KR840000992B1 - Process for preparing imidazo diazepin derivatives - Google Patents

Abstract

Title compds. (I; A = a, b, c; R5 = H, CF3, halogen; R6 = H, CF3, halogen, lower alkyl; R2 = H; R3 = lower alkyl; R2R3 = (CH2)3, CH:CHCH2: R4 = Me, Et, iso-Pr, 2-hydroxyethyl; D = >C=0, >C=S) were prepd. by trans-esterification of XI R7 = lower alkyl. Thus, 24 g 5-fluoroisatoic anhydride was treated with 11.8 g sarcosine, and stirred at 100oC for 1.5 hr to give I(m.p. 262-263oC). I had a diazepam antagonist ED50 at 5.8 mg/kg orally in mice.

Description

Method for preparing imidazodiazepine derivative

The present invention relates to a novel imidazo [1,5-a] [1,4] diazepine derivative of the following general formula (I) and a pharmaceutically acceptable acid addition salt thereof.

In the above general formula

A represents one of the following groups (a), (b) and (c) together with the two carbon atoms represented by α and β,

Dashed lines represent double bonds in groups (a) and (b),

또는

이고,D is

or

ego,

R ⁴ is methyl, ethyl, isopropyl or 2-hydroxyethyl,

R ⁵ is hydrogen, trifluoromethyl or halogen,

R ⁶ is hydrogen, trifluoromethyl, halogen or lower alkyl,

R ² is hydrogen,

R ³ is hydrogen or lower alkyl,

R ² and R ³ together represent trimethylene or propenylene,

The carbon atom represented by γ has S or R and S configuration.

The compounds mentioned above are novel and exhibit useful pharmacodynamic properties.

The object of the present invention is to provide compounds of general formula (I) and their pharmaceutically acceptable acid addition salts themselves, methods of preparing these compounds as pharmaceutically effective substances, intermediates in the preparation of these compounds, compounds of general formula (I) or pharmaceutical Drugs containing acceptable acid addition salts thereof, methods for preparing such drugs, and the use of compounds of general formula (I) or pharmaceutically acceptable acid addition salts thereof for the treatment or prevention of diseases.

As used herein, the term "lower-alkyl" is preferably up to 7 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, etc., preferably A straight or branched chain saturated hydrocarbon group containing up to 4 is represented, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and tertiary butyl. The term “halogen” refers to fluorine. , Chlorine, bromine and iodine.

R ⁴ is preferably methyl, ethyl or isopropyl.

When R ² is hydrogen, R ³ is preferably metal. When R ² and R ³ together are trimethylene, the carbon atom represented by γ in General Formula (I) preferably has an S-configuration.

The symbol A is preferably group (a), where the dashed line means a double bond present in this group. In group (a), R ⁵ is preferably hydrogen or fluorine, R ⁶ is preferably hydrogen, fluorine, chlorine or methyl, and at least one of R ⁵ and R ⁶ is preferably hydrogen.

Particularly preferred compound of formula (I) is 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a]-[1,4] benzodiazepine-3 -Carboxylate.

Particularly preferred compounds of formula (I) are as follows:

Ethyl 7-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo- [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Ethyl (S) -8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine -1-carboxylate,

Ethyl (R, S) -11,13a-dihydro-9-oxo-9H-imidazo [1,5-a] -pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate And

Ethyl (R, S) -8-fluoro-11,13a-dihydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine- 1-carboxylate.

Other preferred compounds of formula (I) are as follows:

Ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Methyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo- [1,5-a] [1,4] benzodiazepine-3-carboxylate, isopropyl 5,6-dihydro-5 -Methyl-6-oxo-4H-imidazo- [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Methyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Isopropyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Ethyl 5,6-dihydro-5,7-dimethyl-6-oxo-4H-imidazo- [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Ethyl (S) -11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxyl Rate,

Methyl (S) -11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxyl Rate,

Isopropyl (S) -11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1- Carboxylate,

Ethyl (S) -7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] Benzodiazepine-1-carboxylate,

Ethyl (S) -11,12,13,13a-tetrahydro-8-methyl-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine -1-carboxylate,

Ethyl 5,6-dihydro-5-methyl-6-thioxo-4H-imidazo- [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Ethyl 8-fluoro-5,6-dihydro-5-methyl-6-thioxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Methyl (S) -10,11,12,12a-tetrahydro-8-oxo-8H-imidazo [5,1-c] pyrrolo [1,2-a] thieno [3,2-e] [ 1,4] diazepine-1-carboxylate,

Ethyl (S) -10,11,12,12a-tetrahydro-8-oxo-8H-imidazo [5,1-c] pyrrolo [1,2-a] thieno [3,2-e] [ 1,4] diazepine-1-carboxylate,

Methyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] -thieno [2,3-f] [1,4] diazepine-3-carboxylate and

Methyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] thieno [2,3-f] [1,4] diazepine-3-carboxylate.

The following compounds are also representative compounds of general formula (I).

Ethyl 5,6-dihydro-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Ethyl 8-fluoro-5,6-dihydro-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine ethyl-3-carboxylate,

Ethyl 8-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Ethyl 8-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Ethyl (S)-(+)-7-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1 , 4] benzodiazepine-1-carboxylate,

Ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] thieno [3,4-f] [1,4] diazepine-3-carboxylate,

(2-hydroxyethyl) 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate,

(2-hydroxyethyl) 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepines 3-carboxylate ,

(2-hydroxyethyl) (S) -10,11,12,12a-tetrahydro-8-oxo-8H-imidazo [5,1-c] pyrrolo [2,1-c] [1,4 ] Benzodiazepine-1-carboxylate,

Ethyl (R, S) -13,13a-dihydro-9-oxo-9H-imidazo [1,5-a] -pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate ,

Ethyl 5,6-dihydro-5-methyl-8-trifluoromethyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Ethyl 5,6-dihydro-5-methyl-7-trifluoromethyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate,

Ethyl 7-chloro-5,6-dihydro-8-fluoro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate and

Ethyl (S) -8-chloro-7-fluoro-9-oxo-9H-11,12,13,13a-tetrahydro-imidazo [1,5-a] pyrrolo [2,1-c] [ 1,4] benzodiazepine-1-carboxylate.

Imidazo [1,5-a] [1,4] diazepines of Formula (I) and their pharmaceutically acceptable acid addition salts are transesterified compounds of the following Formula (XI) according to the present invention. Then, if necessary, the resulting compounds of formula (I) are prepared by converting them into their pharmaceutically acceptable acid addition salts.

In the general formula, A, dashed line, D, R ² and R ³ are as described above, and R ⁷ is lower alkyl.

According to the process of the present invention, the compound of formula (XI) is trans-esterified, i.e., the alkyl group represented by R ⁷ in the compound of formula (XI) is substituted with R ⁴ group, wherein R ⁷ and R ⁴ are different groups), to give a compound of formula (I). As long as R ⁷ in formula (XI) represents methyl, ethyl or isopropyl, the compound of formula (XI) belongs to the compound of formula (I). Of course, at this time, R ⁷ may represent a lower alkyl group other than the above.

This trans-esterification reaction allows the compound of general formula (XI) to be heated at room temperature or from about 25 ° C. to 150 ° C., with an alcohol corresponding to the target group represented by R ⁴ (ie methanol, ethanol, isopropane or ethylene). Glycol). This transesterification reaction is preferably carried out in the presence of a base, particularly suitably in the presence of potassium cyanide or a similar weak base. As the solvent, it is preferable to use an alcohol corresponding to the group represented by R ⁴ in the compound of general formula (I). However, this transesterification reaction may also be carried out in inert organic solvents such as aromatic hydrocarbons (e.g. benzel or xylene), ethers (e.g. dioxane, tetrahydrofuran or ethyleglycol dimethyl ether), dimethylformamide, dimethylsulfoxide, etc. Can be done. In this trans-esterification reaction, not only the low boiling alcohol can be replaced by the high boiling alcohol, but also the high boiling alcohol can be replaced by the low boiling alcohol; In other words, ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] -benzodiazepine-3-carboxylate is converted into metal 5,6 with methanol. -Dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] -benzodiazepine-3-carboxylate can be converted.

This trans esterification reaction may also be carried out in several steps. For example, a compound of formula (XI) is hydrolyzed to the corresponding free carboxylic acid, from which a reactive functional derivative (such as an acid chloride) is prepared, and then the compound of formula (I) is prepared for this reactive carboxylic acid derivative. React with an alcohol corresponding to R ⁴ in the reaction.

Compounds of formula (I) may be converted into their pharmaceutically acceptable salts. The preparation of such pharmaceutically acceptable salts is by conventional methods. Salts produced by the present invention are (eg hydrochloride, bromate, sulfate, metalsulfonic acid salts, p-toluene sulfonate salts, oxalates, etc.) with inorganic and organic acids.

Compounds of formula (XI) used as starting materials in the present invention can be prepared by the following method:

(a) isocyanate acetic acid esterification of the following general formula (III) in the presence of a base, or

In the above general formula

A and the dotted line are as defined above,

X is an exit group,

R ²¹ is hydrogen, R ³¹ is lower alkyl, or

R ²¹ and R ³¹ together represent trimethylene or propenylene,

a carbon atom represented by γ has an S or R or S configuration

R ⁷ is as defined above

(b) appropriately substituting a secondary amino group of the general formula (XIa)

In the general formula, A, dotted line, D and R ⁷ are as defined above.

(c) removing the protecting group of the following general formula

In the general formula, A, dotted line, D and R7 are as defined above, Z represents a protecting group.

(d) The carbonyl group in the compound of formula (XIb) is converted to a thiocarbonyl group.

In the general formula, A, dashed line, R ² and R ³ and R ⁷ are as defined above.

According to this method (a), the compound of general formula (XI) can be prepared from the compound of general formula (II) and the isocyanoacetic acid ester of general formula (III). Examples of leaving groups represented by the symbol X in the compound of the formula (II) include easily removable phosphinyl groups, that is, groups represented by the following general formula, halogen atom, alkylthio group, aralkylthio group, N-nitro Small alkylamino groups, alkoxy groups and mercapto groups (wherein X is a mercapto group, the corresponding compound of formula (II) is the iminothiol form of the corresponding thiolactam).

In the above general formula, R ⁸ is lower alkyl, R ⁹ and R ¹⁰ are lower alkyl, allyl, phenyl or substituted phenyl, respectively, or a 3-8 membered hetero group in which R ⁹ and R ¹⁰ are unsubstituted or substituted with a nitrogen atom. Cyclic ring (eg, morphine).

The reaction of the compound of formula (II) with the isocyanoacetic acid ester of formula (III) is carried out in an inert solvent such as dimethylformamide, hexamethylphosphate triamide, dimethylsulfoxide, tetrahydrofuran or other suitable inert organics. Solvent), in the presence of a strong base sufficient to produce the isocyanoacetic acid ester anion of formula (III). Suitable bases used here include alkali metal alkoxides (e.g. sodium methoxide or potassium tert-butoxide), alkali metal hydrides (e.g. sodium hydride), alkali metal amides (e.g. lithium amide or lithium diisopropylamide). ), And tertiary amines (eg, triethylamine). This reaction is conveniently carried out at temperatures between about −40 ° C. and room temperature.

According to the method (b), the general formula (XI) compound can be prepared by appropriately replacing the secondary amino group at the 5-position of the general formula (XIa) compound. This substitution reaction may be carried out by reaction with the reagent to produce the desired substituent R ³¹ [e.g., the corresponding organosulfonate alkylester (e.g. methyl p-toluenesulfonate), the corresponding dialkylsulfate (e.g. dimethylsulfate or diethylsulfate), Or the corresponding alkyl halides (eg methyl iodide, ethyl iodide or ethyl bromide, etc.). Compounds of formula (XIa) are conveniently used in the form of alkali metal salts, which are conveniently reacted in the presence of strong bases or by converting compounds of formula (XIa) to alkali metal salts prior to reaction with alkylating agents. Suitable bases include alkali metal alkoxides (eg sodium ketoxide or potassium tert-butoxide), alkali metal hydrides (eg sodium hydride) or alkali metal amides (eg lithium amide or lithium diisopropylamide). have. This reaction is conveniently carried out in the presence of an inert organic solvent. Examples of suitable solvents for this purpose include dimethylformamide, dimethylsulfoxide, ethyl acetate, lower alkanols and the like, and many other solvents and mixtures of these solvents are suitably used and those skilled in the art They do not have difficulty in solvent selection, the reaction temperature range is quite wide and is generally the temperature between room temperature and the boiling point of the reaction mixture.

According to method (c), the compound of general formula (XI) can be prepared by removing the protecting group represented by Z from the compound of general formula (III). The protection group requirements in this case are dilute aqueous inorganic acids (e.g. dilute hydrochloric acid or dilute sulfuric acid), trifluoro acetic acid and the like and optionally co-Solvent (e.g. tetrahydrofuran, dioxane, acetic acid or N, N-dimethylformamide, etc.) should be separated under mildly acidic conditions. This reaction is conveniently carried out at temperatures between room temperature and the boiling point of the mixture, with the latter being preferred. Particularly suitable protecting groups are 2,4-dimethoxybenzyl groups, which are conveniently separated using trifluoroacetic acid, preferably at the boiling point of the mixture.

인 상응하는 일반식(XI)의 화합물로 전환시킬 수도 있다. 이러한 황화제의 예로는 오황화인이 있는데, 이를 과량 사용하는 것이 바람직하며, 이 반응은 불활성 유기용매(예, 디옥산 또는 메틸렌클로라이드등)내에서, 트리에틸아민 존재하 약 50℃ 내지 반응혼합물의 환류온도에서 바람직하게 수행된다.According to method (d), the compound of formula (XIb) is reacted with a sulfiding agent to

It may also be converted to a compound of the corresponding general formula (XI). An example of such a sulfiding agent is phosphorus pentasulfide, which is preferably used in excess, and the reaction is carried out in an inert organic solvent (e.g., dioxane or methylene chloride, etc.) from about 50 ° C. to the reaction mixture in the presence of triethylamine. It is preferably carried out at reflux temperature.

Other suitable sulfiding agents include compounds such as 2,4-bis (p-methoxyphenyl) -1,3,2,4-dithiaphospherane-2,4-disulfide, which sulfides of this kind are almost The reaction is carried out in the presence of an inert organic solvent (eg toluene or xylene), conveniently at the reflux temperature of the reaction mixture, or at about 60 ° C. to 110 ° C. in hexamethyl phosphate triamide.

Compounds of formula (II) used as starting materials in process (a) can be prepared from compounds of the following formula (XII) according to known methods [see: Belgian Kingdom Patent Nos. 802, 233, 833,249. And 865,653, US Patent Nos. 3,681,341 and J. Or g. Chemistry 29 , 231 (1964).

In the above formula,

A, dashed line, R ²¹ and R ³¹ are as defined above.

In the examples described below, a detailed description of the method for preparing the compound of the general formula (II) from the compound of the general formula (XII) is given.

Compounds of formula (XII) are known compounds or can be readily prepared by known methods, for example, corresponding carboxylic anhydrides of formula (XIII) are prepared by reacting amino acids of formula (XIV) .

In the above formula,

A, dashed line, R ²¹ and R ³¹ are as defined above.

Compounds of the general formula (XII) wherein R ²¹ is hydrogen and R ³¹ is lower alkyl can also be prepared by using compounds of the general formula (XV) shown below as starting materials.

In the above formula,

A, dashed line and R ⁷ are as defined above.

For example, after treating a compound of general formula (XV) with a reactive derivative of α-haloacetic acid (e.g., α-chloroacetyl chloride), the intermediate product thus obtained is treated with a lower alkylamine (e.g., methylamine, Ethylamine, etc.) to produce a compound of formula (XVI), which is then ring-closed to produce a compound of formula (XII) wherein R ²¹ is hydrogen and R ³¹ is lower alkyl.

In the above formula,

A, dashed line and R ⁷ are as defined above and R ³² is lower alkyl.

This ring closure reaction is carried out, for example, by briefly heating the compound of formula (XVI) at a temperature of about 100 ° C to about 300 ° C.

Compounds of the general formula (XII) may also be reacted with reactive derivatives of carboxylic acids of the general formula (XVII), such as carboxylic acid chlorides, to give the following general formula (XVIII) compounds. It may be prepared by removing the protecting group represented by Z from the compound of general formula (XVIII) and then ring-closing similarly to the preparation of the general formula (XII) compound from the general formula (XVI) compound.

In the above formula,

A, dashed line, R ²¹ , R ³¹ , R ⁷ and Z are as defined above.

In order to prepare the compound of the general formula (XIIa), the leaving group represented by X in the compound of the following general formula (XIX) can be removed by a known method.

In the above formula,

A and the dotted line are as defined above, and X 'is a leaving group.

Examples of such leaving groups include sulfonic acid groups (eg, methanesulfonyloxy, P-toluenesulfonyloxy, etc.) and halogen atoms (eg, chlorine, bromine and iodine). Removal of this leaving group is obtained by a base such as sodium hydride in an inert organic solvent such as dimethylformamide.

The compound of general formula (XIX) can be prepared by a method similar to the method for preparing a compound of general formula (XII) from a compound of general formulas (XIII) and (XIV) or from a compound of general formula (XVIII).

Compounds of formula (VII) used as starting materials in process (c) are those described above in connection with the preparation of compounds of formula (XI) wherein R ² is hydrogen and R ³ is lower alkyl, i.e. It can be prepared from compounds of the general formula (XX) in a similar manner to a) and (b) and in a similar manner as described for preparing the corresponding starting materials.

In the above formula,

A, dashed line and Z are as defined above.

Compounds of formula (XI) wherein R ⁷ is a group other than methyl, ethyl or isopropyl are novel and part of the present invention.

As described above, the compounds of general formula (I) are novel and have extremely useful pharmacodynamic properties.

These compounds have very low toxicity and have a high affinity for the central benzodiazepines receptors and can antagonize the central nervous system depression, muscle relaxation, ataxia, hypotension and respiratory depression of sedative 1,4-benzodiazepines. have.

The affinity of the benzodiazepine to the central receptor of the general formula (I) compound is measured by the methods described in the literature (Life Science 20. 2101-2110 (1977) and Scien ce 198, 849-851 (1977)). . According to this method, it was confirmed that the binding of tritium diazepam to the benzodiazepine native receptor in the cerebral cortex was inhibited by the test substance. IC ₅₀ (0% inhibitory concentration) is the test substance concentration required to inhibit approximately 50 percent of the intrinsic binding of tritium diazepam to the benzodiazepines high receptor in the cerebral cortex.

One of the representative features of 1,4-benzodiazepines exhibiting sedation is obvious anticonvulsant action, which can be demonstrated, for example, in generally stable pentetrazole animal studies. This feature is used as the basis for the test described below which allows the determination of compounds that can antagonize the central action of sedating 1,4-benzodiazepines.

In this trial, 5 mg / kg (intraperitoneal) of diazepam (extreme dose at which no convulsive seizure was seen in the pentetrazole test in more than 900 rats) was given pentetrazole (120 mg / kg, intraperitoneally 1 hour before administration, and the test compound is administered 5 minutes before pentetrazol administration. The antagonism of the test compound, ie its ability to antagonize diazepam in the pentetrazol test, can be determined by the number of mice causing convulsive seizures.

The following table shows the results obtained from representative compounds of the general formula (I). The ED ₅₀ value of each compound was shown. ED ₅₀ represents the amount of test compound that antagonizes the diazepam effect in 50% of the test animals in the test, and the unit is mg / kg (oral administration). In addition, the IC ₅₀ values of all test compounds were recorded, as well as the values for acute toxicity of some compounds (LD _{50 at} single oral dose, mg / kg).

[table]

In the test described later, ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine- which is one of the compounds of the general formula (I)- It is confirmed that 3-carboxylate (hereinafter abbreviated as "test substance") antagonizes the central action of the known 1,4-benzodiazepine derivative diazepam.

Almino species males (weight 165g) are used for this test. Intravenous injection of diazepam to these animals at a dose of 5 mg / kg immediately leads to sleep, sleeping for more than 60 minutes in the lateral position and slowly waking up after 1.5 hours. When intraperitoneally administered diazepam to these animals at a dose of 10 mg / kg, they wake up within minutes and wake up slowly after about 2-3 hours of sleep. After 5 or 15 minutes of intravenous diazepam 5 mg / kg or 30 minutes after intraperitoneal administration of diazepam 10 mg / kg, 5 mg / kg of the test compound is immediately awakened and awakened. Lasts 30 minutes to 1 hour.

If the test substance is administered intraperitoneally at the 20 mg / kg dose, the animal wakes up and takes normal action; If diazepam is administered at a dose of 5 mg / kg after 30 minutes, mild sedation and ataxia develop for 2 minutes after injection, but these symptoms disappear rapidly and the arousal period lasts for at least 30 minutes.

Ethyl (S) -11,1 2,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo which is one of the compounds of general formula (I) from the test mentioned later. [2,1-c] [1,4] -benzodiazepine-1-carboxylate (hereinafter abbreviated as "test substance") antagonizes the proliferation of known 1,4-benzodiazepine derivative flunitrazepam Able to know.

Four tests are performed by artificial respiration of a conscious rat, sponsored by Curare.

The bipolar-induced EEG of seahorses (dorsal hippocampus) is used as a measurement variable. Ten minutes after induction, flunitrazepam is administered at a dose of 0.1 mg / kg intravenously. The test substance is administered intravenously to one test animal 10 minutes after the administration of flunitrazepam at a dose of 1 mg / kg and intravenously to three animals 30 minutes after the administration of flunitrazepam.

The EEG is analyzed continuously in accordance with the rules of the Fourier transformation, where each of the compounded spectra is about one minute.

The hallmark of normal EEG from curated anesthetized, hippocampus of conscious rats is a stable theta wave of 3.75-4.25 hertz, which has not changed until at least 3 hours after initiation of ventilation. At this dosage, flunitrazepam completely inhibits this thetapa for about 15 minutes. Thereafter, theta wave gradually decreased to 2.75 to 3.25 hertz, and gradually increased and recovered to the normal frequency of 4 hertz 1 to 1.5 hours after the injection.

If the test substance is administered at a certain time after the administration of flunitrazepam at a dose, an immediate and sustained normalization of 4 hertz thetapa is indicated. If the test substance is administered 10 minutes after the administration of flunitrazepam, theta wave inhibited by flunitrazepam immediately appears and has a normal frequency from the beginning. When the test substance is administered 30 minutes after the administration of flunitrazepam, it accelerates the theta which already reappears gradually and immediately shows a normal frequency of 4 hertz.

As mentioned above, the compound of general formula (I) antagonizes the central inhibition, muscle relaxation, ataxia, hypotension and respiratory depression of 1,4-benzodiazepines, which exhibit sedation. 1,4-benzodiazepine is widely used for treatment, and sometimes in large doses, the above action may be strongly indicated as a side effect. The compound of general formula (I) can be used as an antidote at the time of poisoning by the excessive ingestion of the 1, 4- benzodiazepines which show sedation. They are also suitable for shortening the induced anesthesia in the surgical and obstetrics caused by 1,4-benzodiazepines that exhibit sedation. In newborns, sedative 1,4-benzodiazepines are administered to the mother to prevent possible respiratory depression. In addition, the compound of general formula (I) can suppress undesirable action on the central nervous system when 1,4-benzodiazepines are used in other indications. Examples of 1,4-benzodiazepines that may be used in other indications include 1,4-benzodiazepines derivatives of the following general formulas (XXII) and (XXIII) having hyperlipidemic activity, which is described in British Patent Nos. 1,444, 529 And 1,474,305.

In the above formula,

R and R ⁸ are hydrogen or lower alkyl,

R ⁹ is halogen,

R ¹⁰ is hydrogen, halogen or trifluoromethyl.

Examples of the 1,4-benzodiazepine derivatives having such a chemobactericidal activity include (+)-5- (0-chlorophenyl) -1,3-dihydro-3-methyl-7-nitro-2H-1,4- Benzodiazepine-2-one.

Through the following test, the typical compound of the general formula (I) is (+)-5- (0-chlorophenyl) -1,3-dihydro-3-3, which is a highly active hematopoietic deprivation agent that acts on the carnivorous nervous system. It was confirmed that the strong and undesired central activity of methyl-7-nitro-2H-1,4-benzodiazepine-one was suppressed without reducing its chemobactericidal activity.

Mice and golden hamsters are subcutaneously infected with 60-sercaria of cystozoa mansoni. Approximately 42 days after infection, the test compound is orally administered once. Five animals are used for each test formulation and dose. 10 untreated animals are used for control. Two weeks after treatment (hamster), or three weeks (rat), animals are beheaded and dissected. Record the mesenteric veins, portal vein, and number and status (live or dead) of insects in the liver. The chemobactericidal activity of the test formulation was demonstrated by the discovery of dead worms in the hepatic vessels.

No worms were found in untreated control animals. Percent mortality in hepatic vessels of infected and treated animals is calculated and evaluated.

To test the activity of the formulation in vitro, cystozoa mansonia is isolated from the rats and cultured in a nutrient medium at 37 ° C. Test formulations are added in the form of solutions or suspensions. Record the motility of the larvae under a microscope during the 120-hour test. The chemobactericidal activity of the test formulation demonstrates a rapid loss of motility of the worm.

Control insects in nutrient medium without test formulation exhibited normal motility during the entire 120-hour test period.

(+)-5- (0-chlorophenyl) -1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepine-one (1) to a compound of the following general formula (I) Inhibition of the chemobactericidal activity of compound s) is tested by the assay described above.

Ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate (Compound A)

Ethyl (s) -11,12,13,13a-tetrahydro-3-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] -benzodiazepine-1- Carboxylate (Compound B)

Ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate (Compound C)

Ethyl 5,6-dihydro-5-methyl-6-thioxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate (Compound D)

As can be seen from the following table describing the results of the test animals and the in vitro test, (+)-5- (0-chlorophenyl) -1,3-dihydro-3-methyl-7-nitro-2H- The chemotactic activity of 1,4-benzodiazepine-2-one (compound S) was not affected by any test compound of the general formula (I) compound tested.

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts can be used in the form of pharmaceutical preparations as medicaments. Such agents can be administered orally, e.g. in the form of tablets, capsular tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. It may also be administered rectally (eg suppositories) or parenterally (eg injections).

To prepare tablets, coated tablets, dragees and hard gelatine capsules, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts can be used with pharmaceutically inert inorganic or organic carriers. Carriers that can be used in tablets, dragees and hard gelatin capsules include lactose, cornstarch or derivatives thereof, talc, stearic acid or salts thereof.

Suitable carriers for soft gelatin capsules include vegetable oils, waxes, fats, semisolid and liquid polyols.

Suitable carriers for the production of solutions and syrups include water, polyols, saccharose, invert sugar, glucose and the like.

Suitable carriers for injection include water, alcohols, polyols, glycerin, vegetable oils and the like.

Suitable carriers for suppositories include natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

Pharmaceutical formulations may also include preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, osmotic salts, buffers, coatings, antioxidants, and the like. In addition, therapeutically effective substances may also be included.

As mentioned above, the compounds of general formula (I) and their pharmaceutically acceptable acid addition salts can be used for the treatment or prevention of diseases, in particular the central-inhibitory and muscle relaxation of 1,4-benzodiazepines that exhibit sedation Antagonizes ataxia, hypotension and respiratory-inhibition. The compound of the general formula (I) can be used in the treatment of schistosomiasis by mixing with 1,4-benzodiazepine having the above-described hypolipidemic eradication activity of the general formulas (XXII) and / or (XXIII). In this case, ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] -benzodiazepine-3-carboxylate is a general formula It is used suitably as a compound of (I), and it is (+)-5- (0-chlorophenyl) -1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepines-2-ones. It is preferably used as the 1,4-benzodiazepine derivative having the chemobactericidal killing activity.

The compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof may be administered before, simultaneously with or after administration or ingestion of 1,4-benzodiazepine that exhibits sedative action. If a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof is administered concurrently with sedating 1,4-benzodiazepines, a particular (ad-hoc) mixture or compound of formula (I) or pharmaceutical It may be administered in the form of a drug mixture containing 1,4-benzodiazepine derivatives that exhibit acceptable acid addition salts and sedative effects, and such drug mixtures are also part of the present invention. The doses of the compounds of formula (I) and their pharmaceutically acceptable acid addition salts can vary widely and are adjusted on a case by case basis. Generally, a daily dose of about 2 mg to about 500 mg is appropriate.

As mentioned above, one or more compounds of formula (I) or pharmaceutically acceptable acid addition salts thereof, and, if necessary, one or more other therapeutically effective substances, are formulated in a herbal dosage form Similarly to the process for the preparation of medicaments containing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, are also part of the present invention and the abovementioned pharmaceutical mixtures also form part of the present invention. In particular, a pharmaceutical mixture containing a compound of formula (I) and a benzodiazepine derivative of formula (XXII) and / or (XXIII), preferably ethyl 8-fluoro-5,6-dihydro-5-methyl-6 -Oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate and (+)-5- (0-chlorophenyl) -1,3-dihydro-3-methyl-7- Mixtures containing nitro-2H-1,4-benzodiazepine-2-one also form part of the invention. Mixtures of this kind are suitable for the treatment of schistosomiasis.

The present invention will be described in more detail in the following examples.

Example 1

(a) 24 g (132.5 mmol) of 5-fluoroisatoic anhydride are dissolved in 140 ml of dimethyl sulfoxide and treated with 11.8 g (132.5 mmol) of sarcosine. The solution is stirred at 100 ° C. until the end of gas evolution (duration: about 1.5 hours) and poured into about 1.2 L of water. After stirring for 10 minutes, the solid crystallizes. The crystals are suction filtered and washed with 1 L of water and then dried. Thus, 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5 (1H) -dione having a melting point of 262 ° to 263 ° C is obtained.

(b) To 30 ml of anhydrous dimethylformamide, 6.5 g (32 mmol) of 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5 (1H) -dione was added. The resulting solution is treated with 4.3 g (38 mmol) of potassium tertiary butyrate under an argon atmosphere. This raises the temperature to 35 ° C. After 10 minutes, the mixture is cooled to −30 ° C. and then 5.8 g (34 mmol) of diethylchlorophosphate are added dropwise at −30 ° C. to −20 ° C. Then, this solution is stirred for 10 minutes at -20 ° C.

Separately, 4 g (35 mmol) of potassium tert-butylate are dissolved in 10 ml of dimethylformamide and then treated with 4 g (35 mmol) of ethyl isocyanoacetate at about -40 ° C. This solution is added dropwise to the mixture prepared by the above method at -10 ° C to -20 ° C. The resulting mixture was stirred for 1 hour without cooling, after which 3.2 ml of glacial acetic acid was added, and the mixture was poured into about 400 ml of water and extracted three times with 150 ml of ethyl acetate each time. The combined organic extracts were washed five times with 200 ml of water each time, dried in the presence of magnesium sulfate and evaporated. The oily residue thus obtained was subjected to column chromatography on silica gel and then recrystallized from ethyl acetate and ether to give ethyl 8-fluoro-5,6-dihydro-5-methyl-6-melting point of 199 ° to 200 ° C. Oxo-4H-imidazo- [1,5a] [1,4] benzodiazepine-3-carboxylate is obtained.

(c) 3.5 g (11.5 mmol) of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxyl Rate, 0.15 g of potassium cyanide and 40 ml of methanol mixture are stirred at the boiling point for 2.5 hours. After distilling off the solvent on a rotary evaporator, the residue is dissolved in chloroform. After filtering the insoluble material, the filtrate is concentrated. The residue was recrystallized from ethyl acetate to give methyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1 having a melting point of 195 ° to 196.5 ° C. , 4] benzodiazepine-3-carboxylate is obtained.

Example 2

100 ml of 2-propanol are treated with 100 mg of sodium hydride. After adding 5 g of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate to it, The mixture is heated to boiling for 1 hour under reflux. After cooling the mixture to room temperature, the precipitated crystals were filtered off and washed with 2-propanol and water to obtain isopropyl-8-fluoro 5,6-dihydro- with a melting point of 243 ° to 244 ° C. 5-Methyl-6-oxo-4H-imidazo- [1,5a] [1,4] benzodiazepine-3-carboxylate is obtained.

Example 3

6.08 g (20 mmol) ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate , 100 mg of potassium cyanide and 60 ml of ethylene glycol mixture are stirred at 130 ° C. for 6 hours and then evaporated. After the residue is dissolved in chloroform, the solution is washed with water, then dried in the presence of magnesium sulfate and evaporated. This crude product was recrystallized from ethyl acetate to give 2-hydroxyethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo having a melting point of 202 DEG C to 204 DEG C. [1, 5-a] [1,4] benzodiazepine-3-carboxylate is obtained.

Example 4

(a) 19.0 g (0.10 mol) of 3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5 (1H) -dione is added to 100 ml of anhydrous dimethylformamide under an argon atmosphere. . When 15.5 g (0.12 mol) of potassium tertiary butyrate was added thereto, the temperature was raised from 25 ° C to 39 ° C. After the mixture is cooled to room temperature, 18.2 g (0.105 mol) of diethylchlorophosphate is added dropwise at a temperature of 18 to 22 占 폚.

Separately, 11.2 g (0.10 mol) of potassium tertiary butyrate is dissolved in 30 ml of dimethylformamide. The solution is cooled to about −50 ° C. and treated with 11.3 g (0.10 mol) of ethyl isocyanoacetate under an argon atmosphere. Subsequently, the mixture is cooled and added dropwise to the mixture prepared above at 18 ° C to 23 ° C. The resulting mixture was stirred at room temperature for 1 hour, after which 5 ml of acetic acid were added, the mixture was poured into 500 ml of water and extracted twice with 200 ml of chloroform each time. The chloroform extracts were combined, washed three times with 300 ml of water each time, dried and evaporated in the presence of magnesium sulfate. 150 ml of ethyl acetate is added to this oily residue and left to crystallize at 0 ° C. The precipitated crystals were suction filtered and washed with cold ethyl acetate, and then ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,5-a] having a melting point of 163 to 165 占 폚. 1,4] Benzodiazepine-3-carboxylate is obtained. This was recrystallized from 50 ml of ethyl acetate to give a product having a melting point of 164 ° to 165 ° C.

(b) 285 mg (1 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate and 66 mg Potassium cyanide is boiled under reflux for 24 hours in 10 ml of methanol. The mixture was concentrated on a rotary evaporator, and then the residue was partitioned between water and chloroform, then extracted twice with chloroform, and then the chloroform phase was dried in the presence of magnesium sulfate and evaporated. Thus, methyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate having a melting point of 212 DEG to 214 DEG C was obtained. do. It was confirmed by thin layer chromatography that this product was homogeneous.

Example 5

285 mg (1 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate and 50 mg of potassium cyanide Add 10 ml of 2-propanol and stir at 60 ° C. for 72 hours. The mixture is concentrated on a rotary evaporator, then partitioned between residue water and chloroform, extracted twice with chloroform, the chloroform phase is dried in the presence of magnesium sulfate and evaporated. In this way, isopropyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate having a melting point of 190 ° to 192 ° C was obtained. To obtain. It was confirmed by thin layer chromatography that this product was uniform.

Example 6

1.42 g (5 mmol) ethyl 5,6-dihydro-5-methyl-6-oxo-4H-oxoimidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, 100 mg cyanide The potassium and 10 ml ethylene glycol mixtures are stirred at 130 ° C. for 6 hours, diluted with chloroform, washed with water, dried in the presence of magnesium sulfate and evaporated. The residue was recrystallized from ethyl acetate to give 2-hydroxyethyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] having a melting point of 222 ° to 223 ° C. [1,4] -benzodiezepine-3-caroxineate is obtained.

Example 7

(a) 21.6 g (0.10 mol) of (S)-(+)-1,2,3,11a-tetrahydro-5H-pyrrolo [2,1-c] [1, in 100 ml of anhydrous dimethylformamide 4] When a solution prepared by adding benzodiazepine-5,11 (1OH) -dione is treated with 13.5 g (0.12 mol) of potassium tertiary butyrate under an argon atmosphere, the temperature rises from 24 ° C to 46 ° C. After the mixture is cooled to room temperature, 18.2 g (0.105 mole) of diethylchlorophosphate is added dropwise at 10 占 폚 to 23 占 폚.

Separately, 11.2 g (0.10 mol) of potassium tertiary butyrate is dissolved in 30 ml of dimethylformamide. The solution is cooled to about -50 [deg.] C. and then treated with 11.3 g (0.10 mol) of ethyl isocyanoacetate under an argon atmosphere. The solution is cooled and added dropwise to the mixture at 18 ° C to 23 ° C. The resulting mixture was stirred at room temperature for 1 hour, after which 5 ml of acetic acid was added, and the mixture was poured into 500 ml of water and extracted twice with 200 ml of chloroform each time. The chloroform phases are combined and washed three times with 300 ml of water each time, then dried in the presence of magnesium sulfate and evaporated. 150 ml of acetic acid is added to this oily residue and left to crystallize at 0 ° C. The separated crystals were suction filtered and washed with cold ethyl acetate, and the ethyl (S) -11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5--1 having a melting point of 196 ° C to 197 ° C. a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylate is obtained. After evaporation of the mother liquor, the remaining residue is dissolved in 50 ml of ethyl acetate. The obtained product (melting point 195 ° C to 196 ° C) is further crystallized from this solution.

(b) 311 mg (1 mmol) of ethyl (S) -11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] Benzodiazepine-1-carboxylate, 6 6 mg potassium cyanide and 10 ml anhydrous methanol mixture are heated and boiled under reflux for 6 hours. After concentrating the mixture, a small amount of water was added, extracted three times with 10 ml of couloform each time, dried in the presence of magnesium sulfate, evaporated, and recrystallized with ethyl acetate / hexane to give a melting point of 165 DEG C to 167 DEG C. Phosphorus methyl (S) -11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1- Obtain a carboxylate.

Example 8

934 mg (3 mmol) of ethyl (S) -11,12,13,13a-tetrahydro-9-9H-oxoimidazo [1,5-a] pyrrolo [2,1-c] [1,4] The benzodiazepine-1-carboxylate is stirred with 198 mg (3 mmol) potassium cyanide in 30 ml of anhydrous 2-propanol for 48 hours at 60 ° C. and then the mixture is evaporated in vacuo. This residue is treated with 30 ml of 2-propanol and 198 mg (3 mmol) of potassium cyanide and then heated to reflux for 22 hours under reflux. The residue obtained by evaporation in vacuo was treated with water and extracted three times with 30 ml of chloroform each time. The combined chloroform phases are washed three times with 20 ml of water each time, then dried in the presence of magnesium sulfate and evaporated. This was recrystallized from ethyl acetate / n-hexane, and isopropyl (S) -11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-- which has a melting point of 207 ° C to 208 ° C. a] Pyrrolo [2,1-c] [1,4] benzobenzozepine-1-carboxylate is obtained.

Example 9

(a) 175 g (0.93 mole) of methyl 3-amino-2-thiophencarboxylate hydrochloride, 1.8 L of n-butanol and 77 g of sodium hydride mixture are heated to reflux for 30 minutes under reflux. The suspension thus made is concentrated on a rotary evaporator and then a mixture of sodium 3-amino-2-thiophencarboxylate and sodium chloride is used directly in the next step. For this purpose, this mixture is treated with 800 ml of water, 280 ml of concentrated hydrochloric acid and 230 ml of tetrahydrofuran. Phosgene is added to the mixture at 15 ° C. to 25 ° C. for 2.5 hours and then air is injected for 15 minutes. The solid material thus separated is filtered off with suction, washed with water and dried. As a result, 2H-thieno [3,2-d] [1,3] -oxazine-2,4- [1H] -dione having a melting point of 220 ° to 221 ° C is obtained.

(b) 34.3 g (202 mmol) of 2H-thieno [3,2-d] [1,3] oxazine-2,4- [1H] -dione and 23.3 g (202 mmol) of proline solution Stir for 1 h in 200 ml of dimethyl sulfoxide at < RTI ID = 0.0 > The brown solution thus obtained is poured into 2 liters of water and stirred at room temperature. The separated product is filtered off with suction, dried on a rotary evaporator and washed with about 200 ml of boiling ethyl acetate. Thus (S) -5a, 6,7,8-tetrahydro-5H-pyrrolo [1,2-a] thieno [3,2-e] [1,4] having a melting point of 244 ° to 247 ° C. Diazepine-5, 10 (4) -dione is obtained.

(c) 7 g (31.5 mmol) of (S) -5a, 6,7,8-tetrahydro-5H-pyrrolo [1,2-a] thieno [3,2-e] [1,4] dia Zepin-5,10 (4) -dione is suspended in 30 ml of dimethylformamide under an argon atmosphere and treated with 3.92 g (35 mmol) of potassium tert-butylate at -50 ° C. The solution is stirred at −50 ° C. for 10 minutes, after which 6.0 g (35 mmol) of diethylchlorophosphate is added dropwise at this temperature, followed by stirring for 0.5 hour.

Separately, 3.92 g (35 mmol) potassium tertiary butyrate is dissolved in 7 ml of dimethylformamide, then cooled in an acetone / dry ice bath and treated with 3.95 g (millimoles) of ethyl isocyanoacetate. The orange solution thus obtained is added dropwise to the mixture prepared above at 50 ° C., and then the mixture is stirred for 10 minutes at −50 ° C. to 60 ° C., then neutralized with 3.2 ml of acetic acid and poured into about 250 ml of water. The mixture is extracted twice with 200 ml of chloroform each time, then the combined chloroform phases are washed five times with 300 ml of water each time, dried in the presence of magnesium sulfate and evaporated. After column chromatography, the mixture was recrystallized with ethyl acetate, and the ethyl (S) -10,11,12,12a-tetrahydro-8-oxo-8H-imidazo having a melting point of 212.5 ° C to 213 ° C [5,1]. -C] Pyrrolo- [1,2-a] thieno [3,2-e] [1,4] diazepine-1-carboxylate is obtained.

(d) 1.50 g of ethyl (S) -10,11,12,12a-tetrahydro-8-oxo-8H-imidazo [5,1-c] pyrrolo- [1,2-a] thieno [ 3,2-e] [1,4] Diazepine-1-carboxylate is stirred at 50 ° C with 100 g of powdered potassium cyanide in 10 ml of methanol for 20 hours. After this solution is concentrated, the residue is dissolved in chloroform. Infiltration of insoluble material is followed by evaporation of the filtrate. This residue was recrystallized from chloroform / hexane to give methyl ethyl (S) -10,11,12,12a-tetrahydro-8-oxo-8H-imidazo [5,1-c with a melting point of 192 ° to 193 ° C. ] Pyrrolo- [1,2-a] thieno [3,2-e] [1,4] diazepine-1-carboxylate is obtained.

Example 10

(a) 30.0 g (177 mmol) of 2H-thieno [3,2-d] [1,3] -oxazine-2,4- (1H) -dione and 17.3 g (195) in 100 ml of dimethyl sulfoxide Millirol) sacosincin is added and the mixture is stirred at 110 ° C for 1.5 hours. This dark brown solution is poured into about 600 ml of ice water. The separated oil is dissolved in about 200 ml of ethyl acetate, and then the aqueous phase is evaporated in vacuo until crystallization starts. The mixture is cooled in an ice bath for about 3 hours, then the isolate is aspirated and the isolate is suction filtered and washed with a small amount of water. This was dried on a rotary evaporator and 3,4-lahydro-4-methyl-2H-thieno [3,2-e] [1,4] diazepine-2,5 (1H having a melting point of 270 ° C to 272 ° C). ) -Dione is obtained.

(b) 4.8 g (24.5 mmol) of 3,4-dihydro-4-methyl-2H-thieno [3,2-e] [1,4] diazepine-2,5 (in 30 ml of dimethylformamide) 1H)-Suspension, suspended in dione and cooled to 15 ° C., is treated with 3.28 g (29.4 mmol) of caldium tertiary butyrate under an argon atmosphere. After cooling this dark brown solution to -40 degreeC, 3.7 ml (25.7 millolol) of diethylchlorophosphate is added dropwise at -40 degreeC-30 degreeC. When this cooling bath is removed and the mixture is stirred for 20 minutes, the temperature rises to -15 占 폚.

Separately, 3.0 g (27 mmol) of caldium tertiary butyrate was dissolved in 8 ml of dimethylformamide, cooled in an acetone / dry ice bath, and then treated with 3.1 ml (27 mmol) of ethyl isocyanoacetate. do. This orange solution is added dropwise to the mixture prepared above at -15 ° C to -10 ° C. After the cooling bath is removed, the mixture is stirred until the temperature is raised to 20 ° C. The mixture is then neutralized with 2 ml of acetic acid and then poured into about 150 ml of water and extracted three times with 150 ml of chloroform each time.

The chloroform phases are combined and washed three times with 100 ml of saturated sodium chloride solution each time, then dried in the presence of magnesium sulfate and evaporated in vacuo. This was subjected to column chromatography, and then recrystallized from ethyl acetate / n-hexane to give ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo having a melting point of 160 ° C to 162 ° C [1,5-a. ] Thieno [2,3-f] [1 4] diazepine-3-carboxylate is obtained.

(c) 430 mg (1.5 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] thieno [2,3-f] in 15 ml of anhydrous methanol A suspension made by suspending [1,4] -diazepine-3-carboxylate and 99 mg (1.5 mmol) of potassium cyanide is heated under reflux for 3 hours with stirring. After evaporation in vacuo, the residue is treated with about 20 ml of ice water and then extracted three times with about 30 ml of chloroform each time. The combined chloroform phases are washed twice with about 20 ml of water each time, then dried in the presence of magnesium sulfate and evaporated. This was washed with boiling ethyl acetate and methyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] thieno [2,3-f having a melting point of 244 ° C to 245 ° C. ] [1,4] diazepine-3-carboxylate is obtained.

Example 11

3.12 g (10 mmol) of ethyl (S) -10,11,12,12a-tetrahydro-8-oxo-8H-imidazo [5,1-c] pyrrolo (1,2-a] thieno [3,2-e] [1,4] Diazepine-1-carboxylate, 80 mg of powdered potassium cyanide and 30 ml of ethylene glycol mixture are stirred overnight at 100 ° C. After removal of ethylene glycol, the residue remains Water is purified by column chromatography in this manner 2-hydroxyethyl (S) -10,11,12,12a-tetrahydro-8-oxo-8H-imidazo- [melting | fusing point 182 degreeC-184 degreeC] [ 5,1-c] pyrrolo [1,2-a] thieno [3,2-e] [1,4] diazepine-1-carboxylate is obtained.

Example A

A tablet containing the following ingredients is prepared.

Example B

A capsule containing the following ingredients is prepared.

Ethyl (S) -11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxyl Rate, lactose and cornstarch are first mixed in a mixer and then mixed with a grinder. Transfer this mixture back to the mixer, add talc and mix thoroughly. This mixture is mechanically filled into hard gelatin capsules.

Example C

An injection solution containing the following ingredients is prepared.

50 g of ethyl (S) -11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo [2,1-c for the preparation of 10,000 ml of injection solution ] [1,4] Benzodiazepene-1-carboxylate is dissolved in 150 ml of benzyl alcoholol and then 4000 ml of propylene glycol and 1000 ml of ethanol are added. After dissolving 12 g of benzoic acid in the mixture, a solution of 488 g of sodium benzoate was added to 300 ml of distilled water for injection. Distilled water for injection was added to the solution thus prepared to a volume of 10,000 ml, followed by filtration to fill an ampoule of appropriate size; Extra space in the ampoule is filled with nitrogen; The ampoule is sealed and sterilized for 30 minutes in a 0.7 atm autoclave.

Example D

Suppositories containing the following ingredients are prepared.

Cocoa butter and canova wax are melted in a glass or steel container, mixed thoroughly and cooled to 45 ° C. Fine powdered ethyl (S) -11,12,13,13a-tetrahydro-9-oxo-9H-imidazo [1,5-a] pyrrolo- [2,1-c] [1, 4] After adding benzodiazepine-1-carboxylate, the mixture is stirred until completely dispersed. The mixture is poured into suppository molds of the appropriate size and cooled. The suppository is removed from the suppository mold and stored in wax or metal foil, respectively.

Example E

A capsule containing the following ingredients is prepared.

A 250.0 mg mixture made by mixing the two active substances with the adjuvant is filled into a properly sized capsule.

Example F

A tablet containing the following ingredients is prepared.

The two active substances, powdered lactose and the total first white cornstarch are mixed and sieved. The mixture is kneaded with an aqueous solution of povidone k30, granulated, dried and sifted. The granules are mixed with the remaining white cornstarch and magnesium stearate, and then compressed into tablets of 110 mg.

Example G

A tablet containing the following ingredients is prepared:

The two active substances, powdered lactose and the first white cornstarch are mixed and sifted. The mixture is kneaded with an aqueous povidone k30 solution, granulated, dried and sieved. The granules are mixed with the remaining white cornstarch and magnesium stearate, and then compressed into 200 mg tablets.

Claims (1)

A process for preparing a compound of the general formula (I) and pharmaceutically acceptable acid addition salts thereof, characterized by trans-esterifying the compound of the general formula (XI).

In the general formula, A represents one of the following groups (a), (b) and (c) together with two carbon atoms represented by α and β,

The dotted line represents the double bond in groups (a) and (b) and D is

or

R ⁴ is methyl, ethyl or isopropyl or 2-hydroxyethyl, R ⁵ is hydrogen, trifluoromethyl or halogen, R ⁶ is hydrogen, trifluoromethyl, halogen or lower alkyl, R ² Is hydrogen, R ³ is hydrogen or lower alkyl, or R ¹ and R ³ together are trimethylene or propenylene, R ⁷ is lower alkyl different from R ^4, and the carbon atom represented by γ is S- or R, It has S-coordination.