KR810000006B1 - Process for preparation of imidazole benzodiazepines - Google Patents

Abstract

Title compds.[I; R1 = H, halogen, nitro, trifluoromethyl; R2 = H, halogen; R3 = H, methyl; R4, R5 = H, C1-5 alkyl, C1-5 hydroxyalkyl, aminoalkyl, aryl, cycloalkyl; Alk = C1-5 lower alkyl were prepd. Thus, 8-chloro-1,2-dihydro-2-(piperazine-1-yl)methylene-6-(O-chlorophenyl)-1H,4H-imidazo[1,2-a [1,4 benzodiazepine-1-one was mixed with chloromethyl-dimethyl phosphine oxide and sodium iodide, cooled and crystallized to give 8-chloro-1,2-dihydro-2-[N-dimethylphosphinyl-1-yl methylene-6-(O-chlorophenyl)-1H, 4H-imidazo[1,2-a [1,4 benzodiazepin-1-one.

Description

Method for preparing benzodiazepines

//1,4/벤조디아제핀-1-온 화합물과 그것의 산부가염들의 제법에 관한 것이다.The present invention relates to a method for the preparation of benzodiazepines by imidazolo, in particular 1,2-dihydro 6-phenyl 1H, 4H having the following structural formula (I) which can be used as a pharmaceutical for humans or livestock -Imidazo-/ l, 2-

It relates to the preparation of // 1,4 / benzodiazepin-1-one compounds and their acid addition salts.

Wherein R ¹ represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group, R ² is a suitable position in the phenyl ring, represents a hydrogen atom or a halogen atom, R ³ represents a hydrogen atom or a methyl group, R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, an alkyl group having 1-5 carbon atoms, a hydroxy alkyl group having 1-5 carbon atoms, an aminoalkyl or an alkylaminoalkyl group (each having 1-5 carbon atoms) Alkyl moiety having an alkyl moiety), an aryl group, or a cycloalkyl group, or R ⁴ and R ⁵ are saturated with a nitrogen atom and substituted or unsubstituted heterocycle (which may optionally include another heteroatom) Indicates.

In the above formula, R ¹ represents a halogen atom, and fluorine, chlorine and bromine atoms are good, but chlorine atoms are particularly good.

R ² represents a halogen atom and also has good fluorine, chlorine and bromine atoms, but particularly fluorine and chlorine atoms. Furthermore, the halogen atom R ² is particularly preferably in the ortho-position. R ³ has the best hydrogen atom.

When one of R ⁴ and R ⁵ represents an alkyl group, methyl, ethyl, propyl, isopropyl, butyl, t-butyl or pentyl groups are generally preferred, especially methyl, ethyl, n-propyl, n-butyl or t-butyl groups Do.

When one of R ⁴ and R ⁵ represents a hydroxyalkyl group, the alkyl moiety usually represents a methyl, ethyl, propyl, butyl, or pentyl group and is particularly excellent in the ethyl group.

One of R ⁴ and R ⁵ represents an aminoalkyl or alkylaminoalkyl group (alkylaminoalkyl groups include monoalkyl- and dialkylaminoalkyl), each of the alkyl moieties usually having a methyl, ethyl, propyl or butyl group but especially Methyl and ethyl groups are excellent.

In particular, R ⁴ or R ⁵ represents an aminomethyl, aminoethyl, dimethylaminoethyl or diethylaminoethyl group but may also represent an aminopropyl, aminobutyl, methylaminomethyl, methylaminoethyl or dimethylaminopropyl group.

When one of R ⁴ and R ⁵ represents an aryl group it may be a mono- or di-atom nucleus thereby representing for example phenyl or naphthyl. Excellent phenyl group. When one of R ⁴ and R ⁵ represents a cycloalkyl group, it is preferable to contain 3-8 carbon atoms, and in particular, cyclohexyl group is excellent.

R ⁴ and R ⁵ may be the same (they may each be a methyl group, for example) and may be different from each other, one of which is preferably hydrogen. R ⁴ and R ⁵ together are bonded to a nitrogen atom to form a heterocycle group which may be saturated, substituted or unsubstituted and optionally contain a second heteroatom. Representative examples of the unsaturated heterocycle group include pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazin-1-yl.

Excellent substituents on heterocycle groups are alkyl groups having 1-5 carbon atoms, such as methyl, ethyl, propyl, and hydroxyalkyl groups having 1-5 carbon atoms, such as hydroxyethyl, and dialkylphosphinyl As an alkyl group, each alkyl moiety thereof represents something like methyl containing 1 to 5 carbon atoms, and as a cycloalkyl alkyl group containing 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkyl moiety It is the same as cyclopropylmethyl, and is an alkenyl group having 2-5 carbon atoms, such as allyl, and there are aryl groups such as phenyl and 1-phenyl-5-imidazolyl-4-one as nitroheterocycle groups. .

Representative examples of substituted heterocycle groups are 4-alkyl-piperazin-1-yl, in particular 4-methyl-, 4-ethyl- and 4-propyl-piperazin-1-yl, and 4-hydroxyalkyl- Piperazin-1-yl is especially 4-hydroxyethyl-piperazin-1-yl and 4-dialkylphosphinylalkyl-piperazin-1-yl is particularly 4-dimethylphosphinylmethyl-piperazin-1 -Yl, 4-cycloalkylalkyl-piperazin-1-yl, in particular 4-cyclopropylmethyl-piperazin-1-yl, 4-alkenyl-piperazin-1-yl, especially 4-allyl -Piperazin-1-yl, 4- (1'-phenyl-5'-imidazoyl-4'-one) -piperidin-1-yl as 4-phenyl-piperazin-1-yl have.

Among the broad range covered by general formula (1), a small number of groups of the following compounds are excellent.

a) In the imidazolobenzodiazepine compound of general formula (I), R ⁴ and R ⁵ may be the same or the same as each other, a hydrogen atom, an alkyl group having 1-5 carbon atoms, a hydroxyethyl group, a dimethyl- or diethylaminoethyl group, Phenyl group or cyclohexyl group, or R ⁴ and R ⁵ together with nitrogen atom may be pyrrolidinyl, piperidino, morpholino, thiomorpholino, piperazin-1-yl, 4-alkyl-piperazin-1- 1, 4-hydroxyalkyl-piperazin-1-yl, 4-phenyl-piperazin-1-yl or 4- (1'-phenyl-5'-imidazolyl-4'-one) piperidine- A 1-diary group is shown.

b) In the imidazolo benzodiazepine compound represented by formula (1), R ¹ represents a chlorine atom or a nitro group, R ² represents a hydrogen atom, a chlorine atom or a fluorine atom, R ³ represents a hydrogen atom, R ⁴ and R ⁵ may be the same or different and each represents a hydrogen atom, a straight alkyl group having 1 to 5 carbon atoms, a hydroxyethyl group, a phenyl group or a cyclohexyl group, and R ⁴ and R ⁵ together with a nitrogen atom are piperidino, Morpholino, piperazin-1-yl, 4-alkyl-piperazin-1-yl or 4-hydroxyethyl-piperazin-1-yl group.

c) In the imidazolobenzodiazepine compound represented by formula (1), R ¹ represents a chlorine atom or a nitro group, R ² represents a hydrogen, chlorine or fluorine atom, R ³ represents a hydrogen atom, and R ⁴ represents a hydrogen atom R ⁵ represents methyl, ethyl, propyl, or butyl or R ⁴ and R ⁵ together with the nitrogen atom piperazin-1-yl, 4-methyl-piperazin-1-yl, 4-ethyl- Form a piperazin-1-yl, 4-propyl-piperazin-1-yl or 4-hydroxyethyl-piperazin-1-yl group.

d) In the imidazolobenzodiazepine compound represented by formula (1), R ¹ represents a chlorine atom or a nitro group, R ² represents a hydrogen, chlorine or fluorine atom, R ³ represents a hydrogen atom, R ⁴ and R ⁵ Together with the nitrogen atom forms a 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl or 4-propyl-piperazin-1-yl group.

e) In the imidazolobenzodiazepine compound represented by formula (1), R ¹ represents a hydrogen atom, a chlorine atom or a nitro group, R ² represents a hydrogen atom, a chlorine atom or a fluorine atom, R ³ represents a hydrogen atom, R ⁴ and R ⁵ together with the nitrogen atom form a 4-dialkylphosphinylalkyl-piperazin-1-yl group.

f) In the imidazolobenzodiazepine compound represented by formula (1), R ¹ represents a hydrogen atom, a chlorine atom or a nitro group, R ² represents a hydrogen atom or a chlorine atom, R ³ represents a hydrogen atom, and R ⁴ and R ⁵ together with the nitrogen atom forms a 4-dimethylphosphinylmethyl-piperazin-1-yl group.

Imidazolo benzodiazepines (1) are in the form of acid addition salts, which may be salts with inorganic or organic acids. Representative inorganic acids include hydrochloric acid, bromic acid, iodic acid, nitric acid, sulfuric acid and phosphoric acid, while typical organic acids include acetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid and aspartic acid. Alkalsulfonic acid and arylsulfonic acid. In particular, acid addition salts include tartarate and alkanesulfonates, and methane sulfonates are particularly excellent.

Among the compounds represented by the general formula (1) in the form of acid addition salts, there are the following better groups.

g) In the acid addition salt of the imidazobenzobenzodiazepene compound represented by the general formula (1), R ¹ represents a hydrogen atom chlorine or nitro group, R ² represents a hydrogen atom, a chlorine atom or a fluorine atom, and R ³ represents a hydrogen atom R ⁴ and R ⁵ together with the nitrogen atom form a 4-alkyl-piperazin-1-yl group.

h) In the tartarate and alkanesulfonates (particularly methanesulfonates) of the imidazolobenzodiazepine compound represented by formula (1), R ¹ represents a chlorine atom or a nitro group, R ² represents a hydrogen atom or a chlorine atom, R ³ Represents a hydrogen atom, and R ⁴ and R ⁵ together with the nitrogen atom form a 4-methyl-piperazin-1-yl or 4-ethyl-piperazin-1-yl group.

In particular, the excellent imidazolobenzodiazepine compounds represented by the general formula (1) and their salts are as follows:

][1,4] 벤조디아제핀-1-온;8-chloro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

][1,4] 벤조디아제핀-1-온 타르타르산염;8-chloro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepine-1-one tartarate;

][1,4] 벤조디아제핀-1-온;8-chloro-1,2-dihydro-2- (N-hydroxyethyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

-클로로페닐)-1H, 4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온;8-chloro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (

-Chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

-클로로페닐)-1H, 4H-이미다조 [1,2-

][1,4] 벤조디아제핀-1-온 타르타르산염;8-chloro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (

-Chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepine-1-one tartarate;

][1,4] 벤조디아제핀-1-온;8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

-부틸-아미노) 메틸렌-6-페닐-1H, 4H-이미다조 [1,2-

][1,4] 벤조디아제핀-1-온;8-chloro-1,2-dihydro-2- (

-Butyl-amino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

-플루오로페닐)-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온;8-chloro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (

-Fluorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

-프로필-아미노) 메틸렌-6-페닐-1H, 4H-이미다조 [1,2-

][1,4] 벤조디아제핀-1-온;8-chloro-1,2-dihydro-2- (

-Propyl-amino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

-클로로페닐)-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온;8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (

-Chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

-클로로페닐)-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온 메탄술폰산염8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (

-Chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodeazin-1-one methanesulfonate

-플루오로페닐)-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온;8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (

-Fluorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

][1,4] 벤조디아제핀-1-온;8-chloro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

][1,4] 벤조디아제핀-1-온;8-chloro-1,2-dihydro-2- (N-propyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

-클로로페닐)-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온;8-chloro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) methylene-6- (

-Chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

-플루오로페닐)-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온;8-chloro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) methylene-6- (

-Fluorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

-클로로페닐)-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온;8-nitro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) methylene-6- (

-Chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

-플루오로페닐)-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온;8-nitro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) methylene-6- (

-Fluorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

][1,4] 벤조디아제핀-1-온;8-chloro-1,2-dihydro-2- (ethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

][1,4] 벤조디아제핀-1-온;8-chloro-1,2-dihydro-2- (N-dimethylphosphinylethyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

-클로로페닐)-1H,4H-이미다조-[1,2-

][1,4] 벤조디아제핀-1-온;8-chloro-1,2-dihydro-2- (N-dimethylphosphinylmethyl-piperazin-1-yl) methylene-6- (

-Chlorophenyl) -1H, 4H-imidazo- [1,2-

] [1,4] benzodiazepin-1-one;

][1,4] 벤조디아제핀-1-온;1,2-dihydro-2- (N-dimethylphosphinylmethyl-piperazin-1-yl) methylene-6-phenyl-1H, H-imidazo [1,2-

] [1,4] benzodiazepin-1-one;

-클로로페닐)-1H,4H-이미다조-[1,2-

][1,4] 벤조디아제핀-1-온.8-nitro-1,2-dihydro-2- (N-dimethylphosphinylmethyl-piperazin-1-yl) methylene-6- (

-Chlorophenyl) -1H, 4H-imidazo- [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-은 메탄술폰산염 화합물이 특별히 우수한 약리학적인 활성을 나타내었다.Among these excellent compounds 8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (0-chlorophenyl) -1H, 4H-imidazo [1, 2-

] [1,4] Benzodiazepine-1- showed a particularly good pharmacological activity of the methanesulfonate compound.

Imidazolobenzodiazepine compounds represented by formula (1) may be prepared by a process initiated from unsubstituted compounds in the 2-position, which in turn are 2-alkoxycarbonyl- or 2-carboxy-methylamino-benzodiazepine compounds Can be prepared from them.

These preparation methods are also indicated in the reaction structure shown in the accompanying drawings and will not be described here.

Roman numerals in this figure are indicated with respect to the general formula in the reaction scheme and the symbols of each substituent group are first defined here.

The present invention relates to a method for preparing a compound represented by formula (1), wherein R ¹ represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group, and R ² is present at an appropriate position in the phenyl ring. A hydrogen atom or a halogen atom, R ³ represents a hydrogen atom or a methyl group, R ⁴ and R ⁵ are the same or different from each other, each having an alkyl group having 1-5 carbon atoms and a hydroxyalkyl group having 1-5 carbon atoms , Aminoalkyl or alkylaminoalkyl groups (the alkyl moieties each comprise 1-5 carbon atoms), an aryl group or a cycloalkyl group, or R ⁴ and R ⁵ are saturated with a nitrogen atom and optionally contain another hetero atom Denotes a substituted or unsubstituted heterocycle.

In addition, these acid addition salts are compounds of the formula

(Wherein R ¹ and R ² are as described above)

It is characterized by reacting with dimethylformamide acetal of the following structural formula.

(Alk-0) ₂ = CH-N = (CH ₃ ) ₂ (VI)

In the above formula, Alk represents a lower alkyl group having 1-5 carbon atoms, and 8-R ¹ -1,2-dihydro-2- (dimethylamino) methylene-6- represented by general formula (Ia) in the above reaction. (R ² -phenyl) -1H, 4H-imidazo / 1,2a / 1,4 / benzodiazepin-1-one are obtained.

In the above formula, R ¹ and R ² have the above meaning, and if desired, the compound represented by the general formula (Ia) is chlorinated or amino group transfer reaction occurs by reaction with a suitable amine of the following structure.

In the above formula, R ⁴ and R ⁵ are the same as described above except that neither represents a methyl group, and this compound gives the desired compound represented by the structural formula (Ic) by the above reaction.

Wherein R ¹ , R ² , R ⁴ and R ⁵ are as described above except that both R ⁴ and R ⁵ do not represent a methyl group, and if desired, the compound is chlorinated.

In addition, the compound represented by general formula (V) is reacted with N-dimethyl-acetamide represented by general formula (VII).

The above reaction yields a compound represented by general formula (Ib).

In the above formula, R ¹ and R ² are as described above, and if desired, the compound represented by the general formula (Ib) is chlorinated or the amino group transfer reaction occurs by reacting with a suitable amine of the following structure.

In the above formula, R ⁴ and R ⁵ are the same as described above except that neither represents a methyl group, and the above reaction gives a compound represented by the general formula (Id).

Wherein R ¹ , R ² , R ⁴ and R ⁵ are as described above except that both R ⁴ and R ⁵ do not represent a methyl group, and if desired, the compound may be chlorinated.

The reaction with acetal (VI) is conveniently carried out in an organic solvent (for example an arene such as benzene) and in the presence of a base (a nitrogen base of an amine such as triethylamine is preferred).

The reaction with acetamide (VII) is a condensation promoter (Promter), for example, in anhydrous organic solvents, such as methylene chloride, at an ambient temperature below room temperature (especially below 10 °) and halogenated derivatives such as phosphorus oxychloride. Is carried out in the presence of.

The reaction with amine (VIII) is easily carried out in an organic solvent (arene such as toluene) and at a high temperature with good boiling point of the reaction mixture.

When it is desired to produce compound (I), wherein R ⁴ and R ⁵ are both hydrogen, compound (VIII) used in the amino group transfer reaction may itself be ammonia.

The imidazolobenzodiazepines (Ic) or (Id) prepared are further reacted if desired to convert to other compounds of the general formula (Ic) or (Id). In particular, compounds wherein R ⁴ and R ⁵ together with the nitrogen atom represent a heterocycle can be reacted further to allow substituents to be attached on the heterocycling.

R ¹ , R ² and R ³ are as described above, R ⁴ and R ⁵ together with the nitrogen atom form a R ⁶ -piperazin-1-yl- group, R ⁶ is a cycloalkylalkyl group, an alkenyl group or 4- When it is preferable to prepare a compound of formula (I) representing a dialkylphosphinylalkyl group, R ⁴ and R ⁵ together with the nitrogen atom form a suitable formula of formula (Ic) or (Id) which forms a piperazine-1-yl group. A compound is prepared, which is reacted with a suitable halo-R ⁶ , where halo refers to a halogen atom and the above reaction forms an R ⁶ -piperazin-1-yl compound of formula (Ic) or (Id). .

-디알킬포스피닐-알킬-피페라진-1-일) 화합물(Ic) 또는 (Id)를 형성한다.R ⁴ and R ⁵ is 4-alkyl, together with the nitrogen atom-piperazine -1 with halttaeneun preferred to prepare a compound that forms a piperazine-1-yl group wooseol R ⁴ and R ⁵ is a nitrogen atom-phosphinylmethyl alkyl Preparing a suitable compound (Ic) or (Id) which forms a -group, and then reacting the compound with a suitable haloalkyl-dialkylphosphine oxide to give 2- (

-Dialkylphosphinyl-alkyl-piperazin-1-yl) compound (Ic) or (Id).

An excellent haloalkyl-dialkylphosphine oxide used in this conversion is chloroalkyl-dialkylphosphine oxide and the reaction is preferably carried out in an earthen organic solvent (for example, arene such as toluene).

Imidazolobenzodiazepine, the starting material (V), may be prepared from a compound represented by the following general formula (II).

In the above formula, R ¹ and R ² are as described above, and the compound is reacted with a compound having the following structure.

In the above formula, R is an alkyl group having 1-5 hydrogen atoms or carbon atoms, and a compound of the following structural formula is obtained by the above reaction.

Wherein R, R ¹ and R ² are as described above, and the compound is reacted with a dehydrating agent to produce the desired compound of formula (V).

The reaction of formula (II) with the compound of formula (III) is advantageously carried out in an organic solvent of an alcohol such as ethanol and at a high temperature with good boiling point of the reaction mixture.

The dehydrating agent which reacts with the acid (IV) is preferably carbodiimide such as dicyclohexylcarbodiimide, and this reaction is advantageously performed in alkane chloride such as methylene chloride. Pyrolysis of ester (IV) is easy to carry out in a high boiling solvent of arene such as toluene.

The prepared compounds (Ia), (Ib), (Ic) and (Id) can be chlorided by conventional methods. In another aspect, the present invention provides a process for preparing acid addition salts of compounds of general formula (I), wherein suitable compounds (Ia), (Ib), (Ic), and (Id) are substantially stoichiometric Reacts with a suitable inorganic or organic acid in proportion to form the desired acid addition salt.

The chlorination reaction is easily effected in organic solvents or mixtures of organic solvents of one or more alkanols, for example methanol or ethanol and one or more alkyl halides, for example methylene chloride.

Imidazolobenzodiazepin-1-ones of general formula (I) and their acid addition salts exhibit interesting pharmacological properties, which have particularly pronounced sedative action, hypnotics, anti-anxiety agents, neurostabilizers, anticonvulsants and muscle relaxants Compounds (I) and their pharmacologically acceptable acid addition salts due to these actions may cause mental anxiety or irritant stimulants, insomnia, symptoms of any mental body, behavioral disorders and any convulsions or muscle contractions. It is used as a medicine in the treatment.

However, the compounds of formula (I) and their pharmacologically acceptable acid addition salts must be combined with suitable pharmacological excipients into pharmaceutical product compositions before being used as a medicament.

The term “pharmaceutical” is used here to exclude any possibility that the characteristics of the excipient under consideration can be harmful rather than beneficial relative to the route of administration of the drug.

It is believed that the selection of the appropriate type of agent together with the appropriate excipients is within the capabilities of those engaged in the manufacture of pharmaceuticals.

Compounds of formula (I) may be used to prepare pharmacological compositions in which one or more imidazolobenzodiazepin-1-ones (I) and pharmacologically acceptable acid addition salts thereof are combined with suitable pharmacological excipients.

These compositions may be administered orally, through the skin, rectally, and pharmacological excipients for such dosage forms are as follows.

a) ingestible excipients of tablets, dragees, sublingual tablets or pills, ingestible containers of capsules or cachets, carriers of ingestible micropowder solids, syrups, solutions, Ingestible liquid medium in suspension or elixir.

b) sterile injectable solutions or suspensions.

c) Low melting bases, which can release the active ingredient in order to carry out pharmacological functions, which form suppositories when in proper form.

Excipients may be any suitable solids (such as talc, gum arabic, lactose, starch, animal or vegetable fats, magnesium stearate or cocoa butter), and aqueous or non-aqueous liquids (such as animal or vegetable oils, paraffin derivatives or glycols). These may be combined with a suitable wetting agent, dispersant, emulsifier, preservative, etc. if desired.

The compound represented by formula (1) and its pharmacologically acceptable acid addition salts can be administered in the form of tablets, ampoules in a single dose, and injections in several doses of small bottles. It is preferably in the form of a solution or suspension, and in the form of suppositories. On the other hand, the dosage of the pharmacologically active ingredient depends to some extent on the route the compound is taken, but as a general indication, the useful dosage ranges from 1 mg-50 mg of active ingredient per day for adults and the unit dose is 0.5 mg. Contains -20 mg of active ingredient.

2-carboxymethylamino-7-R ¹ -5- (R ² -phenyl) -3H-1,4-benzodiazepine (IV) and the corresponding 2-alkoxy carbonyl-methylamino-7-R ¹ -5- (R ² -phenyl) -3H-1,4-benzodiazepine (IV) compounds, wherein alkyl group R is other than ethyl group, are new compounds.

The examples, prescriptions, and test results described below have been described for the purpose of illustrating various details in accordance with the present invention.

Example 1

][1,4] 벤조디아제핀-1-온(I

)8-chloro-1,2-dihydro-2- (dimethylamino) methylene-6-phenyl-1H, 4H-imidazo- [1,2-

] [1,4] benzobenzozepine-1-one (I

)

Step A, 2-carboxymethylamino-7-chloro-5-phenyl-3H-1, 4-benzodiazepine (IV)

7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione (II) (3.5 g), glycine (III) (5.5 g) and sodium carbonate (5.5 g) (100 ml) and water (30 ml) were suspended, stirred and refluxed for 1 hour. The suspension is poured into water to give a clear solution which is acidified to pH 4 with 2N HCl and extracted with chloroform.

Some solids precipitate from the extract which is removed by filtration.

The organic layer is dried over MgSO ₄ and evaporated to give a gum which is crystallized by grinding with methanol. This solid and the above-described filtered solid were crystallized from a large amount of ethanol to yield 3.1 g (77%) of 2-carboxymethylamino-7-chloro-5-phenyl-3H-1, 4-benzodiazepine. Melting point 215 ° -220 ℃

][1,4] 벤조디아제핀-1-온(V)Step B, 8-Chloro-1,2-dihydro-6-phenyl-1 H, 4H-imidazo [1,2-

] [1,4] benzobenzozepine-1-one (V)

][1,4] 벤조디아제핀-1-온(V)의 화합물이 만들어지며 이는 다음 단계에서 그대로 사용된다.2.5 g of 2-carboxymethylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine (IV) was suspended in dry CH ₂ Cl ₂ (120 ml) and stirred followed by dicyclohexylcarbodiimide ( 2.1 g) is added. The suspension was stirred at room temperature for 3 hours, then filtered and the filtrate was evaporated to yield 8-chloro-1,2-dihydro-6-phenyl-1H, 4H-imidazo in the form of colorless oil [1, 2-

] [1,4] A compound of benzodiazepin-1-one (V) is made which is used as such in the next step.

][1,4] 벤조디아제핀-1-온(I

)Step C, 8-Chloro-1,2-dihydro-2- (dimethylamino) -methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzobenzozepine-1-one (I

)

][1,4] 벤조디아제핀-1-온(V)을 건조한 벤젠에 용해시키고, 디메틸포름아미드디에틸아세탈(VI) 1.5g과 트리에틸아민 1ml를 가한다.8-chloro-1,2-dihydro-6-phenyl-1H, 4H-imidazo obtained in step B described above [1,2-

] [1,4] Benzodiazepin-1-one (V) is dissolved in dry benzene, and 1.5 g of dimethylformamide diethyl acetal (VI) and 1 ml of triethylamine are added.

][1,4] 벤조디아제핀-1-온(I

)의 2.7g(97%)를 얻게된다. 융점=264°-5℃The solution is stirred at room temperature for 1.5 hours and then evaporated to yield a tan residue. The residue was recrystallized from a mixture of ethyl acetate and methanol to give 8-chloro-1,2-dihydro-2- (dimethylamino) methylene-6-phenyl-1H, 4H-imidazo as pale yellow rod crystals. [1,2-

] [1,4] benzobenzozepine-1-one (I

You get 2.7 g (97%). Melting point = 264 ° -5 ° C

Coloring: C ₂₀ H ₁₇ ClN ₄ O = 364.9

Calculated: C% 65.85 H% 4.66 N% 15.37 Cl% 9.74

Experimental Value: 65.87 4.67 15.37 9.79

IR spectrum (KBr disc): C = 0 at 1690 cm ⁻¹ ; 1621 cm ^-1 to C = N

Example 2-6

)가 제조되었다.Compounds (IV), (V) and (I) as follows using the same method as used in Example 1

) Was prepared.

EXAMPLE

[compound]

2. Compound IV; 2-carboxymethylamino-7-nitro-5-phenyl-3H-1,4-benzodiazepine.

][1,4] 벤조디아제핀-1-온.Compound V; 8-nitro-1,2-dihydro-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

; 8-니트로-1,2-디하이드로-2-(디메틸아미노) 메틸렌-6-페닐-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온.Compound I

; 8-nitro-1,2-dihydro-2- (dimethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

3. Compound IV; 2-carboxymethylamino-7-chloro-5-0-chlorophenyl-3H-1,4-benzodiazepine.

][1,4] 벤조디아제핀-1-온.Compound V; 8-chloro-1,2-dihydro-6-0-chlorophenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

; 8-클로로-1,2-디하이드로-2-(디메틸아미노)메틸렌-6-0-클로로페닐-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온.Compound I

; 8-chloro-1,2-dihydro-2- (dimethylamino) methylene-6-0-chlorophenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

4. Compound IV; 2-carboxymethylamino-7-nitro-5-0-chlorophenyl 3H-1,4-benzodiazepine.

][1,4] 벤조디아제핀-1-온.Compound V; 8-nitro-1,2-dihydro-6-0-chlorophenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

; 8-니트로-1,2-디하이드로-2-(디메틸아미노)메틸렌-6-0-클로로페닐-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온.Compound I

; 8-nitro-1,2-dihydro-2- (dimethylamino) methylene-6-0-chlorophenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

5. Compound IV; 2-carboxymethylamino-7-chloro-5-0-fluorophenyl-3H-1,4-benzodiazepine.

][1,4] 벤조디아제핀-1-온.Compound V; 8-chloro-1,2-dihydro-6-0-fluorophenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

; 8-클로로-1,2-디하이드로-2-(디메틸아미노) 메틸렌-6-0-플루오로페닐-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온.Compound I

; 8-chloro-1,2-dihydro-2- (dimethylamino) methylene-6-0-fluorophenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

6. Compound IV; 2-carboxymethylamino-7-nitro-5-0-fluorophenyl 3H-1,4-benzodiazepine.

][1,4] 벤조디아제핀-1-온.Compound V; 8-nitro-1,2-dihydro-6-0-fluorophenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

; 8-니트로-1,2-디하이드로-2-(디메틸아미노) 메틸렌-6-0-플루오로페닐-1H,4H 이미다조[1,2-

][1,4] 벤조디아제핀-1-온.Compound I

; 8-nitro-1,2-dihydro-2- (dimethylamino) methylene-6-0-fluorophenyl-1H, 4H imidazo [1,2-

] [1,4] benzodiazepin-1-one.

)에 대한 결정화 용매는 메탄올이었다. 이들 화합물들(화합물(V)를 제외한것)에 대한 데이타는 아래표 I에 요약하였다.In each case where compound (III) is glycine, compound (VI) was dimethylformamideethylacetal, compound (V) was used without further purification and compound (I)

The crystallization solvent for) was methanol. Data for these compounds (except compound (V)) is summarized in Table I below.

TABLE 1

Example 7

][1,4]벤조디아제핀-1-온(I

)8-chloro-2- [1 '-(dimethylamino) ethylidene] -1,2-dihydro-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one (I

)

][1,4]벤조디아제핀-1-온(V)를 건성 염화메틸렌(200ml)에 디메틸아세트아미드(VII)(2.0g)과 함께 용해시킨다.8-Chloro-1,2-dihydro-6-phenyl-1H, 4H-imidazo [1,2- prepared as described in step B of Example 1

] [1,4] benzodiazepin-1-one (V) is dissolved in dry methylene chloride (200 ml) together with dimethylacetamide (VII) (2.0 g).

The solution is cooled to 0 ° C. and phosphorus oxychloride (3.7 g) is added dropwise with good stirring over 5 minutes. The solution is then stirred at room temperature for at least 20 hours and placed in saturated N _a HC0 ₃ solution (500 ml).

The mixture is stirred until the volatilization of CO ₂ is stopped, the organic layer is removed and the aqueous layer is extracted with methylene chloride (2 x 100 ml).

This mixed organic extract was washed with saturated N _a HC0 ₃ solution and water, dried over M _g SO ₄ and evaporated to give a yellow solid.

][1, 4]벤조디아제핀-1-온(I

)의 화합물 2.3g(40%)가 얻어진다. 융점=251-2℃.The solid was recrystallized from a mixture of chloroform and ether to give 8-chloro-2- [1 '-(dimethylamino) ethylidene) -1,2-dihydro-6-phenyl-1H, 4H-imidazo [1,2 -

] [1, 4] benzodiazepin-1-one (I

2.3 g (40%) of the compound) are obtained. Melting point = 251 < -2 >

Analysis: C ₂₁ H ₁₉ ClN ₄ 0 = 378.9

Calculated: C% 66.58 H% 5.02 N% 14.79 Cl% 9.38

Experimental Value: 66.32 4.91 14.77 9.02

IR spectrum (KBr disc); 165.3 Cm ⁻¹ to C = 0; C = N at 1610 Cm ⁻¹ .

Example 8

][1,4]벤조디아제핀-1-은(I

)와 이 화합물의 타르타르산염.8-chloro-1,2-dihydro-2- (N-methylpiperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepine-1-silver (I

) And tartarate salts of this compound.

][1,4] 벤조디아제핀-1-온(I

)(2.3g)과 N-메틸-피페라진(4.0g)을 24시간 동안 건성 톨루엔(50ml)중에서 환류시키면서 교반시킨다.(A) 8-chloro-1,2-dihydro-2- (dimethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2- obtained in step C of Example 1

] [1,4] benzobenzozepine-1-one (I

) (2.3 g) and N-methyl-piperazine (4.0 g) are stirred with reflux in dry toluene (50 ml) for 24 hours.

][1,4] 벤조디아제핀-1-온(I

)의 화합물 2.3g(87%)가 얻어진다. 융점=255-6℃.Upon cooling the crystals appear to separate and are filtered off. Evaporation of the solvent gives a pale yellow solid which is treated with methanol and filtered. Two solids are combined and recrystallized from methanol and ethyl acetate to give 8-chloro-1,2-dihydro-2- (N-methylpiperazin-1-yl) methylene-6-phenyl-1H, 4H- Imidazo [1,2-

] [1,4] benzobenzozepine-1-one (I

2.3 g (87%) of the compound) are obtained. Melting point = 255-6 ° C .;

Analysis: C ₂₃ H ₂₂ ClN ₅ 0 = 419.9

Calculated: C% 65.80 H% 5.24 N% 16.69 Cl% 8.46

Experimental Value: 65.64 5.27 16.63 8.56

IR spectrum (KBr disc); C = 0 at 1705Cm ⁻¹ ; 1635Cm ⁻¹ at C = N.

][1,4] 벤조디아제핀-1-온(Ic)화합물에 첨가함으로서 8-클로로-1,2-디하이드로-2-(N-메틸피페라진-1-일) 메틸렌-6-페닐-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온(Ic)화합물의 타르타르산 염이 제조된다. 이렇게 제조된 조악한 염은 원하는 생성물을 얻기 위하여 메탄올로부터 재결정화된다. 융점=146-150℃(B) The stoichiometric amount of tartaric acid in methanol was changed to 8-chloro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [ 1,2-

] [1,4] 8-chloro-1,2-dihydro-2- (N-methylpiperazin-1-yl) methylene-6-phenyl-1H, by addition to a benzodiazepin-1-one (Ic) compound, 4H-imidazo [1,2-

] 1,4 A tartaric acid salt of a benzodiazepin-1-one (Ic) compound is prepared. The crude salt thus prepared is recrystallized from methanol to obtain the desired product. Melting point = 146-150 ° C

Analysis: C ₂₇ H ₂₈ ClN ₅ 0 ₇ = 570.1

Calculated: C% 56.89 H% 4.92 N% 11.29 Cl% 6.23

Experimental Value: 56.44 4.93 11.79 5.93

IR spectrum (KBr disc); OH at 3400 Cm ⁻¹ and 2500 Cm ⁻¹ ; C = 0 at 1730 Cm ⁻¹ and 1690 Cm ⁻¹ ; C = N at 1630 cm ⁻¹ .

Example 9-46 / 32B

][1,4] 벤조디아제핀-1-은(Ic) 화합물을 제조하는데 사용한 것과 유사한 방법을 사용하여 다음과 같은 화합물(I)을 제조하였다.In these examples, 8-chloro-1,2-dihydro-2- (N-methylpiperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,8] in Example 8 2-

] [1,4] Benzodiazepine-1- was prepared using the method similar to that used to prepare the (Ic) compound as follows.

EXAMPLE

[compound]

][1,4] 벤조디아제핀-1-온.9. 8-chloro-1,2-dihydro-2- (morpholino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.10. 8-Chloro-1,2-dihydro-2- (N-hydroxyethyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.11. 8-Chloro-1,2-dihydro-2- (N-phenyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

-클로로페닐)-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온.12. 8-Chloro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (

-Chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

-클로로페닐)-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온 타르타르산염. 방법 : 실시예 8B에서와 유사함.12B. 8-chloro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) methylene-6- (

-Chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepine-1-one tartarate. Method: Similar to Example 8B.

][1,4] 벤조디아제핀-1-온.13. 8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.14. 8-chloro-1,2-dihydro-2- (piperazin-1-yl) methylene-6-phenyl-1,4-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

-부틸-아미노)메틸렌-9-페닐-1H, 4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온.15. 8-chloro-1,2-dihydro-2- (

-Butyl-amino) methylene-9-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.16. 8-Chloro-1,2-dihydro-2- (amino) methylene 6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

Way :

][1,4] 벤조디아제핀-1-온(I

)화합물(2.1g)을 건성메탄올(100ml)중에 현탁시킨다. 이 현탁액을 교반시킨 후 드라이아이스와 아세톤의 수조내에서 냉각시키고, 암모니아 기체(VIII)를 통과시켜 15분간 기포를 발생시킨다. 이 현탁액을 상온으로 온도를 올리고, 2일동안 교반시킨 후 용매를 증발시킨다. 이 고형물 잔사류를 메탄올과 에틸아세테이트로 재결정시키면 8-클로로-1,2-디하이드로-2-(아미노)메틸렌-6-페닐-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온(I

)의 화합물 1.9g(98%)이 얻어진다. 융점=265°-7℃.8-chloro-1,2-dihydro-2- (dimethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzobenzozepine-1-one (I

Compound (2.1 g) is suspended in dry methanol (100 ml). The suspension is stirred and then cooled in a water bath of dry ice and acetone and passed through ammonia gas (VIII) to generate bubbles for 15 minutes. The suspension is raised to room temperature, stirred for 2 days and the solvent is evaporated. The solid residue was recrystallized from methanol and ethyl acetate to give 8-chloro-1,2-dihydro-2- (amino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzobenzozepine-1-one (I

1.9 g (98%) of the compound) are obtained. Melting point = 265 ° -7 ° C .;

EXAMPLE

[Compound I]

][1, 4] 벤조디아레핀-1-온.17. 8-Chloro-1,2-dihydro-2- (piperidino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1, 4] benzodialepin-1-one.

][1, 4] 벤조디아제핀-1-온.18. 8-Chloro-1,2-dihydro-2- (thiomorpholino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1, 4] benzodiazepin-1-one.

][1, 4] 벤조디아제핀-1-온.19. 8-Chloro-1,2-dihydro-2- (diethylaminoethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1, 4] benzodiazepin-1-one.

][1, 4] 벤조디아제핀-1-온.20. 8-Chloro-1,2-dihydro-2- (N-methyl-N-dimethylamino) ethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1, 4] benzodiazepin-1-one.

][1, 4] 벤조디아제핀-1-온.21. 8-Chloro-1,2-dihydro-2- (methylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1, 4] benzodiazepin-1-one.

][1, 4] 벤조디아제핀-1-온.22. 8-Chloro-1,2-dihydro-2- (cyclohexylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1, 4] benzodiazepin-1-one.

-플루오로페닐-1H, 4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온.23. 8-Chloro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (

-Fluorophenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.24. 8-Chloro-1,2-dihydro-2- [4- (1'-phenyl-5'-imidazolyl-4'-one) piperidin-1-yl] methylene-6-phenyl- 1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1, 4] 벤조디아제핀-1-온.25. 8-Chloro-1,2-dihydro-2- (phenylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1, 4] benzodiazepin-1-one.

][1, 4] 벤조디아제핀-1-온.26. 8-Chloro-1,2-dihydro-2- [1- (N-methyl-piperazino) ethylidene] -6-phenyl-1H, 4H-imidazo [1,2-

] [1, 4] benzodiazepin-1-one.

Way:

][1,4] 벤조디아제핀-1-온(I_b)화합물(2.3g)과 N-메틸-피페라진(VIII)(15ml)를 9시간 동안 질소 존재하에서 120℃에서 교반시킨다. 냉각된 용액을 물에 붓고 완전한 침전물에 NaCl을 가한 다음 갈색 침전은 여과시켜서 제거하고 HCl₃중에 용해하여 물로 세척한 후 M_gS0₄상에서 건조시키고 이를 증발 시키면 알직색유(油)가 얻어진다. 이 기름을 에테르/메탄올과 함께 분쇄시키면 결정화되고 에틸아세테이트로 재결정시킴으로서 8-클로로-2-[1'-N-메틸피페라진-1-일)에틸리덴]-1,2-디하이드로-6-페닐-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온(I_d)의 화합물 1.0g(38%)가 얻어진다. 융점=193°-5℃.8-chloro-2- [1 '-(dimethylamino) ethylidene] -1,2-dihydro-6-phenyl-1H, 4H-imidazo [1,2- obtained in Example 7

] [1,4] Benzodiazepin-1-one (I _b ) compound (2.3 g) and N-methyl-piperazine (VIII) (15 ml) are stirred at 120 ° C. for 9 hours in the presence of nitrogen. The cooled solution was poured into water, NaCl was added to the complete precipitate, and the brown precipitate was removed by filtration, dissolved in HCl ₃ , washed with water, dried over M _g SO ₄ and evaporated to give a plain oil. The oil was triturated with ether / methanol to crystallize and recrystallize with ethyl acetate to give 8-chloro-2- [1'-N-methylpiperazin-1-yl) ethylidene] -1,2-dihydro-6- Phenyl-1H, 4H-imidazo [1,2-

] 1.0 g (38%) of a compound of [1,4] benzodiazepin-1-one (I _d ) is obtained. Melting point = 193 ° -5 ° C.

EXAMPLE

[Compound I]

-부틸아미노) 메틸렌-6-페닐-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온.27. 8-chloro-1,2-dihydro-2- (

-Butylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.28. 8-Chloro-1,2-dihydro-2- (hydroxyethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

-프로필아미노) 메틸렌-6-페닐-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온.29. 8-chloro-1,2-dihydro-2- (

-Propylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.30. 8-Nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (0-chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,2] 벤조디아제핀-1-온.31. 8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (0-fluorophenyl) -1H, 4H-imidazo [1,2-

] [1,2] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.32. 8-Chloro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온 타르산염.32B. 8-chloro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one tartarate.

Method: Similar to Example 8B.

][1,4] 벤조디아제핀-1-온.33. 8-Chloro-1,2-dihydro-2- (N-propyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

-부틸)-피페라진-1-일) 메틸렌-6-페닐-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온.34. 8-Chloro-1,2-dihydro-2- [N- (

-Butyl) -piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.35. 8-Chloro-1,2-dihydro-2- [N- (isopropyl) -piperazin-1-yl] methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

Way :

][1,4] 벤조디아제핀-1-온(실시예-14의 화합물로서 실시예 8에서와 같이 얻어진 화합물)(1.5g)과 이소프로필 아이오다이드(2.5g)과 탄산나트륨(3.0g)을 18시간 동안 염화메틸렌(5ml)와 아세토니트릴(25ml)중에서 80℃에서 교반시킨다. 냉각시킨 용액을 물에 넣고 클로로포름으로 추출한다.8-chloro-1,2-dihydro-2- (piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzobenzoazin-1-one (compound obtained in Example 14 as the compound in Example 14) (1.5 g), isopropyl iodide (2.5 g) and sodium carbonate (3.0 g) were added to 18 Stir at 80 ° C. in methylene chloride (5 ml) and acetonitrile (25 ml) for hours. The cooled solution is poured into water and extracted with chloroform.

][1,4] 벤조디아제핀-1-온(Ic)의 화합물 1.2g(73%)이 얻어진다.The extract is washed with water, dried over MgSO ₄ and evaporated to yield an emerald solid. This solid was recrystallized from ethyl acetate to obtain 8-chloro-1,2-dihydro-2- (N-isopropyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2 -

] 1.2 g (73%) of a compound of [1,4] benzodiazepin-1-one (Ic) is obtained.

Melting point = 146 ° -8 ° C

EXAMPLE

[Compound I]

][1,4] 벤조디아제핀-1-온.36. 8-Chloro-1,2-dihydro-2- (N-allyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

Method: similar to Example 35.

][1,4] 벤조디아제핀-1-온.37. 8-Chloro-1,2-dihydro-2- (N-cyclopropylmethyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

Method: similar to Example 35.

][1,4] 벤조디아제핀-1-온.38. 8-Chloro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) methylene-6- (0 chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.39. 8-Chloro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) methylene-6- (0 fluorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.40. 8-nitro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) methylene-6- (0 chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.41. 8-nitro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) methylene-6- (0 fluorophenyl) -1,4-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.42. 8-Chloro-1,2-dihydro-2- (ethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.43. 8-Chloro-1,2-dihydro-2- (N-dimethylphosphinylmethyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

Way :

][1,4] 벤조디아제핀-1-온.(실시예 14의 화합물로서 실시예 8에서와 같이 얻어짐) (2.5g)과 클로로메틸디 메틸 포스핀 옥사이드(1.5g)과 탄난나트륨(5.0g)을 3일동안 톨루엔(80ml)중에서 환류하에서 교반시킨다. 냉각된 현탁액을 클로로포름과 물 사이에 분배시키고 클로로포름 추출물을 분리시키어 MgS0₄상에서 건조시킨 후 증발시키면 메탄올로서 결정화되는 담황색 기름이 얻어진다. 고형물(불필요한 부생성물)을 여과제거하고 여과물을 증발시키면 엷은 오랜지색의 기름이 떨어진다. 이 기름을 클로로포름에 용해시키고 키절겔60상에서 크로마토그래프 분리시킨다. 클로로포름과 메탄올(5%)혼액으로 용리시키면 담황색의 고형물이 얻어지며 이를 염화메틸렌/에테르로 재결정 시킴으로써 8-클로로-1,2-디하이드로-2-(N-디메틸포스피닐메틸-피페라진-1-일)메틸렌-6-페닐-1H,4H-이미다조 [1,2-

][1,4] 벤조디아제핀-1-온, (Ic)의 화합물 (1.25g)(41%)이 얻어진다.8-chloro-1,2-dihydro-2- (piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] Benzodiazepen-1-one (obtained as in Example 8 as a compound of Example 14) (2.5 g), Chloromethyldimethyl phosphine oxide (1.5 g) and Sodium tannan (5.0 g) ) Is stirred under reflux in toluene (80 ml) for 3 days. The cooled suspension is partitioned between chloroform and water, the chloroform extract is separated, dried over MgSO ₄ and evaporated to yield a pale yellow oil which crystallizes as methanol. The solids (unnecessary by-products) are filtered off and the filtrate is evaporated, leaving a pale orange oil. This oil is dissolved in chloroform and chromatographed on Kijegel 60. Elution with a mixture of chloroform and methanol (5%) yields a pale yellow solid that is recrystallized from methylene chloride / ether to 8-chloro-1,2-dihydro-2- (N-dimethylphosphinylmethyl-piperazine-1 -Yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] Benzodiazepin-1-one and (Ic) compound (1.25 g) (41%) are obtained.

TABLE 2

Melting point = 261 ° -2 ° C

EXAMPLE

[Compound I]

][1,4] 벤조디아제핀-1-온.44. 8-Chloro-1,2-dihydro-2- (N-propyl-piperazin-1-yl) methylene-6-0 chlorophenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온.45. 8-Chloro-1,2-dihydro-2- (ethylacyno) methylene-6-0 chlorophenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

-프로필아미노) 메틸렌-6-0 클로로-페닐-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온.46. 8-chloro-1,2-dihydro-2- (

-Propylamino) methylene-6-0 chloro-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

Example 47

-클로로-페닐)-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온.8-chloro-1,2-dihydro-2- (N-dimethylphosphinyl-methyl-piperazin-1-yl) methylene-6- (

-Chloro-phenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-은(Ic)(실시예 8에서 설명한 것과 유사한 방법에 의하여 제조된 화합물)(850mg), 클로로메틸-디메틸포스핀옥사이드(1.0g), 나트륨아이오다이드(1.0g)과 탄산나트륨(2.0g)을 24시간 동안 50ml의 건성 톨루엔내에서 환류하에 교반시킨다. 냉각시킨 용액을 클로로포름과 물 사이에 분배시키고 클로로포름 추출물을 분리시키어 황산마그네슘상에서 건조하고 증발시키면 고무질의 고체가 얻어진다. 이것을 실리카겔상에서 크로마토그래프 분리하고 클로로포름으로 용리시키면 고체가 얻어지며 이것을 메탄올/에틸아세테이트/에테르로부터 결정화시키면 8-클로로-1,2-디하이드로-2-(N-디메틸포스피닐-1-일) 메틸렌-6-(0-클로로페닐)-1H,4H-이미다조[1,2-

][1,4] 벤조디아제핀-1-온(I

)가 얻어진다. 융점=231-4℃.8-chloro-1,2-dihydro-2- (piperazin-1-yl) methylene-6- (0-chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] Benzodiazepine-1-silver (Ic) (compound prepared by a method similar to that described in Example 8) (850 mg), chloromethyl-dimethylphosphine oxide (1.0 g), sodium iodide ( 1.0 g) and sodium carbonate (2.0 g) are stirred under reflux in 50 ml of dry toluene for 24 hours. The cooled solution is partitioned between chloroform and water, the chloroform extract is separated, dried over magnesium sulfate and evaporated to give a gummy solid. This was chromatographed on silica gel and eluted with chloroform to give a solid which was crystallized from methanol / ethylacetate / ether to give 8-chloro-1,2-dihydro-2- (N-dimethylphosphinyl-1-yl) methylene -6- (0-chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzobenzozepine-1-one (I

) Is obtained. Melting point = 231-4 ° C.

Infrared spectrum (KBr disc): C = 0 at 1700 cm ⁻¹ ; C = N at 1630 cm ⁻¹ .

Example 48

][1,4] 벤조디아제핀-1-온.1,2-dihydro-2- (N-dimethylphosphinylmethyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온(I

)혼합물로 부터 제조되며 ;이 화합물은 또한 실시예 8에서 설명한 것과 유사한 방법에 의하여 제조된다.The compound described above was prepared by the method analogous to that used in Example 47.

] [1,4] benzobenzozepine-1-one (I

From the mixture; this compound is also prepared by a method similar to that described in Example 8.

][1,4] 벤조디아제핀-1-온(I

) 화합물은 245°-7℃의 온도에서 녹는다.1,2-dihydro-2- (N-dimethylphosphinylmethyl-piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] benzobenzozepine-1-one (I

) The compound melts at a temperature of 245 ° -7 ° C.

IR spectrum (KBr disc): C = 0 at 1695 cm ⁻¹ ; C = N at 1630 cm ⁻¹ .

Example 49

][1,4] 벤조디아제핀-1-온.8-nitro-1,2-dihydro-2- (N-dimethylphosphinylmethyl-piperazin-1-yl) methylene-6- (0-chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one.

][1,4] 벤조디아제핀-1-온(I

)의 화합물로 부터 제조되며 이 화합물은 차례로 실시예 8에서 설명된 것과 유사한 방법에 의해서 제조된다.The compound described above was prepared by 8-nitro-1,2-dihydro-2- (piperazin-1-yl) methylene-6- (0 chlorophenyl) -1H, 4H- by a method similar to that used in Example 47. Imidazo [1,2-

] [1,4] benzobenzozepine-1-one (I

) Compound, which in turn is prepared by a method analogous to that described in Example 8.

][1,4] 벤조디아제핀-1-온(I

)의 화합물은 245°-8℃에서 녹는다.8-Nitro-1,2-dihydro-2- (N-dimethylphosphinyl-methyl-piperazin-1-yl) methylene-6- (0-chlorophenyl) -1H, 4H-imidazo [1 prepared ,2-

] [1,4] benzobenzozepine-1-one (I

) Compound is soluble at 245 ° -8 ° C.

I. R spectrum (KBr disc): C = 0 at 1700 cm ⁻¹ ; C = N at 1642 cm ⁻¹ .

Example 50

][1,4] 벤조디아제핀-1-온 메탄술폰산염.8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (0 chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] benzodiazepin-1-one methanesulfonate.

][1,4] 벤조디아제핀-1-온(실시예 30에서 얻어진 화합물임)(4.6g)에 한 방울씩 가한다. 표면을 긁었을 때 결정이 형성될 때까지 건성 에테르를 천천히 가하고 완전한 결정화가 이루어질 때까지 에테르를 더욱 첨가한다.Methanesulfonic acid (1.1 g) was dissolved in dry methylene chloride (100 ml) and methanol (5 ml) in 8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (0 Chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4] To benzodiazepin-1-one (compound obtained in Example 30) (4.6 g) was added dropwise. When scratching the surface, dry ether is slowly added until crystals form and more ether is added until complete crystallization is achieved.

][1,4] 벤조디아제핀-1-온 메탄술포네이트 혼합물(5.4g)이 얻어진다.The pale yellow solid was filtered off, washed with ether and recrystallized from a mixture of methylene chloride and methanol to give 8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (0 Chlorophenyl) 1H, 4H-imidazo [1,2-

] [1,4] A benzodiazepin-1-one methanesulfonate mixture (5.4 g) is obtained.

Melting point = 205-10 ° C .;

Formulation type

Formulation 1: Tablet

Tablets are prepared from the following compositions in one party.

8-chloro-1,2-dihydro-2- (N-methylpiperazin-1-yl)

][1,4]Methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4]

Benzodiazepine-1-one ‥‥‥‥‥‥‥‥‥‥‥‥ 5mg

Excipients (for tablet manufacturing) ‥‥‥‥‥‥‥ Up to 100mg.

Excipients include lactose, starch, talc and magnesium stearate.

Formulation 2; capsule

The components of the gelatin capsules are prepared with the following composition per capsule.

8-chloro-1,2-dihydro-2- (N-methylpiperazin-1-yl)

][1,4]Methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4]

Benzodiazepine-1-one tartarate ‥‥‥‥‥ 5mg

Excipients (appropriate for gelatin capsules) ‥‥‥‥‥ Up to 100mg.

Excipients include talc, starch and magnesium stearate.

Formulation form 3: injection ampoule

Injectable ampoules are prepared as solutions having the following composition.

8-chloro-1,2-dihydro-2- (N-methyl piperazin-1-yl)

][1,4]Methylene-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4]

Benzodiazepine-1-one tartarate ‥‥‥‥‥ 10mg

Aqueous solvent ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 2ml

Formulation 4: Tablet

Tablets are prepared with the following compositions.

8-chloro-1,2-dihydro-2- (N-methylpiperazin-1-yl)

][1,4]Methylene-6- (0 chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4]

Benzodiazepine-1-one ‥‥‥‥‥‥‥‥‥‥‥‥‥ 5mg

Excipients (Tablet dosage) ‥‥‥‥‥‥‥‥‥‥‥ 100mg

Excipients include lactose, starch, talc and magnesium stearate.

Formulation 5: Tablet

This tablet is prepared with the following composition.

8-chloro-1,2-dihydro-2- (N-methylpiperazin-1-yl)

][1,4]Methylene-6- (0-fluorotophenyl) -1H, 4H-imidazo [1,2-

] [1,4]

Benzodiazepine-1-one ‥‥‥‥‥‥‥‥‥‥‥ 5mg

Excipients (Tablet Volume) up to 100mg.

Excipients include lactose, starch, talc and magnesium stearate.

Formulation 6: Tablet

This tablet is prepared with the following composition.

][1,4]8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) -methylene-6- (0 chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4]

Benzodiazepine-1-one methanesulfonate ‥‥‥‥‥ 5mg

Excipients (table volume) up to 100 mg.

Excipients include lactose, starch and magnesium stearate.

Formulation 7: Tablet

The tablets are prepared with the following compositions in one party.

][1,4]8-chloro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) -methylene-6- (0 chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4]

Benzodiazepine-1-one methane sulfonate ‥‥‥‥‥ 5mg

Excipients (for tablets) ‥‥‥‥‥‥‥‥‥‥‥ 100mg

Excipients include lactose, starch, talc and magnesium stearate.

Formulation 8: Tablet

The tablets are prepared with the following compositions in one party.

][1,4]8-chloro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) methylene-6- (0 chlorophenyl) -1H, 4H-imidazo [1,2-

] [1,4]

Benzodiazepine-1-one tartarate ‥‥‥‥‥ 5mg

Excipients (for tablets) ‥‥‥‥‥‥‥ 100mg.

Excipients include lactose, starch, talc and magnesium stearate.

[Reaction Structure Diagram]

Claims (1)

Then, the compound of formula (V) is reacted with dimethylformamide acetal of formula (VI) or N-dimethyl-acetamide of formula (VII) to prepare a compound of formula (Ia) or (Ib), respectively. Reacting with an amine to produce a compound of formula (Ic) or (Id), wherein 1,2-dihydro-6-phenyl-1H, 4H-imidazo [1,2-

] [1,4] A process for producing benzodiazepin-1-one and its salts.

Wherein R ¹ is hydrogen, halogen, nitro or trifluoro methyl group and R ² is hydrogen or halogen which may be present at any suitable position of the phenyl ring, R ³ is hydrogen or methyl group and R ⁴ and R ⁵ are the same Or other hydrogen, alkyl having 1 to 5 carbon atoms, hydroxy alkyl having 1 to 5 carbon atoms, aminoalkyl or alkylamino alkyl, wherein each alkyl group has 1 to 5 carbohydrates, an aryl group, a cycloalkyl group, or R ⁴ and R ⁵ together with the nitrogen atom may form a heterocyclic ring which may have a saturated or optionally substituted hetero atom, provided that R ⁴ and R ⁵ in the formulas (VIII), (Ic) and (Id) Are not all methyl groups, and AIK is a lower alkyl group having 1-5 carbon atoms.