DK161647B - Isoxazole- or -isoxazoline-beta-carboline derivatives, medicaments comprising them, and process for preparing them - Google Patents

Description

DK 161647 B

This invention relates to novel β-carboline derivatives substituted at 3-position with isoxazole or isoxazoline derivatives, a process for their preparation and drug based thereon.

EP-A 54,507 discloses β-carbolines which are substituted at the 3-position with the isoxazolone residue. These compounds exhibit little affinity for the benzodiazepine receptors.

DK Patent Application No. 5541/81 discloses, inter alia, compound 3- (51 - (31-methyl-isoxazole) -yl) -β-carboline, which has useful effect on the central nervous system and is suitable for use as a psycopharmacum.

It has now been found that the β-carbol in the nines, which are substituted in the 3-position by isoxazole or isoxazoline residues, surprisingly exhibit a high specific affinity for the benzodiazepine receptors, displacing radiolabeled phenitrazepam from the benzodiazepine receptors and has a clearly improved affinity for the benzodiazepine receptors compared to the known compounds of DK Patent Application No. 5541/81.

The compounds of the invention have the general formula I

25 ** R4 igcé1 "- 30 N / N

H

wherein Y is the residue 35 2

DK 161647 B

/ N O ✓O N

- \ 3 or '/ X5 a A ^ d A-

Ra pd Dc I

R 5 R 5 and R a and R b are the same or different and represent hydrogen, C 1-6 alkoxy, C 3-7 cycloalkyl, phenyl optionally with hydroxy or C 1-6 alkoxy, substituted C 1-6 alkyl or C 1-6 alkoxycarbonyl, and R c and Rd is the same or different and means hydrogen or C 10 C_alkyl or together a bond and R er is hydrogen, C.g.galkalkyl or C ^galkalkoxy-C ^galkyl, and R5 is halogen, OR6 or C1__ alkyl, where R6 means Cj_gal -Kyl or an optionally halogen-substituted aralkyl, aryl or pyridine, pyrimidine, pyridazine or pyrazine residue.

The substituent R5 can be found one or two times in the 5, 6, 7, 20 and / or 8 positions, with substitution in the 5 or 6 position being preferred.

By C1-6alkyl is meant a straight or branched alkyl group having 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, isobutyl, pentyl and hexyl, with C 1-6 alkyls being preferred.

If R4 represents an alkoxyalkyl group, C1-4 alkoxy-C1-2 alkyl is preferred.

30

As cycloalkyl residues Ra, Rb and R6, e.g. are mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

Halogen is meant fluorine, chlorine, bromine or iodine, with 35 chlorine and bromine being preferred.

The aralkyl residue R6 may have 7-10 carbon atoms and be straight or branched in the alkyl residue. Preferred are Ar-C1-2 alkyls,

DK 161647 B

3 which may optionally be substituted once or twice in the aryl residue.

Suitable substituents in the aralkyl residue are halogen.

5

Preferred are Ar-C 1-6 alkyls which in the aryl residue may be substituted by 1 to 2 halogens.

The aryl residue R6 can have 6-10 carbon atoms and optionally be 10 substituted once or twice with halogen.

Preferably, mention should be made of phenyl, 2-chlorophenyl, 4-chlorophenyl and 2,4-dichlorophenyl.

If r6 means pyridine, pyrimidine, pyridazine or pyrazine, this may optionally be substituted one to three times.

Suitable substituents in the heteroaryl residue are the substituents mentioned for the aryl residue R6.

20

The heteroaromatic group may contain one to two nitrogen atoms.

The novel compounds of general formula I are pharmacologically active substances which include is distinguished by an effect on the central nervous system and is particularly suitable as psychopharmaceuticals in human medicine. Since the compounds of the invention not only have a high specific affinity for the benzodiazepine receptors but also a very low toxicity, they have a particularly favorable therapeutic index. At the same time, the metabolic stability compared with the known (8-carbol) is clearly improved. Due to the surprisingly good effect in the PTZ cramp test, the compounds of the invention are particularly suitable for the treatment of epilepsy and anxiety.

The compounds of the invention can be used for the composition of pharmaceutical compositions, e.g. for oral and parenteral use according to known methods in galenics.

35 4

DK 161647 B

As an adjuvant for the composition of pharmaceutical compositions, such physiologically tolerable organic and inorganic carriers are suitable for enteral and parenteral use which are inert to the compounds of the invention.

5

As carriers, e.g. Mention is made of water, salts, alcohols, polyethylene glycols, polyhydroxylated castor oil, gelatin, lactose, amyl ose, magnesium stearate, talc, silicic acid, in fatty acid mono- and diglycerides, pentaerythritite fatty acid ester, hydroxymethyl cellulose and polyvinyl acid cellulose.

in

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

For parenteral use, injection solutions or suspensions, especially aqueous solutions of the active compounds in polyhydroxyethylated castor oil, are particularly suitable.

20

Interface active excipients such as salts of bile acid or animal or vegetable phospholipids, but also mixtures thereof, as well as liposomes or their constituents, may also be used as carrier systems.

25

For oral use, in particular, tablets, dragons or capsules with talc and / or hydrocarbon carriers or binders such as e.g. lactose, corn starch or potato starch. Use can also be made in liquid form, such as e.g. such as juice, to which may be added a sweetener.

The compounds of the invention are introduced into a dosage unit of 0.05 to 100 mg of active substance in a physiologically useful carrier.

The compounds of the invention are used at a dose of 0.1 to 300 mg / day, preferably 0.1 to 30 mg / day, especially 1 to 20 mg / day.

DK 161647 B

5

The preparation of the compounds according to the invention takes place in ways known per se.

The invention further relates to a process for the preparation of the compounds of the general formula I, which is characterized by a) cyclizing nitrile oxides of the general formula II, wherein the nitrogen atom in the 9 position is optionally protected.

H

Wherein

R4 and R5 have the above meaning, having a compound of general formula III

20

Ra Rb \ / III, c = c c / \ d RC R ° 25 wherein Ra, Rb, Rc and Rd have the above meaning, for compounds of general formula I wherein Y has the meaning

N - O

30 DaA K.Rd R RC R ^ wherein Ra, Rb, Rc and Rd have the above meaning, or

b) cyclizing nitrile oxides of the general formula IV

35

Rb-CsN + -0- IV,

wherein Rb is as defined above with compounds of general formula V

DK 161647B

6 PQQ> · J l in

R a, R c, R 4, R 4 and R 5 have the above meaning, for compounds of the general formula I wherein Y has the meaning R c '15

wherein Ra, Rb, Rc and Rb have the above meaning, or 2qT c) translates compounds of the general formula VI

R5 4 X I ° ϋυύί -

H

wherein R a, R 4 and R 5 have the aforementioned meaning to the enaminone 30 and cyclize with hydroxyl amine-O-sulfonic acid to compounds of general formula I wherein Y has the meaning 35

DK 161647 B

7

, O-- N

_in

Ra 5 wherein Ra has the above meaning.

The cycloaddition of the compounds of general formulas II and IV takes place at temperatures of 0-40 ° C in an aprotic solvent and is generally completed after 4-20 hours. Suitable as aprotic solvent are aliphatic and cyclic ethers such as diethyl ether, tetrahydrofuran, dioxane, halogenated hydrocarbons such as dichloroethane, methylene chloride, chloroform, hydrocarbons such as hexane, pentane and dimethylformamide, dimethyl sulfoxide and others.

If the starting compounds are gaseous, e.g. acetylene, it is advantageous for the reaction to use the corresponding liquid compounds having a group which can be readily decomposed afterwards. As a readily leaving group, e.g.

trialkylsily1 group.

The cleavage takes place before working up the reaction mixture in known ways, e.g. by adding bases at room temperature. Suitable bases are e.g. alkali hydroxides and alcoholates such as sodium or potassium hydroxide, methylate or ethylate, or fluorides such as cesium fluoride or tetra-n-butyl ammonium fluoride.

If desired, the reaction may also be used in the 9-position with a protecting group, such as the tosyl group, substituted / 5-carbolines. This protecting group is cleaved as described above by working up the reaction mixture or afterwards by treatment with alkali alcoholates.

If the compounds of the invention are prepared by process c), e.g. proceed in the way that is 35 8

DK 161647 B

written by 0. J. Lin, S.A. Lang, J. Org. Chem. 1980, 4857, first forming the enaminone which is generally cyclized with hydroxylamine-Q-sulfonic acid without reprocessing. The reaction is carried out at room temperature to 100 ° C with or without the addition of solvent. For enaminone formation, e.g. dialkylformamide dialkyl acetal or amine ester. The cycling can be done in protic solvents such as alcohols, e.g. methanol, ethanol, propanol and others and are completed after 1 to 24 hours.

10

The preparation of the starting compounds is known or done in known ways.

Eg. For example, the nine triloxides are produced by the decomposition of halo hydrogen from the hydroxamic acid halides with bases such as sodium or cold in unalcoholic acids, trialkylamines, Hyngbase, DBU or diazabicyclooctane at room temperature. The hydroxamic acid halides are obtained e.g. by reacting the corresponding oxymers with N-hydrobromic acid imide, N-chloro succinic acid, tertiary butoxy chlorite or Na-hypohalogenide in the aforementioned scarred solvents (R. Annunziata et al., J. Chem. Soc. Chem.

Comm. 1987, 529, K. Larsen and others, Tetr. 1984, 2985).

The nine triloxides can also be obtained by forming aqueous cleavage from the corresponding nine faith compounds by reaction with an acid chloride or arylisocyanate in the presence of a base such as trialkylamine or alkali alcoholate in the aforementioned aprotic solvents at temperatures of -10 to 40 ° C (K Harada and others,

Chem. Pharm. Bull. Jpn 1980, 3296, H. Kawakami et al. Chem.

30 Lightweight. 1987, 85).

The preparation of starting material is e.g. disclosed in EP-A 54,507, EP-A.218.541, EP-A 130.140 and EP-A 237.467.

The invention is further illustrated by the following examples.

DK 161647 B

9

Preparation of starting compound looks at 6-benzyl oxy-4-methoxymethyl- / 3-carbol in n-3-carbide dehyd.

To a suspension of 24.3 g (60 mmol) of 6-benzyloxy-4-methoxy-methyl-1-carbol in n-3-carboxylic acid sopropyl ester in 250 ml of dry toluene is added 15 ml of chlorotrimethylsilane and 48 ml of triethylamine. . The reaction mixture is heated to 50 ° C for 1 hour and then evaporated to half volume. Then, the reaction mixture is cooled to -78 ° C and, under nitrogen, 100 ml of DIBAH (1M solution in toluene) is added over 1 hour and stirred for 3 hours at -78 ° C. Then 10 ml of ethanol is added and warmed to room temperature, 200 ml of 0.5 M sodium hydroxide solution and 200 ml of ethanol are added and stirred overnight. The precipitate is filtered off, washed with water, dried and used without further purification in the next reaction step.

Analogously prepared: islet carboline-3-carbaldehyde.

6-benzyloxy-4-methoxymethyl-β-carbolin-3-carbaldehyde oxime.

Dissolve 13.5 g of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carbaldehyde in 150 ml of dry DMF and add 6 g of hydroxy 1 amine hydrochloride and a solution of 6 g of potassium hydroxide in 30 ml of ethanol. The reaction mixture is stirred for 1 hour at room temperature, filtered and the residue washed with 2 x 20 ml DMF. To the DMF fraction ion is added 200 ml of ice water, the precipitate is filtered off, washed with water and dried. Yield 9.6 g.

30

Analogously prepared: 6- (2-pyrazinyloxy) -4-methoxymethyl-β-carboline-3-carbaldehydo-xylm, 6- (4-cisorphenoxy) -4-methoxymethyl-β-carboxylic n-3 -carbal dehyd ό χι m,

DK 161647B

6- (2-pyridyloxy) -4-methoxymethyl 1- / 3-carboline in 4-carbaldehyde oxime, 6-methyl-4-methoxymethyl-β-carboline in n-4-carbaldehyde oxime, 5 6- {5-bromoylurea d-2-yl) -4-methoxymethyl-β-carbol in n-3-cabaldehyde oxime, 6-benzyloxy-4-methyl-β-carbol in n-3-carbaldehyde oxime.

5-Benzyloxy-4-methoxymethyl-9-tosyl-β-carbol in n-3-carbaldehyde oxy.

500 mg of 5-benxyloxy-4-methoxymethyl-9-tosyl-β-carboline-3-carb aldehyde is heated to 70 ° C in 15 ml of ethanol, 84 mg of hydroxylamine hydrochloride is added in 10 ml of ethanol and heated for 1¾ to 70 ° C. Then, evaporate to 5 ml and pour into 40 ml of water and suction. After drying, the residue (450 mg) is used in the next step without further purification.

Analogously prepared: 5-isopropoxy-4-methyl-9-tosyl-β-carbalin-3-carbaldehyde oxime 5- (4-chlorophenoxy) -4-methoxymethyl-9-tosyl-β-carboline-3-carbene aldehydoxime, 5- (2-pyrazi nyloxy) -4-methoxymethyl-9-tosyl-β-carbolin-3-carbaldehyde oxime, 5- (5-bromo-2-pyridine nyloxy) -4-methoxymethyl-9 -tosyl-β-carboli n-3-carbaldehyde oxime, 6,7-dimethoxy-4-ethyl-9-tosyl-β-carboli n-3-carbaldehyde oxime.

3-acetyl-5-benzyloxy-4-methoxymethyl-9-tosyl-β-carboline.

3.3 g of 5-benzyl oxy-4-methoxymethyl-9-tosyl-β-carboline carboxylic acid ethyl ester are suspended in 26 ml of absolute THF and cooled to 35 -60 ° C under an N 2 atmosphere. To this suspension is added 5.2 ml of a 1.5 m ethereal methyl lithium solution and stirred for 2 hours at -60 ° C. After heating to room temperature

DK 161647 B

11, saturated ammonium chloride or id solution is added to the reaction mixture and extracted with vinegar ester. The crude product is purified by chromatography on silica gel with toluene + vinegar ester = 95 + 5.

5 3-Acetyl-6-benzyloxy-4-methoxymethyl - / 3-c ar bol i n.

To 3.70 g (22 mmol) of methanesulfine-p-toluidide in 100 ml of dry THF is dripped at -78 ° C under an atmosphere of 45 mmol of n-butyl 1 for 10 µm over 10 minutes. 5.58 g (10 mmol) of 6-benzyloxy-4-methoxy-methyl-9-tosyl / 3-carbol in n-3-carboxylic acid isopropyl ester dissolved in 50 ml of dry THF are added. Reaction mixtures turn dark blue. Stir for 1 hour at -78 ° C, pour into water and extract with ether. The ether is extracted and the remaining oil is dissolved in 100 ml of methanol. Then 5 g of KOH is added and stirred for 1 hour under reflux. After cooling, ice water is added and the precipitate is filtered off. Yield 3.5 g.

The crude product is purified by chromatography on silica gel with ethyl acetate. Yield 2.80 g.

Example 1 6-Benzyloxy-3- (3-isoxazolyl) -4-methoxymethyl 1- / 3-carboline.

Dissolve 0.55 g (1.5 mmol) of 6-benzyloxy-4-methoxymethyl- / 3-carbolin-3-carbaldehyde oxime in 30 ml of dry DMF, and add 0.3 g (1.7 mmol) of N- hydrobromic acid mid (dissolved in 5 ml DMF). The reaction mixture is stirred for 10 minutes at room temperature and then 30 equivalents of trimethylsilylacetylene and 1 ml of triethylamine are added. After stirring at room temperature for 4 hours, add 5 ml of 1M sodium hydroxide solution and then stir for an additional 1 hour. The solution is poured into ice water and extracted with vinegar ester. The organic phase is dried over magnesium sulfate 35 and the solvent is extracted. The resulting product is purified column chromatographically on silica gel with vinegar ester as the eluent. Melting point 123-126 ° C.

Example 2 12

DK 16164 7 B

6-Benzyloxy-3- (5-ethoxy-3-isoxazolyl) -4-methoxymethyl-β-carbo-1 in.

Dissolve 1.1 g (3.0 mmol) of 6-benzyloxy-4-methoxymethyl 1-β-carbolin-3-carbaldehyde oxime in 40 ml of dry DMF and add 0.56 g (3.1 mmol) of N hydrobromic acid imide (dissolved in 5 ml DMF). The reaction mixture is stirred for 15 minutes at room temperature and then 10 equivalents of ethoxyacety 1 and 1.5 ml of triethylamine are then added. The reaction mixture is stirred overnight at room temperature and then poured onto ice water and extracted with vinegar ester. The organic phase is dried over magnesium sulfate, filtered, the solvent is extracted and the residue is purified by column chromatography on silica gel with vinegar ester. Melting point 139-140 ° C.

Analogously prepared: 6-benzyloxy-3- (5-hydroxymethyl-3-isoxazoly) -4-methoxymethyl-20-island carboline with hydroxymethyl acetylene. Melting point 220-221 ° C.

6-Benzyloxy-3- (5-methoxymethyl-3-isoxazolyl) -4-methoxymethyl-β-carboline with methoxymethylacetylene. Melting point 80-90 ° C.

With propargylic acid ethyl ester, column column chromatographic 6-benzyloxy-3- (5-carbethoxy-3-isoxazoly) -4-methoxymethyl-β-carboline, m.p. 202-203 ° C and 6-benzyloxy-3- (4-carbethoxy) 3-isoxazolyl) -4-methoxymethyl-β-carboline, mp 145-146 ° C.

6-Benzyl oxy-3- (4-carbethoxy-4,5-di hydro-3-isoxazoly) -4-methoxymethyl-β-carbol in with acrylic acid ethyl ester, mp 183 ° C.

6-Benzyloxy-3- (4-carbethoxy-4,5-di hydro-4-methyl-3-isoxazolyl) -4-methoxymethyl-β-carboline with methacrylic acid ethyl ester, m.p. 187-189 ° C.

35

DK 161647 B

13 6-Benzyloxy-3 (5-ethoxy-4,5-dihydro-3-1-soxazoly 1) -4-methoxymethyl-o-carboline with vinyl ethyl ether, mp 149-150 ° C.

6-benzyloxy-3- (5-methyl-3-isoxazolyl) -4-methoxymethyl-o-carboline, mp 160-162 ° C.

6- (2-pyrazi nyloxy) -3- (5-methoxymethyl-3-isoxazoly) -4-methoxy-methyl-β-carboline, mp 184 ° C.

6-methyl-3- (5-methyl-3-isoxazolyl) -4-methoxymethyl-O-carbol, m.p. 178 ° C.

6-methyl-3- (5-methoxymethyl-3-isoxazolyl) -4-methoxymethyl-O-carboline, m.p. 160 ° C.

6- (5-bromopyrid-2-yl) -oxy-4-methoxymethyl-3- (3-isoxazolyl) o-carboline, m.p. 203 ° C.

6- (5-bromopyrid-2-yl) -oxy-3- (5-methyl-3-isoxazolyl) -4-methoxy-methyl-β-carboline, m.p. 197-198 ° C.

6- (5-bromopyrid-2-yl) -oxy-3- (5-methoxymethyl-3-isoxazolyl) -4-methoxymethyl-3-carboline, mp 164 ° C.

6-benzyloxy-4-methoxymethyl-3- (5-isopropyl-3-isoxazolyl) ~ β ~ carboline, m.p. 125 -26 ° C (isopropanol).

6-benzyloxy-4-methoxymethyl-3- (5-cyclopentyl-3-isoxazoly) -8 ”carboline, mp 128-129 ° C (isopropanol).

6-benzyl oxy-4-methoxymethyl-3- (5-phenyl-3-soxazolyl) -β-orebo-1 in n, mp 173-175 ° C (methylene chloride or id).

35

Example 3

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14 6-Bromo-3- (3-isoxazolyl) -? -Carboline.

1.05 g (5 mmol) / 3-carbo 1 in 3 carbo 1 dehydoxime is suspended in 50 ml of dry THF and at 0 ° C 1.8 g of N-hydrobromic acid imide is added in 20 ml of dry THF. The reaction mixture is warmed to room temperature, stirred for 95 hours and 1.5 equivalents of trimethylsilyl acetylene and 2 ml of triethylamine are added. The mixture is stirred overnight, poured onto ice water and extracted with ether. The organic phase is dried over magnesium sulfate, filtered and the solvent is extracted. The remaining oil is dissolved in 10 ml of DMF and 10 ml of sodium hydroxide solution (1M) is added. The reaction mixture is stirred overnight at room temperature, poured onto water and extracted with vinegar ester. The resulting product is purified column chromatographically with vinegar ester as the eluent. Melting point 292-293 ° C.

Example 4 5-Benzyloxy-4-methoxymethyl-3- (3-isoxazolyl) -β-carboline.

To 103 mg of 5-benzyloxy-4-methoxymethyl-9-tosyl-is-carbol in-3-carboxaldehyde oxime in 5 ml of methylene chloride is added 22 mg of N-chloro-succinic acid imide and stirred for 1 hour at room temperature. Then add 30 mg of tri methyls ilyl acetylene and 0.13 ml of triethylamine and stir for 2 hours at room temperature. Then 1 ml of 1 N sodium hydroxide solution is added and stirred for 1 hour at room temperature, poured into 25 ml of water, extracted with 25 ml of methylene chloride and the organic phase is dried, filtered and evaporated. The residue in 15 ml of methanol is refluxed for 1¾ hours with 54 mg of sodium methylate. After evaporation, take up in 25 ml of water and extract with vinegar ester. After drying and filtration, the organic phase is evaporated and the residue is chromatographed over 35 silica gel with toluene: vinegar ester = 1: 1 as the solvent.

DK 161647 B

EXAMPLE 15 5-Benzyl oxy-4-methoxymethyl 1- 3- (5-methoxymethyl 1-3-3-soxazoly 1) -3-carboline, 5

To 155 mg of 5-benzyloxy-4-methoxymethyl-9-tosyl-β-carbolin-3-carbaldoxime hydrochloride in 6 ml of absolute tetrahydrofuran drop 1.4 ml of sodium hypochloride solution at room temperature under a protective gas. Stir until the oxime has disappeared (DC control) for 1 hour at room temperature and then 210 mg of methyl propargyl ether is added and stirred overnight at room temperature. After distillation of the solvent, partition into acetic acid / water and the organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is dissolved in 8 ml of methanol, 54 mg of sodium methylate is added and heated at reflux for 1 hour. After evaporation and distribution in vinegar ester / concentrated brine, the organic phase is dried, filtered and evaporated. The residue is chromatographed over silica gel with two 1: acetic acid = 1: 1. The desired fractions 20 are collected and crystallized by the vinegar ester. 70 mg are obtained, m.p. 133-135 ° C (vinegar ester).

Analogously prepared: 5- (4-chlorophenoxy) -4-methoxymethyl-3- (5-methoxymethyl-3-isoxazolyl) - S-carboline, mp 176-177 ° C (isopropanol).

5-isopropoxy-4-methyl-3- (5-methoxymethyl 1-3-isoxazolyl) -8-carboline.

6,7-dimethoxy-4-ethyl-3- (5-methoxymethyl 13-isoxazolyl) -β-carboline.

5- (2-pyrazyloxy) -4-methoxymethyl-3- (5-methoxymethyl-3-isoxazolyl) -α-carboline.

5- (5-bromo-2-pyridinyloxy) -4-methoxymethyl-3- (5-methoxymethyl-3-isoxazolyl) -p-carboline.

Example 6

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16 6-Benzyloxy-3- (3-methyl-5-isoxazolyl) -4-methoxymethyl-β-carbonyl.

5

To 340 mg of nitroethane in 20 ml of dry dimethyl acetamide was added 4.5 ml of methanolic 1 N sodium methylate solution and cooled in an ice bath to 5 ° C. To this are added, in succession, 0.32 ml of acetyl chloride and 510 ml of 6-benzyloxy-4-methoxy-methyl-3-ethinyl- / 3-carboline.

After 16 hours of stirring at room temperature, an additional 3 equivalents of methanolic IN sodium methylate solution, nitroethane and acetyl chloride are added and stirred for 16 hours at room temperature. This addition is repeated and after a total of 3 days 100 ml of water is added and stirred again overnight at room temperature. The reaction mixture is extracted with vinegar ester. The organic phase is separated, dried, filtered and evaporated.

After chromatography over silica gel with vinegar ester, there are obtained 130 ml of 6-benzyl oxy-3- (3-methyl-5-isoxazolyl) -4-methoxymethyl-β-carboline, m.p.

Example 7 6-Benzyloxy-4-methoxymethyl-3- (5-isoxazolyl) + - carboline.

500 mg of 3-acetyl-6-benzyloxy-4-methoxymethyl-β-carboline is stirred overnight at 100 ° C in 5 ml of N, N-dimethylformamide diethyl acetal. After evaporation, without further purification, take up 20 ml of absolute ethanol, add 600 mg of hydroxylamine-0-sulfonic acid in 5 ml of methanol and stir for 5 hours at room temperature. After neutralization with triethylamine, the reaction mixture is stirred overnight, introduced into water and extracted with acetic ester. The organic phase is dried over magnesium sulfate and evaporated in vacuo. After chromatography over silica gel with acetone / triethylamine = 10: 1 as eluent, 130 mg 6-5 are obtained.

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17 benzyl oxy-4-methoxymethyl-3- (5-isoxazolyl) - / 3-carbonyl, m.p. 125-126 ° C.

10 15 2 0 25 30 35 18

DK 1616 4 7 B

Comparable results over H3-βunitrazepam binding.

R4? R * RC Rb

H

10 P— --—-, ----- 5 4 3.

R R H -Flunitrazepam Binding in vitro in vivo

Na-Ι, μ JC5Q ng / ml DE5Q mg / kg

Rb CH 2 OCH 3 5- (4-Cl-Phenoxy) CH 2 OCH 3 - 0.7 '1 - “-----“ “H 5-Benzyloxy CH 2 OCH 3 0.35 0.61 CH 3 6-CH 3 CH OCH , 5 CH 6- (5-Br-Pyridyloxy) CH 2 OCH 3 0.15 1.1 _H 6 - 8 R__H__3 ^ 7__9_ ^ 6__ 20 CH2CCH3 5-Isopropoxy CH3 1.0 2.1 CH ^ CH 6-Benzyloxy CHCCII 0.35 30 o ----- i '25 | _ »---- -r ----- r ------ P *** - ...... I 1 -

Ra RC Rb 6-Benzyloxy CH „0CH 2.9 30

C 0 C „H CH., H

C C D__J __ ^ H QCjiy 6-Benzyloxy CH2 OCH3 1.0 14 EP-54507 156 100 35 DK 5541/81 '-; 3- (5 '- (3'-Methylisoxazol) yl) -B-carboline'? 90 ί! _I__I _; _ 1_

Claims (3)

A drug based compound according to claims 1 and 2. Process for the preparation of compounds of general formula I, characterized in that a) cyclizing nitrile oxides of general formula II wherein the nitrogen atom in the 9 position is optionally protected "30" H wherein R 4 and R 5 has the aforementioned meaning, with a compound of the general formula III, in which Ra, Rb, Rc and Rd have the above meaning, for compounds having the general formula I where v has the meaning ~ ir +. Ra ct, »d RC R ° 15 where Ra, Rb, Rc and Rd have the above meaning, or b) cycles in serine nitrile oxides of the general formula IV Rb-csN + - 0- IV, 20 wherein Rb has the meaning given above with compounds of the general formula V '- Cc :: - NN / H 30 wherein Ra, Rc, Rd, R4 and R5 have the above meaning, for compounds having the general formula I wherein Y has the meaning 22 4-I RC. R3 R6 5 wherein Ra, Rb, Rc and R4 have the aforementioned meaning, or c) convert compounds of the general formula VI into R 15 wherein Ra, R4 and r5 have the aforementioned meaning to the enaminone and cyclize with hydroxylamine-O-sulfonic acid for compounds 20 of the general formula I wherein Y has the meaning ✓ on x_I 25 wherein Ra has the above meaning. 30 35