FI59244B - FREEZER FOR FARMING OF PHARMACEUTICAL EQUIPMENT - Google Patents

Description

RSF ^ l M (11, PUBLICATION PUBLICATION c O o 4 4 JSTf l J '' UTLÄGGNINGSSKRIFT -5 y ** ** C (45) Patent granted 10 07 1931 XrVgd Patent mcddelat V 'T ^ (51) Kv.lk.3 /lnt.CI.3 C 07 D 209/82 FINLAND — FINLAND (21) iwttihak # mu.-p «« «t» M6k «rfng 2311/73 (22) Hakamiipllvl - AraBkningtdtg 23.07.73 (23) Alkupllv! - GMtlgtimdag 23.07 * 73 (41) Tullut | ulklMlul - Bllvlt offtmlig 25 01 γ1 +

Patanttl. and register managed Niht ** k.ip «o« |. month | U.k ^ n pvm._

Patent- och ragistarstyralsan Ana & kan utligd och utUkrtfttn pubikend 31.03.81 (32) (33) (31) Pretty etuoikeus — Begird prlorltat 2k. 07.72 USA 27 ^ 142 (71) F. Hoffmann-La Roche & Co. Aktiengesellschaft, Grenzacherstrasse 12L-18L,

Basel, Switzerland-Schweiz (CH) (72) Leo Berger, Montclair, NJ, Alfred John Corraz, Wayne, NJ, USA (US) - (7 * +) Oy Kolster Ab (5M Process for the preparation of pharmaceutical carbazoles -Förfarande för framställning The present invention relates to a process for the preparation of pharmaceutically acceptable carbazoles of the general formula in which H is hydrogen or a halogen atom, R 1 is a halogen atom, a cyano, methyl, methoxy, methylthio, trifluoromethyl or nitro group, R 1 is a halogen atom, is of the formula Φ- / 2 59244 wherein A is hydroxy or a group 0 11

-C-B

wherein B is a hydroxy group, an alkoxy group having 1 to U carbon atoms or a dialkylaminoalkoxy group having 1 to U carbon atoms in the alkyl atom, Y and X are hydrogen atoms or alkyl groups having 1 to U carbon atoms, n is an integer from 1 to 3 and is an atom or an alkyl group containing 1-U carbon atoms, and to prepare salts of these compounds.

The process according to the invention is characterized in that the formula R is given

^

Β'ΠP ^ Jj "j“ R2 II

K

to react with a flavoring agent such as p-chloroaniline to form an ester of formula I wherein B is an alkoxy having 1 to U carbon atoms is reacted with an aromatizing agent such as p-chloroaniline. an acid of formula I wherein B is hydroxy, to prepare an acid of formula I wherein B is hydroxy, to hydrolyze the resulting ester of formula I wherein B is alkoxy containing 1 to U carbon atoms to prepare an alcohol of formula I wherein A is hydroxy, reducing the resulting ester of formula I wherein B is alkoxy having 1 to U carbon atoms to convert, if desired, the group B in the resulting acid of formula I wherein B is hydroxy or an acid base salt to di-alkylaminoalkoxy having 1-U carbon atoms in the alkyl moieties that to prepare an optically active isomer of a compound of formula I, the racemate of formula I obtained is divided into its optically active isomers and, if desired, the desired isomer is isolated, and if desired, the compound of formula I is converted into a salt.

Preferred compounds of formula I are those in which n is 1, A or B is hydroxy, R is hydrogen and / or R 1 is halogen.

Other preferred carbazoles of the present patent application are compounds of formula 6 C-A '1' i -3 352424, wherein A 'is club or hydroxymethyl,

R f is halogen, methyl or methoxy, R f is hydrogen or alkyl having 1 to 1 carbon atoms, and X and Y are as defined above, and if X and Y are different, their enantiomers and salts of the compounds of formula IJ with bases.

In preferred compounds of formula 1 ', R' is halogen and / or R 'is hydrogen.

Other preferred compounds of formula 1 'are 2-carboxymethylcarbazoles.

Preferred compounds of formula I are: 6-chloro-α-methylcarbazole-2-acetic acid racemate, (+) - 6-chloro-α-methylcarbazole-2-acetic acid, (-) - 6-chloro-ε-methylcarbazole- 2-acetic acid, 2- (6-chloro-2-carbazolyl) -propanol, (+) - 2- (6-chloro-2-carbazolyl) -propanol, (-) - 2- (6-chloro-2-carbazolyl) ) -propanol, 6-chlorocarbazole-2-acetic acid and 6-chloro-9-methylcarbazole-1-acetic acid.

Examples of compounds of formula I are: 6-chlorocarbazole-1-acetic acid, 6-chlorocarbazole-2-acetic acid ethyl ester, 6-methylcarbazole-3-acetic acid, 6-methoxycarbazole-t-acetic acid, 6-chloro-α-methylcarboxylates acetic acid, 6-nitrocarbazole-3-acetic acid, T-chlorocarbazole-1-acetic acid, 6-chlorocarbazole-2-acetic acid, 6-chlorocarbazole-3-acetic acid ethyl ester, 6-methylcarbazole-t-acetic acid, 6-methoxylic acid, 6-methoxylic acid -Chloro-ethylcarbazole-2-acetic acid, 6-nitrocarbazole-4-acetic acid, T-chlorocarbazole-1-acetic acid, 6-chlorocarbazole-3-acetic acid, β-chlorocarbazole-U-acetic acid ethyl ester, 6-methyl-carboxylate acetic acid, 6-methoxycarbazole-2-acetic acid, 6-chloro-ofc-methylcarbazole-3-acetic acid, 11 59244 6-nitrocarbazole-1-acetic acid, 7-chlorocarbazole-2-acetic acid, 6-chlorocarbazole-U-acetic acid, chlorocarbazole-1-acetic acid ethyl ester, 6-methylcarbazole-2-acetic acid, 6-methoxycarbazole-3-acetic acid , 6-chloro-β-methylcarbazole-U-acetic acid, 6-nitrocarbazole-2-acetic acid, 7'-chlorocarbazole-3-acetic acid, 7-methylcarbazol-1-acetic acid, 8-chlorocarbazole-2-acetic acid, | 6-fluorocarbazole-3-acetic acid, 6-bromocarbazole-k-acetic acid, 6,7-dichlorocarbazole-1-acetic acid, 5,6-dichlorocarbazole-2-acetic acid, 6-trifluoromethylcarbazole-3-acetic acid, 6-chloro-7-methyl-7-methyl acetic acid, 6-chloro-5-methylcarbazole-1-acetic acid, 9-methylcarbazole-2-acetic acid, 7.8-dichlorocarbazole-3-acetic acid, 7-methylcarbazole-2-acetic acid, 8-chlorocarbazole-3-acetic acid, 6-fluoroacid, 6-fluoroacetic acid acetic acid, β-bromocarbazole-1-acetic acid, 6.7-dichlorocarbazole-2-acetic acid, 5.6-dichlorocarbazole-3-acetic acid, 6-trifluoromethylcarbazole-4-acetic acid, 6-chloro-7-methyl-carbazole-1-ethyl-carbazole-1-acetic acid -5-methylcarbazole-2-acetic acid, 9-methylcarbazole-3-acetic acid, 7.8-dichlorocarbazole-U-acetic acid, 7-methylcarbazole-3-acetic acid, 8-chlorocarbazole-U-acetic acid, 6-fluorocarbazole-1-acetic acid -bromocarbazole-2-acetic acid, 2- (6-chloro-2-carbazolyl) -propanol methyl ether racemate, 6.7-dichlorocarb Bazole-3-acetic acid, 59244 5,6-Dichlorocarbazole-4-acetic acid, 6-trifluoromethylcarbazole-1-acetic acid, 6-chloro-7-methylcarbazole-2-acetic acid, 6-chloro-5-methylcarbazole-3-acetic acid, 9-acetic acid, 9-acetic acid, 9-acetic acid , 7,8-dichlorocarbazole-1-acetic acid, 7-methylcarbazole-U-acetic acid, 8-chlorocarbazole-1-acetic acid, 6-fluorocarbazole-2-acetic acid, 6-bromocarbazole-3-acetic acid, 6.7-dichloroacetic acid-H , 5,6-dichlorocarbazole-1-acetic acid, 6-trifluoromethylcarbazole-2-acetic acid> 6-chloro-7-methylcarbazole-3-acetic acid, 6-chloro-5-methylcarbazole-4-acetic acid, 9-methylcarbazole-1-acetic acid - dichlorocarbazole-2-acetic acid, 6-methylthiocarbazole-2-acetic acid, 6-cyanocarbazole-1-acetic acid, 6-ethylcarbazole-2-acetic acid, 6-iodocarbazole-1-acetic acid, 6-chloroacetic acid, 6-chloroacetic acid 2-chloroacetic acid -3-Acetic acid, 6-chlorocarbazole-4-acetic acid dimethylaminoethyl ester hydroxide chloride, 6-methylcarbazole-2-acetic acid ethyl ester, 6-methylthiocarbazole-3-acetic acid, 6-cyanocarbazole-1-acetic acid, 6-ethylcarbazole-3-acetic acid, 6-iodocarbazole-2-acetic acid, 6-chloroacetic acid, 6-chloroacetic acid dimethylcarbazole-1 * -acetic acid, 6-chlorocarbazole-1-acetic acid dimethylaminoethyl ester hydrochloride, 6-methylcarbazole-3-acetic acid ethyl ester, 6-methylthiocarbazole-4-acetic acid, 6-cyanoacetic acid, 6-cyano-carbazole-2-acetic acid -acetic acid, 6 59244 δ-chlorocarbazole-U-acetic acid dimethylaminoethyl ester, 6.9-dimethylcarbazole-1-acetic acid, carbazole-2-acetic acid dimethylaminoethyl ester hydrochloride, 6-methylcarbazole-1-ethyl-acetic acid, β-acetic acid, β-acetic acid , 6-ethylcarbazole-1-acetic acid, β-iodocarbazole-U-acetic acid, 6-chlorocarbazole-1-acetic acid dimethylaminoethyl ester, 6.9-dimethylcarbazole-2-acetic acid , 6-chlorocarbazole-3-acetic acid dimethylaminoethyl ester hydrochloride, 6-methylcarbazole-1-acetic acid ethyl ester, T-chlorocarbazole-2-acetic acid ethyl ester, 8-chlorocarbazole-2-acetic acid azole, 2-bromoacetyl ester, 6-bromoethyl ester, 6-bromo -chlorocarbazole-3-acetic acid ethyl ester, 6-chloro-9-benzylcarbazole-2-acetic acid ethyl ester, 6-chloro-9-methylcarbazole-2-acetic acid ethyl ester, 6-chloro-ei, 9-dimethylcarbazole-2-acetic acid-6-acetic acid-ethyl -acetic acid ethyl ester, 6-chlorocarbazole-2-propionic acid ethyl ester, 6-chloro-ethyl,? T, 8-dichlorocarbazole-2-acetic acid ethyl ester, 5.6-dichlorocarbazole-2-acetic acid ethyl ester, 6-methylthiocarbazole-2-acetic acid ethyl ester, 6-fluoro carbazole-2-acetic acid ethyl ester, α-methylcarbazole-2-acetic acid ethyl ester, eth-methylcarbazole-3-acetic acid ethyl ester, 6-cyanocarbazole-2-acetic acid ethyl ester, 6,7-chloro-carbazole-2-acetic acid-6-acetic acid

7 59244

Compounds of formula II may be converted to compounds of formula I by reaction with an aromatising agent, e.g. p-chloroaniline, o-chloroaniline, 2,3-dichloro-5,6-dicyanobenzoquinone, sulfur, palladium on carbon or lead oxide. This reaction is preferably carried out in a solvent, e.g. xylene, benzene, toluene, quinoline, dimethyl sulfoxide or dimethylformamide. The aromatization can be performed at a temperature between about room temperature and the reflux temperature of the reaction mixture, preferably at the reflux temperature of the reaction mixture. The compounds of the formula I can be isolated by means known per se, e.g. by filtration.

The acid of formula I having a carboxy can be converted into an ester by means known per se. Thus e.g. a) an acid of formula I may be reacted with an alkanol, e.g. methanol, ethanol or propanol in the presence of an acid catalyst, e.g. hydrohalic acid such as hydrochloric acid or hydrobromic acid at a temperature between room temperature and the reflux temperature of the reaction mixture, or b) an acid of formula I may be e.g. the sodium salt is reacted in a manner known per se with an optionally substituted alkyl halide, e.g. in an unreacted solvent, e.g. benzene, toluene or dimethylformamide at a temperature between about room temperature and the reflux temperature of the reaction mixture.

A compound of formula I in which B is alkoxy containing 1 to U carbon atoms can be hydrolysed in a manner known per se to a compound of formula I in which B is hydroxy, e.g. with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in the presence of a solvent, e.g. an alkanol such as methanol or ethanol. The hydrolysis can be performed at a temperature between about room temperature and the reflux temperature of the reaction mixture, preferably at the reflux temperature of the reaction mixture. The compound of the formula I can be isolated from the reaction mixture in a manner known per se.

The ester of the formula I can be converted in a manner known per se into an ester of the formula I in which A is e.g. hydroxy, e.g. by reacting with a reagent, e.g. lithium aluminum hydride, at a temperature between about room temperature and the reflux temperature of the reaction mixture. The alcohol formed can be isolated from the reaction mixture in a manner known per se.

An acid of formula I, e.g. a compound of formula I in which B is hydroxy, or a base salt of such an acid, can be converted in a manner known per se into a compound of formula I in which B is a dialkylaminoalkoxy, e.g. by reacting 8 59244 with a dialkylaminoalkyl halide. , e.g. with aminoethyl chloride, methylaminoethyl bromide or diethylaminomethyl chloride to give the desired product each time. The reaction temperature is not critical. However, it is convenient to carry out the reaction at a temperature between room temperature and the reflux temperature of the reaction mixture. It is convenient to carry out the reaction in a polar solvent, e.g. dimethylformamide or dimethyl sulfoxide. The ratio of reagents is not critical. However, it is an advantage that it is 1: 1.

Compounds of formula I wherein B is hydroxy form salts with pharmaceutically acceptable bases. Examples of such bases are alkali metal hydroxides, e.g. sodium hydroxide or potassium hydroxide, alkaline earth hydroxides, e.g. calcium hydroxide or barium hydroxide, sodium alkoxides, e.g. sodium ethanolate or potassium ethanolate, and organic bases, e.g. Aluminum salts of the compounds of formula I can also be prepared.

Compounds of formula I in which X and Y are different generally precipitate as racemic mixtures. The cleavage of such racemates into their optically active isomers can be carried out in a manner known per se. For example, some racemic mixtures can be precipitated as eutectics, which are separated from each other. However, chemical separation is recommended. The racemic mixture then forms diastereomers with an optically active cleavage agent, e.g. an optically active base such as d-oC-methylbenzylamine, which reacts with the carboxyl group. The diastereomers formed are selectively separated by crystallization and converted into the corresponding optical isomers. Thus, the present invention relates both to racemates of formula I and to their optically active isomers.

The starting compounds of the formula II can be prepared as described in German application 2 337 3 ^ 0.

The compounds of formula I and their pharmaceutically acceptable salts are effective in inflammation and rheumatism and relieve pain. Thus, they can be used as effective and analgesic drugs for inflammation and rheumatism, in particular because the compounds of the formula I cause very few ulcers. These pharmacologically valuable effects can be demonstrated by standard methods.

Thus, for example, 6-chloro-o (-methylcarbazole-2-acetic acid has an anti-inflammatory effect of LD ^ * + 00 mg orally in mice with an ED50 of 0.17 mg orally and a dose of 0.03 mg orally. also has an antipyretic effect in mice of 9,524,244 with an ED 2 of 15 mg orally As described above, the compounds of formula I, their enantiomers and salts have a similar qualitative effect to phenylbutazone and indomethacin, which are known for their therapeutic use and properties in these diseases.

Pharmacological experiments and their results The anti-inflammatory effect of the test compounds was determined using Albino rats (Hart strain) weighing 125-155 g as experimental animals. The test animals were administered the test compound daily (10 or 30 mg / kg) for 5 days. Three hours after the first treatment, the experimental animals were given 0.05 ml of a 0.5% bacterial suspension (heat-inactivated ttycobacterium butyricum, in olive oil; steam sterilized for 30 min) on the right hind leg. Foot volume was measured immediately thereafter, and again after 96 hours. The difference indicates the degree of swelling. The anti-inflammatory effect was calculated by subtracting the difference obtained with the control animal from the above measurement result (shown as #). The results of the experiments are shown in the following table.

Test compound Dose Anti-inflammatory _ (mg / kg) _effect (%) _ 6-nitrocarbazole-2-acetic acid 30 -22.6 6-methylthiocarbazole-2-acetic acid 30 -8.0 ras. 6-chloro-o (, - methylcarbazole-2-acetic acid ~ 70.3 6-chloro-9-methylcarbazole-1-propionic acid 30 -19.2 ras 6-chloro-ol, 9-dimethylcarbazole-2-acetic acid 30 - 35.6 6-Chloro-9-methylcarbazole-1-acetic acid 10 -30.3 6-Cyanocarbazole-2-acetic acid ethyl ester 30 "5.5 6-Bromocarbazole-2-acetic acid 30" 57.6 6-chloro-8-methoxy -eth-methylcarbazole-2-acetic acid ethyl ester 30 -12.0 6-chloro-8-methoxy-o (.-ethylcarbazole-2-acetic acid 30 "7.0 6-chlorocarbazole-2-acetic acid 30" 50, 8 6-Chlorocarbazole-2-propionic acid 30 -22.1 ras 6-chloro-ofc-methylcarbazole-3-acetic acid 30 -38.3

The following compounds are known from German Offenlegungsschrift No. 21 25 926: __ 6-methyls-1,2,3,3-tetrahydrocarbazole-2-acetic acid 30 +17,6 6-cyano-1,2, 3,5-Tetrahydrocarbazole-2-acetic acid ethyl ester 30 +18.0 6-chloro-8-methoxy-α-methyl-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester 30 +0.1 "6 -Chloro-8-methoxy-ethyl-1,2,3,10-tetrahydrocarbazole-2-acetic acid 30 -3.3 10 592 4 4

As can be seen from the experimental results shown in the table, the new compounds of formula I are much more active than the known compounds.

The compounds of the formula I, their enantiomers and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. These form mixtures with a pharmaceutical, organic or inorganic, unreacted carrier suitable for enteral or parenteral administration, e.g. water, gelatin, acacia, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and petrolatum. The pharmaceutical preparations can be solid, e.g. tablets, granules, suppositories or capsules, or semi-solids, e.g. creams or liquids, e.g. solutions, suspensions or emulsions. Optionally, they are sterilized and / or contain adjuvants, e.g. preservatives, stabilizers or emulsifiers, as well as salts for altering the osmotic pressure or buffering. In addition, they may contain other pharmaceutically valuable substances.

Example 1 for the preparation of 6-chloro-tert-methylcarbazole-2-acetic acid ethyl ester

"XjuOl - * cirViQ

- ^^ choooc2h5 COOO K

* ΓΗ i i ^ j H 3 H CH3 (d) (e)

Heat the air to dryness under dry nitrogen and stirring a mixture of 3.9 g of 6-chloro-n-methyl-1,2,3,1 + -tetrahydrocarbazole-2-acetic acid ethyl ester (diastereomeric mixture), 350 ml of xylene and 56 ml of 0 g of p-chloroaniline. After stirring for 6 hours at reflux temperature, the reaction mixture is allowed to cool overnight at room temperature. Decant the liquid through the filter, triturate the residue in 100 ml of benzene, decant the liquid through the filter and repeat the procedure three times. To the combined filtrates is added 300 ml of ether, the solution is extracted three times with 100 ml portions of 2N sodium hydroxide solution, washed neutral with water and dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration and evaporation of the solvent, 35.5 g of residue are obtained. Crystallization from 50 ml of methanol gives 1U, 8 g of 6-chloro-α-methylcarbazole-2-acetic acid ethyl ester, m.p.

106-107.5 ° C (1 + 3.2%).

59244

In a similar manner, the following compounds can be prepared: Using 6-chloro-1,2,3β-tetrahydrocarbazole-2-acetic acid ethyl ester in place of compound (d), 6-chlorocarbazole-2-acetic acid ethyl ester is obtained, m.p. 1Τ6-1Τ800 (methanol).

When 7-chloro-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester is used in place of compound (d), 7-chlorocarbazole-2-acetic acid ethyl ester is obtained, m.p. 200-202 ° C (methanol).

When 8-chloro-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester is used in place of compound (d), 8-chlorocarbazole-2-acetic acid ethyl ester is obtained, m.p. 110-113 ° C (methanol).

Using 6-chloro-9-ethyl-1,2,3,4-tetrahydro-carbazole-1-acetic acid ethyl ester instead of compound (d) gives 6-chloro-9-ethylcarbazole-1-acetic acid ethyl ester.

Using 6-chloro-1,2,3,1-tetrahydrocarbazole-2-propionic acid ethyl ester, 6-chlorocarbazole-2-propionic acid ethyl ester is obtained, m.p. 11 * 9 ~ 150.5 ° C (methanol).

Using 6-chloro-N, N-dimethyl-1,2,3,10-tetrahydrocarbazole-2-acetic acid ethyl ester instead of compound (d), 6-chloro-N, N-dimethylcarbazole-2-acetic acid ethyl ester is obtained. .

Using 6-chloro-1,2,3,1 + -tetrahydrocarbazole-1-acetic acid ethyl ester instead of compound (d), 6-chlorocarbazole-1-acetic acid ethyl ester is obtained, m.p. 152.5-15 ^ 0 (methanol).

Using 6-chloro-1,2,3,10-tetrahydrocarbazole-U-acetic acid ethyl ester instead of compound (d), 6-chlorocarbazole-4-acetic acid ethyl ester is obtained, m.p. 15 DEG-155 DEG C. (methanol).

Using 6-trifluoromethyl-1,2,3,4-tetrahydro-carbazole-2-acetic acid ethyl ester instead of compound (d), 6-trifluoromethylcarbazole-2-acetic acid ethyl ester is obtained, m.p. 130-131 ° C (carbon tetrachloride).

Using 7,8-dichloro-1,2,3, k-tetrahydrocarbazole-2-acetic acid ethyl ester instead of compound (d), 7,8-dichlorocarbazole-2-acetic acid ethyl ester is obtained, m.p. 15 DEG-155 DEG C. (methanol).

Using 5,6-dichloro-1,2,3,1 + -tetrahydrocarbazole-2-acetic acid ethyl ester instead of compound (d) gives 5,6-dichlorocarbazole-2-acetic acid ethyl ester, m.p. 139-140 ° C (methanol).

Using 6-methylthio-1,2,3,10-tetrahydrocarbazole-2-acetic acid ethyl ester instead of compound (d), 6-methylthiocarbazole-2-acetic acid ethyl ester is obtained.

1224244 Using 6-fluoro-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester instead of compound (d), 6-fluorocarbazole-2-acetic acid ethyl ester is obtained, m.p. 1T8-179 ° C (methanol).

When oC-methyl-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester is used in place of compound (d), o-methylcarbazole-2-acetic acid ethyl ester is obtained, m.p. 10 DEG-105 DEG C. (hexane).

Using o-methyl-1,2,3,4-tetrahydrocarbazole-3-acetic acid ethyl ester in place of compound (d) gives ε-methylcarbazole-3-acetic acid ethyl ester, m.p. 97.5-99 ° C (methanol).

Using o-cyano-1H-tetrahydrocarbazole-2-acetic acid ethyl ester in place of compound (d) gives 6-cyano-carbazole-2-acetic acid ethyl ester, m.p. 157-15 ° C (methanol).

Using 6,7-dichloro-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester instead of compound (d), 6,7-dichlorocarbazole-2-acetic acid ethyl ester is obtained, m.p. 186-187 ° C (methanol).

When 6-nitro-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester is used instead of compound (d), 6-nitrocarbazole-2-acetic acid ethyl ester is obtained, m.p. 161 + -165 ° C (methanol).

Example 2 Preparation of 6-chloro-N-methylcarbazole-2-acetic acid (racemate).

[I I Hydrolysis ^ | j | j J

ΰ CH? CH

H CH3 H 3 (e) (f)

A mixture of 11 g of 6-chloro-α-methylcarbazole-2-acetic acid ethyl ester, 100 ml of ethanol and 100 ml of 3N sodium hydroxide solution is heated under stirring under a nitrogen blanket. After refluxing at potassium for 1 hour, the reaction mixture is evaporated to dryness in vacuo, 300 ml of water and 200 g of ice are added to the mixture, and the mixture is made slightly acidic by adding concentrated hydrochloric acid. The acidic mixture is extracted three times with 200 ml portions of ether, the combined extracts are washed three times with 100 ml portions of water and dried over anhydrous magnesium sulfate. After filtration of the desiccant and evaporation of the solvent, 9.8 g (98.2%) of material are obtained. After recrystallization from chloroform, 6.2 g (62.0%) of 6-chloro-α-methylcarbazole-2-acetic acid are obtained, m.p. 197-198 ° C. 1.6 g of material were obtained from the mother liquors, m.p. 195 ~ 199 ° C.

In a similar manner, the following compounds can be prepared: Using 6-chlorocarbazole-2-acetic acid ethyl ester instead of compound (e), 6-chlorocarbazole-2-acetic acid is obtained, m.p. 255-257 ° C (ethyl acetate).

Using 7-chlorocarbazole-2-acetic acid ethyl ester in place of compound (e) gives 7-chlorocarbazole-2-acetic acid, m.p. 252-25 ° C (methanol).

Using 8-chlorocarbazole-2-acetic acid ethyl ester instead of compound (e) gives 8-chlorocarbazole-2-acetic acid, m.p. 210-211 ° C (chloroform).

Using 6-bromocarbazole-2-acetic acid ethyl ester instead of compound (e) gives 6-bromocarbazole-2-acetic acid, m.p. 21 + 9-25 ° C (methanol).

Using 6-methylcarbazole-2-acetic acid ethyl ester instead of compound (e) gives 6-methylcarbazole-2-acetic acid, m.p. 272-27 ° C (decomposes, ethyl acetate).

Using 6-methoxycarbazole-2-acetic acid ethyl ester instead of compound (e) gives 6-methoxycarbazole-2-acetic acid, m.p. 205-206 ° C (decomposes, ethyl acetate).

Using 6-chloro-9-methylcarbazole-1-acetic acid ethyl ester instead of compound (e) gives 6-chloro-9-methylcarbazole-1-acetic acid, m.p.

223-225 ° C (ethyl acetate).

Using 6-chloro-9-methylcarbazole-2-acetic acid ethyl ester instead of compound (e) gives 6-chloro-9-methylcarbazole-2-acetic acid, m.p.

235-236 ° C (ethyl acetate).

When racemic 6-chloro- [9-dimethylcarbazole-2-acetic acid ethyl ester is used instead of compound (e), racemic 6-chloro-9,9-dimethylcarbazole-2-acetic acid, m.p. 176-178 ° C (benzene).

Using 6-chlorocarbazole-3-acetic acid ethyl ester instead of compound (e) gives 6-chlorocarbazole-3-acetic acid, m.p. 2k6-2hj ° C (ethyl acetate).

Using 7-chlorocarbazole-3-acetic acid ethyl ester instead of compound (e) gives 7-chlorocarbazole-3-acetic acid, m.p. 236-237 ° C (ethyl acetate).

Using 6-chloro-9-ethylcarbazole-1-acetic acid ethyl ester instead of compound (e) gives 6-chloro-9-ethylcarbazole-1-acetic acid, m.p. 192-193 ° C (methanol).

Using 6-chlorocarbazole-2-propionic acid ethyl ester instead of compound (e), 6-chlorocarbazole-2-propionic acid is obtained, m.p. 230-231 ° C (methanol).

Using 6-chloro-oi, eE-bimethylcarbazole acetic acid esters instead of compound (e) gives 6-chloro-oi, o (dimethylcarbazole-2-acetic acid, mp 221-222.5 ° C (ethyl acetate-hexane)).

Using 6-chlorocarbazole-1-acetic acid ethyl ester instead of compound (e) gives 6-chlorocarbazole-1-acetic acid, m.p. 155-157 ° C (dec.). The piperidine salt of this substance m.p. 118-120 ° C (acetone-ether).

Using 6-chlorocarbazole-1-acetic acid ethyl ester instead of compound (e) gives 6-chlorocarbazole-4-acetic acid, m.p. 175-176 ° C (decomposes, benzene).

Using 6-methylthiocarbazole-2-acetic acid ethyl ester instead of compound (e) gives 6-methylthiocarbazole-2-acetic acid, m.p. 202-20 U ° C (ethyl acetate).

When oi-methylcarbazole-2-acetic acid ethyl ester is used instead of compound (e), α-methylcarbazole-2-acetic acid is obtained, m.p. 2U6-2 ^ 7 ° C (decomposes, chloroform).

Using o-methylcarbazole-3-acetic acid ethyl ester instead of compound (e) gives o? -Methylcarbazole-3-acetic acid, m.p. 213-216 ° C (decomposes, ethyl acetate).

Using 6-nitrocarbazole-2-acetic acid ethyl ester instead of compound (e) gives 6-nitrocarbazole-2-acetic acid, m.p. 262-26i + ° C (methanol).

Example 3 Preparation of (-) - 6-chloro-eC-methylcarbazole-2-acetic acid.

To a solution of 8.0 g of (+) -? - methylbenzylamine (Mf = + 39 °) in 10 ml of acetone is slowly added a solution of 18.0 g of racemic 6-chloro-.alpha.-methylcarbazole-2-acetic acid 360 in ml of acetone. The mixture is allowed to stand for three days at room temperature, filtered and the filter cake is washed with a small amount of cold acetone to give, after drying, 10.6 g of (-) - 6-chloro-α-methyl-carbazole-2-acetic acid (+) - methylbenzylamine salt, / * 7 ^ ° = + 9.9 ° · The combined filtrates and washings are evaporated to dryness and the remaining free acid is collected for later resolution. After recrystallization of the salt from 22 o 200 ml of acetone, 6.0 g of substance are obtained, £ c7n = +11.1. After two additional concentrations of the salt, 1.85 g of material are obtained, M-q ~ +13.2. Upon recrystallization of the salt from acetone, no increase in specific rotation is observed. Dissolve 1.85 g of salt in 50 ml of warm methanol. The insoluble matter is removed by filtration and the solution is poured into a mixture of ice and hydrochloric acid with stirring. After filtration and drying, 1.2 g of acid are obtained. After crystallization from chloroform, 1.0 g of (-) - 6-chloro-cis-methylcarbazole-2-acetic acid is obtained, m.p. 198-201 ° C, ~ 53.0 ° (c = 1, H methanol).

15 59244

Example U

Preparation of (+) - 6-chloro-o-methylcarbazole-2-acetic acid.

A solution of U, 3 g of (-) - e (methylbenzylamine in 20 ml of acetone) is added to a solution of 9.7 g of partially decomposed 6-chloro-oL-methylcarbazole-2-acetic acid obtained by filtration of the previously resolved racemate. .

The mixture is allowed to stand overnight at room temperature, filtered and the filter cake is washed with cold acetone to give 7.3 g of material after drying.

After double crystallization from acetone, 1.9 g of (+) - 6-chloro-α-methylcarbazol-22-sol-2-acetic acid (-) -? -Methylbenzylamine salt are obtained, = -13.6. When recrystallized from acetone, no increase in specific rotation was observed. The salt is dissolved in 50 ml of warm acetone, the solution is filtered and poured into 500 ml of dilute hydrochloric acid. After filtration and drying, 1. g of substance is obtained. Crystallization from chloroform gives 0.9 g of (+) - 6-chloro-o-methylcarbazole-2-acetic acid, m.p. 198-201 ° C, = + 53.2 ° (c = 1.33, methanol).

Example 5 Preparation of 6-chloro-α-methylcarbazole-2-acetic acid tert-butyl ester.

A solution of 2 g of 6-chloro-.beta.-methylcarbazole-2-acetic acid (prepared according to the method of Example 2) in 10 ml of tetrahydrofuran is added dropwise with stirring to a solution of 1.2 g of carbonyldiimidazole in 10 ml of tetrahydrofuran. The mixture is heated to reflux with stirring. The mixture is kept under reflux (carbon dioxide is formed) with stirring for one hour and then cooled to 25 ° C. A solution of 0.5 g of sodium tert-butoxide, 5 g of tert-butyl alcohol and 10 ml of tetrahydrofuran is added over 5 minutes. The mixture is then heated at reflux for 1 hour, cooled to room temperature and evaporated to dryness in vacuo. The residue is partitioned between ether and 2N potassium carbonate solution. The ether layer is isolated, washed with extraction with water and dried over anhydrous magnesium sulfate. After filtration of the desiccant and evaporation of the ether, 2.2 g of material are obtained. Crystallization from ethanol-water gives 1.7 g of 6-chloro-ethyl-methylcarbazole-2-acetic acid tert-butyl ester, m.p. 152-155 ° ^ 0.

Example 6

Preparation of racemic 6-chloro-C-methylcarbazole-2-acetic acid methyl ester.

A mixture of 1 g of 6-chloro-ethylcarbazole-4-acetic acid (prepared according to the method of Example 1), 100 ml of methanol and three drops of concentrated sulfuric acid are stirred and allowed to stand at room temperature. The solution is evaporated to dryness in vacuo and the residue is extracted with a mixture of ether and dilute sodium carbonate solution. The ether layer is isolated, washed with water and dried over anhydrous sodium sulfate. After filtration of the desiccant and evaporation of the ether, 1.2 g of ester are obtained. Recrystallization from hexane gives 0.7 g of racemic 6-chloro-c (.-Methylcarbazole-2-acetic acid methyl ester, mp 111-112 ° C).

Example 7 Preparation of 6-chloro-α-methylcarbazole-2-acetic acid-2-dimethylaminoethyl ester.

A solution of 3 g of 6-chloro-cC-methylcarbazole-2-acetic acid in 10 ml of dimethylformamide is added with stirring to a mixture of 0.1 * 8 g of a 51 * dispersion of sodium hydride in mineral oil in 30 ml of dimethylformamide.

The mixture is allowed to stand for one hour at room temperature and a solution of freshly prepared dimethylaminoethyl chloride in 10 ml of dimethylformamide is added dropwise over 10 minutes. The reaction mixture is then allowed to stand for four hours with stirring at about 70 ° C. The warm mixture is poured onto 300 g of ice and, after the ice has closed, extracted with ether. The ether solution is then extracted with dilute potassium carbonate solution and then with water, and the washed ether solution is dried over anhydrous magnesium sulfate. After filtration of the desiccant and evaporation of the ether in vacuo, 2.7 g of material are obtained. After crystallization of the residue from a mixture of ether and hexane, 2.1 g of 6-chloro-o-methylcarbazole-2-acetic acid-2-dimethylaminoethyl ester are obtained, m.p. 89_90 ° C.

Example 8

Preparation of racemic 6-chloro-α-methylcarbazole-2-acetic acid ethyl ester.

A mixture of 10 g of 6-chloro-ethyl-carbazole-2-acetic acid and 1 * 00 ml of ethanol containing 2 g of hydrogen chloride is kept at reflux temperature for 12 hours under nitrogen, stirring and then overnight at room temperature. After adding 50 ml of benzene, the reaction mixture is evaporated to dryness in vacuo, the residue is dissolved in 200 ml of ethanol and, after adding 2 g of hydrogen chloride, the solution is again kept at reflux for five hours. After cooling to about 50 ° C and adding 50 ml of benzene, the solution is evaporated to dryness, the residue is dissolved in 1 * 00 ml of ether and the ether solution is extracted with 100 ml portions of 0.01 M potassium carbonate solution and then twice with 100 ml: n dose of water. After drying over anhydrous magnesium sulfate, the desiccant is filtered off and the ether is evaporated off to give 10.6 g (96%) of material. Recrystallization from methanol gives 8.1 g of racemic 6-chloro-α-methylcarbazole-2-acetic acid ethyl ester (7 **%), m.p. 106-107 ° C.

17 59244

Example 9 2- (6-Chloro-2-carbazolyl) -propanol.

To a mixture of 30 ml of ether and 0.5 g of lithium aluminum hydride was added dropwise with stirring over 20 minutes a solution of 1 g of 6-chloro-4-methylcarbazole-2-acetic acid ethyl ester in 80 ml of ether. The reaction mixture is then stirred for 10 hours at reflux temperature. The reaction mixture is then cooled in an ice bath and 30 ml of cold water are added dropwise so that the temperature does not exceed + 10 ° C. The mixture is allowed to stand for 1 1/2 hours with stirring at room temperature, filtered and the filter cake is washed twice with 25 ml of ether. The combined filtrates and washings are dried over anhydrous magnesium sulfate. After filtration of the desiccant and evaporation of the ether, 0.8 g (93.3%) of a residue are obtained. After crystallization from benzene, 0.7 g (81.5%) of 2- (6-chloro-2-carbazolyl) -propanol are obtained, m.p. 170 to 171.5 ° C.

Example 10

In the same manner as in Example 8, (-J-δ-chloro-4-methylcarbazole-2-acetic acid is converted to the corresponding optically active 6-chloro-β-methylcarbazole-2-acetic acid ethyl ester. In the same manner as in Example 9, the optically active 6-chloro ° C-methylcarbazole-2-acetic acid ethyl ester to (+) - 2- o 22 (6-chloro-2-carbazolyl) -propanol, m.p. 186-187.5 ° C (benzene), c = 1.8l, methanol).

Example 11

In the same manner as in Example 8, (+) - 6-chloro-α-methylcarbazole-2-acetic acid is converted to the corresponding optically active ethyl 6-chloro-ethylcarbazole-2-acetic acid. In the same manner as in Example 9, the optically active 6-chloro-N-methylcarbazole-2-acetic acid ethyl ester is converted into (-) - 2- (6-chloro-2-carbazolyl) -propanol, m.p. 186-186.5 ° C = -20.6 ° (c = 1.6, methanol).

Claims (5)

18 59244 A process for the preparation of pharmaceutically acceptable cara-sols of the general formula f, wherein R is a hydrogen or halogen atom, R 1 is a halogen atom, a cyano, methyl, methoxy, methylthio, trifluoromethyl or nitro group, R 8 is a n wherein A is a hydroxy group or a group 0 n -CB wherein B is a hydroxy group, an alkoxy group having 1 to 1 carbon atoms or a dialkylaminoalkoxy group having 1 to 1 carbon atoms in its alkyl moieties, Y and X are hydrogen atoms or having 1 to 3 carbon atoms alkyl groups, n is an integer from 1 to 3 and is a hydrogen atom or an alkyl group having 1 to 1 carbon atoms, and for the preparation of salts of these compounds, characterized in that a compound of formula R 1, R 2, E 3 and R 1 is as defined above to react with an aromatizing agent such as p-chloroaniline, and to prepare an ester of formula I having an alkoxy group of 1-1 + carbon atoms in formula B, the resulting acid of formula I is esterified. po, where B is a hydroxy group, or to prepare an acid of formula 1, wherein B is a hydroxy group, hydrolyze the resulting ester of formula I, wherein B is an alkoxy group having 1-1 + carbon atoms, or kn, a- to prepare an alcohol of formula I, wherein A is a hydroxy group, the resulting ester of formula I wherein B is an alkoxy group having 1 carbon atom is reduced and, if desired, in the resulting acid of formula I wherein B is a hydroxy group or an acid base salt, the group B is converted to a di-alkylaminoalkoxy group have 1-U carbon atoms, and to prepare an optically active isomer of a compound of formula I, the resulting racemate of formula I is divided into its optically active isomers, and if desired, the desired isomer is isolated, and if desired, the compound of formula I is converted to a salt. Process for the preparation of racemic 6-chloro-of-methyl-cartazole-2-acetic acid according to Claim 1, characterized in that the starting material used is 6-chloro-tert-methyl-1,2,3,1 + -tetrahydrocarbazole of the formula II -2-acetic acid ethyl ester. Process for the preparation of 2- (6-chloro-2-carbazolyl) propanol according to Claim 1, characterized in that the starting material used is 6-chloro-O-methyl-1,2,3-tetrahydrocarbazole-2 -acetic acid ethyl ester 2o 5 92 4 4 A process for the preparation of pharmaceutical products containing carbazoles of the formula V_ ^ E1 - II 5-E2 B3 color R is a halogen atom, a halogen atom, a cyano-, methyl-, methoxy-, methylthio-, trifluoromethyl - with a nitro group, R 1 is a group with a formyl group} · color A with a hydroxyl group or a group 0 M -CB color B with a hydroxyl group with an alkoxy group 1-1 + 1-3 cholatomers in an alkyldelarium, Y and X are vateatomers or alkyl groups in 1-3 cholatomers, in which case 1-3 and R ^ is not a vateatom or an alkyl group in groups of 1-1 + cholaters in the same group as k nc βίε cknat därav, att man omsätter en förening med formula '' CcO- ·· R3 color R, R ^, R2 and R ^ haran angivna betydelse, med ett aromatiseringsmedas, säsom p-chloranilin, och att manf framställning av en Ester with formula I, color B is an alkoxy group with 1-1 + cholesterol, for which a mixture is given with formula I,