DE1445892B2 - 5- (2-pyridyl) benzodiazepine derivatives - Google Patents

Description

(VII)

C = O

IO

15th

20th

in which R ^{2 has} the meaning given above and X is a halogen atom, reacts with ethylenediamine and, if desired, converts a reaction product obtained in this way into an acid addition salt thereof.

The invention relates to 5- (2-pyridyl) benzodiazepine derivatives of the general formula I.

35

3CH,

(I)

(H)

in which R ¹ and R ^{2 have} the meaning given above, is reacted with lithium aluminum hydride in a manner known per se. This reaction can be carried out at room temperature as well as below or above room temperature. The reaction is preferably carried out in an inert organic solvent, such as. B. tetrahydrofuran; Benzene, dioxane, diethyl ether or the like. Executed. The reaction is effected under anhydrous conditions.

A second embodiment of the process according to the invention is characterized in that a compound of the general formula III

40

45

(III)

C = O

wherein R ¹ denotes a hydrogen atom or a methyl group and R ² denotes a bromine atom or a trifluoromethyl group, as well as their acid addition salts.

The connections made by being general Are formally defined, form acid addition salts with both inorganic and organic acids, such as. B. nitric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, maleic acid, acetic acid, "' Succinic acid, formic acid, p-toluenesulfonic acid etc.

The invention also relates to processes for the preparation of the compounds of general formula 1. The compounds mentioned can by means of meh in which R ¹ and R ^{2 have} the meaning given above, is reacted with ethyleneimine in a manner known per se.

The above reaction can be carried out at room temperature,;, or above or below room temperature, but is preferably carried out using caused by heat, Temperatures of about 20 to about 100 ° C are preferred. Furthermore, the reaction is preferably carried out in the presence of an inert organic solvent, such as. B. tetrahydrofuran, Benzene, dioxane, diethyl ether or the like., Executed.

Another embodiment of the method according to the invention is characterized in that a

Compound of the general formula IV

(IV)

15th

in which R ¹ and R ^{2 have} the meaning given above, is treated in a manner known per se with Raney nickel in the presence of a solvent. The reaction can be effected at room temperature or below, or with the application of heat. It is preferably effected by refluxing the reaction mixture. The reaction can preferably be carried out in an inert organic solvent, such as. B. acetone, ethanol, dioxane, tetrahydrofuran or the like., Are carried out.

Yet another embodiment of the invention Process is characterized in that a compound of the general formula V

NH

C = O

N-CH ₇ CH, -R ⁸

C == O

(VI)

25th

30 acylamino portion of the abovementioned / j'-Acylaminoülhylhalogenid-Rcaktionspartncr represents, is hydrolyzed in an acidic medium.

Although acylaminoethyl bromides are preferred, can other halides, such as. B. the chlorides can be used. Accordingly, connections are such as B. / i-bromoethylbenzamide, / j'-bromoethylphthalimide, // - tosylaminoethyl bromide and the like examples of // - acylaminoethyl halide reactants.

The condensation of the // - acylaminoethyl halide with the compound of the above formula V can preferably be effected in an inert organic solvent, such as. B. nitromethane, N ₅ N-dimethylformamide, dichlorobenzene, pyridine, etc. The condensation is preferably effected at elevated temperatures, such as between about 100 and about 200 ^° C. The solvent should be sufficiently high-boiling that it is at the reaction temperature not volatilized. The second stage of the above process, ie the hydrolysis of the acyl group, is preferably carried out in acidic media. A preferred embodiment comprises the use of strong mineral acids, such as. Sulfuric acid, hydrochloric acid, and the like. The hydrolysis reaction can be carried out at room temperature or elevated temperatures and is preferably carried out with the application of heat.

Another valuable embodiment of the invention The process consists in that a compound of the general formula VIl

35

40

where R ^{1 has} the meaning given above and R ^{4 is} a bromine atom, reacted in a manner known per se with a / i-halogenoethyl-lower alkanoylamide, β- halogenoethyl-benzoylamide, β- halogenoethylphthaloylamide or β- tosylamino-ethyl halide and the thereby resulting compound of the general formula VI

R ¹

wherein R, ¹ . and R ⁴ ; have the same meanings as in the above general formula V · and R ⁸ denotes

(VII)

C = O

wherein R ^{2 has} the meaning given above and X is a halogen atom, is reacted with ethylenediamine in a manner known per se.

The process according to this embodiment either provides compounds of the general formula directly I or an intermediate of the general formula IX

55

60 C = O

NH-CH ₂ CH ₂ -NH ₂

(K)

in which R ^{2 has} the meaning given above, which can be cyclized to give corresponding compounds of the formula I. This cyclization can be brought about by standing for a long time or by applying heat. - .: _; . ... · ... ■ · - _: ■ · - /. <

When converting compounds of the general formula VII into those of the general formula I by means of reaction with ethylenediamine is preferably used at elevated temperatures, for. B. over about 65 ° C. The ethylenediamine can be present in excess and serve as a reaction medium. Alternatively, any conventional inert organic solvent, e.g. B. a lower one Use alcohol or a tertiary base such as pyridine, picoline or quinoline as the reaction medium. One The preferred embodiment consists in reacting a 2- (chloro-benzoyl) pyridine with ethylenediamine.

Part of the above embodiments is similarly disclosed in Belgian patent 6,20773 described.

Compounds corresponding to the above general formula I in which R ^{1 is} hydrogen can be converted into the corresponding compounds in which the hydrogen has been replaced by a methyl group by methylation. The methylation can be effectively carried out by reacting a compound in which R ^{1 is} hydrogen with sodium hydride or a sodium alcoholate such as sodium methylate in the presence of an inert organic solvent such as toluene and reacting the sodium derivative formed with dimethyl sulfate or a methyl halide in an inert solvent such as a hydrocarbon or dimethylformamide can be achieved. Dimethyl sulfate and methyl iodide are the preferred methylating agents.

Compounds of general formula VII can be prepared by reacting a pyridyl Grignard reagent, for. B. Pyridyllithium or pyridyl magnesium halide, can be obtained with a 2-halo-benzonitrile. Man can also be a 2- (2-halophenyl) -pyridyl-carbinol with a conventional oxidizing agent, e.g. B. chromic acid, oxidize.

Compounds of the above general formula I and medically acceptable acid addition salts of such Compounds are valuable therapeutic agents that act as muscle relaxants, sedatives and anticonvulsants are useful.

When testing the muscle-relaxing effect of process end products in the standard experiment on the awake cat in comparison with 7-chloro-1,3 - dihydro -1 - methyl - 5 - phenyl - 2 H -1,4 - benzodiazepin-2-one shows that the products of the process are more active with comparable toxicity.

Thus, for the two compounds, 7-bromo-2,3-dihydro-5 - (2-pyridyl) -1 H -1,4-benzodiazepine hydrochloride (Compound A) and 2,3 - dihydro-1 - methyl - 5 - (2 - pyridyl) - 7 - trifluoromethyl -LH -1,4-benzodiazepine (Compound B) as well as for - ^ - chlorine-1,3 - dihydro -1 - methyl - 5 - phenyl - 2 H - 1,4 - benzodiazepin-2-one (Comparison compound) determined the following figures (MED = minimum effective dose):

Try on toxicity Mouse) the guards LD ₅₀ p. O. cat (mg / kg; Mg, C> i. p. 750 (mg / kg) - Connection A 1.0 720 Connection B 0.5 > 100 Comparison 1.6 220 link

The following examples are intended to explain the preparation of the compounds according to the invention. All temperatures are given in degrees Celsius.

B ei s.ρ i e 1 1

A solution of 9.5 g of 7-bromo-1,3-dihydro-5- (2-pyridyl) -2H-1,4-benzodiazepin-2-one in 0.41 tetrahydrofuran is over the course of 30 minutes added to a suspension of 4.0 g of lithium aluminum hydride in 0.1 l of tetrahydrofuran. One heats up reflux the reaction mixture for 5 minutes and then cool it with stirring for 45 minutes in one Ice bath. After careful addition of about 0.61 ether, which is saturated with water, and then 20 ml Water, the reaction mixture is suction filtered through a layer of a filter aid. The yellow filtrate is dried over anhydrous sodium sulfate, filtered and evaporated. The remaining red-brown, rubbery material is stirred with 250 ml of anhydrous ether for 2 hours. The reaction mixture is then filtered and the filtrate is evaporated.

The residue is dissolved in benzene and passed through a column of 270 g of aluminum oxide (neutral, degree of activity) Chromatographies. Washing with benzene removes impurities. By elution with benzene / ethyl acetate (3: 1), fractions are obtained which contain a yellow, solid reaction product. These fractions are combined, dissolved in anhydrous ether and coated with activated charcoal and. water-

. stirred free magnesium sulfate. It is filtered through a sintered glass funnel and the filtrate is evaporated.

One receives a. yellow, crystallized product which, after recrystallization from ether, yellow crystals of 7 - bromo - 2,3 - dihydro - 5 - (2 - pyridyl) -1 H -1,4 - benzodiazepine supplies. The product sinters at 182 ° and melts with decomposition between 183 and 184 ° (corrected).

The production of the raw material is in Belgian U.S. Patent 6,19,101.

At game 1 2

A solution of 20 g of 2- (2-chloro-5-trifluoromethylbenzoyl) pyridine in 200 ml of pyridine and 50 ml of ethylenediamine is refluxed for 5 1/2 hours. The reaction mixture is then evaporated to dryness in vacuo and the residue is partitioned between methylene chloride and dilute sodium carbonate solution. The organic layer is separated, washed with saturated saline and dried over sodium sulfate. The solvent is distilled off and the residue is dissolved in 600 ml of 1η hydrochloric acid. A precipitate forms, which is filtered off. The filtrate is made alkaline by adding ammonia. The aqueous solution is extracted with methylene chloride and the organic layer is dried over sodium sulfate. The residue obtained after distilling off the methylene chloride is dissolved in 500 ml of toluene. The resulting solution is refluxed for 3 hours with azeotropic distillation of water. The> toluene is then distilled off and the residue is crystallized from a mixture of benzene and hexane, 2,3-dihydro-5- (2-pyridyl) -7-trifluoromethyl-1 Hl, 4-benzodiazepine melting at 181 ° to 183 ° receives.
To a solution of 4.6 g of 2,3-dihydro

509 522/366

5 - (2 - pyridyl) - 7 - trifluoromethyl - 1 H - 1,4 - benzodiazepine 850 mg of sodium hydride (53% in mineral oil) are added to 50 ml of Ν, Ν-dimethylformamide. To Stirring for 45 minutes is slowly added to 1.6 ml of dimethyl sulfate in 5 ml of Ν, Ν-dimethylformamide. The reaction mixture warms up and is cooled to about 20 ° in a water bath. The reaction mixture is then stirred for 3 hours at room temperature and then poured into 600 to 700 ml of cold water. One extracts with ether, washes the ethereal layer with water, dries over sodium sulfate and evaporates to dryness. The residue is added to a mixture of benzene and hexane. The crystallized product formed will removed by filtration. The filtrate is brought to dryness in vacuo, dissolved in benzene and added to 60 g Absorbs aluminum oxide. Obtained by eluting with a mixture of benzene and methylene chloride 2,3-dihydro-1-methyl-5- (2-pyridyl) -7-trifluoromethyl-1 H-1,4-benzodiazepine, which is made from hexane in the form of light yellow rods with a melting point of 127 to 129 ° crystallized.

The starting material can be made as follows:

A solution of 125 ml of butyllithium (15% in hexane) in 250 ml of ether is cooled to -50 ° and, while maintaining this temperature, carefully mixed with 18.2 ml of 2-bromopyridine in 75 ml of ether. After 15 minutes, a solution of 38.2 g of 2-chloro-5-trifluoromethylbenzonitrile in 100 ml of ether is carefully added. The cooling bath is then removed and the reaction mixture stirred for 90 minutes. It is ^{cooled to 0 °} C. and decomposed by adding 200 ml of water and then 150 ml of 3N hydrochloric acid. The aqueous phase is separated off and the ethereal layer is diluted by adding 500 ml of ether, washed with dilute sodium hydrogen carbonate solution and dried over sodium sulfate. The residue obtained is freed from ether and recrystallized from hexane, giving 2- (2-chloro-5-trifluoromethylbenzoyl) pyridine with a melting point of 59 to 60 °. Repeated recrystallization from hexane gives colorless rhombuses with a melting point of 67 to 69 °.

Claims (5)

Patent claims: 1. 5- (2-Pyridyl) -benzodiazepine derivatives of the general formula IR ¹ N-CH, C = N CH, (D wherein R ¹ denotes a hydrogen atom or a methyl group and R ² denotes a bromine atom or a trifluoromethyl group, as well as their acid addition salts. 2. 7 - Bromo - 5 - (2 - pyridyl) - 2,3 - dihydro -1 H-1,4-benzodiazepine. 3.7- trifluoromethyl -1 - methyl - 5 - (2 - pyridyl) -2,3-dihydro- IH-1,4-benzodiazepine. 4. A pharmaceutical preparation consisting of a compound according to claim 1 to 3 and a pharmaceutical carrier. 5. Process for the preparation of the compounds according to Claim 1 to 3, characterized in that that one in a known manner a) a compound of the general formula II / -C CH ₇ (H) C = N 40 45 wherein R ¹ and R ^{2 have} the meaning given above, or reacts with lithium aluminum hydride
b) a compound of the general formula III R ¹ I. NH C = O 60 meanings, are reacted with ethyleneimine or
c) a compound of the general formula IV CH ₂ (IV) wherein R ¹ and R ^{2 have} the meaning given above, treated with Raney nickel in the presence of a solvent or
d) a compound of the general formula V. (V) C = Q where R ^{1 has} the meaning given above and R ^{4 is} a bromine atom, with a / f-halogenoethyl-lower alkanoylamide, // - halogenoethylbenzoylamide, (i - halogenoethylphthaloylamide or ft - tosylaminoethylhalide and the resulting compound of the general formula VI wherein R ¹ and R ^{2 have} the abovementioned wherein, R ¹ and R ^{4 have} the same meanings as in the * above general formula V sen and R ^{8 represents} the acylamino portion of the above // - acylaminoethyl halide reactants, hydrolyzed or in an acidic medium
e) a compound of the general formula VIl rer different reactions can be prepared from a variety of starting materials. An embodiment of the method according to the invention is characterized in that a connection with the general formula II