CA1050021A - 6-aza-3h-1,4-benzodiazepines - Google Patents
6-aza-3h-1,4-benzodiazepinesInfo
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- CA1050021A CA1050021A CA198,389A CA198389A CA1050021A CA 1050021 A CA1050021 A CA 1050021A CA 198389 A CA198389 A CA 198389A CA 1050021 A CA1050021 A CA 1050021A
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Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides a process 6-aza-3H-1,4-benzodiazepines and 6-aza-1,2-dihydro-3H-1,4-benzodiazepines having the general formula wherein 1,3-dihydro-5-phenyl-2H-pyrido[3,2-e]-[1,4]-diazepin-2-ones having the general formula I
The present invention provides a process 6-aza-3H-1,4-benzodiazepines and 6-aza-1,2-dihydro-3H-1,4-benzodiazepines having the general formula wherein 1,3-dihydro-5-phenyl-2H-pyrido[3,2-e]-[1,4]-diazepin-2-ones having the general formula I
Description
The present in~e~tion relates to 1,3-dihydro-5-phenyl-2H-pyridol3,2-e]-~1,4]-diazepin-2-ones having the general formula I
~ N CO ~
1 ~ 6 ~ 5 4 ~ 2 C --~
~
Rl represents an amino, a C2 - C4 hydroxyalkyl-amino group, a mono- Cl - C4-alkyl-amino group, a di-Cl - C4-al~yl-amino group, a phenyl-alkyl-amino group, the alkyl portion of ~hich consists of 1 to 4 C atoms or is a morpholino pyrollidino, piferazino or Cl - C~ alkyl piferazino group, R2 represents hydrogen or a halogen atom and R5 represents a hydrogen a-tom, a Cl - C4-alkyl group or a Cl - C4 -alkyl group substituted by a dialkyl amino group in which each alkyl group has 1 to 4 carbon atoms or a C2 - C6-alkenyl group, their tautomeric forms, their pharmaceutically acceptible acid addition salts and their pharmaceutically acceptible quaternary ~ compounds.
The halogen atoms are chlorine, fluorine, bromine, particularly chlorine and fluorine. The alkyl, alkenyl and hydroxy-a~kyl groups mentioned hereinbefore suitably contain 1 to 4 carhon atoms. The alkyl groups as such or as components of other groups can also be straight ~r branched chain. Examples _ of the meanings mentioned last are methyl, ethyl, isopropyl, butyl, t-butyl, isobutyl, hydroxy-ethyl, dimethyl amino, diethyl - 30 amin~, dibutyl amino, allyl and hutenyl-(2).
_ The ~uaternary compounds have physiologically compati~le anions of inorganic or organic acids.
~ N CO ~
1 ~ 6 ~ 5 4 ~ 2 C --~
~
Rl represents an amino, a C2 - C4 hydroxyalkyl-amino group, a mono- Cl - C4-alkyl-amino group, a di-Cl - C4-al~yl-amino group, a phenyl-alkyl-amino group, the alkyl portion of ~hich consists of 1 to 4 C atoms or is a morpholino pyrollidino, piferazino or Cl - C~ alkyl piferazino group, R2 represents hydrogen or a halogen atom and R5 represents a hydrogen a-tom, a Cl - C4-alkyl group or a Cl - C4 -alkyl group substituted by a dialkyl amino group in which each alkyl group has 1 to 4 carbon atoms or a C2 - C6-alkenyl group, their tautomeric forms, their pharmaceutically acceptible acid addition salts and their pharmaceutically acceptible quaternary ~ compounds.
The halogen atoms are chlorine, fluorine, bromine, particularly chlorine and fluorine. The alkyl, alkenyl and hydroxy-a~kyl groups mentioned hereinbefore suitably contain 1 to 4 carhon atoms. The alkyl groups as such or as components of other groups can also be straight ~r branched chain. Examples _ of the meanings mentioned last are methyl, ethyl, isopropyl, butyl, t-butyl, isobutyl, hydroxy-ethyl, dimethyl amino, diethyl - 30 amin~, dibutyl amino, allyl and hutenyl-(2).
_ The ~uaternary compounds have physiologically compati~le anions of inorganic or organic acids.
2~
The compounds acc~rding to the invention have valuable pharmadynamic properties. For example, they have psychosedative and particularly anxiety-reducing pr~perties. Moreover, they also have an antiphlogistic effect.
The compounds of formula I can be produced in a conventional manner in that a) a compound having the formula IT
R ~L~
1 ~ N
~ -F'2 wherein the symbols Rl to R5 have the meanings specified herein-before and W represents either an oxygen atom or the group =~1~
or =NOH, is condensed with a compound having the general formula III
A
R7 - C C~12 X III
and R7 represents a hydroxy group, a halogen atom, a lower alkoxy - group or a lower alkyl-mercapto group, and X represents an amino group, a protected amino group or a halogen a-tom, the amino group always containing a protected group when R7 is hydroxy, if required with the addition of acid-binding agents, the conden-sation being carried out in the presence of ammonia or of an ammonia derivative when W is oxygen and X is halogen and, when required, the products obtained are subsequently treated in an alkaline medium or b) a compound having the formula I, wherein Rl is a halogen atom, preferably chlorine, and the other meanings _ are the same as those specified hereinbefore, is reacted with ammonia, a C2 - C4-hydroxy--alkyl amine, a mono-Cl - C~-alkyl amine, a di-Cl - C4-alkyl amine, a phenyl-alkyl amine, the alkyl portion of which consists O F 1 to 4 carbon atoms morDholine or c) in a compound having the form~ll.a I wherein R5 is hydroyen introducing a Cl - C~-alkyl group a C2 - C6-alkenyl group is introduced and when requi.red, the compounds obtained are con-verted into their (~uaternary salts or into their acid addition salts.
The process a) is carried out in the usual solvents or dispexsing agents at temperatures between 0 and 2QO~C, preferably between 20 and 150GC. ~olar solvents such as alcohols, dioxane, tetrahydrofurans, dimethyl sulphoxide, dimethyl formamide and the like are particularly suitable. When ~ is oxygen then, for example, a~ents such as pyridine and quinoline are suitable. If required, the addition of acid or basic substances, as for example pi~eridine or aliphatic carboxylic acids is effected when X
represents a halogen atoms, then it is ex~edient to add basic substances which cause acids to be split off. I~hen R7 represents a hydroxy group, then the addition of special conventional agents which split off water such as dicyclohexyl carbo diimide is desirable or required. Moreover solvents or methocls of compounds having the structure (a) ~ N ~ CH
Y N -~ Z
where Y and Z can be carbon hridcse meters containing 0 to 3 carbon atoms for example imidazole, tetrahydropyrozine and pyro-zoline were found to be favourable.
A compound having the general formula Il, wherein ~5 represents hydrogen and W represents oxygen and R1 and R2, has the meanings specified hereinbefore, is acylated with an aliphatic acid halide, ester, anhydride or ke-tone or benzoyl chloride in an inert solvent such as dioxane, benzene tetrahydrofuran or dimethyl formamide at temperatures between 0 and 150C. Upon , ~ "
J
lOSO~D21 eonverting the compound obtained into the alkali salts with for example, sodium hydride or sodium amide, said compound is reacted with a compound having the formula IIl, for example, in a non-basic solvent such a dioxane, dinle~thyl formamide or di-methyl sulphoxi~ at temperatur~s between 0 and 200C. The acyl group, which is at the nitrogen atom in the 3 position of the pyridine rinq, can subsequently b~ split off in an aeid or basic medium, if required with simultaneous cyclization to form eompounds having the formula I.
It is frequently possible to so carry out the process a) that the amino group in the 3 position which has the formula Il and/or the amino ~roup having the formula III (X=N~2) carries a eonventional protective group. This kind of protective group is frequently required for the produetion of these starting eompounds.
In many cases these protectiv~ groups are split off simultaneously with the eyclization.
These proteetive yroups can be easily split off. They are either aeyl aroups whieh ean be readily split off solvolytie-ally or groups which can be split off by hydrogenation, forexample, the benzyl radical. The proteetive groups which can be split off solvolytically are split off, for example, by saponifieation with dilute acids or by means of basic substances sueh as potash, soda, aqueous alkali solutions, alcoholic alkali solutions or ammonia at room temperature or even by boiling for a short period. Groups whieh ean be split off by hydrogenation sueh as the benzyl group or the earbo-benzoxy radieal are suitably split-off by catalytie hydrogenation in the presenee of conven-tional hydrogenation catalysts, partieularly palladium eatalysts, in a solvènt or dispersing agent, if required under inereased _ pressure. For example, water, lower aliphatic aleohols, eyelie ethers sueh dioxane or tetrahydrofuran, aliphatie ethers aeid dimethyl formamide and mixtures of these agents are suitable as ".,~
105~121 solvents or dispersing agents.
For example, the benzyl group, the -phenyl-ethyl group, ben~yl groups which are substituted in the benzene nucleus, as for example, the p-bromo- or p-nitro-benzyl group, the carbobenzoxy ~roup, the carbo-benzthio ~roup, the trifluoro-acetyl grou~, the phthalyl radical, the trityl radical and the p-toluene sulphonyl radical as well as simple acyl ~roups such as the acetyl group, formyl group and t-butyl-carboxy yroup are suitable as protective ~roups for the amino group. Particularly the protective groups used in the peptide synthesis and the cleavage methods used therein are suitable. In this connection attention is drawn to the boo~ of Jess P. Greestein and Milton Winitz "Chemistry of Amino Acids", John Wiley and Sons, Inc., Vol. 2, for example, ~age 883 ff. The carbalkoxy arou~ (i.e.
the lower one) is also suitable.
The process can also be so carried out that ~rior to the actual cyclization the intermediate staye having the formula . _ IV
~5 ~ ,~ C
1~ C=W
is isolated and can then be purified or it can be cyclized in -the form in which it is obtained. For this ~urpose temperatures between -70 and 150C, preferably between 0 and 150C are suitable.
The following solvents or dispersing ayents are par-_ ticularly suitable in addition to those mentioned hereinbefore, for example, ~lacial acetic acid, lower aliphatic alcohols such ~" .~, ,-,;
Z~
as methanol, ethanol, aeetie anhydridc~ polyphosphorie aeid, aliphatie ethers, and chloroform. If re(luired, this cyelization ean be earried out with the use of aeid eondensing agents sueh as sulphurie aeid, hydroehlorie acid, hydrobromic aeid, toluene sulphonie aeid or polyphosphoric asid or even basic condensing agents, such as pyridine or tertiary amines.
When X represents a halogen atom, the cyelization is earried out in the presenee of ammonia ineluding for example, liquid ammonia, and tertiary, non-quaternizing amines. For example, sterieally hindered amines such as disopropyl ethyl amine or 1,8-bio-(dimethyl-amino) naphthalene, can be present.
'rhe haloyen atoms concerned are chlorine, bromine or iodine.
For example, other dcrivatives of ammonia can },e used instead of or in addition to ammonia. Thus ammonia derivatives which replaee a halogen atom with the group ~ll2, as for example, Urotropin, alkali amides earboxylie amides, alkali metal com-pounds or earboxylie amides or diear~oxylie imides ean be used.
For example, phthalimide or phthalimides which earry inert sub-stituents in the benzene nucleus or succinimide, are suitable as diearboxylic imides. Moreover the protective groups mentioned hereinbefore inelucling the other proteetive ~roups used in the peptide chemistry are suitable as acid radicals for the earboxy-lic amids. These protective groups are deserihed, for example, in the book of Jesse P. Greenstein and Mil-ton Winitz, "C~emistry of Amino Aeids", N.Y. 1961, John Wiley ~ Sons, Ine., Vol. 2, i.e. page 883 ff. For example, if Urotropin is used, then the process can be carried out as follo~s: -boiling in ehloroform from 1/2 to 8 hours, and cleaveage of the separated Urotropin eompound with aqueous or aqueous - alcoholie inorganic acid i.e,, (13CL or 1l2S~) at temperatures between i.e. 20 and 150~C.
_ When aeid amides are used, then it is reeommended that condensing agents sueh as sodium, alkali metal hydrides, alkali , ~
11DS~021 metal amides particularly those of sodium Gri~nard compounds lithium alXyls (lithium butyl) be used or in special cases, such as the tosyl arnides, more weakly basic condensing agents such as potassium carbonate, po~ldered sodium hydroxide. Pri-marily dimethyl sulphoxide and dimethyl formamide as well as dioxane, tetrahydrofuran, alcohols and ethers are suitable as solvents. ~1hen using acid amides the compounds having the formula IV, wherein X is an amino group which is protected by the corresponding acid radicals, are usually obtained from the intermediate compound IV. The cyclization is then carried out simultaneously ~ith or subsequent to the cleavage of the pro-tective groups. When splitting off the protective group with an acid it is usually possihle to isolate the compounds having the formula IV (wherein X represent the amino group) as a salt or e~en as the base.
When a starting substance havinq the formula II, wherein R5 represents an acyl group, is used in the process a), then, if required, said starting substance is solvolytically split off upon termination of the reaction under the conditions specifled herein before. However, when the acyl group is purely aliphatic, then it is also possible to re~uce said acyl group to the alkyl group, for example, by means of complex alkali metal hydrides such as LiAlH4.
It is also possible that in the cyclization according to the process a) the 6-membered ring compound having the formula V
C - CH - Hal(Cl or sr) . ~ ~ NO
R -~ ~ ~ ~ C i V
11 `J- ~2 ~'`;''' ,~.
2~
wherein llal is chlorine or bromine is partially or exclusively formed instead of the 7-membered ring. In this case a subse~uent treatment in an alkaline medium wo~ld also be re~uired. This I treatment is usually carried out in polar a~ents such as lower alcohols i.e., methanol, ethanol or ter~iary butyl alcohol, chloroform and dioxane at temperatures between 0 and 150C.
For example, aqueous or alcoholic, particularly methanolic or ethanolic sodium or potassiurn hydroxide, if required in mixture with the above solvents are suitable as alkaline media. ~he same rea~ents in a solid, powdered form as well as potash and aqueous solutions of tertiary amines, primarily those which do not quaternize, such as diisopropyl methyl amine are also suitable. Further, alkali ion exchanges either in the form of columns or in suspension are also suitable.
In this ring extension compounds are formed in which the grouping -N(R5)C(O) -in the formula I has the following structures -N=C~OII)-, -N=C(~IIR5)-, N=C(OR5)-, -N=C(NHR5-NHR5) or -~=C(NR5R5)-In the ring extension of compounds having the formulaV the compound, which is obtained from the compound having the formula V without rin~ extension by substituting the reactants concerned for the halo~en atom, is sometimes formed in acldition to the desired diazepine. The desired compound can then be separated from these and possibly other by-products by conven-tional fractional distillation, or chromatography.
The process b) is carried out, for example, in an inert solvent or dispersing agent such as tetrahydrofuran, dioxane, ethanol, n-propanol, dimethyl sulphoxide or dimethyl formamide or also in the presence of an excess of the basic reactant at temperatures between 50 and 200C, preferably between 80 and ,~',`'"
~SO~
130C. Acid acceptors such as potash, sodium carbonate, calcium carbonate or non-quaternizing amines such as diisopropyl methyl amine may be added. In order to react the components of the `~H2 acyl type, the reaction is carried out in the presence of alkali metal compounds such as sodiun hydride, sodium amide and butyl lithium. In this case only solvents which contairl no functional grou~s, such as dioxane, dimethyl formamide or benzene are suitable. The temperatures usually are slightly lower than those mentioned above, for example, between 20 and 1~ 100 C .
According to the ~rocess c) aza-benzodiazepines having the formula I can be substituted in a suitable manner or further reacted.
~mino groups present in the products including the nitrogen in the 1 position can be alkylated or quaternized by R5. For example, com~ouncls ha~Jing the formula I, wherein R5 represents a hydrogen atom and/or Rl represent an amino group can be alkylated at the nitroc~en in a conventional manner.
Suitable alkylation agents are, for example, esters having the formula ~5Hal, ArSO2OR5 and SO2(O~5)2, wherein Hal represents a haloqen a-tom, particularly chlorine, bromine or iodine and Ar represents an aromatic radical, as for example, a phenyl or naphthyl radical, which, if required, is substituted by one or several alkyl radicals, and R5 has the meaninys specified here-inbefore ~or R5, excluding hydrogen. Moreover R5 can also represent an al~yl group, which contains 1 to 4 carbon atoms and is substituted by a phenyl group. This must he additionally con5idered when Rl represent an amino groups. Examples are p-toluenesulphonic alkyl esters, and lower dialkyl sulphates.
The alkylation reaction is carried out at temperatures between 0 and 150C in inert solvents such as alcohols, cioxane, dimethyl formamide, dimethyl sulphoxide, aromatic hydrocarbons such as g ,~.
. .
1050~1~21 benzene, toluene or acetone and in mixtures of these solvents, if required, with the addition of conventional acid-hindin~
agents such as alkali metal carbonates, pyridine or other conventional tertiary amines For the alkylation by means of alkyl halides (for examp~e, iodid~s) in th~ presence of sodium hydride, for example, a mixture of toluene and a small amount of dimeth~l formamide such as 0.1 to 5~O~ for example, 0.5% was found to he favourable.
The alkylation can also he so carried out when an alkali metal compound is first produced from the compound which is to be reacted anc1 has the formula I, by reacting it in an inert so]vent such as dioxane, dimethyl formamide, benzene or toluene, with an alkali metal, alkali hydrides or alkali amides, particularly sodium or sodium compounds, at temperatures between 0 and 150~C, whereupon the alkylating is added.
Other chemically equivalent agents may be used instead of the aforesaid alkylating agents. (See, for example, L.F.
and Mary Fieser "Reagents for Organic Synthesis", John Wiley and Sons, Inc. New York, 1967, Vol. 1, page 1303-04 and Vol. 2, page 471). Of course, acyl groups in compounds having the formula I can be split off again in known manner.
Basic compounds havin~ the general formula I can be converted into the salts by known methods. The known therapeu-tically applicable acid radica~s are suitable as anions for these salts. Examples o~ these acids are ll2SO4, phosl)horic acid, halogen hydracids, ethylene diamine tetracetic acid, sulphanic acid, benzosulphonic acid, p-toluenesulphonic acid, camphor ~ sulphonic acid, methane sulphonic acid, cluaiazulene sulphonic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, latic acid, citric acid, abcorbic acid, qlyco~ic acid, salicyclic - acid, acetic acid, propionic acid, gluconic acid, benzoic acid, citric acid, acetamino acetic acid and oxy-ethane sulphonic acid.
~' .
.. , . ~ :
The free bases can be produced from the salts of the compounds in the usual manner, for example, by treatinq a solution in an organic agent such as alcohols i.e., methanol with soda or with a solution of caustic soda.
Compounds having the formula 1 can also ~e in the form of tautomers, These tautomeric forms are, for example, the followinq structural pairs:
In these cases the compounds can be entirely or partially in one of the possible tautomeric forms. Under stan-dard conditions of operation and storage there usually is an equilihrium.
Compounds which have the formula I and contain asym-metric carbon atoms and are usually obtained as racemates can be split into the optically active isomers in a conventional manner, for example, with the aid of an optically active acid.
However, it is also possihle to use an optically active substance from the outset and a corres~onding optically active or diaster-eomeric form is then obtained as the final product.
The compounds accordin~ to the invention are suitable for the production of pharmaceutical composition and preparations The pharmaceutical compositions or drugs contain, as the active substance, one or several compounds according to the invention, if required in mixture with other pharmacologically or pharma-ceutically active substances. The drugs can he produced with the use of the known and conventional pharmaceutical auxiliaries and other conventional fillers and diluents.
For example, substances which are recommended and/or ~.,~
listed in the following references from the literature as auxiliaries for pharmacy, cosmetics and related fields are suitahle as this kind of fillers and auxiliaries: Ullmann'~
Encyklopadie der technischen Chemie, Vol. 4 (1953), pa~e 1 to 39, Journal of ~harrnaceutical Sciences, Vol. 52 (1963), page 918 ff, Il.v. Czetsch-Lindenwald, ~iilfsstoffe fur Pharmazie und angrenzende Gebiete: Pharm. Ind., ~o. 2, 1961, page 72 ff;
Dr. Il.P. Fiedler, Lexikon der ~ilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gehiete, Cantor KG., Aulendorf i. Wurtt. 1971.
~xamples are gelatin, natural sugar such as sucrose or lactose, lecithin, pectin, starch, for example, cornstarch, tylose, talc, lycopodium, silica for example, collGidal silica, cellulose, cellulose derivatives for example, cellulose ethers in which the cellulose-hydroxy groups are partially etherified with lower saturated aliphatic alcohols and/or lo~er saturated aliphatic oxy-alcohols, for example, methyl oxy-propyl cellulose, stearates, magnesium and calcium salts of fatty acids containing 12 to 22 car~on atoms, particularly of the saturated ones for example, stearates, emulsifiers, oils and fats, particularly vegetable oils for example, peanut oil, castor oil, oli~e oil, sesame oil, cottonseed oil, corn oil, mono-, di- and triglycerid~s or saturated fatty acids C12l-l24O2 to C18H36O2 and their mixtures, pharmaceutically compati~le monohydric or polyhydric alcohols and polyglycols such as polyethylene glycols as well as derivat-ives thereof, esters of aliphatic saturated or unsaturated fatty acids of 2 to 22 carbon atoms particularly 10 to 18 carbon atoms with monohydric aliphatic alcohols of 1 to 20 carbon atoms or polyhydric alcohols such as glycols, glycerin, diethylene glycol, pentaerythritol, sorbitol, or manni-tol, which, if re~uired, can also be etherified, benzyl benzoate, dioxolanes, glycerin formals, glycol furoles, dimethyl acetar,~ide, lactamides, lactates, ethyl carbonates and silicones particularly medium-~ 12 --: ,. ~, .;.
~L05~(~2~
viscosity dimethyl polysiloxanes.
Water or physiologically com~atible or~3anic solvents are suitable for the production of solutions, as for example, ethanol, 1,2-propylene glycol, polyglycols and their derivatives, dimethyl sulphoxide, fat alcohols, tric~lycerides, partial esters of glycerin and paraffins.
For the production of the preparation k~o~m and con-ventional dissolving intermediaries can be used, for example, polyoxyethylated fa-ts, polyoxy-ethylated oleotri~lycerides and linolized oleotriglycerides. Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil and corn oil (see Dr. ~I.P. Fiedler "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and an~renzende Gebiete" 1971, page 191 to 195). In this connection "polyoxyethylated" means that the substances containing polyoxyethylene chains whose degree of polymerization usually is between 2 and 40 and particularly between 10 and 20. These polyoxyethylated substanced can be obtained, for example, by reaction of the corresponding glycerides with ethylene oxide (for example, 40 moles of ethylene oxide per mole of glyceride).
The addition of preservatives, stabilizers, buffer substances, taste corrigents, antioxidants and complexing agents (for example, ethylene diaminotetraacetic acid) and the like is possible. If required, the p~ range may be adjusted for the stabilization of the active substance molecule to approximately
The compounds acc~rding to the invention have valuable pharmadynamic properties. For example, they have psychosedative and particularly anxiety-reducing pr~perties. Moreover, they also have an antiphlogistic effect.
The compounds of formula I can be produced in a conventional manner in that a) a compound having the formula IT
R ~L~
1 ~ N
~ -F'2 wherein the symbols Rl to R5 have the meanings specified herein-before and W represents either an oxygen atom or the group =~1~
or =NOH, is condensed with a compound having the general formula III
A
R7 - C C~12 X III
and R7 represents a hydroxy group, a halogen atom, a lower alkoxy - group or a lower alkyl-mercapto group, and X represents an amino group, a protected amino group or a halogen a-tom, the amino group always containing a protected group when R7 is hydroxy, if required with the addition of acid-binding agents, the conden-sation being carried out in the presence of ammonia or of an ammonia derivative when W is oxygen and X is halogen and, when required, the products obtained are subsequently treated in an alkaline medium or b) a compound having the formula I, wherein Rl is a halogen atom, preferably chlorine, and the other meanings _ are the same as those specified hereinbefore, is reacted with ammonia, a C2 - C4-hydroxy--alkyl amine, a mono-Cl - C~-alkyl amine, a di-Cl - C4-alkyl amine, a phenyl-alkyl amine, the alkyl portion of which consists O F 1 to 4 carbon atoms morDholine or c) in a compound having the form~ll.a I wherein R5 is hydroyen introducing a Cl - C~-alkyl group a C2 - C6-alkenyl group is introduced and when requi.red, the compounds obtained are con-verted into their (~uaternary salts or into their acid addition salts.
The process a) is carried out in the usual solvents or dispexsing agents at temperatures between 0 and 2QO~C, preferably between 20 and 150GC. ~olar solvents such as alcohols, dioxane, tetrahydrofurans, dimethyl sulphoxide, dimethyl formamide and the like are particularly suitable. When ~ is oxygen then, for example, a~ents such as pyridine and quinoline are suitable. If required, the addition of acid or basic substances, as for example pi~eridine or aliphatic carboxylic acids is effected when X
represents a halogen atoms, then it is ex~edient to add basic substances which cause acids to be split off. I~hen R7 represents a hydroxy group, then the addition of special conventional agents which split off water such as dicyclohexyl carbo diimide is desirable or required. Moreover solvents or methocls of compounds having the structure (a) ~ N ~ CH
Y N -~ Z
where Y and Z can be carbon hridcse meters containing 0 to 3 carbon atoms for example imidazole, tetrahydropyrozine and pyro-zoline were found to be favourable.
A compound having the general formula Il, wherein ~5 represents hydrogen and W represents oxygen and R1 and R2, has the meanings specified hereinbefore, is acylated with an aliphatic acid halide, ester, anhydride or ke-tone or benzoyl chloride in an inert solvent such as dioxane, benzene tetrahydrofuran or dimethyl formamide at temperatures between 0 and 150C. Upon , ~ "
J
lOSO~D21 eonverting the compound obtained into the alkali salts with for example, sodium hydride or sodium amide, said compound is reacted with a compound having the formula IIl, for example, in a non-basic solvent such a dioxane, dinle~thyl formamide or di-methyl sulphoxi~ at temperatur~s between 0 and 200C. The acyl group, which is at the nitrogen atom in the 3 position of the pyridine rinq, can subsequently b~ split off in an aeid or basic medium, if required with simultaneous cyclization to form eompounds having the formula I.
It is frequently possible to so carry out the process a) that the amino group in the 3 position which has the formula Il and/or the amino ~roup having the formula III (X=N~2) carries a eonventional protective group. This kind of protective group is frequently required for the produetion of these starting eompounds.
In many cases these protectiv~ groups are split off simultaneously with the eyclization.
These proteetive yroups can be easily split off. They are either aeyl aroups whieh ean be readily split off solvolytie-ally or groups which can be split off by hydrogenation, forexample, the benzyl radical. The proteetive groups which can be split off solvolytically are split off, for example, by saponifieation with dilute acids or by means of basic substances sueh as potash, soda, aqueous alkali solutions, alcoholic alkali solutions or ammonia at room temperature or even by boiling for a short period. Groups whieh ean be split off by hydrogenation sueh as the benzyl group or the earbo-benzoxy radieal are suitably split-off by catalytie hydrogenation in the presenee of conven-tional hydrogenation catalysts, partieularly palladium eatalysts, in a solvènt or dispersing agent, if required under inereased _ pressure. For example, water, lower aliphatic aleohols, eyelie ethers sueh dioxane or tetrahydrofuran, aliphatie ethers aeid dimethyl formamide and mixtures of these agents are suitable as ".,~
105~121 solvents or dispersing agents.
For example, the benzyl group, the -phenyl-ethyl group, ben~yl groups which are substituted in the benzene nucleus, as for example, the p-bromo- or p-nitro-benzyl group, the carbobenzoxy ~roup, the carbo-benzthio ~roup, the trifluoro-acetyl grou~, the phthalyl radical, the trityl radical and the p-toluene sulphonyl radical as well as simple acyl ~roups such as the acetyl group, formyl group and t-butyl-carboxy yroup are suitable as protective ~roups for the amino group. Particularly the protective groups used in the peptide synthesis and the cleavage methods used therein are suitable. In this connection attention is drawn to the boo~ of Jess P. Greestein and Milton Winitz "Chemistry of Amino Acids", John Wiley and Sons, Inc., Vol. 2, for example, ~age 883 ff. The carbalkoxy arou~ (i.e.
the lower one) is also suitable.
The process can also be so carried out that ~rior to the actual cyclization the intermediate staye having the formula . _ IV
~5 ~ ,~ C
1~ C=W
is isolated and can then be purified or it can be cyclized in -the form in which it is obtained. For this ~urpose temperatures between -70 and 150C, preferably between 0 and 150C are suitable.
The following solvents or dispersing ayents are par-_ ticularly suitable in addition to those mentioned hereinbefore, for example, ~lacial acetic acid, lower aliphatic alcohols such ~" .~, ,-,;
Z~
as methanol, ethanol, aeetie anhydridc~ polyphosphorie aeid, aliphatie ethers, and chloroform. If re(luired, this cyelization ean be earried out with the use of aeid eondensing agents sueh as sulphurie aeid, hydroehlorie acid, hydrobromic aeid, toluene sulphonie aeid or polyphosphoric asid or even basic condensing agents, such as pyridine or tertiary amines.
When X represents a halogen atom, the cyelization is earried out in the presenee of ammonia ineluding for example, liquid ammonia, and tertiary, non-quaternizing amines. For example, sterieally hindered amines such as disopropyl ethyl amine or 1,8-bio-(dimethyl-amino) naphthalene, can be present.
'rhe haloyen atoms concerned are chlorine, bromine or iodine.
For example, other dcrivatives of ammonia can },e used instead of or in addition to ammonia. Thus ammonia derivatives which replaee a halogen atom with the group ~ll2, as for example, Urotropin, alkali amides earboxylie amides, alkali metal com-pounds or earboxylie amides or diear~oxylie imides ean be used.
For example, phthalimide or phthalimides which earry inert sub-stituents in the benzene nucleus or succinimide, are suitable as diearboxylic imides. Moreover the protective groups mentioned hereinbefore inelucling the other proteetive ~roups used in the peptide chemistry are suitable as acid radicals for the earboxy-lic amids. These protective groups are deserihed, for example, in the book of Jesse P. Greenstein and Mil-ton Winitz, "C~emistry of Amino Aeids", N.Y. 1961, John Wiley ~ Sons, Ine., Vol. 2, i.e. page 883 ff. For example, if Urotropin is used, then the process can be carried out as follo~s: -boiling in ehloroform from 1/2 to 8 hours, and cleaveage of the separated Urotropin eompound with aqueous or aqueous - alcoholie inorganic acid i.e,, (13CL or 1l2S~) at temperatures between i.e. 20 and 150~C.
_ When aeid amides are used, then it is reeommended that condensing agents sueh as sodium, alkali metal hydrides, alkali , ~
11DS~021 metal amides particularly those of sodium Gri~nard compounds lithium alXyls (lithium butyl) be used or in special cases, such as the tosyl arnides, more weakly basic condensing agents such as potassium carbonate, po~ldered sodium hydroxide. Pri-marily dimethyl sulphoxide and dimethyl formamide as well as dioxane, tetrahydrofuran, alcohols and ethers are suitable as solvents. ~1hen using acid amides the compounds having the formula IV, wherein X is an amino group which is protected by the corresponding acid radicals, are usually obtained from the intermediate compound IV. The cyclization is then carried out simultaneously ~ith or subsequent to the cleavage of the pro-tective groups. When splitting off the protective group with an acid it is usually possihle to isolate the compounds having the formula IV (wherein X represent the amino group) as a salt or e~en as the base.
When a starting substance havinq the formula II, wherein R5 represents an acyl group, is used in the process a), then, if required, said starting substance is solvolytically split off upon termination of the reaction under the conditions specifled herein before. However, when the acyl group is purely aliphatic, then it is also possible to re~uce said acyl group to the alkyl group, for example, by means of complex alkali metal hydrides such as LiAlH4.
It is also possible that in the cyclization according to the process a) the 6-membered ring compound having the formula V
C - CH - Hal(Cl or sr) . ~ ~ NO
R -~ ~ ~ ~ C i V
11 `J- ~2 ~'`;''' ,~.
2~
wherein llal is chlorine or bromine is partially or exclusively formed instead of the 7-membered ring. In this case a subse~uent treatment in an alkaline medium wo~ld also be re~uired. This I treatment is usually carried out in polar a~ents such as lower alcohols i.e., methanol, ethanol or ter~iary butyl alcohol, chloroform and dioxane at temperatures between 0 and 150C.
For example, aqueous or alcoholic, particularly methanolic or ethanolic sodium or potassiurn hydroxide, if required in mixture with the above solvents are suitable as alkaline media. ~he same rea~ents in a solid, powdered form as well as potash and aqueous solutions of tertiary amines, primarily those which do not quaternize, such as diisopropyl methyl amine are also suitable. Further, alkali ion exchanges either in the form of columns or in suspension are also suitable.
In this ring extension compounds are formed in which the grouping -N(R5)C(O) -in the formula I has the following structures -N=C~OII)-, -N=C(~IIR5)-, N=C(OR5)-, -N=C(NHR5-NHR5) or -~=C(NR5R5)-In the ring extension of compounds having the formulaV the compound, which is obtained from the compound having the formula V without rin~ extension by substituting the reactants concerned for the halo~en atom, is sometimes formed in acldition to the desired diazepine. The desired compound can then be separated from these and possibly other by-products by conven-tional fractional distillation, or chromatography.
The process b) is carried out, for example, in an inert solvent or dispersing agent such as tetrahydrofuran, dioxane, ethanol, n-propanol, dimethyl sulphoxide or dimethyl formamide or also in the presence of an excess of the basic reactant at temperatures between 50 and 200C, preferably between 80 and ,~',`'"
~SO~
130C. Acid acceptors such as potash, sodium carbonate, calcium carbonate or non-quaternizing amines such as diisopropyl methyl amine may be added. In order to react the components of the `~H2 acyl type, the reaction is carried out in the presence of alkali metal compounds such as sodiun hydride, sodium amide and butyl lithium. In this case only solvents which contairl no functional grou~s, such as dioxane, dimethyl formamide or benzene are suitable. The temperatures usually are slightly lower than those mentioned above, for example, between 20 and 1~ 100 C .
According to the ~rocess c) aza-benzodiazepines having the formula I can be substituted in a suitable manner or further reacted.
~mino groups present in the products including the nitrogen in the 1 position can be alkylated or quaternized by R5. For example, com~ouncls ha~Jing the formula I, wherein R5 represents a hydrogen atom and/or Rl represent an amino group can be alkylated at the nitroc~en in a conventional manner.
Suitable alkylation agents are, for example, esters having the formula ~5Hal, ArSO2OR5 and SO2(O~5)2, wherein Hal represents a haloqen a-tom, particularly chlorine, bromine or iodine and Ar represents an aromatic radical, as for example, a phenyl or naphthyl radical, which, if required, is substituted by one or several alkyl radicals, and R5 has the meaninys specified here-inbefore ~or R5, excluding hydrogen. Moreover R5 can also represent an al~yl group, which contains 1 to 4 carbon atoms and is substituted by a phenyl group. This must he additionally con5idered when Rl represent an amino groups. Examples are p-toluenesulphonic alkyl esters, and lower dialkyl sulphates.
The alkylation reaction is carried out at temperatures between 0 and 150C in inert solvents such as alcohols, cioxane, dimethyl formamide, dimethyl sulphoxide, aromatic hydrocarbons such as g ,~.
. .
1050~1~21 benzene, toluene or acetone and in mixtures of these solvents, if required, with the addition of conventional acid-hindin~
agents such as alkali metal carbonates, pyridine or other conventional tertiary amines For the alkylation by means of alkyl halides (for examp~e, iodid~s) in th~ presence of sodium hydride, for example, a mixture of toluene and a small amount of dimeth~l formamide such as 0.1 to 5~O~ for example, 0.5% was found to he favourable.
The alkylation can also he so carried out when an alkali metal compound is first produced from the compound which is to be reacted anc1 has the formula I, by reacting it in an inert so]vent such as dioxane, dimethyl formamide, benzene or toluene, with an alkali metal, alkali hydrides or alkali amides, particularly sodium or sodium compounds, at temperatures between 0 and 150~C, whereupon the alkylating is added.
Other chemically equivalent agents may be used instead of the aforesaid alkylating agents. (See, for example, L.F.
and Mary Fieser "Reagents for Organic Synthesis", John Wiley and Sons, Inc. New York, 1967, Vol. 1, page 1303-04 and Vol. 2, page 471). Of course, acyl groups in compounds having the formula I can be split off again in known manner.
Basic compounds havin~ the general formula I can be converted into the salts by known methods. The known therapeu-tically applicable acid radica~s are suitable as anions for these salts. Examples o~ these acids are ll2SO4, phosl)horic acid, halogen hydracids, ethylene diamine tetracetic acid, sulphanic acid, benzosulphonic acid, p-toluenesulphonic acid, camphor ~ sulphonic acid, methane sulphonic acid, cluaiazulene sulphonic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, latic acid, citric acid, abcorbic acid, qlyco~ic acid, salicyclic - acid, acetic acid, propionic acid, gluconic acid, benzoic acid, citric acid, acetamino acetic acid and oxy-ethane sulphonic acid.
~' .
.. , . ~ :
The free bases can be produced from the salts of the compounds in the usual manner, for example, by treatinq a solution in an organic agent such as alcohols i.e., methanol with soda or with a solution of caustic soda.
Compounds having the formula 1 can also ~e in the form of tautomers, These tautomeric forms are, for example, the followinq structural pairs:
In these cases the compounds can be entirely or partially in one of the possible tautomeric forms. Under stan-dard conditions of operation and storage there usually is an equilihrium.
Compounds which have the formula I and contain asym-metric carbon atoms and are usually obtained as racemates can be split into the optically active isomers in a conventional manner, for example, with the aid of an optically active acid.
However, it is also possihle to use an optically active substance from the outset and a corres~onding optically active or diaster-eomeric form is then obtained as the final product.
The compounds accordin~ to the invention are suitable for the production of pharmaceutical composition and preparations The pharmaceutical compositions or drugs contain, as the active substance, one or several compounds according to the invention, if required in mixture with other pharmacologically or pharma-ceutically active substances. The drugs can he produced with the use of the known and conventional pharmaceutical auxiliaries and other conventional fillers and diluents.
For example, substances which are recommended and/or ~.,~
listed in the following references from the literature as auxiliaries for pharmacy, cosmetics and related fields are suitahle as this kind of fillers and auxiliaries: Ullmann'~
Encyklopadie der technischen Chemie, Vol. 4 (1953), pa~e 1 to 39, Journal of ~harrnaceutical Sciences, Vol. 52 (1963), page 918 ff, Il.v. Czetsch-Lindenwald, ~iilfsstoffe fur Pharmazie und angrenzende Gebiete: Pharm. Ind., ~o. 2, 1961, page 72 ff;
Dr. Il.P. Fiedler, Lexikon der ~ilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gehiete, Cantor KG., Aulendorf i. Wurtt. 1971.
~xamples are gelatin, natural sugar such as sucrose or lactose, lecithin, pectin, starch, for example, cornstarch, tylose, talc, lycopodium, silica for example, collGidal silica, cellulose, cellulose derivatives for example, cellulose ethers in which the cellulose-hydroxy groups are partially etherified with lower saturated aliphatic alcohols and/or lo~er saturated aliphatic oxy-alcohols, for example, methyl oxy-propyl cellulose, stearates, magnesium and calcium salts of fatty acids containing 12 to 22 car~on atoms, particularly of the saturated ones for example, stearates, emulsifiers, oils and fats, particularly vegetable oils for example, peanut oil, castor oil, oli~e oil, sesame oil, cottonseed oil, corn oil, mono-, di- and triglycerid~s or saturated fatty acids C12l-l24O2 to C18H36O2 and their mixtures, pharmaceutically compati~le monohydric or polyhydric alcohols and polyglycols such as polyethylene glycols as well as derivat-ives thereof, esters of aliphatic saturated or unsaturated fatty acids of 2 to 22 carbon atoms particularly 10 to 18 carbon atoms with monohydric aliphatic alcohols of 1 to 20 carbon atoms or polyhydric alcohols such as glycols, glycerin, diethylene glycol, pentaerythritol, sorbitol, or manni-tol, which, if re~uired, can also be etherified, benzyl benzoate, dioxolanes, glycerin formals, glycol furoles, dimethyl acetar,~ide, lactamides, lactates, ethyl carbonates and silicones particularly medium-~ 12 --: ,. ~, .;.
~L05~(~2~
viscosity dimethyl polysiloxanes.
Water or physiologically com~atible or~3anic solvents are suitable for the production of solutions, as for example, ethanol, 1,2-propylene glycol, polyglycols and their derivatives, dimethyl sulphoxide, fat alcohols, tric~lycerides, partial esters of glycerin and paraffins.
For the production of the preparation k~o~m and con-ventional dissolving intermediaries can be used, for example, polyoxyethylated fa-ts, polyoxy-ethylated oleotri~lycerides and linolized oleotriglycerides. Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil and corn oil (see Dr. ~I.P. Fiedler "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and an~renzende Gebiete" 1971, page 191 to 195). In this connection "polyoxyethylated" means that the substances containing polyoxyethylene chains whose degree of polymerization usually is between 2 and 40 and particularly between 10 and 20. These polyoxyethylated substanced can be obtained, for example, by reaction of the corresponding glycerides with ethylene oxide (for example, 40 moles of ethylene oxide per mole of glyceride).
The addition of preservatives, stabilizers, buffer substances, taste corrigents, antioxidants and complexing agents (for example, ethylene diaminotetraacetic acid) and the like is possible. If required, the p~ range may be adjusted for the stabilization of the active substance molecule to approximately
3 to 7 with physiologically compatible acids or buffers. In general, a pH value as neutral as possible to weakly acid (to pH 5) is preferred.
Sodium metabisulphite, absorbic acid, gallic acid, gallic alkyl ester, butyl hydroxyanisole, nordihydro guaiaric _ acid, tocopherols as well as tocopherols + synergists (substances which bind heavy metals by com~plexing action, Eor example, lOSalOZ~
lecithina, absorhic acid, phosphoric acid) may be used as antioxidants. The addition of the synergists substantially increases the antioxygenating action of the tocopherols.
Sorbic acid, p-hydroxy ~enæoic esters, for example, lower alkyl ester, benzoic acid, sodium benzoate, trichloro isobutyl alcohol, phenol, cresol, ~enzethoniu~ chloride and formalin derivatives are suitable as preservatives.
The pharmacological and galenic hancllinq of the com-pounds according to the invention is carried out by means of the conventional standard methods. For example, active sub-stance(s) and auxiliaries and/or fillers are properly mixed by stirring or homogenizing (for example, by means of colloid mills, ball mills) usually at temperatures between 20 and 80C, pre-ferably between 20 and 50C.
The druys can be applied, for example, orally, parent-erally, rectally, vaginally, perlingually or locally. The addition of other active medical substances is possible. ~he compounds according to the invention show a good anticonvulsive and anxiety-reducing effect in the Cardiazol shock test (mice) and in the fiyhting test according to Tedeschi (mice). This effect is comparable to that of the known drugs diazepam, i medazepam.
The lowest eifective dose in the animal test mentioned above is, for example, 5 mg per ky orally 1 my per ky sublinaually 0.5 mg per kg intravenously As a general dose range for obtaining an effect (animal test as above) the followina dose is suitable, for example, 5 to 100 mg per ka orally 1 to 20 mg per kg sublingually 0.5 to 10 mg per ka intravenously .~ ~
OSOC);~l The compounds according to the invention are indicated for excitation, tension, anxiety, increased irritability, psychoneurotic disorders in children; vegetative dystonia, psychosomatic disorders, neuroses of organs, somnipathy; myos-pasms (as well as rheumatic disorders); treatment of crams; to facilitate childbirth, Ab~rtus imminens, impending and starting premature birth or miscarria~e, Placenta praevia and prior to operations.
The pharmaceutical preparations usually contain be-tween 0.5 and 5% of the active component~s) according to the invention.
They can be dispensed, for example, in the form oftablets, capsules, pills, gragees, suppositories, ointments, jellies, creams, powders, liquids, dusting po~ders or aerosols.
For example, oily or aqueous solution or suspensions or emulsions are suitable as liquids. Tablets containing between 5 and 100 mg of the active substance or solutions containina between 1 and 10% of the active substance are preferred forms of application.
The single dose of the active component can be, for example, a) for oral drug forms between 5 and lS0 mg o b) for parenteral drug forms (for example, intravenously and intramuscularly) between 0.5 and 10 mg c) for drug forms to be inhaled (solutions or aerosols) between 1 and 20 mg d) for drug forms to be applied rectally or vaginally between 5 and 150 mg (In all these cases the doses are relative to the free base) -For example, three times daily from 1 to 3 tablets containinq from 1 to 100 mq of active substance can be recom-, ~ ,, , ~
,,~
.
5~
mended or, for exa~ple, for intrave~ous injectlon 1 to 3 tim~s daily l ampule containing 0.5 to 2 ml with 0.5 to lO mg of substance~ When dispensed orally the minimum daily dose is, for example, lO m~ and the maximum daily dose must no~ exceed lO00 mq.
The parenteral dose is between approximately 0.5 and lO my per kg o~ body weic;ht.
For the treatment of cats and doys the sinyle oral dose usually is between approximately S and lO0 mg per kg of body weight.
For the treatment of horses and cattle the single oral dose usually is ~etween approximately 5 and 500 my per kg of body weight and the sinyle parenteral dose between approximately 0.5 and 50 m~ per ky.
In mice the acute toxicity of tlle compounds according to the invention (expressed by the LD 50 mg/k; method accordiny to Miller and Tainter: Proc. Soc. Exper. siol. a. ~1ed. 57 (1944) 261) is, for example, for oral application between 500 and 2000 my per kg (or above 2000 mg per ky).
The drugs can be used in human medicine, veterinary medicine and in agriculture either alonq or in mixture with other pharmacoloqically active substances.
Co~pounds havina the general formula I, wherein the symbols Rl to R5 have the following meanings, are particularly suitable:
Rl is NH2, lower dialkyl-amino ~roup in which the alkyl radicals contain l to 3 carbon atom, morpholino ~roup, piperazino group, hydroxy-ethyl amino ~roup;
R2 is hydrogen or fluroine or chlorine in the o-position.
R5 is an alkyl or alkenyl yroup containiny l to 4 carbon atoms, particularly the methyl group, the isopropyl ~050~)Z~
group, the allyl group or the butenyl- (2) -group or a dialkyl amino-ethyl group, dialkyl-amino-propyl group or dialkyl-amlno-isopropyl group, particularly hydrogen or a lower alkyl group containing 1 to 4 carbon atoms, for example, the methyl group.
Compounds having the formula I, wherein Rl represents a dimethyl-amino, diethyl-amino, triethyl-amino, morpholino or hydroxy-ethyl-amino group, R2 represents hydrogen, fluorine or chlorine, preferably in the o-position and R5 represents hydrogen or a lower alkyl group containing 1 to 4 carbon atoms, particularly the methyl group, have a particularly favourable effect.
Unless the starting compounds used in the processes a) and b) are known they can be obtained, for example, in the following manner:
Process a) -A compound having the formula .
R2 ~
<~ CH2 - CN
~
or R2 ~ C~2 - C02R~
I
`
(Ra represent hydrogen or a lower alkyl group) is first reacted with an acti~e alkali metal compound such as sodium amide, potassium amide, sodium hydride or finally dis-tributèd sodium, in an inert solvent such as dioxane, dimethyl 32~
formamide or benzine, whereupon the calculated amount of 2,6-dichloro-3-nitro-pyridine, dissolved in the same solvent, is added dropwise under ~n atmosphere of nitrogen while stirring.
In many cases it is expedient to change the sequence of addition, .
for example, to add the alkali compound to a solution of the phenyl-acetic-acid or benzyl cyanide derivative and 2,6-dichlo~o-3-nitro-pyridine. From the reaction, which usually is exothermic, an alkali salt of the compound having the formula ~III is obtained, i.e., Cl ~ C ~ R2 VII
wherein Cy represents CN or CO2 Ra where Ra = hydrogen or a lower alkyl group which has an intense blue to violet colour.
At the end of the reaction this product is filtered with suction, washed and dissolved in water, whereupon it is mixed with dilute glacial acetic until the natural colour disappears. The crystal-lizing compound having the formula VIII, usually is sufficiently pure.
For example, the 2-l~C-cyano)-o-chlorobenzyl]-3-nitro-chloro pyridine is produced in the following manner:
42 g of 80% sodium hydride (in white oil) are added to a solution of 120 g of o-chloro benzyl cyanide in 1 5 litres of dioxane at 45C under an atmosphere of nitrogen while stirr-ing. The solution is then cooled and at 20 to 22C 140 g of 2,6-dichloro-3-nitro pyridine in 500 ml of dioxane are added dropwise within 30 minutes. The reaction is allowed to continue at this temperature for three hours. The sodium salt, which ~ 18 - . . . . .
1050~21 has an intense colour, is f:ilte~ed with suction, washed with dioxane and dissol~ed in water/methanol (1:1), whereupon dilute acetic acid is added until th~ colour changes. The desired compound crystallizes out and is filtered with suction, where-upon it is thoroughly washed with methanol; m.p. = 174 to 175C
yield = 91 g.
From the compounds having the formula VIII the corres-ponding 2-benzoyl-3-nitro-6-chloro-pyridine derivatives (formula IX) ~ ~ ~ )l ~ R2 IX
o are produced by oxidation. For example, said oxidation can be carried out with selenium oxide in dioxane or tetrahydrofuran at 50 to 150C or it can be so carried out that a 30% hydrogen peroxide solution in acetone-water is used at temperatures below 100C, preferably between 20 and 50C and the stoichio-metric amount of an aqueous concentrated KOH solution is added dropwise at such a fast rate that the colour does not yet change. In the latter method a major portion of the chlorine atom in the 6 position is hydrolytically split of at the same time. Therefore, the compound having the formula IX, wherein Rl is hydroxyl, is isolated in addition to the desired compound.
Said compound having the formula IX is then chlorinated again in a known manner with a mixture of PC13 and PC15. At the same time the PC13 deoxygenates the N-oxides, which were formed as a by-product. In the compounds having the formula IX the chlorine is substituted by the radical Rl by reaction with NH3 or amines having the formula NHRaRb in a solvent or dispersing agent such as tetrahydrofuran, n-propanol at temperatures between .
50 and 200C. Rl can also be quartered by reaction with a '9~
compound RcHal, wherein ~al rePreSentS bromine, iodine, under the conditions mentioned hereinbefore.
The nitro group in the 3 position is then reduced to the amino group either catalytically e.g. with Pd, Pt~ Rancy-Ni in alcohols, dioxane, tetrahydrofuran at temperatures between 0 and 6GC and at 1 to 5~ atmospheres excess pressure or chem-ically e.g. with LiAlH4 or Al/Hg/H20 in other, dioxane, tetra-hydrofuran at temperatures between 0 and 60C. This amino group can be substituted by the radical R5 according to the processes mentioned heretobefore. In -this reduction further nitro groups, for example, if R2 and/or R3 represen-t nitro groups, can be reduced to amino ~roups if required.
For the production of compounds havin~ the formula XIII
1 ~NC02 o ~ 2 wherein Rl represents F or Br, for example, a compound having the formula IX is heated with a saturated aqueous-alcoholic ammonia solution in an autoclave at 100 to 120C for 2 to 4 hours and the 6-amino-pyridine derivative thus formed is then diazotized in a known manner and reacted according ~o the conditions of the Sandmeyer reaction or of the modified Sandmeyer reaction in the presence of fluoride or bromide ions and/or corresponding copper ~I) salts (CuBr, CuCl) or even fluoro-borate ions while heating. Water-alcohol mixtures or mixtures of water, dimethyl formamide and dimethyl sulphoxide are suitable as solvents for this purpose. For the production of the fluorine derivatives the dry diazonium fluoro borates can also be thermally decomposed~
Compounds having the formula XIII, wherein Rl represents 2~
a bromine atom, can also be ~1-ominated from compounds having the formula XIII, wherein R~=OH, ~Jith bro~inating agents such as PO~r3, PBr5, or SOBr2, if required, in an inert agent at temperatures between 20 and 200~C. Compounds having the formula XIII, wherein Rl = F, can be produced in that NaNO2 is gradually added to a solution of compounds having the formula XIII, wherein Rl represents an amino group, in concentrated aqueous hydrofluoric acid at tem~er~tures between 0 and 50C
or that a flow of nitrous gases is slowly injec-ted.
The reduction of the nitro group ~nd the subsequent introduction of R5 is carried out in the manner described here-inbefore.
Compounds having the general formula II, wherein W
represents the group =NH or =NOH, can he obtained, for example, from compounds having the formula II, wherein W represents oxygen and the other symbols Rl, R2 and R5 have the meanings specified hereinbefore, by reacting with ammonia or with hydro-xyl amine.
This reaction is carried out preferably in polar solvents (aliphatic alcohols, dioxane, tetrahydrofuran, pyridine, liquid ammonia) preferably at temperatures between 0 and 150C
and, if required, at excess pressures between 1 and 100 atm.
Process b) The starting compounds for this process can be produced according to the German Specification ~o. 2259471 or in a manner exactly analogous to the process described therein.
Example 1 5-phenyl-6-aza-7-dimethylamino-1,2-dihy~ro-3H-1,4-benzodiazapinone-(2) H _ C~
~ N
(CH3~2N ~ N 1 C N / 2 ~5~;1C~2~
A mixture of 22 g 2-benzoyl-3-amino~6-dimethylamino-pyridine, 22 q carbobenzoxyqlycine, 200 ml dio~ane and 22 g ethyl-1,2-dihydro-2-ethoxy-1-c~uinoline carboxylate is stirred for 90 minutes at room temperature. To the resultinc; solution are added ether and petroleum ether to t~r~idity. Upon scratch-ing, the 2-benzoyl-3-carbobenzoxyaminoacetyl-amino-6-dimethyl-aminopyridine crystallizes. Yield 20 ~; M.P. 114C.
19 q of the compound obtained in this manner is added in small amounts to 150 ml of a a0% solution of hydrogen bromide in glacial acetic acid at room temperature with stirring, whereby carbon dioxide is evolved. After the addition, the solution is left for one hour, then diluted with 600 ml ether with stirring.
The precipitate crystallizes on prolonged stirring. It is removed by suction filtration dissolved in 50 ml methanol, made alkaline with aqueous ammonia, and mixed with water until turbid.
The resulting crystals are obtained by suction filtration.
Yield 11 g.
A mixture of the substance which has been ohtained by this method, 1 ml pyridine and 150 ml toluene is boiled with stirring for 6 hours under reflux. ~he evaporated water is separated off with a water separator. The substance already commences to crystallize during the reaction. It is finally removed by suction filtration and recrystallized from ethanol.
Yield: 9.6 g; m.p. 241 to 245C ~decomposition).
The starting compound is produced by the following method:
a~ 2-benzoyl-3~nitro-6-dimethylaminopyridine 124 g 2-benzoyl~3-nitro-6-chloropyridine is dissolved in S00 ml of n-propanol and reacted with 50 g of dimethylamine ~ith stirring at 100C for 3 hours. Stirring is continued for a further hour and the solution is left over night. The above compound crystallizes upon scratching. It is removed by suction ,, ~
,,"~
~05~
filtration and washed with et~1anol. Yield: 114 g; M.P. 115 to b) 2-benzoyl-3-amino-6-dimethylaminopyridine.
50 ~ of the above nitro compound, is dissol~ed in 500 ml of methanol, and 20 g hydrazine-hydrate is added. Then S g Raney-nic~el is added in portions with stirrin~ at 30~C
over 90 minutes. After standing overnight the mixture filtered, the filtrate concentrated in ~acuo and the residue is dissolved in 500 ml of chloroform and chromatographed on silica gel. The eluate is evaporated. The product is used for the further reaction without additional purification. Yield: 24 g.
Example 2 N-(5-phenyl-6-aza-1,2-dihydro-3Hl,4-benzodiazepinon-(2)-yl-(7)-N,N,N-trimethyl ammonium iodide H
( 3)3 C - N
I( ) 5 g of 5-phenyl-6-aza-7-dimethyl-amino-1,2-dihydro-3H-benzo-1,4-diazcpinone-(2) are boiled in 100 ml of methyl iodide with reflux for 30 minutes. The dark red crystals pre-cipitated upon coolin~ are recrystallized from n-propanol.
Yield = 4 g, m.p. - 231 to 233~C (decomposition).
_ ample 3 5-phenyl-6-aza-7-morpholino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) NH - C ~
/~~~ ~ CH2 O N N C ==~N
2~
A mixture of 13.S q (0.05 mole) of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-diazepinon-(2) and 50 ml of anhydrous morpholine is kept at a temperature of 130C while stirring.
The mixture is then cooled ~nd poured on ice. Af~er one hour the solid subs-tance is filtered with suction and dissolved in chloroform. The chioroform so1ution is shake out with 200 ml of 2% hydrochloric acid and the aqueous phase is separated, whereupon it is neutralized with aqueous ammonia while cooling.
The desired product thus crystallizes out. Yield = 10 g, m.p.
= 265 to 270C.
The product can be recrystallized from a small amount of n-propanol.
Example 4 ~ -(o-fluoro-phenyl)-6-aza-7-morpholino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) NH _ ~
~--~ br F
A mixture of 10 g of 5-(o-fluoro-phenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) and 50 ml of anhydrous morpholine is heated for 1 hour to 130C while stirring.
The mixture is poured on ice upon cooling. After 1 hour the precipitates substance is filtered with suction and dissolved in chloroform, whexeupon it is shaken out wi-th 200 ml of 2~ ;
HCl. The aqueous phase is then neutralized with dilute ammonia while cooling. The dèsired product (4g) crystallizes out of the aqueous solution and is recrystallized from a small amount of ethanol while ber-zine is added;
m.p. = 227 to 240~C.
.xample 5 5-phenyl-6-aza-7-(2-hydroxy-ethyl-amino)-1,2-dihydro-3~l-1,4-benzodiazepinone-(2) NH ~CO
H ~ - N
HO-CH -C13 -N ~
A mixture of 13.5 g (0.05 mole) of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) and 50 ml of dry ethanolamine is stirred for one hour at 100C. It is then poured on ice, whereupon it is extracted with 100 ml of ether.
The ether layer is washed several times with water and dried.
The hydrochloride of the desired compound is then precipitated with isopropanolic HCl. The desired compound crystallizes upon trituration, whereupon it is filtered with suction and recrystallized from n-prepanol.
Yield = 5 g; m.p. = 210 to 215C.
Example 6 5-(o chloro-phenyl)-6-aza-7-benzyl-amino-1,2-dihydro-33~-1,4-benzodiazepinone-(2) fi~ I ~ C~32 CH2-N~ C--N /
~_.Cl -' ~J ~
26 g of bromoacetylbromide is added with stirring to a solution of 45 g 2-(o-chlorohenzoyl)-3-amino-6-benzyl-aminopyridine in 100 ml dry dioxane and 10 ml pyridine, whereon the temperature rises to 25~C. After 15 min., the mixture is Z~
poured into 750 ml water. The thick oi7 which is separated off, is decanted, added to ether, twice washed with water, the ether phase is then dried Wit~l sodium sulphate and the ether is evaporated. The residue is added to a small quantity of n propanol. The product, which crystallizes upon scratching, is hea-ted in an autoclave for 90 minu~es to 80C after drying (20 g) with 400 g of methanol and 65 g of ammonia. The autoclave solution is then reduced to 200 ml, mixed with 1 litre of water, decanted from the precipitated amorphous substance, and finally recrystallized from benzene. M.p. 195C to 197C.
The starting material is produced in the following manner.
a) 2-(O-chlorobenzoyl-)-3-nitro-6-benzylaminopyridine.
~a-ch~o ~ -A mixture of 52,5 grams of 21benzoyl~3-nitro-6-chlorpyridine, 300 ml n-propanol, 32,5 grams benzylamine and 28 grams potassium carbonate was stirred with reflux for 5 hours. The hot solution was filtered. The product crystallized on cooling. It was filtered with suction and washed with n-propanol.
Yield 44,5 grams; M.P. 140 to 143C.
b) 2-(o-chlorobenzoyl)-3-amino-6-benzylaminopyridine.
The nitro compound described above was reduced with hydrazine and Raney nickel in the manner shown under starting materials for example 1. The compouna crystallized after chromatographing. 45 grams of the nitro compound yielded 28 grams of the amino compound. ~I.P. 130~C.
Example 7 5-(0-chloro-phenyl)-6-aza-7-dimethyl-amino-1,2-dihydro-3H-1,4-benzodiazepinone-(2).
H C~O
( 3)2 N~ 2 _Cl m.ixture of 14 ~ o~ 2-(o-chloro-benzoyl)-3 amino-6-dimethyl-amino-pyridine, 15 ~ glycine-methyl ester HCl and 15 q of imidazole is melted and stirred for go minutes at 110 to 120C. The melt is diluted with a small amount of methanol and poured on 200 lm of water. Tne separated oil is isolated and dissolved in 100 ml of toluene while hot. The substance crystallized out of the solution upon cooling and is once more recrystallized from ethanol:
m.p. = 242 to 243C
The starting material is produced in the following ~yridine.
100 grams of 2-(o-chlorohenzoyl-)-3-nitro-6-chloro-pyridine (prepared acc. to U,S. Patent No. 4,008,223; issued February 15, 1977) were reacted as described above for starting materials of example 1.
Yield 90 grams; M.P. 142C.
b) 2-(o-chlorobenzoyl-)-3-amino-6-dimethyl-amino-pyridine.
The reduction of a) was carried out as shown under starting material for example 1 with hydrazine and Raney nickel.
30 grams of the nitro compound gave 17 grams of the sirupy amine.
Example 8 l-methyl-5-(o-chloro-phenyl-6-aza-7-dimethyl-amino-1,2-dihydro-3H-1,4 benzodiazepinone-(2).
I1~3 r ( 3)2 ~ / 2 ~Cl `~
0.9 g of 57~ sodium hydride ~in white oil) is added to ~ 050~Z~
a solution of 6 g of 5-(o-chl~o-phenyl)-6-aza-7-dimethyl-amino-l~2~dihydro-3H-l~4-dia~epinone-(2) (Example 7) in 50 ml of dry dimethyl formamide while stirring and under nitrogen at room temperature. The mixture is stirred for one hour while the temperature temporarily increases to 40C. 3 g of methyl iodide are then added dropwise, ~hereupon the temperature increased to 50C. This is followed by stirring for 2 hours, whereupon 200 ml of water are added. The precipitated oil crystallizes upon triturating and being allowed to stand. The substance is recrystallized from a small amount of rethanol;
m.p. = 158 to 162C
Example 9 l-allyl-5-(o-chloro-phenyl)-6-aza-7-dimethyl-amino-1,2-dihydro-3H-1,4-diazepinone-(2).
CH2 -CH=CH2 ~ o (CH3)2N ~ ~ Cl Starting with 5.5 g of 5-(o-chloro-~henyl)-6-aza-7-dimethyl-amino-1,2-dihydro-3H-1,4-diazepinone-(2) and 3 g of allyl bromide the produce is produced analogously to Example 8 and recrystallized;
m.p. = 113 to 115C
Example 10 5-phenyl-6-aza-7-amino-1,2-dihydro-3H-1,4-benzo-diazepinone-(2).
H2~ ~ \CH
2~
~ melt of 80 ~ra~s of cJlycine methyl ester hydro-chloride, 59 ~rams of 2-benzoyl-3,6-diaminopyridine and ~00 grams of imiclazole were heated at 11~-115C ~or 30 minutes.
Initially the mixture was stirred, after about 10 minutes the melt solidified. The solid cake was triturated with 60 ml of methanol, filtered with suetion, the filtrate coneentrated to 200 ml and poured into 1 liter of water. The produet which erystallized out was filtered off with suction and recrystalliz-ed from methanol. Yield 41 ~rams; ~1,1', 242~ - 244C.
The startin~ material for Example 1~ was obtained as follows:
A solution of 180 cJrams of 2-benzoyl-3-nitro ehloro-pyridine and 80 clrams of ammonia in 1 liter of aleohol was heated at 100 - 120C for 5 hours in an autoelave. The reaetion solution was evaporated to dryness, the residue thoroughly stirred with 1.5 liters of acetone and filtered. There were added 100 ml of concentrated hydrochloric acid and 3 liters of water, the crystallized reaction proclucts, the 2-benzoyl-3-nitro-6-aminopyridine, was washed with water. Yield 161 ~rams;
M.P. 196 - 198C.
153 grams of 2-benzoyl-3-nitro-6-aminopyridine were hydro~enated in 900 ml of dioxane with 20 (Jrams of Raney nickel at 40 atmosphers absolute and 60-70 C. The product was separated from the catalyst by filtering with suction and the filtrate treated with 6N ethanolic hydrochloric acid. The crystallized 2-benzoyl-3,6-diaminopyridine hydrochloride formed was filtered oEf with suction and washed with acetone. It was dissolved in some water, made alkaline with aqueous sodium hydroxide whereupon the ~ase first separated out as an oil and later crystallized. It was filterecl off with suetion and recrystallized from etha~ol. Yield 84 ~rams; M.P. 100-102~C.
`
32~
Exa~ple 11 ~ dimethylaminoethyl-(2)~-5-(o-chloropllenyl)-6-aza~7-dimethylamino-1,2-dih~dro-3EI-1,4-benzodiazepinone-(2 CH2-CH2- N(CE~3)2 (CH3)~N `~-C~
[~Cl ;' -To a solution of 32 ~rams of 5-~o-chlorophenyl)-6-azà-7-dimethylamino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) in 200 ml of dry dimethyl formamide there were added with stirring 3.3 grams of sodium hydride (80% in white oil) and allowed to react for 30 minutes. The mixture was then heated to 70C and there were added 20 grams of freshly produced dimethylaminoethyl chloride (base) in a little dimethyl formamide. Then the mixture was heated to 100C and stirred for 30 minutes. The solution , -was filtered, then,there were added 6N isopropanolic hydrochloric acid up to an acid reaction and 700 ml of ether. The top layer was decanted from the precipitated syrup, the syrup washed with acetone and dissolved in a little water. The solution was made ammoniacal, whereupon the base first precipitated as an oil and after some time crystallized. It was recrystallized from methylene chloride-cyclohexane (: by volume). Yield 12 grams;
~,P. 119~-120C.
Examp 12 5-phenyl-6-aza 7-(N'-methylpiperazino)-1,2-dihydro-3H-1,4-benzodiazepinone-(2) N-C~
H C ~ N ~ ~ C ~ 2 3 ~ ~ ~
~5~alZl A mixture of 10 gr~ms of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) and 100 ml of N-methyl-piperazine were heated for 2 hours under reflux. The solution was then evaporated to dryness in a vacuum, the residue dissolved in chloroform, washed with some water, then the solution dried and gasoline added until turbidity was observed.
The material then crystallized upon rubbing. It was recrystal-lized from ethanol with addition of activated carbon. Yield 3.5 grams; M.P. 226-228C.
Example 13 5-(o-chlorophenyl)-6-aza-7-pyrrolidino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) El ~0 C12-CH~2 ~ N-C~
CE~2-C~2 ~ Cl A mixture of 10 grams of 5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) and 15 ml of pyrrolidine were heated at reflux for 1 hour. The solution was evaporated to dryness in a vacuum, the residue dissolved in chloroform, washed with some water, then the solution dried and gasoline was added until turbidity. The substance crystallized upon rubbing. It was recrystallized from ethanol with addition of activated carbon. Yield 6 grams; M.P. 158-160C.
Example 14 Example of an Acid Addi-tion Salt The compound prepared in Example 7 was dissolved in a little acetone, then isopropanolic hydrochloric acid solution was added until an acid reaction, whereupon the hydrochloride crystallized out. It was filtered off with suction, the yield was nearly quantitative, M.P. above 300C.
. . - - . . . : :
Sodium metabisulphite, absorbic acid, gallic acid, gallic alkyl ester, butyl hydroxyanisole, nordihydro guaiaric _ acid, tocopherols as well as tocopherols + synergists (substances which bind heavy metals by com~plexing action, Eor example, lOSalOZ~
lecithina, absorhic acid, phosphoric acid) may be used as antioxidants. The addition of the synergists substantially increases the antioxygenating action of the tocopherols.
Sorbic acid, p-hydroxy ~enæoic esters, for example, lower alkyl ester, benzoic acid, sodium benzoate, trichloro isobutyl alcohol, phenol, cresol, ~enzethoniu~ chloride and formalin derivatives are suitable as preservatives.
The pharmacological and galenic hancllinq of the com-pounds according to the invention is carried out by means of the conventional standard methods. For example, active sub-stance(s) and auxiliaries and/or fillers are properly mixed by stirring or homogenizing (for example, by means of colloid mills, ball mills) usually at temperatures between 20 and 80C, pre-ferably between 20 and 50C.
The druys can be applied, for example, orally, parent-erally, rectally, vaginally, perlingually or locally. The addition of other active medical substances is possible. ~he compounds according to the invention show a good anticonvulsive and anxiety-reducing effect in the Cardiazol shock test (mice) and in the fiyhting test according to Tedeschi (mice). This effect is comparable to that of the known drugs diazepam, i medazepam.
The lowest eifective dose in the animal test mentioned above is, for example, 5 mg per ky orally 1 my per ky sublinaually 0.5 mg per kg intravenously As a general dose range for obtaining an effect (animal test as above) the followina dose is suitable, for example, 5 to 100 mg per ka orally 1 to 20 mg per kg sublingually 0.5 to 10 mg per ka intravenously .~ ~
OSOC);~l The compounds according to the invention are indicated for excitation, tension, anxiety, increased irritability, psychoneurotic disorders in children; vegetative dystonia, psychosomatic disorders, neuroses of organs, somnipathy; myos-pasms (as well as rheumatic disorders); treatment of crams; to facilitate childbirth, Ab~rtus imminens, impending and starting premature birth or miscarria~e, Placenta praevia and prior to operations.
The pharmaceutical preparations usually contain be-tween 0.5 and 5% of the active component~s) according to the invention.
They can be dispensed, for example, in the form oftablets, capsules, pills, gragees, suppositories, ointments, jellies, creams, powders, liquids, dusting po~ders or aerosols.
For example, oily or aqueous solution or suspensions or emulsions are suitable as liquids. Tablets containing between 5 and 100 mg of the active substance or solutions containina between 1 and 10% of the active substance are preferred forms of application.
The single dose of the active component can be, for example, a) for oral drug forms between 5 and lS0 mg o b) for parenteral drug forms (for example, intravenously and intramuscularly) between 0.5 and 10 mg c) for drug forms to be inhaled (solutions or aerosols) between 1 and 20 mg d) for drug forms to be applied rectally or vaginally between 5 and 150 mg (In all these cases the doses are relative to the free base) -For example, three times daily from 1 to 3 tablets containinq from 1 to 100 mq of active substance can be recom-, ~ ,, , ~
,,~
.
5~
mended or, for exa~ple, for intrave~ous injectlon 1 to 3 tim~s daily l ampule containing 0.5 to 2 ml with 0.5 to lO mg of substance~ When dispensed orally the minimum daily dose is, for example, lO m~ and the maximum daily dose must no~ exceed lO00 mq.
The parenteral dose is between approximately 0.5 and lO my per kg o~ body weic;ht.
For the treatment of cats and doys the sinyle oral dose usually is between approximately S and lO0 mg per kg of body weight.
For the treatment of horses and cattle the single oral dose usually is ~etween approximately 5 and 500 my per kg of body weight and the sinyle parenteral dose between approximately 0.5 and 50 m~ per ky.
In mice the acute toxicity of tlle compounds according to the invention (expressed by the LD 50 mg/k; method accordiny to Miller and Tainter: Proc. Soc. Exper. siol. a. ~1ed. 57 (1944) 261) is, for example, for oral application between 500 and 2000 my per kg (or above 2000 mg per ky).
The drugs can be used in human medicine, veterinary medicine and in agriculture either alonq or in mixture with other pharmacoloqically active substances.
Co~pounds havina the general formula I, wherein the symbols Rl to R5 have the following meanings, are particularly suitable:
Rl is NH2, lower dialkyl-amino ~roup in which the alkyl radicals contain l to 3 carbon atom, morpholino ~roup, piperazino group, hydroxy-ethyl amino ~roup;
R2 is hydrogen or fluroine or chlorine in the o-position.
R5 is an alkyl or alkenyl yroup containiny l to 4 carbon atoms, particularly the methyl group, the isopropyl ~050~)Z~
group, the allyl group or the butenyl- (2) -group or a dialkyl amino-ethyl group, dialkyl-amino-propyl group or dialkyl-amlno-isopropyl group, particularly hydrogen or a lower alkyl group containing 1 to 4 carbon atoms, for example, the methyl group.
Compounds having the formula I, wherein Rl represents a dimethyl-amino, diethyl-amino, triethyl-amino, morpholino or hydroxy-ethyl-amino group, R2 represents hydrogen, fluorine or chlorine, preferably in the o-position and R5 represents hydrogen or a lower alkyl group containing 1 to 4 carbon atoms, particularly the methyl group, have a particularly favourable effect.
Unless the starting compounds used in the processes a) and b) are known they can be obtained, for example, in the following manner:
Process a) -A compound having the formula .
R2 ~
<~ CH2 - CN
~
or R2 ~ C~2 - C02R~
I
`
(Ra represent hydrogen or a lower alkyl group) is first reacted with an acti~e alkali metal compound such as sodium amide, potassium amide, sodium hydride or finally dis-tributèd sodium, in an inert solvent such as dioxane, dimethyl 32~
formamide or benzine, whereupon the calculated amount of 2,6-dichloro-3-nitro-pyridine, dissolved in the same solvent, is added dropwise under ~n atmosphere of nitrogen while stirring.
In many cases it is expedient to change the sequence of addition, .
for example, to add the alkali compound to a solution of the phenyl-acetic-acid or benzyl cyanide derivative and 2,6-dichlo~o-3-nitro-pyridine. From the reaction, which usually is exothermic, an alkali salt of the compound having the formula ~III is obtained, i.e., Cl ~ C ~ R2 VII
wherein Cy represents CN or CO2 Ra where Ra = hydrogen or a lower alkyl group which has an intense blue to violet colour.
At the end of the reaction this product is filtered with suction, washed and dissolved in water, whereupon it is mixed with dilute glacial acetic until the natural colour disappears. The crystal-lizing compound having the formula VIII, usually is sufficiently pure.
For example, the 2-l~C-cyano)-o-chlorobenzyl]-3-nitro-chloro pyridine is produced in the following manner:
42 g of 80% sodium hydride (in white oil) are added to a solution of 120 g of o-chloro benzyl cyanide in 1 5 litres of dioxane at 45C under an atmosphere of nitrogen while stirr-ing. The solution is then cooled and at 20 to 22C 140 g of 2,6-dichloro-3-nitro pyridine in 500 ml of dioxane are added dropwise within 30 minutes. The reaction is allowed to continue at this temperature for three hours. The sodium salt, which ~ 18 - . . . . .
1050~21 has an intense colour, is f:ilte~ed with suction, washed with dioxane and dissol~ed in water/methanol (1:1), whereupon dilute acetic acid is added until th~ colour changes. The desired compound crystallizes out and is filtered with suction, where-upon it is thoroughly washed with methanol; m.p. = 174 to 175C
yield = 91 g.
From the compounds having the formula VIII the corres-ponding 2-benzoyl-3-nitro-6-chloro-pyridine derivatives (formula IX) ~ ~ ~ )l ~ R2 IX
o are produced by oxidation. For example, said oxidation can be carried out with selenium oxide in dioxane or tetrahydrofuran at 50 to 150C or it can be so carried out that a 30% hydrogen peroxide solution in acetone-water is used at temperatures below 100C, preferably between 20 and 50C and the stoichio-metric amount of an aqueous concentrated KOH solution is added dropwise at such a fast rate that the colour does not yet change. In the latter method a major portion of the chlorine atom in the 6 position is hydrolytically split of at the same time. Therefore, the compound having the formula IX, wherein Rl is hydroxyl, is isolated in addition to the desired compound.
Said compound having the formula IX is then chlorinated again in a known manner with a mixture of PC13 and PC15. At the same time the PC13 deoxygenates the N-oxides, which were formed as a by-product. In the compounds having the formula IX the chlorine is substituted by the radical Rl by reaction with NH3 or amines having the formula NHRaRb in a solvent or dispersing agent such as tetrahydrofuran, n-propanol at temperatures between .
50 and 200C. Rl can also be quartered by reaction with a '9~
compound RcHal, wherein ~al rePreSentS bromine, iodine, under the conditions mentioned hereinbefore.
The nitro group in the 3 position is then reduced to the amino group either catalytically e.g. with Pd, Pt~ Rancy-Ni in alcohols, dioxane, tetrahydrofuran at temperatures between 0 and 6GC and at 1 to 5~ atmospheres excess pressure or chem-ically e.g. with LiAlH4 or Al/Hg/H20 in other, dioxane, tetra-hydrofuran at temperatures between 0 and 60C. This amino group can be substituted by the radical R5 according to the processes mentioned heretobefore. In -this reduction further nitro groups, for example, if R2 and/or R3 represen-t nitro groups, can be reduced to amino ~roups if required.
For the production of compounds havin~ the formula XIII
1 ~NC02 o ~ 2 wherein Rl represents F or Br, for example, a compound having the formula IX is heated with a saturated aqueous-alcoholic ammonia solution in an autoclave at 100 to 120C for 2 to 4 hours and the 6-amino-pyridine derivative thus formed is then diazotized in a known manner and reacted according ~o the conditions of the Sandmeyer reaction or of the modified Sandmeyer reaction in the presence of fluoride or bromide ions and/or corresponding copper ~I) salts (CuBr, CuCl) or even fluoro-borate ions while heating. Water-alcohol mixtures or mixtures of water, dimethyl formamide and dimethyl sulphoxide are suitable as solvents for this purpose. For the production of the fluorine derivatives the dry diazonium fluoro borates can also be thermally decomposed~
Compounds having the formula XIII, wherein Rl represents 2~
a bromine atom, can also be ~1-ominated from compounds having the formula XIII, wherein R~=OH, ~Jith bro~inating agents such as PO~r3, PBr5, or SOBr2, if required, in an inert agent at temperatures between 20 and 200~C. Compounds having the formula XIII, wherein Rl = F, can be produced in that NaNO2 is gradually added to a solution of compounds having the formula XIII, wherein Rl represents an amino group, in concentrated aqueous hydrofluoric acid at tem~er~tures between 0 and 50C
or that a flow of nitrous gases is slowly injec-ted.
The reduction of the nitro group ~nd the subsequent introduction of R5 is carried out in the manner described here-inbefore.
Compounds having the general formula II, wherein W
represents the group =NH or =NOH, can he obtained, for example, from compounds having the formula II, wherein W represents oxygen and the other symbols Rl, R2 and R5 have the meanings specified hereinbefore, by reacting with ammonia or with hydro-xyl amine.
This reaction is carried out preferably in polar solvents (aliphatic alcohols, dioxane, tetrahydrofuran, pyridine, liquid ammonia) preferably at temperatures between 0 and 150C
and, if required, at excess pressures between 1 and 100 atm.
Process b) The starting compounds for this process can be produced according to the German Specification ~o. 2259471 or in a manner exactly analogous to the process described therein.
Example 1 5-phenyl-6-aza-7-dimethylamino-1,2-dihy~ro-3H-1,4-benzodiazapinone-(2) H _ C~
~ N
(CH3~2N ~ N 1 C N / 2 ~5~;1C~2~
A mixture of 22 g 2-benzoyl-3-amino~6-dimethylamino-pyridine, 22 q carbobenzoxyqlycine, 200 ml dio~ane and 22 g ethyl-1,2-dihydro-2-ethoxy-1-c~uinoline carboxylate is stirred for 90 minutes at room temperature. To the resultinc; solution are added ether and petroleum ether to t~r~idity. Upon scratch-ing, the 2-benzoyl-3-carbobenzoxyaminoacetyl-amino-6-dimethyl-aminopyridine crystallizes. Yield 20 ~; M.P. 114C.
19 q of the compound obtained in this manner is added in small amounts to 150 ml of a a0% solution of hydrogen bromide in glacial acetic acid at room temperature with stirring, whereby carbon dioxide is evolved. After the addition, the solution is left for one hour, then diluted with 600 ml ether with stirring.
The precipitate crystallizes on prolonged stirring. It is removed by suction filtration dissolved in 50 ml methanol, made alkaline with aqueous ammonia, and mixed with water until turbid.
The resulting crystals are obtained by suction filtration.
Yield 11 g.
A mixture of the substance which has been ohtained by this method, 1 ml pyridine and 150 ml toluene is boiled with stirring for 6 hours under reflux. ~he evaporated water is separated off with a water separator. The substance already commences to crystallize during the reaction. It is finally removed by suction filtration and recrystallized from ethanol.
Yield: 9.6 g; m.p. 241 to 245C ~decomposition).
The starting compound is produced by the following method:
a~ 2-benzoyl-3~nitro-6-dimethylaminopyridine 124 g 2-benzoyl~3-nitro-6-chloropyridine is dissolved in S00 ml of n-propanol and reacted with 50 g of dimethylamine ~ith stirring at 100C for 3 hours. Stirring is continued for a further hour and the solution is left over night. The above compound crystallizes upon scratching. It is removed by suction ,, ~
,,"~
~05~
filtration and washed with et~1anol. Yield: 114 g; M.P. 115 to b) 2-benzoyl-3-amino-6-dimethylaminopyridine.
50 ~ of the above nitro compound, is dissol~ed in 500 ml of methanol, and 20 g hydrazine-hydrate is added. Then S g Raney-nic~el is added in portions with stirrin~ at 30~C
over 90 minutes. After standing overnight the mixture filtered, the filtrate concentrated in ~acuo and the residue is dissolved in 500 ml of chloroform and chromatographed on silica gel. The eluate is evaporated. The product is used for the further reaction without additional purification. Yield: 24 g.
Example 2 N-(5-phenyl-6-aza-1,2-dihydro-3Hl,4-benzodiazepinon-(2)-yl-(7)-N,N,N-trimethyl ammonium iodide H
( 3)3 C - N
I( ) 5 g of 5-phenyl-6-aza-7-dimethyl-amino-1,2-dihydro-3H-benzo-1,4-diazcpinone-(2) are boiled in 100 ml of methyl iodide with reflux for 30 minutes. The dark red crystals pre-cipitated upon coolin~ are recrystallized from n-propanol.
Yield = 4 g, m.p. - 231 to 233~C (decomposition).
_ ample 3 5-phenyl-6-aza-7-morpholino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) NH - C ~
/~~~ ~ CH2 O N N C ==~N
2~
A mixture of 13.S q (0.05 mole) of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-diazepinon-(2) and 50 ml of anhydrous morpholine is kept at a temperature of 130C while stirring.
The mixture is then cooled ~nd poured on ice. Af~er one hour the solid subs-tance is filtered with suction and dissolved in chloroform. The chioroform so1ution is shake out with 200 ml of 2% hydrochloric acid and the aqueous phase is separated, whereupon it is neutralized with aqueous ammonia while cooling.
The desired product thus crystallizes out. Yield = 10 g, m.p.
= 265 to 270C.
The product can be recrystallized from a small amount of n-propanol.
Example 4 ~ -(o-fluoro-phenyl)-6-aza-7-morpholino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) NH _ ~
~--~ br F
A mixture of 10 g of 5-(o-fluoro-phenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) and 50 ml of anhydrous morpholine is heated for 1 hour to 130C while stirring.
The mixture is poured on ice upon cooling. After 1 hour the precipitates substance is filtered with suction and dissolved in chloroform, whexeupon it is shaken out wi-th 200 ml of 2~ ;
HCl. The aqueous phase is then neutralized with dilute ammonia while cooling. The dèsired product (4g) crystallizes out of the aqueous solution and is recrystallized from a small amount of ethanol while ber-zine is added;
m.p. = 227 to 240~C.
.xample 5 5-phenyl-6-aza-7-(2-hydroxy-ethyl-amino)-1,2-dihydro-3~l-1,4-benzodiazepinone-(2) NH ~CO
H ~ - N
HO-CH -C13 -N ~
A mixture of 13.5 g (0.05 mole) of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) and 50 ml of dry ethanolamine is stirred for one hour at 100C. It is then poured on ice, whereupon it is extracted with 100 ml of ether.
The ether layer is washed several times with water and dried.
The hydrochloride of the desired compound is then precipitated with isopropanolic HCl. The desired compound crystallizes upon trituration, whereupon it is filtered with suction and recrystallized from n-prepanol.
Yield = 5 g; m.p. = 210 to 215C.
Example 6 5-(o chloro-phenyl)-6-aza-7-benzyl-amino-1,2-dihydro-33~-1,4-benzodiazepinone-(2) fi~ I ~ C~32 CH2-N~ C--N /
~_.Cl -' ~J ~
26 g of bromoacetylbromide is added with stirring to a solution of 45 g 2-(o-chlorohenzoyl)-3-amino-6-benzyl-aminopyridine in 100 ml dry dioxane and 10 ml pyridine, whereon the temperature rises to 25~C. After 15 min., the mixture is Z~
poured into 750 ml water. The thick oi7 which is separated off, is decanted, added to ether, twice washed with water, the ether phase is then dried Wit~l sodium sulphate and the ether is evaporated. The residue is added to a small quantity of n propanol. The product, which crystallizes upon scratching, is hea-ted in an autoclave for 90 minu~es to 80C after drying (20 g) with 400 g of methanol and 65 g of ammonia. The autoclave solution is then reduced to 200 ml, mixed with 1 litre of water, decanted from the precipitated amorphous substance, and finally recrystallized from benzene. M.p. 195C to 197C.
The starting material is produced in the following manner.
a) 2-(O-chlorobenzoyl-)-3-nitro-6-benzylaminopyridine.
~a-ch~o ~ -A mixture of 52,5 grams of 21benzoyl~3-nitro-6-chlorpyridine, 300 ml n-propanol, 32,5 grams benzylamine and 28 grams potassium carbonate was stirred with reflux for 5 hours. The hot solution was filtered. The product crystallized on cooling. It was filtered with suction and washed with n-propanol.
Yield 44,5 grams; M.P. 140 to 143C.
b) 2-(o-chlorobenzoyl)-3-amino-6-benzylaminopyridine.
The nitro compound described above was reduced with hydrazine and Raney nickel in the manner shown under starting materials for example 1. The compouna crystallized after chromatographing. 45 grams of the nitro compound yielded 28 grams of the amino compound. ~I.P. 130~C.
Example 7 5-(0-chloro-phenyl)-6-aza-7-dimethyl-amino-1,2-dihydro-3H-1,4-benzodiazepinone-(2).
H C~O
( 3)2 N~ 2 _Cl m.ixture of 14 ~ o~ 2-(o-chloro-benzoyl)-3 amino-6-dimethyl-amino-pyridine, 15 ~ glycine-methyl ester HCl and 15 q of imidazole is melted and stirred for go minutes at 110 to 120C. The melt is diluted with a small amount of methanol and poured on 200 lm of water. Tne separated oil is isolated and dissolved in 100 ml of toluene while hot. The substance crystallized out of the solution upon cooling and is once more recrystallized from ethanol:
m.p. = 242 to 243C
The starting material is produced in the following ~yridine.
100 grams of 2-(o-chlorohenzoyl-)-3-nitro-6-chloro-pyridine (prepared acc. to U,S. Patent No. 4,008,223; issued February 15, 1977) were reacted as described above for starting materials of example 1.
Yield 90 grams; M.P. 142C.
b) 2-(o-chlorobenzoyl-)-3-amino-6-dimethyl-amino-pyridine.
The reduction of a) was carried out as shown under starting material for example 1 with hydrazine and Raney nickel.
30 grams of the nitro compound gave 17 grams of the sirupy amine.
Example 8 l-methyl-5-(o-chloro-phenyl-6-aza-7-dimethyl-amino-1,2-dihydro-3H-1,4 benzodiazepinone-(2).
I1~3 r ( 3)2 ~ / 2 ~Cl `~
0.9 g of 57~ sodium hydride ~in white oil) is added to ~ 050~Z~
a solution of 6 g of 5-(o-chl~o-phenyl)-6-aza-7-dimethyl-amino-l~2~dihydro-3H-l~4-dia~epinone-(2) (Example 7) in 50 ml of dry dimethyl formamide while stirring and under nitrogen at room temperature. The mixture is stirred for one hour while the temperature temporarily increases to 40C. 3 g of methyl iodide are then added dropwise, ~hereupon the temperature increased to 50C. This is followed by stirring for 2 hours, whereupon 200 ml of water are added. The precipitated oil crystallizes upon triturating and being allowed to stand. The substance is recrystallized from a small amount of rethanol;
m.p. = 158 to 162C
Example 9 l-allyl-5-(o-chloro-phenyl)-6-aza-7-dimethyl-amino-1,2-dihydro-3H-1,4-diazepinone-(2).
CH2 -CH=CH2 ~ o (CH3)2N ~ ~ Cl Starting with 5.5 g of 5-(o-chloro-~henyl)-6-aza-7-dimethyl-amino-1,2-dihydro-3H-1,4-diazepinone-(2) and 3 g of allyl bromide the produce is produced analogously to Example 8 and recrystallized;
m.p. = 113 to 115C
Example 10 5-phenyl-6-aza-7-amino-1,2-dihydro-3H-1,4-benzo-diazepinone-(2).
H2~ ~ \CH
2~
~ melt of 80 ~ra~s of cJlycine methyl ester hydro-chloride, 59 ~rams of 2-benzoyl-3,6-diaminopyridine and ~00 grams of imiclazole were heated at 11~-115C ~or 30 minutes.
Initially the mixture was stirred, after about 10 minutes the melt solidified. The solid cake was triturated with 60 ml of methanol, filtered with suetion, the filtrate coneentrated to 200 ml and poured into 1 liter of water. The produet which erystallized out was filtered off with suction and recrystalliz-ed from methanol. Yield 41 ~rams; ~1,1', 242~ - 244C.
The startin~ material for Example 1~ was obtained as follows:
A solution of 180 cJrams of 2-benzoyl-3-nitro ehloro-pyridine and 80 clrams of ammonia in 1 liter of aleohol was heated at 100 - 120C for 5 hours in an autoelave. The reaetion solution was evaporated to dryness, the residue thoroughly stirred with 1.5 liters of acetone and filtered. There were added 100 ml of concentrated hydrochloric acid and 3 liters of water, the crystallized reaction proclucts, the 2-benzoyl-3-nitro-6-aminopyridine, was washed with water. Yield 161 ~rams;
M.P. 196 - 198C.
153 grams of 2-benzoyl-3-nitro-6-aminopyridine were hydro~enated in 900 ml of dioxane with 20 (Jrams of Raney nickel at 40 atmosphers absolute and 60-70 C. The product was separated from the catalyst by filtering with suction and the filtrate treated with 6N ethanolic hydrochloric acid. The crystallized 2-benzoyl-3,6-diaminopyridine hydrochloride formed was filtered oEf with suction and washed with acetone. It was dissolved in some water, made alkaline with aqueous sodium hydroxide whereupon the ~ase first separated out as an oil and later crystallized. It was filterecl off with suetion and recrystallized from etha~ol. Yield 84 ~rams; M.P. 100-102~C.
`
32~
Exa~ple 11 ~ dimethylaminoethyl-(2)~-5-(o-chloropllenyl)-6-aza~7-dimethylamino-1,2-dih~dro-3EI-1,4-benzodiazepinone-(2 CH2-CH2- N(CE~3)2 (CH3)~N `~-C~
[~Cl ;' -To a solution of 32 ~rams of 5-~o-chlorophenyl)-6-azà-7-dimethylamino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) in 200 ml of dry dimethyl formamide there were added with stirring 3.3 grams of sodium hydride (80% in white oil) and allowed to react for 30 minutes. The mixture was then heated to 70C and there were added 20 grams of freshly produced dimethylaminoethyl chloride (base) in a little dimethyl formamide. Then the mixture was heated to 100C and stirred for 30 minutes. The solution , -was filtered, then,there were added 6N isopropanolic hydrochloric acid up to an acid reaction and 700 ml of ether. The top layer was decanted from the precipitated syrup, the syrup washed with acetone and dissolved in a little water. The solution was made ammoniacal, whereupon the base first precipitated as an oil and after some time crystallized. It was recrystallized from methylene chloride-cyclohexane (: by volume). Yield 12 grams;
~,P. 119~-120C.
Examp 12 5-phenyl-6-aza 7-(N'-methylpiperazino)-1,2-dihydro-3H-1,4-benzodiazepinone-(2) N-C~
H C ~ N ~ ~ C ~ 2 3 ~ ~ ~
~5~alZl A mixture of 10 gr~ms of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) and 100 ml of N-methyl-piperazine were heated for 2 hours under reflux. The solution was then evaporated to dryness in a vacuum, the residue dissolved in chloroform, washed with some water, then the solution dried and gasoline added until turbidity was observed.
The material then crystallized upon rubbing. It was recrystal-lized from ethanol with addition of activated carbon. Yield 3.5 grams; M.P. 226-228C.
Example 13 5-(o-chlorophenyl)-6-aza-7-pyrrolidino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) El ~0 C12-CH~2 ~ N-C~
CE~2-C~2 ~ Cl A mixture of 10 grams of 5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) and 15 ml of pyrrolidine were heated at reflux for 1 hour. The solution was evaporated to dryness in a vacuum, the residue dissolved in chloroform, washed with some water, then the solution dried and gasoline was added until turbidity. The substance crystallized upon rubbing. It was recrystallized from ethanol with addition of activated carbon. Yield 6 grams; M.P. 158-160C.
Example 14 Example of an Acid Addi-tion Salt The compound prepared in Example 7 was dissolved in a little acetone, then isopropanolic hydrochloric acid solution was added until an acid reaction, whereupon the hydrochloride crystallized out. It was filtered off with suction, the yield was nearly quantitative, M.P. above 300C.
. . - - . . . : :
Claims (38)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing 1,3-dihydro-5-phenyl-2H-pyrido[3,2-e]-[1,4]-diazepin-2-ones having the general formula I
X1 represents an amino a C2-C4 hydroxyalkyl-amino group, a mono-C1-C4-alkyl-amino group, a di-C1-C4-alkylamino group, a phenyl alkyl-amino-group, the alkyl portion of which consists of 1 to 4 C atoms or is a morpholino pyrollidino, piperazino or C1-C4 alky]
piperazino group, R2 represents hydrogen or a halogen atom and R5 represents a hydrogen atom, a C1-C4-alkyl group or a C1-C4 alkyl group substituted by a dialkyl amino group in which each alkyl group has 1 to 4 carbon atoms or a C2-C6-alkenyl group, their tautomeric forms, their pharmaceutically acceptible acid addition salts and their pharmaceutically acceptible quaternary compounds, which comprises a) reacting a compound having the formula II
wherein W is an oxygen atom or the group =NH or =NOH the symbols R1 to R5 have the meanings defined above with a compound having the general formula wherein R7 represents a hydroxy group, a halogen atom, a lower alkoxy group or a lower alkyl-mercapto group and X represents an amino group, an amino group protected by a group which is an acyl group which is solvolytically cleavable or a group cleavable by hydrogenation, or a halogen atom, the amino group always con-taining said protective group when R7 represents a hydroxy group, if required, in the presence of acid-binding agents,condensation being carried out in the presence of ammonia or an ammonia derivative when W is oxygen and X is halogen, b) reacting a compound having the formula I, wherein R1 represents a halogen atom, and the other symbols have the meanings defined above, with ammonia a C2-C4-hydroxy-alkyl amine, a mono-C1-C4-alkyl amine, a di-C1-C4 alkyl amine, a phenyl-alkyl amine, the alkyl portion of which consists of 1 to 4 carbon atoms,morpholine,pyrollidine, piperizine or a C1-C4 alkyl piperazine or c) C1-C4-alkylating or C2-C6-alkenylating a compound having the formula I, wherein R5 represents hydrogen, and when required, the compounds obtained are converted into their pharmaceutically acceptable quaternary salts or into their pharmaceutically acceptable acid addition salts.
X1 represents an amino a C2-C4 hydroxyalkyl-amino group, a mono-C1-C4-alkyl-amino group, a di-C1-C4-alkylamino group, a phenyl alkyl-amino-group, the alkyl portion of which consists of 1 to 4 C atoms or is a morpholino pyrollidino, piperazino or C1-C4 alky]
piperazino group, R2 represents hydrogen or a halogen atom and R5 represents a hydrogen atom, a C1-C4-alkyl group or a C1-C4 alkyl group substituted by a dialkyl amino group in which each alkyl group has 1 to 4 carbon atoms or a C2-C6-alkenyl group, their tautomeric forms, their pharmaceutically acceptible acid addition salts and their pharmaceutically acceptible quaternary compounds, which comprises a) reacting a compound having the formula II
wherein W is an oxygen atom or the group =NH or =NOH the symbols R1 to R5 have the meanings defined above with a compound having the general formula wherein R7 represents a hydroxy group, a halogen atom, a lower alkoxy group or a lower alkyl-mercapto group and X represents an amino group, an amino group protected by a group which is an acyl group which is solvolytically cleavable or a group cleavable by hydrogenation, or a halogen atom, the amino group always con-taining said protective group when R7 represents a hydroxy group, if required, in the presence of acid-binding agents,condensation being carried out in the presence of ammonia or an ammonia derivative when W is oxygen and X is halogen, b) reacting a compound having the formula I, wherein R1 represents a halogen atom, and the other symbols have the meanings defined above, with ammonia a C2-C4-hydroxy-alkyl amine, a mono-C1-C4-alkyl amine, a di-C1-C4 alkyl amine, a phenyl-alkyl amine, the alkyl portion of which consists of 1 to 4 carbon atoms,morpholine,pyrollidine, piperizine or a C1-C4 alkyl piperazine or c) C1-C4-alkylating or C2-C6-alkenylating a compound having the formula I, wherein R5 represents hydrogen, and when required, the compounds obtained are converted into their pharmaceutically acceptable quaternary salts or into their pharmaceutically acceptable acid addition salts.
2. 1,3-Dihydro-5-phenyl-2H-pyrido[3,2-e]-[1,4]-diazepin-2-ones having the general formula I
I
R1 represents an amino a C2-C4 hydroxyalkyl-amino group, a mono-C1-C4-alkyl-amino group, a di-C1-C4-alkyl-amino group, a phenyl-alkyl-amino group, the alkyl portion of which consists of 1 to 4 atoms or is a morpholino pyrollidino, piperazino or C1-C4 alkyl piperazino group, R2 represents hydrogen or a halogen atom and R5 represents a hydrogen atom, a C1-C4-alkyl group or a C1-C4 alkyl group substituted by a dialkyl amino group in which each group has 1 to 4 carbon atoms or a C2-C6-alkenyl group, their tautomeric forms, their pharmaceutically acceptible acid addition salts and their pharmaceutically acceptible quaternary compounds whenever prepared or produced by the process as claimed in claim 1 or an obvious chemical equivalent thereof.
I
R1 represents an amino a C2-C4 hydroxyalkyl-amino group, a mono-C1-C4-alkyl-amino group, a di-C1-C4-alkyl-amino group, a phenyl-alkyl-amino group, the alkyl portion of which consists of 1 to 4 atoms or is a morpholino pyrollidino, piperazino or C1-C4 alkyl piperazino group, R2 represents hydrogen or a halogen atom and R5 represents a hydrogen atom, a C1-C4-alkyl group or a C1-C4 alkyl group substituted by a dialkyl amino group in which each group has 1 to 4 carbon atoms or a C2-C6-alkenyl group, their tautomeric forms, their pharmaceutically acceptible acid addition salts and their pharmaceutically acceptible quaternary compounds whenever prepared or produced by the process as claimed in claim 1 or an obvious chemical equivalent thereof.
3. A process as claimed in claim 1 in which the reactants R1 represents an alkylamino group containing 1 to 4 carbon atoms or a dialkylamino group with alkyl radicals contain-ing 1 to 4 carbon atoms or a hydroxy alkylamino group containing 2 to 4 carbon atoms a benzylamino group or a morpholino, radical and R1 may also be quaternized by a further additional alkyl group containing 1 to 3 carbon atoms, R2 represents hydrogen, fluorine, chlorine or bromine and R5 represents hydrogen or an alkyl group containing 1 to 4 carbon atoms.
4. A compound of formula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1, R2 and R5 are as in claim 3 whenever prepared by the process as claimed in claim 3 or an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 in which in the reactants R1 represents an alkylamino group containing 1 to 4 carbon atoms or a dialkylamino group with alkyl radicals containing 1 to 4 carbon atoms or a hydroxy alkylamino group containing 2 to 4 carbon atoms, a benzylamino group or a morpholino radical, R2 represents hydrogen, chlorine, fluorine or bromine and R5 repre-sents hydrogen or an alkyl group containing 1 to 4 carbon atoms.
6. A compound of formula I given in claim 1 or a pharmaceutically acceptable salt thereof and R1, R2 and R5 are as in claim 5 whenever prepared by the process as claimed in claim 5 or an obvious chemical equivalent thereof.
7. A process as claimed in claim 5 in which in the reactants R2 is hydrogen or chlorine or fluorine in the o-position.
8. A compound of formula I given in claim 1 or a pharmaceutically acceptable salt thereof in which R2 is hydrogen chlorine or fluorine in the o-position and R1 and R5 are as in claim 5 whenever prepared by the process as claimed in claim 7 or an obvious chemical equivalent thereof.
9. A process as claimed in claim 7 in which in the reactants R5 is hydrogen or methyl.
10. A compound of formula I given in claim 1 or a pharmaceutically acceptable salt thereof in which R2 is hydrogen chlorine or fluorine in the o-position, R1 is as in claim 5, and R5 is hydrogen or methyl whenever prepared by the process as claimed in claim 9 or an obvious chemical equivalent thereof.
11. A process as claimed in claim 9 in which in the reactants R1 is morpholino, benzylamino, dimethyl amino or .beta.-hydroxy ethyl amino.
12. A compound of formula I given in claim 1 or a pharmaceutically acceptable salt thereof in which, R1 is as in claim 11, R2 is hydrogen, fluorine or chlorine in the o-position and R5 is hydrogen or methyl whenever prepared by the process as claimed in claim 11 or an obvious chemical equivalent thereof.
13. A process as claimed in claim 1, in which in the reactants R1 is dimethylamino and R2 and R5 are hydrogen.
14. A process as claimed in claim 1 which comprises boiling reacting 2-benzoyl-3-amino- -6-dimethylamino-pyridine with carbobenzoxy glycine in dioxane and in the presence of ethyl 1,2-dihydro-2-ethoxy-1-quinoline carboxylate, treating the 2-benzoyl-3-carbobenzoxy amino acetyl amino-6-dimethylamino pyridine so obtained with hydrogen bromide in glacial acetic acid and the product obtained in toluene under reflux and in the presence of pyridine.
15. The compound 5-phenyl-6-aza-7-dirnethylamino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) when prepared by the process as claimed in claim 13 or 14 or an obvious chemical equivalent thereof.
16. A process as claimed in claim 14, in which the product obtained is boiled in methyl iodide.
17. The compound N-(5-phenyl-6-aza-1,2-dihydro-3H-1,4-benzodiazepinon-(2)-yl-(7)-N,N,N-trimethyl ammonium iodide when prepared by the process as claimed in claim 16 or an obvious chemical equivalent thereof.
18. A proeess as claimed in claim 1, in which in the reactants R1 is morpholino and R2 and R5 is hydrogen.
19. A process as claimed in claim 1 which comprises heating a mixture of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-diazepinone-(2) and anhydrous morpholine.
20. The compound 5-phenyl-6-aza-7-morpholino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) when prepared by the process as claimed in claim 18 or 19 or an obvious chemical equivalent thereof.
21. A process as claimed in claim 1, in which in the reactants R1 is morpholino, R2 is fluorine in the o-position and R5 is hydrogen.
22. A process as claimed in claim 1 which comprises heating a mixture of 5-(o-fluorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) and anhydrous morpholine.
23. The compound 5-(o-fluorophenyl)-6-aza-7-morpholino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) when prepared by the process as claimed in claim 21 or 22 or an obvious chemical equivalent thereof.
24. A process as claimed in claim 1, in which in the reactants R1 is .beta.-hydroxyethylamino, and R2 and R5 are hydrogen.
25. A process as claimed in claim 1 which comprises heating a mixture of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) and dry ethanolamine.
26. The compound 5-phenyl-6-aza-7-(2-hydroxyethyl-amino)-1,2-dihydro-3H-1,4-benzodiazepinone-(2) when prepared by the process as claimed in claim 24 or 25 or an obvious chemical equivalent thereof.
27. A process as claimed in claim 1, in which in the reactants R1 is benzoylamino, R2 is chlorine in the o-position, and R5 is hydrogen.
28. A prosess as claimed in claim 1 which comprises heating under auto gaseous pressure a mixture of 2-(o-chloro-benzoyl)-3-(bromo-acetamino)-6-benzoylamino-pyridine, methanol and ammonia.
29. The compound 5-(o-chlorophenyl)-6-aza-7-benzoyl-amino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) when prepared by the process as claimed in claim 27 or 28 or an obvious chemical equivalent thereof.
30. A process as claimed in claim 1, in which in the reactants R1 is dimethylamino, R2 is chlorine in the o-position, and R5 is hydrogen.
31. A process as claimed in claim 1 which comprises heatinq a mixture of 2-(o-chlorobenzoyl)-3-amino-6-dimethyl-amino-pyridine, glycine methyl ester hydrochloride and imidazole.
32. The compound 5-(o-chlorophenyl)-6-aza-7-dimethyl-amino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) when prepared by the process as claimed in claim 30 or 31 or an obvious chemical equivalent thereof.
33. A process as claimed in claim 1, in which in the reactants R1 is dimethylamino, R2 is chlorine in the o-position, and R5 is methyl.
34. A process as claimed in claim 31 which comprises reacting the product ohtained in dry dimethyl formamide with sodium hydride under a nitrogen atmosphere at room temperature and reacting the sodium salt obtained with methyl iodide.
35. The compound 1-methyl-5-(o-chlorophenyl-6-aza-7-dimethylamino-1,2-dihydro-3H-1,4-benzodiazepinone-(2) when prepared by the process as claimed in claim 33 or 34 or an obvious chemical equivalent thereof.
36. A process as claimed in claim 1, in which in the reactants R1 is dimethylamino, R5 is allyl, and R2 is chlorine in the o-position.
37. A process as claimed in claim 31 which comprises reacting the product obtained in dry dimethyl formamide with sodium hydride under a nitrogen atmosphere at room temperature and reacting the sodium salt ohtained with allyl bromide.
38. The compound 1-allyl-5-(o-chlorophenyl)-6-aza-7-dimethylamino-1,2-dihydro-3H-1,4-diazepinone-(2) when prepared by the process as clamed in claim 36 or 37 or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT3772A AT304473B (en) | 1967-03-10 | 1968-03-08 | Process for the preparation of new substituted 1-amino-2-hydroxy-3- [2'-cyclopentyl- or (δ 2 -cyclopentenyl) -phenoxy] -propanes, their optically active isomers and salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1050021A true CA1050021A (en) | 1979-03-06 |
Family
ID=3555215
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA198,389A Expired CA1050021A (en) | 1968-03-08 | 1974-04-29 | 6-aza-3h-1,4-benzodiazepines |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1050021A (en) |
-
1974
- 1974-04-29 CA CA198,389A patent/CA1050021A/en not_active Expired
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