FI56379C - FRAME FOR THE PREPARATION OF THERAPEUTIC THERAPEUTIC 6-AZA-3H-1,4-BENZODIAZEPIN-2-ONER OCH DERAS SALTER - Google Patents

Description

r.i, „. ANNOUNCEMENT * ISU,,,, q wj | lBJ <"> utlXgcningsskrift bbJ / 9 B C (45) Patent granted on 10 01 1900

Patent patent ^ '(51) Kv.lk. * / Lnt.CI. * C 07 D 471/04 C O? D 243/06 FINLAND —FINLAND (21) Patent application - PatentansOknlnf 771584 (22) Hakamlspllvl - An * eknlng * dtj l8.05 · 77 (23) Introductory note - Glltighetsdag 30.11.72 (41) Become public - Bllvlt offentllg j_8.05.7

Patent and registry offices » Date of issue and date of publication

Patent and regulatory authorities' Anniölum utligd och utl.skrtften publlc «r * d 28.09.79 (32) (33) (31) Pyydatty etuoikeus —Begird prlorltet 09.12.71

Austria-Österrike (AT) A 1θ6θ4 / 71 (71) Deutsche Gold- und Silber-Scheideanstalt vormals Roessler, Weiss-Frauenstrasse 9 »6000 Frankfurt 1, Federal Republic of Germany-Förbunds-republiken Tyskland (DE) (72) Walter von Bebenburg, Buschlag , Heribert Offermanns, Grossauheim,

Federal Republic of Germany-Förbundsrepubliken! Fyskland (DE) (74) Oy Kolster Ab (54) Method for the preparation of new therapeutically useful 5-aza-3H-1,1'-benzodiazepin-2-ones and their salts -FÖrfarande för framställning av nya terapeutiskt -aza-3H-1,1-benzodiazepin-2-one and other salts (62) Separated from application 3390/72 (patent 54710) -Avdelad frän trap 3390/72 (patent 54710)

The invention relates to a process for the preparation of new therapeutically useful 6-aza-3H-1,1-benzodiazepin-2-ones of the general formula r ° \ || CH-R 1, (I) R 1 = m wherein R 1 is a halogen atom, R 2 represents hydrogen, halogen or a trifluoromethyl group, is a hydroxy group or an aliphatic cell having 2 to 6 carbon atoms. Ia is a hydroxy group acylated with a mono- or dicarboxylic acid S6379 2, and R 1 is hydrogen or a lower alkyl group, and for the preparation of their optical isomers and salts thereof.

The halogen atom is chlorine, fluorine or bromine, preferably chlorine or fluorine. Said lower alkyl groups are alkyl groups having 1 to 6 carbon atoms, especially 1-U carbon atoms. Aliphatic acyl groups contain from 2 to 6 carbon atoms, and in particular saturated acyl groups. Examples of alkyl groups include methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, isobutyl and acyl groups such as acetyl, propionyl, butyryl, pentanoyl, isovaleroyl and isobutyryl.

The compounds of the invention have valuable pharmacodynamic properties. For example, they have psychosedative and especially anxiolytic properties. In addition, they also have anti-inflammatory effect.

Pharmacological tests and their results

Methodology (experimental conditions):

Kardiatsoli- okki method?:

Experiments with the cardiazole shock method were performed according to Berger, F.M. et al. J. Pharmacol. Exper. Therap. 116, 337-3 ^ 2 (1956).

Mice lead. Subcutaneous injection of cardiazole 150 mg / kg first for short-term, then for long-term and severe seizures, followed by death of all animals involved within 10-15 minutes. Pre-administration (1 hour before) of an oral anticonvulsant at different doses reduces the initial lethal effect of cardiazole according to the dose. The percentage of surviving animals in the different experimental groups gives a ED 50 as a result of a dose-response plot.

The ED 50 is the dose that produces a clear anticonvulsant effect in 50% of the animals studied.

Rotating rod test In this experiment, animals (mice) are placed on the rotating rod for the first time 15 minutes after administration of the substance, then every 15 minutes (test time 120 minutes), and animals that fall down within 2 minutes are considered positive. As a percentage of the number of fallen animals, time-effect curves are plotted and the area bounded by them is recorded as a percentage of effect in the probability network, dose-effect lines and ED 50 values are obtained. An ED value of 50 mg / mouse body weight indicates the dose at which 50 μl of all animals show a typical atactic effect.

3

„. S637J

Results of pharmacological tests Table:

Example number Substance ED 50 mg / kg per Ataxia Ataxia

Cardiazole- Cardiazole- ^ shock 'Shock 1 D 12 539 15> 1600> 107 2 D 12 52k 2.0 89 months 3 D 12 362 16 155 9.7 h D 12 898 1.3 7.1 5.5 5 D 12 857 2k 51 ^ 21 6 D 12 721 1, ¾ 8 5.7 8 D 12 986 71 1000 -1¾ 3 0, U7 2.0 ¾, 2 FI advertisement publication ¾6 8¾ 9 ^ extrapolated

The experimental results show that the compounds according to the invention have a significantly lower atactic side effect than the known compounds.

The novel compounds are prepared according to the invention as a compound of general formula b3.

"-CN (II> hf LZ" 2 R1- ^ SC = .N ^ 0 \ - «2 wherein R ^, R ^ and R ^ have the same meaning as above, is treated at 0-150 ° C with lower aliphatic mono and acid anhydrides of dicarboxylic acids, in which case the nitrogen atom in the 1-position may also have an acyl group (when R 1 is hydrogen in the starting compound), after which this acyl group is cleaved and optionally cleaved from the compound of formula (i) with the substance in a solvent or suspension medium at temperatures of 20-150 ° C.

It S6379

The process according to the invention is carried out in a lower acid anhydride (e.g. acetic anhydride), optionally in admixture with an inert solvent. The method comprises a rearrangement reaction in which the oxygen attached to the N atom forms a hydroxy group on an adjacent carbon atom. This recurrence can be performed at temperatures of 0-150 ° C, especially 0-100 ° C.

The open-ended basic compounds of formula I can be converted into salts by known methods. Suitable anions for these salts are known, therapeutically acceptable acid residues.

If the compounds of formula (I) contain acidic groups, these can be converted into alkali, ammonium or substituted ammonium salts in the customary manner. Substituted ammonium salts include tertiary alkylamines, lower amino alcohols and salts of bis- and tris (hydroxyalkyl) amines (alkyl residues each having 1 to 6 carbon atoms), such as triethylamine, aminoethanol and di (hydroxyethyl) amine.

The salts of the compounds can again be prepared in the usual manner, for example by treating a solution of the salt in an organic solvent such as alcohol (methanol) with sodium carbonate or sodium hydroxide solution.

Those of the compounds of formula (i) which have asymmetric carbon atoms and which are generally obtained as racemates can be divided into optically active isomers in a manner known per se, for example by means of optically active acids. However, it is also possible to use an initially optically active starting material to give the corresponding optically active or diastermomeric form, respectively.

The compounds according to the invention are suitable for the preparation of pharmaceutical compositions.

A particularly preferred effect is for those compounds of formula (i) in which R 1 is chlorine, fluorine or bromine, represents hydrogen, or preferably fluorine or chlorine in the o-position, R 1 is a hydroxy group, and R 1 is. is hydrogen or an alkyl group containing a 1-U carbon atom, especially a methyl group.

The starting compounds used in the process according to the invention can, when they are not known, be prepared according to German application publication 2,259.

Example 1 1-Acetyl-3-acetoxy-5-o-chlorophenyl-6-aza-7-chloro-1,2-dihydro-3H-1,1-benzodiazepinone- (2) COOH_ 1 3 if · 0

Λ ___- N - C

CH - OCOCH, 6 "· 56379

Heat, under reflux for 30 minutes, a mixture of 23 g of 5-o-chlorophenyl-6-aza-7-chloro-1,2-dihydro-3-yl-1,4'-benzodiaflepinone (2) -4-oxide and 120 ml of acetic anhydride. , Then pour 700 any ice water. The crystallized material is recrystallized from methanol.

Yield 15 g, m.p. 203 ° -207 ° C.

Example 2 3-Hydroxy-5-o-chlorophenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone- (2) H

^ CH -OH

Cl_f T / ~ ~ m

300 g of potassium hydroxide solution are added with stirring to a solution of 110 g of 1-acetyl-3-acetoxy-5-o-chlorophenyl-6-aza-7-chloro-3H-1,4-benzodiazepinone (2). In 400 ml of ethanol »Stir for 30 minutes at room temperature. The pH of the clear solution is adjusted to five with acetic acid and 250 ml of water are added. Activated carbon is added to the amorphous precipitate and filtered. Add 11/21 water to the filtrate and shake with chloroform. The organic phase is dried and evaporated to dryness. The residue is crystallized twice from ethanol. Yield 23 g, m.p. 200 ° -202 ° C.

Ealmeykk λ 3-Hydroxy-5-phenyl-6-Atea-7-chloro-1,2-dihydro-3H-1,4'-benzodiazepine- (2) H

Cl _I1 Y '^ CH-OH

- N ^

O

6 56379

Heating 24 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone (2) -4-oxide with 160 ml of acetic anhydride (30 minutes in a water bath) gives 500 ml: after pouring into water, 1-acetyl-3-acetoxy-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone (2) and 3-acetoxy-5 -A-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-1,5-benzodiazepinone- (2) in. This mixture is deacetylated at 15 ° C with three portions of 30 potassium hydroxide solution and four portions of ethanol. After acidification and dilution with water, the chloroform is shaken and the chloroform residue is crystallized twice from ethanol.

Yield 11 g m.p. 177 ° C.

Example 4 1-Methyl-3-acetoxy-5- (2-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone (2)

CH

15 g of 1-methyl-5- (2-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4 the benzodiazepinone (2) -4-oxide is heated to reflux with stirring for 15 minutes in a mixture of 33 ml of acetic anhydride and 29 ml of glacial acetic acid. The mixture is cooled and seeded to crystallize the title compound. It is washed with glacial acetic acid and then with water, m.p. 178-179 ° C.

Example 5 3-Acetoxy-5- (2-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone- (2) E

01 -CX,. OF

ι ^ Γδ1 7 56379

To a stirred mixture of 1150 ml of acetic anhydride and 1020 ml of glacial acetic acid at 100 ° C are added 724 g of 5- (2-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone- ( 2) 4-oxide. The solution is then heated to 120 ° C. An exothermic reaction occurs and the mixture begins to boil. After 15 minutes, the reaction is complete and the mixture is allowed to cool on its own while stirring. The title compound separates as crystals. It is kept with water and methanol, m.p. 243 ° C (decomposes).

Example 6 3-Hydroxy-5- (2-fluorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone- (2) H 0

χ N

|| CH- OH

Cl N c _

F

O

85 g of 5- (2-fluorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone (2) -4-oxide (crude) in 130 ml of acetic anhydride are heated to 130 ° C: while stirring. An exothermic reaction then begins. This ends after 10 minutes. The reaction mixture is cooled and poured onto ice. The precipitate is filtered off and washed with water. It is a mixture of mono- and dlase-style derivatives of the desired compound. 30 g of this mixture (dry) are suspended in 100 ml of n-propanol. A solution of sodium (3 g) in 40 ml of n-propanol is added to the cooled (0-5 ° C) suspension with stirring. After 15 minutes, 700 ml of water are added and the mixture is acidified with glacial acetic acid. The desired compound crystallizes on cooling. After standing overnight, it is filtered and recrystallized from n-propanol, m.p. 177-179 ° C.

Example 7 1-Methyl-3-hydroxy-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodazepinone- (2) is

^^ TCH - OH

ci _I II // - N ^

Cl kk 56379 24 g of 1-methyl 3-acetoxy-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4 "benzodiateepinone (2) are added to the solution, with 1.3 g of sodium metal in 130 ml of n-propanol, and the mixture is stirred at room temperature for 20 minutes. A clear solution is obtained, from which part of the product precipitates as the sodium salt.

The solution is acidified with glacial acetic acid and the product is precipitated by adding 200 ml of water * The filtered compound is recrystallized from methanol. Yield 11 g, m.p. 247-250 ° C.

Example 8 1-Allyl-3-acetoxy-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone- (2) CH2-CH-CH .

1 ^ 0

N - C

24 H-OCOCH 3 O-24 g of 1-Allyl-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone- (2 ) -4-Oxide is heated to reflux with stirring for 13 minutes in a mixture of 29 ml of glacial acetic acid and 33 ml of acetic anhydride * The mixture is cooled and seeded with crystals, whereupon the desired product crystallizes * It is washed with glacial acetic acid and then with water. Yield 20 g, m.p. lj6-LTF ° C,

Claims (1)

Claim: A process for the preparation of new therapeutically useful 6-aza-3H-1,1-benzodiazepine ions of the general formula Tfy (1) (2) i «>„ <7> (J (5) U 1 is CH-E 4 wherein R 1 is a halogen atom, R 2 is hydrogen, halogen or trifluoromethyl, R 1 is a hydroxy group or a hydroxy group acylated with an aliphatic mono- or dicarboxylic acid having 2 to 6 carbon atoms, and R 1 is is hydrogen or a lower alkyl group, as well as the preparation of their optical isomers and their acid addition salts, characterized in that the compound of general formula I 2 CH (R 2) 4 wherein the residues R 2, R 2 and have the same meaning as above, or the optical isomer of this compound is treated at 0-150 ° C with acid anhydrides of lower aliphatic mono- or dicarboxylic acids having 2 to 6 carbon atoms, in which case the nitrogen atom in the 1-position (when R 1 = H in the starting compound) may also have an acyl group , after which this acyl group is cleaved, and obtained In the compounds of formula (I), the acyloxy group in the 3-position is optionally converted to the hydroxy group by saponification with a dilute acid or base in a solvent or suspension medium at temperatures of 20-150 ° C, the resulting racemates are optionally divided into optical isomers, and the resulting compounds of formula . 10 56379 For the preparation of a therapeutically active compound 6-aza-3H-1,4-benzodiazepin-2-one with the formula H * I y (2) C \ \ A, I —I — r2 color with halogen atom , Rg is a hydrogen group, a halogen or a trifluoromethyl group, a hydroxy group or a medically 2-6 cholesterol aliphatic mono- or a dicarboxylic acid acylated hydroxyl group, or a hydrogenated alkyl group, the same is an optical isomer; syraadditions-salter, kännetecknat därav, att en förening med den allmänna formuleln n> 0 „I li (k) R1 ______ S 'Λ O-- color reetema R ^, Rg ooh R ^ har ovangiven betydelse, eller en optisk isomer av denna for use at 0-150 ° C with an aliphatic aliphatic mono- or dicarboxylic acid with 2-6 cholaters, a color of the acyl group can be obtained from the quaternary reaction (R & D) of the acyl group. avspaltae, den i de erh & llna föreningarna med formeln I föreliggande aoyloxigruppen i 3-ställning In this case, the reactants of the hydroxyl group are separated from the base or the suspension at a temperature of from 20 to 150 ° C, but the effluent is optionally separated from the optics of the optimum form of the mixture. i syraadditionssalter.