DK150073B - ANALOGY PROCEDURE FOR THE PREPARATION OF OXAZOLO (3,2-D) (1,4) BENZODIAZEPINES - Google Patents

Description

in 150073 o

The present invention relates to an analogous process for the preparation of novel therapeutically useful oxazolo [3,2-d] [1,4] benzodiazepines of the general formula 5ch2-ch2-oh R0- (ch2) 2 in which R means hydrogen, halogen, nitro or trifluoromethyl, and R 5 represents phenyl or phenyl substituted with halogen. The term "halogen" includes all four halogens, i. fluorine, chlorine, bromine and iodine, unless otherwise stated.

Among the compounds of the general formula I, those in which R · is hydrogen or halogen are preferred, with chlorine being the preferred halogen and bonded to the benzodiazepine moiety at its 7-position and R betyder being phenyl or phenyl which in ortho the position is substituted with halogen, preferably fluorine, i.e. compounds of the general formula ch2-ch2-oh

.XO

o- <ch 2) 2 30 _

OvR7 and 1 "7 in which R is hydrogen or halogen and R is hydrogen or halogen.

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Particularly preferred among the compounds of the above Formula I are those compounds in which R chlor represents chlorine and is attached to the benzodiazepine moiety at its 7-position, 5 and R represents phenyl or phenyl which is substituted with fluoro in the ortho position 5.

The benzodiazepine derivatives of the above formula I can be prepared according to the invention by a process which is characterized by reacting a 4,5-unsaturated 1,4-benzodiazepine of the general formula 10

.. .N-CO H

15 R5 15 21

in which R and R have the meaning given above and R

means hydrogen or hydroxyethyl, with ethylene oxide in the presence of an acidic agent.

In accordance with the present process, compounds of formula I are obtained by reacting a 4,5-unsaturated 1,4-benzodiazepine of formula III with ethylene oxide in the presence of an acidic agent, e.g. may be an aprotic acid such as aluminum chloride, ferric chloride, zinc chloride, titanium tetrachloride or boron trifluoride, or p-25-toluenesulfonic acid or benzenesulfonic acid. The most preferred acidic agent is aluminum chloride.

The reaction of the compounds of formula III and ethylene oxide is advantageously carried out in an anhydrous, inert organic solvent, e.g. an aromatic hydrocarbon such as benzene, toluene or xylene, ethers such as tetrahydrofuran or diethyl ether, or carbon disulfide. This reaction can be carried out at a temperature in the range of approx. -10 ° C to the reflux temperature of the reaction medium, preferably between 10 ° C and the reflux temperature. The choice of temperature is not critical and will, of course, depend on the properties of the compounds selected as reagents, the solvent medium used, and the nature of the acidic agent used.

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3 150073

It should be noted that in addition to forming the heterocyclic ring between the 4- and 5-positions of the benzodiazepine moiety upon reaction with the compounds of formula III, the ethylene oxide can also react with the nitrogen atom in the 1-position of the compounds of formula III when the nitrogen 2 * is unprotected, i.e. when R represents hydrogen. Thus, the reaction 2 'of a compound of formula III in which R is hydrogen with ethylene oxide can result in a mixture of two compounds, the first one exhibiting no substitution at the 1 nitrogen and the second being correspondingly substituted at 1- nitrogen. Thus, if a compound of Formula III in which R is hydrogen is reacted with ethylene oxide, one can isolate from the reaction mixture, as appropriate, both the corresponding compound of Formula I and the corresponding compound which is unsubstituted by nitrogen.

Examples of compounds of formula I representative of the compounds which can be prepared by the process of the present invention are the following: 10-Chloro-2,3,5, 11b-tetrahydro-7- (2-hydroxyethyl) - 11b- -phenyloxazolo- [3,2-d] [1,4] -benzodiazepin-6 (7H) -one and 10-chloro-11b- (2-fluorophenyl) -2,3,5,11b-tetrahydro- 7- (2-hydroxyethyl) -oxazolo- [3,2-d] [1,4] benzodiazepin-6 (7H) -one.

The tricyclic benzodiazepine derivatives of formula I 25 can be used as drugs and are characteristic of being active as sedatives, muscle relaxants and anticonvulsants.

The pharmacological activity of two representative of the compounds of this invention has been determined by standard experiments. The compounds used in these experiments are the following: 10-Chloro-2,3,5, 11b-tetrahydro-7- (2-hydroxyethyl) -11b - phenyloxazolo- [3,2-d] [1, 4] -benzodiazepine-6 (7H) -one (Compound A) 35 and 10-chloro-11b- (2-fluorophenyl) -2,3,5-11b-tetrahydro-7- (2-hydroxyethyl) oxazolo [3,2] [1,4] -benzodiazepine-6- (7H) -one 4 150073

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(Compound B)

The tests used in these experiments are the following: Fight trials

This test is suitable for testing compounds 5 with muscle relaxant properties and / or tranquillizers. mice are placed under an inverted one-liter beaker on a grid through which they are subjected to impact on the paws. This results in the mice in an agitated state, which occasionally manifests itself in short matches. Mouse pairs are selected, which have struggled 5 times in a 2 minute trial period. The test substance is administered orally and the test is repeated after 1 hour using logarithmically increasing doses up to a maximum of 100 mg / kg. The 100% inhibitory dose is the one that prevents battle in 3 out of 3 mouse pairs.

15 Inclined plan

This experiment is used to determine muscle relaxant activity and / or sedative activity. Groups of every 6 male mice are given the test compound (maximum dose 20,500 mg per kg) and then left on a sloping surface for at least 4 hours to observe paralyzing effects that are powerful enough to cause the mice to slip off the surface. If activity is observed, additional doses are attempted until at least 2 doses are obtained, at which some, but not all, animals slide down from the surface. Doses at which mice slip off the surface due to toxicity or excitation are not included in the calculation of PD ^ q. PD ^ q is determined from a curve where the dose is plotted against the percentage of mice that are paralyzed. This PDj-g value is defined as the 30 dose in mg per day. kg, which is expected to cause 50% of the mice to slip off the surface.

Unaesthetized cat.

Cats are treated orally and observed for symptoms, usually ataxia. One cat is used at a dose of 50 mg 35 per day. kg. If activity is present, varying doses and up to 3 cats per day are used. dosage. The results show the minimum effective dose (MED). This experiment is used to determine muscle relaxant activity.

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5 150073

Antimetrazol test

This experiment is used to determine the anticonvulsant and / or sedative effect of the compounds in mice. The test compound is administered orally to groups of 4 mice each at 5 different dose levels. One hour later, metrazole (at a dose level previously determined to be sufficient to induce convulsive effects in all test animals, about 125 mg per kg) is administered subcutaneously, and the animals are observed for anti-seizure effects. The results are given as the number of animals protected from cramps.

The dose at which 50% of the animals are protected from seizures is referred to as the ED ^ g value.

The test results obtained using the above compounds are set forth in the following Table I.

6 150073

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7 150073

The following examples serve to elucidate the method of the invention.

Example 1 To 5 g (18.5 mmol) of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 90 ml of dry benzene are added 5.0 g ( 37 mmol) of aluminum chloride. The reaction mixture is stirred at reflux for 6 hours, cooled to room temperature and treated with 4.4 g (0.1 mole) of ethylene oxide. The reaction mixture is stirred for 18 hours, then the benzene is removed and the residue is treated with aqueous ammonium hydroxide solution and 100 ml of methylene chloride. The resulting precipitate is removed by filtration. The organic layer is then separated, washed with aqueous sodium chloride and dried, and the solvent is evaporated to give a residue which is crystallized from ether and recrystallized from a mixture of methylene chloride and hexane to give 10-chloro-2. 3,5, 11b - tetrahydro-11b-phenyloxazolo [3,2-d] [1,4] benzodiazepine-6 (7H) -one in the form of colorless prisms, m.p. 125-135 ° C, then solidification and m.p. 173-177 ° C.

The above filtrates are dissolved in methylene chloride and chromatographed on 200 g of silica gel with 300 ml of methylene chloride and with 700 ml of ethyl acetate. The ethyl acetate fraction is evaporated to dryness and crystallized from ether. Recrystallization from methylene chloride-hexane gives 10-chloro-2,3,5,11b-tetrahydro-7- (2-hydroxyethyl) -11b-phenyloxazolo [3,2-d] [1,4] benzodiazepine -6 (7H) -one in the form of colorless prisms with m.p. 134-137 ° C.

Analogous to the process described above, 11b- (2-chlorophenyl) -7- (2-hydroxyethyl) -30 -lo-nitro-2,3,5,11b-tetrahydrooxazolo [3,2-d] [1] can also be prepared [1 , 4] benzodiazepine-6 (7H) -one, m.p. 185-190 ° C with decomposition.

Example 2

To 15 g (51.9 mmol) of 7-chloro-5- (2-fluorophenyl) -

OC

-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 150 ml of dry benzene was added 9 g (67.7 mmol) of aluminum chloride and the mixture was stirred for 15 minutes. The reaction mixture is cooled in an ice bath and 8.8 g (0.2 mole) of ethylene oxide are added dropwise. After stirring at room temperature for 18 hours, the reaction mixture is heated to 40 ° C for 1 hour and then cooled to 5 room temperature and treated with 5 g (37.6 mmol) of aluminum chloride, followed by 4.4 g (0.1 mole) of ethylene oxide. The reaction mixture is heated to 45-50 ° C for 4 hours and then evaporated to dryness. Methylene chloride, ice and ammonium hydroxide are added and the solid is removed by filtration. The filtrate is separated and the organic phase is evaporated to dryness in vacuo. The residue is dissolved in dilute hydrochloric acid and the pH of the solution is adjusted to 5 with ammonium hydroxide solution. The acidic solution is washed with ether, made basic and extracted with methylene chloride. The organic extract is washed with aqueous sodium chloride solution, dried and evaporated to dryness. Recrystallization from a mixture of methylene chloride and hexane gives 10-chloro-11b- (2-fluorophenyl) -2,3,5,11b-tetrahydrooxazolo [3,2-d] [1,4] benzodiazepine-6 (7H) -one in the form of colorless rods with m.p. 183-184 ° C.

The etheric wash of said solution at a pH of 5 is evaporated to dryness, dissolved in methylene chloride and chromatographed over 200 g of silica gel with methylene chloride and ethyl acetate. The fractions are collected and the solvent removed to give a crude product. Recrystallization from methylene chloride and petroleum ether gives 10-chloro-11b- (2-fluorophenyl) -2,3,5,11b-tetrahydro-7- (2-hydroxyethyl) oxazolo- [3, 2-d] [1,4] -benzodiazepine-6 (7H) -one in the form of colorless plates, m.p. 147-151 ° C.

Example 3

To a solution of 3.3 g (0.01 mole) of 7-chloro-1- (2-hydroxyethyl) -5- (2-fluorophenyl) -1,3 dihydro-2H-1,4-benzodiazepine 2-one in 40 ml of 1,2-dichloroethane is added under nitrogen and with stirring 5.2 g (0.002 mol) of tin tetrachloride.

After 20 minutes, the mixture is cooled in an ice bath and 2.6 g (0.06 mol) of ethylene oxide is added. The mixture is recommended

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9 150073 for 1 hour at room temperature, then basified with ammonium hydroxide solution and filtered. The filter residue is washed with dichloromethane and the filtrates are combined, after which the organic phase is washed with 40 ml of dilute ammonium hydroxide solution, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is crystallized from one; mixture of ether and petroleum ether and recrystallized from toluene to give 10-chloro-11b- (2-fluorophenyl) - 7- (2-hydroxyethyl) -2,3,5,11b-tetrahydrooxazolo [3,2-d] [1,4] -10 benzodiazepine-6 (7H) -one in the form of white prisms, m.p. 142-147 ° C.

Claims (4)

150073 or Patent Claims. 1. Analogous Process for the Preparation of Oxazolo [3,2-d] [1,4] Benzodiazepines of the General Formula CH 2 -CH 2 -OH R 0 - (CH 2) 2 in which R 1 represents hydrogen, halogen, nitro or trifluoromethyl, and r 5 means phenyl or phenyl substituted with halogen, characterized by reacting a 4, 5-unsaturated 1,4-benzodiazepine of the general formula 2'-COH R 1 in which R 1 and R 5 are as defined above, 2 'and R is hydrogen or hydroxyethyl, with ethylene oxide in the presence of an acidic agent. Process according to claim 1, characterized in that R 2 represents hydrogen or halogen which is forch 2 -ch 2 -oh bonded with the benzene ring in para position with respect to the -N group, 5 and R phenyl or phenyl substituted with halo at the ortho position. A process according to claim 2, characterized in that R 1 is chloro and R 2 is phenyl or o-fluoro-phenyl. Process according to claim 3, characterized in that 10-chloro-2,3,5,11b-tetrahydro-7- (2-35-hydroxyethyl) -11b-phenyloxazolo [3,2-d] [1] is prepared. 4] benzodiazepine - 6 (7H) -one.