CA1063107A - Process for producing 2-substituted 1,4-benzodiazepine derivatives - Google Patents
Process for producing 2-substituted 1,4-benzodiazepine derivativesInfo
- Publication number
- CA1063107A CA1063107A CA252,134A CA252134A CA1063107A CA 1063107 A CA1063107 A CA 1063107A CA 252134 A CA252134 A CA 252134A CA 1063107 A CA1063107 A CA 1063107A
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- Prior art keywords
- methyl
- phenyl
- benzodiazepine
- bromo
- substituted
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
- C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D245/06—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
2-substituted 1-methyl-5-phenyl-1,4-benzodiazepines corresponding to the formula in which R1 represents a hydrogen or halogen atom, R2 repre-sents a hydrogen atom, a halogen atom or a trifluoromethyl group and R3 represents a hydrogen atom or a C1-6 alkyl group, having pharmacological properties, are prepared by direct alkoxylation or hydroxylation of the mixture of the corres-ponding 2-chloromethyl-1,4-benzodiazepine and 3-chloro-1,5-benzodiazocine as prepared in turn by cyclising a correspond-ing N1-phenyl-N1-methyl-N2-benzoyl-2-hydroxy-1,3-diaminopropane by reaction with an excess of phosphorus oxychloride generally at the boiling point of such phosphorus oxychloride.
Several of the 7-bromo-1,4-benzodiazepines so obtained are novel compounds exhibiting extremely valuable and surprising pharmacological properties.
2-substituted 1-methyl-5-phenyl-1,4-benzodiazepines corresponding to the formula in which R1 represents a hydrogen or halogen atom, R2 repre-sents a hydrogen atom, a halogen atom or a trifluoromethyl group and R3 represents a hydrogen atom or a C1-6 alkyl group, having pharmacological properties, are prepared by direct alkoxylation or hydroxylation of the mixture of the corres-ponding 2-chloromethyl-1,4-benzodiazepine and 3-chloro-1,5-benzodiazocine as prepared in turn by cyclising a correspond-ing N1-phenyl-N1-methyl-N2-benzoyl-2-hydroxy-1,3-diaminopropane by reaction with an excess of phosphorus oxychloride generally at the boiling point of such phosphorus oxychloride.
Several of the 7-bromo-1,4-benzodiazepines so obtained are novel compounds exhibiting extremely valuable and surprising pharmacological properties.
Description
~ i,310~ ~
BACKGROUND OF THE INVENTION
The present invention relates to a process for produc ing certain 2-substituted 1,4-benzodiazepines. The products wh~ch can be prepared by the process of this invention are those which correspond to the following formula I:
~H3 /CH2OR3 N - CH
10 ~ ~ CH~ ................. I
~1~ R2 J
~ . .
and acid addition compounds thereo, and wherein Rl represents a hydrogen atom or a halogen atom;
R2 represents a hydrogen atom, a halogen atom or a trofluoromethyl groupt and R3 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.
Particularly suitable halogen atoms for the group Rl are chlorine, bromine and iodine atoms and, for the group R2, are fluorine, bromine, iodine and chlorine atoms. The alkyl groups represented by R3 in the formula I are preferably methyl, ethyl, propyl, isopropyl, butyl and sec-butyl groups but R3 may also represent an amyl or hexyl group. Some of the products obtained by the process of the present invention are ~`~
novel 1,4-benzodiazepines.
Some compounds corresponding to the formula I and pro-cesses for producing such compounds were first described in the published specification of German Patent Application No ~, i ~ : ', , ' '' , ' '
BACKGROUND OF THE INVENTION
The present invention relates to a process for produc ing certain 2-substituted 1,4-benzodiazepines. The products wh~ch can be prepared by the process of this invention are those which correspond to the following formula I:
~H3 /CH2OR3 N - CH
10 ~ ~ CH~ ................. I
~1~ R2 J
~ . .
and acid addition compounds thereo, and wherein Rl represents a hydrogen atom or a halogen atom;
R2 represents a hydrogen atom, a halogen atom or a trofluoromethyl groupt and R3 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.
Particularly suitable halogen atoms for the group Rl are chlorine, bromine and iodine atoms and, for the group R2, are fluorine, bromine, iodine and chlorine atoms. The alkyl groups represented by R3 in the formula I are preferably methyl, ethyl, propyl, isopropyl, butyl and sec-butyl groups but R3 may also represent an amyl or hexyl group. Some of the products obtained by the process of the present invention are ~`~
novel 1,4-benzodiazepines.
Some compounds corresponding to the formula I and pro-cesses for producing such compounds were first described in the published specification of German Patent Application No ~, i ~ : ', , ' '' , ' '
2,221,558. The substances corresponding to the formula I have valuable pharmacoloqical properties. They present, for example, valuable anti-convulsive, sedative, muscle-relaxing and pro-nounced anxiety-relieving and anti-aggressive properties, justi-fying their therapeutical use as tranquilize!rs, hypnotics, and anti-epileptics. ~:
Compounds corresponding to the formula I can be prepared by converting a compound which corresponds to the following formula II: ~ :
fH3 CH2 ~ ~CH
R1 f N ...... ~......... II
~ / ~2 ~ `~ .
wherein Rl and R2 are as already defined and X represents a reactive group, and particularly a chlorine atom, ak an eleva-20 ted temperature by reaction with an alkali metal hydroxide or :
carbonate in a suitable solvent lnto the corresponding 2-hydroxy-methyl derivative or with an alkali metal in the presence of the corresponding alcohol into the corresponding 2-alkoxymethyl deri- ~
vative. .
It is also possible to prepare compounds corresponding to formula I by such kreatment with an alkali metal hydroxide or alkoxide of a substituted l-methyl-6-phenyl-1,5-benzodiazo- ::
cine corresponding to the following formula III: :
; ~
:
~63~ 7 i~
H3 ~
I
CH-X -C - N .......... ...... III
~2 /J
\~ :
10 wherein ~1~ R2 and X are as hereinbefore dafined. ~;
The 1,4-benzodiazepine and 1,5-benzodiazocine deriva~
tives of formulae II and III respectively can be prepared from acyldiamines corresponding to the following formula IV:
Rl ~ 1 2 1 , 2 ll ~ ........................................ IV
wherein Rl and R2 are as hereinbefore defined. ~
Such preparation of the compounds corresponding to `
formulae II and III from acyldiamines of formula IV can be effected using phosphorus oxychloride at certain reaction tem-peratures and, if necessary, by using suitable solvents. The natures of the substituent groups have a definite effect on the reaction conditions which must be maintained. Highly accu-rate and complex control of the reaction is generally necessary.
If it is desired to obtain-compounds of the general formula II from acyldiamines corresponding to the formula IV by reaction according to the known process with phosphorus oxy-chloride, the volume ratios of the reactants must be selected .,, to ensure that the temperature of the reaction mixture is that which is most effective for the formation of ~uch 1,4-benzodia-~'~' .
Compounds corresponding to the formula I can be prepared by converting a compound which corresponds to the following formula II: ~ :
fH3 CH2 ~ ~CH
R1 f N ...... ~......... II
~ / ~2 ~ `~ .
wherein Rl and R2 are as already defined and X represents a reactive group, and particularly a chlorine atom, ak an eleva-20 ted temperature by reaction with an alkali metal hydroxide or :
carbonate in a suitable solvent lnto the corresponding 2-hydroxy-methyl derivative or with an alkali metal in the presence of the corresponding alcohol into the corresponding 2-alkoxymethyl deri- ~
vative. .
It is also possible to prepare compounds corresponding to formula I by such kreatment with an alkali metal hydroxide or alkoxide of a substituted l-methyl-6-phenyl-1,5-benzodiazo- ::
cine corresponding to the following formula III: :
; ~
:
~63~ 7 i~
H3 ~
I
CH-X -C - N .......... ...... III
~2 /J
\~ :
10 wherein ~1~ R2 and X are as hereinbefore dafined. ~;
The 1,4-benzodiazepine and 1,5-benzodiazocine deriva~
tives of formulae II and III respectively can be prepared from acyldiamines corresponding to the following formula IV:
Rl ~ 1 2 1 , 2 ll ~ ........................................ IV
wherein Rl and R2 are as hereinbefore defined. ~
Such preparation of the compounds corresponding to `
formulae II and III from acyldiamines of formula IV can be effected using phosphorus oxychloride at certain reaction tem-peratures and, if necessary, by using suitable solvents. The natures of the substituent groups have a definite effect on the reaction conditions which must be maintained. Highly accu-rate and complex control of the reaction is generally necessary.
If it is desired to obtain-compounds of the general formula II from acyldiamines corresponding to the formula IV by reaction according to the known process with phosphorus oxy-chloride, the volume ratios of the reactants must be selected .,, to ensure that the temperature of the reaction mixture is that which is most effective for the formation of ~uch 1,4-benzodia-~'~' .
- 3 ~
" . i ', 1~31(~7 zepine derivativ~s. Compounds corresponding to the formula II and especially those in which R2 represents a hydrogen a~om, -may be produced with good yield in this way, preferably using a reaction temperature of between 115 and 125C. The disadvan~
tage of this known process is that the reaction times required ~;
are relatively long. If a series of substituted acyldiamines corresponding to the formula IV are used in such known process, the reaction conditions may result in an increased formation of resinified by-products, so that it then becomes dificult to process the reaction mixture obtained and the method becomes uneconom.ical.
If it is desired to produce substituted 1,5-benzodiazo-cines of the formula III, while it is possible to operate at temperatures of about 100C to obtain adequate yields, it i8 necessary to operate in solvents such as nitrobenzene and again ;
to use relatively long reaction times. Furthermore, the use of toxic nitrobenzene makes processing more difficult, especially on an industrial scale. In order to eliminate the formation of ;
undesired by-products, it has already been proposed to convert the hydroxy group of the acyldiamines of formula IV into an acyloxy group. However, the reaction temperatures and relative-ly long reaction times required may then reduce the yield.
In order to overcome these difficulties of the known ,~
process and to improve the yield of ~he 1,4-benzodiazepine compound of formula II, it has heretofore been proposed to carry out the conversion of the acyldiamines of formula IV into such 1,4-benzodiazepines in several stages. It has, for example, been suggested initially to convert ~uch acyldiamine using phosphorus pentachloride in dichlorethane into the correspond-ing imidoyl halide and then to close the ring using a Friedel-,':, "
~. .
~C~6310~
Crafts catalyst such as AlC13 in nitrobenzene since it has been found that closing the imidoyl halide ring can, in many cases, be carried out under milder reaction conditions. This las~-mentioned process produces bet~er yielcls, especially if R2 represents a fluorine atom. However, it presents the dis-advantage that operating in stages with difi-erent solvents and reagents is time-consuming and labour-intensive.
SUMMARY OF THE INVENTION
It has now been found that, by starting with acyldia-mines corresponding to the formula IV, it i5 possible to obtain2-substituted 1,4-benzodiazepines corresponding to the formula I, without the necessity of isolatîng the intermediate compounds corresponding to the formulae II or III in the purest possible form, and of then converting such 2-halomethyl~1,4-benzodiaze-pine and/or 3-halo-1,5-benzodiazocine der$vatives into ~he desired compounds. - ~;
It has surprisingly been found that, if acyldiamines corresponding to the formula IV are reacted with phosphorus oxychloride, complete cyclisation takes place within a short 20 time, generally within a few hours, forming a mixture of com- ;
pounds of formulae II and III, so long as the amount of excess phosphorus oxychloride in the reaction mixture is such that the boiling point of the phosphorus oxychloride is attained and maintained throughout the reaction.
It has also been found that this mixture of isomers can -then be converted directly into the desired compounds corres-ponding to the formula I, without being separated into individu-al components.
Thus, the process of the present invention for produc-ing 2-substituted 1-methyl-5-phenyl-1,4-benzodiazepine~ corres-.. , . ~
.
~3:~07 ponding to the formula I together with the acid addition com-pounds thereof can broadly be defined as comprising cyclising an acyldiamine corresponding to the formula IV by reaction with an excess of phosphorus oxychloride generally at the boil-ing point of such phosphorus oxychloride throughout such cycli-sation to provide a mixture of isomers corresponding to the formulae II and III; separating said mixture of isomers from ~.
remaining unreacted phosphorus oxychloride and other inorganic material; and converting said mixture of isomers at elevated `
temperature and in solution into a corresponding 2-substituted 1-methyl-5-phenyl-1,4-benzodiazepine corresponding to the for-mula I.
The amount of phosphorus oxychloride which must be used in order to raise the reaction mixture to the boiling point of the phosphorus oxychloride,is easily determined in practice as will be readily understood from the subsequent Examples herein. : :
The conversion of the mixture of isomers into the cor-responding 2-hydroxymethyl- or 2-alkoxymethyl-1,4-benzodiaze- ::
pines corresponding to the formula I takes place, if necessary 20 after rough cleaning, under the conditions described for the ~ .
production of those compounds from isolated compounds of the formulae II and III using appropriate nucleophilic reagents such as alkali metal alkoxides, alkali metal carbonates, alkali metal hydroxides and alkali metal acetates, the sodium or potassium compounds generally being preferrçd. .
If alkali metal alkoxides are used to prepare the cor- ~.
responding 2-alkoxymethyl derivatives, the solvents used should :
preferably be the corresponding alcohols, but it is also pos-sible to carry out such conversion in other suitable proton- ..
free solvents, such as dimethylsulfoxide, dimethylformamide and ~ :
i;
.~.. , .. . - . . .
~C~6310~ -hexamethylphosphoric triamide.
If alkali metal hydroxides ~r alkali metal carbonates are used -to prepare the corresponding 2-hydroxymethyl derivatives, such reagents are generally used in the form of aqueous solutions, if neces6ary, together with a wat~r-miscible solvent such as dioxane or tetrahydrofuran. If, however, an alkali metal acetate is used to form the hydroxymethyl derivative, the mixture of isomers is useflllly first treated with such a~ ace-tate in the presence of a solvent such as dimethylformamide and then with a dilute solution of an alkali metal hydroxide, use-fully in the presence of methanol. If desired, these conver-sion rea~ctions may be carried out in two-phase systems. Suit-able reac~tion temperatures are the relevant re~lux temper~tures.
The initial materials used for the preparation; of the substituted l,4-benzodiazepines may be acyldiamines of formula IV, in which the phenyl rings may already contain the substitu-ents desired in the final product. It is, however, also pos-sibIe to produce the substituent group Rl,if it represents chlorine~, bromine or iodine, subsequently, i.e. after the cyclisin~g reaction, or even after obtaining the 2-substituted 1,4-benzodiazepine corresponding to the formula I, wherein Rl is a hydrogen atom, by treatment with a suitable halogenating agent, N-bromosuccinimide and N-chlorosuccinimide being prefer- ~ ;
red. Iodine monochloride is particularly suitable for the in~
tr~duction of iodine. `
The process of this invention has the important advan-tages tha-t the 2-substituted 1,4-benzodiazepines may be produc-ed with little labour, i.e. without complex reaction controls ~
and cleaning operations, and with short reaction times. Fur- ~ -thermorè, the yields are usually higher than with known proces-' - 7 - ~
., ~, .
. ~.
.k.~ . ' : ' `" ' . -: . .
:. . . ~ . : . .
~ 3107 ~ ~
ses. The present method is also particularly suitable for producing compounds wherein the R2 group is a halogen atom or a trofluoromethyl group. This was hardly to be expected, since cyclisation to form the intermediate compounds of the formulae II and III required lengthy reaction times, and it was possible to obtain a number of R2-substituted compounds of the formula I
only with unsatisfactory yields. The good yields obtained and the wide scope in producing the desired compounds of this in-vention are also surprising since it is generally to be observ-ed in preparatory organic chemistry that, when mixtures, or raw materials which have been only roughly cleaned, are used, a ~ `
loss in yield has to be accepted as a result of the secondary reactions which develop.
In carrying out the process of this invention, thecompounds corresponding to;the formula I may be obtained as free bases, either directly from the reaction mixture or, in known fashion, by hydrolysis of the acid addition compounds, preferably hydrochlorides, using bases such as sodium hydroxide, `
sodium carbonate and ammonia solution. The desired acid addi-20 tion compounds may, of course, be produced from the free bases ; ~ -according to known chemical processes.
If the compounds obtained by the process o this in-vention are to be ùsed as intermediate products in the produc-tion of other compounds or for any non-pharmaceutical purpose, the toxicity or non-toxicity of the salts is immaterial. If, however, the compounds are ~o be used for pharmaceutical pur~
poses, they are preferably used in the form of their non-toxic acid addition compound 8.
Acids which may be used in producing the preferred non-30 toxic acid addition compounds of the 1,4-benzodiazepine deri- r - 8 - ~
' ~.
~;3 ~ 07 vatives are those which, ir. conjunction with the free bases, form salts of which the anions are harmless to human beings in ;~
therapeutical doses, so that no doubt can then be cast upon the useful physiological properties of the bases themselves.
For the purpose of obtaining such acid addition compounds, the bases can be reacted with the correct amount o an organic or inorganic acid in a water-miscible solvent ~uch as ethanol or isopropanol, the salt then being isolated by concentration and cooling. Alternatively, the bases can be reacted with an excess of acid in a solvent which does not mix with water, such as diethyl ether or diisopropyl ether, whereupon the desired salt is immediately precipitated. Organic acid addition salts o this lcind may be produced, for example, using the following acids: maleic, fumaric, benæoic, ascorbic, suacinic, methane-sulphonic, acetic, propionic, tartaric, citric, lactic, malic, cyclohexane-sulphamic, p-aminobenzoic, toluene sulphonic, glu-taminic and stearic acids. Inorganic salts may be produced `~
using, for example, hydrochloric, hydrobromic, sulphuric, sul-phamic, phosphoric and nitric acids.
The use of non-toxic salts of compounds of the formula I in pharmaceutical preparations has the advantage, as compared with the bases, that such salts are generally water soluble.
The 2-substituted 1,4-benzodiazepines corresponding to :~
the following formula V:
.
' " "
_ 9 _ .,.. , . . . . . ~
~631~7 :
~ N - C
Br ~ ~ C N / ................ V
~ / R5 10 and the acid addition compounds thereof, wherein R4 represents ~;~
an alkyl group having from 1 to 3 carbon atoms and R5 repre-sents a halogen atom or a trifluoromethyl group, are new com-pounds which differ surprisingly from previously well known substances having a ahlorine atom in the 7-position, in that they possess a noveL and favourable effective profile. Thus, `~
with comparably satisfactory toxicity, the new compounds are noted for a clear differentiation between the doses required for relieving anxiety and as a sedative - a fact which indicates that these new compounds are particularly valuable in treating 20 anxietyl tension, stress, neuroses, and pathologically aggres- ` ;
sive behaviour. This makes it possible to make use of their satisfactory therapeutical properties, without the disadvan- ~ ;
tage of strong sedation, which in turn often leads to an im- -~
pairment of the waking sta~e, especially in the case of day-time tranquilizers. Furthermore, when compared with the com-pounds specifically identified in the aforementioned patent application, thes~ new compounds have a definitely superior anti-convulsive action and a substantially more favourable dose differentiation between the anxiety-relieving, tension-reliev-ing and anti-aggressive dose and the dose affecting musc:Le -- 10 -- .
~3107 tonus. This property is of considerable significance for am-bulatory treatment of psychically disturbed persons.
The novel, unpredictable and, thereEore, surprising and favourable pharmacological properties oE the compounds according to the present invention will become more apparent ~ ~
as the description herein proceeds. In all of the animal ex- ;
periments reported herein, 7-chloro-1-methyl-2-methoxymethyl-5-(2-chlorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydro- ~;
chloride was used as a standard of comparison. Diazepam (7-chloro-l-methyl 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine) was used as another comparison substance and to represent an agent in current medical use.
DESCRIPTION OF P~ARMACOLOGICAL INVESTIGATIONS
1. Acute toxicity. ~i Acute 7-day toxicity values were determined, after single oral and intraperitoneal application, in white, fast-ing NMRI mice. LD50 values were calculated by electronic-data-processing by means of a probit analysis ~Cavelli-Sforza, Gustav Fischer Verlag, 1964, "Grundbegriffe der Biometrie").
2. Tests for anti-convulsive properties.
:, .
(a) The pentetrazol convulsion method.
The substances under investigation were checked, after peroral administration of groups of 6 mice each. 100 mg/kg of pentetrazol were injected subcutaneously 60 minutes after the application of the substances under investigation. The appear- ~
ance of clonic and tonic convulsions was monitored over a total ~ ;
observation period of 45 minutes. The protective action of the test substances against convulsions was determined in compari-son with control tests. The effective ED50 doses were calcula- ~
30 ted from the probit log. dosage curves~ (Modified according to ~-.
, ,~ . ., -.
J.E. BLUM et al.("~rzneimittel Forsch." 23, 377 (1973~).
Ib) Maximal shock therapy method.
The test substances were administered perorally to the animals. Sixty minutes laker, electrodes were fitted to the ears of the mice and an electric stimulus was released. A de-termination was made of the doses which prevented the occurrence of tonic convulsions in the rear extremities of half of the ani-mals. The ED50 values were again calculated by means of the ~
above-mentioned probit analysis. (Modified according to J. ~ -SWINYARD, J. Pharmacol. exptl, Therap. 106, 93 (1952)). ~-~
The results so obtained indicated the anti-convulsive ~ 'action of the test substances and, according to the relevant literature, they are an important criterion in assessing the clinical effectiveness of the products as tranquilizers. ~A.
SURIA and E. COSTA, Journa~ de Pharmacologie, suppl. No. 1, 5, 94 (1974~ and G. ZBINDEN and L.O. RANDALL, "Advances in Pharma-. . . .
col. 5, 213 (1967)). ;
3. Testing anxiety-relieving and anti-aggressive effectiveness.
Inhibition of aggressiveness in mice as brought on by iso-lation. ;~
For four weeks prior to the test, the mice were kept in strict isolation in separate cages. At the end of this time, the isolated mice attacked any non-isolated mice which were ;;introduced. The test substances were administered perorally to the isolated mice and, after 30 minutes, determinations were made of the doses leading to a 50% reduction in aggressive be-haviour. (Modified according to WEISCHER and OPITZ, Arch. int.
Pharmacodyn. 195, 252 (1972)).
The results obtained în these tests allowed satisfac-tory conclusions to be drawn regarding the anxiety- and stress-1~63~7 relieving properties of the substances.
" . i ', 1~31(~7 zepine derivativ~s. Compounds corresponding to the formula II and especially those in which R2 represents a hydrogen a~om, -may be produced with good yield in this way, preferably using a reaction temperature of between 115 and 125C. The disadvan~
tage of this known process is that the reaction times required ~;
are relatively long. If a series of substituted acyldiamines corresponding to the formula IV are used in such known process, the reaction conditions may result in an increased formation of resinified by-products, so that it then becomes dificult to process the reaction mixture obtained and the method becomes uneconom.ical.
If it is desired to produce substituted 1,5-benzodiazo-cines of the formula III, while it is possible to operate at temperatures of about 100C to obtain adequate yields, it i8 necessary to operate in solvents such as nitrobenzene and again ;
to use relatively long reaction times. Furthermore, the use of toxic nitrobenzene makes processing more difficult, especially on an industrial scale. In order to eliminate the formation of ;
undesired by-products, it has already been proposed to convert the hydroxy group of the acyldiamines of formula IV into an acyloxy group. However, the reaction temperatures and relative-ly long reaction times required may then reduce the yield.
In order to overcome these difficulties of the known ,~
process and to improve the yield of ~he 1,4-benzodiazepine compound of formula II, it has heretofore been proposed to carry out the conversion of the acyldiamines of formula IV into such 1,4-benzodiazepines in several stages. It has, for example, been suggested initially to convert ~uch acyldiamine using phosphorus pentachloride in dichlorethane into the correspond-ing imidoyl halide and then to close the ring using a Friedel-,':, "
~. .
~C~6310~
Crafts catalyst such as AlC13 in nitrobenzene since it has been found that closing the imidoyl halide ring can, in many cases, be carried out under milder reaction conditions. This las~-mentioned process produces bet~er yielcls, especially if R2 represents a fluorine atom. However, it presents the dis-advantage that operating in stages with difi-erent solvents and reagents is time-consuming and labour-intensive.
SUMMARY OF THE INVENTION
It has now been found that, by starting with acyldia-mines corresponding to the formula IV, it i5 possible to obtain2-substituted 1,4-benzodiazepines corresponding to the formula I, without the necessity of isolatîng the intermediate compounds corresponding to the formulae II or III in the purest possible form, and of then converting such 2-halomethyl~1,4-benzodiaze-pine and/or 3-halo-1,5-benzodiazocine der$vatives into ~he desired compounds. - ~;
It has surprisingly been found that, if acyldiamines corresponding to the formula IV are reacted with phosphorus oxychloride, complete cyclisation takes place within a short 20 time, generally within a few hours, forming a mixture of com- ;
pounds of formulae II and III, so long as the amount of excess phosphorus oxychloride in the reaction mixture is such that the boiling point of the phosphorus oxychloride is attained and maintained throughout the reaction.
It has also been found that this mixture of isomers can -then be converted directly into the desired compounds corres-ponding to the formula I, without being separated into individu-al components.
Thus, the process of the present invention for produc-ing 2-substituted 1-methyl-5-phenyl-1,4-benzodiazepine~ corres-.. , . ~
.
~3:~07 ponding to the formula I together with the acid addition com-pounds thereof can broadly be defined as comprising cyclising an acyldiamine corresponding to the formula IV by reaction with an excess of phosphorus oxychloride generally at the boil-ing point of such phosphorus oxychloride throughout such cycli-sation to provide a mixture of isomers corresponding to the formulae II and III; separating said mixture of isomers from ~.
remaining unreacted phosphorus oxychloride and other inorganic material; and converting said mixture of isomers at elevated `
temperature and in solution into a corresponding 2-substituted 1-methyl-5-phenyl-1,4-benzodiazepine corresponding to the for-mula I.
The amount of phosphorus oxychloride which must be used in order to raise the reaction mixture to the boiling point of the phosphorus oxychloride,is easily determined in practice as will be readily understood from the subsequent Examples herein. : :
The conversion of the mixture of isomers into the cor-responding 2-hydroxymethyl- or 2-alkoxymethyl-1,4-benzodiaze- ::
pines corresponding to the formula I takes place, if necessary 20 after rough cleaning, under the conditions described for the ~ .
production of those compounds from isolated compounds of the formulae II and III using appropriate nucleophilic reagents such as alkali metal alkoxides, alkali metal carbonates, alkali metal hydroxides and alkali metal acetates, the sodium or potassium compounds generally being preferrçd. .
If alkali metal alkoxides are used to prepare the cor- ~.
responding 2-alkoxymethyl derivatives, the solvents used should :
preferably be the corresponding alcohols, but it is also pos-sible to carry out such conversion in other suitable proton- ..
free solvents, such as dimethylsulfoxide, dimethylformamide and ~ :
i;
.~.. , .. . - . . .
~C~6310~ -hexamethylphosphoric triamide.
If alkali metal hydroxides ~r alkali metal carbonates are used -to prepare the corresponding 2-hydroxymethyl derivatives, such reagents are generally used in the form of aqueous solutions, if neces6ary, together with a wat~r-miscible solvent such as dioxane or tetrahydrofuran. If, however, an alkali metal acetate is used to form the hydroxymethyl derivative, the mixture of isomers is useflllly first treated with such a~ ace-tate in the presence of a solvent such as dimethylformamide and then with a dilute solution of an alkali metal hydroxide, use-fully in the presence of methanol. If desired, these conver-sion rea~ctions may be carried out in two-phase systems. Suit-able reac~tion temperatures are the relevant re~lux temper~tures.
The initial materials used for the preparation; of the substituted l,4-benzodiazepines may be acyldiamines of formula IV, in which the phenyl rings may already contain the substitu-ents desired in the final product. It is, however, also pos-sibIe to produce the substituent group Rl,if it represents chlorine~, bromine or iodine, subsequently, i.e. after the cyclisin~g reaction, or even after obtaining the 2-substituted 1,4-benzodiazepine corresponding to the formula I, wherein Rl is a hydrogen atom, by treatment with a suitable halogenating agent, N-bromosuccinimide and N-chlorosuccinimide being prefer- ~ ;
red. Iodine monochloride is particularly suitable for the in~
tr~duction of iodine. `
The process of this invention has the important advan-tages tha-t the 2-substituted 1,4-benzodiazepines may be produc-ed with little labour, i.e. without complex reaction controls ~
and cleaning operations, and with short reaction times. Fur- ~ -thermorè, the yields are usually higher than with known proces-' - 7 - ~
., ~, .
. ~.
.k.~ . ' : ' `" ' . -: . .
:. . . ~ . : . .
~ 3107 ~ ~
ses. The present method is also particularly suitable for producing compounds wherein the R2 group is a halogen atom or a trofluoromethyl group. This was hardly to be expected, since cyclisation to form the intermediate compounds of the formulae II and III required lengthy reaction times, and it was possible to obtain a number of R2-substituted compounds of the formula I
only with unsatisfactory yields. The good yields obtained and the wide scope in producing the desired compounds of this in-vention are also surprising since it is generally to be observ-ed in preparatory organic chemistry that, when mixtures, or raw materials which have been only roughly cleaned, are used, a ~ `
loss in yield has to be accepted as a result of the secondary reactions which develop.
In carrying out the process of this invention, thecompounds corresponding to;the formula I may be obtained as free bases, either directly from the reaction mixture or, in known fashion, by hydrolysis of the acid addition compounds, preferably hydrochlorides, using bases such as sodium hydroxide, `
sodium carbonate and ammonia solution. The desired acid addi-20 tion compounds may, of course, be produced from the free bases ; ~ -according to known chemical processes.
If the compounds obtained by the process o this in-vention are to be ùsed as intermediate products in the produc-tion of other compounds or for any non-pharmaceutical purpose, the toxicity or non-toxicity of the salts is immaterial. If, however, the compounds are ~o be used for pharmaceutical pur~
poses, they are preferably used in the form of their non-toxic acid addition compound 8.
Acids which may be used in producing the preferred non-30 toxic acid addition compounds of the 1,4-benzodiazepine deri- r - 8 - ~
' ~.
~;3 ~ 07 vatives are those which, ir. conjunction with the free bases, form salts of which the anions are harmless to human beings in ;~
therapeutical doses, so that no doubt can then be cast upon the useful physiological properties of the bases themselves.
For the purpose of obtaining such acid addition compounds, the bases can be reacted with the correct amount o an organic or inorganic acid in a water-miscible solvent ~uch as ethanol or isopropanol, the salt then being isolated by concentration and cooling. Alternatively, the bases can be reacted with an excess of acid in a solvent which does not mix with water, such as diethyl ether or diisopropyl ether, whereupon the desired salt is immediately precipitated. Organic acid addition salts o this lcind may be produced, for example, using the following acids: maleic, fumaric, benæoic, ascorbic, suacinic, methane-sulphonic, acetic, propionic, tartaric, citric, lactic, malic, cyclohexane-sulphamic, p-aminobenzoic, toluene sulphonic, glu-taminic and stearic acids. Inorganic salts may be produced `~
using, for example, hydrochloric, hydrobromic, sulphuric, sul-phamic, phosphoric and nitric acids.
The use of non-toxic salts of compounds of the formula I in pharmaceutical preparations has the advantage, as compared with the bases, that such salts are generally water soluble.
The 2-substituted 1,4-benzodiazepines corresponding to :~
the following formula V:
.
' " "
_ 9 _ .,.. , . . . . . ~
~631~7 :
~ N - C
Br ~ ~ C N / ................ V
~ / R5 10 and the acid addition compounds thereof, wherein R4 represents ~;~
an alkyl group having from 1 to 3 carbon atoms and R5 repre-sents a halogen atom or a trifluoromethyl group, are new com-pounds which differ surprisingly from previously well known substances having a ahlorine atom in the 7-position, in that they possess a noveL and favourable effective profile. Thus, `~
with comparably satisfactory toxicity, the new compounds are noted for a clear differentiation between the doses required for relieving anxiety and as a sedative - a fact which indicates that these new compounds are particularly valuable in treating 20 anxietyl tension, stress, neuroses, and pathologically aggres- ` ;
sive behaviour. This makes it possible to make use of their satisfactory therapeutical properties, without the disadvan- ~ ;
tage of strong sedation, which in turn often leads to an im- -~
pairment of the waking sta~e, especially in the case of day-time tranquilizers. Furthermore, when compared with the com-pounds specifically identified in the aforementioned patent application, thes~ new compounds have a definitely superior anti-convulsive action and a substantially more favourable dose differentiation between the anxiety-relieving, tension-reliev-ing and anti-aggressive dose and the dose affecting musc:Le -- 10 -- .
~3107 tonus. This property is of considerable significance for am-bulatory treatment of psychically disturbed persons.
The novel, unpredictable and, thereEore, surprising and favourable pharmacological properties oE the compounds according to the present invention will become more apparent ~ ~
as the description herein proceeds. In all of the animal ex- ;
periments reported herein, 7-chloro-1-methyl-2-methoxymethyl-5-(2-chlorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydro- ~;
chloride was used as a standard of comparison. Diazepam (7-chloro-l-methyl 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine) was used as another comparison substance and to represent an agent in current medical use.
DESCRIPTION OF P~ARMACOLOGICAL INVESTIGATIONS
1. Acute toxicity. ~i Acute 7-day toxicity values were determined, after single oral and intraperitoneal application, in white, fast-ing NMRI mice. LD50 values were calculated by electronic-data-processing by means of a probit analysis ~Cavelli-Sforza, Gustav Fischer Verlag, 1964, "Grundbegriffe der Biometrie").
2. Tests for anti-convulsive properties.
:, .
(a) The pentetrazol convulsion method.
The substances under investigation were checked, after peroral administration of groups of 6 mice each. 100 mg/kg of pentetrazol were injected subcutaneously 60 minutes after the application of the substances under investigation. The appear- ~
ance of clonic and tonic convulsions was monitored over a total ~ ;
observation period of 45 minutes. The protective action of the test substances against convulsions was determined in compari-son with control tests. The effective ED50 doses were calcula- ~
30 ted from the probit log. dosage curves~ (Modified according to ~-.
, ,~ . ., -.
J.E. BLUM et al.("~rzneimittel Forsch." 23, 377 (1973~).
Ib) Maximal shock therapy method.
The test substances were administered perorally to the animals. Sixty minutes laker, electrodes were fitted to the ears of the mice and an electric stimulus was released. A de-termination was made of the doses which prevented the occurrence of tonic convulsions in the rear extremities of half of the ani-mals. The ED50 values were again calculated by means of the ~
above-mentioned probit analysis. (Modified according to J. ~ -SWINYARD, J. Pharmacol. exptl, Therap. 106, 93 (1952)). ~-~
The results so obtained indicated the anti-convulsive ~ 'action of the test substances and, according to the relevant literature, they are an important criterion in assessing the clinical effectiveness of the products as tranquilizers. ~A.
SURIA and E. COSTA, Journa~ de Pharmacologie, suppl. No. 1, 5, 94 (1974~ and G. ZBINDEN and L.O. RANDALL, "Advances in Pharma-. . . .
col. 5, 213 (1967)). ;
3. Testing anxiety-relieving and anti-aggressive effectiveness.
Inhibition of aggressiveness in mice as brought on by iso-lation. ;~
For four weeks prior to the test, the mice were kept in strict isolation in separate cages. At the end of this time, the isolated mice attacked any non-isolated mice which were ;;introduced. The test substances were administered perorally to the isolated mice and, after 30 minutes, determinations were made of the doses leading to a 50% reduction in aggressive be-haviour. (Modified according to WEISCHER and OPITZ, Arch. int.
Pharmacodyn. 195, 252 (1972)).
The results obtained în these tests allowed satisfac-tory conclusions to be drawn regarding the anxiety- and stress-1~63~7 relieving properties of the substances.
4. TestincJ the musculotropic properties.
For the traction test, the test substances were ad-ministered perorally to the mice. After 120 minutes, the mice were suspended by their front paws from a taut horizontal wire.
The ED50 dose was that at which half the mice failed to touch the wire with their rear paws, again within 5 seconds ( W.
THEOBALD et al., Arzneim. Forsch. 17, 561 tl967)~- This checks the effects of the test substance on muscle tonus. -
For the traction test, the test substances were ad-ministered perorally to the mice. After 120 minutes, the mice were suspended by their front paws from a taut horizontal wire.
The ED50 dose was that at which half the mice failed to touch the wire with their rear paws, again within 5 seconds ( W.
THEOBALD et al., Arzneim. Forsch. 17, 561 tl967)~- This checks the effects of the test substance on muscle tonus. -
5. Testing the central-damping pro~rties.
(Hexobarbital sleeping-time extension).
The test substances were administered perorally to the mice. After 30 minutes, the animals were also given an i.v.
injection of 64 mg/kg of hexobarbital. The time at which the lateral position was assumed was determined and the duration of thc lateral position was compared with that of a control group treated with hexobarbital only. The ED50 dose is that at which half of the animals maintain a lateral position increased by a factor of 4 as compared with the control group. tG.M.
20 EVERETT, Nature 177, 1238 (1956)).
The following compounds were investigated by the fore-~O i nCJ methods:
Compound #1 : 7~bromo-1-methyl-2-methoxymethyl-5-(2'-chloro-phenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydro-chloride. ~-Compound #2 : 7-bromo-1-methyl-2-ethoxymethyl-5-(2'-chloro-phenyl)-lH-2,3-dihydro-1,4-benzodiazeplne hydro-chloride.
Compound ~3 ~ 7-bromo-1-methyl-2-methoxymethyl-5-(2'-fluoro-phenyl)-lH-2,3-dihydro-1,4-benzodiazep:ine hydro-~11 631~7 "
.
chloride.
Standard #1 : 7-chloro-1-methyl-2-methoxymel:hyl-5-(~'-chloro-phenyl~-lH-2,3-dihydro-1,4-benzodiazepine hydro-chloride.
Standard #2 : 7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one (Diazeparn).
Table 1 shows the values for toxicity and anti-convul-sive action of the above-mentioned compounds according to the invention as compared to the two standard compounds. -~
~ . :
_. _ __ .. _. . ~ : .. . .
Substance LD50 P ~ Pentetrazol Convulsion Shock Therapy ~:
(mg/kg) ED50 (mg/k~) ED50 (mg/kg) ~ ~;
_ _ _ _ ~ _ ,. .
Compound #11578 0.9 3.0 Compound #2~1470 2.224.5 ;~
Compound #31580 O.5 5.0 Standard #11779 2.026.0 Standard #2887 0.5 9O0 . .. _ . ~ . , _ . _ _ _ Table 2 shows the results relating to anxiolytic and 1 ~
anti-aggressive qualities. I ;
TABLE 2 ;
. . . ~ . I:
Substance Isolation Aggression - ~Ds o (''I/~Y
Compound #1 3.1 Compound #2 4.1 Compound #310.7 i~
Standard ~168.0 Standard #2 3.6 . _ . . __ _ :
Table 3 shows the results for muscle co-ordination ~Traction Test) and sedation (hexobarbital sleeping-t.ime ex-tension).
~31~7 _ ___.......... . _____~___ SubstanceTraction TastSleeping Time Extension ED50 (mg/kg)HexobarbiLtal ED50 ~mg/kg) , ~ .
Compound ~1 87.0 15.2 ~ ~
Compound #2 34.9 41.9 ~.
Compound #3 58.3 10.6 Standard #1163.0 11.7 Standard #2 _4.2 _ 1.5 : . .
Table 4 indicates the superiority of the new compound~
10 in the separation between sedating and anxiolytic doses, and .
the favourable relation between muscle relaxation and anxio~
lytic action, by orming the quotient ED50 hexobarbital sleep-ing-time extension/ED50 isolated combat mouse a Quotient 1, and ED50 Traction Test/ED50 isolated combat mouse - Quotient 2.
, _ , Substance Quotient 1 Quotient 2 !.;
. = __ _ ~- , .
Compound #1 4.9 28.1 . ~ .
Compound #2 10.2 8.5 . .
. Compound #3 0.9 5.4 20Standard #1 0.17 2.4 Standard ~2 0.42 1.2 This fact is.also indicated in Table 5 which is de-rived from Table 4 in that the Quotient Values for Standard #l are made equal to 1.
., , ' ;31()7 :
'`.`
~ ~ . - . .
Substance Quotient l Quotient 2 (Standard #l = l) (S1:andard ~l = l) ___~__ ___ __ Compound ~l 28.8 ll.7 `~-Compound #2 60.0 3.5 Compound ~3 5.3 2.3 Standard #l l.0 l.0 Standard #2 2.4 0.5 The pharmacological results indicated in Tables l to 5 -~
lO show very clearly the superiority of the new compounds accord- ~;
ing to the invention over the standard compounds. The new compounds show, especially, superior anti-convulsive properties and a distinct redution of the components producing sedation and muscle relaxation in favour of anxiety-relieving and anti-agressive properties. The,new compounds according to the in-vention thus distinguish themselves by their novel action pro-files and thus constitute anxiolytics which are distinctly superior to known compounds in this field.
Consequently, compounds of the formula I and their pharmaceutically useful acid addition compounds may be used as medications, for instance, in the form of pharmaceutical pre-parations containing such compounds of the formula I, or their acid addition compounds, in admixture with carriers suitable ~-for en~eral or parenteral administration and containing inor-ganic or organic, inert, pharmaceutical carrier materials, such as: water, gelatine, lactose, starch, magnesium stearate, ' ¦
talcum, vegetable oils, rubber, polyalkylene glycols, Vaseline and the like. The said pharmaceutical preparations may be in solid form (e~g. in the form of tablets, drag~es, suppositories, capsules) or in liquid form (e.g. in the form of solutions, 1~31~7 suspensions, or emulsions~. They may be sterilized and~or contain additives such as preserving, stabilizing, wetting and emulsifying agents, salts for altering the osmotic pressure and buffers. They may also contain other therapeutically valu- -able substances.
The invention will now be described in more detail and merely by way of illustration in the following Examples.
Example 1.
70 g of Nl-phenyl-Nl-methyl-N2-(2'-chlorobenzoyl)-2-hydroxy-1,3-diaminopropane were heated for 2.5 hours under re-flux in 350 ml of phosphorus oxychloride. The excess phos-phorus oxychloride was then distilled of in vacuo and the re- ~
sulting residue was then dissolved in 500 ml of chloroform and ~`
the resulting solution thoroughly stirred with 200 g of ice, 200 ml of water and 200 ml'of concentrated aqueous caustic soda solution. The organic phase was separated, washed until neutral waith water, dried over sodium sulphate, and the solvent distilled off. The resulting residue was then stirred for three hours with 250 ml of ether mixed with 100 g of y-alumina, and then filtered. After the ether had been distilled off, there was obtained 50 g of a raw product consisting of a mix-ture of l-methyl-2-chloromethyl-5-~2'-chlorophenyl)-2,3-dihydro-lH-1,4-benzodiazepine and l-methyl-3~chloro-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-l,S-benzodiazocine.
This raw product mixture was then dissolved in 750 ml of methanol in which 4 g of sodium had previously been dis,solv-ed and the resulting solution was heated under reflux for five -hours. The solvent was then distilled off and the resulting residue was dissolved in 250 ml of toluene and then washed until neutral with wa~er. The organic phase was next thoroughly stir-~ i3~
baS;C ..
red with 200 g of A12O3 of Activity Stage II-III/(Merck stan-dard) and then ~ ~c=~ filtered. The solvent was then dis-tilled off from the filtrate.
The resulting residue ~43 g), consisting of l-methyl-2-methoxymethyl-5-[2'-chlorophenyl)-2,3-dihydro-lH-1,4-benzo~
diazepine, was then dissolved in 800 ml of methylene chloride ~ -and heated for 24 hours under reflux with 24.5 g of N-bromo-succinimide. The solvent was then distilled off and the re-sulting residue was dissolved in a mixture of 125 ml of ether and 125 ml of toluene. The base was next extracted using an adequate amount of dilute (20%) hydrochloric acid. ~he base was then separated by the addition of concentrated a~ueous caustic soda solution and e.xtracted with 125 ml o~ ether. The hydrochloride was then precipitated by the addition of a solu-tion of hydrochloric acid gas in ether and recrystallized from 150 to 250 ml of ethanol. ~ ~
The yield amounted to 25.3 g of 7-bromo~l-methyl-2- ~ `
methoxymethyl~5-(2'-chlorophenyl)-2,3 dihydro-lH-1,4-benzo- ;
diazepine in the form of the hydrochloride.
jThe product had the following properties:
Melting point : 193-196C
Bromine content : calc. : 18.6%
actual: 18.8~
Chlorine content: calc. : 16.4%
-,~ . ~
actual: 16.1%
By proceeding in a similar manner but using sodium in ethanol instead of in methanol, it was possible to produce 7-bromo-l-methyl-2-ethoxymethyl-5-(2'-chlorophenyl)-2,3~dihydro-lH-1,4-benzodiazepine which was identical to the product ob-tained according to Example 2.
1~63i~7 ; :
Example 2.
70 g of Nl-phenyl-N1-methyl-N2-(2'-chlorobenzoyl)-2-hydroxy-1,3-diaminopropane were heated with 350 ml of phos-phorus oxychloride for 2.5 hours under reflux. The excess phosphorus oxychloride was then distilled o1Ef and the resulting residue was then dissolved in 400 ml of chloroform and the re- ;~
sulting solution shaken with 400 ml of ice-water and 200 ml of ~;
concentrated aqueous caustic soda solution. The chloroform phase was then washed until neutral with water, dried over sodium sulphate, and the solvent distilled off. The resulting residue (74.6 g) was ~hen dissolved in 1000 ml of methylene chloride and heated with 41.6 g of N-bromosuccinimide for 24 hours under reflux. The solvent was then distilled off and the resulting residue dissolved in a mixture of 250 ml of toluene and 250 ml of ether. The base was then extracted with dilute (20%) hydrochloric acid and transferred into the toluene phase by treatment with caustic soda and toluene. That toluene phase was then basically filtered (Merck standard) consecutively ~ ~-through 150 g of A1203 II-III (Merck standard) and 150 g of A1203 I.
Ater the toluene had been evaporated off, there were isolated 35.5 g of an oily mixture consisting of 7-bromo-1-methyl-2-chloromethyl-5-(2'-chlorophenyl)-2,3-dihydro-lH-1,4 benzodiazepine and 8-bromo-1-methyl-3-chloro-6-(2'-chloro-phenyl)-1,2,3,4-tetrahydro-1,5-henzodiazocine. This raw pro-duct was then dissolved in 750 ml of ethanol in which 6.5 g of sodium had previously been dissolved, and the resulting solu-tion was heated for 24 hours under reflux. The ethano:L was then distilled off and the resulting residue dissolved in 300 ml of chloroform and finally washed until neutral with water.
.
7 ~ ~
The organic phase was then separated and dried with sodium sulphate. The solven~ was distilled off and the residue (24 g) was filtered with a mixture of toluene/chlor.oform (9:1) through 500 g of aluminum oxide I (Merck standard). After the solvent had been distilled off, the residue wa~ dissolved in acetone and the resulting solution mixed with a solution of hydrochloric acid gas in ether until an acid reaction wa~ obtained. This caused the hydrochloride to precipitate in the form of a yellow crystalline product which was then collected and recrystallized ~ `
from ethanol (100-200 ml).
7-bromo-1-methyl-2-ethoxymethyl-5-(2'-chlorophenyl)~
2,3-dihydro-lH-i,4-benzodiazepine wa~ obt~ined in the form of the hydrochloride, with a yield of 15.6 g. The produat had the following properties:
Melting point , : 191-194C
Bromine content : calc. : 18.0%
actu~l: 18.3%
Chlorine content: calc. : 15.9% ; -~
actual: 15.6%
By proceeding in a similar way but using a solution of sodium in methanol instead of in ethanol, it was possible to obtain 7-bromo-1-methyl-2-methoxymethyl-5-(2l-chlorophenyl)-2,3-dihydro-lH-1,4-benzodiazepine from the intermediate pro-duct mixture.of 7-bromo-1-methyl-2-chloromethyl-5-(2'-chloro-phenyl)-2,3-dihydro-lH-1,4-benzodiazepine and 8-bromo-1-methyl-3-chloro-6-(2'-chlorophenyl)-1,2,3~4-tetrahydro-1,5-benzodiazo-cine.
Example 3.
70 g of Nl-~4-bromophenyl)-Nl-methyl N2-(2'-chloro-ben~oyl)-2-hydroxy-1,3-diaminopropane were heated in 250 ml of ~;3~07 ~ ~
phosphorus oxychloride for 2.5 hours under reflux. The excess phosphorus oxychloride was then distilled off and the resul~-ing residue was stirred with 50 ml of water and 500 ml of methyl isobutyl ketone until shining red crystals separated out. Those crystals were collected and then stirred with chloroform, ice, water and caustic soda as described in the preceding Examples. The residue obtained from the chloroform phase was then treated with 200 ml of ether in 100 g of y-alumina. After filtering and distilling off the solvent, an 1~ oily residue (30 g) was obtained, which consisted of a mixture of 7-bromo-1-methyl-2-chloromethyl-5-(2'-chlorophenyl)-2,3-dihydro-lH-1,4-benzodiazepine and 8-bromo-1-methyl-3-chloro-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine. From this mixture it was possible to obtain, with the procedure described in Example 2, by using a solution of sodium in metha-nol, 7-bromo-1-methyl-2-methoxymethyl-5-(2'-chlorophenyl)-2,3-dihydro-lH-1,4-ben~odiazepine and, by using a solution of sodium in ethanol, 7-bromo-1-methyl-2-ethoxymethyl-5-(2'-chloro-phenyl)-2,3-dihydro-lH-1,4-benzodiazepine.
Example 4 ~ :.
250 g of Nl-methyl-Nl-phenyl-N2-(2'-chlorobenzoyl)-2- ;
hydrox~-1,3-diaminopropane were heated in 500 ml of phosphorus oxychloride for four hours under reflux. The mixture was then poured into ice-water and extracted with chloroform. The com-bined organic phases were washed with caustic soda, dried over sodium sulphate and concentrated in vacuo. This produced 255 g of a raw product which was then dissolved in toluene and heated, ;
after admixture with a solution of 50 g of sodium in 1.4 litres of methanol, for 24 hours under reflux. The solution was then concentrated to about 800 ml, poured into ice-water, ar.d ex-: . :, ,-:,: , : . . .. . .
::
~310~
tracted with about 4 litres of methylene chloride. After dry~
ing over sodium sulphate, the solution was concentrated to ahout 3 litres and then heated with 150 g of N-bromosuccinimide for seven hours under ref~ux. The reaction solution was then washed with dilute caustic soda, dried over sodium sulphate and concentrated in vacuo. The residue was then taken up in tolu-ene and filtered through y-alumina. The toluene was distilled off, the residue taken up in 2.5 litres of acetone and the hydrochloride precipitated by ~he introduction of HCl gas. This produced 163.5 g of 7-bromo-1-methyl-2-methoxymethyl-5-(2'-chlorophenyl)-2,3-dihydro-lH-1,4-benzodiazepine hydrochloride having a melting point of 193-196C.
Example 5.
270 g of Nl-methyl-Nl-~4'-chlorophenyl)-N2-~2'-chloro-benzoyl~-2-hydroxy-1,3-diaminopropane were introduced, with stirring, into 550 ml of phosphorus oxychloride. This was followed by four hours of heating under reflux. The mixture was then allowed to cool to 80C, poured into ice-water, and then extracted with methylene chloride. The combined oryanic phases were then shaken with caustic soda, dried over sodium sulphate, and concentrated in vacuo. This produced 275 g of raw product which was then heated with 330 g of sodium acetate in 1.1 litres o dimethylformamide for two hours at 130C.
After filtering, the dimethylformamide was distilled off in -vacuo, and the resulting residue was dissolved in 1.2 litres of methanol and heated with 240 ml of 20% caustic soda for 30 minutes under reflux. This was followed by filtering, dis-tilling off the solvent in vacuo and pouring the resulting residue into S litres of water. The precipitated product was drawn off, washed with water, and stirred with acetone for two .. . .
1~63:1~7 hours. This produced 112 g of 7-chloro-1-methyl-2-hydroxy- `
methyl-5-(2'-chlorophenyl)-2,3-dihydro-lH-1,4-benzodiazepine whicht when recrystallized from 1 litre of ;sopropanol, had a melting point of 172-174C.
Example 6.
600 g of Nl-methyl-Nl-(4'-chlorophenyl)~N2-(2'-ChlOrO-benzoyl)-2-hydroxy-1,3-diaminopropane were introduced into 2.6 litres of phosphorus oxychloride and heated for 2.5 hours under reflux. The unreacted, excess phosphorus oxychloride was then distilled off and the resulting residue taken up in chloroform and the solution poured into ice-water. The chloro-form phase was then separated, dried over sodium sulphate and concentrated in vacuo. The resulting residue was taken up in methyl/isobutyl/ketone for recrystallization, and the resulting crystalline material was separated. This produced 320.7 g of ~;;
a mixture of 7-chloro-1-methyl-2-chloromethyl-5-(2'-chloro-phenyl)-2,3~dihydro-lH-1,4-benzodiazepine hydrochloride and 8-chloro--methyl-3-chloro-6-(2'-chlorophenyl)-1,2,3,4-tetra-hydro~l,5-benzodiazocine hydrochloride. A further 131 g of the hydrochloride mixture was isolated from the mother liquor.
125 g of this mixture were then heated in 1.2 litres of dioxane and 820 ml o water, after admixture with 880 ml of a 20% aqueous sodium carbonate solution, for one hour under reflux. The solvent was then distilled off in vacuo and the aqueous phase was extracted with chloroform. The chloroform solution was then dried over sodium sulphate and concentrated.
The resulting solid residue was then stirred with acetone to produce 68.5 g of 7-chloro-1-methyl-2-hydroxymethyl-5-(2'-chlorophenyl~-2,3-dihydro-lH-1,4-benzodiazepine having a melting point of 172-174C.
1~63~
Example 7.
. ~ ., 151 g of Nl-phenyl-Nl-methyl-N2-(2'-~fluoroben20yl)-2-hydroxy-1,3-diaminopropane were heated in 4.30 ml of phosphorus oxychloride for three hours under reflux. ~rhe excess phos-phorus oxychloride was then distilled off in vacuo and the re sulting residue was dissolved in 1000 ml of chloroform and the resulting solution thoroughly stirred with 200 g of ice, 200 ml of water and 200 ml of concentrated aqueous caustic soda solu-tion. The organic phase was then separated, washed until neu-10 tral with water, dried over sodium sulphate and then concentra- , ted. The resulting residue was then stirred for three hours with 500 ml of ether, mixed with 100 g of r-alumina and filter-ecl. ~fter the ether had been evaporated o~f, there remained 110 g o~ a raw product consisting of a mixture of l-methyl~2-chloromethyl-5-(2'-fluorophenyl)-lH-2,3-dihydro-1,4-benzodiaze-pine and l-methyl-3-chloro-6-(2'-fluorophenyl)-1,2,3,4,-tetra-hydro-1,5-benzodiazocine. This raw product was then dissolved in 1.5 litres of methanol in which 8.9 g of sodium had pre- ~-viously been dissolved and the resulting solution was heated 20 for five hours under reflux. The solvent was then distilled -off and the residue dissolved in 500 ml of toluene and washed until neutral with water. The organic phase was basically filtered (Merck standard), thoroughly stirred with 200 g of A1203 Activity Stage II-III. The solvent was then distilled off.
The residue (93 g), which consisted of 1-methyl-2-methoxymethyl-5-(2'-fluorophenyl~-lH-2,3-dihydro-1,4-ben20-diazepine, was then dissolved in 1200 ml of methylene chloride, and the resulting solution boiled with 53 g of N-bromosuccini-mide for 24 hours under reflux. The solvent was then distilled . .
~, . . . . ..
~63~7 - ~
off and the resulting residue dissolved in a mixture of 250 ml of ether and 250 ml of toluene. The base was then extracted using an adequate amount of dilute (20%) hydrochloric acid.
The base was then separated by adding concentrated aqueous ~ `~
caustic soda solution and extracted with ether (250 ml~. The hydrochloride was then precipitated by addi;ng a solution of hydrochloric acid gas in ether and recrystallized from 200 to 300 ml of ethanol.
The yield amounted to 60.2 g of 7-bromo-1-methyl-2-methoxymethyl-5-(2'-fluorophenyl)-lH-2,3-dihydro-1,4-benzo-diazepine in the form of the hydrochloride. It had the follow-ing properties:
,~
Melting point : 183-185C
Element analysis~
Calculated: C = 52.3%; H 8J 4.6%; N - 6.8%; Br - 19.3%; Cl = 8.6 Actual : C = 52.3%; H = 4.7%; N = 6.4%; Br = 19.~; Cl = 8.3%
Example 8.
~ g of N1-phenyl-Nl-methyl-N2-~2'-chlorobenzoyl)-2-hydroxy-1,3-diaminopropane were heated with 350 ml of phos-phorus oxychloride for 2.5 hours under reflux. The excessphosphorus oxychloride was then distilled of and the resiaue was dissolved in 400 ml of chloroform and shaken out with ice-water ~400 ml) and 200 ml of concentrated aqueous caustic soda solution. The chloroform phase was then washed until neutral with water, dried with sodium sulphate and concentrated. The residue (74.6 g) was then dissolved in 1000 ml of methylene chloride and boiled with 41.6 g of N-bromosuccinimide for 24 hours under reflux. The solvent was then distilled off and the resulting residue was dissolved in a mixture of 250 ml of toluene and 250 ml of ether~ The base was then extracted with `' 1~3107 ~ ~
dilute (20%) hydrochloric acid and isolated by treatment with concentrated aaueous caustic soda solution and toluene. The toluene phase was basically (Merck standard) filtered through 150 g of ~12O3 II-III (Merck standard) and 150 g of A12~3 I
tMerck standard). After the toluene had evaporated, 35.5 g of an oily mixture a 7-bromo-1-methyl-2-chloromethyl-5-(2'-chlorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine and 8-bromo-l-methyl-3-chloro-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine were isolated. That mixture was then heated with 750 ml of isopropanol, in which 6.5 g of sodium had pre-viously been dissolved, for 24 hours under reflux. The isopro-panol was then distilled off and the resulting residue was dissolved in 300 ml of chloroform and then washed until neutral with water. The organic phase was then separated and dried with sodium sulphate, and the solvent distilled off. The resi-due (24 g) was filtexed with a mixture of toluene/chloroform (9:1) through 500 g of aluminum oxide I (Merck standard).
After the solvent had been distilled off, the residue was dissolved in acetone and mixed with a solution of hydrochloric acid gas in ether until an acid reaction was obtained. This caused the hydrochloride to precipitate in the form of yellow crystals which were collected and recrystallized from ethanol (100-200 ml). The product had the foLlowing properties:
Melting point : 189-191C
Element analysis:
Calculated: C = 52.4~; H - 5.1%; N = 6.1%; Br = 17.4%; Cl = 15.5~
Actual : C = 52.6%; H = 5.0%; N = 6.0~; Br = 17.2~; Cl = 15.2%
_xamples 9 to 16.
By following the procedures described in Examples 1 to 8, other compounds corresponding to the following formu:La V
- - ": - . . . ~ . . .
33L~7 were prepared: CH3 CH2R4 [~CH2 Br I ~ N / .................. V
~ / R5 1~ J ~-~
~ .
The identities of the ~ubstituent groups are indicated ;
in Table 6 together with the melting points and elemental analyses of the products.
__ ~ ~ _. ~
# R3 R2 Melting Point Elemental Analys-s C Calculated % Actual . . -- ., __ ~
g C3H7 Cl 152-154 Cl = 15.515.5 (hydrochloride) Br = 17.417.1 ~ _____~__ ____ CH3 CF3 128-130 Cl = 7.57.5 (hydrochloride) Br - 16.~17.2 x 1/2 H2O
_ .__ ~ ~
11 C2H5 CF3 102-104 Br - 18.118.3 _ . __._ . ... . ... --___ 12 CH3 Br 185-187 Cl = 7.5 7.5 :
(hydrochloride) Br = 33.7 33.4 __ . __ __ ~ , ~.. .
13 C2H5 Br 154-156 Cl = 7.3 7.2 : ;~
(hydrochloride) Br = 32.7 32.8 ~: -__ _ __ _ : 14 C3H7 Br 143 146 . C1 = 7.1 7.3 ~:
(hydrochloride) Br = 31.8 31.5 .
__ _. _ _ ~ _,.____ __ ~
15 CH3 I 223-225Cl = 6.8 6.7 (hydrochloride) Br = 15.3 15.7 . _ ____ _ _ ,____._. _ 16 C~H5 I 204-207 C1 = 6.6 6.6 ~___ ~ _ ~ de~ Br = 14.9 15.1 :~
~ :
~: :
~ .
.,. . . . : , . :
(Hexobarbital sleeping-time extension).
The test substances were administered perorally to the mice. After 30 minutes, the animals were also given an i.v.
injection of 64 mg/kg of hexobarbital. The time at which the lateral position was assumed was determined and the duration of thc lateral position was compared with that of a control group treated with hexobarbital only. The ED50 dose is that at which half of the animals maintain a lateral position increased by a factor of 4 as compared with the control group. tG.M.
20 EVERETT, Nature 177, 1238 (1956)).
The following compounds were investigated by the fore-~O i nCJ methods:
Compound #1 : 7~bromo-1-methyl-2-methoxymethyl-5-(2'-chloro-phenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydro-chloride. ~-Compound #2 : 7-bromo-1-methyl-2-ethoxymethyl-5-(2'-chloro-phenyl)-lH-2,3-dihydro-1,4-benzodiazeplne hydro-chloride.
Compound ~3 ~ 7-bromo-1-methyl-2-methoxymethyl-5-(2'-fluoro-phenyl)-lH-2,3-dihydro-1,4-benzodiazep:ine hydro-~11 631~7 "
.
chloride.
Standard #1 : 7-chloro-1-methyl-2-methoxymel:hyl-5-(~'-chloro-phenyl~-lH-2,3-dihydro-1,4-benzodiazepine hydro-chloride.
Standard #2 : 7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one (Diazeparn).
Table 1 shows the values for toxicity and anti-convul-sive action of the above-mentioned compounds according to the invention as compared to the two standard compounds. -~
~ . :
_. _ __ .. _. . ~ : .. . .
Substance LD50 P ~ Pentetrazol Convulsion Shock Therapy ~:
(mg/kg) ED50 (mg/k~) ED50 (mg/kg) ~ ~;
_ _ _ _ ~ _ ,. .
Compound #11578 0.9 3.0 Compound #2~1470 2.224.5 ;~
Compound #31580 O.5 5.0 Standard #11779 2.026.0 Standard #2887 0.5 9O0 . .. _ . ~ . , _ . _ _ _ Table 2 shows the results relating to anxiolytic and 1 ~
anti-aggressive qualities. I ;
TABLE 2 ;
. . . ~ . I:
Substance Isolation Aggression - ~Ds o (''I/~Y
Compound #1 3.1 Compound #2 4.1 Compound #310.7 i~
Standard ~168.0 Standard #2 3.6 . _ . . __ _ :
Table 3 shows the results for muscle co-ordination ~Traction Test) and sedation (hexobarbital sleeping-t.ime ex-tension).
~31~7 _ ___.......... . _____~___ SubstanceTraction TastSleeping Time Extension ED50 (mg/kg)HexobarbiLtal ED50 ~mg/kg) , ~ .
Compound ~1 87.0 15.2 ~ ~
Compound #2 34.9 41.9 ~.
Compound #3 58.3 10.6 Standard #1163.0 11.7 Standard #2 _4.2 _ 1.5 : . .
Table 4 indicates the superiority of the new compound~
10 in the separation between sedating and anxiolytic doses, and .
the favourable relation between muscle relaxation and anxio~
lytic action, by orming the quotient ED50 hexobarbital sleep-ing-time extension/ED50 isolated combat mouse a Quotient 1, and ED50 Traction Test/ED50 isolated combat mouse - Quotient 2.
, _ , Substance Quotient 1 Quotient 2 !.;
. = __ _ ~- , .
Compound #1 4.9 28.1 . ~ .
Compound #2 10.2 8.5 . .
. Compound #3 0.9 5.4 20Standard #1 0.17 2.4 Standard ~2 0.42 1.2 This fact is.also indicated in Table 5 which is de-rived from Table 4 in that the Quotient Values for Standard #l are made equal to 1.
., , ' ;31()7 :
'`.`
~ ~ . - . .
Substance Quotient l Quotient 2 (Standard #l = l) (S1:andard ~l = l) ___~__ ___ __ Compound ~l 28.8 ll.7 `~-Compound #2 60.0 3.5 Compound ~3 5.3 2.3 Standard #l l.0 l.0 Standard #2 2.4 0.5 The pharmacological results indicated in Tables l to 5 -~
lO show very clearly the superiority of the new compounds accord- ~;
ing to the invention over the standard compounds. The new compounds show, especially, superior anti-convulsive properties and a distinct redution of the components producing sedation and muscle relaxation in favour of anxiety-relieving and anti-agressive properties. The,new compounds according to the in-vention thus distinguish themselves by their novel action pro-files and thus constitute anxiolytics which are distinctly superior to known compounds in this field.
Consequently, compounds of the formula I and their pharmaceutically useful acid addition compounds may be used as medications, for instance, in the form of pharmaceutical pre-parations containing such compounds of the formula I, or their acid addition compounds, in admixture with carriers suitable ~-for en~eral or parenteral administration and containing inor-ganic or organic, inert, pharmaceutical carrier materials, such as: water, gelatine, lactose, starch, magnesium stearate, ' ¦
talcum, vegetable oils, rubber, polyalkylene glycols, Vaseline and the like. The said pharmaceutical preparations may be in solid form (e~g. in the form of tablets, drag~es, suppositories, capsules) or in liquid form (e.g. in the form of solutions, 1~31~7 suspensions, or emulsions~. They may be sterilized and~or contain additives such as preserving, stabilizing, wetting and emulsifying agents, salts for altering the osmotic pressure and buffers. They may also contain other therapeutically valu- -able substances.
The invention will now be described in more detail and merely by way of illustration in the following Examples.
Example 1.
70 g of Nl-phenyl-Nl-methyl-N2-(2'-chlorobenzoyl)-2-hydroxy-1,3-diaminopropane were heated for 2.5 hours under re-flux in 350 ml of phosphorus oxychloride. The excess phos-phorus oxychloride was then distilled of in vacuo and the re- ~
sulting residue was then dissolved in 500 ml of chloroform and ~`
the resulting solution thoroughly stirred with 200 g of ice, 200 ml of water and 200 ml'of concentrated aqueous caustic soda solution. The organic phase was separated, washed until neutral waith water, dried over sodium sulphate, and the solvent distilled off. The resulting residue was then stirred for three hours with 250 ml of ether mixed with 100 g of y-alumina, and then filtered. After the ether had been distilled off, there was obtained 50 g of a raw product consisting of a mix-ture of l-methyl-2-chloromethyl-5-~2'-chlorophenyl)-2,3-dihydro-lH-1,4-benzodiazepine and l-methyl-3~chloro-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-l,S-benzodiazocine.
This raw product mixture was then dissolved in 750 ml of methanol in which 4 g of sodium had previously been dis,solv-ed and the resulting solution was heated under reflux for five -hours. The solvent was then distilled off and the resulting residue was dissolved in 250 ml of toluene and then washed until neutral with wa~er. The organic phase was next thoroughly stir-~ i3~
baS;C ..
red with 200 g of A12O3 of Activity Stage II-III/(Merck stan-dard) and then ~ ~c=~ filtered. The solvent was then dis-tilled off from the filtrate.
The resulting residue ~43 g), consisting of l-methyl-2-methoxymethyl-5-[2'-chlorophenyl)-2,3-dihydro-lH-1,4-benzo~
diazepine, was then dissolved in 800 ml of methylene chloride ~ -and heated for 24 hours under reflux with 24.5 g of N-bromo-succinimide. The solvent was then distilled off and the re-sulting residue was dissolved in a mixture of 125 ml of ether and 125 ml of toluene. The base was next extracted using an adequate amount of dilute (20%) hydrochloric acid. ~he base was then separated by the addition of concentrated a~ueous caustic soda solution and e.xtracted with 125 ml o~ ether. The hydrochloride was then precipitated by the addition of a solu-tion of hydrochloric acid gas in ether and recrystallized from 150 to 250 ml of ethanol. ~ ~
The yield amounted to 25.3 g of 7-bromo~l-methyl-2- ~ `
methoxymethyl~5-(2'-chlorophenyl)-2,3 dihydro-lH-1,4-benzo- ;
diazepine in the form of the hydrochloride.
jThe product had the following properties:
Melting point : 193-196C
Bromine content : calc. : 18.6%
actual: 18.8~
Chlorine content: calc. : 16.4%
-,~ . ~
actual: 16.1%
By proceeding in a similar manner but using sodium in ethanol instead of in methanol, it was possible to produce 7-bromo-l-methyl-2-ethoxymethyl-5-(2'-chlorophenyl)-2,3~dihydro-lH-1,4-benzodiazepine which was identical to the product ob-tained according to Example 2.
1~63i~7 ; :
Example 2.
70 g of Nl-phenyl-N1-methyl-N2-(2'-chlorobenzoyl)-2-hydroxy-1,3-diaminopropane were heated with 350 ml of phos-phorus oxychloride for 2.5 hours under reflux. The excess phosphorus oxychloride was then distilled o1Ef and the resulting residue was then dissolved in 400 ml of chloroform and the re- ;~
sulting solution shaken with 400 ml of ice-water and 200 ml of ~;
concentrated aqueous caustic soda solution. The chloroform phase was then washed until neutral with water, dried over sodium sulphate, and the solvent distilled off. The resulting residue (74.6 g) was ~hen dissolved in 1000 ml of methylene chloride and heated with 41.6 g of N-bromosuccinimide for 24 hours under reflux. The solvent was then distilled off and the resulting residue dissolved in a mixture of 250 ml of toluene and 250 ml of ether. The base was then extracted with dilute (20%) hydrochloric acid and transferred into the toluene phase by treatment with caustic soda and toluene. That toluene phase was then basically filtered (Merck standard) consecutively ~ ~-through 150 g of A1203 II-III (Merck standard) and 150 g of A1203 I.
Ater the toluene had been evaporated off, there were isolated 35.5 g of an oily mixture consisting of 7-bromo-1-methyl-2-chloromethyl-5-(2'-chlorophenyl)-2,3-dihydro-lH-1,4 benzodiazepine and 8-bromo-1-methyl-3-chloro-6-(2'-chloro-phenyl)-1,2,3,4-tetrahydro-1,5-henzodiazocine. This raw pro-duct was then dissolved in 750 ml of ethanol in which 6.5 g of sodium had previously been dissolved, and the resulting solu-tion was heated for 24 hours under reflux. The ethano:L was then distilled off and the resulting residue dissolved in 300 ml of chloroform and finally washed until neutral with water.
.
7 ~ ~
The organic phase was then separated and dried with sodium sulphate. The solven~ was distilled off and the residue (24 g) was filtered with a mixture of toluene/chlor.oform (9:1) through 500 g of aluminum oxide I (Merck standard). After the solvent had been distilled off, the residue wa~ dissolved in acetone and the resulting solution mixed with a solution of hydrochloric acid gas in ether until an acid reaction wa~ obtained. This caused the hydrochloride to precipitate in the form of a yellow crystalline product which was then collected and recrystallized ~ `
from ethanol (100-200 ml).
7-bromo-1-methyl-2-ethoxymethyl-5-(2'-chlorophenyl)~
2,3-dihydro-lH-i,4-benzodiazepine wa~ obt~ined in the form of the hydrochloride, with a yield of 15.6 g. The produat had the following properties:
Melting point , : 191-194C
Bromine content : calc. : 18.0%
actu~l: 18.3%
Chlorine content: calc. : 15.9% ; -~
actual: 15.6%
By proceeding in a similar way but using a solution of sodium in methanol instead of in ethanol, it was possible to obtain 7-bromo-1-methyl-2-methoxymethyl-5-(2l-chlorophenyl)-2,3-dihydro-lH-1,4-benzodiazepine from the intermediate pro-duct mixture.of 7-bromo-1-methyl-2-chloromethyl-5-(2'-chloro-phenyl)-2,3-dihydro-lH-1,4-benzodiazepine and 8-bromo-1-methyl-3-chloro-6-(2'-chlorophenyl)-1,2,3~4-tetrahydro-1,5-benzodiazo-cine.
Example 3.
70 g of Nl-~4-bromophenyl)-Nl-methyl N2-(2'-chloro-ben~oyl)-2-hydroxy-1,3-diaminopropane were heated in 250 ml of ~;3~07 ~ ~
phosphorus oxychloride for 2.5 hours under reflux. The excess phosphorus oxychloride was then distilled off and the resul~-ing residue was stirred with 50 ml of water and 500 ml of methyl isobutyl ketone until shining red crystals separated out. Those crystals were collected and then stirred with chloroform, ice, water and caustic soda as described in the preceding Examples. The residue obtained from the chloroform phase was then treated with 200 ml of ether in 100 g of y-alumina. After filtering and distilling off the solvent, an 1~ oily residue (30 g) was obtained, which consisted of a mixture of 7-bromo-1-methyl-2-chloromethyl-5-(2'-chlorophenyl)-2,3-dihydro-lH-1,4-benzodiazepine and 8-bromo-1-methyl-3-chloro-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine. From this mixture it was possible to obtain, with the procedure described in Example 2, by using a solution of sodium in metha-nol, 7-bromo-1-methyl-2-methoxymethyl-5-(2'-chlorophenyl)-2,3-dihydro-lH-1,4-ben~odiazepine and, by using a solution of sodium in ethanol, 7-bromo-1-methyl-2-ethoxymethyl-5-(2'-chloro-phenyl)-2,3-dihydro-lH-1,4-benzodiazepine.
Example 4 ~ :.
250 g of Nl-methyl-Nl-phenyl-N2-(2'-chlorobenzoyl)-2- ;
hydrox~-1,3-diaminopropane were heated in 500 ml of phosphorus oxychloride for four hours under reflux. The mixture was then poured into ice-water and extracted with chloroform. The com-bined organic phases were washed with caustic soda, dried over sodium sulphate and concentrated in vacuo. This produced 255 g of a raw product which was then dissolved in toluene and heated, ;
after admixture with a solution of 50 g of sodium in 1.4 litres of methanol, for 24 hours under reflux. The solution was then concentrated to about 800 ml, poured into ice-water, ar.d ex-: . :, ,-:,: , : . . .. . .
::
~310~
tracted with about 4 litres of methylene chloride. After dry~
ing over sodium sulphate, the solution was concentrated to ahout 3 litres and then heated with 150 g of N-bromosuccinimide for seven hours under ref~ux. The reaction solution was then washed with dilute caustic soda, dried over sodium sulphate and concentrated in vacuo. The residue was then taken up in tolu-ene and filtered through y-alumina. The toluene was distilled off, the residue taken up in 2.5 litres of acetone and the hydrochloride precipitated by ~he introduction of HCl gas. This produced 163.5 g of 7-bromo-1-methyl-2-methoxymethyl-5-(2'-chlorophenyl)-2,3-dihydro-lH-1,4-benzodiazepine hydrochloride having a melting point of 193-196C.
Example 5.
270 g of Nl-methyl-Nl-~4'-chlorophenyl)-N2-~2'-chloro-benzoyl~-2-hydroxy-1,3-diaminopropane were introduced, with stirring, into 550 ml of phosphorus oxychloride. This was followed by four hours of heating under reflux. The mixture was then allowed to cool to 80C, poured into ice-water, and then extracted with methylene chloride. The combined oryanic phases were then shaken with caustic soda, dried over sodium sulphate, and concentrated in vacuo. This produced 275 g of raw product which was then heated with 330 g of sodium acetate in 1.1 litres o dimethylformamide for two hours at 130C.
After filtering, the dimethylformamide was distilled off in -vacuo, and the resulting residue was dissolved in 1.2 litres of methanol and heated with 240 ml of 20% caustic soda for 30 minutes under reflux. This was followed by filtering, dis-tilling off the solvent in vacuo and pouring the resulting residue into S litres of water. The precipitated product was drawn off, washed with water, and stirred with acetone for two .. . .
1~63:1~7 hours. This produced 112 g of 7-chloro-1-methyl-2-hydroxy- `
methyl-5-(2'-chlorophenyl)-2,3-dihydro-lH-1,4-benzodiazepine whicht when recrystallized from 1 litre of ;sopropanol, had a melting point of 172-174C.
Example 6.
600 g of Nl-methyl-Nl-(4'-chlorophenyl)~N2-(2'-ChlOrO-benzoyl)-2-hydroxy-1,3-diaminopropane were introduced into 2.6 litres of phosphorus oxychloride and heated for 2.5 hours under reflux. The unreacted, excess phosphorus oxychloride was then distilled off and the resulting residue taken up in chloroform and the solution poured into ice-water. The chloro-form phase was then separated, dried over sodium sulphate and concentrated in vacuo. The resulting residue was taken up in methyl/isobutyl/ketone for recrystallization, and the resulting crystalline material was separated. This produced 320.7 g of ~;;
a mixture of 7-chloro-1-methyl-2-chloromethyl-5-(2'-chloro-phenyl)-2,3~dihydro-lH-1,4-benzodiazepine hydrochloride and 8-chloro--methyl-3-chloro-6-(2'-chlorophenyl)-1,2,3,4-tetra-hydro~l,5-benzodiazocine hydrochloride. A further 131 g of the hydrochloride mixture was isolated from the mother liquor.
125 g of this mixture were then heated in 1.2 litres of dioxane and 820 ml o water, after admixture with 880 ml of a 20% aqueous sodium carbonate solution, for one hour under reflux. The solvent was then distilled off in vacuo and the aqueous phase was extracted with chloroform. The chloroform solution was then dried over sodium sulphate and concentrated.
The resulting solid residue was then stirred with acetone to produce 68.5 g of 7-chloro-1-methyl-2-hydroxymethyl-5-(2'-chlorophenyl~-2,3-dihydro-lH-1,4-benzodiazepine having a melting point of 172-174C.
1~63~
Example 7.
. ~ ., 151 g of Nl-phenyl-Nl-methyl-N2-(2'-~fluoroben20yl)-2-hydroxy-1,3-diaminopropane were heated in 4.30 ml of phosphorus oxychloride for three hours under reflux. ~rhe excess phos-phorus oxychloride was then distilled off in vacuo and the re sulting residue was dissolved in 1000 ml of chloroform and the resulting solution thoroughly stirred with 200 g of ice, 200 ml of water and 200 ml of concentrated aqueous caustic soda solu-tion. The organic phase was then separated, washed until neu-10 tral with water, dried over sodium sulphate and then concentra- , ted. The resulting residue was then stirred for three hours with 500 ml of ether, mixed with 100 g of r-alumina and filter-ecl. ~fter the ether had been evaporated o~f, there remained 110 g o~ a raw product consisting of a mixture of l-methyl~2-chloromethyl-5-(2'-fluorophenyl)-lH-2,3-dihydro-1,4-benzodiaze-pine and l-methyl-3-chloro-6-(2'-fluorophenyl)-1,2,3,4,-tetra-hydro-1,5-benzodiazocine. This raw product was then dissolved in 1.5 litres of methanol in which 8.9 g of sodium had pre- ~-viously been dissolved and the resulting solution was heated 20 for five hours under reflux. The solvent was then distilled -off and the residue dissolved in 500 ml of toluene and washed until neutral with water. The organic phase was basically filtered (Merck standard), thoroughly stirred with 200 g of A1203 Activity Stage II-III. The solvent was then distilled off.
The residue (93 g), which consisted of 1-methyl-2-methoxymethyl-5-(2'-fluorophenyl~-lH-2,3-dihydro-1,4-ben20-diazepine, was then dissolved in 1200 ml of methylene chloride, and the resulting solution boiled with 53 g of N-bromosuccini-mide for 24 hours under reflux. The solvent was then distilled . .
~, . . . . ..
~63~7 - ~
off and the resulting residue dissolved in a mixture of 250 ml of ether and 250 ml of toluene. The base was then extracted using an adequate amount of dilute (20%) hydrochloric acid.
The base was then separated by adding concentrated aqueous ~ `~
caustic soda solution and extracted with ether (250 ml~. The hydrochloride was then precipitated by addi;ng a solution of hydrochloric acid gas in ether and recrystallized from 200 to 300 ml of ethanol.
The yield amounted to 60.2 g of 7-bromo-1-methyl-2-methoxymethyl-5-(2'-fluorophenyl)-lH-2,3-dihydro-1,4-benzo-diazepine in the form of the hydrochloride. It had the follow-ing properties:
,~
Melting point : 183-185C
Element analysis~
Calculated: C = 52.3%; H 8J 4.6%; N - 6.8%; Br - 19.3%; Cl = 8.6 Actual : C = 52.3%; H = 4.7%; N = 6.4%; Br = 19.~; Cl = 8.3%
Example 8.
~ g of N1-phenyl-Nl-methyl-N2-~2'-chlorobenzoyl)-2-hydroxy-1,3-diaminopropane were heated with 350 ml of phos-phorus oxychloride for 2.5 hours under reflux. The excessphosphorus oxychloride was then distilled of and the resiaue was dissolved in 400 ml of chloroform and shaken out with ice-water ~400 ml) and 200 ml of concentrated aqueous caustic soda solution. The chloroform phase was then washed until neutral with water, dried with sodium sulphate and concentrated. The residue (74.6 g) was then dissolved in 1000 ml of methylene chloride and boiled with 41.6 g of N-bromosuccinimide for 24 hours under reflux. The solvent was then distilled off and the resulting residue was dissolved in a mixture of 250 ml of toluene and 250 ml of ether~ The base was then extracted with `' 1~3107 ~ ~
dilute (20%) hydrochloric acid and isolated by treatment with concentrated aaueous caustic soda solution and toluene. The toluene phase was basically (Merck standard) filtered through 150 g of ~12O3 II-III (Merck standard) and 150 g of A12~3 I
tMerck standard). After the toluene had evaporated, 35.5 g of an oily mixture a 7-bromo-1-methyl-2-chloromethyl-5-(2'-chlorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine and 8-bromo-l-methyl-3-chloro-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine were isolated. That mixture was then heated with 750 ml of isopropanol, in which 6.5 g of sodium had pre-viously been dissolved, for 24 hours under reflux. The isopro-panol was then distilled off and the resulting residue was dissolved in 300 ml of chloroform and then washed until neutral with water. The organic phase was then separated and dried with sodium sulphate, and the solvent distilled off. The resi-due (24 g) was filtexed with a mixture of toluene/chloroform (9:1) through 500 g of aluminum oxide I (Merck standard).
After the solvent had been distilled off, the residue was dissolved in acetone and mixed with a solution of hydrochloric acid gas in ether until an acid reaction was obtained. This caused the hydrochloride to precipitate in the form of yellow crystals which were collected and recrystallized from ethanol (100-200 ml). The product had the foLlowing properties:
Melting point : 189-191C
Element analysis:
Calculated: C = 52.4~; H - 5.1%; N = 6.1%; Br = 17.4%; Cl = 15.5~
Actual : C = 52.6%; H = 5.0%; N = 6.0~; Br = 17.2~; Cl = 15.2%
_xamples 9 to 16.
By following the procedures described in Examples 1 to 8, other compounds corresponding to the following formu:La V
- - ": - . . . ~ . . .
33L~7 were prepared: CH3 CH2R4 [~CH2 Br I ~ N / .................. V
~ / R5 1~ J ~-~
~ .
The identities of the ~ubstituent groups are indicated ;
in Table 6 together with the melting points and elemental analyses of the products.
__ ~ ~ _. ~
# R3 R2 Melting Point Elemental Analys-s C Calculated % Actual . . -- ., __ ~
g C3H7 Cl 152-154 Cl = 15.515.5 (hydrochloride) Br = 17.417.1 ~ _____~__ ____ CH3 CF3 128-130 Cl = 7.57.5 (hydrochloride) Br - 16.~17.2 x 1/2 H2O
_ .__ ~ ~
11 C2H5 CF3 102-104 Br - 18.118.3 _ . __._ . ... . ... --___ 12 CH3 Br 185-187 Cl = 7.5 7.5 :
(hydrochloride) Br = 33.7 33.4 __ . __ __ ~ , ~.. .
13 C2H5 Br 154-156 Cl = 7.3 7.2 : ;~
(hydrochloride) Br = 32.7 32.8 ~: -__ _ __ _ : 14 C3H7 Br 143 146 . C1 = 7.1 7.3 ~:
(hydrochloride) Br = 31.8 31.5 .
__ _. _ _ ~ _,.____ __ ~
15 CH3 I 223-225Cl = 6.8 6.7 (hydrochloride) Br = 15.3 15.7 . _ ____ _ _ ,____._. _ 16 C~H5 I 204-207 C1 = 6.6 6.6 ~___ ~ _ ~ de~ Br = 14.9 15.1 :~
~ :
~: :
~ .
.,. . . . : , . :
Claims (27)
1. A process for producing 2-substituted 1-methyl-5-phenyl-1,4-benzodiazepines corresponding to the formula:
and acid addition compounds thereof, and wherein R1 represents a hydrogen atom or a halogen atom, R2 represents a hydrogen atom, a halogen atom or a trifluoromethyl group, and R3 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, and which process comprises cyclising an acyldiamine corres-ponding to the formula:
wherein R1 and R2 have the specified meanings, by reaction with an excess of phosphorus oxychloride generally at the boiling point of such phosphorus oxychloride throughout such cyclisa-tion to provide a mixture of isomers corresponding to the formulae:
and wherein R1 and R2 have the specified meanings; (b) separating said mixture of isomers from remaining unreacted phosphorus oxychloride and other inorganic material; and (c) converting said mixture of isomers at elevated temperature and in solution into a corresponding said 2-substituted 1-methyl-5-phenyl-1,4-benzodiazepine.
and acid addition compounds thereof, and wherein R1 represents a hydrogen atom or a halogen atom, R2 represents a hydrogen atom, a halogen atom or a trifluoromethyl group, and R3 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, and which process comprises cyclising an acyldiamine corres-ponding to the formula:
wherein R1 and R2 have the specified meanings, by reaction with an excess of phosphorus oxychloride generally at the boiling point of such phosphorus oxychloride throughout such cyclisa-tion to provide a mixture of isomers corresponding to the formulae:
and wherein R1 and R2 have the specified meanings; (b) separating said mixture of isomers from remaining unreacted phosphorus oxychloride and other inorganic material; and (c) converting said mixture of isomers at elevated temperature and in solution into a corresponding said 2-substituted 1-methyl-5-phenyl-1,4-benzodiazepine.
2. A process as claimed in Claim 1 and in which said mix-ture of isomers is converted into a corresponding 2-hydroxyme-thyl-substituted 1-methyl-5-phenyl-1,4-benzodiazepine by reaction with an alkali metal hydroxide or carbonate.
3. A process as claimed in Claim 2 and in which said reaction with an alkali metal hydroxide or carbonate is carried out in an aqueous medium.
4. A process as claimed in Claim 3 and in which said reaction with an alkali metal hydroxide or carbonate is carried out in the presence of a water-miscible solvent.
5. A process as claimed in Claim 4 and in which said water-miscible solvent is dioxane or tetrahydrofuran.
6. A process as claimed in Claim 1 and in which said mix-ture of isomers is converted into a corresponding 2-hydroxyme-thyl-substituted ,1-methyl-5-phenyl-1,4-henzodiazepine by reac-tion with an alkali metal acetate and then with a dilute solu-tion of an alkali metal hydroxide.
7. A process as claimed in Claim 6 and in which said reaction with an alkali metal acetate is carried out in dimethylformamide.
8. A process as claimed in Claim 7 and in which said reaction with a dilute solution of an alkali metal hydroxide is carried out in the presence of methanol.
9. A process as claimed in Claim 1 and in which said mix-ture of isomers is converted into a corresponding 2-alkoxyme-thyl-substituted 1-methyl-5-phenyl-1,4-benzodiazepine by reation with a corresponding alkali metal alkoxide.
10. A process as claimed in Claim 9 and in which said reaction with an alkali metal alkoxide is carried out in the presence of the corresponding alcohol or a proton-free solvent.
11. A proeess as claimed in Claim 10 and in which said reaction with an alkali metal alkoxide is carried out in the presence of dimethylsulfoxide, dimethylformamide or hexamethyl-phosphoric triamide.
12. A proeess as claimed in Claim 1 and which comprises halogenating said mixture of isomers to produce a mixture of the corresponding 1-methyl-2-chloromethyl-5-phenyl-7-halo-1,4-benzodiazepine and 1-methyl-3-chloro-6-phenyl-8-halo-1,5-benzodiazocine for conversion into a corresponding 2-substitu-ted 1-methyl-5-phenyl-7-halo-benzodiazepine.
13. A process as claimed in Claim 1 and which comprises the additional step of halogenating a said 2-substituted 1-methyl-5-phenyl-1,4-benzodazepine to form the corresponding 2-substi-tuted 1-methyl-5-phenyl-7-halo-1,4-benzodiazepine.
14. A process as claimed in Claim 1 and in which the free base of a said 2-substituted 1-methyl-5-phenyl-1,4-benzodiazepine is prepared by hydrolysis of a corresponding said acid addition compound, such acid addition compound in turn being prepared by reaction of such a free base with an acid.
15. A process as claimed in Claim 1 in which said acyl-diamine corresponds to the formula:
wherein R5 represents a halogen atom or a trifluoromethyl group, and in which the intermediate mixture of isomers is converted into a corresponding 7-bromo-2-substituted-1-methyl-5-phenyl-1, 4-benzodiazepine corresponding to the formula:
in which R4 represents an alkyl group having from 1 to 3 carbon atoms.
wherein R5 represents a halogen atom or a trifluoromethyl group, and in which the intermediate mixture of isomers is converted into a corresponding 7-bromo-2-substituted-1-methyl-5-phenyl-1, 4-benzodiazepine corresponding to the formula:
in which R4 represents an alkyl group having from 1 to 3 carbon atoms.
16. A process as claimed in Claim 15 for producing a 7-bromo-1-methyl-2-methoxymethyl-5-phenyl-1,4-benzodiazepine in which R4 represents a methyl group and R5 represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or a trifluoromethyl group.
17. A process as claimed in Claim 16 for producing 7-bromo-1-methyl-2-methoxymethyl-5-(2'-chlorophenyl)-lH-2, 3-dihydro-1,4-benzodiazepine.
18. A process as claimed in Claim 15 for producing a 7-bromo-1-methyl-2-ethoxymethyl-5-phenyl-1,4-benzodiazepine in which R4 represents an ethyl group and R5 represents a chlorine atom, a bromine atom, an iodine atom or a trifluoromethyl group.
19. A process as claimed in Claim 15 for producing a 7-bromo-1-methyl-2-propoxymethyl-5-phenyl-1,4-benzodiazepine in which R4 represents a propyl group and R5 represents a chlorine atom or a bromine atom.
20. A process as claimed in Claim 15 for producing a 7-bromo-1-methyl-2-isopropoxymethyl-5-phenyl-1,4-benzodiazepine in which R4 represents an isopropyl group and R5 represents a chlorine atom.
21. A 2-substituted-1-methyl-5-phenyl-1,4-benzodiazepine corresponding to the formula:
when prepared by the process claimed in Claim 1.
when prepared by the process claimed in Claim 1.
22. A 7-bromo-2-substituted-1-methyl-5-phenyl-1,4-benzodi-azepine corresponding to the formula:
wherein R4 represents an alkyl group having from 1 to 3 carbon atoms , and R5 represents a halogen atom or a trifluoromethyl group, when prepared by the process claimed in Claim 15.
wherein R4 represents an alkyl group having from 1 to 3 carbon atoms , and R5 represents a halogen atom or a trifluoromethyl group, when prepared by the process claimed in Claim 15.
23. A 7-bromo-1-methyl-2-methoxymethyl-5-phenyl-1,4-benzodiazepine when prepared by the process claimed in Claim 16.
24. A 7-bromo-1-methyl-2-methoxymethyl-5-(2'-chlorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine when prepared by the process claimed in Claim 17.
25. A 7-bromo-1-methyl-2-ethoxymethyl-5-phenyl-1,4-benzodiazepine when prepared by the process claimed in Claim 18.
26. A 7-bromo-1-methyl-2-propoxymethyl-5-phenyl-1,4-benzodiazepine when prepared by the process claimed in Claim 19.
27. A 7-bromo-1-methyl-2-isopropoxymethyl-5-phenyl-1,4-benzodiazepine when prepared by the process claimed in Claim 20.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2520937A DE2520937C3 (en) | 1975-05-10 | 1975-05-10 | 7-Bromo-1-methyl ^ -alkoxymethyl-S- (2-halophenyl) -lH-23-dihydro-1,4-benzodiazepine derivatives, their acid addition salts and pharmaceutical preparations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1063107A true CA1063107A (en) | 1979-09-25 |
Family
ID=5946275
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA252,134A Expired CA1063107A (en) | 1975-05-10 | 1976-05-10 | Process for producing 2-substituted 1,4-benzodiazepine derivatives |
Country Status (28)
| Country | Link |
|---|---|
| JP (2) | JPS51149293A (en) |
| AR (1) | AR209361A1 (en) |
| AT (1) | AT353274B (en) |
| AU (1) | AU498994B2 (en) |
| BE (1) | BE841549A (en) |
| CA (1) | CA1063107A (en) |
| CH (1) | CH626076A5 (en) |
| CS (1) | CS193075B2 (en) |
| DD (1) | DD124600A5 (en) |
| DE (1) | DE2520937C3 (en) |
| DK (1) | DK145930C (en) |
| ES (1) | ES447737A1 (en) |
| FI (2) | FI62072C (en) |
| FR (1) | FR2310765A1 (en) |
| GB (1) | GB1477999A (en) |
| GR (1) | GR60311B (en) |
| HU (1) | HU174020B (en) |
| IL (1) | IL49548A (en) |
| MX (1) | MX3903E (en) |
| NL (1) | NL187631C (en) |
| NO (1) | NO146238C (en) |
| NZ (1) | NZ180812A (en) |
| PH (1) | PH14964A (en) |
| PT (1) | PT65083B (en) |
| SE (1) | SE422938B (en) |
| SU (1) | SU1126209A3 (en) |
| YU (1) | YU117076A (en) |
| ZA (1) | ZA762785B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2720968C2 (en) * | 1977-05-10 | 1986-05-07 | Kali-Chemie Pharma Gmbh, 3000 Hannover | N? 1? -Acyl-2-hydroxy-1,3-diaminopropanes and drugs |
| DE2835708A1 (en) | 1978-08-16 | 1980-03-06 | Kali Chemie Pharma Gmbh | NEW ANGLE BRACKET TO 1.2 ANGLE BRACKET TO-FURNISHED 7-PHENYL-1,4-BENZODIAZEPINE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS |
| DE3138769A1 (en) * | 1981-09-30 | 1983-04-14 | Kali-Chemie Pharma Gmbh, 3000 Hannover | 7-BROM-5- (2-HALOGENPHENYL) -1H-2,3-DIHYDRO-1,4-BENZODIAZEPINE COMPOUNDS, AND METHODS AND METHODS FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| JP4940065B2 (en) * | 2007-08-29 | 2012-05-30 | トヨタ紡織株式会社 | How to apply grease |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2265370C2 (en) * | 1972-05-03 | 1982-12-02 | Kali-Chemie Ag, 3000 Hannover | 6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine derivatives |
-
1975
- 1975-05-10 DE DE2520937A patent/DE2520937C3/en not_active Expired
-
1976
- 1976-05-04 CH CH558376A patent/CH626076A5/en not_active IP Right Cessation
- 1976-05-06 BE BE166811A patent/BE841549A/en not_active IP Right Cessation
- 1976-05-06 SE SE7605200A patent/SE422938B/en not_active IP Right Cessation
- 1976-05-07 FI FI761284A patent/FI62072C/en not_active IP Right Cessation
- 1976-05-07 AT AT335776A patent/AT353274B/en not_active IP Right Cessation
- 1976-05-07 NO NO761581A patent/NO146238C/en unknown
- 1976-05-07 HU HU76KA1459A patent/HU174020B/en unknown
- 1976-05-07 CS CS763060A patent/CS193075B2/en unknown
- 1976-05-07 FR FR7613858A patent/FR2310765A1/en active Granted
- 1976-05-07 SU SU762356801A patent/SU1126209A3/en active
- 1976-05-07 DK DK205676A patent/DK145930C/en not_active IP Right Cessation
- 1976-05-08 ES ES447737A patent/ES447737A1/en not_active Expired
- 1976-05-08 GR GR50664A patent/GR60311B/en unknown
- 1976-05-10 JP JP51053113A patent/JPS51149293A/en active Granted
- 1976-05-10 CA CA252,134A patent/CA1063107A/en not_active Expired
- 1976-05-10 DD DD192758A patent/DD124600A5/xx unknown
- 1976-05-10 AU AU13779/76A patent/AU498994B2/en not_active Expired
- 1976-05-10 NZ NZ180812A patent/NZ180812A/en unknown
- 1976-05-10 PH PH18415A patent/PH14964A/en unknown
- 1976-05-10 GB GB1919676A patent/GB1477999A/en not_active Expired
- 1976-05-10 IL IL49548A patent/IL49548A/en unknown
- 1976-05-10 NL NLAANVRAGE7604974,A patent/NL187631C/en not_active IP Right Cessation
- 1976-05-10 AR AR263241A patent/AR209361A1/en active
- 1976-05-10 PT PT65083A patent/PT65083B/en unknown
- 1976-05-10 YU YU01170/76A patent/YU117076A/en unknown
- 1976-05-10 ZA ZA762785A patent/ZA762785B/en unknown
- 1976-05-10 MX MX76218U patent/MX3903E/en unknown
-
1981
- 1981-11-19 FI FI813680A patent/FI813680L/en not_active Application Discontinuation
-
1985
- 1985-07-09 JP JP60149411A patent/JPS61178970A/en active Pending
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