DD218889B3 - PROCESS FOR PREPARING NEW 5-CARBAMOYL-10,11-DIHYDRO-5H-DIBENZ | B, FAZAZINE - Google Patents

Description

test report

Substance ED ₆₀ in mg / kg

(D) (3)

A 210 39 47

B ineffective (x) 28 28

(x) see also THEOBALD, W., et al., Arzneimittelforschung 13, 122 (1963).

As can be seen from the experimental report, B does not work against pentylenetetrazole-induced convulsions, whereas A is also protective in this model.

Noteworthy is also the twice as high compatibility of A as determined in the determination of the acute toxicity (mouse, ρ.o.) in comparison to B.

For the determination of the aritikonvulsiven effectiveness mice were used male and female sex from a standardized breeding strain. Thirty-five minutes after oral administration of the test substance A or B, 135 mg / kg of pentylenetetrazole or 1.2 mg / kg of strychnine subcutaneously or 12 mg / kg of thiosemicarbazide were injected intraperitoneally. The selected dosages of the spasms correspond to the DLg ^ ₁₀₀ and lead in untreated control animals in 100% of cases to spasm or death. The effect of the test substances A or B is measured as the ED ₅₀ value, which indicates the respective dose of A or B, in which 50% of the animals are protected against seizures (modified method according to MARUCCI, F., et al., J. J. Pharmacol., 16, 311 [1971]).

The invention will be explained in more detail by the following examples.

example 1

22.5 g (about 0.08 mol) of S-chlorocarbonyl-10-methoxy-iCH-dihydro-SH-dibenz / bjf / azepine (F.97-99 ⁰ C) are heated in 200 ml of methanol to a gentle boil and in the Solution initiated within 60 minutes of gaseous ammonia. The reaction solution is then filtered and the filtrate concentrated to dryness. This gives 24 g of 5-carbamoyl O-methoxy-10,11-dihydro-5H-dibenz / b, f / azepine as a yellowish-brownish residue, which, after recrystallization, melts from 100 ml of CCI ₄ at 146-149 ° C. A second recrystallization from the five-fold amount of n-butanol provides a colorless substance.

F. 151.5-152.5 ° C. The substance is halogen-free.

Analysis calculated for 5-carbamoyl-10-methoxy-10,11-dihydro-5H-dibenz / b, f / azepine:

C H N calculated: 71.60% 6.01% 10.42% found: 71.50% 6.20% 10.45% 71.70% 6.21% 10.66%

The starting 5-chlorocarbonyl-10-methoxy-10,11-dihydro-5H-dibenz / b, f / azepine can be prepared as follows:

34g (about 0.1 mol) S-chlorocarbonylMO-bromo-IO ,! 1-dihydro-5H-dibenz / b, f / azepine (mp 125 ° C.) are refluxed in 700 ml of methanol for 4 hours, then 400 ml of methanol are distilled off and the remaining solution, after filtration, is left to crystallize at 5-10 × 22.5g, £ 78.5% of theory δ-chlorocarbonyl-IO-metoxy-IO / 1-dihydro-5H-dibenz / b, f / azepine, almost colorless crystals, mp 97-99-C.

Example 2

The procedure is as in Example 1, but using instead of gaseous ammonia to 0.08 mol of 5-chloro-carbonyl-10-methoxy-10,11-dihydro-5H-dibenz / b, f / azepine about 0.3 mol (30 ml ) of a concentrated aqueous ammonia solution, obtained after 2 hours of reaction, ritration and concentration of the filtrate in vacuo (water jet pump) 5-CarbamoyMO-methoxy-10,11-dihydro-5H-dibenz / b, f / azepine as a yellowish-brownish discolored residue in about the same amount as in Example 1. After recrystallization from n-butanol, the product melts at 151.5-152.5 ⁰ C.

Example 3

From 28 g (about 0.1 mol) of S-chlorocarbonyl-IO-ethoxy-IO.H-dihydro-SH-dibenz / b ^ / azepine (mp 125-126Ό in 280 ml of absolute ethanol is obtained upon introduction of gaseous Ammonia by the same procedure as in Example 1, 28 g of a crude, pale yellowish product, mp 145-155 ° C. After recrystallization from acetone, 11.5 g of 5-carbamoyl-10-ethoxy-10,11-dihydro-5H- dibenz / b, f / -azepine obtained as colorless crystals, mp 161-163 ° C. The product is halogen-free Analysis calculated for 5-carbamoyMO-ethoxy-i, 0,11-dihydro-5H-dibenz / b, f / azepine:

C H N calculated: 72.30% 6.38% 9.96% found: 72.38% 6.35% 10.27%

Example 4

47 g (about 0.15 mol) of 5-chlorocarbonyl-10-allyloxy-10,11-dihydro-5H-dibenz / b, f / azepine (mp 85-87 ° C) are refluxed in 300 ml of methanol to boiling , In the bare boiling solution ammonia gas is introduced. After about 1 hour of initiation time, a gradually increasing deposition of NH ₄ Cl begins. After 3 hours reaction time, the gas introduction is terminated. Methanol is distilled off largely. The remaining dry residue is mixed with 400 ml of 50% aqueous methanol. The settling viscous layer crystallizes after some time. It is poured off the supernatant solution, added again with 200 ml of 50% methanol and filtered. The colorless crystals are washed with 50 ml of 50% aqueous methanol and dried.

F. 127-129 ° C. Yield: 36 g of S-carbamoyl-10-allyloxy-10H-dihydro-1H-dibenz / b ^ / azepine ^ 77% of theory. The product obtained is recrystallized in 4 times the amount of ethyl acetate. F. after recrystallization: 137.5 to 138 ⁰ C. Analysis calculated for 5-carbamoyl-IO-allyloxy-i 0,11-dihydro-5H-dibenz / b, f / azepine (molecular weight 294):

C H N calculated: 73.47% 6.12% 9.52% found: 73.77% 6.10% 9.70%

1δ sg

II

III

Claims (3)

A process for the preparation of novel 5-carbamoyl-10,11-dihydro-5H-dibenz / b, f / azepines of general formula I in which R represents a methyl, ethyl or alkyl group, characterized in that a compound of the general Formula II, in which R has the meaning already mentioned, in a conventional manner with ammonia. The invention relates to a process for the preparation of novel 5-carbamoyl-10,11-dihydro-5H-dibenz / b, f / azepines of the general formula I in which R is a methyl, ethyl or allyl group. The compounds of general formula I have valuable pharmacological properties and can be used in particular as psychotropic drugs. The compounds of the invention are not described in the literature. They represent new substances from the substance class of 10,11-dihydro-5H-dibenz / b, f / azepines. In addition to the known as anticonvulsant 5-carbamoyl-dibenz / b, f / azepine (carbamazepine) is still the 5-carbamoyl 10-hydroxy-10,11-dihydro-5H-dibenz / b, f / azepine have been described (DE-AS 2011045). The invention makes it possible to produce new potential drugs, in particular psychotropic drugs. Because of their anticonvulsant effects, the new compounds can be used as drugs for the treatment of mental and neurological disorders. The invention has the object to develop a process for the preparation of novel compounds of general formula I, which can be used as psychotropic drugs, in particular as anticonvulsants. According to the invention, this is achieved by reacting a compound of general formula II, in which R has the same meaning as above, in a manner known per se with NH 3 to give a compound of general formula I. The amidation of compounds of formula II to compounds of formula I can in known manner in organic or organic-aqueous solvents such as alcohols, esters, hydrocarbons, halogenated hydrocarbons, optionally in the presence of water, both using gaseous ammonia and aqueous Ammonia solutions are carried out. The reaction can be carried out at room temperature or at elevated temperature, preferably at the Siedetemperatu r of the solvent or solvent mixture used. The compounds of general formula I according to the invention are crystalline and are characterized by good texture for further galenic processing into tablets or dragees. The new compounds of the general formula II used as starting materials for the process according to the invention can be prepared in a simple manner in accordance with DD-PS 219191 by reacting 5-chlorocarbonyl-10-bromo-10,11-dihydro-5H-dibenz / b, f / azepine of the formula III with methanol, ethanol or allyl alcohol at temperatures of 50 to 100 ° C., preferably at the boiling point of the alcohol used, in comparison with the known, introduced as anticonvulsant and proven 5-carbamoyl-5H-dibenz / b, f / azepine (carbamazepine) have the compounds of general formula I with approximately the same and sometimes better pharmacological effects a half lower acute toxicity and thus twice as high tolerability and a more favorable therapeutic index, as from the following comparison of the inventively available ö-carbamoyl-IO-ethoxy-IOjH-dihydro-SH-dibenz / b ^ / azepine (substance A) with carbamazepine (substance B) below r Use of the following animal experimental models (1) pentylenetetrazolone agonism (2) strychnine antagonism (3) thiosemicarbazide antagonism
can be seen.