FI88035B - Process for the preparation of novel therapeutically useful β-carboline-3-oxadiazole derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of novel therapeutically useful β-carboline-3-oxadiazole derivatives, substituted in the 5 or 6 position, of the formula I <IMAGE> wherein R1 is C1-4 alkyl or optionally phenyl substituted with fluoro; R5 is hydrogen, C1-4 alkyl, 2,2,2- trifluoroethyl or phenyl; z is sulphur or oxygen; R4 is hydrogen, C1-4 alkyl or C1-4-alkoxy-C1-4-alkyl, and R2 is hydrogen, C1-4 alkyl or cycloalkyl.

Description

j 8 D O 3 5 »

Process for the preparation of new therapeutically useful β-carboline-3-oxadiazole derivatives

Divided by application 86 4618 5

The invention relates to a process for the preparation of new therapeutically useful 5- or 6-substituted 6-carboline-3-oxadiazole derivatives of the formula I.

B

wherein R 1 represents C 1-4 alkyl; R 5 represents hydrogen, C 1-4 alkyl, 2,2,2-trifluoroethyl or phenyl; Z represents sulfur or oxygen; R 4 represents hydrogen, C 1-4 alkyl or C 1-4 alkoxy-C 1-4 alkyl, and R 2 represents C 1-4 alkyl.

The compounds prepared by the process of the invention have valuable pharmacological properties. They "... act in particular on the central nervous system and are thus suitable for use as psychiatric drugs.

The compounds according to the invention surprisingly show better psychoactive properties in a pharmacological test compared to the A-ring unbranched β-carbolines described in EP 54,507, as shown in Table 1.

2 3G035

table 1

B

10 ic50 ed50 ptz ng / ml mg / kg ED50

Ra R4 X in (mg / kg) __vitro_vivo_ 5-CH2OC2H5 CH3 COOC2H5 0.8 1.0> 100 15 6-CH2OCH3 CH3 C00C2H5 0.45 2.0> 100

0 N

5-CH (CH3) OC2H5 CH3 - (li 0.3 0.09 0.4 ^ _JL_c2h5

20 O — N

5-CH (CzH5) OC2H5 CH3 ~ (; | 0.4 3 0.6 N-L “C2H5

: .0 - N

5- CH (C2H5) OC2H5 CH2OCH3 0.2 3 0.3 25 n C2H5

IS

;;; 6-CH (CH3) OC2H5 C2H5_ / .j 0.7 1.1 2.3 n-L-c2h5

30 EP-161 574 0_N

: 5-CH2OCH3 CH3 -I 0.3 1.0> 30 N-J-C2H5 FI-73 427

····; 0 N

6- Br H / il 2.8 26> 100 1 i

JL

N —C2H5 3 L ’C O 3 5

It is known that certain sites in the central nervous system of vertebrates have a clear specific affinity for the binding of 1,4- and 1,5-benzodiazepines [R. F. Squires and C. Braestrup, Nature (London) 266 (1977), p.

5,734]. These sites are termed benzodiazepine receptors.

The pharmacological properties of the compounds of the invention were determined by examining the binding of radiolabeled flunitrazepam from es-10 sea buckthorn to benzodiazepine receptors.

The displacement activity of the compounds of the invention is expressed as IC50 and ED50 values. The IC50 value is the concentration that produces 50% displacement of the specific binding of 3 H-flunitrazepam (1.0 nM, 0 ° C) in samples with a total volume of 0.55 ml of, for example, rat membrane suspension.

The displacement test is performed as follows: 0.5 ml of untreated rat forebrain in 25 mmol KH 2 PO 4 (pH 7.1) (5-10 mg tissue / sample) is incubated for 40-60 minutes at 0 ° C together with 3H- f with lunitrazepam (specific activity 87 Ci / mmol; 1.0 nM). After incubation, the suspension is filtered through a laser filter and the radioactivity is riveted with a scintillation counter.

The experiment is then repeated, however, so that before; ·; Addition of 25 radiolabelled benzodiazepines * · Add a specified amount or excess of a compound with displaceable activity. Based on the values · ... · obtained, the IC50 value can then be calculated.

The ED50 value is the dose of test compound that reduces the specific binding of flunitrazepam to the benzodiazepine receptor in living brain by 50% of the control value.

%

The in vivo test is performed as follows:

Groups of mice are injected with test compound 35 normally intraperitoneally, i.e., intraperitoneally, in different doses. After 15 minutes, mice are injected intravenously with 3H-flunitrazepam. After a further 20 minutes, the mice are sacrificed, their forebrain is removed, and the meninges are specifically bound.

5 radioactivity is measured with a scintillation counter.

In the pharmacological test, the compounds according to the invention show a particularly anxiolytic effect, i.e. an alleviation of anxiety and tension conditions, as well as an anticonvulsant effect.

10 To investigate the anticonvulsant effect, the onset of seizures induced by pentylenetetrazole (pentazole) was studied.

Pentazole was administered as 150 mg / kg hydrochloric acid solution (pH 2-3) by subcutaneous injection 15 to 30 minutes after intraperitoneal administration of the test compound. This amount causes twitching and continuous convulsions that lead to death in untreated animals. Both the number of mice that experienced seizures and the number of mice that died 30 minutes after pentazole administration are recorded.

The ED50 values reported in the table were determined according to the method of Licht-field and Wilcoxon [J. Pharmacol. Exp. Ther. 96 (1949), ss. 99-103] in an amount of an antagonistically active substance that protects 50% of the animals from convulsions and death.

The new compounds of formula I have valuable pharmacological properties. They affect the central nervous system in particular and are therefore suitable for use as psychiatric drugs. The compounds can be used in particular in the treatment of anxiety and pain conditions associated with depression, as well as in the treatment of epilepsy, sleep disorders, spasticity, and muscle tension relief, muscle relaxation during anesthesia. The compounds prepared according to the invention also show 35 memory loss and memory enhancing properties.

i in O? r

° o υ υ O J

The compounds of the formula I are prepared according to methods known per se, for example in such a way that the compound of the formula II 5 f

d1 1 COOH

B

10 wherein R 1, R 5, Z and R 4 are as defined above, is reacted with a compound of formula

NOH

2 S

15 R2-C

NH 2 in which R 2 represents C 1-4 alkyl, to the β-carboline-3-oxadiazole derivative of the formula I.

To attach the 1,2,4-oxadiazol-5-yl group, condense the β-carbolinecarboxylic acid of formula II, amidocaiimil, 1.1a, of the formula R 2 -C (= NOH) NH 2 in an inert solvent boiling above 100 ° C. and is inert to the reactants, returning the reaction mixture at cooling temperature. Suitable solvents for use in the condensation reaction include, for example, toluene and dimethylformamide. Suitably the free β-carboline-3-carboxylic acid is suitably activated prior to the condensation reaction. For this purpose, the free acid can be converted, for example, into a mixed anhydride, an activated ester or a chloride.

35, ::: 035 p

Activation to the imidazole with imidazole / thionyl chloride (or also carbonyldiimidazole) in an aprotic solvent such as dioxane, tetrahydrofuran, dimethylformamide or N-methylpyrrolidone at a temperature between 0 and 50 ° C, preferably at room temperature, has also proved useful.

The following examples are intended to illustrate the method of the invention.

Example 1 5- (1-Ethoxy-ethyl) -4-methyl-β-carboline-3-carboxylic acid ethyl ester A) to 25 g (83 mmol) of 1-tosyl-4-hydroxymethyl-indole in 600 ml of methylene chloride 72.5 g (830 mmol) of manganese IV-oxide were added portionwise with stirring and cooling. After stirring for 4 hours, the solution was filtered and evaporated.

Yield: 22.8 g of 4-formyl-1-tosylindole; mp. 140-145 ° C.

B) 22.6 g (86.7 mmol) of chlorotitanium triisopropoxide 20 were suspended in 50 ml of ether under a nitrogen atmosphere at -78 [deg.] C. without the exclusion of moisture. To this was added dropwise 86.7 mmol of methylmagnesium iodide in 90 ml of ether. The resulting yellow solution stirred for 5 minutes at -78 ° C. Finally, 20 g (66.9 25 mmol) of 4-formyl-1-tosylindole in 150 ml of anhydrous tetrahydrofuran were added dropwise. At -78 [deg.] C., stirred for a further 75 minutes at room temperature, then 25 ml of saturated ammonium fluoride solution and 250 ml of saturated brine were carefully added successively, the organic phase was separated and the aqueous phase was extracted twice with 200 ml of ethyl acetate. The combined organic phases were dried, filtered, evaporated and the residue was taken up in isopropyl ether.

Λ f "\ ρ 7 ·: tob

Yield: 15 g of 4- (1-hydroxyethyl) -1-tosylindole; mp. 78-80 ° C.

C) To 11.9 g (37.8 mmol) of 4- (1-hydroxyethyl) -1-tosylindole in 150 ml of methylene chloride at 5 room temperature under argon was added 13.3 g (85 mmol) of ethyl iodide, 6.7 g. g of tetrabutylammonium hydrogen sulfate and 6.7 g (119.3 mmol) of ground potassium hydroxide in succession. The solution was stirred for 2 hours. After filtration through diatomaceous earth, the same amount of ethyl iodide, tetrabutylammonium hydrogen sulfate and potassium hydrogen oxide were added again to the solution. The reaction mixture was stirred for 2 hours at room temperature, washed with 200 ml of water and the organic phase was dried, filtered and evaporated. Finally, chromatography on silica gel using cyclohexane / ethyl acetate (8: 2) gave 8.5 g of 4- (1-ethoxyethyl) -1-tosylindole as an oil.

D) 3.75 g (10.9 mmol) of 4- (1-ethoxyethyl) -1-tosylindole suspended in any ethanol were added to a freshly prepared solution of 628 mg (27 mmol) of sodium in 25 ml of ethanol, and the mixture was heated to reflux for 1.5 hours. After evaporation of the solvent, the residue was dissolved in 50 ml of water and extracted 3 times with ethyl acetate. The combined organic phases were washed with water, dried, filtered and evaporated. Yield: 2 g of 4- (1-ethoxyethyl) -indole; was used for the final reaction without further purification.

E) A solution of 15 g of acetaldehyde-isopropylimine in 5 ml of toluene was added at 10 ° C to a solution of 2 g of 4- (1-ethoxyethyl) -indole in 10 ml of glacial acetic acid. minutes. After 36 hours at 0-5 ° C, the solution was stirred in 50 ml of ice-water. The mixture was extracted with toluene and the pH of the aqueous phase was adjusted to 12 with 2N sodium hydroxide solution under ice-cooling. The solution was extracted with ether, washed with half-saturated brine and the solution evaporated in vacuo. The crude product (2.8 g) was used for the final reaction without further purification.

F) 2.8 g of the amine obtained from E) in 150 ml of toluene and 1.3 ml of nitroacetic acid ethyl ester were kept for 4 hours at 80 ° C under a nitrogen atmosphere. After cooling, it was washed with 0.1 N HCl and water. The solvent was distilled off, and the crude product (3.3 g) was chromatographed on silica gel using hexane / ethyl acetate.

Yield: 2.7 g of 4- (1-ethoxyethyl) -indole-3- (2-nitro-3-methyl) -propionic acid ethyl ester as an oil.

G) 2.65 g (7.6 mmol) of 4- (1-ethoxyethyl) -indole-3- (2-nitro-3-methyl) -propionic acid ethyl ester were hydrogenated at room temperature and normal pressure for 1.25 hours in 140 ml of ethanol. using 4 ml of Raney nickel (type B

15 115 Z; Degussa AG). Finally, the solution was filtered and evaporated.

Yield: 2.3 g of 4- (1-ethoxyethyl) -indole-3- (2-amino-3-methyl) -propionic acid ethyl ester as an oil.

H) 2.17 g (6.82 mmol) of 4- (1-ethoxyethyl) -indole-3-20 (2-amino-3-methyl) -propionic acid ethyl ester were dissolved in 30 ml of xylene and added to 231 mg of suspended paraformaldehyde. ml of xylene. The reaction mixture was refluxed for 75 minutes. It was then evaporated and chromatographed on silica gel using - 25 methylene chloride / ethanol (10: 1).

Yield: 1.35 g of 5- (1-ethoxyethyl) -4-methyl-1,2,3,4-tetrahydro-6-carboline-3-carboxylic acid ethyl ester.

:) I) 2.25 g (6.8 mmol) of 5- (1-ethoxyethyl) -N-methylamine, 3,4-tetrahydro-β-carboline-3-carboxylic acid ethyl ester in 20 ml of dimethyl sulfoxide were stirred 437: mg of sulfur in an argon atmosphere at a bath temperature of 140 ° C for 30 minutes. After evaporation, the oily residue was chromatographed on silica gel using first hexane / acetone (1: 1) and finally methylene chloride / ethanol-35 (10: 1).

9 UCGSS

Yield: 426 mg of 5- (1-ethoxyethyl) -4-methyl-β-carboline-3-carboxylic acid ethyl ester; mp. 159-160 ° C. Accordingly, the following were prepared: 5- (1-methoxyethyl) -4-methyl-β-carboline-3-carboxylic acid ethyl ester; mp. 161-163 ° C; 5- (1-Propoxy-ethyl) -4-methyl-β-carboline-3-carboxylic acid ethyl ester; mp. 155-156 ° C; 5- (1-Ethoxy-propyl) -4-methyl-β-carboline-3-carboxylic acid ethyl ester; mp. 185-186 ° C; 5- (1-Ethoxy-ethyl) -4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester; mp. 144-148 ° C; 5- (1-propoxyethyl) -4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, and 5- (1-methoxyethyl) -4-ethyl-β-carboline-3-carboxylic acid ethyl ester; mp. 127-130 ° C.

The required carboxylic acids were prepared as follows: 500 mg of 5- (1-ethoxyethyl) -4-methyl-β-carboline-3-carboxylic acid ethyl ester was refluxed for 3 hours with 5 ml of 1N sodium hydroxide solution and 20 ml of ethanol. Finally, it was acidified with glacial acetic acid, filtered off with suction and washed with water. 400 mg of 5- (1-ethoxyethyl) -4-methyl-β-carboline-3-carboxylic acid were obtained, which was allowed to react further after drying well over phosphorus pentoxide in vacuo.

:. In a similar manner there were prepared: 6- (1-hydroxyethyl) -β-carboline-3-carboxylic acid, 6- (1-hydroxyethyl) -4-methyl-β-carboline-3-carboxylic acid, 6- (1-methoxyethyl) -4-methyl-β-carboline-3-carboxylic acid, 6- (1-ethoxyethyl) -4-methyl-β-carboline-3-carboxylic acid, 6- [1- (2,2,2-trifluoroethoxy) ) -ethyl] -4-methyl-β-carboline-3-carboxylic acid.

10 ο τ n 7 r '' uUJ3 6- (1-Isopropoxyethyl) -β-carboline-3-carboxylic acid, 6- (1-ethylthioethyl) -4-methyl-β-carboline-3-carboxylic acid, 6- ( 1-ethoxyethyl) -4-ethyl-β-carboline-3-carboxylic acid 5-po, 6- (1-butoxyethyl) -β-carboline-3-carboxylic acid, 5- (1-ethoxypropyl) -4-methyl-S- carboline-3-carboxylic acid, 5- (1-ethoxyethyl) -4-methoxymethyl-β-carboline-3-carboxylic acid, 6- (1-propoxyethyl) -6-carboline-3-carboxylic acid, 5- ( 1-methoxyethyl) -6-carboline-3-carboxylic acid, 6- (1-methoxyethyl) -6-carboline-3-carboxylic acid, 6- (1-hydroxybenzyl) -5-carboline-3-carboxylic acid, 6- (1 hydroxyethyl) -4-ethyl-β-carboline-3-carboxylic acid, 6- (1-phenoxyethyl) -4-methyl-6-carboline-3-carboxylic acid and 5- (1-ethoxypropyl) -4- methoxymethyl-6-carboline-3-carb-20-acid.

Example 2 3- [5- (3-ethyl-1,2,4-oxadiazol) -yl] -5- (1-methoxyethyl) -4-methyl-β-carboline to 500 mg of 5- ( 1-Methoxyethyl) -4-methyl-β-carboline-3-carboxylic acid was added 500 mg of carbonyldiimide in 20 ml of anhydrous dimethylformamide at room temperature and stirred for 4 hours at this temperature. Finally, 600 mg of propion dioxide was added and stirred overnight at room temperature. After evaporation of the solvent, it was dissolved in 50 ml of toluene and boiled for 4 hours in a water separator. After dilution with ethyl acetate, the mixture was shaken successively with water and brine, dried, filtered and evaporated. The residue was chromatographed on silica gel using hexane / acetone (1: 1) as eluent. 250 mg of compound were obtained; melting point 213-214 ° C.

Correspondingly, the following compounds were prepared: 3- [5- (3-ethyl-1,2,4-oxadiazol) -yl] -6- (1-hydroxyethyl-5H-β-carboline, mp 220-231 ° C, 4 - [5- (3-ethyl-1,2,4-oxadiazol) -yl] -4-methyl-6- (1-hydroxyethyl) -β-carboline, mp 263-267 ° C, 3- [5- (3-ethyl-1,2,4-oxadiazol) -yl] -4-methyl-6- (1-methoxyethyl) -β-carboline, mp 255-265 ° C, 3- [5- (3- ethyl-1,2,4-oxadiazol) -yl] -4-methyl-6- (1-ethoxyethyl) -β-carboline, mp 172-176 ° C, 3- [5- (3-ethyl-1, 2,3-oxadiazol) -yl] -4-methyl-6- [1- (2,2,2-trifluoroethoxy) -ethyl] -β-carboline, mp 140-155 ° C, 3- [5- (3-ethyl-1,2,3-oxadiazol) -yl] -4-ethyl-6- (1-ethoxyethyl) -β-carboline, mp 192-195 ° C, 3- [5- (3-ethyl) -1,2,4-oxadiazol) -yl] -4-methyl-5- (1-ethoxyethyl) -β-carboline, mp 180-184 ° C, 3- [5- (3-ethyl-1,2 , 4-oxadiazol) -yl] -6- (1-butoxyethyl-20'-yl) -β-carboline, mp 220-226 ° C, 3- [5- (3-ethyl-1,2,4-oxadiazole) -yl] -4-methyl-5- (1-ethoxypropyl) -β-carboline, mp 202-204 ° C, 3- [5- (3-ethyl-1,2,4-oxadiazol] -yl] -4-methoxymethyl-5- (1-ethoxyethyl) -β-carboline; mp. 175-178 ° C, 3- [5- (3-ethyl-1,2,4-oxadiazol) -yl] -6- (1-isopropoxyethyl) -β-carboline; mp. 225 ° C, 3- [5- (3-ethyl-1,2,4-oxadiazol) -yl] -4-methyl-6- (1- (isopropoxyethyl) -β-carboline; mp. 179-184 ° C, 3- [5- (3-ethyl-1,2,4-oxadiazol) -yl] -4-methyl-6- (1-30 ethylthioethyl) -β-carboline; mp. 165-170 ° C, 5- (1-methoxyethyl) -4-ethyl-3- [5- (3-ethyl-1,2,4-oxadiazol) -yl] -β-carboline; mp. 195-202 ° C, 6- (1-methoxyethyl) -3- [5- (3-ethyl-1,2,4-oxadiazol) -yl] -β-carboline; mp. 137-141 ° C, 12 3 3 035 6- (1-phenoxyethyl) -4-methyl-3- [5- (3-ethyl-1,2,4-oxadiazol) -yl] -β- carboline; mp. 150-160 ° C, 6- (1-hydroxybenzyl) -3- [5- (3-ethyl-1,2,4-oxadiazol) -yl] -β-carboline; mp. 124 ° C, 6- (1-hydroxyethyl) -4-ethyl-3- [5- (3-ethyl-1,2,4-oxadiazol) -yl] -β-carboline; mp. 174-177 ° C, and 5- (1-ethoxypropyl) -4-methoxymethyl-3- (3-ethyl-1,2,4-oxadiazol-5-yl) -β-carboline.

Claims (6)

R 5 represents hydrogen, C 1-4 alkyl, 2,2,2-trifluoroethyl or phenyl; Z represents sulfur or oxygen; R 4 represents hydrogen, C 1-4 alkyl or C 1-4 alkoxy-C 1-4 alkyl, and R 2 represents C 1-4 alkyl, characterized in that the compound of formula R 4 represents a C 1-4 alkyl; R 5 represents hydrogen, C 1-4 alkyl, 2,2,2-trifluoroethyl or phenyl; Z represents sulfur or oxygen; and R 4 represents hydrogen, C 1-4 alkyl or C 1-4 alkoxy-C 1-4 alkyl, '35 14:' -> n C v · 'b J vj is reacted with a compound of formula, NOH 2 S 5 R2-C Nvnh2 wherein R2 is C1-4 alkyl. iV 'o? Γ 15 οουύΟ For use in the preparation of therapeutically active compounds with 5 or 6 substituents of β-carboline-3-oxadiazole derivatives of formula I „4 R1 f H color R1 is C1-4 alkyl; R5 is methyl, C 1-4 alkyl, 2,2,2-trifluoroethyl or phenyl; Z betecknar svavel elly syre; R4 is selected from the group consisting of C1-4-alkyl or C1-4-alkoxy-C1-4-alkyl, and R2 is C1-C4-alkyl, 20 parts of which are selected from the group consisting of R4 and C1-4-alkyl. . H - color R1 is C1-4 alkyl; 30 R5 is methyl, C 1-6 alkyl, 2,2,2-trifluoroethyl or phenyl; Z betecknar svavel elly syre; and R 4 is a C 1-4 alkyl or C 1-4 alkyl or C 1-4 alkoxy-C 1-4 alkyl ring having a reagent with a formulation of 35 'to N 7 and NOH R 2 -C 2 NH 2 5 color R 2 is C 1-4. 4-alkyl. i