JPS61263979A - Oxadiazol imidazobenzodiazepine,its production and drug composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention Field of the Invention 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.

The unique parts of the animal's central nervous system are 1,4- and 1,
It is well known that 5-benzodiazepines exhibit a high specific affinity for binding (Squires,
R, F, and Braestrup+C, Nature
(London) 266, (1977) 732
), these sites are called benzodiazepine receptors.

European Patent Application Publication No. 109,921 (published March 30, 1984) and corresponding U.S. Pat. No. 4,507.313 (1
Filed on November 15, 1983, published on March 26, 1985) and Tenmark Patent Application No. 5102/82, the general formula IR'' (where R'' is hydrogen, chlorine, fluorine, or nitro, R1 is hydrogen or lower alkyl with up to 3 carbon atoms, R3 is oxadiazolyl of the formula (R'' is lower alkyl with up to 3 carbon atoms), Compounds are disclosed in which A = B is a group of the formula (R5 is hydrogen or a methyl group and R++'' is hydrogen or chlorine).

Page 2, No. 1 of this European Patent Application No. 109,921
From line 7 to page 3, line 3, European Patent Application Publication No. 27.2
No. 14 (U.S. Pat. No. 4,316,839), page 7, No. 4
Oxadiazolylhenzodiazepines and more recent European Patent Applications Publication Box 54,50 as listed in
Oxadiazolyl-β-carbolines, such as those disclosed in U.S. Pat. It is disclosed that it exhibits strong condensation affinity.

Roche European Patent Application Publication Box 150
．． No. 040 (published July 31, 1985) and the corresponding Danish patent application No. 245/85 (available for viewing from July 22, 1984) also discloses oxadiazoleimidazobenzodiazepines.

The disclosure of Rososh European Patent Application Publication Box 150,040 is very extensive. The disclosure regarding L2,4-oxadiazolyl-benzodiazepine compounds is exemplified by the following general formulas (1) and (2).

Niko R1 is alkyl, cycloalkyl, methoxymethyl R'' is H, CH3, and R4, R5 is H, halogen, where X is (where R1 is alkyl, cycloalkyl, CF3, or methoxymethyl) R4, R5 is H, halogen, CI+3, and n=2 or 3°. This European Patent Application Publication No. 150.040 of Rossosh does not contain any examples of compounds represented by the general formula (2).

Not shown. Furthermore, this Roche application discloses compounds of the above general formula (III) in which R4 or R5 is cyano, lower alkyl, or methyl trifluoride, and R4 is fluorine, cyano, lower alkyl, or methyl trifluoride. No such compounds are disclosed. And, of course, it does not disclose compounds represented by the general formula (1), which are F-7, CF3, CH3, or CN.

Examples 2, 3, 16 of European Patent Application Publication No. 150,040 to Rossosh. and 43 are known compounds described in page 3, lines 4-5 of Ferrosan European Patent Application Publication Box No. 109,921, and Examples 2 and 3 are disclosed in Roche European Patent Application Publication Box No. 150,040. No. 5, page 34-
Line 37 and Danish Patent Application No. 245/85 No. 5
These are preferred compounds described on page 14-17.

Roche European Patent Application Publication Box No. 150.04Q Example 2, 3.16, 29, 32, 43, 44, 45, 4
9,50,51,52゜53, and 56 are 5,6-sihydro-6-oxo 4H-imidazo (L5-a) (
1,4) benzodiazepine compounds (compounds of formula (1)).

Compounds of Examples 1.8, 9, 17.1B, 23.30 of Roche European Patent Application Publication Box No. 150,040 are 10
,11,12゜12a-tetrahydro-9-oxo-9
H-imidazo(1,5-a) azeto(2,1-c)
(L4) is a benzodiazepine compound (compound of formula (■)).

Examples 4, 5, 6, 7, 10, 11, 12, 13, 14, 1 of Roche European Patent Application Publication Box No. 150.040
5,19,20.21゜22,24,25,26,27
,28,3L33,34,35,36,37,38,3
9°40.4L42,46,48,54,55,57.
58 and 59 are ICl2,13゜13a-te1helahydro9-oxo-9■-imidazo(1,5-a)pyrrolo(2,1-c) (L4) benzodiazepine compounds (compounds of formula ■) .

The compound of Example 47 of European Patent Application Publication No. 150,040 to Rososh is ICl3a-dihydro-9-oxo-9H-imidazo(L5-a)pyrrolo(2°1-c)(
1,4) It is a benzodiazepine compound.

Examples 11, 15, 26 and 40 of Rososch European Patent Application Publication No. 150,040 are examples of 1,2,4-oxadiazole-3-Morosh European Patent Application Publication No. 150,040 Compounds of LL15.26 and 40 are IL 12.13
．． It is a 1,2,4-oxadiazol-3-yl compound having a 13a-tetrahydro-9-oxo-9H-imidazo(L5-a)pyrrolo(2,1-c)-(L4) benzodiazepine skeleton. (Compound of formula ■).

The compound of Example 40 of European Patent Application Publication No. 150,040 to Rososh is 11.12.13.13a-tetrahydro-9-oxo-911-imidazo(L5-a)pyrrolo(2,1-c) (L 4) It is a 5-cyclopropyl-1,2,4-,iquizadiazol-3-yl compound having a benzodiazepine skeleton (compound of formula (1)).

5-Cyclopropyl-1,2,4, which is the compound of Example 40 of European Patent Application Publication No. 150.040 of Rososs.
-Oxadiazol-3-yl was found to be generally inferior in pharmacological and biochemical evaluation as described below.

On the next page, 5,6-sihydro6-oxo4H-
A conventional example of an imidazo(1,5-a) (L4) benzodiazepine compound (compound of formula (1)) is shown.

Of particular relevance to the present invention, EP-A-150,040 discloses the following compounds:

Example 44 and the yl compound 1-oxadiazol-3-yl compound Rososh's European Patent Application Publication No. 150,040 further describes the formulas ■ and ■ (where R4, R5 and n have the meanings given above and
is a leaving group. ) and a compound having 2CN-C12-
It also claims a method for synthesizing such compounds (■ and ■) by reacting compounds having X (where X has the meaning given above in 2).

All of the oxadiazoles in the Rososh published application are, in fact, intermediates ■ or V and CN CHz,
React C0zR to synthesize a compound of the general formula ■ or ■ having 10O□R instead of the oxadiazole ring,
They are then produced by converting these compounds into oxadiazoles in several steps.

Although the novel compounds provided by the present invention have similar types of structure and activity as those disclosed in the prior art, the special and unique compounds of the present invention, i.e., not only in terms of their chemical structure but also in terms of their pharmacological action, Overall, special and unique materials have been found to be advantageous from a technical point of view in this field.

An object of the present invention is to provide novel compounds of the following general formula (■) (where X is chlorine, bromine, fluorine, CF3, C13 or CN) and pharmaceutically acceptable addition salts thereof; The compounds are used in the treatment of disorders or diseases of the central nervous system,
It is particularly useful as an anticonvulsant and anxiolytic. It is also an object of the present invention to provide methods for the preparation of said compounds, pharmaceutical compositions of said compounds, intermediates of said compounds, and methods of treatment with said compounds. Additional purposes will become apparent later.

And the technology will become clear in other respects as well.

Honkorishoku! In summary, the invention consists of: 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-cyhydro-5-methyl-6-oxo-7
-X-411~imidazo(1,5-a)-(C4)benzodiazepine and its pharmaceutically acceptable acid addition salts; an effective amount of 3-(5-cyclopropyl-1,2,4-oxadiazole-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 compound of the present invention has the formula melting point 165.1-169.2°C when X=CI and when X=Br 21! -213℃ X=F 17) When 188.2-189.0℃X=C
200.1℃ when F, X=C) 175.0-175.5℃ when 13X=CN
It has a temperature of 237-9℃.

These compounds are described in Example 3 of Ferrosan, EP 109,921, Example 40 of Rosos, EP 150,040, or Schering, as exemplified below. The new structure, Y
is a leaving group such as the 10P(0)(0-ethyl)2 group described in Example 6 below, which leaving group is described in U.S. Pat.
No. 031,079 or No. 4,359,420, for example, halogen, alkylthio such as methylthio, aralkylthio, N-nitrosoalkylamino, alkoxy, mercapto, OP (0) (OR) 2
(where R is lower alkyl) or -OP(0)(
NR'R'') (where R'' and R'' are each lower alkyl, or phenyl, or together with the nitrogen atom to which they are attached constitute a heterocyclic group such as morpholino, pyrrolidino, piperidino, or methylpiperazino), etc. It is.

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;-
A temperature range of 40° C. to room temperature is usually particularly preferred.

■Bottle bottom! The compounds of the 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 solids, such as capsule-filled tablets, or liquids,
For example, it can be administered orally in the form of solutions, suspensions, emulsions, elixirs, capsule fillers, rectally in the form of suppositories, and parenterally (including subcutaneous injections) in the form of sterile injection solutions. Ru. 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, according to conventional galenic pharmaceutical techniques.

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, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,
These include gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid mono- and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidone.

Pharmaceutical preparations are sterilized and, if necessary, treated with e.g. oil lubricants,
Auxiliary agents which do not have a detrimental effect on the active compounds are admixed, such as preservatives, stabilizers, wetting agents, emulsifiers, salts that influence the osmotic pressure, buffers and/or colorants.

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 and the like are particularly suitable, said carrier being more preferably lactose and/or corn starch and/or potato starch.

When a sweetened vehicle is used, it is used in the form of a syrup, elixir, etc. In general, the compounds of the present invention will be used in a wide quantitative range, from 0.05 to 10% per unit dose.
0 mg of a compound of the invention is used dispersed in a pharmaceutically acceptable carrier.

Because of their high affinity for benzodiazepine receptors, the compounds of the present 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. It is. Important CNS of compounds of the invention
The activity exhibits anticonvulsant and anxiolytic activity, low toxicity and a very favorable therapeutic index. The compounds of the invention may therefore be administered to a subject, such as an animal body, including humans, to which administration is required for the treatment, alleviation, amelioration or elimination of an indication, such as for the treatment of psychopharmaceutical treatment, in particular for the treatment of convulsions and/or anxiety conditions. It associates with so-called benzodiazepine receptors in the central nervous system that require If necessary, pharmaceutically acceptable acid addition salts, such as hydrobromide, hydrochloride or sulfate salts, can be prepared by conventional methods such as evaporation of a solution of the acid-containing free base to dryness. Synthesized using methods such as The compounds of the present invention are also typically used together with or in combination with a pharmaceutically acceptable carrier or diluent, particularly preferably as a pharmaceutical composition, which is administered orally, rectally or parenterally (including subcutaneously); Also, the amount is used in an amount necessary to alleviate central nervous system disease, such as an anticonvulsant and/or anxiolytic, but at no time is an amount effective for alleviating central nervous system disease. Ru. A suitable dosage range is 1-
200 mg', more preferably 10-100 mg, especially 30-70 mg, but usually depending on the method of administration, the form of the medicament administered, the symptoms of the subject, the type and weight of the subject, and the choices of the attending physician or veterinarian. Determined by experience. The dosage range of the compounds of the invention is wide, when administered as a drug to a patient, e.g. a human, from 0.1 to 300
mg/day, preferably 1-30 mg/day.

The following examples are given by way of illustration only and are not to be construed as limiting.

5.6-Sihydro-5-methyl-6-ox-2-chloro-4H-imidazo(1,5-a)(1°4)benzodiazepine-3-carboxamide oxime.

1.2 g of 3-cyano-5,6-cyhydro-5-methyl-6-ox2-chloro-4-imidazo (L5-a
) (L4) Benzodiazepine (U.S. Patent No. 4.316
, 0.45 g of hydroxylamine hydrochloride, 20 ml of 99% ethanol, 2
- of water and 1.2 g of potassium carbonate
- Refluxed for 1/2 hour. The reaction mixture was filtered and the filtrate was concentrated. The residue was treated with 50 m7 of water and the crystalline solid was filtered and washed with water.

Melting point 227.6-228.4°C Implementation ±(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-cyhydro-5-methyl-6
-oxicu2chloro-411-imidazo(1,5-a
) (1,4) Benzodiazepines.

580 mg of 5.6-sihydro-5-methyl-6-oxu2-chloro-41-imidazo(1,5-a')(1,4)benzodiazepine-3-carboxamide oxime produced according to Example 1, 0.3 mf of cyclopropylcarboxylic acid chloride mixture in 15 ml of TH
The mixture was stirred and evaporated in F for 2 hours at 20°C. After evaporation, 20 n+J 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-carpoxamide 0.55 mol of newly liberated hydroxylamine dissolved in 370 ml of methanol was dissolved in 53.6 g of N-formylamino-acetonitrile (0,638 mole)
added to. A water bath was used to maintain the addition temperature below 20°C. 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℃ ” 5y-nthesis, Vol, lO, pp,
681-682 Example 4 35ml ethyl cyclopropylcarboxylate, 30g formylaminomethyl-carboxamide oxime, 1g
of sodium and 30 g of crushed molecular sieves (4 people)
The mixture 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 300 ml of CHCl3, filtered, and the filtrate was evaporated to give the title compound as an oil.

Old NMR (60Mtlz, CD1+) 6 (pp
m): 1.2 (411, m), 2.8
(Itl, m), 4.5 (2■, d, j=6
Hz), 7.8 (IH.

broad-NH), 8.2 (LH, s).

-1,2,4-oxadiazole 5-cyclopropyl-3-formylamino-methyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176
POCl3 at 0 °C with stirring into a solution of mmo + ).
(60 mmol) was added dropwise, and the water (50 n
A solution of NazCO3 (60 mmol) in +1) 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 decantation, the solution was evaporated to give the title compound as an oil.

This oil was used without further purification.

IR (cm-'): 2160゜Dog construction 3.4-dihydro-4-methyl-6-diatu 21-1
．． 4-Benzodiazepine-2,5(Ill)-dione 2.3 g of 3,4-dihydro-4-methyl-6-bromo-2H-1,4-benzodiazepine-2,5(11()
-dione and 1.26 g of cuprocyanide were dissolved in 5 ml of dimethylformamide. Add this mixture to 30
Heated to 110°C for minutes. The mixture was then cooled to 50° C. and 2.4 g of sodium cyanide in 5 ml of water were added. The resulting mixture was then stirred for 10 minutes before 3Qml of water was added. 25ml of this mixture
Extracted twice with ethyl acetate. After drying the organic phase over calcium chloride and filtration, the organic solution was evaporated under reduced pressure to yield 0.78 g of the title compound.

Melting point 261-269°C0 3-5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-cyclopropyl-5-methyl-6-
ox22chloro-411-imidazo (L5-a) (
L4) Benzodiazepine 3,4-dihydro-4-methyl-6-chloro-2H-1,4 benzodiazepine-2,
5(Il+)-dione (U.S. Pat. No. 4,316,839
No.) (9.17 mmol) in dry DMF (20 ml
) and added sodium hydride (10 mmol). The resulting solution was cooled to -20°C under N2,
Diethyl chlorophosphate (llmmol) was then added.

The reaction mixture was maintained at -20°C with stirring under N2,
A -30 °C chilled solution of 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole (llmmol) and potassium t-butyrate (llmmol) in dry DMF (15 mmol) was then added. 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 is
Purified in 5t (h7) using ethyl acetate as eluent. The title compound was obtained as white crystals.

Melting point 165-168.5°C Example 8 3-5-cyclopropyl-L2,4-oxadiazol-3-yl)-5,6-cyhydro-5-methyl-6-ox2-bromo-411-imidaz( 1,5~a)(
L4) 2.5 g of benzodiazepine 3,4-dihydro-
4-Methyl-6-bromo-2H-1,4benzodiazepine-2,5(LH)-dione (U.S. Pat. No. 4,352
, No. 817) (8.5 mmol) in a dry DM.
Dissolved in F2 (30m7) and added 480111g of sodium hydride. The resulting solution was cooled to -20°C under N2 atmosphere and then diluted with diethyl chlorophosphate (1,
6mZ) was added.

The reaction mixture was maintained at -20°C with stirring under N2,
Then 5-cyclopropyl-3-isocyanomethyl-L2,4-oxadiazole (1,64 g) and potassium t-butyrate (
A chilled solution of -30°C consisting of 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. The crude product was partitioned between 50 ml of ethyl acetate/diethyl ether (1/1) and 100 ml of 4M hydrochloric acid. The organic phase was removed and the product was coagulated by neutralizing the aqueous phase with 2 molar sodium hydroxide. The coagulated product was crystallized from ethyl acetate to give the title compound as white crystals.

Melting point: 212-213°C.

Sanitakuro 3-5-cyclopropyl-L2,4-oxadiazol-3-yl)-5,6-cyhydro-5-methyl-6-ox2-methyl-411-imidazo(1,5-a)
(1,4)Benzodiazepine 3,4-dihydro-4-
Methyl-6-methyl-211-1,4henzodiazepine-2,5(Il+)-dione (U.S. Pat. No. 4,316.
Example 28 of No. 839) Dry (4,0 open o1) D
Sodium hydride (5 mZ) dissolved in MF (20 mZ)
mmol) was added. The resulting solution was cooled to -20°C under N2 atmosphere and then diluted with diethyl chlorophosphate (ll
mmol) was added.

The reaction mixture was maintained at -20°C with stirring under N2,
A -30 °C cooled solution of 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole (5 mmol) and potassium t-butyrate (5 mn+ol) in dry DMF (15 mmo+) was then added. 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 from ethanol, yielding 0.45 g of the title compound.

Melting point: 175-175.5℃ The following compounds were synthesized by exactly the same method.

7-Fluoro-3-(5-cyclopropyl-1,2,4
-oxadiazol-3-yl) -5,6-sihydro5-methyl-6-oxo-4■-imidazo(L5-
a) (1,4) Benzodiazepines.

Melting point 188.2-189.0°C HNMR (60mHz, DMSO-D6): δ = 8.2
(S, 18), 7.2-8.0 (m, 311. aromatic), 5.1-4.2 (degenerate coupling, 2H), 3
．． 1 (S, 3H, NME), 2.3 (m, IH),
1.1-1.5 (m, 41().

This is US Pat. No. 4,316. Synthesized by a modified procedure of Example 10 of es9, melting point 247.2
3,4-dihydro-4-methyl-6- at ~247.7°C
Fluoro-21(-1,4-benzodiazepine-2',
Obtained from 5(Ill)-dione. As a correction, 6
-fluoro-isatoic anhydride to 3,4-dihydro-4
The reaction conditions in the reaction step leading to -methyl-6-fluoro-2H-1,4-benzodiazepine-2,5'(Ill)-dione were 130°C for 8 hours instead of 100°C for 30 minutes. , N-methyl-N-(2-amino-
6-Fluoro-hendiyl)-glycine was added repeatedly. 3,4-dihydro-4-methyl-6-fluoro-2H
The melting point for -1,4-benzodiazepine-2,5(LH)-dione is not 214-217°C as reported in U.S. Pat. No. 4,316,839, but is much different at 247.2 It was found to be ~247.7°C.

7-Diatu-3-(5-cyclopropyl-1゜2.4-
oxadiazol-3-yl)-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a) (
L4) Benzodiazepines.

Melting point 237-239℃ IR: 0.3% potassium bromide dish is 2230
cm-'NU (60mlz, CDCl++DMSO-
D6) showed the characteristics of C=N band: δ=8.2(S,
IH), 7.2-8.0 (m, 31 (.

aromatic), 5.2-4.3 (2 m, degenerate coupling.

2+1>, 3.1 (S, 311.N-ME), 2.3
(m, IH), 1.1-1.5 (m, 4n).

This is 3,4-dihydro-4-methyl-6-diatu2
Synthesized from H-1,4-benzodiazepine-2,5(IH)-dione (Example 6).

7-trifluoromethyl-3-(5-cyclopropyl-
i, 2,4-oxodiazol-3-yl)-5,6-
Cyhydro-5-methyl-6-oxo-4■-imidazo (
1,5-a) (1,4) Benzodiazepine.

H'NMR (60 mtlz, DMSO-D6+CDCl
+): δ= (S, 1) 1), 8.0 to 7.5 (m
, 3H, aromatic), 5.3-4.4 (m, degenerate coupling, 2+1), 3.1 (S, 3H, N-ME),
2.3 (m.

1) 1), 1.1~x, s(j++>.

It is 3,4-dihydro-4-methyl-6-trifluoromethyl-21(-1,4-benzodiazepine-2,5(IH)-dione (U.S. 4th.
3t, prepared according to the method of No. s39).

a) Typical tablets for the treatment of undiagnosed conditions manufactured by conventional tablet technology include the compound of the present invention" 1.0 mg lactose 67.4 mg (European Pharmacy Act) Av'1ceIP (microcellulose) 31.4
mg eight berlite P (IRP 88)
” Contains 1.0 mg magnesium stearate 0.25 mg (European Pharmacopoeia).

Exactly the same tablets are used to treat convulsions.

*Preferably in salt form**Ion exchange resinsb) In Ill drugs, customary suppository bases are used to impregnate the active ingredient in a conventional manner, e.g. polyethylene glycol is used; It is solid at room temperature but melts at body temperature. C) Parenteral (including subcutaneous)
In sterile solution, 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), benzyl alcohol, pH 1) used with sodium hydroxide and double-distilled water,
Processing follows 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 action The compounds of the present invention exhibit i
It was found to have an unexpectedly favorable high degree of activity in standard typical tests to measure in vivo affinity and in standard tests for pharmacological activity against convulsive and anxiety conditions transmitted through benzodiazepine receptors.

The following tests were performed on compounds identical to the present invention and representative examples of prior art compounds.

Treatment 311-flunitrazepam ('H-FNM) (2
00 μCi/kg intravenously), the amount of specific H-FNM binding to benzodiazepine receptors in the brain reached its maximum value 20 minutes later.
It can be partially or completely prevented by concurrent or prior administration of pharmacologically active benzodiazepines and by administration of certain benzodiazepine-like drugs (Chang
and 5nyder, Eur, J.

Pharmacol, 48, 212-218 (197
8) ).

Suspension of test substance (2 mg/m/) in a clay dish was prepared by Branson
B15 microchip ultrasonic generator (setting 7)
5% Dupha by sonication for 10 min using
3 mice (female, NMR, 18-22 g) were prepared in 3 mice (female, NMR, 18-22 g). 10 in group
0 mg/kg of test substance was administered intraperitoneally. 3 in 200 ml of physiological saline 15 minutes after test substance administration.
H-FNM (70-90 Ci/mole) was administered intravenously at 4 μC+. After 20 minutes, the 3H-FNM-administered mouse was put into speech, the forebrain was immediately removed (within 30 seconds), and an Ultra-Turra tube with a NIO shaft was placed.
x 25mM K on ice using a homogenizer.
Homogenization treatment was carried out in 12 mJ of a solution of HzPOn, pH 7.1. Immediately take 2 ml of Whatma
n Filter using a GF/C glass fiber filter, 5 m
The cells were washed twice with 1 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. One to three mice were given 25n+g/30 minutes before H-FNM to measure the amount of non-specific H-FNM binding (which should be between 8-15% of total binding). kg clonazepam was injected.

More than 50% specific 311 at a dose of 100 mg/kg
- When inhibiting flunitograzepam binding; the test substance is administered at a rate 3.16 times lower than 100 mg/kg.

ED in the test substance. is 50% specific 3H-FN
Defined as the dose that inhibits M binding. Specific binding is the amount bound in the control minus the amount bound in clonazepam-treated mice.

Cat ED5° values were determined from dose-response curves. EDs if the test substance is administered only once.

The values are calculated as follows, provided that the inhibition of specific binding is within the range of 25-75%.

(Here Co is the specific binding in the control and Cx is the specific binding in the mice treated with the test substance.) The current concentration of pentylentitrazole is 60-120 mg/kg (
subcutaneous) doses cause clonic and tonic convulsions in mice. Although the mechanism is unknown, GA
This is thought to be due to several effects via the BA receptor/benzodiazepine receptor/chloride ionophore complex. The antagonism of convulsions produced by administration of maximum doses of pentylentitrazole predicts an effective drug for petit mal seizures and anxiety conditions.

After 30 minutes of intraperitoneal injection of the test compound,
15 for male or female N'MHI mice weighing 25 g.
150 mg/kg of pentylentitrazole dissolved in 0.9% NaCl was administered via subcutaneous route in an amount of m1/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 EDso were used.

Hiroshi Litchfield and Wilcoxon (194
9) Dosage X that prevents disease onset in 50% of animals using a computer program based on the law
The EDso value was calculated as g.

■ Pentylentitrazole is effective at reducing clonic and tonic convulsions at doses of 60-120 mg/kg (s.c.) in convulsive mice (intraperitoneal) - (Step 401) Wake up the mouse. Although the mechanism is unknown, it is thought to be due to the influence of GABA receptor/benzodiazepine receptor/chloride ionophore complex. The antagonism of convulsions elicited by the highest doses of pentylentitrazole predicts the drug to be effective in petit mal seizures and anxiety conditions.

Thirty minutes after intraperitoneal injection of the test compound into male or female mice weighing 20-25 g per mouse, 0.9% NaC1 was administered.
150 mg/kg of pentylentitrazol (Pentazol, Sigma) dissolved in
kg amount was administered subcutaneously. The number of mice that developed tonic convulsions within 30 minutes was determined. At least 3 doses of each test compound were administered, using 4 or 8 mice per dose, and using doses above or below the EDso value.

Li tchf 1eld and Wilcoxon (1
949) ED as the dose that inhibits disease onset in 50% of animals using a method-based computer program. The value was calculated.

Table The results of testing the compounds of the invention and the closest prior art compound are shown in Table 1 below.

8 Compound of the present invention Ferrosan European Patent Application No. 109.92.1 Compound of Example 3 Ferrosan European Patent Application No. 109,921, page 3, line 5 Compound Dan Lonosch European Patent Application Publication No. 109,921, page 3, line 5 Compound described in EP-A-150,040 Example 44 and Compound described in Example 40 of EP-A-150,040 Compound t as described in Example 31 of EP-A-150,040 Ferrosan Compounds described in EP 109,921 Example 1 From the table above, it can be seen that the compounds of the present invention are remarkable in all respects and more than expected compared to the most structurally similar prior art compounds. It is clear that it is superior to

European Patent Application No. 109,921 (Example 1) of Ferrosan compared to the corresponding 3-ethyl-L2.4-oxadiazol-5-yl analogue (G) of Ferrosan European Patent Application No. 109,921 (Example 1). The compound of No. 109,921 (Example 3) has approximately the same activity, with 5-ethyl-1,2,
It is concluded that the 4-oxadiazol-(3-yl) substituent is approximately equivalent to the corresponding 3-ethyl-1°2.4-oxadiazol-5-yl substituent.

Roche's European Patent Application No. 150,040 (Example 31) in comparison to the 3-cyclopropyl-1,2,4-oxadiazol-5-yl analogue (F) of Roche's European Patent Application No. 150,040 (Example 31). Publication No. 150,040 (Example 40)
The corresponding 5-cyclopropyl i,2.4-oxadiazol-3-yl compound (E) is considerably inferior, with 5
-cyclopropyl-1,2,4-oxadiazole-3
-Ile Rosos European Patent Application Publication No. 150,040
It can be said that this is a rather inferior concrete example.

The corresponding 3-cyclopropyl = 1.2.4-
Compared to the oxadiazol-5-yl analog (D),
The chloride compounds of the present invention have more than 2 times the binding affinity for henzodiazepine receptors, about 2+ times as much activity in preventing bentetrazole-induced clonic convulsions, and 10 times as much activity in preventing bentetrazole-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 times more binding affinity to the henzodiazepine receptor, 325 times more convulsive activity, and 325 times less bendetrazole-induced tonicity. It is 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, 6500 times more activity in preventing bentetrazole-induced clonic convulsions, and It is 5000 times more active in preventing tetrazole-induced tonic convulsions.

Finally, in view of the foregoing, the present invention provides novel anticonvulsant and anxiolytic active agents, 3-(5-cyclopyl-1,2,4-oxadiazine), with highly advantageous and unpredictable properties. azol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-X-411-imidazo(1,5
-a) (L4) It is clear that henzodiazepine and its acid addition salts are provided.

Furthermore, the present invention provides a new synthetic method and a new synthetic intermediate therefor.

The present invention relates to the detailed operations shown or described; 3. ■Seiryu,
It is to be understood that there is no limitation to the methods, procedures or embodiments, and that obvious modifications and equivalents are obviously within the scope of the invention, and the invention therefore encompasses the scope of the claims. and should be limited only by the full scope set forth in .

Claims (1)

[Claims] 1 Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Here, X is chlorine, bromine, fluorine, CF_3, CH_3
or CN) with 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. 2 Formulas for amounts effective for central nervous system diseases ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Here, X is chlorine, bromine, fluorine, CF_3, CH_3
or CN) with 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 the above diseases, comprising a (1,4) benzodiazepine and a pharmaceutically acceptable carrier or diluent. 3 a) The following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Here, X is chlorine, bromine, fluorine, CF_3, CH_3
or CN, Y are leaving groups) and a compound having the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or b) The process of reacting a compound having the following formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (Here, X has the same meaning as above) A compound having NH_2OH is reacted with the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Here, X has the same meaning as above) ▲
There are mathematical formulas, chemical formulas, tables, etc. It consists of a process of reacting with ▼, and there are formulas, chemical formulas, tables, etc. ▼ (Here,
or CN) with 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-7-X-4H-imidazo( 1,5-
a) A method for producing a (1,4) benzodiazepine. 4 Claim 3 in which the reaction is carried out under alkaline conditions
The method described in section. 5 Claim 3 in which the reaction is carried out in the presence of an organic solvent
or the method described in paragraph 4. 6 The 7-X-substituents in the starting compounds and final products are 7-chloro, 7-bromo, 7-fluoro, 7-CF_
3 or 7-CN.