JPH0329795B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to novel oxadiazolyl imidazobenzodiazepine compounds, pharmaceutical compositions thereof, methods of treatment using the same, and methods of synthesizing the compounds. This new compound is useful for use as a psychotherapeutic, for example in the treatment of central nervous system diseases such as anticonvulsants or anxiolytics. Prior art The unique parts of the central nervous system of vertebrates are 1,4-
and 1,5-benzodiazepines (Squires, RF and Braestrup, C, Nature
(London) 266, (1977) 732). These sites are called benzodiazepine receptors. European Patent Application Publication No. 109921 (published on March 30, 1984) by Ferrosan, the applicant of the present application
and corresponding U.S. Pat. No. 4,507,313 (November 15, 1983)
(published on March 26, 1985) and Danish Patent Application No. 5102/85, the general formula (where R' is hydrogen, chlorine, fluorine, or nitro in the 7 or 8 position, R ¹ is hydrogen or lower alkyl having up to 3 carbon atoms, and R ³ is of the formula

[Formula] or

[Formula] (R″ is lower alkyl having up to 3 carbon atoms) is oxadiazolyl, and A–B is the formula

[Formula] or

Compounds having the formula: (R ⁵ is hydrogen or a methyl group, and R is hydrogen or chlorine) are disclosed. Page 2, number 17 of this European Patent Application Publication No. 109921
line - Page 3, line 3 contains European patent application publication no.
No. 27214 (U.S. Pat. No. 4,316,839), page 7, line 4, of oxadiazolylbenzodiazepines and more recent European Patent Application Publication No.
Oxadiazolyl-β-carbolines, such as those disclosed in US Pat. It is disclosed that it shows. Roche European Patent Application Publication No.
No. 150040 (published July 31, 1985) and the corresponding Danish patent application No. 245/85 (available for viewing from July 22, 1984) also disclose oxadiazolyl imidazobenzodiazepines. The disclosure of Rotsuyu's European Patent Application No. 150040 is very extensive. The disclosure regarding 1,2,4-oxadiazolyl-benzodiazepine compounds is exemplified by the following general formulas and. Here, R ¹ is alkyl, cycloalkyl, methoxymethyl R ³ is H, CH ₃ and R ⁴ and R ⁵ are H, halogen, Here X is

[Formula] and

[Formula] (where R ¹ is alkyl, cycloalkyl, CF ₃ or methoxymethyl) R ⁴ and R ⁵ are H, halogen, CF ₃ and n=2
Or 3. The compounds of Examples 2, 3, 16, and 43 of European Patent Application Publication No. 150040 of Rotsuyu are known compounds described on page 3, lines 4 to 5 of European Patent Application No. 109921 of Ferosan, and Examples 2 and 3 are from Rossiyu European Patent Application No. 150040, page 5, page 34.
~line 37 and Danish patent application no. 245/85 no. 5
This is a preferred compound described on page 14-17. Examples 2, 3, 16, 29, 32, 43, 44, 45, 49, 50 of Rotsuyu European Patent Application Publication No. 150040,
51, 52, 53, and 56 are 5,6-dihydro-6-oxo-4H-imidazo(1,5-a)(1,4) benzodiazepine compounds (compounds of formula). The compounds of Examples 1, 8, 9, 17, 18, 23, and 30 of Rotsuyu European Patent Application No. 150040 are 10,
11,12,12a-tetrahydro-9-oxo-9H-
imidazo(1,5-a) azeto(2,1-c)
(1,4) is a benzodiazepine compound (compound of formula). Examples 4, 5, 6, 7, 10, 11, 12, 13, 14, 15 of Rotsuyu European Patent Application Publication No. 150040,
19, 20, 21, 22, 24, 25, 26, 27, 28, 31, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 46, 48,
54, 55, 57, 58 and 59 are 11, 12, 13, 13a-tetrahydro-9-oxo-9H-imidazo (1,5
-a) Pyrrolo(2,1-c)(1,4) benzodiazepine compound (compound of formula). The compound of Example 47 of Rotsuyu European Patent Application No. 150040 is 11,13a-dihydro-9-oxo-9H-imidazo(1,5-a)pyrrolo(2,1
-c) (14) It is a benzodiazepine compound. The compounds of Examples 11, 15, 26 and 40 of European Patent Application No. 150040 to Rotsuyu are 1,2,4-oxadiazol-3-yl compounds. The compounds of Examples 11, 15, 26 and 40 of Rotsuyu European Patent Application No. 150040 are 11, 12, 13, 13a
-Tetrahydro-9-oxo-9H-imidazo(1,5-a)pyrrolo(2,1-c)-(1,4)
It is a 1,2,4-oxadiazol-3-yl compound having a benzodiazepine skeleton (compound of the formula). The compound of Example 40 of Rotsuyu European Patent Application No. 150040 is 11,12,13,13a-tetrahydro-9-oxo-9H-imidazo(1,5-a)pyrrolo(2,1-c)-( 1,4) 5-cyclopropyl-1,2,4 with benzodiazepine skeleton
-oxadiazol-3-yl compound (compound of formula). 5-cyclopropyl-1, which is the compound of Example 40 of European Patent Application Publication No. 150040 of Rotsuyu,
It was found that 2,4-oxadiazol-3-yl was generally inferior in pharmacological and biochemical evaluation as described below. The next page shows conventional examples of 5,6-dihydro-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine compounds (compounds of the formula).

【table】

【table】

【table】

Table: Of particular relevance to the present invention, Rotsus European Patent Application No. 150 040 discloses the following compounds: Example 44 3-cyclopropyl-1,2,4-oxadiazol-5-yl compound and

【formula】 Example 31

[Formula] 3-cyclopropyl-1,2,4-oxadiazol-5-yl compound example 40

[Formula] 5-Cyclopropyl-1,2,4-oxadiazol-3-yl compound Rotsuyu's European Patent Application No. 150040 further describes the formula and (Here, R ⁴ , R ⁵ and n have the above-mentioned meanings,
Y is a leaving group. ) and a compound having the formula CN—CH ₂ —X, where X has the meaning given above in the formula. There is. All of the oxadiazoles in the published application of Rotsuyu are in fact intermediates or
By reacting CH ₂ --CO ₂ R to synthesize compounds with the general formula or having --CO ₂ R instead of the oxadiazole ring, and then converting these compounds into oxadiazole through several steps. Manufactured. Although the novel compounds provided by the present invention have similar types of structures and activities as those disclosed in the prior art, the special and unique compounds of the present invention, i.e., not only their chemical structure but also their pharmacological action. Overall, it has been found that special and unique materials are advantageous from a technical point of view in this field. Purpose The object of the present invention is to develop a novel compound, 3-(5-cyclopropyl-1,2,4-oxadiazole-
3-yl)-5,6-dihydro-5-methyl-6
-Oxo-4H-imidazo (1,5-a) (1,
4) To provide benzodiazepines and pharmaceutically acceptable acid addition salts thereof, which compounds are useful in the treatment of disorders or diseases of the central nervous system, particularly as anticonvulsants and anxiolytics. It is also an object of the present invention to provide processes for the preparation of said compounds, pharmaceutical compositions of said compounds, intermediates and methods of treatment with said compounds. Additional purposes will become apparent later. And the technology will become clear in other respects as well. SUMMARY OF THE INVENTION In summary, the invention consists of: 3-
(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)
-(1,4)benzodiazepine and its pharmaceutically acceptable acid addition salt; an effective amount of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5 -Methyl-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine or a pharmaceutically acceptable acid addition salt thereof, suitable for the treatment of central nervous system diseases, especially convulsions and anxiety states. Pharmaceutical composition; for these purposes, an effective amount of 3-(5-cyclopropyl-1,
2,4-oxadiazol-3-yl)-5,6
-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine or a pharmaceutically acceptable acid addition salt thereof to a patient in need thereof; A method of treating anxiety conditions; and said method of treatment comprising administering the active compound in the form of a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent. The invention also encompasses methods of synthesizing the compounds of the invention and novel intermediates therefor. The free base compounds of the present invention have the formula Melting point 179-180.8℃. has. This compound is described in Example 3 of Ferrosan European Patent Application No. 109921, as exemplified below.
Examples of Rotsuyu's European Patent Application Publication No. 150040
40, or synthesized by conventional methods similar to that shown in Example 70 of European Patent Application No. 54507 to Schering, It is also synthesized by a novel method provided by the present invention as described below. where Y is -OP as described in Example 6 below
A leaving group such as (O)(O-ethyl) ₂ , which is described in US Pat. No. 4,031,079 or US Pat. Nitrosoalkylamino, alkoxy, mercapto, -OP
(O) (OR) ₂ (where R is lower alkyl) or -OP(O) (NR'R'') (where R' and R'' are each lower alkyl, or phenyl, or Together with the nitrogen atom to which it is bonded, it constitutes a heterocyclic group such as morpholino, pyrrolidino, piperidino, or methylpiperazino). The reaction is preferably carried out under alkaline conditions, for example in the presence of a base, where bases are preferably alkali metals such as potassium or sodium, alkoxides or hydrides. The reaction is preferably carried out in the presence of an organic solvent, especially an anhydrous solvent, more preferably an anhydrous aprotic solvent such as dimethyl formaldehyde (DMF), which does not react with the reaction components and reaction products under the reaction conditions. The temperature range employed is one suitable for the reaction to proceed at a reasonable rate without significant retardation or decomposition, with a temperature range of -40°C to room temperature usually being particularly preferred. Pharmaceutical Compositions The compounds of the present invention, together with conventional auxiliaries, carriers, or diluents, if necessary in the form of their pharmaceutically acceptable acid addition salts, are put into the form of pharmaceutical compositions or unit doses thereof. . and can be administered orally in the form of solids, e.g. capsule-filled tablets, or liquids, e.g. solutions, suspensions, emulsions, elixirs, capsule-filling liquids, rectally in the form of suppositories, and parenterally (subcutaneous injections). ) is used in the form of a sterile injection. The pharmaceutical compositions and unit dosage forms may contain conventional ingredients in conventional proportions with or without additional active compounds, and the unit dosage forms may contain central nervous system disease-mitigating amounts ( The active ingredient may also be contained in an amount corresponding to the daily dose (or benzodiazepine active dose).
1 mg of active ingredient per tablet or more commonly
Tablets containing 10 to 30 mg of active ingredient are representative of suitable unit dosage forms. The compounds of the invention are thus used for the formulation of pharmaceutical preparations for oral and parenteral administration to mammals, including humans, in accordance with conventional galenic compounding methods. Conventional excipients are pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral applications that do not have a deleterious effect on the active compound. Examples of such carriers include water, salt solutions, alcohol,
These include polyethylene glycol, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidone. Pharmaceutical preparations are sterilized and, if necessary, free of substances harmful to the active compound, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts influencing osmotic pressure, buffers and/or colorants. Adjuvants that do not have a negative effect are mixed. For parenteral use, particularly suitable are injectable solutions or suspensions, more preferably aqueous solutions of the active compound dissolved in polyhydroxylated castor oil. Ampules are also a convenient unit dosage form. For oral use, tablets, dragees or capsules containing talc and/or carbohydrate carriers or binders etc. are particularly suitable, said carrier being more preferably lactose and/or corn starch and/or the like.
Or potato starch. When a sweetened vehicle is used, it is used in the form of syrups, elixirs, etc. Generally, the compounds of the present invention are used in wide quantitative ranges, with 0.05 to 100 mg of the compound of the present invention per unit dose dispersed in a pharmaceutically acceptable carrier. Methods of Treatment Due to their high affinity for benzodiazepine receptors, the compounds of this invention have a high affinity for the central nervous system when administered in an amount that reduces, ameliorates, or eliminates a disease or disorder (which is also, of course, a benzodiazepine-active dose). Very useful in treating diseases or disorders.
The important CNS activities of the compounds of the present invention include anticonvulsant and anxiolytic activity, and they exhibit very favorable therapeutic indices along with low toxicity. Accordingly, the compounds of the invention may be administered to a subject in need of treatment, alleviation, amelioration or elimination of an indication, such as an animal body, including a human being, for the treatment of psychotherapeutic conditions, particularly for the treatment of convulsive and/or anxiety conditions. It associates with so-called benzodiazepine receptors in the central nervous system that require treatment. If necessary, pharmaceutically acceptable acid addition salts, such as hydrobromide, hydrochloride or sulfate salts, can be prepared by common conventional methods, e.g. by evaporating a solution of the free base containing the acid to dryness. (synthesized by methods, etc.). The compounds of the invention are also usually used simultaneously or together with pharmaceutically acceptable carriers or diluents, particularly preferably as a pharmaceutical composition, which can be administered orally, rectally or parenterally (including subcutaneously); The amount is used in the amount necessary to alleviate the central nervous system disease, e.g. as an anticonvulsant and/or anxiolytic, but at any time effective for the relief of the central nervous system disease due to the benzodiazepine effect. used in large quantities. A suitable dosage range is 1-200 doses per day.
mg, more preferably 1-100 mg, especially 30-70 mg
However, it will usually be determined by the method of administration, the form of the drug administered, the condition of the subject, the type and weight of the subject, and the preference and experience of the attending physician or veterinarian. The dosage range of the compounds of the invention is wide, when administered as a drug to a patient, e.g. a human, 0.1
-300 mg/day, preferably 1-30 mg/day. EXAMPLES The following examples are given by way of illustration only and are not intended to be limiting. Example 1 5,6-dihydro-5-methyl-6-oxo-
4H-imidazo(1,5-a)(1,4)benzodiazepine-3-carboxamide oxime. 0.0125 mol of 3-cyano-5,6-dihydro-
5-methyl-6-oxo-4H-imidazo (1,
5-a) A mixture consisting of (1,4) benzodiazepine (synthesized according to US Pat. No. 4,316,839), 1.1 g of hydroxylamine hydrochloride, 200 ml of 99% ethanol and 5.2 ml of 20% aqueous potassium carbonate solution was Heat with stirring for an hour. The reaction mixture was filtered and the filtrate was concentrated. The residue was treated with 100ml of water and the crystalline solid was filtered and washed with water. Melting point 224.6-225.9°C Example 2 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1 , 5-a) (1,4) benzodiazepine. 580 mg of 5,6-dihydro-5-methyl-6-
Oxo-4H-imidazo (1,5-a) (1,4)
Benzodiazepine-3-carboxamide oxime, 3 ml ethyl cyclopropylcarboxylate, 50
A mixture of mg sodium and 3 g molecular sieves (4 Å) was refluxed in 50 ml dry ethanol for 6 hours. The reaction mixture was cooled, filtered, and the filtrate was evaporated to give oily crystals as a residue. The residue was treated with water to give the title compound as white crystals. Melting point 179-180.8°C Example 3 Formaminomethyl-carboxamide oxime 0.55 mol of freshly liberated hydroxylamine dissolved in 370 ml of methanol was added to 53.6 g (0.638 mol) of N-formylamino-acetonitrile ^* . An ice bath was used to maintain the temperature below 20° C. during the addition. The solution was allowed to stand at room temperature for a day and night, and then evaporated to give a light-colored crystalline compound. Decomposition concentration 104-110℃ ^* Sy・nthesis, Vol. 10, pp. 681-682 Example 4 3-formylaminomethyl-5-cyclopropyl-1,2,4-oxadiazole 35 ml of ethyl cyclopropylcarboxylate , 30g
A mixture of formylaminomethyl-carboxamide oxime, 1 g of sodium and 30 g of ground molecular sieves (4 Å) was refluxed in 300 ml of absolute ethanol for 8 hours, after which an additional 1 g of sodium was added. The reaction mixture was filtered and the filtrate was evaporated. Remove the dark oily residue with 300 ml of CHCl ₃
The title compound was obtained as an oil by suspension treatment, filtration, and evaporation of the filtrate. H-NMR (60MH ₂ , CDL ₃ ) σ (ppm): 1.2
(4H, m), 2.8 (1H, m), 4.5 (2H, d, j=6
Hz), 7.8 (1H, broad-NH), 8.2 (1H, s). Example 5 5-cyclopropyl-3-isocyanomethyl-
1,2,4-oxadiazole 5-cyclopropyl-3 in CH ₂ Cl ₂ (100 ml)
-Formylamino-methyl-1,2,4-oxidiazole (60m mol) and triethylamine (176m mol) in a solution of POCl ₃ at 0 °C with stirring
(60m mol) was added dropwise followed by water (50ml).
A solution of Na ₂ CO ₃ (60 mmol) in solution was added. The mixture was allowed to warm to room temperature, after which the organic phase was separated, dried and subsequently evaporated under reduced pressure. The residue was treated with ether and, after decanting, the solution was evaporated to give the title compound as an oil. This oil was used without further purification. IR(cm ^-1 ): 2160. Example 6 3-5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-
5-methyl-6-oxo-4H-imidazo (1,
5-a) (1,4) Benzodiazepine 3,4-dihydro-4-methyl-2H-1,4
Benzodiazepine-2,5(1H)-dione ^*
(16.5m mol) was dissolved in dry DMF (25ml) and
Potassium t-butyrate (18 mmol) was added. The resulting solution was cooled to −20 °C under _N2 ,
Diethyl chlorophosphate (20 mmol) was then added. *US Pat. No. 4,316,839 The reaction mixture was maintained at -20 °C with stirring under N ₂ and then 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole in dry DMF (20 ml). (20m mol) and potassium t
A cold solution of -butyrate (20 mmol) at -30°C was added. The resulting reaction mixture was warmed to room temperature and then evaporated to dryness under reduced pressure. The oily residue containing the crude product was purified on SiO ₂ using ethyl acetate as eluent. The indicated compound was obtained as white crystals. Melting point 179-180°C Example 7 Representative pharmaceutical composition a) A representative tablet for the treatment of anxiety conditions manufactured by conventional tablet technology is: Compound of the invention ^* 1.0 mg Lactose 67.4 mg (European Pharmacopoeia Act) ) Contains Avicel (Microcellulose) 31.4mg Amberlite (IRP88) ^** 1.0mg Magnesium Stearate 0.25mg (European Pharmacy Law). Exactly the same tablets are used to treat convulsions. *preferably in the form of a salt **Ion exchange resin b) In suppositories, the usual suppository bases are used to contain the active ingredient in a conventional manner, e.g. polyethylene glycols are used;
It is solid at room temperature but melts at body temperature. c) In parenteral (including subcutaneous) sterile solutions, the active ingredient may be present in the usual amounts of conventional ingredients such as sodium chloride, sodium dihydrogen phosphate, disodium edetate (disodium salt of ethylenediaminetetraacetic acid), benzene. It is used with alcohol, sodium hydroxide for pH adjustment and double distilled water and processed according to conventional procedures such as filtration, sterile filling into ampoules and autoclaving for sterilization. It will be apparent that other suitable pharmaceutical compositions are within the scope of the present technology. Pharmacological Effects The compounds of the present invention have shown unexpectedly favorable results in standard typical tests measuring in vivo affinity for benzodiazepine receptors and in standard tests for pharmacological activity against convulsive and anxiety conditions transmitted through benzodiazepine receptors. It was found that it has the activity of The following tests were performed on compounds of the invention and representative examples of prior art compounds. Binding of ^3H -flunitrazepam to the mouse forebrain membrane by intraperitoneally administered test substances.
Vivo Inhibition (Step 130) Principle ³ H-Flunitrazepam ( ^3H -FNM) (200μ
Twenty minutes after administration of Ci/Kg (intravenous injection), the amount of specific ^3H -FNM binding to brain benzodiazepine receptors reached its maximum value. This specific binding of ³ H-FNM can be partially or completely prevented by simultaneous or prior administration of pharmacologically active benzodiazepines and by administration of certain benzodiazepine-like drugs (Chang and Snyder , Eur.J.
pharmacol. 48 , 212–218 (1978)). The compounds of the present invention are benzodiazepines,
By binding to benzodiazepine receptors similar to benzodiazepines such as diazepam, it has been shown to be effective as anxiolytic and anticonvulsant agents, similar to these known benzodiazepine compounds. Test procedure Test substance suspension (2 mg/ml) was prepared by Branson
5% by sonication for 10 minutes using a B15 microchip ultrasonic generator (setting 7)
Prepared in Duphasol-X ^** (Trade Mark, Duphar Company; castor oil-ethylene oxide derivative for emulsifying or solubilizing oils and other water-insoluble substances).
Groups of 3 mice (female, NMR, 18-22 g) were administered 100 mg/Kg of test substance intraperitoneally.
15 minutes after administering the test substance, ^3H -FNM (70-90Ci/mole) in 200ml of physiological saline was administered intravenously.
4μCi was administered. After 20 minutes, ^3H -FNM-treated mice were decapitated and the forebrains were immediately removed (within 30 seconds) and chilled on ice using an Ultra-Turrax homogenizer with an N10 shaft.
Homogenization was carried out in 12 ml of a solution of 25 mM KH ₂ PO ₄ , pH 7.1. 2 aliquots of 1ml immediately
Filter using a Whatman GF/C glass fiber filter and wash twice with 5 ml of the buffer described above.
The amount of radioactivity on the filter was measured with a conventional scintillation counter. A group of untreated mice was used as a standard. The amount of non-specific ^3H -FNM binding in 1-3 mice (this accounts for 8-15% of the total binding)
to measure (which should be between %)
30 minutes before ^H -FNM, 25 mg/Kg clonazepam was injected. If a dose of 100 mg/Kg inhibits specific ³ H-flunitograzepam binding by 50% or more; the test substance is administered at a rate 3.16 times lower than 100 mg/Kg. ED ₅₀ in the test substance is 50% specific ³ H-
Defined as the dose that inhibits FNM binding.
Specific binding is the amount bound in the control minus the amount bound in clonazepam-treated mice. Results ED ₅₀ values were determined from dose-response curves. If the test substance is administered only once, the ED ₅₀
The value is calculated as follows, provided that the inhibition of specific binding is within the range of 25-75%. ED ₅₀ = Dose x 1 x 1000/(Co/Cx-1) μg/Kg (where Co is the specific binding in the control and Cx is the specific binding in mice treated with the test substance.) Pentasol Clonic convulsive mice (intraperitoneal administration) (procedure 400) Principle Pentitetrazole 60-120 mg/Kg (s.c.)
A dose of 100% causes clonic and tonic convulsions in mice. The mechanism is unknown, but GABA receptor/benzodiazepine receptor/
This is thought to be due to several effects via the chloride ionophore complex. The antagonism of convulsions produced by administration of maximum doses of pentylenetetrazole predicts an effective drug for petit mal seizures and anxiety conditions. Method The test compound was injected intraperitoneally, and 30 minutes elapsed.
Male or female NMRI mice weighing 20-25 g were administered subcutaneously with 150 mg/Kg of pentylenetetrazole dissolved in 0.9% NaCl in a volume of 15 ml/Kg. They then counted the number of mice that showed clonic seizures within 30 minutes. At least three doses of at least each test compound were administered, with 4 or 8 mice per dose, and doses above and below the ED ₅₀ were used. Results ED ₅₀ as the dose in μg/Kg that prevents disease in 50% of the animals using a computer program based on the Litchfield and Wilcoxon (1949) method.
The value was calculated. Pentasol Tonic Convulsions in Mice (Intraperitoneal) (Procedure 401) Principle Pentylenetetrazole causes clonic and tonic convulsions in mice at doses of 60-120 mg/Kg (s.c.). The mechanism is unknown, but
This appears to be due to the effects of the GABA receptor/benzodiazepine receptor/chloride onophore complex. The antagonism of convulsions caused by maximum doses of pentylenetetrazole predicts the drug to be effective in petit mal seizures and anxiety conditions. Method Male or female mice weighing 20-25 g were injected intraperitoneally with the test compound.
150 mg/Kg of pentylenetetrazol (Pentazol, Sigma) dissolved in NaCl was administered subcutaneously in an amount of 15 mg/Kg. The number of mice that developed tonic convulsions within 30 minutes was determined. At least 3 doses were given for each test compound, using 4 or 8 mice per dose;
Doses above or below the _ED50 value were used. Results Using a computer program based on the Litchfield and Wilcoxon (1949) method, the dose that prevented disease onset in 50% of the animals was determined.
_ED50 values were calculated. Acute Toxicity to Mice At each increasing dose level of the test substance, male or female NMRI mice (a special type of mouse commercially available in Europe) (20-
25g) orally. Mice were observed for 48 hours, and mortality rates were recorded after 48 hours. Three or four doses were administered to four mice per dose, with doses above and below the ED ₅₀ value.
_LD50 values were determined in mice using a computer program based on the Litchfield and Wilcoxon method (1949).
Calculated as the dose that causes 50% mortality. Table The results of testing the compounds of the present invention and the closest prior art compounds are shown in Table 1 below.

【table】

Table: From the table above, it is clear that the compounds of the present invention are significantly and unexpectedly superior in all respects to the structurally similar prior art compounds. European Patent Application Publication No. 109921 (Example 1) of Ferrosan compared to the corresponding 3-ethyl-1,2,4-oxadiazol-5-yl analogue (G) of Ferrosan European Patent Publication No. 109921 (Example 1). The compound of No. 109921 (Example 3) has almost the same activity,
5-ethyl-1,2,4-oxadiazole-
(3-yl) substituent is the corresponding 3-ethyl-1,
It is concluded that it is approximately equivalent to the 2,4-oxadiazol-5-yl substituent. Compared to the 3-cyclopropyl-1,2,4-oxadiazol-5-yl analog (F) of Rotsuyu's European Patent Application Publication No. 150040 (Example 31), Rotsuyu's European Patent Application Publication No. 5-cyclopropyl-1 corresponding to No. 150040 (Example 40),
The 2,4-oxadiazol-3-yl compound (E) is considerably inferior, and 5-cyclopropyl-1,2,4-oxadiazol-3-yl is It can be said that this is a rather inferior example. However, Rotsuyu's published European patent application
3-Cyclopropyl-1 corresponding to No. 150040,
Compared to the 2,4-oxadiazol-5-yl analogue (D), the compounds of the present invention have more than 4 times the binding affinity for benzodiazepine receptors;
It is approximately 40 times more active in preventing pentetrazole-induced clonic convulsions and 10 times more active in preventing pentetrazole-induced tonic convulsions. However, the exact same oxadiazole-3
Compared to compound E with the -yl substituent, the compounds of the invention have 12-fold higher binding affinity to benzodiazepine receptors, 185-fold higher activity in preventing pentetrazole-induced clonic convulsions, and 185-fold higher activity in preventing pentetrazole-induced tonic convulsions. 33 times more effective in preventing convulsions. Finally, from the foregoing, the present invention provides novel anticonvulsant and anxiolytic active compounds with highly advantageous and unexpected properties. -3-yl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine and its acid addition salts. It is. Furthermore, the present invention provides a new synthetic method and a new synthetic intermediate therefor. It is understood that this invention is not limited to the detailed operations, compositions, methods, procedures or embodiments shown or described; it is obvious that obvious modifications and equivalents are within the skill of the invention. and the invention is therefore to be limited only by the full scope of the claims.

Claims (1)

[Claims] 1 formula 3-(5-cyclopropyl-1,2,4
-oxadiazol-3-yl)5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine. 2 Formula for effective amount for central nervous system diseases 3-(5-cyclopropyl-1,2,4
-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine and a pharmaceutically acceptable carrier or diluent. An anticonvulsant consisting of 3 Formula for effective amount for central nervous system diseases 3-(5-cyclopropyl-1,2,4
-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine and a pharmaceutically acceptable carrier or diluent. An anti-anxiety agent consisting of. 4 The following equation (where Y is a leaving group) and a compound having the following formula [formula] 3-
(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)
(1,4) Method for synthesizing benzodiazepines. 5. The method according to claim 4, wherein the reaction is carried out under alkaline conditions. 6. The method according to claim 4 or 5, wherein the reaction is carried out in the presence of an organic solvent.