DK151809B - Analogy process for preparing oxadiazolylimidazo-(1,4)- benzodiazepine derivatives - Google Patents

Description

DK 151809B

The invention relates to an analogous process for the preparation of novel oxadiazolylimidazo [1,4] benzodiazepine derivatives.

The novel compounds of the invention have valuable pharmacological properties, in particular they act on the central nervous system and are suitable for use in psychopharmaceuticals.

Danish Patent Application No. 5541/81 discloses a series of β-carboline derivatives which are strongly bound to the so-called benzodiazepine receptors (cf. Squires, R. F. and Braestrup, C., Nature (London) 10 266 (1977) 732). Among the compounds described herein are a variety of 3- (5-oxadiazole) -p-carbolines.

Upon closer examination of these 3- (5-oxadiazole) -β-carbolines, it has surprisingly been found to bind significantly more strongly to the benzodiazepine receptors than analog 3-substituted β-carbolines.

From the disclosure of European Patent Application No. 27214, imidos [1,5-a] [1,4] benzodiazepines substituted with a cyano, alkanoyl or alkoxycarbonyl group are known and are capable of to bind to benzodiazepine receptors.

It has now surprisingly been found that, compared with the latter 20 known compounds, a particularly strong bond and / or a great activity against cramps are obtained with some novel oxadiazolyl derivatives of imidazo- [1,4] benzodiazepines, cf. the table below.

The invention relates to an analogous process for the preparation of oxadiazolylimidazo [1,4] benzodiazepine derivatives of the general formula I: wherein R represents hydrogen, chlorine, fluorine or a nitro group in 7 or 8 position, R represents hydrogen or an alkyl group of up to 3 carbon atoms,

R "represents an alkyl group of up to 3 carbon atoms and A ---- B

is a group of formula 5 -C-N / e "is O v \ - - R" TO where R4 represents hydrogen or methyl and RIM represents hydrogen or chlorine, the process of which is a compound of formula II in

15 R \ _CN

20

T

wherein A ---- B, R and R1 have the meaning previously defined, if

is added with NH 2 OH to give a compound of formula III

25

com, N. NOH

\ II

wherein: A ---- B, R and R1 are as previously defined and know that the compound thus obtained is reacted with (R '^ O ^ O, 35 where R "has the meaning previously defined.

Oxadiazoles and other heterocyclic substituted derivatives of heterocyclic fused benzodiazepines are mentioned in the disclosure of DE Publication No. 2,242,918, but none of the heteroaromatic derivatives of the present invention are synthesized.

DK 151809B

3

As mentioned, the compounds of the invention bind more strongly to benzodiazepine receptors than the corresponding known benzodiazepine receptor-active compounds, and this results in the pharmacologically active compounds of the invention having a substantially increased pharmacological effect.

The increased binding strength can with compounds without its own pharmacological action, i.e. with benzodiazepine antagonistic effect, is utilized to displace other pharmacologically active compounds, i.e. benzodiazepine agonists where such an entrapment is desired, e.g. to abolish the effect of benzodiazepines upon treatment with such.

The pharmacologically active compounds of the invention can be used to formulate pharmaceutical compositions, e.g. for oral and parenteral administration in mammals including humans, in accordance with traditional methods of galenic pharmacy.

Conventional additives are such pharmaceutically acceptable organic or inorganic carriers which are suitable for parenteral or enteral administration and which do not adversely react with the active compounds.

Examples of such carriers are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid and ethyl acetate fatty acid

The pharmaceutical compositions can be sterilized and, if desired, blended with such adjuvants as e.g. lubricants, preservatives, stabilizers, wetting agents, emulsifiers, osmotic pressure salts, buffers and / or dyes, and the like, which do not adversely react with the active compounds.

For parenteral use, injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxyethoxylated castor oil, are particularly suitable.

Ampoules are convenient as unit doses.

For oral use, tablets, dragees or capsules containing talc and / or a charcoal hydrate carrier or binder or the like, the carrier being preferably lactose and / or corn starch and / or potato starch, are particularly suitable. A syrup, elixir or the like can be used in which a sweetening agent can be used.

DK 151809B

In general, the compounds of the present invention are used in unit dosage form comprising from 0.05 to 100 mg in a pharmaceutically acceptable carrier per day. unit dose.

The dose of the compounds of the present invention is 0.1-300 mg / day, preferably 1-30 mg / day when administered to patients, e.g. people, as a drug.

It is well known (Squires, RF and Bræstrup, C., Nature (London) 266 (1977), 734) that specific sites in the central nervous system of vertebrates exhibit a specific high affinity for binding of 1,4-10 and 1,5-benzodiazepines. . These sites are called benzodiazepine receptors.

The pharmacological properties of the compounds of the invention have been investigated by determining their ability to displace radiolabeled flunitrazepam from such benzodiazepine receptors.

The displacement activity of the compounds of the invention has been determined by determining the IC IC value and the EDQQ value.

The ICgQ value represents the concentration at which displacement of 50% of the specific binding of 3 H-flu-nitrazepam (1.0 nM, 0 ° C) occurs in samples comprising a total volume of 0.55 ml of a suspension of brain membrane, e.g. from rats.

The displacement test is carried out as follows: 0.50 ml of a suspension of untreated rat brain for 25 mM ΚΗ, ΡΟ. at 0 ° C together with ° H-diazepam (specific activity 14.4 Ci / mmol, 3 1.9 nM) or H-flunitrazepam (specific activity 87 Ci / mmol, 1.0 nM). After incubation, the suspension is filtered through "Whatman GF / C" fiberglass filters, the filter residue is washed twice with cold buffer solution and radioactivity measured by scintillation counting.

The experiment is repeated, prior to the addition of the radiolabelled benzodiazepine, a given amount or excess of the compound whose displacement is desired is added. Based on the obtained measurement results, the IC ^ q value can be calculated.

The EDsQ value represents the dose (mg / kg) of a test substance, thereby reducing the specific binding of flunitrazepam to benzodiazepine receptors in a living brain to 50% of the control value. Such an in vivo experiment is carried out in the following manner:

Groups of mice are injected with the test substance at various 3 doses and usually subcutaneously. 15 minutes later, H-flunia is given.

DK 151809 B

5 trazepam intravenously to the mice and after a further 20 minutes the mice are killed and their forebrain membranes removed and radioactivity in the forebrain membranes measured by scintillation counting. The EDsQ value is determined from dose-response curves.

The experimental results obtained by testing a compound prepared by the process of the invention as well as some well-known benzodiazepine receptor active compounds will appear in the following table.

10 15 20 25 30 35

DK 151809B

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DK 151809B

EXAMPLE

3- [3- (5-Ethyl-1,2,4-oxadiazol) -yl] -5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] 1,4 benzodiazepine 5 A: 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine 3-carboxamidoxime

A mixture of 0.0125 mol of 3-cyano-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine, 1.1 g of hydroxylamine hydrochloride, 200 ml of 99% ethanol and 5.2 ml of a 20% potassium carbonate solution in water were refluxed for 22 hours. The reaction mixture was filtered and the filtrate concentrated. The residue obtained was treated with 100 ml of water and the crystalline solid was filtered off and washed with water.

B. 3- [3- (5-Ethyl-1,2,4-oxadiazol) -yl] -5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [ 1,4] benzodiazepin._

A mixture of 0.0056 mol of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxyamidoxime and 10 ml of propionic anhydride was stirred. for 2 hours at 20 ° C and then for 5 hours at 20 ° C. After evaporation, 100 ml of THF was added and the mixture was saturated with gaseous methylamine. The reaction mixture was allowed to stand overnight at room temperature, after which the mixture was concentrated under vacuum. 100 ml of methylene chloride was added and the mixture was filtered. The filtrate was concentrated and treated with 10 ml of ethyl acetate.

The yield was 0.0015 mol; m.p. 167-74 ° C.

The starting material for the compound of the example can be readily prepared by known methods. See, e.g. the description of US Patent No.

30 4,280,957 and EP Publication No. 27,214.

35

Claims (2)

DK 151809B Analogous Process for Preparation of Oxadiazolylimide-Azo- [1,4] Benzodiazepine Derivatives of General Formula I wherein R1 represents hydrogen, chlorine, fluorine or a nitro group at the 7 or 8 position, R represents hydrogen or an alkyl group of up to 3 carbon atoms, R "represents an alkyl group of up to 3 carbon atoms and A ---- B is a group of formula 20 ! wherein R 2 represents hydrogen or methyl, and R m represents hydrogen or chlorine, characterized in that a compound of formula II is in O 15 in A 15 - - B, R and R1 are as previously defined, reacted with NH 2 OH to form a compound of formula III "ν / \ _ Πη2 ^ \ _Γ 2 (HO "-OC /. Where A 21H B, R and R1 have the previously given meaning, and the compound thus obtained is reacted with (R" CO) 20 where R "has the previously given meaning.