CA1162536A - 2-azidomethyl-1,4-benzodiazepine derivatives and their salts, and process for their preparation - Google Patents
2-azidomethyl-1,4-benzodiazepine derivatives and their salts, and process for their preparationInfo
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Abstract
ABSTRACT OF THE DISCLOSURE
Novel 2-azidomethyl-1H-2,3-dihydro-1,4-benzodiazepine derivatives are disclosed which possess the Formula I
I
wherein R1 represents hydrogen or lower alkyl and the aromatic groups A and B may be unsubstituted or substituted by 1 to 3 substituents such as halogen, lower alkylthio, lower alkoxy, lower alkyl, hydroxy, nitro, trifluoromethyl or methylene-dioxy or ethylenedioxy and optical isomers and acid addition salts of the compounds. The novel compounds of Formula I provide valuable intermediates for the preparation of novel 2-acylaminomethyl-1H-2,3-dihydro-1,4-benzodiazepine compounds yet also possess themselves pharmacological activities.
Novel 2-azidomethyl-1H-2,3-dihydro-1,4-benzodiazepine derivatives are disclosed which possess the Formula I
I
wherein R1 represents hydrogen or lower alkyl and the aromatic groups A and B may be unsubstituted or substituted by 1 to 3 substituents such as halogen, lower alkylthio, lower alkoxy, lower alkyl, hydroxy, nitro, trifluoromethyl or methylene-dioxy or ethylenedioxy and optical isomers and acid addition salts of the compounds. The novel compounds of Formula I provide valuable intermediates for the preparation of novel 2-acylaminomethyl-1H-2,3-dihydro-1,4-benzodiazepine compounds yet also possess themselves pharmacological activities.
Description
- ~ 1 62~36
2~AZIDO~ETHYL-1,4-BENZODIAZEPINE
DERIVATIVES AND THEIR SALTS, AND PROCESS FOR THEIR PREPARATION
The present application is a divisional appli-cation divided out of application Serial No. 367,417 filed December 23, 1980 which relates to novel 2-acylaminomethyl-7,4-benzodiazepine derivatives.
BACKGROUND OF THE INVENTION
The present invention relates to novel 2-azido-methyl-1,4-benzodiazepine derivatives, their salts and processes for their preparation.
The German Offenlegungsschrift No. 2,353,187 discloses inter alia 2-acylaminomethyl-1,4-benzodiazepine derivatives wherein the acyl group is a lower alkanoyl.
These compounds possess a primarily anti-convulsive activity.
~ 1 6253~
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel intermediates for the preparation of novel 2-acylaminomethyl-1,4-benzodiazepine derivatives and pharmaceutical compositions thereof which possess a novel pharmacological activlty profilel in particular strong analgesic activities in addition to psycho phar-macological, diuretic and anti-arrhythmic properties.
It is a further object of the present invention to provide novel 2-azidoaminomethyl-1,4-benzodiazepine derivatives which are useful intermediates in the preparation of the novel 2-acylaminomethyl-1,4-benzodiazepine derivatives and which themselves possess valuable pharmacological properties.
It is a fu.rther object of the present invention to provide a process for preparing such novel 2-azido-methyl-1,4-benzodiazepine derivatives with improved pharmacological properties.
In order to accomplish the foregoing objects according to the present invention, there are provided novel 2-azidomethyl-lH-2,3-dihydro-1,4-benzodiazepine derivatives of the Formula I
~ ~,N _._CH
~ C = N /
wherein Rl represents hydrogen or lower alkyl and the aromatic groups A and B independently from each other ~ 1 62S36 may be unsubstituted or be substituted by l to 3 sub-stituents selected from the group consisting of halogen, lower alkythio, lower alkoxy, lower alkyl, hydroxy, nitro and trifluoromethyl, or be substituted at two adjacent carbon atoms by methylene-dioxy or ethylene-dioxy, and optical isomers and pharmaceutically-acceptable acid addition salts thereof.
According to the present invention, there are further provided processes for preparing the compounds of Formula I in good yields.
According to the present invention, compounds of Formula I can be prepared by reacting a compound of Formula II or a compound of Formula III
,Rl / CH2-X ll CH
N - CH N ~ \ 2 \CH II ~ CH-X
I C N
wherein A and B and R are as defined above and X
represents halogen, preferably chloride, or mixtures thereof with an alkali metal azide, preferably sodium or potassium azide.
The compounds of Formula I may be recovered from the respective reaction solutions in the form of optical isomers or of racemic mixtures in form of the free bases or in form of the acid addition salts.
Acid addition salts may be transformed into free bases and vice versa according to conventional methods.
Racemic mixtures may be separated into the optical isomers according to conventional methods.
The compounds of Formula I are novel and represent valuable intermediates for the preparation of corresponding analgesically active novel 2-acyl-aminomethyl-5-phenyl-lH-2,3-dihydro-l,~-benzodiaze-pine derivatives of Formula A
~ 1 ~2536 ~ CH2 NH acyl ~f i CH2 A
~B
wherein A and B and Rl are as defined above and acyl represents an acyl group CO-R3 wherein R3 represents a group of the formula ~ , 4 ~ ~ 4 4 or wherein R4 is hydrogen, halogen lower alkyl lower alkoxy or nitro, R and R4' each are hydrogen or lower alkyl.
The compounds of formula A, their preparation and their pharmacological properties are disclosed in the co-pending application Serial No. 367,477. Additionally, the compounds of Formula I themselves exhibit valuable pharmacological properties, in particular, bronchal-dilating, sedative and antiarrhythmic properties, due to which they are useful as sedatives, broncholytic and antiarrhythmic agents.
Further objects, features and advantages of the present invention will become apparent from the detailed description of the invention which follows.
DETAILED DESCRIPTION OF THE INVENTION AND ITS
PREFERRED EMBODIMENTS
If in the compounds of Formula I, Rl represents lower al~yl, this group may contain up to four carbon ~ ~ 6253~
atoms and may be straight or branched. Suitable such groups are methyl, ethyl, propyl, isopropyl, n-butyl, l-methylpropyl, 2-methylpropyl or tert.-butyl.
The alkyl group within alkyl, alkylthio or alko~y substituents of the phenyl groups ~ and/or s also may contain 1 to 4 carbon atoms and may be one of the above-mentioned groups. Methyl and ethyl substituents are preferred in particular in the case of di- and tri- substi-tution of the phenyl ring. Suitable halogen substituents include fluorine, chlorine and ~romine. In the case of substitution of the phenyl ring with alkylthio, nitro or trifluoromethyl, mono-substltution is preferred. In the case of substitution with halogen and/or alkyl and/or alkoxy or hydroxy, mono- and disubstitution are preferred. In the case of lower alkoxy substituents, in particular methoxy, tri-substitution is also favorable.
For medical applications the compounds of Formula I can be used in the form of free bases as well as in the form of pharmaceutically acceptable acid addition salts, that is, salts with such acids the anions of which are non-toxic at the dosage in question.
Furthermore, it is advantageous to use such salts for the medical applications which are readily crystallizable and are not or only slightly hygroscopic. Examples of acids which are suitable for salt-formation with compounds of Formula I are the following: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methylsulfonic acid, ethylsulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, citric acid, acetic acid, lactic acid, succinic acid, maleic acid, furmaric acid, malic acid, tartaric acid, benzoic acid, phenylacetic acid and mandelic acid.
According to a feature of the present invention, there are further provided pharmaceutical compositions containing an effective amount of at least one of the ~ 1 6~536 compounds of Formula I or their pharmaceutically accept-able salts. The amount of active ingredient per dosage unit form may vary between about 0.1 and about 100 mg whereby the dosage is chosen depending on the type of species to be treated and the r2quirement for a given individual treatment. Generally, compositions for parental administration would contain lower amounts of active ingredient than compositions for oral applica-tion. The compounds of Formula I may be applied alone or in combination with pharmaceutically acceptable carrier materials and/or adjuvants in many different dosage forms. For example, formulations for oral application may be in the form of solid formulations such as tablets, capsules, powders, granulates, coated tablets and the like. Suppositories can also be used. Solid formulations may comprise conventional pharmaceutically acceptable inorganic carrier materia~s such as talcum or an organic carrier material such as lactose or starch. Conventional pharmaceutical adjuvants such as magnesium stearate (as lubricant) may also be included.
Liquid formulations such as solutions, suspensions, or emulsions may comprise conventional pharmaceutical diluents such as water, vaseline, suspending agents such as polyoxyethylene glycols and the like. Furthermore, conventional adjuvants such as preserving agents, stabilizing agents and emulsifiers may be added.
By means of the process according to the present invention, the compounds of Formula I are obtained in racemic form. The present invention includes the compounds of Formula I in the form of racemic mixtures as well as in optically active forms. The optically active compounds can be obtained from racemic mixtures of compounds of Formula I in conventional manner by salt for-mation with suitable optically active acids and subsequent fractionated crystallization of the optically active ~ J 62~.~6 antipodes of the resulting salts (see S. ~. Wlllen, A.
Collet, J. Jacques, Tetrahedron 33, (1977) 2725-2736).
Examples of suitable optically active acids include tar-taric acid, O,O'-dibenzoyl tartaric acid, mandelic acid, di-O-isopropylidene-2-oxo-L-gulonic acid. The obtained salts can be transformed into the free bases which, if desired, subsequently can be transformed into phar-macologically acceptable salts. The racemic mixtures, as well as the optically actlve isomers and the acid addi-tion salts can be purified by recrystallization fromsolvents such as lower alkyl alcohols and/or ethers.
Yet the separation of racemic mixtures into the optically active compounds may also be performed at a ~uitable primary reaction step.
The preparation of the starting materials, can be done in a known manner according to processes which are disclosed in German Offenlegungsschrift No. 2,221,558.
l-acyl-2-hydro~y-1,3-diaminopropane compounds are used as starting materials for compounds o~ Formulae II and III and can be prepared according to the method disclosed in German Offenlegungsschrift Nos. 2,221,558, 2,314,993, 2,720,915 and 2,720,968.
The 2-hydroxy-1,3-diaminopropane compounds of Formula V
OH ,~
H2N-CH2-CH CH2 N ~ ~ (V) wherein Rl and A are as defined above can be reacted with an optionally substituted benzoylchloride to obtain compounds of Formula VI
\i/ B ~ -CO-NH-CH2-CH-CH2-N-~ jA ~ (VI) OH `---wherein A, B and Rl are as defined above.
-~ ~ 6~536 The starting materials of Formula V can be prepared in the manner described by M. Chadwick et al in J~ Med. Chem. 9, Page 874 (1966).
At this reaction stage, compounds of Formula VI
wherein Rl represents hydrogen can subsequently be alkylated in conventional manner into the corresponding N-alkyl compounds. This alkylation can be carried out, for example, according to the methods of reductive carbonyl-amination which are known in the art such as the Leuckart-Wallach or the Eschweiler-Clarke reaction (see H. Krauch, W. Kunz, Reaktionen der Organischen Chemie (1976) page 126 and 131) or by alkylation with dialkylsulfates (see Houben-Weyl XI/l (1957), S. 207 ff).
The compounds of Formula VI which are obtained in the above-described manner can subsequently be cyclized by reaction with phosphoroxyhalogenides, preferably phosphoroxychloride in conventional manner, for example, as is known from German Offenlegungsschrift Nos. 2 221 558, 2 314 993 and 2 520 937. Suitably the compounds o~ Formula VI or acid addition salts thereof are treated with a cyclizillg agent at a temperature of between about 100C. and 150C. as is disclosed in German Offenlegungsschrift No. 2 520 937 and subsequently the resulting mixture of the two isomer compounds of Formula II and Formula III is isolated.
The two isomeric compounds of Formula II and Formula III are present in the reaction mixture in varying proportions depending on the type of substituents in the aromatic nuclei A and B as well as on the position of such substituents. This,however, is of no importance for the subsequent reaction of this mixture since both isomers yield compounds of Formula I wherein A, B and Rl are as defined above in the subsequent reaction step. There-fore, no time consuming separation or analysis of themixture of isomers is necessary.
~ .~ 62536 Thus, afte~ roughly removing by-products yet without separation into the isomeric components, the mixture of isomeric compounds o~ Formula II and Formula III which is obtained as described above can be reacted with an alkali metal azide. Suitably the reaction takes place in an inert solvent at a temperature of from about 30 to 150C. The compounds of Formula I can be isolated in the form of the free bases or in the form of acid addition salts thereof.
Yet the compounds also may be subjected to further reaction without separation from the reaction mixture optionally after removal of the solvent.
Examples of suitable solvents for the pre-paration of the azides of Formula I include methylene-chloride, chloroform, tetrahydro~urane, dioxane,dimethylformamide, dimethylsulfoxide, hexamethyl-phosphortriamide, methanol, ethanol, t-butanol, acetone, or methylisobutylketone.
The compounds of Formula I are novel com-pounds which provide valuable intermediates for thepreparation of 2-acylaminomethyl-1,4-benzodiazepine compounds. Furthermore, the compounds of Formula I themselves also possess valuable pharmacological properties. In particular, the compounds of Formula I according to the present invention possess psycho pharmacological activities which have been demon-strated in standard screening tests of PANLABS Inc.
The compounds further possess bronchodilatory pro-perties which have been demonstrated in guinea pig lungs through which a flow of compound solution is passed, and antiarrhythmic properties which are demonstrated after chloroform-induced arrhythmia in the mouse heart.
~ I ~;2536 The pharmacological tests gave satisfactory results in a disage range of from about 0.5 to about 100 mg/kg. Accordingly, the compounds of Formula I
of the present invention are therapeutically useful as sedatives, broncholytic agents and antiarrhythmic agents.
By subsequent splitting of these 2-azido-methyl compounds in known manner by reaction with hydrazine hydrate/Raney-nickel with basic cataly-zation or with propanedithiol 2-aminomethyl-1,4-benzodiazepine compunds are obtained. The reduction with hydrazine sultably is carried out in an alcohol such as methanol or ethanol under addition of a tertiary amine such as triethylamine at room temper-ature. The reduction with propanedithiol suitablyis carried out by using methanol, ethanol, dimethyl-formamide or pyridine/water as a solvent.
The 2-aminomethyl compounds subsequently can be acylated into the desired 2-acylaminomethyl-1,4-benzodiazepine derivatives.
It is especially noted at this point that for the above-described reaction for the preparation of compounds of Formula I, the mixture of isomeric compounds of Formula II and III suitably is used yet that it is evident to anyone skilled in the art that the mixture of isomers also can be separated into its components which later can separately be converted into compounds of Formula I according to the above-described reaction.
Subsequent substitution of the nucleus A
of the 1,4-benzodiazepine system by halogen or nitro substituents is possible in a conventional manner as has already been described in German Offenlegungsschrift No. 2 221 558. Such substitution i ~ 6253~
suitably can be effected on compounds of Formula I
and II. N-chlorosuccinimide or N-bromosuccinimide may for example serve as a halogenating agent.
For introducing the nitro substituent conventional nitrating agents can be used such as KNO3 in H2SO4 or copper~ nitrate-trihydrate in acetie aeid anhydride.
The compounds of Formula I which are obtained by the processes according to the present invention may be isolated in the form of the free bases or, if desired, may be converted into acid addition salts with inorganic or organic acids in conventional manner. For example, in order to obtain the salt, the desired acid is added to a solution of the compound of Formula I in a suitable solvent. Preferably, an organie solvent is used wherein the resulting salt is unsoluble so that it ean be separated by filtration. Examples of sueh solvents inelude ethanol, isopropanol, ether, aeetone, aeetie aeid ethyl ester, aeetone/ether, aeetone/ethanol, ethanol/ether.
The following examples are intended to illustrate the preparation of the novel compounds of Formula I but are not intended to limit the scope of the present invention in any way.
The chemical structure of the novel com-pounds has been verified by spectroseopie analysis, in particular by exaet analysis of the NMR-spectra.
In the following table the melting points of the monohydroehlorides of the eompounds are given where no other data are reeited. The presenee of any ineluded amounts of water, acetone, ethanol or the like is noted.
I :7 fi?,53~
Example l:
l-methyl-2-azidomethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine.
a) A mixture of 202 g of Nl-benzoyl-N-methyl-N2-phenyl 2-hydroxy-1,3-diaminopropane and lO00 ml of phosphoroxychloride is heated under reflux for a period of 2.5 hours. Subsequently the excess phosphoroxychloride is distilled off and the residue is dissolved in 1000 ml of chloro-form. The chloroform solution is agitated with1000 ml of ice/water, the organic phase is separated and is washed five to six times wlth 200 ml of water each. Subsequently the organic phase is agitated with 1200 ml of sodium hydroxide solution (20%) and then washed with water until neutral reaction. The chloroform phase then is dried and decolorized by addition of sodium sulfate and ~-aluminum oxide (aluminum oxide "Giulini"). After filtering the solution is evaporated. 202 g of an oily base are obtained which comprises a mixture of 1-methyl-2-chloromethyl-5-phenyl-lH-2,3-dihydro-1,4~benzodiaze pine and l-methyl-3-chloro-6-phenyl-1,2,3,4-tetrahydro-benzodiazocine.
b) A mixture of 68.4 g of the cyclization mixture obtained according to Example 1 a) and containing l-methyl-2-chloromethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine and 1-methyl-3-chloro-6-phenyl-1,2,3,4-tetrahydro-benzodiazocine, 47.2 g of sodium azide and 420 ml of dimethylform-amide is heated to 100C for a period of 4 hours.Subsequently, the dimethylformamide is distilled off under vacuum and 300 ml of toluene and 200 ml of water are added to the residue. The organic phase is separated, washed with sodium chloride t 3 ~253~
solution (10%), dried over sodium sulfate and filtered. The solvent is distilled off and 56.1 g of raw product are obtained as residue. The resi-due is dissolved in ether and a saturated solution of hydrogen chloride in ether is added. The pre-cipitated crystals are filtered off and are recrystallized from acetone/isopropanol.
36.7 g of 1-methyl-2-azidomethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiazeplne hydrochloride having a melting point of 181-183C are obtained.
_xample 2_ l-methyl-2-[(thiophene-3-carbonyl)-amino-methyl]-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine.
a) 21.7 g of 1-methyl-2-azidomethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine hydrochloride are dissolved in 325 ml of methanol. 9.5 ml of ~ri-ethylamine and subsequently 13.5 ml of hydrazine hydrate are added. Then 10 g of Raney-nickel are added portionwise to the reaction solution under agitation at room temperature. After three hours, the addition of Raney-nickel is completed. The reaction mixture is agitated for another one hour, then the ~aney-nickel is filtered off. The filtrate is evaporated under vacuum, the residue is dissolved in methylene chloride and the solution is washed with water and sodium chloride solution (10~). Subse-quently, the organic phase is dried over sodium sulfate, filtered and evaporated. 17.1 g of l-methyl-2-aminomethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiaze-pine are obtained. Its dihydrochloride has a meltingpoint of 209 to 213C.
b) 13.5 g of thiophene-3-carboxylic acid are dissolved in 300 ml of methylene chloride and are cooled to a temperature of 0 to 5C. Then 14.5 ml of triethylamine are added and subsequently 11.2 ml of chloroformic acid ethyl ester are added dropwise within a period of 5 to 10 minutes. Then the reaction solution is agitated for another 30 minutes at the temperature of 0 to 5C and subse-quently is added dropwise and under cooling to a solution of 27.9 g of 1-methyl-2-aminomethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine in 200 ml of methylene chloride in such a manner that the temperature is retained at between 0 to 5C. Sub-sequently, the reaction solution is agitated for another four hours at room temperature, then is washed with water, diluted ammonium hydroxide solution (10%) and sodium chloride solution, dried over sodium sulfate and filtered. The solvent is distilled off. 37.8 g of raw product are obtained.
The raw base is dissolved in ether and a saturated solution of hydrogen chloride in ether is added. The precipitated crystals are filtered off and are heated to boiling temperature in a mixture of acetone/acetic acid ethyl ester. 21.9 g of l-methyl-2-[(thiophene-3-carbonyl)-aminomethyl]-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine hydro-chloride having a melting point of 234 to 237.5C
are obtained.
Analogous to the method described in Fxample I, 2-azidomethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine derivatives of Formula I can be prepared wherein A and ~ are substituted and Rl is defined as follows:
~ 1 62536 A B R Melting Point C
_ 1 Hvdrochloride 7-F 3,4,5-OCH CH3 123-126 base 7-CH3 3,4,5-OCH3 CH3 187-188 7-C1 2-Cl CH3 170-173 Ø25 H2O
7-Cl H CH3 147-151.5 H 2-F C2H5 Oil*
7-Br H CH3 Oil*
H 2-B~ CH3 Oil*
7-NO2 H CH3 Oil*
8-F H H Oil*
*IR-Spectra: 2120 cm (Azid/base) Perkin-Elmer IR-Spectrophotometer 157 G
DERIVATIVES AND THEIR SALTS, AND PROCESS FOR THEIR PREPARATION
The present application is a divisional appli-cation divided out of application Serial No. 367,417 filed December 23, 1980 which relates to novel 2-acylaminomethyl-7,4-benzodiazepine derivatives.
BACKGROUND OF THE INVENTION
The present invention relates to novel 2-azido-methyl-1,4-benzodiazepine derivatives, their salts and processes for their preparation.
The German Offenlegungsschrift No. 2,353,187 discloses inter alia 2-acylaminomethyl-1,4-benzodiazepine derivatives wherein the acyl group is a lower alkanoyl.
These compounds possess a primarily anti-convulsive activity.
~ 1 6253~
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel intermediates for the preparation of novel 2-acylaminomethyl-1,4-benzodiazepine derivatives and pharmaceutical compositions thereof which possess a novel pharmacological activlty profilel in particular strong analgesic activities in addition to psycho phar-macological, diuretic and anti-arrhythmic properties.
It is a further object of the present invention to provide novel 2-azidoaminomethyl-1,4-benzodiazepine derivatives which are useful intermediates in the preparation of the novel 2-acylaminomethyl-1,4-benzodiazepine derivatives and which themselves possess valuable pharmacological properties.
It is a fu.rther object of the present invention to provide a process for preparing such novel 2-azido-methyl-1,4-benzodiazepine derivatives with improved pharmacological properties.
In order to accomplish the foregoing objects according to the present invention, there are provided novel 2-azidomethyl-lH-2,3-dihydro-1,4-benzodiazepine derivatives of the Formula I
~ ~,N _._CH
~ C = N /
wherein Rl represents hydrogen or lower alkyl and the aromatic groups A and B independently from each other ~ 1 62S36 may be unsubstituted or be substituted by l to 3 sub-stituents selected from the group consisting of halogen, lower alkythio, lower alkoxy, lower alkyl, hydroxy, nitro and trifluoromethyl, or be substituted at two adjacent carbon atoms by methylene-dioxy or ethylene-dioxy, and optical isomers and pharmaceutically-acceptable acid addition salts thereof.
According to the present invention, there are further provided processes for preparing the compounds of Formula I in good yields.
According to the present invention, compounds of Formula I can be prepared by reacting a compound of Formula II or a compound of Formula III
,Rl / CH2-X ll CH
N - CH N ~ \ 2 \CH II ~ CH-X
I C N
wherein A and B and R are as defined above and X
represents halogen, preferably chloride, or mixtures thereof with an alkali metal azide, preferably sodium or potassium azide.
The compounds of Formula I may be recovered from the respective reaction solutions in the form of optical isomers or of racemic mixtures in form of the free bases or in form of the acid addition salts.
Acid addition salts may be transformed into free bases and vice versa according to conventional methods.
Racemic mixtures may be separated into the optical isomers according to conventional methods.
The compounds of Formula I are novel and represent valuable intermediates for the preparation of corresponding analgesically active novel 2-acyl-aminomethyl-5-phenyl-lH-2,3-dihydro-l,~-benzodiaze-pine derivatives of Formula A
~ 1 ~2536 ~ CH2 NH acyl ~f i CH2 A
~B
wherein A and B and Rl are as defined above and acyl represents an acyl group CO-R3 wherein R3 represents a group of the formula ~ , 4 ~ ~ 4 4 or wherein R4 is hydrogen, halogen lower alkyl lower alkoxy or nitro, R and R4' each are hydrogen or lower alkyl.
The compounds of formula A, their preparation and their pharmacological properties are disclosed in the co-pending application Serial No. 367,477. Additionally, the compounds of Formula I themselves exhibit valuable pharmacological properties, in particular, bronchal-dilating, sedative and antiarrhythmic properties, due to which they are useful as sedatives, broncholytic and antiarrhythmic agents.
Further objects, features and advantages of the present invention will become apparent from the detailed description of the invention which follows.
DETAILED DESCRIPTION OF THE INVENTION AND ITS
PREFERRED EMBODIMENTS
If in the compounds of Formula I, Rl represents lower al~yl, this group may contain up to four carbon ~ ~ 6253~
atoms and may be straight or branched. Suitable such groups are methyl, ethyl, propyl, isopropyl, n-butyl, l-methylpropyl, 2-methylpropyl or tert.-butyl.
The alkyl group within alkyl, alkylthio or alko~y substituents of the phenyl groups ~ and/or s also may contain 1 to 4 carbon atoms and may be one of the above-mentioned groups. Methyl and ethyl substituents are preferred in particular in the case of di- and tri- substi-tution of the phenyl ring. Suitable halogen substituents include fluorine, chlorine and ~romine. In the case of substitution of the phenyl ring with alkylthio, nitro or trifluoromethyl, mono-substltution is preferred. In the case of substitution with halogen and/or alkyl and/or alkoxy or hydroxy, mono- and disubstitution are preferred. In the case of lower alkoxy substituents, in particular methoxy, tri-substitution is also favorable.
For medical applications the compounds of Formula I can be used in the form of free bases as well as in the form of pharmaceutically acceptable acid addition salts, that is, salts with such acids the anions of which are non-toxic at the dosage in question.
Furthermore, it is advantageous to use such salts for the medical applications which are readily crystallizable and are not or only slightly hygroscopic. Examples of acids which are suitable for salt-formation with compounds of Formula I are the following: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methylsulfonic acid, ethylsulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, citric acid, acetic acid, lactic acid, succinic acid, maleic acid, furmaric acid, malic acid, tartaric acid, benzoic acid, phenylacetic acid and mandelic acid.
According to a feature of the present invention, there are further provided pharmaceutical compositions containing an effective amount of at least one of the ~ 1 6~536 compounds of Formula I or their pharmaceutically accept-able salts. The amount of active ingredient per dosage unit form may vary between about 0.1 and about 100 mg whereby the dosage is chosen depending on the type of species to be treated and the r2quirement for a given individual treatment. Generally, compositions for parental administration would contain lower amounts of active ingredient than compositions for oral applica-tion. The compounds of Formula I may be applied alone or in combination with pharmaceutically acceptable carrier materials and/or adjuvants in many different dosage forms. For example, formulations for oral application may be in the form of solid formulations such as tablets, capsules, powders, granulates, coated tablets and the like. Suppositories can also be used. Solid formulations may comprise conventional pharmaceutically acceptable inorganic carrier materia~s such as talcum or an organic carrier material such as lactose or starch. Conventional pharmaceutical adjuvants such as magnesium stearate (as lubricant) may also be included.
Liquid formulations such as solutions, suspensions, or emulsions may comprise conventional pharmaceutical diluents such as water, vaseline, suspending agents such as polyoxyethylene glycols and the like. Furthermore, conventional adjuvants such as preserving agents, stabilizing agents and emulsifiers may be added.
By means of the process according to the present invention, the compounds of Formula I are obtained in racemic form. The present invention includes the compounds of Formula I in the form of racemic mixtures as well as in optically active forms. The optically active compounds can be obtained from racemic mixtures of compounds of Formula I in conventional manner by salt for-mation with suitable optically active acids and subsequent fractionated crystallization of the optically active ~ J 62~.~6 antipodes of the resulting salts (see S. ~. Wlllen, A.
Collet, J. Jacques, Tetrahedron 33, (1977) 2725-2736).
Examples of suitable optically active acids include tar-taric acid, O,O'-dibenzoyl tartaric acid, mandelic acid, di-O-isopropylidene-2-oxo-L-gulonic acid. The obtained salts can be transformed into the free bases which, if desired, subsequently can be transformed into phar-macologically acceptable salts. The racemic mixtures, as well as the optically actlve isomers and the acid addi-tion salts can be purified by recrystallization fromsolvents such as lower alkyl alcohols and/or ethers.
Yet the separation of racemic mixtures into the optically active compounds may also be performed at a ~uitable primary reaction step.
The preparation of the starting materials, can be done in a known manner according to processes which are disclosed in German Offenlegungsschrift No. 2,221,558.
l-acyl-2-hydro~y-1,3-diaminopropane compounds are used as starting materials for compounds o~ Formulae II and III and can be prepared according to the method disclosed in German Offenlegungsschrift Nos. 2,221,558, 2,314,993, 2,720,915 and 2,720,968.
The 2-hydroxy-1,3-diaminopropane compounds of Formula V
OH ,~
H2N-CH2-CH CH2 N ~ ~ (V) wherein Rl and A are as defined above can be reacted with an optionally substituted benzoylchloride to obtain compounds of Formula VI
\i/ B ~ -CO-NH-CH2-CH-CH2-N-~ jA ~ (VI) OH `---wherein A, B and Rl are as defined above.
-~ ~ 6~536 The starting materials of Formula V can be prepared in the manner described by M. Chadwick et al in J~ Med. Chem. 9, Page 874 (1966).
At this reaction stage, compounds of Formula VI
wherein Rl represents hydrogen can subsequently be alkylated in conventional manner into the corresponding N-alkyl compounds. This alkylation can be carried out, for example, according to the methods of reductive carbonyl-amination which are known in the art such as the Leuckart-Wallach or the Eschweiler-Clarke reaction (see H. Krauch, W. Kunz, Reaktionen der Organischen Chemie (1976) page 126 and 131) or by alkylation with dialkylsulfates (see Houben-Weyl XI/l (1957), S. 207 ff).
The compounds of Formula VI which are obtained in the above-described manner can subsequently be cyclized by reaction with phosphoroxyhalogenides, preferably phosphoroxychloride in conventional manner, for example, as is known from German Offenlegungsschrift Nos. 2 221 558, 2 314 993 and 2 520 937. Suitably the compounds o~ Formula VI or acid addition salts thereof are treated with a cyclizillg agent at a temperature of between about 100C. and 150C. as is disclosed in German Offenlegungsschrift No. 2 520 937 and subsequently the resulting mixture of the two isomer compounds of Formula II and Formula III is isolated.
The two isomeric compounds of Formula II and Formula III are present in the reaction mixture in varying proportions depending on the type of substituents in the aromatic nuclei A and B as well as on the position of such substituents. This,however, is of no importance for the subsequent reaction of this mixture since both isomers yield compounds of Formula I wherein A, B and Rl are as defined above in the subsequent reaction step. There-fore, no time consuming separation or analysis of themixture of isomers is necessary.
~ .~ 62536 Thus, afte~ roughly removing by-products yet without separation into the isomeric components, the mixture of isomeric compounds o~ Formula II and Formula III which is obtained as described above can be reacted with an alkali metal azide. Suitably the reaction takes place in an inert solvent at a temperature of from about 30 to 150C. The compounds of Formula I can be isolated in the form of the free bases or in the form of acid addition salts thereof.
Yet the compounds also may be subjected to further reaction without separation from the reaction mixture optionally after removal of the solvent.
Examples of suitable solvents for the pre-paration of the azides of Formula I include methylene-chloride, chloroform, tetrahydro~urane, dioxane,dimethylformamide, dimethylsulfoxide, hexamethyl-phosphortriamide, methanol, ethanol, t-butanol, acetone, or methylisobutylketone.
The compounds of Formula I are novel com-pounds which provide valuable intermediates for thepreparation of 2-acylaminomethyl-1,4-benzodiazepine compounds. Furthermore, the compounds of Formula I themselves also possess valuable pharmacological properties. In particular, the compounds of Formula I according to the present invention possess psycho pharmacological activities which have been demon-strated in standard screening tests of PANLABS Inc.
The compounds further possess bronchodilatory pro-perties which have been demonstrated in guinea pig lungs through which a flow of compound solution is passed, and antiarrhythmic properties which are demonstrated after chloroform-induced arrhythmia in the mouse heart.
~ I ~;2536 The pharmacological tests gave satisfactory results in a disage range of from about 0.5 to about 100 mg/kg. Accordingly, the compounds of Formula I
of the present invention are therapeutically useful as sedatives, broncholytic agents and antiarrhythmic agents.
By subsequent splitting of these 2-azido-methyl compounds in known manner by reaction with hydrazine hydrate/Raney-nickel with basic cataly-zation or with propanedithiol 2-aminomethyl-1,4-benzodiazepine compunds are obtained. The reduction with hydrazine sultably is carried out in an alcohol such as methanol or ethanol under addition of a tertiary amine such as triethylamine at room temper-ature. The reduction with propanedithiol suitablyis carried out by using methanol, ethanol, dimethyl-formamide or pyridine/water as a solvent.
The 2-aminomethyl compounds subsequently can be acylated into the desired 2-acylaminomethyl-1,4-benzodiazepine derivatives.
It is especially noted at this point that for the above-described reaction for the preparation of compounds of Formula I, the mixture of isomeric compounds of Formula II and III suitably is used yet that it is evident to anyone skilled in the art that the mixture of isomers also can be separated into its components which later can separately be converted into compounds of Formula I according to the above-described reaction.
Subsequent substitution of the nucleus A
of the 1,4-benzodiazepine system by halogen or nitro substituents is possible in a conventional manner as has already been described in German Offenlegungsschrift No. 2 221 558. Such substitution i ~ 6253~
suitably can be effected on compounds of Formula I
and II. N-chlorosuccinimide or N-bromosuccinimide may for example serve as a halogenating agent.
For introducing the nitro substituent conventional nitrating agents can be used such as KNO3 in H2SO4 or copper~ nitrate-trihydrate in acetie aeid anhydride.
The compounds of Formula I which are obtained by the processes according to the present invention may be isolated in the form of the free bases or, if desired, may be converted into acid addition salts with inorganic or organic acids in conventional manner. For example, in order to obtain the salt, the desired acid is added to a solution of the compound of Formula I in a suitable solvent. Preferably, an organie solvent is used wherein the resulting salt is unsoluble so that it ean be separated by filtration. Examples of sueh solvents inelude ethanol, isopropanol, ether, aeetone, aeetie aeid ethyl ester, aeetone/ether, aeetone/ethanol, ethanol/ether.
The following examples are intended to illustrate the preparation of the novel compounds of Formula I but are not intended to limit the scope of the present invention in any way.
The chemical structure of the novel com-pounds has been verified by spectroseopie analysis, in particular by exaet analysis of the NMR-spectra.
In the following table the melting points of the monohydroehlorides of the eompounds are given where no other data are reeited. The presenee of any ineluded amounts of water, acetone, ethanol or the like is noted.
I :7 fi?,53~
Example l:
l-methyl-2-azidomethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine.
a) A mixture of 202 g of Nl-benzoyl-N-methyl-N2-phenyl 2-hydroxy-1,3-diaminopropane and lO00 ml of phosphoroxychloride is heated under reflux for a period of 2.5 hours. Subsequently the excess phosphoroxychloride is distilled off and the residue is dissolved in 1000 ml of chloro-form. The chloroform solution is agitated with1000 ml of ice/water, the organic phase is separated and is washed five to six times wlth 200 ml of water each. Subsequently the organic phase is agitated with 1200 ml of sodium hydroxide solution (20%) and then washed with water until neutral reaction. The chloroform phase then is dried and decolorized by addition of sodium sulfate and ~-aluminum oxide (aluminum oxide "Giulini"). After filtering the solution is evaporated. 202 g of an oily base are obtained which comprises a mixture of 1-methyl-2-chloromethyl-5-phenyl-lH-2,3-dihydro-1,4~benzodiaze pine and l-methyl-3-chloro-6-phenyl-1,2,3,4-tetrahydro-benzodiazocine.
b) A mixture of 68.4 g of the cyclization mixture obtained according to Example 1 a) and containing l-methyl-2-chloromethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine and 1-methyl-3-chloro-6-phenyl-1,2,3,4-tetrahydro-benzodiazocine, 47.2 g of sodium azide and 420 ml of dimethylform-amide is heated to 100C for a period of 4 hours.Subsequently, the dimethylformamide is distilled off under vacuum and 300 ml of toluene and 200 ml of water are added to the residue. The organic phase is separated, washed with sodium chloride t 3 ~253~
solution (10%), dried over sodium sulfate and filtered. The solvent is distilled off and 56.1 g of raw product are obtained as residue. The resi-due is dissolved in ether and a saturated solution of hydrogen chloride in ether is added. The pre-cipitated crystals are filtered off and are recrystallized from acetone/isopropanol.
36.7 g of 1-methyl-2-azidomethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiazeplne hydrochloride having a melting point of 181-183C are obtained.
_xample 2_ l-methyl-2-[(thiophene-3-carbonyl)-amino-methyl]-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine.
a) 21.7 g of 1-methyl-2-azidomethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine hydrochloride are dissolved in 325 ml of methanol. 9.5 ml of ~ri-ethylamine and subsequently 13.5 ml of hydrazine hydrate are added. Then 10 g of Raney-nickel are added portionwise to the reaction solution under agitation at room temperature. After three hours, the addition of Raney-nickel is completed. The reaction mixture is agitated for another one hour, then the ~aney-nickel is filtered off. The filtrate is evaporated under vacuum, the residue is dissolved in methylene chloride and the solution is washed with water and sodium chloride solution (10~). Subse-quently, the organic phase is dried over sodium sulfate, filtered and evaporated. 17.1 g of l-methyl-2-aminomethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiaze-pine are obtained. Its dihydrochloride has a meltingpoint of 209 to 213C.
b) 13.5 g of thiophene-3-carboxylic acid are dissolved in 300 ml of methylene chloride and are cooled to a temperature of 0 to 5C. Then 14.5 ml of triethylamine are added and subsequently 11.2 ml of chloroformic acid ethyl ester are added dropwise within a period of 5 to 10 minutes. Then the reaction solution is agitated for another 30 minutes at the temperature of 0 to 5C and subse-quently is added dropwise and under cooling to a solution of 27.9 g of 1-methyl-2-aminomethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine in 200 ml of methylene chloride in such a manner that the temperature is retained at between 0 to 5C. Sub-sequently, the reaction solution is agitated for another four hours at room temperature, then is washed with water, diluted ammonium hydroxide solution (10%) and sodium chloride solution, dried over sodium sulfate and filtered. The solvent is distilled off. 37.8 g of raw product are obtained.
The raw base is dissolved in ether and a saturated solution of hydrogen chloride in ether is added. The precipitated crystals are filtered off and are heated to boiling temperature in a mixture of acetone/acetic acid ethyl ester. 21.9 g of l-methyl-2-[(thiophene-3-carbonyl)-aminomethyl]-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine hydro-chloride having a melting point of 234 to 237.5C
are obtained.
Analogous to the method described in Fxample I, 2-azidomethyl-5-phenyl-lH-2,3-dihydro-1,4-benzodiazepine derivatives of Formula I can be prepared wherein A and ~ are substituted and Rl is defined as follows:
~ 1 62536 A B R Melting Point C
_ 1 Hvdrochloride 7-F 3,4,5-OCH CH3 123-126 base 7-CH3 3,4,5-OCH3 CH3 187-188 7-C1 2-Cl CH3 170-173 Ø25 H2O
7-Cl H CH3 147-151.5 H 2-F C2H5 Oil*
7-Br H CH3 Oil*
H 2-B~ CH3 Oil*
7-NO2 H CH3 Oil*
8-F H H Oil*
*IR-Spectra: 2120 cm (Azid/base) Perkin-Elmer IR-Spectrophotometer 157 G
Claims (13)
1. A process for the preparation of 2-azido-methyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine derivatives having the general formula (I):
(I) wherein R1 represents hydrogen or lower alkyl, and the phenylene group A and the phenyl group B independently from each other may be unsubstituted or be substituted by 1 to 3 substituents selected from the group consist-ing of halogen, lower alkylthio, lower alkoxy, lower alkyl, hydroxy, nitro and trifluoromethyl, or be substituted at two adjacent carbon atoms by methylene-dioxy or ethylenedioxy, and optical isomers and phar-maceutically acceptable acid addition salts thereof, which comprises:
a) reacting a compound of formula (II) or (III):
(II) (III) wherein R1, A and B are as defined above and X repre-sents halogen, or a mixture thereof, with an alkali metal azide to obtain a compound of the formula (I) in the form of a racemic mixture;
b) if desired, separating the racemic mixture thus obtained into optical isomers; and c) where a pharmaceutically acceptable acid addition salt is desired, further reacting the compound of formula (I) thus obtained with a pharmaceutically acceptable acid to provide the desired salt.
(I) wherein R1 represents hydrogen or lower alkyl, and the phenylene group A and the phenyl group B independently from each other may be unsubstituted or be substituted by 1 to 3 substituents selected from the group consist-ing of halogen, lower alkylthio, lower alkoxy, lower alkyl, hydroxy, nitro and trifluoromethyl, or be substituted at two adjacent carbon atoms by methylene-dioxy or ethylenedioxy, and optical isomers and phar-maceutically acceptable acid addition salts thereof, which comprises:
a) reacting a compound of formula (II) or (III):
(II) (III) wherein R1, A and B are as defined above and X repre-sents halogen, or a mixture thereof, with an alkali metal azide to obtain a compound of the formula (I) in the form of a racemic mixture;
b) if desired, separating the racemic mixture thus obtained into optical isomers; and c) where a pharmaceutically acceptable acid addition salt is desired, further reacting the compound of formula (I) thus obtained with a pharmaceutically acceptable acid to provide the desired salt.
2. A process according to claim 1, wherein the reaction in step (a) is carried out at a temperature of from about -30°C to about 150°C in an inert solvent.
3. A process according to claim 1, wherein use is made of a compound of the formula (II) in which R1, A, B and X have the aforesaid meanings, as starting material.
4. A process according to claim 3, wherein use is made of a compound of the formula (II) in which R1 is hydrogen, methyl or ethyl, A is unsubstituted phenylene or phenylene substituted by 7-fluoro, 8-fluoro, 7-chloro, 7-bromo, 7-methoxy, 8-methoxy, 7-methyl, 7-trifluoromethyl or 7-nitro, B is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl or 3,4,5-trimethoxyphenyl, and X has the aforesaid meaning.
5. A process according to claim 1, wherein use is made of a compound of the formula (III) in which R1, A, B and X have the aforesaid meanings, as starting material.
6. A process according to claim 5, wherein use is made of a compound of the formula (III) in which R1 is hydrogen, methyl or ethyl, A is unsubstituted phenylene or phenylene substituted by 7-fluoro, 8-fluoro, 7-chloro, 7-bromo, 7-methoxy, 8-methoxy, 7-methyl, 7-trifluoromethyl or 7-nitro, B is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl or 3,4,5-trimethoxyphenyl, and X has the aforesaid meaning.
7. A process according to claim 1, wherein use is made of a mixture of compounds of the formulae (II) and (III) in which R1, A, B and X have the afore-said meanings, as starting material.
8. A process according to claim 7, wherein use is made of a mixture of compounds of the formulae (II) and (III) in which R1 is hydrogen, methyl or ethyl, A is unsubstituted phenylene or phenylene substituted, by 7-fluoro, 8-fluoro, 7-chloro, 7-bromo, 7-methoxy, 8-methoxy, 7-methyl, 7-trifluoromethyl or 7-nitro, B is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromo-phenyl or 3,4,5-trimethoxyphenyl, and X has the afore-said meaning.
9. The 2-azidomethyl-5-phenyl-1H-2,3-di-hydro-1,4-benzodiazepine derivatives having the general formula (I):
(I) wherein R1 represents hydrogen or lower alkyl, and the phenylene group A and the phenyl group B independently from each other may be unsubstituted or be substituted by 1 to 3 substituents selected from the group consist-ing of halogen, lower alkylthio, lower alkoxy, lower alkyl, hydroxy, nitro and trifluoromethyl, or be substi-tuted at two adjacent carbon atoms by methylenedioxy or ethylenedioxy, their optical isomers as well as their pharmaceutically acceptable acid addition salts, when-ever prepared by a process according to claim 1 or its obvious chemical equivalents.
(I) wherein R1 represents hydrogen or lower alkyl, and the phenylene group A and the phenyl group B independently from each other may be unsubstituted or be substituted by 1 to 3 substituents selected from the group consist-ing of halogen, lower alkylthio, lower alkoxy, lower alkyl, hydroxy, nitro and trifluoromethyl, or be substi-tuted at two adjacent carbon atoms by methylenedioxy or ethylenedioxy, their optical isomers as well as their pharmaceutically acceptable acid addition salts, when-ever prepared by a process according to claim 1 or its obvious chemical equivalents.
10. The compounds as defined in claim 9, wherein R1, A and B have the aforesaid meanings, when-ever prepared by a process according to claims 3 or 5, or their obvious chemical equivalents.
11. The compounds as defined in claim 9, wherein Rl, A and B have the aforesaid meanings, when-ever prepared by a process according to claim 7 or its obvious chemical equivalents.
12. The compounds as defined in claim 9, wherein R1 is hydrogen, methyl or ethyl, A is un-substituted phenylene or phenylene substituted by 7-fluoro, 8-fluoro, 7-chloro, 7-bromo, 7-methoxy, 8-methoxy, 7-methyl, 7-trifluoromethyl or 7-nitro, and B is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl or 3,4,5-trimethoxyphenyl, whenever prepared by a process according to claims 4 or 6, or their obvious chemical equivalents.
13. The compounds as defined in claim 9, wherein R1 is hydrogen, methyl or ethyl, A is un-substituted phenylene or phenylene substituted by 7-fluoro, 8-fluoro, 7-chloro, 7-bromo, 7-methoxy, 8-methoxy, 7-methyl, 7-trifluoromethyl or 7-nitro, and B is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromo-phenyl or 3,4,5-trimethoxyphenyl, whenever prepared by a process according to claim 8 or its obvious chemical equivalents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000418562A CA1162536A (en) | 1979-12-24 | 1982-12-23 | 2-azidomethyl-1,4-benzodiazepine derivatives and their salts, and process for their preparation |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2952279.0 | 1979-12-24 | ||
| DE19792952279 DE2952279A1 (en) | 1979-12-24 | 1979-12-24 | NEW 2-ACYLAMINOMETHYL-1,4-BENZODIAZEPINE AND ITS SALTS AND METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| CA000367417A CA1169425A (en) | 1979-12-24 | 1980-12-23 | 2-acylaminomethyl-1,4-benzodiazepines and their salts as well as the preparation thereof, and use of pharmaceutical compositions containing these compounds |
| CA000418562A CA1162536A (en) | 1979-12-24 | 1982-12-23 | 2-azidomethyl-1,4-benzodiazepine derivatives and their salts, and process for their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1162536A true CA1162536A (en) | 1984-02-21 |
Family
ID=27166920
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000418562A Expired CA1162536A (en) | 1979-12-24 | 1982-12-23 | 2-azidomethyl-1,4-benzodiazepine derivatives and their salts, and process for their preparation |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1162536A (en) |
-
1982
- 1982-12-23 CA CA000418562A patent/CA1162536A/en not_active Expired
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