PT100593A - 3-ARYL-BETA-CARBOLINES OR 3-HETEROARYL-BETA-CARBOLINES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

i

Description of the patent of invention of SOEERIEG% German, industrial and commercial, established in Berlin and Bergkaiaen (address

Postal ϊ 1 * 70-178 llullerstrasse * Berlin 65), Federal Republic of Germany (inventors, Mr. Andreas Huth.) Mr. Sieter

Seidelmann, Mr. Ealph. Sch.miecb.en, Mr. Eerbert Schneider and Mr. Lechos-law furski, residing in the Federal Republic of Germany), for η5-ΑΗΙΙ.-β -g / il-BQLI1TAS QtJ 3-HETSRQARIH (UOAESQLLAÀSl

PEOPLE TO YOUR PEBBLES IN A3

The invention relates to novel 3-aryl-p > and 3-heteroaryl-β-carbolines, for their preparation and use in pharmaceutical compositions. It is known from numerous publications, such as ISP-A-110314, that β-carbolines will influence the central nervous system * and are therefore suitable as psycophrenes. It has surprisingly been found that the β-3-substituted β-carotins according to the invention have a bioavailability for a longer time and also have a good affinity for the benzodiazepine receptors.

The compounds according to the invention,

has the general formula I

Halogen, -OHR2-2, phenyl optionally substituted by halogen, -O-alkoxy- or amino- heteroaryl or may be present once or twice, and means hydrogen or alkyl, means hydrogen, alkyl-O-C1-4 alkyl. or a phenyl, benzoyl or phenoxy optionally substituted group, and R3 is hydrogen, C1-6 -alkyl, cycloalkyl-O-O, or a benzofused, optionally substituted phenyl, benoyl, heteroaryl or heteroaryl group; E '% means hydrogen, C1-4 alkyl or C1-4 alkoxy-C1-4 alkyl and it means an aryl or heteroaryl group -Gg2 * optionally substituted by one or more times by C1-4 alkyl Cycloalkyl, halogen, C1-4 alkoxy or amino, the isomers being further according to the invention the acid addition salts of the compounds of formula I. The substituent E * k may be on the ring A in 5S * positions, preferably at positions 5, & or 7 * 2-

By alkyl are meant both straight and branched chain groups, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, see-butyl, ber-butyl perethyl, isoperyl and hexyl. by lialogen I understood fluorine, chlorine, bromine and iodine.

Oxyloalkyl may be cyclopropyl, cyclobutyl, cyclopeuylG, cyclohexyl, cyclohexylethyl and 2-methylcyclopropyl, with cycling of 3 to 5 carbon atoms being preferred. In the case of iP or sA stands for a heteroaryl group this is a 5- or 6-membered ring and contains 1 to 3 beteroatoms, such as nitrogen, oxygen and / or sulfur. As an example the following 6-membered heterocyclic rings are exemplified; pyridine, pyrimidine * pyrazine, pyridazine, furan, liophene, pyrrole, thiazole, imidazole and triazine.

As the preferred heteroaryl group 'J' * means pyridine, thiophene and furan *

In case of a benzofused 7-roaryl group, it preferably contains 1 to 2 nitrogen atoms, as in the case of quinoline, isoquinoline, chiralaxine or benzimidazole. Substituent of the phenyl, benzyl, heteroaryl and beno-fused heteroaryl group E * 'may be present from 1 to 3 times in any position. Suitable buffers are halogeno, nitro, exaro, C1-7 alkyl, C1-6 alkoxy, C1-4 alkoxy, C1-6 alkyloxy, and trifluoromethyl, with the substitution by halogen for the phenyl and benzyl group 1 or 2 times. - 3 -

i I

As heteroaryl and heteroaryl groups

t; Preferred benzocondensates Preferred are nitrogen heteroaryls, which may be substituted, as the case may be, 1 to 2 times, by halogen, C1 -C4 -alkoxy-O- or trifluoromethyl, especially by halo, genius·

As substituents of the phenyl group,

Benzyl or phenoxy 3 ', the substituents of the aromatic rings indicated for B * 3, especially halogen such as chloro and bromo, the aryl and heteroaryl group B 2 may exist as a monocycle or bicyclo and contain from 5 to 12 members , especially 5 to 9, such as phenyl, biphenyl, naphthyl, indenyl as aryl group, and thienyl, furyl, pyranyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyridazinyl, oxidazolyl, isoxazolyl, thiazolyl, isothiazolyl , 1,2,4-oxadiazole-2-yl, quinolyl, isoquinolyl, benzo / TTtienyl, benzofuryl as a heteroaryl group with 1 to 3 heteroatoms of sulfur, oxygen and / or nitrogen. The substituent of the aryl and heteroaryl group may be in the range of 1 to 5 times, especially 1 time. Ί-4

Preferred embodiments refer to the following: Fr 3 * means 0E-3, wherein V? is phenyl or benzyl optionally substituted 1 to 2 times, gu is a 5- or 6-membered heterocycle (benzofused or not) with 1 to 3 nitrogen atoms, which may be, as 0 case, replaced 1 to 2 times: e ti? means phenyl optionally substituted by halogen or C1-6 alkoxy, or a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 heteroatoms, such as 1,3,4-oxadiazole-2-yl, thienyl, pyrrolyl, pyridyl, thiazolyl, oxazolyl, or a benzofused heterocyclic such as benzothienyl · As substituents of the group 4-

J

thiazolyl, phenyl and phenyl are preferred, and as substituents of the group 3,4,5-oxazolyl, C1-4 -alkoxy, C1-4 -alkoxy-C1-4-alkyl And amino. In case of a chiral center, the compounds of formula I may be in the form of the stereoisomers or mixtures thereof.

The physiologically acceptable acid addition salts are the derivatives of the known organic inorganic acids, for example hydrochloric, hydrochloric, hydrohalic, sulfuric, phosphoric, formic, acetic, benzoic, nitric, fumaric, succinic, tartaric, citric , oxalic acid, as well as alkanesulfonic and arylsulfonic acids, for example ethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, among others.

The compounds of formula I and the respective acid addition salts thereof may be used as medicaments because of their affinity for hensodiazepine receptors, having an inverse anthogonal, agonist and agonist effect over the known properties of benzodiazepines . At the same time the compounds according to the invention have an effect of prolonged duration and are distinguished by their effectiveness as anxiolytics. The affinity for benzodiazepine receptors is determined by studying the ability of radiolabeled replacement of flunitrazepam from the henzodiazepine receptors. For testing the anxiolytic effect the compounds are tested by the 4-plate test, according to the method of Boissier et al., Eur. J. Pharmacol., 4, 145-50 (1968). To this end, the minimum dose (USB) capable of increasing the locomotor activity of the hard mouse after i.p. A decrease in activity in the test of the 4 plates without stiffness is indicative of sedative properties.

The compounds of formula I are particularly suitable for the treatment of fear accompanied by sleep depressions and disorders. 5

For the use of the compounds according to the invention as medicaments they are converted into a pharmaceutical composition which in addition to the active ingredient contains an inorganic or organic inert pharmaceutical carrier suitable for oral or parenteral application such as water, gelatin Gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols,

The pharmaceutical preparations may be in the solid form, for example tablets, suppositories, capsules, or liquid, for example solutions or emulsions. As the case may be, additives such as preservatives, stabilizers, humectants or emulsions, salts for adjusting the oem pressure or buffers may also be present.

Particularly suitable for parenteral administration are injection solutions or suspensions, in particular aqueous solutions of the active ingredients in polyhydroxyethoxylated castor oil.

As surfactants, surfactant additives may also be used as salts of the animal or plant bile acids or phospholipids, and mixtures thereof, such as liposomes or their components,

For oral application, tablets, dragees or capsules, talc and / or carriers or hydrocarbons linkers, for example lactose, corn starch or potato starch, are particularly suitable. The application may further be carried out in liquid form, for example in juice, to which a sweetener has been added as the case may be.

The compounds according to the invention are administered in a unit dosage of 0.05 to 100 mg of active ingredient in a physiologically assimilable carrier. - 6 -

The compounds according to the invention are generally administered in a dose of 0.1 to 300 mg / day, preferably 0.1 to 30 mg / day, most especially 1 to 20 mg / day, for as anxiolytic analogues of diazepam.

The preparation of the compounds according to the invention is carried out according to processes known per se. Compounds of formula I

a) by proceeding with I arylation of a compound of formula II

& you. T

ial ri, wherein λ> i and Xt have the abovementioned meanings and Hal stands for lialogento,

in the presence of a nickel or palladium catalyst, with an organometallic compound of the formula III ## STR3 ##

III in which T? has the abovementioned meaning, means me. metal atom, 2 1 is halogen, hydroxyl or alk-01 <> ZZ, and η. I is an integer from 1 to 3, or

b) by cleaving a compound of formula IV

ηα which Η and ₂ have the abovementioned meanings with orthosteres of carboxylic acids, to give compounds of the formula I in which Έ? means a 1,3,4-oxadiazol-1-yl group, which may be optionally substituted by C1-4 alkyl, C1-6 alkoxy-C1-4 alkyl or C1-4 alkyloyl-O-, or bicyclic with brosocyan, to give a compound of formula I wherein V ' means a 5-amino-1,3,4a-α-dia2ol-2-yl group, or c) by cyanating a compound of formula

in which - 8 -

Sr 1, 2, 3, 4 and 5 have the abovementioned meanings, 1 represents halogen and I ' is hydrogen or a protecting group, cop. amides of thiocarboxylic acids, 2 being obtained compounds of formula I which is Br means a thiazomethyl group substituted in the 2-position, and thereafter proceeding, as the case may be, to removal of the protecting group ,

d) by cycling a compound of formula

with tosyl isocyanate in the presence of bases to give a compound of formula I in which P represents an oxazole-5-yl group or, if desired, then removing the benzyl group Λ *. or when E is a hydroxyl group, proceeding to the etherification thereof, or separating the isomers or converting the obtained compounds into their acid addition salts, according to the variant Process (a) is carried out or suspended in inert solvents at temperatures from 0 ° to the boiling point of the reaction mixture

Suitable solvents are for example cyclic and acyclic ethers such as diethyl ether, tetrahydrofuran and dioxane, hydrocarbons such as toluene and benzene, as well as aprotic polar solvents such as dimethylformamide, dimethylacetamide, N-ethylpyrrolidone, among others, the case of boron is not suitable for the addition of pre-solvents such as alcohols

The halogen atom of the general formula III may contain lithium, magnesium, zinc, tin, or boron as the metal atoms, with the substituent being present at 1 to 5 times, depending on the valence of the and in which R 1 represents a halogen, especially chlorine or bromine.

Suitable Î ± -oleucyl and palladium catalysts are for example 1,3-diphenylphosphinopropane-nickel (II) chloride, bis-tri-O-tolylphosphinopalladium (II) chloride, bis-triphenylphosphino palladium (II) chloride, tetrakis-triphenylphosphino-palladium (O) 1,1apos; -bis-diphenylphosphino-pentanedioate palladium (II) chloride. The preparation of 1,5,4-oxadiazals, with process variant b) is effected by heating the carbonic acid β-carboline-5-carboxylic acid esters of carboxylic acid esters, in solution or in suspension, in the presence of cyclization in the presence of a base such as for example alkali oxides such as sodium or potassium ethoxide or tert-butoxide *

As solvents, the corresponding alcohols are suitable. 10

The reaction is stirred at temperatures up to the boiling point of the reaction mixture and quenched after 2-10 hours.

The 5-oxa-3,4,5-oxadiazoles are prepared according to process variant b) by heating the compounds of formula IV with bromocyano in protic solvents such as alcohols at elevated temperatures , preferably 20-50 ° C, followed by treatment with copious bases, for example ammonia *

For the introduction of the tiasole group, according to process variant c), compounds of formula V, in particular 3-bromoacetyl-carbolines or 5-chloro-cetyl-β-carbolines, are heated under reflux with amides of. carboxylic acid such as thioformamide, thio-propionic acid alkyl, in protic solvents such as alkoxy,

Protecting groups optionally present in the 9-position of the urea, for example the alkanoyl, arylsulfonyl, allylsulfonyl or trialkylsilyl groups may be removed according to usual methods, such as treatment with bases, for example alkali metal alkoxides or alkali metal hydroxides, or with acids, for example dilute mineral acids, or with fluorides, such as calcium fluoride, at room temperature or at higher temperatures.

For the preparation of oxazoles, according to process variant d), 5-carbaldehyde-γ-carbolines of formula VI are reacted with tosylmethylisocyanate, the suspension or in solution, the reaction is carried out in the presence of bases such as alkali metal carbonates or alkali metal alkoxides, in rare traffic as alcohols, at temperatures up to the boiling point of the reaction mixture, and is terminated after about 1-5 hours. 11 -

And if it is desired to remove the 2apos; group, the procedure of 13.3-130Â ° C is carried out as described, or a hydrogenolytic cleavage is carried out. The following are examples of the free hydroxy groups, according to the procedure described in EP-A-2, pp. 377, in which the reactive compounds EÀ-I are reacted in wherein X stands for halogen, tosylate, mesylate or triflate, in the presence of a base such as alkoxy or alkali hydroxides, in polar solvents with diaethylsulfoxide, diaethylformamide, acetonitrile or alcohols, at ambient temperatures or at elevated temperatures, presence of phase transfer catalysts. Mixtures of isomers may be separated according to customary methods, such as crystallization, chromatography or salt formation to provide isolated diastereomers or enantiomers.

For the formation of the physiologically assimilable acid addition salts a compound of the formula X is dissolved, for example a small amount of sodium, solution of the desired acid. in those cases where the preparation of the starting reagents is not described herein, it is because such compounds are known or analogous to known compounds, or they are then measured to be prepared by the processes described herein.

The 3β-balosarbolin Perl virole of formula 3 are obtained according to the method described in XP-q-120 014, or according to one of the following procedures. variant of the reaction of CJandmeyer in bromine as the solvent with isoamyl nitrite in the presence of polyethylene glycol. - 12 -

Preparation of the compounds of formula I is effected by heating the carboline-3-carboxylic acid alkyl ester with hydrazine hydrate.

For the oxidation of 3-hydroxymethyl-β-carbolines according to the process described in BP-A-54507 the 3-carbaldehyde-3-carbolines, of formula 1, are obtained, or following the synthesis described therein -A-305 322 *

The following examples illustrate the processes according to the invention:

Preparation of the starting reagents; A) 6-Benzyloxy-4-methoxymethyl-β-carboline-5-carboxylic acid

Prepared according to the procedure described in EP-A-161 574 from 6-benzyloxy-4-methoxymethyl-3-carboline-3-carboxylic acid isopropyl ester. 243 ° G. B *) 5-trimethylsilylethyloxycarbamylamide 6-behyloxy-4-methoxy-

3.62 g of 6-benzyloxy-4-methoxymethyl-3-furanyl-3-carboxylic acid in 50 ml of dimethylformamide is added, until a clear solution is obtained, 4.3 g of of phosphoric acid and 1.4 ml of triethylamine are added and the mixture is stirred for 2 hours with humectant heating at 80 ° C under argon. After cooling, 2.9 ml of trimethylsilylethanol are added and the mixture is heated for 4 hours in a 80Â ° C bath. After standing overnight, the residue is concentrated in vacuo and the residue is partitioned between ethyl acetate- washed with saturated sodium hydrogen carbonate solution and sodium chloride solution. The organic phase is dried, filtered and concentrated. The residue is used for the next step without further purification. Amino-6-benzyloxy-4-methoxy-3- (3-carboline

5 S of trimethylsilylethoxycarbonylamino-6-benzyloxy-4-methoxymethyl-4-carboline are heated in 40 ml of tetrahydrofuran with 22 ml of tetrabutylammonium fluoride for 3 hours at 50 DEG C. After distillation of the solution The residue is partitioned between ethyl acetate and washed with a saturated solution of sodium carbonate and a solution of sodium chloride. The organic phase is dried, filtered and concentrated. The residue is chromatographed on silica gel with methylene chloride. * 10 s2 as eluent. After evaporation of the reactions containing the stirring compound with cyclohexane / ethyl acetate, 1.32 g of 3-amino-6-benzyloxy-4-methoxy-ethyl- carboline. Z &gt;.) 5-Bromo-6-benzyloxy-4-methoxymethyl-β-carboline

1 g of 3-amino-6-beuzyloxy-4-methoxymethyl-β-carboline in 32 ml of bromoform is mixed with 0.6 ml of HBr / acetic acid (33%) and 5E of PGE200. At 9 ° C, 0.4 ml of isoamyl nitrite is added and maintained for 30 minutes at this temperature. Then, 0.56 g of copper (X) bromide is added to the mixture. After heating the mixture to room temperature for about 1 hour, dilute with methylene chloride and extract with a dilute solution of of ammonia and with water. The organic phase is dried, filtered and concentrated. The residue was chromatographed on silica gel with methylene chloride: ethanol. The combined fractions containing the compound were combined and shaken with ethyl acetate / hexane. 0.54 g of 3 "bromo-6-benzyloxy-4-methoxymethylcarboline are obtained. E.) 6-benzyloxy-4-methoxymethyl-3-acetyl-9-tosylcarboline

8.4 g of 6-benzyloxy-4-methoxymethyl-9-tosyl-β-carboline-3% isopropyl ester

Carboxylic acid in 500 ml of absolute tetrahydrofuran and the solution is cooled to -60 ° C. To this solution, under argon atmosphere, 15 ml of a 1.5 molar solution of methyl lithium in ether are added dropwise, and the mixture is stirred for 4 hours at -60 ° C. After warming to room temperature, saturated ammonium chloride solution is added to the reaction solution, extracted with methylene chloride, dried and concentrated. The resulting crude product is chromatographed on silica gel with hexane-hexanes of ethyl * 8; 2. 4.1 g of 6-benzyloxy-4-methoxymethyl-3-methyl-9-tosyl-β-carboxylic acid are obtained as the melting point: 173-1750 °. ) Bromination

2.29 g of 6-benzyloxy-4-methoxymethyl-5-acetyl-9-tosylate are shaken. -carboline with twice the molar amount of phenyltrimethylammonium tribromide in 100 ml of absolute tetrahydrofuran for 4 days at room temperature. The reaction mixture is concentrated to dryness, the residue is taken up in methylene chloride, washed with a saturated NaCl solution, dried over molecular sieves and concentrated. The crude product is chromatographed on silica gel (cyclohexane / ethyl acetate = 8, 2). There are obtained 1.9 g of 6-benzyloxy-3-bromoacetyl-4-methoxymethyl-9-tosyl- -carboline *

Melting point: 165 ° C (with decomposition). G.) 5-Benzyloxy-4-methoxymethyl-β-carboline-

1.56 g of 5-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester in 20 ml of hydrazine hydrate (80%) are heated under reflux for 4 hours. After cooling, the precipitated crystals are filtered and dried. 1.2 g of 5-benzyloxy-4- -methoxymethyl-β-carboline-3-

Melting point: 212-213 °.

In an analogous manner the following compounds are prepared.

6-Benzyloxy-4-methoxyethylsulfanylhydrazide; -carboline-3-carboxylic acid.

Melting point: 228-231 ° C *

5- (4-Fluorobenzyloxy) -1H-methoxymethyl-? - carboline-3-carboxylic acid hydrazide.

Fusion point; 218-225¾.

5- (4-Chlorophenoxy) -4-methoxy-methyl} p -caroline-3-carboxylic acid hydrazide.

Fusion point; 194-198¾.

5 "isopropoxy-4-methyl-β-carboline-3-carboxylic acid hydrazide.

Fusion point; 240-243Â °.

6,7-Dimethoxy-4-ethyl-β-carboline-3-carboxylic acid hydrazide *

Fusion point; 253-255¾ *

6-Benzyloxy-4-ethyl-β-carballe-3-carboxylic acid hydrazide.

Fusion point; 265-268¾. 6-Benzyloxy-3-phenyl-4-metexymethyl-β-carboline. - - - - - - - - - - - - - - - - - - - - - - - - - A solution of the compound of formula (II): ## STR1 ## nnl < ll * r

476 mg of 3-bromo-6-benzyloxy-4-methoxymethyl-4-carboline are dissolved in 10 ml of toluene and 5 ml of ethanol, 41 mg of tetrakis (triphenylphosphine) (O) and stirred for 5 minutes under argon. 177 mg of phenytoic acid and 1.5 ml of a 2M solution of

sodium hydroxide and then heated for 3 hours at 95 DEG C. After concentration the residue is partitioned between ethyl acetate and washed with water and saturated sodium chloride solution. After drying, filtration and concentration, the residue is recrystallized from 3-benzyloxy-3-phenyl-4-methoxymethyl-3-methoxymethylacetamide, mp 205-206 ° C (ethanol, methylene chloride , hexane)

The following compounds are prepared analogously;

5-benzyloxy-4-methoxymethyl-3- (2-thienyl) -choline hydrochloride Melting point: 1 9-191Â ° C

5-tenzyloxy) -4-methoxyphenylethyl-3- (2-pyrrolyl) - [t -butanol] Melting point; 203-205 ° C

6-tenzyloxy-4-methoxymethyl-3- (2-thienyl) -β-tartrate Melting point: 179 ° C

6-tenzyloxy-4-methoxymethyl-3- (3-thienyl) -β-cardoline Melting point 211-213 ° C

6-benzyloxy-4-methoxymethyl-3- (2-tert-butyl) -β-tartrate Melting point: 195 - 196 ° C 6-benzyloxy-4-methoxymethyl- 224-226Â ° C

6-tenzyloxy-4-methoxymethyl-3- (2-methoxyphenyl) -β-tartoline Melting point: 202 ° C

Example 26 Preparation of 6-benzyloxy-3-thioacetoxy-4-methyl-4-thiazole-4-carboxylate -methoxymethyl-9-tosyl-β-cardol in 50 ml of thioacetamide -0.07 S ethanol. After concentration, the residue was chromatographed on silica gel with cyclohexane.

hexane-ethyl acetate: 1: 1 as eluent: 0.600 g of 6-benzyloxy-4-methoxyethyl-3- (2-methyl-4-thiazolyl) ) -9-tosyl-β-carboline, m.p. 131-182Â ° C.

E-Bengyloxy-4-Hetoxymethyl-3- (2-phenyl-4-thiazolyl) -9-tosylcarboline is prepared analogously. 0.260 g of 6-benzyla-4-methoxymethyl-3- (2-methyl-4-thiazolyl) -9- (0.015 g of sodium in 30 ml of methanol). After evaporation of the organic phase the residue and silica gel were rinsed with hexane: acetone (1300 g) 700 g (0.180 g) of 5-benzyloxy-4-methoxymethyl-3- (2-methyl-4-thiazolyl) carbonyl, m.p. 260Â ° C (with decomposition) is obtained.

In an analogous manner, 6-benzyloxy- is prepared. -4-methoxymethyl-3- (2-phenyl-4-thiazolyl) -bolboline, m.p. 134-135 ° C.

EXAMPLE 3 6-Benzyloxy-4-methoxymethyl-3- (5-oxazolyl) -β-carboline A suspension of 1 g of powdered potassium carbonate in 30 ml of methanol was added 1.04 g of 6-benzyloxy-4- -methoxymethyl- [b-carboline-3-carbaldehyde and 0.68 g of tosylmethyl isocyanate. The reaction mixture is stirred first for 2 hours at room temperature and then refluxed for 1 hour. After evaporation the residue is taken up in 100 ml of ethyl acetate and the organic phase is washed twice with 50 ml of The combined organic extracts were dried over sodium sulfate, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was evaporated with ether to give 6-benzyloxy-4-methoxymethyl-3- ( 5-oxazolyl) -pi-carboline, m.p. 208-210 ° C. -18-

Example 4 5-Benzyloxy-4-methoxymethyl-5- (5-ethyl-1 H -3,4-oxafliazol-2-yl) - (β-carboline λ, a 0 ° C suspension of β-benzyloxy carboxylic acid methyl ester in 20 ml of methanol is added 1.6 g of orthopropionic acid triethyl ester and then refluxed for 4 hours. After further concentration 20 ml of n-butanol and 0.114 g of potassium tert-butoxide were added to the residue and heated to reflux for a further 5 hours. After distillation of the solvent the residue was taken up in methylene chloride and washed with a saturated solution of sodium hydrogencarbonate and a solution of sodium chloride The organic phase is dried, filtered and concentrated The residue is chromatographed on silica gel with methylene chloride: ethanol, 5-Benzyloxy-4-methoxy-3-methyl-3- (3-oxo-1,3-oxadiazol-2-yl) - N -carboline (0.236 g), mp 230-233 ° C

The following compounds are prepared analogously: 6-benzyloxy-4-methoxymethyl-3- (5-methyl-1,3,4-oxadiazole-2-yl) -β-carboline.

234-335Â ° .06 * 7-dimethoxy-4-ethyl-3- (5-methyl-1 *, 3 * 4-oxadiazole-5-yl) -p-carboline.

Melting point: 265-268 ° C. 6-benzyloxy-4-ethyl-3- (5-methyl-1,3,4-oxadiazole-2-yl) - 8 -carboline.

Melting point: 259-260 ° C. 5- (4-chlorophenoxy) -4-methoxymethyl-3- (5-methyl-1 H -3,4-oxadiazole-2-yl) -b-carboline, m.p. 257-259 ° C. 19 -

5- (4-chlorophenoxy) -4-methoxymethyl-3- (5-n-butyl-1,3,4-oxadiazol-2-11) -β-carboline.

Fusion point; 5-oxo-oxymethyl-1,5-oxadiazol-2-yl) -benzoic acid; -caroline.

Fusion point; 3- (5-Methoxymethyl-1,3,4-oxadiazol-2-yl) -β-carboline.

Fusion point; 216-218¾. 6-benzyloxy-4-methoxymethyl-3- (5-chlorophenyl) -1,3,4-oxadiazol-

Fusion point; 235-237Â °. 5-isopropyloxy-4-ethyl-3- (5-chloropropyl-1,3,4-oxadiazole-2-yl) -β-carboline.

Fusion point; 228-232¾. 5-isopropyloxy-4-methyl-3- (5-Botoxymethyl-1,3,4-oxadiazole-2-yl) -3-carboline.

Fusion point; 220-222¾. 5-benzyloxy-4-methoxymethyl-3- (5-ethoxymethyl-1,3,4-oxadiazole-2-yl) -β-carboline *

Fusion point; 195-198. 5-benzyloxy-4-methoxymethyl-3- (5- [1-yl] -1,4-oxadiazole-2-yl) p-carboline.

Fusion point; 215-216¾. Benzyloxy-4-methoxymethyl-3- (5-H -1,3,4-oxadiazole-2-yl) -carboline.

Fusion point; 200-205¾. Benzyloxy-4-methoxymethyl-3- (5-H -1,3,4-oxadiazole-2-yl) -benzoic acid. ; Fusion point; 233-235¾ «1 - 20 -

Claims (1)

* 1 (4-fluorobenzyl) -2-methoxymethyl-3- (5-ethyl-> 1,3,4-diazale-2-yl) p-carboline Melting point 243-244 ° C, (5-amino-1,2,4-triazol-2-yl) -p-carboline 0.376 g of Mdrazide of 3-carboxylic acid in 10 ml of methanol was treated with 0.106 g of bromoanane and dried for 1 hour at 40 DEG-45 DEG C. After cooling, The residue was dissolved in water and dried under stirring with cyclohexane / ethyl acetate to give 0.23 g of 6 -benzyloxy] methoxymethyl-3- (5-methoxytetrahydro-3-oxadiazol-2-yl) -pyrazole, m.p. 290-293 ° C., BBI BI 0 APOE S Compounds of -formula I Ϊ, - 21 â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ means hydrogen or C1-4 -alkyl means hydrogen, C1-4 alkyl, or a phenyl group * benzyl or phenoxy optionally substituted, and denotes hydrogen, C1-4 alkyl or a phenyl, behzyl, heteroaryl, or heteroaryl optionally substituted benzocon diene. B4-a signifies hydrogen, alkyl or alkoxy-O-.beta.-allyl-1-2 * and B ? means an aryl or heteroaryl group which is optionally substituted one or more times by C1-4 alkyl, C1-4 alkyl, halogen, C1-4 alkoxy, -alkyl-O-amino or amino and the like isomers and acid addition salts thereof. Benzyl-4-methoxy-β-methoxy-β-carboline 5-benzyloxy-4-methoxymethyl-3- (2-thienyl) -β-carboline 5-benzyloxy-4-methyl oxo-4-methoxy-4-methoxymethyl-3- (2-pyridyl) carbamoyl-6-benzyloxy-4-methoxymethyl-3- 2-methoxyphenyl) -β-carboline 6-Benzyloxy-4-methoxymethyl-3- (5-tert-butoxy-4-methoxy- asalyl) -? 5 -carboline 5-Enzyloxy-4-methoxymethyl-3- (5-ethyl-1,3,4-oxadiazol-2-yl) 6,7-dimethoxy-4-ethyl-3- (5-methyl-1,3,4-oxadiazol-2-yl) -carboline R 5 -Ace-Xn III in which P has the abovementioned meaning, R 1 denotes a metal atom, denotes a halogeno, heterocyclic or C 1 -C 4 -alkyl and is (are) an integer from 1 to 3; cyclizing a compound of formula In which R3 and R4 have the meanings given above. with orthoesters of carboxylic acids to give compounds of formula I in which is meant a 1,5,4-oxadiazole-2-yl group, which may be optionally substituted by C1-4 alkyl, C1-4 alkoxy- cycloalkyl, or cyclized with bromocyano to give a compound of formula I in which it means a 5-amino-1,3,4-triazolyl group, : (a) cyclization of a compound of the formula V: Wherein R 2 and R 3 have the abovementioned meanings; Z represents oxygen and is hydrogen or a protecting group, for thiocarboxylic acid amides, to give compounds of the formula I in which: R 3 is a thiazol-4-yl group optionally substituted at the 2-position and then, as the case may be, the removal of the protecting group, or (d) a compound of the formula YI Wherein in the presence of bases, a compound of formula X is obtained in which bP represents a compound of formula oxazole-5-yl group or, if desired, the benzyl group is subsequently removed or, when a hydroxyl group is present, its etherification is carried out, or the isomers are separated or the compounds obtained are converted into the addition salts thereof of acid. The applicant claims the priority of the German application, filed on June 15, 1991 under ST 2 * P 41 20 109.4. Lisbon, June 15, 1992 0 ΑΘΜΪΕ OFFICIAL »A pffiOPKSEDABE BfflTEJSTBIAS - 26 -