CH617937A5 - Process for the preparation of 8-chloro-1-hydroxymethyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine and 8-chloro-1-hydroxymethyl-6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benz odiazepine - Google Patents

Description

The present invention relates to a process for the preparation of the compounds 8-chloro-l- (hydroxymethyl) -6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine and 8-chloro-1 - (hy droxymethyl ) -6- (o-chlorophenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine.

Comparable but different substitution 4 H-imidazo [1,2-a] [1,4] benzodiazepines have already been described in U.S. Patent No. 3,910,946.

According to the following reaction scheme, the compounds of formula III are obtained by reacting a 2-thio-benzodiazepine of formula I with a reagent of formula IV and cyclizing the resulting compound of formula II with a concentrated acid to a compound of formula III and if necessary, converts them into their pharmacologically acceptable acid addition salt:

Cl s

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617 937

n

NHg-CHa ^ C ^ CHa.OH IV

N /

from n

HOHsC— C-CHÎ

I I

N /

HQCHa

111

in which formulas Ri denotes hydrogen or chlorine.

The synthesis of intermediate IV can be carried out as follows:

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N-CH2-C-CH3 V

8F3 ^ Pb (OAc) 4

0

il

N-CHa-C-CH2-0-C-CHa Vi

O.

4 ^

n

N-CHa-C ^ CHa-OH VII.

vk o

NH2-0H2-C-CH20H IV

The present invention also relates to the preparation of the pharmacologically acceptable acid addition salts of the compounds of the formula III.

The two compounds encompassed by the present preparation processes are 8-chloro-l- (hydroxymethyl) -6-phenyl-4H-imidazo [1,2-a] [1,4] -benzodiazepine and 8-chloro-1- (hydroxymethyl) -6- (o-chlorophenyl) -4H-imidazo-40 [1,2-a] [1,4] benzodiazepine as well as their pharmacologically acceptable acid addition salts.

The process according to the invention is characterized in that a compound of the formula I is heated with a reagent of the formula IV, generally in an inert organic solvent, for example butanol, usually to 60 to 120 ° C. to form the compound II and the compound II with a concentrated acid,

which generally contains less than 5% of water, is treated in the presence or absence of an inert organic solvent to form compound III and then optionally forms the pharmacologically acceptable acid addition salt.

The compounds produced according to the invention have sedative and tranquilizer effects. The compounds ss are suitable for the treatment of mammals and birds. The sedative and anxiolytic effect is, for example, beneficial for the treatment of animals during transport or of animals that are kept in asylums while their owners are absent.

60 The activity of the compounds of the formula III prepared according to the invention was determined by standard tests:

Chimney test

65 [Med. Exp. 4,145 (1961)]: This test determines the ability of the mice to climb and exit a vertical glass cylinder within 30 seconds. At the effective dose, 50% of the mice fail.

617 937

Shell test

Mice in petri dishes (10 cm in diameter, 5 cm in height, partially embedded in wood shavings) that are untreated,

climb out of the shell very quickly. Mice left in the shell for more than 3 minutes are an indication of tranquillization. The ED50 is the dose of the test compound at which 50% of the mice remain in the dish.

Podium test

The untreated mouse leaves the pedestal in less than 1 minute and climbs back onto the floor of the mouse cage. Tranquilized mice remain on the pedestal for more than 1 minute.

Nicotine antagonism test

Mice in a group of six are injected with the test compound. 30 minutes later, the mice, including untreated control animals, were injected with 2 mg / kg nicotine salicylate. The control animals showed overstimulation, i.e. (1) ongoing convulsions, (2) tonic extensor attacks, followed by (3) death. The intraperitoneal dose of the test compound at which 50% of the animals are protected against (3) is the EDso.

The intended pharmaceutical forms include preparations for oral, parenteral and rectal use, for example tablets, powder packs, sachets, dragees, capsules, solutions, suspensions, sterile injectable forms, suppositories, bougien and the like. Suitable diluents or carriers such as carbohydrates (lactose), proteins, lipids, calcium phosphate, corn starch, stearic acid, methyl cellulose or the like can be used as carriers or for coating purposes. Water or oils, for example coconut oil, sesame oil, saffron oil, cottonseed oil, peanut oil and the like, can be used to prepare solutions or suspensions of the active ingredient. Sweeteners, colors and flavors can be added.

For mammals and birds, feed mixes with starch, oatmeal, dried fish meat, fish meal, corn meal or the like can be prepared.

As a tranquilizer, the compounds of the formula III can be used in dosage units of 0.1 to 5 mg / kg and preferably 0.2 to 3 mg / kg in oral or injectable preparations of the type described above to relieve tension and anxiety in mammals or birds facilitate how these are caused, for example, during shipping. The lower dose range of 0.2 mg / kg is usually appropriate for animals with a body weight of more than 10 kg.

The starting materials of the formula I used according to the invention are known, for example from US Pat. No. 3,422,091.

The reagent of formula IV is new and can be prepared as can be seen from the preparation examples.

When carrying out the process according to the invention for the preparation of the compounds of the formula III, the procedure is generally as follows: a compound of the formula I is used in an inert organic solvent with a boiling point of more than 60 ° C., for example 1-butanol, cyclohexa- nol, hexanol, benzene, toluene or the like, preferably in butanol, suspended and heated with a reagent of the formula IV1 to 24 hours to a temperature between 60 and 120 ° C. The product of formula II obtained in this way is worked up and purified in a conventional manner, for example by extraction, chromatography and crystallization.

The compound of formula II is used with an excess of a mineral acid containing less than 5% water

Example with concentrated sulfuric acid or polyphosphoric acid, cycled at a temperature between 10 and 35 ° C and expediently at room temperature (20 to 25 ° C), or with glacial acetic acid between 100 and 130 "coder with methanesulfonic acid between 30 and 100 ° C. Preferably "The compound II is stirred with about 5 to 20 times the amount by weight of concentrated sulfuric acid at room temperature for 6 to 24 hours in a nitrogen atmosphere. The resulting product of formula III is isolated by pouring the reaction mixture onto ice, neutralizing the aqueous suspension, for example with Sodium or potassium hydroxide, carbonate or bicarbonate and the product of formula III are extracted with an organic, water-immiscible solvent, for example chloroform, methylene chloride, benzene or the like, and product III is obtained from this solution by concentration Purification is carried out by chromatography and / or crystallization and recrystallization in ko conventionally.

Preparation 1 N- (3-acetoxy-2-oxopropyl) phthalimide To a mixture of 3.04 g (15.0 millimoles) of N- (2-oxopropyl) phthalimide and 9.3 g (21.0 millimoles) Lead tetraacetate in 210 ml of a 95: 5 mixture of benzene and methanol, 27.9 ml of boron trifluoride atherate are added dropwise over 5 minutes with vigorous stirring at 0.5 ° C. After 4 hours of stirring at room temperature, the reaction mixture is poured onto ice and extracted with ethyl acetate. The organic phase is separated off, washed with a saturated sodium chloride solution and a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo, with 2.0 g of N- (3-acetoxy-2-oxopropyl) phthalimide from F 140-142 ° C.

Preparation 2

N - [[2- (hydroxymethyl) -1, 3-dioxolan-2-yl] methyljphthalimide A solution of 15 g (57.5 millimoles) of N- (3-acetoxy-2-oxopropyl) phthalimide, 14.25 g (230.0 millimoles) of ethylene glycol, 10 mg of p-toluenesulfonic acid and 1 drop of concentrated sulfuric acid in 150 ml of benzene is refluxed for 5 hours in a nitrogen atmosphere with removal of water. The mixture is concentrated in vacuo to give an orange oil which is dissolved in chloroform. The solution is washed twice with water and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and crystallized from ethyl acetate, giving 10 g (70% yield) of N - [[2- (hydroxymethyl) -1, 3-dioxolane 2-yl] methyl] phthalimide of mp 114-117 ° C.

Analysis for C13H15NO5:

C H N

Calculated 59.31 4.98 5.32 Found 59.55 5.05 5.15

Preparation 3

2- (aminomethyl) -1,3-dioxolan-2-methanol A solution of 10.0 g (40.0 millimoles) of N - [[2- (hydroxymethyl) -l, 3-dioxolan-2-yl] methyl] phthalimide and 10.0 g hydrazine hydrate (200.0 millimoles) in 250 ml absolute ethanol is stirred at room temperature under nitrogen overnight. The resulting precipitate is filtered off and washed with ethanol. The combined ethanol fractions are concentrated in vacuo to give 3.3 g of 2- (amino-methyl) -1,3-dioxolane-2-methanol.

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Example la

2 - [[[7-chloro-5- (o-chlorophenyl) -3H-l, 4-benzodiaze-pin-2-yl] amino] methyl] -l, 3-dioxolan-2-methanol A suspension of 3, 85 g (12.0 millimoles) 7-chloro-l, 3-dihydro-5- (o-chlorophenyl) -2H-1,4-benzodiazepin-2-thione and 3.3 g (24.0 millimoles) 2- (Aminomethyl) -1, 3-dioxolane-2-methanol in 150 ml of 1-butanol is heated to 65 ° C. for 5 hours under nitrogen, then cooled to room temperature, poured into cold water and extracted with chloroform. The combined chloroform extracts are dried over anhydrous sodium sulfate and evaporated to dryness to give an oil which crystallizes from ethyl acetate. 4.1 g (82%) of 2 - [[[7-chloro-5- (o-chlorophenyl) -3H-l, 4-benzodiazepin-2-yl] amino] methyl] -l, 3-dioxolane 2-methanol of mp 195-199 ° C obtained. The analysis sample melts at 198 to 200 ° C.

Analysis for C20H19CI2N3O3:

C.

H

N

Cl

Calculated

57.15

4.56

10.00

16.87

Found

57.17

4.58

10.15

16.90

Example 1 b

8-chloro-6- (o-chlorophenyl) -l- (hydroxymethyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine A solution of 2.2 g (5.2 millimoles) 2- [ [[7-Chloro-5- (o-chlorophenyl) -3H-l, 4-benzodiazepin-2-yl] amino] methyl] -l, 3-dioxolan-2-methanol in 10 ml of concentrated sulfuric acid at room temperature under nitrogen stirred overnight. The resulting solution is poured onto ice, neutralized with a 10% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extracts are combined, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give an orange oil. This oil gives 900 mg (50%) of 8-chloro-6- (o-chlorophenyl) -1- (hydroxymethyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine from F. 192- 194 ° C. The analytical sample melts at 193 to 195 ° C.

Analysis for C18H13CI2N3O2:

C.

H

N

Cl

Calculated

60.35

3.66

11.73

19.79

Found

60.39

3.66

11.64

19.78

Example 2a

2 - [[(7-Chloro-5-phenyl-3H-l, 4-benzodiazepin-2-yl) amino] methyl] -l, 3-dioxolan-2-methanol According to the procedure of Example la, 7-chlorine is -l, 3-

617937

dihydro-5-phenyl-2H-l, 4-benzodiazepine-2-thione in 1-butanol with 2- (aminomethyl) -l, 3-dioxolane-2-methanol heated to 70 ° C, the 2 - [[ (7-chloro-5-phenyl-3H-l, 4-benzodiazepin-2-yl) amino] methyl] -l, 3-dioxolan-2-methanol of mp 169-171 ° C.

Analysis for C18H14CIN3O:

C.

H

N

Cl

Calculated

62.25

5.22

10.89

9.19

Found

62.39

5.41

11.09

9.26

Example 2b 8-chloro-1- (hydroxymethyl) -6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine According to the procedure of example Ib, 2 - [[(7-chloro-5- phenyl-3H-l, 4-benzodiazepin-2-yl) amino] methyl] -l, 3-dioxolan-2-methanol at room temperature in concentrated sulfuric acid, the 8-chloro-l- (hydroxy-methyl) - 6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine of mp 210-213 ° C.

Analysis for C18H17CIN3O:

C.

H

N

Cl

Calculated

66.77

4.36

12.98

10.95

Found

66.66

4.35

12.96

11.00

If the compounds of the formula III are treated with pharmacologically acceptable acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid, toluenesulfonic acid, methanesulfonic acid, tartaric acid, citric acid, lactic acid, malic acid, maleic acid or cyclohexanesulfamic acid, the pharmacologically acceptable salts of the compounds of the compounds of the compounds are obtained Formula III that can be used like the free bases. Salt formation takes place in a conventional manner by reacting the compounds of formula III with an excess of the respective acid in a suitable medium, for example in water, a lower alcohol, ether or acetone, whereupon the salt is evaporated off, preferably in vacuo, wins.

Comparable but different substitutions for 4H-imidazo [1,2-a] [1,4] benzodiazepines have already been described in U.S. Patent No. 3,910,946.

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Claims (3)

617937 2. The method according to claim 1, characterized in that Ri is chlorine. 2nd PATENT CLAIMS 1. Process for the preparation of a compound of the formula CÌ wherein Ri is hydrogen or chlorine, and their pharmacologically acceptable acid addition salts, characterized in that a 2-thiobenzodiazepine of the formula Cl in which Ri has the meaning given above, with a reagent of the formula n NHs-CHa ^ C ^ CHaOH IV and the resulting compound of the formula r ~ i HOHaC— he cyclized with a concentrated acid to a compound of formula III, and optionally converted this into its pharmacologically acceptable acid addition salt. 3. The method according to claim 1, characterized in that Ri is hydrogen.