DK149817B - METHOD FOR PREPARING OXAZOLO (3,2-D) (1,4) BENZODIAZEPINES - Google Patents

Description

χ 140817 0

The present invention relates to a process for the preparation of oxazolo [3,2-d] [1,4] benzodiazepines of the general formula ch2-ch2-oh 1 "<G <: é®- (CH2) hydrogen, halogen, nitro or trifluoromethyl and R represents phenyl or phenyl substituted with halogen The term "halogen" includes all four halogens, i.e., fluorine, chlorine, bromine and iodine, unless otherwise expressly indicated.

Among the compounds of the general formula I, those in which hydrogen or halogen are preferred, with chlorine being the preferred halogen and being linked to the benzodiazepine moiety in its 7-position, and R means phenyl or phenyl, which in the ortho position are substituted by halogen, preferably fluorine, i.e. compounds of the general formula? h2-ch2-oh N-qo _ </ Ό- (CH2) 2 x xl 1 "7 in which R represents hydrogen or halogen and R represents hydrogen or halogen.

U9817

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2 Particularly preferred among the compounds of the above formula I are those compounds in which R 1 represents cilyl and R with flour.

The benzodiazepine derivatives of the above Formula I may be prepared according to the invention by a process which is characterized by cyclizing a compound of the general formula 10 ch2-ch2-oh

t / N - CO - CH, - NH - (CE0) 0 - O - H

\ f II

R5

15 R

in which R 1 and R 1 have the meaning given above.

Thus, in the process of the present invention, the compounds of the general formula I are obtained by cyclizing a compound of the general formula II. The compounds of general formula II used as starting materials in this process can advantageously be prepared by reacting a corresponding 2-aminophenyl ketone of the general formula ch2-ch2-oh

j '. / N - CO - CH 2 - X 'V

* '- <X

Wherein R and R are as defined above and X 'is chlorine, bromine or iodine, with 2-aminoethanol.

35

The compounds of formula V can be readily prepared in a manner known per se. The turnover between relations with

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Formula V and the 2-aminoethanol are carried out in the presence of a base in an inert organic solvent. Suitable bases are inorganic bases such as sodium acetate, and organic bases such as tertiary amines, e.g. trialkylamines, with triethylamine and pyridine being preferred. As solvents suitable for example. lower alkanols, e.g. methanol, ethanol and propanol, with ethanol being preferred; aromatic hydrocarbons, e.g. benzene, toluene and xylene, high boiling ethers, e.g. tetrahydrofuran and dioxane, as well as amides, e.g.

10 dimethylformamide and diethylformamide. If in the compounds of the general formula V X 'denotes chlorine or bromine, the reaction mixture may also contain sodium iodide to replace the chlorine or bromine atom with the more reactive iodine atom.

It is not necessary to isolate the intermediate thus formed of the general formula II from the reaction mixture, since this product readily cycles to the desired compound of formula I, and in a preferred embodiment the intermediate is not isolated but allowed to cyclize in the reaction medium. in which it is prepared, the reaction being carried out between the compounds but the formula V and the 2-aminoethanol at a temperature in the range of between about 25 ° C and the reflux temperature of the reaction medium, preferably around the reflux temperature. However, when using less energy-rich reaction conditions, e.g.

By performing the reaction between the compound of formula V and the 2-aminoethanol around or below room temperature, the intermediate compound of formula II can be isolated and then cyclized to the desired product, for example, by heating in pyridine, ethanol or xylene.

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

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149817 4

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

5 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) -10-11b-phenyloxazolo- [3,2-d] [1 , 4] benzodiazepin-6 (7H) -one.

(Compound A) and 10-chloro-11b- (2-fluorophenyl) -2,3,5,11b-tetrahydro-7- (2-hydroxyethyl) oxazolo- [3,2-d] [1,4] -benzodiazepine-6 (7H) -one (Compound B) The samples used in these experiments are as follows:

Match-trial

This test is suitable for testing compounds with muscle relaxant properties and / or tranquillizers. 2 mice are placed under an inverted one-20 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.

Mice pairs are selected that have struggled at least 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.

Inclining plan

This experiment is used to determine muscle relaxation activity and / or sedative activity. Groups of every 6 male mice are given the text compound (maximum dose 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 slide down the surface. If activity is observed, additional doses are attempted until at least 2 doses are obtained at 5

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some, with not all the animals slipping off the surface.

Doses at which mice slip off the surface due to toxicity or excitation are not included in the calculation of PD50 * PD5o determined from a curve where dose 5 is plotted against the percentage of mice paralyzed.

This PD5Q value is defined as the dose in mg per mg. kg, which can be expected to cause 50 percent of the mice to slip off the surface.

Unaesthetized cat.

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

Antimetrazol test.

This experiment is used to determine the anti-convulsive and / or sedative effect of the compounds in mice. The test compound is administered orally to groups of 20 4 mice each at 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 effects that protect against convulsions. The results are given as the number of animals protected against cramps. The dose at which 50% of the animals are protected from seizures is called the ED ED value.

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

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C

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Ό Ό P

id O '0 A o in

ti -Q..H in H

to m to O 0 Η Ό to

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Ό O 'O' X X O '0 \ \ • Q. Ό O 'O'

me 6 S

M 0 O g o mg cn 6

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7 149817

The compounds of formula I can be used to prepare conventional pharmaceutical compositions, the compounds e.g. may be mixed with conventional inorganic or organic inert pharmaceutical carriers suitable for parenteral or enteral administration, e.g. water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gum arabic, polyalkylene glycols or vaseline. The compounds may be administered in conventional pharmaceutical forms, e.g.

10 solid forms such as tablets, dragees, capsules or suppositories, or liquid forms, e.g. solutions, suspensions or emulsions. Furthermore, the pharmaceutical compositions containing the compounds of this invention may be subjected to conventional pharmaceutical treatments, e.g. sterilization, and may contain conventional pharmaceutical additives such as preservatives, stabilizers, wetting agents, emulsifiers, osmotic pressure control salts or buffers.

The compositions may also contain other pharmaceutically active materials.

A suitable pharmaceutical dosage unit may contain from ca. 1 to approx. 500 mg of the above-mentioned compounds of formula I, with a dose range of approx. 1 mg to approx. 100 mg is preferred for oral administration, and the dose range from about 1 mg to approx. 50 mg is preferred for parenteral administration. However, for any particular object, the specific dose should be adjusted according to the individual need and professional judgment of the person administering or monitoring the administration of said compounds. It will be understood that the said doses are to be construed as examples only.

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

Example 1

To a solution of 10 g (0.04 mole) of 2-amino-5-chloro-2'-fluorobenzophenone in 100 ml of dry benzene is added under nitrogen 10.6 g (0.08 mole) of aluminum chloride.

149817 o 8

Then, over 5 minutes, 7 g (0/16 mole) of ethylene oxide are added to the mixture, keeping the temperature of cooling in an ice bath below 35 ° C. The mixture is then allowed to stand for 65 hours at room temperature 5 and then repeated the measures described above using the same amounts of aluminum chloride and ethylene oxide. The resulting mixture is allowed to stand for 5 hours at room temperature, then the benzene is removed by distillation, the residue is made alkaline with ammonium hydroxide, it is stirred with 100 ml of methylene chloride and filtered. The organic phase of the filtrate is separated, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is recrystallized three times from a mixture of ether and petroleum ether to give 5-chloro-2'-fluoro-2- (2-hydroxyethyl) -aminobenzo-phenone in the form of yellow needles, m.p. 96-101 ° C.

A solution of 10 g (34 mmol) of 5-chloro-2'-fluoro-2-. - (2-hydroxyethyl) -aminobenzophenone in 150 ml of chloroform is mixed with a solution of 2 g (19 mmol) of sodium carbonate 20 in 150 ml of water. The two-phase syrup is then added, with stirring, 7.9 g (39 mmol) of bromoacetyl bromide after 2 hours of stirring 2 g (19 mmol) of sodium carbonate and after a further three hours of stirring an additional 7.9 g (39 mmol) of bromoacetyl bromine. After 1 hour, the organic phase of the mixture is separated, washed with 1N hydrochloric acid and then with water, dried and evaporated in vacuo, leaving a gummy residue.

The above residue is dissolved in 150 ml of benzene and 5 ml of triethylamine and 2.3 g (36 mmol) of ethanolamine are added and the mixture is stirred overnight at room temperature. The mixture is then shaken with vinegar ester and water and the organic phase is separated, dried and evaporated to dryness in vacuo. The residue is partitioned between ether and 1N hydrochloric acid, after which the hydrochloric acid phase is washed with acetic ester and the water removed in vacuo. As the residue, an orange colored gummy mass is obtained which, according to the thin layer chromatography, the tograiran mainly appears to contain 4'-chloro-2 '- (2-fluorobenzoyl) -N- (2-hydroxyethyl) -2- (2- hydroxyethyl-amino) -acetanilide and 10-chloro-11b- (2-fluorophenyl) -7- (2-hydroxyethyl) -2,3,5,11b-tetrahydrooxazolo [3,2-dJ [1,4] -5 benzodiazepin-6 (7H) -one.

A vinegar ester solution of 1.5 g of the gummy residue is chromatographed on 150 g of Florisil and eluted with 200 ml of hexane (fraction 1) and with 250 ml of 50% vinegar ester in hexane (fractions 2-4). Fractions 2-4 are evaporated in vacuo to give 10-chloro-11b- (2-fluorophenyl) -7- (2-hydroxyethyl) -2,3,5,11b-tetrahydrooxazolo [3,2-d] ] [1,4] benzodiazepine-6 (7H) -one in the form of a waxy solid with m.p. 138-146 ° C.

Example 2

A solution of 4.3 g (0.01 mole) of 4'-chloro-2 '- (2-fluorobenzoyl) -N- (2-hydroxyethyl) -2- (2-hydroxyethylamino) -acetanilide hydrochloride ( mp 174-178 ° C) in a mixture of 250 ml of benzene and 5 ml of triethylamine is heated under reflux for 12 hours. The solution is evaporated under reduced pressure and the residue is partitioned between 200 ml of dichloromethane and 200 ml of water. The layers are separated and the organic layer is washed twice with 100 ml of water, dried over sodium sulfate and evaporated. Crystallization 25 and recrystallization of the residue from a mixture of dichloromethane and petroleum ether (bp 30-60 ° C) give 10-chloro-11b- (2-fluorophenyl) -7- (2-hydroxyethyl) -2,3,5 , 11b - tetrahydrooxazolo [3,2-d] [1,4] benzodiazepine-6 (7H) -one in the form of colorless plates with m.p. 147-151 ° C.

Claims (3)

149817 or Patent Claims. A process for the preparation of oxazolo [3,2-d] - [1,4] benzodiazepines of the general formula 5 CH - CHo-OH r1-10 10 R5 O- (CE2) 2 in which R1 represents hydrogen, halogen, nitro or trifluoromethyl, and R is phenyl or phenyl substituted with halogen, characterized in that a compound of the general formula ch2-ch2-oh is terminated 20 N - CO - CH 2 - NH - (CH 2) 2 - o - h r 1 -11 ^ --- ^ c = o έ5 25 1 5 in which R and R have the meaning given above. A process according to claim 1, characterized in that R 1 represents hydrogen or halogen bonded to the benzene ring in para position with respect to the 30-ch 2 -ch 2 -O-N group, and R 1 represents phenyl or phenyl which in the ortho position is substituted by halogen. Process according to claim 2, characterized in that R is chlorine and R is phenyl or o-fluorophenyl.