obvious chemical equivalent thereof.
95. A process as claimed in claim 24, in which the 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester so obtained in dimethyl formamide is treated with a sodium hydride suspension and to the reaction mixture methyl iodide is added.
96. 7-chloro-8,9-dimethyl-carbazole-1-carboxylic acid ethyl ester whenever prepared or produced by the process as claimed in claim 95 or an obvious chemical equivalent thereof.
97. A process as claimed in claim 95 in which the 7-chloro-8,9-dimethyl carbazole-1-carboxylic acid ethyl ester so obtained is refluxed with a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
98. 7-chloro-8,9-dimethyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 97 or an obvious chemical equivalent thereof.
99. A process as claimed in claim 24 in which the 7-chloro-8-methyl-carbazole-1-carboxylic acid ethyl ester so obtained in dimethyl formamide is treated with a sodium hydride suspension and to the reaction mixture benzyl iodide is added.
100. 7-chloro-8-methyl-9-benzyl-carbazole-1-carboxylic acid ethyl ester whenever prepared or produced by the process as claimed in claim 99 or an obvious chemical equivalent thereof.
101. A process as claimed in claim 24 in which the 7-chloro-8-methyl-9-benzyl-carbazole-1-carboxylic acid ethyl ester so obtained is refluxed with a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
102. 7-chloro-8-methyl-9-benzyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 101 or an obvious chemical equivalent thereof.
103. A process as claimed in claim 64 in which the 7-chloro-8-methyl-carbazole-1-carboxylic acid amide so obtained is treated portion wise with phosphorus oxychloride and the mixture obtained heated.
104. 7-Chloro-8-methyl-carbazole-1-carbonitrile whenever prepared or produced by the process as claimed in claim 103 or an obvious chemical equivalent thereof.
105. A process as claimed in claim 103 in which the 7-chloro-8-methyl-carbazole-1-carbonitrile so obtained is admixed with hexamethyl-phosphoric acid triamide and sodium azide and subsequently formic acid is added to the reaction mixture.
106. 7-Chloro-8-methyl-1-(5-tetrazolyl)-carbazole whenever prepared or produced by the process as claimed in claim 105 or an obvious chemical equivalent thereof.
107. A process as claimed in claim 1 which comprises refluxing 4-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester in chlorobenzene in the presence of a palladium-carbon catalyst.
108. 4-Chloro-carbazole-1-carboxylic acid methyl ester whenever prepared or produced by the process as claimed in claim 107 or an obvious chemical equivalent thereof.
109. A process as claimed in claim 107 in which the 4-chloro-carbazole-1-carboxylic acid methyl ester so obtained is a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
110. 4-Chloro-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 109 or an obvious chemical equivalent thereof.
111. A process as claimed in claim 1 which comprises refluxing 3-chloro-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester in chlorobenzene in the presence of a palladium-carbon catalyst.
112. 3-Chloro-carbazole-1-carboxylic acid methyl ester whenever prepared or produced by the process as claimed in claim 111 or an obvious chemical equivalent thereof.
113. A process as claimed in claim 111 in which the 3-chloro-carbazole-1-carboxylic acid methyl ester so obtained is refluxed with a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
114. 3-Chloro-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 113 or an obvious chemical equivalent thereof.
115. A process as claimed in claim 1 which comprises refluxing 4-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester in xylene in the presence of a palladium-carbon catalyst.
116. 4-Methyl-carbazole-1-carboxylic acid methyl ester whenever prepared or produced by the process as claimed in claim 115 or an obvious chemical equivalent.
117. A process as claimed in claim 115 in which the 4-methyl-carbazole-1-carboxylic acid methyl ester so obtained is refluxed with a mixture of aqueous potassium hydroxide and dimethyl sulphoxide.
118. 4-Methyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 117 or an obvious chemical equivalent.
119. A process as claimed in claim 1 which comprises refluxing 3-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid methyl ester in chlorobenzene in the presence of a palladium-carbon catalyst.
120. 1-Methoxycarbonyl-3-methyl-carbazole whenever prepared or produced by the process as claimed in claim 119 or an obvious chemical equivalent thereof.
121. A process as claimed in claim 119 in which the 3-methyl-carbazole-1-carboxylic acid methyl ester so obtained is refluxed with a mixture of aqueous potassium hydrox-ide and dimethyl sulphoxide.
122. 3-methyl-carbazole-1-carboxylic acid whenever prepared or produced by the process as claimed in claim 121 or an obvious chemical equivalent thereof.
123. A process as claimed in claim 62 in which the 7-chloro-1-hydroxymethyl-8-methyl-carbazole so obtained is treated with acetic anhydride in the presence of pyridine.
124. 7-chloro-1-acetoxymethyl-8-methyl-carbazole whenever prepared or produced by the process as claimed in claim 123 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2337154A DE2337154C2 (en) | 1973-07-18 | 1973-07-18 | New carbazole derivatives |
| DE2431292A DE2431292A1 (en) | 1974-06-27 | 1974-06-27 | Anti-inflammatory carbazole derivs - specif. e.g. 1-ethoxycarbonyl-6-methoxy-carbazole and 8-methyl-carbazole-1-carboxylic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1053682A true CA1053682A (en) | 1979-05-01 |
Family
ID=25765532
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA205,063A Expired CA1053682A (en) | 1973-07-18 | 1974-07-18 | Carbazole derivatives and process for their manufacture |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS5069072A (en) |
| AT (1) | AT342583B (en) |
| BG (1) | BG25793A3 (en) |
| CA (1) | CA1053682A (en) |
| CH (1) | CH619213A5 (en) |
| CS (1) | CS190431B2 (en) |
| DD (1) | DD114075A5 (en) |
| DK (1) | DK388074A (en) |
| ES (1) | ES428379A1 (en) |
| FI (1) | FI218874A (en) |
| FR (1) | FR2237628B1 (en) |
| GB (1) | GB1482771A (en) |
| HU (1) | HU173115B (en) |
| IE (1) | IE39624B1 (en) |
| IL (1) | IL45298A (en) |
| NL (1) | NL7409715A (en) |
| NO (1) | NO742601L (en) |
| RO (1) | RO72713A (en) |
| SE (1) | SE396602B (en) |
| SU (1) | SU511855A3 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8946444B2 (en) | 2004-11-23 | 2015-02-03 | Ptc Therapeutics, Inc. | Tetrahydrocarbazoles as active agents for inhibiting VEGF production by translational control |
| US10329254B2 (en) | 2011-10-20 | 2019-06-25 | Aop Orphan Pharmaceuticals Ag | Process for the preparation of 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and intermediates thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060074124A1 (en) * | 2003-09-12 | 2006-04-06 | Andrew Napper | Methods of treating a disorder |
| ES2530972T3 (en) * | 2003-09-12 | 2015-03-09 | Elixir Pharmaceuticals Inc | Methods of treatment of disorders |
| WO2018191418A1 (en) * | 2017-04-11 | 2018-10-18 | Saje Pharma, Llc | Carbazole compounds and methods of use thereof |
| JP2021134141A (en) * | 2020-02-21 | 2021-09-13 | エヌ・イーケムキャット株式会社 | Method for producing aromatic compound using heterogeneous noble metal catalyst |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7008628A (en) * | 1969-06-25 | 1970-12-29 |
-
1974
- 1974-07-15 BG BG027244A patent/BG25793A3/en unknown
- 1974-07-16 DD DD179943A patent/DD114075A5/xx unknown
- 1974-07-17 ES ES428379A patent/ES428379A1/en not_active Expired
- 1974-07-17 NO NO742601A patent/NO742601L/no unknown
- 1974-07-17 HU HU24SC483A patent/HU173115B/en unknown
- 1974-07-17 FI FI2188/74A patent/FI218874A/fi unknown
- 1974-07-17 CS CS745109A patent/CS190431B2/en unknown
- 1974-07-17 SE SE7409330A patent/SE396602B/en unknown
- 1974-07-18 DK DK388074A patent/DK388074A/da not_active Application Discontinuation
- 1974-07-18 GB GB31966/74A patent/GB1482771A/en not_active Expired
- 1974-07-18 FR FR7424991A patent/FR2237628B1/fr not_active Expired
- 1974-07-18 SU SU2048652A patent/SU511855A3/en active
- 1974-07-18 IL IL45298A patent/IL45298A/en unknown
- 1974-07-18 AT AT596074A patent/AT342583B/en active
- 1974-07-18 JP JP49082669A patent/JPS5069072A/ja active Pending
- 1974-07-18 CA CA205,063A patent/CA1053682A/en not_active Expired
- 1974-07-18 NL NL7409715A patent/NL7409715A/en not_active Application Discontinuation
- 1974-07-18 RO RO7479524A patent/RO72713A/en unknown
- 1974-07-18 CH CH990174A patent/CH619213A5/en not_active IP Right Cessation
- 1974-07-18 IE IE1519/74A patent/IE39624B1/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8946444B2 (en) | 2004-11-23 | 2015-02-03 | Ptc Therapeutics, Inc. | Tetrahydrocarbazoles as active agents for inhibiting VEGF production by translational control |
| US10329254B2 (en) | 2011-10-20 | 2019-06-25 | Aop Orphan Pharmaceuticals Ag | Process for the preparation of 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and intermediates thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2237628A1 (en) | 1975-02-14 |
| NL7409715A (en) | 1975-01-21 |
| GB1482771A (en) | 1977-08-17 |
| IE39624B1 (en) | 1978-11-22 |
| SU511855A3 (en) | 1976-04-25 |
| AT342583B (en) | 1978-04-10 |
| ATA596074A (en) | 1977-08-15 |
| HU173115B (en) | 1979-02-28 |
| DD114075A5 (en) | 1975-07-12 |
| CH619213A5 (en) | 1980-09-15 |
| SE7409330L (en) | 1975-01-20 |
| RO72713A (en) | 1982-09-09 |
| IL45298A0 (en) | 1974-10-22 |
| DK388074A (en) | 1975-03-03 |
| SE396602B (en) | 1977-09-26 |
| IL45298A (en) | 1980-01-31 |
| FR2237628B1 (en) | 1977-05-20 |
| JPS5069072A (en) | 1975-06-09 |
| FI218874A (en) | 1975-01-19 |
| CS190431B2 (en) | 1979-05-31 |
| BG25793A3 (en) | 1978-12-12 |
| NO742601L (en) | 1975-02-17 |
| ES428379A1 (en) | 1976-09-16 |
| IE39624L (en) | 1975-01-18 |
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