FI62072C - PROCEDURE FOR FRAMSTRATION OF THERAPEUTIC NETWORK 7-BROMO-1-METHYL-1-ALCOXIMETHYL-5- (2-HALOGENPHENYL) -1H-2,3-DIHYDRO-1,4-BENZODIAZEPINER SAMT DERAS SYRAADDITIONSSALTER - Google Patents

Description

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(4S) c Patc-ntti "vönn? Tfy 10 11 1932 VTV (51) Kv.Mu3 / (teAf ^ 4 0 * '-Q' ^ & ^ 43/16 ENGLISH - FI N LAN D (21) P« Mnttlhtk «mu · - Ptt« «aM6kning 76l28i (22) HakamltpUvi - AiwBknln | fdag 07.05 * 76 ^ ^ (23) AlkupUvt — GHtlghttidag 07.05.76 (41) Tullut lulklMkai - Riivit ^ ^

Patent and Relief Board (44) NlhtivSkslptnon et al moon (. | Excluded date -, n n7 oQ

Patents and registries '' Antftkm uttagd och utl.skrlft * n publkarad JU. U f .Od (32) (33) (31) atuoikaut - Baitrd prtorltat 10.05.75

Federal Republic of Germany-Förbundsrepubliken

Germany (DE) P 2520937 · ^ (71) Kali-Chemie Aktiengesellschaft, Postfach 2 20, Hans-Böcklerallee 20, 3 Hannover 1, Federal Republic of Germany Förbundsrepubliken Germany (DE) (72) Wolfgang Milkowski, Burgdorf, Renke Budden, Hannover, Siegfried Funke, Hanover, Rolf Hiischens, Hanover, Hans Liepmann, Hanover, Werner Stuhmer, Eldagsen, Horst Zeugner, Hanover, Federal Republic of Germany-Förbundsrepubliken lyskland (DE) (TM Oy Borenius & Co Ab (5M Method for Therapeutically Effective 7 _hromi-l for the preparation of methyl 1-alkoxymethyl-5- (2-halophenyl) -1H-2,3-dihydro-1H-benzodiazepines and their acid addition salts - For the preparation of 7-bromo-1-methyl-1-therapeutics alkoxymethyl-5- (2-halophenyl) -1H-2,3-dihydro-1,1'-benzodiazepine and the addition of syrup

The invention relates to novel therapeutically active 7-bromo-1-methyl-2-alkoxymethyl-5- (2-halophenyl) -1H-2,3-dihydro-1H-benzodiazepines of the general formula CH.

I 0 CHrtOR

ό "as well as for the preparation of their acid addition salts, wherein in the formula X represents a chlorine, bromine or fluorine atom and R represents a group having 1 to 3 carbon atoms.

The compounds of the formula I belong to the general formula I of DE patent 2,221,558 and to the general formula II of DE patent 2,353,160.

: 62072 to capped compounds. However, these patents do not mention any compound which falls within the scope of the general formula I according to the invention. Accordingly, DE 2,353,160 does not disclose any bromine-substituted compounds in the 7-position. DE patent 2,221,558 mentions a single 7-bromo-substituted compound which, however, is unsubstituted in the 5-phenyl ring and substituted in the 2-azerase by a chloromethyl group.

According to the invention, these new compounds can be prepared by a) brominating a compound of formula Ia ch3 I ch2or 6 "*, in which X and R have the same meaning as above, with a brominating agent, such as N-bromosuccinimide, or

(b) general formulas II and III

CH3 ch3

! CH9Cl I

rr'T '

Br = n ^ "2

Ά · ^ · X X

A mixture of compounds of formula Li, wherein X is as defined above, is reacted in a suitable solvent at elevated temperature with time alkoxides. an acid addition salt thereof by reacting the compound with an acid.

As the starting compounds of the compounds of the general formulas II and III, acyldiamines of the general formula Y N-CH2-CH-CH2-NH-C-IV CH3 oho can be used, in which Y represents a hydrogen or bromine atom and R2 has the same meaning as above. They are reacted with POCl 3 at certain reaction temperatures and optionally in the presence of suitable solvents to give either compounds of general formula II or general formula III.

The compounds known from DE patents 2,221,558 and 2,353,160 have valuable pharmacological properties, such as anticonvulsant, sedative and muscle tension-reducing effects, as well as anxiety and aggression-relieving effects, which allow these compounds to be used as sedatives, hypnotics and antiepileptics.

However, it has now been found that the incorporation of a bromine atom at the 7-position gives rise to new compounds which, surprisingly because of their new, advantageous profile, differ from hitherto specifically known compounds having a chlorine atom at the 7-position of the benzodiazepine backbone or having a 2-chloromethyl group. Thus, for these new compounds, while having good toxicity of the same order of magnitude, there is a particularly clear dosage difference between the antianxiety and sedative components, which makes the new compounds valuable, especially in the treatment of anxiety, tension, stress, neuroses and morbid aggressive behavior. In this case, it is possible to take advantage of the advantageous therapeutic properties as a sedative which is particularly suitable during the day without the disadvantage caused by intense sedation, which often leads to a change in the state of the hereil. In addition, the new compounds have a markedly improved anticonvulsant effect compared to the compounds specifically mentioned in the above-mentioned patent publications 62072. In addition, the novel compounds have a substantially more advantageous dosage difference between the antianxiety and tension relieving as well as the muscle tension component compared to the compounds of similar structure described in the above-mentioned patents, a feature which is also quite relevant in mentally ill people.

The novel unexpected and thus surprisingly advantageous advantageous pharmacological properties of the compounds according to the invention described above are illustrated below on the basis of animal experimental results. In order to clarify the explained fact, 7-chloro-1-methyl-2-methoxymethyl-5- (2'-chlorophenyl) -1H-3,2-7-chloro-1-methyl-2-methoxymethyl is also presented as a standard compound in all experiments. -dihydro-1,4-benzodiazepine (hydrochloride). As a second reference compound, "diazepam" is presented as the most common substance for medical use.

Explanation of pharmacological test methods 1) Acute toxicity

Acute 7-day toxicity is determined by administering the test compound once orally and intraperitoneally to white, clear-state NMRI mice. LD ^ values are calculated via EDV on the basis of an analysis of the test results (Cavelli-Sforza, Gustav Fischer Verlag, 1964, Grundbegriffe der Biometrie. Kapitel 10, pp. 1 53 .. .1 90).

2) Experimentation of anticonvulsant properties a) Pentetrazole-induced seizure method

Test compounds are tested orally using groups of 6 mice. 60 minutes after administration of the test compounds, pentetrazole is injected subcutaneously at a dose of 100 mg / kg. The occurrence of convulsions and tendon spasms is monitored over a total of 45 minutes. The protective effect of test compounds against convulsions is determined in comparison with control experiments. The effective ED 2 dose is calculated from the experimental results on 5,62072 logarithmic dosing curves (modified from the method of J.E. Blum et al., Arzneimittel-Forsch., 2-3, 377 (1973)).

(b) Method based on maximum electric shock

Test compounds are administered orally to animals. 60 minutes after administration, electrodes are attached to the ears of mice and electrical stimulation is triggered. The dose that prevents the occurrence of tendon spasms in the hind limbs in half the number of animals is determined. The ED 2 value is likewise calculated by the above-mentioned analysis based on experimental results (modified from the method described by J. Swinyard, J. Pharmacol. Exptl. Therap. 106, 93 (1952)).

The results obtained on the basis of the methods described above show the anticonvulsant effect of the test compounds and which, according to the literature, must be considered an important criterion for evaluating the clinical efficacy of the compounds as sedatives (A. Suria und E. Costa, Journal de Pharmacologie, Suppl. No 1, 5, 94 ( 1974) and G. Zbinden and LO Randall. Advances in Pharmacol. 5, 213 (1967)).

3) Experiment with anti-anxiety and anti-aggressive effect

Inhibition of isolation-induced aggression in mice:

Prior to the experiment, mice are kept in isolated isolates for four weeks. After this time, isolated mice spontaneously attack the non-isolated mice placed among them. Test compounds are administered orally to isolated mice, and the dose resulting in a 50% reduction in aggressive behavior is determined after 30 minutes (modified from the method of Weischer and Opitz, Arch. Int. Pharma-Codyn., 1_95, 252 (1 972)). ).

Based on the results obtained from these experiments, good conclusions can be drawn about the anxiety, stress and tension relieving properties of the compounds.

6 62072 H) Experimentation on muscle tensile properties

In the tensile test, mice are orally administered the test compound.

After 120 minutes, the mice are hung on their forelegs, on a thin, horizontally-straightened wire. The ED 2 value is the dose at which half of the animals do not touch the wire on their hind legs within five seconds (W. Theobald et al. Arzneim. Forsch. 17, 561 (1967)). This experiment tests the effect of test compounds on muscle tendency.

5) Experimentation of CNS depressant properties

The test compound is administered orally to mice, and after 30 minutes, the animals are additionally injected intravenously with 64 · mg / kg of "hexobarbital". The time on which the animal is placed on its side is determined and the length of time on the side is compared with a control group treated with "hexobarbital". The ED5Q value is defined as the dose at which half of the animals maintain a prolonged side-lying position by a factor of 4 compared to the control group (J. W. Kemp, M. Tannhauser, E. A. Swinyard, Arch, int. Pharmacodyn. 193 (1971), 37-47).

The following compounds were tested using the methods described above:

Compound 17 7-Bromo-1-methyl-2-methoxymethyl-5- (2-chloritenyl) -1H-2,3-dihydro-1,4-benzodiazepine (as hydrochloride) Compound 2 7-Bromo-1-methyl-2- Ethoxymethyl-5- (2-chlorophenyl) -1H-2,3-dihydro-1,4-benzodiazepine (as hydrochloride) Compound 37 7-Bromo-1-methyl-2-methoxymethyl-5- (2-fluorophenyl) -1H- 2,3-Dihydro-1,4-benzodiazepine (as hydrochloride) Compound 4 7-Bromo-1-methyl-2-methoxymethyl-5- (2-bromophenyl) -1H-2,3-dihydro-1,4-benzodiazepine ( hydrochloride) Compound 5 7-Bromo-1-methyl-2-ethoxymethyl-5- (2-bromophenyl) -1H-2,3-dihydro-1,4-benzodiazepine (as hydrochloride) Compound 6 7-Bromo-1-methyl- 2-Propoxymethyl-5- (2-bromophenyl) -1H-2,3-dihydro-1,4-benzodiazepine (as hydrochloride) Compound 7 7-Bromo-1-methyl-2-propoxymethyl-5- (2-chlorophenyl) - 1H-2,3-Dihydro-1,4-benzodiazepine (as hydrochloride) Compound 8 7-Bromo-1-methyl-2-isopropoxymethyl-5- (2-chlorophenyl-1H-2,3-dihydro-1,4 -benzodiazepine (as hydrochloride) 7 62072

Standard I 7-chloro-1-methyl-2-methoxymethyl-5 * - (2-chlorophenyl) -1H-2,3-dihydro-1,4-benzodiazepine (as hydrochloride) Standard II 7-chloro-1-methyl-5 -phenyl-1,3-dihydro-2H-1,4-benzodiazepin-1-one ("diazepam").

The following Table 1 shows the toxicity and anticonvulsant effects of the above-mentioned compounds of the invention compared to both said standard compounds.

table 1

Compound Oral Pentetrazole- Electric shock Εϋ & 0 LD50 (mg / kg) convulsion ED5Q (mg / kg) __ (mg / kg) _ 1 1578 0.9 3.0 2> 1470 2.2 24.5 3 1580 0.5 5 .0 4 1470 1.3 3.2 5> 1470 1.1 4.8 6> 1470 1.6 9.9 7> 1470 1.5 11.6 8> 1470 0.9 52.7

Standard 11779 2.0 26

Standard II 887 0.5 9.0

The following Table 2 shows the results of the anxiety-relieving and aggression-lowering effects.

Table 2 also shows the results for muscle coordination (traction test) and sedation (prolongation of sleep time induced by "hexobarbital"): 8 62072

Table 2

Isolated Tensile Test with Hexobarbital

Compound in killing ED-Q induced sleep time prolongation ED50 Cmg / kg) mg / kg 1 3.1 87 15.2 2 4.1 34.9 41.9 3 1 0.7 58.3 1 0.6 4 5, 2 63.0 4.6 5 4.5 100.0 6.2 6 5.5 102.0 10.5 7 3.1 1 7.0 3.4 8 7.7 30.0 0.9

Standard I 68 163 11.7

Standard II 3.6 4.2 1.5

Table 3 shows a) the quotient obtained by dividing the ED 2 value of the hexo-barbital prolongation of sleep time by the EDgg value of isolated, fighting mice = quotient 1, and b) the quotient obtained by dividing the EDgQ value of the tensile test by the EDgg value of isolated, fighting mice. with = quotient 2. These quotients clarify the superiority of the new compounds as a dosage difference between the sedative and anxiolytic components as well as the beneficial relationship between the muscle relaxant effect and the anxiolytic effect.

This fact is further illustrated by c) the results obtained by setting the standard 1 = 1.

9 62072

Table 3

Compound Part- Part number 1 Part- Part number 2 _amount 1_Standard 1 = 1 quantity 2 Standard 1 = 1 1 4.9 28.8 28.1 11, 7 2 10.2 60 8.5 3.5 3 0.9 5, 3 5.4 2.3 4 0.9 5.3 12.0 5.0 5 1.4 8.2 22.0 9.2 6 1.9 11.2 18.5 7.7 7 1.1 6.5 5.5 2.3 8 0.1 0.7 3.9 1, 6

Standard I 0.17 1 2.4 1

Standard II 0.42 2.4 1.2 0.5

The pharmacological results shown in Tables 1 to 3 show quite clearly the superiority of the novel compounds according to the invention over the standard compounds. In particular, the new compounds of the formula I have superior anticonvulsant effects and a clear reduction in the sedative and muscle-relaxing action components in favor of the anxiolytic and anti-aggressive properties. The new compounds of the formula I thus have a new profile of action and thus represent stress-relieving products which are clearly superior to the known compounds in this indication.

The compounds of the general formula I as well as their pharmaceutically usable acid addition compounds can thus be used as medicaments containing the compounds of the formula I or their acid addition compounds in admixture with , talc, vegetable oils, gum, polyalkylene glycols, petrolatum, etc. The pharmaceutical preparations may be in solid form (e.g. tablets, dragees, suppositories, capsules) or in liquid form (e.g. solutions, suspensions or emulsions). These preparations are optionally sterilized and / or contain additives such as preservatives, stabilizers, wetting agents or emulsifiers, and further salts to alter the osmotic pressure or buffering effect. They may also contain other therapeutically valuable substances.

By means of the reactions according to the invention, the compounds of the general formula I can be obtained as free bases either directly from the reaction mixture or in a known manner from acid addition compounds, suitably hydrochlorides, by hydrolysis and use of bases, e.g. sodium hydroxide, sodium carbonate, ammonia solution. By using free bases as starting compounds, the desired acid addition compounds can be prepared by applying known chemical methods.

In the event that the compounds will be used as intermediates in the preparation of other compounds or for any other non-pharmaceutical purpose, the toxicity or non-toxicity of the salts is irrelevant. In the event that the compounds are to be used for pharmaceutical purposes, they are suitably converted into non-toxic acid addition compounds.

The acids used in the preparation of suitable non-toxic acid addition compounds are those which, together with the free bases, form salts whose anions, at therapeutic doses, are harmless to man, so that the beneficial physiological properties of the bases are not called into question by the side effects of acid components. The salts are prepared by reacting the bases with calculated amounts of organic or inorganic acids in a water-miscible solvent such as ethanol or isopropanol, isolating the salts by evaporation and cooling, or reacting the bases with excess acid in a water-immiscible solvent such as diethyl ether or diisopropyl ether. By way of example, such organic acid addition salts may be formed from maleic, fumaric, benzoic, ascorbic, amber, methanesulfonic, acetic, propionic, wine, lemon, milk, apple, cyclohexane sulfamine, p -aminobenzoic, toluenesulfonic, glutamic or stearic acid. Inorganic salts can be formed with e.g. hydrochloric, bromic, hydro, sulfuric, sulfamic, phosphoric or nitric acid.

The use of non-toxic salts of the compounds of general formula I in pharmaceutical preparations gives the advantage over the bases that the salts are generally water-soluble.

62072 11

Example 1 7-Bromo-1-methyl-2-methoxymethyl-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine, hydrochloride

Boil 70 g of N, N-phenyl-N-methyl-2-chlorobenzoyl-2-hydroxy-1,3-diaminopropane in 350 ml of phosphorus oxychloride under reflux for 2.5 hours. The excess phosphorus oxychloride is then removed by distillation under reduced pressure, the residue is taken up in 500 ml of chloroform, 200 g of ice, 200 ml of water and 200 ml of concentrated sodium hydroxide solution are added and mixed thoroughly. The organic phase is separated, washed with water until neutral, dried over sodium sulfate and evaporated. The residue is taken up in 250 ml of ether and stirred for 3 hours, after which 100 g of γ-clay are added and filtered. The ether is removed by distillation to leave 50 g of crude product, which is 1-methyl-2-chloromethyl-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine and 1-methyl-3-chloro-6 - (2-chlorophenyl) -1,2,3,4-tetrahydro-1,5-benzodiazocine. The crude product is taken up in 750 ml of methanol in which 4 g of sodium have previously been dissolved, followed by boiling for 5 hours under reflux. The solvent is then removed by distillation, the residue is dissolved in 250 ml of toluene and washed with water until neutral. The organic phase is mixed thoroughly with 200 g of AljOgia, activity grade II-III, basic (Merck Standard Fa.) And filtered. The solvent is removed by distillation. 43 g of a residue of 1-methyl-2-methoxymethyl-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine are obtained, which is dissolved in 800 ml of methylene chloride, is added 24, 5 g of N-bromo-succinimide and boil for 24 hours under reflux. The solvent is then removed by distillation and the residue is dissolved in a mixture of 125 ml of ether and 125 ml of toluene. The base is extracted with a sufficient amount of dilute hydrochloric acid (20%). The base is then separated by adding concentrated sodium hydroxide solution and extracted with 125 ml of ether. An ethereal solution of hydrochloric acid gas is added, whereupon the hydrochloride precipitates and recrystallizes from 150 to 250 ml of ethanol.

25.3 g of 7-bromo-1-methyl-2-methoxymethyl-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine are obtained in the form of the hydrochloride. Melting point 193-196 ° C.

12 62072

Bromine content: calculated »18.6% found 18.8%

Chlorine content: calculated 16.4% found 16.1%

Similarly, 7-bromo-1-methyl-2-ethoxymethyl-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine (same as in Example 2) can be prepared using sodium in ethanol instead of methanol. manufactured product).

Example 2 7-Bromo-1-methyl-2-ethoxymethyl-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine as hydrochloride

Boil 70 g of N, N-phenyl-N1-methyl-N2- (2-chlorobenzoyl) -2-hydroxy-1,3-diaminopropane in 350 ml of phosphorus oxychloride under reflux for 2.5 hours. The excess phosphorus oxychloride is then removed by distillation, the residue is taken up in 400 ml of chloroform and shaken with 40 ml of ice water and 200 ml of concentrated sodium hydroxide solution. The chloroform phase is washed with water until neutral, dried over sodium sulfate and evaporated. 74.6 g of residue are obtained, which is dissolved in 100 ml of methylene chloride, then 41.6 g of N-bromosuccinimide are added and the mixture is refluxed for 24 hours. The solvent is removed by distillation and the residue is dissolved in a mixture of 250 ml of toluene and 250 ml of ether. The base is extracted with dilute hydrochloric acid (20%) and treated with concentrated sodium hydroxide solution and toluene so that it enters the toluene phase. This toluene phase is filtered alternately using 150 g of Αΐ2θ2 II-III (Standard Fa. Merck) and 150 g of AljOj I, basic (Standard Fa. Merck). The toluene is evaporated to leave 35.5 g of an oily mixture of 7-bromo-1-methyl-2-chloromethyl-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine and 8 bromo-1-methyl-3-chloro-6- (2-chlorophenyl) -1,2,3,4-tetrahydro-1,5-benzo-diazocine. The mixture is taken up in 750 ml of ethanol previously dissolved in 6.5 g of sodium and then boiled for 24 hours under reflux. The ethanol is then removed by distillation, the residue is dissolved in 300 ml of chloroform and washed neutral with water. The organic phase is separated and dried over sodium sulfate. The solvent is removed by distillation to give 24 g of a residue which is filtered through a 9: 1 mixture of toluene and chloroform using 50 g of alumina I. The solvent is removed by distillation, then the residue is dissolved in acetone and ethereal hydrochloric acid gas is added until the reaction becomes acidic. The hydrochloride then separates as a yellow crystallite which is collected and recrystallized from 100-200 ml of ethanol.

15.6 g of 7-bromo-1-methyl-2-ethoxymethyl-5- (2-chlorophenyl-2,3-dihydro-1H-1,4-benzodiazepine as hydrochloride are obtained.

Melting point: 191-194 ° C Bromine content: 18.0% calculated 18.3% found

Chlorine content: calculated 15.9% found 15.6%

In a similar manner, using sodium methanol solution, 7-bromo-1-methyl-2-methoxymethyl-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine from a mixture of 7-bromo-1-methyl -2-chloromethyl-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine and 8-bromo-1-methyl-3-chloro-6- (2-chlorophenyl) -1 , 2,3,4-tetrahydro-1,5-bentsodiatsosiinia.

Example 3 7-Bromo-1-methyl-2-methoxymethyl and 7-bromo-1-methyl-2-ethoxymethyl-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine

70 g of - (4-bromophenyl) -N, N-methyl-N2- (2-chlorobenzoyl) -2-hydroxy-1,3-diaminopropane are boiled in 250 ml of phosphorus oxychloride under reflux for 2.5 hours. The excess phosphorus oxychloride is then removed by distillation, and the residue is mixed with 50 ml of water and 500 ml of methyl isobutyl ketone until bright red crystals have separated. The crystals are collected and mixed with chloroform, ice, water and caustic soda as described in the previous examples. The residue from the chloroform phase is treated with 200 ml of ether and 100 g of γ-clay. After filtration and removal of the solvent by distillation, 30 g of an oily residue are obtained, which is 7-bromo-1-methyl-2-chloromethyl-5- (2-chlorophenyl) -2,3-dihydro-1H- 1,4-benzodiazepine and 8-bromo-1-methyl-3-chloro-6- (2-chlorophenyl) -1,2,3,4-tetrahydro-1,5-benzodiazosine. In the same manner as in Example 2, 7-bromo-1-methyl-2-methoxymethyl-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine can be obtained from the mixture in the same manner as in Example 2 with sodium methanol. , 7-bromo-1-methyl-2-ethoxymethyl-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine.

m 62012

Example 4 7-Bromo-1-methyl-2-methoxymethyl-5- (2-chlorophenyl) -2,3-dihydro-1,4-benzodiazepine

Boil 250 g of N, N-methyl-N-phenyl-N2- (2-chlorobenzoyl) -2-hydroxy-1,3-diaminopropane in 500 ml of phosphorus oxychloride under reflux for 4 hours. The reaction mixture is poured into ice water and extracted with chloroform. The combined organic phases are washed with sodium hydroxide solution, dried over sodium sulfate and evaporated under reduced pressure. 255 g of crude product are obtained, which is dissolved in 300 ml of toluene and added to a solution of 50 g of sodium in 1.4 ml of methanol and boiled under reflux for 24 hours. The solution is then evaporated to a volume of about 800 ml, poured into ice water and extracted with about 4 l of methylene chloride. The solution is then dried over sodium sulfate and concentrated to about 3 liters, and 150 g of N-bromosuccinimide are added and the mixture is refluxed for 7 hours. The reaction solution is washed with dilute sodium hydroxide solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is taken up in toluene and filtered through γ-clay. The toluene is removed by distillation, the residue is taken up in 2.5 l of acetone and the hydrochloride is precipitated by introducing HCl gas into the reaction mixture. 163.5 g of 7-bromo-1-methyl-2-methoxymethyl-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine, m.p. 193-196 ° C, are obtained.

Example 5 7-Bromo-1-methyl-2-methoxymethyl-5- (2-fluorophenyl) -2,3-dihydro-1,4-benzodiazepine hydrochloride

Boil 15 g of phenyl-N, N-methyl-N2- (2-fluorobenzoyl) -2-hydroxy-1,3-diaminopropane in 430 ml of phosphorus oxychloride under reflux for 3 hours. Excess phosphorus oxychloride is then removed by distillation under reduced pressure, the residue is taken up in 1000 ml of chloroform and mixed thoroughly with a mixture of 10 g of ice, 200 ml of water and 200 ml of concentrated sodium hydroxide solution. The organic phase is separated, washed with water until neutral, dried over sodium sulfate and evaporated. The residue is taken up in 500 ml of ether and stirred for 15 hours, after which 100 g of γ-clay are added and filtered. The ether is evaporated to give 110 g of crude product which, in a mixture, contains 1-methyl-2-chloromethyl-5- (2-fluorophenyl) -1H-2,3-dihydro-1,4-benzodiazepine and 1-methyl -3-chloro-6- (2-fluorophenyl) -1,2,3,4-tetrahydro-1,5-benzodiazosine. The crude product is dissolved in 1.5 l of methanol, previously dissolved in 8.9 g of sodium, and refluxed for 5 hours. The solvent is then removed by distillation, the residue is dissolved in 500 ml of toluene and washed with water until neutral. The organic phase is mixed thoroughly with 200 g of Al 2 O 3, activity grade II-III, basic (Standard Merc. Merck), then filtered. The solvent is removed by distillation.

93 g of residue 1-methyl-2-methoxymethyl-5- (2-fluorophenyl) -1H-2,3-dihydro-1,4-benzodiazepine are obtained, which is dissolved in 1200 ml of methylene chloride and then 53 g are added. N-bromo-succinimide and boil for 24 hours under reflux. The solvent is then removed by distillation and the residue is dissolved in a mixture of 250 ml of ether and 250 ml of toluene. The base is extracted with a sufficient amount of dilute hydrochloric acid (20%). Concentrated sodium hydroxide solution is then added, whereupon the base precipitates and is extracted with ether (250 ml). Addition of ethereal hydrochloric acid gas causes the hydrochloride to precipitate and recrystallize from 200-300 ml of ethanol.

60.2 g of 7-bromo-1-methyl-2-methoxymethyl-5- (2-fluorophenyl) -1H-2,3-dihydro-1,4-benzodiazepine as hydrochloride are obtained. Melting point: 183 ... 185 ° C Elemental analysis:

Calculated: C = 52.3%; H = 4.6%; N = 6.8%; Br = 19.3%; Cl = 8.6%

Found: C = 52.3%; H = 4.7%; N = 6.4%; Br = 19.4%; Cl = 8.3%

Example 6 7-Bromo-1-methyl-2-isopropoxymethyl-5- (2-chlorophenyl) -2,3-dihydro-1,4-benzodiazepine hydrochloride

Boil 70 g of phenyl-N - methyl - (- (2-chlorobenzoyl) -2-hydroxy-1,3-diaminopropane in 350 ml of phosphorus oxychloride under reflux for 2.5 hours. Excess phosphorus oxychloride is then removed by distillation, the residue is taken up in 400 ml of chloroform and shaken with 400 ml of ice water and 200 ml of concentrated sodium hydroxide solution. The chloroform phase is washed with water until neutral, dried over sodium sulfate and evaporated. 74.6 g of residue are obtained, which is dissolved in 1000 ml of methylene chloride, and 41.6 g of N-bromosuccinimide are added, followed by refluxing for 24 hours. The solvent is removed by distillation and the residue is dissolved in a mixture of 250 ml of toluene and 250 ml of ether. The base is extracted with dilute hydrochloric acid (20%) and isolated by treatment with concentrated sodium hydroxide solution and toluene. The toluene phase is filtered off with 150 g of Al 2 O 3 -III (Standard Merc. Merck) and 150 g of Al 2 O 3, basic (Standard Fa. Merck). The toluene is evaporated to give 35.5 g of an oily mixture of 7-bromo-1-methyl-2-chloromethyl-5- (2-chlorophenyl) -1H-2,3-dihydro-1,4-benzodiazepine and 8-Bromo-1-methyl-3-chloro-6- (2-chlorophenyl) -1,2,3,4-tetrahydro-1,5-benzodiazosine. The mixture is boiled in 750 ml of isopropanol, to which 6.5 g of sodium have previously been added, under reflux for 24 hours. The isopropanol is then removed by distillation, the residue is dissolved in 300 ml of chloroform and washed with water until neutral. The organic phase is separated, dried over sodium sulfate and the solvent is removed by distillation. 24 g of residue are obtained, which is filtered through toluene and chloroform (9: 1) using 500 g of alumina I (Standard Fa. Merck). The solvent is removed by distillation, after which the residue is dissolved in acetone and an ethereal solution of hydrochloric acid-gas is added until the reaction is acidic. The hydrochloride then separates as a yellow crystallite which is collected and recrystallized from 100-200 ml of ethanol.

15.6 g of 7-bromo-1-methyl-2-isopropoxymethyl-5- (2-chlorophenyl) -1H-2,3-dihydro-1,4-diazepine are obtained in the form of the hydrochloride.

Melting point: 189 ... 191.5 ° C Elemental analysis:

Calculated: C = 52.4%; H = 5.1%; N = 6.1%; Br = 17.4%; Cl = 15.5% Found: C = 52.6%; H = 5.0%; N = 6.0%; Br = 17.2%; Cl = 15.2%

The compounds of general formula I shown in the following table can be prepared as described in Examples 1 to 6.

Table 4 “62072

Eg Elemental analysis no_R_X Melting point ° C _Calculated% Found% ~ 7 C-Η- Cl 152 ... 154 Cl = 15.5 15.5 (hydrochloride) Br = 17.4 17.1 8 CHo Br 185 ... 187 Cl = 7.5 7.5 (hydrochloride) Br = 33.7 33.4 9 C9H, Br 1 54 ... 1 56 Cl = 7.3 7.2 (hydrochloride) Br = 32.7 32.8 10 C 3 H 7 Br 1 43 ... 1 46 Cl = 7.1 7.3 (hydrochlorides) Br = 31.8 31.5

Claims (3)

18 62072 A process for the preparation of therapeutically active 7-bromo-1-methyl-2-alkoxymethyl-5- (2-halophenyl) -1H-2,3-dihydro-1,4-benzodiazepines of the general formula CH3 | CH.-OR Cl) O '' as well as for the preparation of their acid addition salts, in which formula X represents a chlorine, bromine or fluorine atom and R represents an alkyl group having 1 to 3 carbon atoms, characterized in that a) ch3 | ch2or J »2 (a compound of formula M in which X and R have the same meaning as above, is brominated with a brominating agent such as N-bromosuccinimide, or b) a compound of general formulas II and III 19 62072 ™ 3 CH3 I CH0C1 IN rtf ^ 1 N-CH0 XX> = «XX x Br A mixture of compounds of formula C-rea 'cirx fr'-II III, in which X is as defined above, is reacted in a suitable solvent at elevated temperature with alkali alkoxides, followed by addition of the acid addition salt of the compound of formula I if desired, the free base of formula I is prepared by hydrolysis, or the resulting free base of formula I is prepared into an acid addition salt thereof by reacting the compound with an acid. A process for the preparation of a therapeutic network of 7-bromo-i-methyl-2-alkoxymethyl-5- (2-halophenyl) -1H-2,3-dihydro-1,4-benzodiazole pine in the form of chel I CH, -0R XX jph2 U) fr '