JPH0127074B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to novel oxadiazolyl imidazobenzodiazepine compounds, pharmaceutical compositions thereof, and methods for 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. 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. 5102/82, the general formula (Here, R' is hydrogen located at the 7th or 8th position,
chlorine, fluorine, or nitro, R ¹ is hydrogen or lower alkyl with 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 on July 31, 1985) and the corresponding Danish patent application No. 245/85 (available for viewing from July 22, 1984) also disclose oxadiazoleimidazobenzodiazepines. 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. This European Patent Application No. 150040 to Rotsuyu does not contain any examples of compounds represented by the general formula. Here R ³ is

[Formula], especially when R ³ is

Compounds of the formula are not further disclosed. Furthermore, this lotus application is
A compound of the above general formula in which R ⁴ or R ⁵ is cyano, lower alkyl or methyl trifluoride, or a compound in which R ⁴ is fluorine, cyano, lower alkyl or methyl trifluoride. Not disclosed. And, of course, R ³ is expressed in the general formula

It does not disclose compounds of the formula where R ⁴ is chlorine, bromine, fluorine, CF ₃ , CH ₃ or CN. 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 the 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) (1,4) 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 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).
Of particular relevance to the present invention, Rossi European Patent Application No. 150 040 discloses the following compounds:

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

【formula】

[Formula] Example 31 3-cyclopropyl-1,2,4-oxadiazol-5-yl compound

[Formula] Example 40 5-Cyclopropyl-1,2,4-oxadiazol-3-yl compound Rotsuyu European Patent Application No. 150040 further describes the formula and

【formula】

[Formula] (wherein R ⁴ , R ⁵ and n have the meanings given above, and Y is a leaving group) and a compound having the formula CN-CH ₂ -X (where X is the formula given above) It also claims a method of synthesizing such a compound (and) by reacting a compound having the following meaning: 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 purpose of the present invention is to create a novel compound of the following general formula (). (Here, X is chlorine, bromine, fluorine, CF ₃ ,
CH ₃ , or CN) and pharmaceutically acceptable 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-7-X-4H-imidazo(1,
5-a)-(1,4)benzodiazepines and pharmaceutically acceptable acid addition salts thereof; an effective amount of 3-(5-
cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-
6-oxo-7-X-4H-imidazo(1,5-
a) A pharmaceutical composition suitable for the treatment of central nervous system diseases, in particular convulsions and anxiety conditions, comprising a (1,4) benzodiazepine or a pharmaceutically acceptable acid addition salt thereof. 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 _When melting _point It has a temperature of 237-9℃. These compounds are described in Example 3 of Ferrosan EP 109921, Example 40 of Rotsuyu EP 150 040, or Schering EP 1 150 040, as exemplified below. Synthesized by a conventional method similar to that shown in Example 70 of No. 54507, It is also synthesized by a novel method provided by the present invention as described below. Here, 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 conventional ingredients in central nervous system ameliorating amounts. It may also contain an amount of active ingredient commensurate with the daily dosage. Tablets containing 1 mg of active ingredient per tablet, or more typically 10-30 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 Because of their high affinity for benzodiazepine receptors, the compounds of the invention are highly useful in the treatment of central nervous system diseases or disorders when administered in amounts that reduce, ameliorate, or eliminate the disease or disorder. . 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;
These are synthesized by common conventional methods, such as evaporation of a solution of the free base containing the acid to dryness. 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 will be used in an amount necessary to alleviate central nervous system disease, such as an anticonvulsant and/or anxiolytic, but at no time will be used in an amount effective to alleviate central nervous system disease. Ru. A suitable dosage range is 1-200 mg per day, more preferably 10-100 mg, especially 30 mg per day.
-70 mg, but is usually determined by the method of administration, the form of the drug being 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, eg a human, from 0.1 to 300 mg/day, preferably from 1 to 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-
7-chloro-4H-imidazo(1,5-a)(1,
4) Benzodiazepine-3-carboxamide oxime. 1.2 g of 3-cyano-5,6-dihydro-5-
Methyl-6-oxo-7-chloro-4H-imidazo(1,5-a)(1,4)benzodiazepine (synthesized according to U.S. Pat. No. 4,316,839), 0.45
A mixture of 1.2 g of hydroxylamine hydrochloride, 20 ml of 99% ethanol, 2 ml of water, and 1.2 g of potassium carbonate was refluxed for 1-1/2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was treated with 50ml of water and the crystalline solid was filtered and washed with water. Melting point 227.6-228.4°C Example 2 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-
5-Methyl-6-oxo-7-chloro-4H-imidazo(1,5-a)(1,4)benzodiazepine. 580 mg of 5,6-dihydro-5-methyl-6-oxo-7-chloro- produced according to Example 1
4H-imidazo(1,5-a)(1,4)benzodiazepine-3-carboxamide oxime, 0.3ml
A mixture of cyclopropylcarboxylic acid chlorides
The mixture was stirred and evaporated in 15 ml of THF for 2 hours at 20°C. After evaporation, 20 ml of acetic acid was added and the mixture was refluxed for 2-1/2 hours and evaporated. The reaction mixture was left overnight at room temperature, then cooled, filtered, and the filtrate was evaporated to give an oily crystalline residue. The residue was treated with ether and filtered to give the title compound as white crystals. Melting point 165-169°C Example 3 Formylaminomethyl-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 temperature 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, during which time 1 g of sodium was added. The reaction mixture was filtered and the filtrate was evaporated. The dark oily residue was suspended in 300ml of _CHCl3 , filtered and the filtrate was evaporated to give the title compound as an oil. H-NMR (60MHz, CDl ₃ ) σ (ppm): 1.2 (4H,
m), 2.8 (1H, m), 4.5 (2H, d, j=6Hz),
7.8 (1H, broad-NH), 8.2 (1H, s). Example 5 5-cyclopropyl-3-isocyanomethyl-
5-Cyclopropyl-3 in 1,2,4-oxadiazole CH ₂ Cl ₂ (100 ml)
-Formylamino-methyl-1,2,4-oxidiazole (60 mmol) and triethylamine (176 mmol) in a solution of POCl ₃ at 0 °C with stirring
(60 mmol) dropwise followed by water (50 ml)
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 3,4-dihydro-4-methyl-6-cyano-
2H-1,4-benzodiazepine-2,5 (1H)
-Dione 2.3g of 3,4-dihydro-4-methyl-6-
Bromo-2H-1,4-benzodiazepine-2,
5(1H)-dione and 1.26 g of cyprocyanide were dissolved in 5 ml of dimethylformamide. This mixture was heated to 110°C for 30 minutes. The mixture was then cooled to 50° C. and 2.4 g of sodium cyanide in 6 ml of water were added. The resulting mixture was then stirred for 10 minutes before 30ml of water was added. This mixture was extracted twice with 25 ml of ethyl acetate. After drying the organic phase with calcium chloride and filtration, the organic solution was evaporated under reduced pressure.
0.78 g of the title compound was obtained. Melting point 261-269℃. Example 7 3-5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5
-Methyl-6-oxo-7-chloro-4H-imidazo(1,5-a)(1,4)benzodiazepine 3,4-dihydro-4-methyl-6-chloro-
2H-1,4 benzodiazepine-2,5(1H)-
The dione (US Pat. No. 4,316,839) (9.17 mmol) was dissolved in dry DMF (20 ml) and sodium hydride (10 mmol) was added. The _resulting solution was −
After cooling to 20°C, diethyl chlorophosphate (11 mmol) was added. The reaction mixture was maintained at −20 °C with stirring under _N2 , then 5-cyclopropyl-3-isocyanomethyl-1,2,4 in dry DMF (15 mmol)
-Oxadiazole (11mmol) and potassium
A -30°C chilled solution of t-butyrate (11 mmol) 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 165-168.5°C Example 8 3-5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5
-Methyl-6-oxo-7-bromo-4H-imidazo(1,5-a)(1,4)benzodiazepine 2.5 g of 3,4-dihydro-4-methyl-6-
Bromo-2H-1,4 Benzodiazepine-2,5
(1H)-dione (Example 9 of US Pat. No. 4,352,817) (8.5 mmol) was dissolved in dry DMF (30 ml),
480 mg of sodium hydride was added. The resulting solution was cooled to −20° C. under a N ₂ atmosphere before diethyl chlorophosphate (1.6 ml) was added. The reaction mixture was maintained at −20 °C with stirring under _N2 , then 5-cyclopropyl-3-isocyanomethyl-1,2,4 in dry DMF (15 mmol)
-Oxadiazole (1.64g) and potassium t
A cooled -30°C solution of -butyrate (1.23g) was added. The resulting reaction mixture was warmed to room temperature and stirred for 30 minutes. The crude product was coagulated by adding 150 ml of water. This crude product was mixed with 50 ml of ethyl acetate/diethyl ether (1/1) and 100 ml.
and 4 molar hydrochloric acid. Remove the organic phase and
The product was coagulated by neutralizing the aqueous phase with molar sodium hydroxide. The coagulated product was crystallized from ethyl acetate to give the title compound as white crystals. Melting point 212-213℃. Example 9 3-5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5
-Methyl-6-oxo-7-methyl-4H-imidazo(1,5-a)(1,4)benzodiazepine 3,4-dihydro-4-methyl-6-methyl-
2H-1,4 benzodiazepine-2,5(1H)-
Zion (Example 28 of U.S. Pat. No. 4,316,839)
(4.0 mmol) was dissolved in dry DMF (20 ml) and sodium hydride (5 mmol) was added. The resulting solution was cooled to −20° C. under N ₂ atmosphere, then diethyl chlorophosphate (11 mmol) was added. The reaction mixture was maintained at −20 °C with stirring under _N2 , then 5-cyclopropyl-3-isocyanomethyl-1,2,4 in dry DMF (15 mmol)
-Oxadiazole (5mmol) and potassium
A cold solution of t-butyrate (5 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 crystallized with ethanol and 0.45 g
The compound described in was obtained. Compounds with melting points of 175-175.5°C and below were synthesized by exactly the same method. 7-fluoro-3-(5-cyclopropyl-
1,2,4-oxadiazol-3-yl)-
5,6-dihydro-5-methyl-6-oxo-
4H-imidazo(1,5-a)(1,4)benzodiazepine. Melting point 188.2-189.0℃ HNMR (60mHz, DMSO-D ₆ ): δ = 8.2 (S,
1H), 7.2-8.0 (m, 3H, aromatic), 5.1-4.2 (degenerate coupling, 2H), 3.1 (S, 3H, NME), 2.3
(m, 1H), 1.1-1.5 (m, 4H). It was synthesized by a modification of the procedure of Example 10 of U.S. Pat. No. 4,316,839, melting point 247.2~
3,4-dihydro-4-methyl-6- at 247.7℃
Fluoro-2H-1,4-benzodiazepine-2,
Obtained from 5(1H)-dione. As a correction, 6
-3,4-dihydro-4-methyl-6-fluoro-2H-1,4- from fluoro-isatoic anhydride
The reaction conditions in the reaction step leading to benzodiazepine-2,5(1H)-dione were 130°C for 8 hours instead of 100°C for 30 minutes, and N-methyl-N
-(2-amino-6-fluoro-benzoyl)-
Glycine was added repeatedly. 3,4-dihydro-4
Melting points for -methyl-6-fluoro-2H-1,4-benzodiazepine-2,5(1H)-dione are reported in U.S. Pat. No. 4,316,839.
Not 214-217℃, quite different from this
It was found to be 247.2-247.7°C. 7-cyano-3-(5-cyclopropyl-1,
2,4-oxadiazol-3-yl)-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine. Melting point 237-239℃ IR: 0.3% potassium bromide date 2230
C≡ in cm ^-1 NMR (60mHz, CDCl ₃ + DMSO-D ₆ )
Showing characteristics of N band: δ = 8.2 (S, 1H), 7.2 ~
8.0 (m, 3H, aromatic), 5.2-4.3 (2m, degenerate coupling, 2H), 3.1 (S, 3H, N-ME), 2.3
(m, 1H), 1.1-1.5 (m, 4H). This is 3,4-dihydro-4-methyl-6-cyano-2H-1,4-benzodiazepine-2,5
Synthesized from (1H)-dione (Example 6). 7-Trifluoromethyl-3-(5-cyclopropyl-1,2,4-oxodiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5 -a) (1,4)benzodiazepines. H ¹ NMR (60mHz, DMSO―D ₆ + CDCl ₃ ): δ=
(S, 1H), 8.0-7.5 (m, 3H, aromatic), 5.3-4.4
(m, degenerate coupling, 2H), 3.1 (S, 3H, N
- ME), 2.3 (m, 1H), 1.1-1.5 (4H). Melting point: 200.1℃ This is 3,4-dihydro-4- with a melting point of 224.0℃
Methyl-6-trifluoromethyl-2H-1,4
-benzodiazepine-2,5(1H)-dione (prepared as per the method of US Pat. No. 4,316,839). Example 10 Representative Pharmaceutical Composition a Representative tablets for the treatment of anxiety conditions manufactured by conventional tablet technology are: Compound of the Invention ^* 1.0 mg Lactose 67.4 mg (European Pharmacy Act) Avicel (microcellulose) 31.4mg Amberlite (IRP88) ^** Contains 1.0mg Magnesium Stearate 0.25mg (European Pharmacopoeia). Exactly the same tablets are used to treat convulsions. * Preferably in salt form ** Ion exchange resin b In suppositories, the usual suppository bases are used to contain the active ingredient in a conventional manner, for example polyethylene glycol, which is solid at room temperature. However, it melts at body temperature. c. In parenteral (including subcutaneous) sterile solutions,
The active ingredient contains the usual amounts of conventional ingredients such as sodium chloride, sodium dihydrogen phosphate, disodium edetate (disodium salt of ethylenediaminetetraacetic acid), benzyl alcohol, sodium hydroxide for pH adjustment and double distilled water. and processed according to conventional procedures such as filtration, sterile filling of 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 identical to the present invention and representative examples of prior art compounds. Determination of the binding of ^3H -flunitrazepam to the mouse forebrain membrane by intraperitoneally administered test substances.
In vivo inhibition (Step 130) Principle ³ H-flunitrazepam ( ³ H-FNM)
After 20 minutes of administration (200 μCi/Kg intravenously), specific ³ H-FNM to benzodiazepine receptors in the brain
The amount of binding reached the 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)). 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 cooled 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 _ED50 values were determined from the dose-response curve. 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)XII/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 convulsions in mice (intraperitoneal administration) (Procedure 400) Principle Pentylenetetrazole causes clonic convulsions and tonic convulsions in mice at doses of 60-120 mg/Kg (s.c.). Although the mechanism is unknown, it is thought to be due to several effects via the GABA receptor/benzodiazepine receptor/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. The number of mice that exhibited clonic convulsions within the next 30 minutes was determined. 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 XII/Kg that prevents disease onset in 50% of animals using a computer program based on the Litchfield and Wilcoxon (1949) method.
The value was calculated. Pentasol tonic convulsions in mice (intraperitoneal) (Step 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 ionophore 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 intraperitoneally injected with the test compound, and 30 minutes later, 0.9%
150 mg/Kg of pentylenetetrazole (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, and
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
_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. Compared to the corresponding 3-ethyl-1,2,4-oxadiazol-5-yl analogue (G) of Ferrosan EP 109921 (Example 1),
The compound of Ferrosan EP 109921 (Example 3) has approximately the same activity and the 5-ethyl-1,2,4-oxadiazole-(3-yl) substituent has the corresponding 3 -Ethyl-1,2,4-
It is concluded that it is approximately equivalent to the 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. No. 150040 (Example
5-cyclopropyl-1,2,4 corresponding to 40)
-Oxadiazol-3-yl compound (E) is considerably inferior to 5-cyclopropyl-1,2,4-
Oxadiazol-3-yl is a rather inferior example in Rotsuyu's European Patent Application No. 150040. 3-Cyclopropyl-1,2, corresponding to Rotsuyu European Patent Application No. 150040 (Example 29)
Compared to the 4-oxadiazol-5-yl analogue (D), the chlorinated compounds of the present invention have more than twice the binding affinity for benzodiazepine receptors and approximately 21 times higher binding affinity for pentetrazole-induced clonic convulsions. /4 times, and 10 times more in the prevention activity of pentetrazole-induced tonic convulsions. Compared to compound E, which has exactly the same oxadiazol-3-yl substituent, the chloride compounds of the present invention have 35-fold higher binding affinity to benzodiazepine receptors, 325-fold higher convulsive activity, and 325-fold higher pentetrazole-induced tonicity. 330 times more active in preventing convulsions. Compared to compound E, which has exactly the same oxadiazol-3-yl substituent, the brominated compound of the present invention has 60 times more binding affinity and 6500 times more activity in preventing pentetrazole-induced clonic convulsions.
And it is 5000 times more effective in preventing pentetrazole-induced tonic convulsions. Finally, from the foregoing, the present invention provides novel anticonvulsant and anxiolytic active agents, 3-(5-cyclopropyl-1,2,4-oxadiazole), with highly advantageous and unpredictable properties. -3-il)-
5,6-dihydro-5-methyl-6-oxo-7
-X-4H-imidazo(1,5-a)(1,4)benzodiazepine and acid addition salts thereof are clearly provided. 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 (where X is chlorine, bromine, fluorine or CF ₃ ) 3-(5-cyclopropyl-1,2,4
-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-X-4H-
Imidazo(1,5-a)(1,4)benzodiazepine. 2 Formula for effective amount for central nervous system diseases (where X is chlorine, bromine, fluorine or CF ₃ ) 3-(5-cyclopropyl-1,2,4
-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-X-4H-
An anticonvulsant and anxiolytic agent consisting of an imidazo(1,5-a)(1,4)benzodiazepine and a pharmaceutically acceptable carrier or diluent.