CA1057286A - Pyridobenzodiazepinones, processes for their preparation and pharmaceuticals containing these compounds - Google Patents
Pyridobenzodiazepinones, processes for their preparation and pharmaceuticals containing these compoundsInfo
- Publication number
- CA1057286A CA1057286A CA227,479A CA227479A CA1057286A CA 1057286 A CA1057286 A CA 1057286A CA 227479 A CA227479 A CA 227479A CA 1057286 A CA1057286 A CA 1057286A
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- methyl
- pyrido
- dihydro
- benzodiazepin
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Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to new pyridobenzodiazepinones which in general possess interesting pharmacological properties, particularly in the treatment of bronchial asthma. Several processes for the preparation and interconversion of these compounds are described and exemplified. Examples of pharmaceutical compositions containing the new compounds are also given.
The invention relates to new pyridobenzodiazepinones which in general possess interesting pharmacological properties, particularly in the treatment of bronchial asthma. Several processes for the preparation and interconversion of these compounds are described and exemplified. Examples of pharmaceutical compositions containing the new compounds are also given.
Description
,, - 1.057Z 516 ~ :.` .i ,`.................................................................. ~. . ;~
This invention relates to new pyridobenzodiazepinones as well ~`.;.~., AS to processes for their preparation and to pharmaceutical compositions containing them.
~ccording to one feature of the present in~ention there are pr~vided compounds of general formula I~
(CH2)n ~
wherein~
.~ ~ either R1 represents a hydrogen atom~ a straigh-t chain or branched alkyl group containing from 1 to 3 carbon atoms or a ~ ~ :
benzyl ~roup and R2 represents a straight chain or branched ~ ?'' ' alkyl~group containing from 1 to 3 carbon atoms, or ~ ;6, "' ~"
: Rl and R2, together with the nitrogen atom to which they are attached7 form a pyrrolidino, piperidino or hexamethyleneimino , gro~p;
;~ . n is 2 or 3;
either A represents a nitrogen atom and B represents the ~roup ,~
.~ -CH-, or ç B represents a nitrogen atom and A represents the~group =CH~ ?'`.:~
and acid addition salts thereof.
: ~, .: , -... " ,. . . ..
~S~286 ~ ~
:. ~
~ :, The compounds of general formula I and the physiologicall~
compatible acid addition salts thereo~, in general possess : useful pharmacological properties, particularly in the treat~
ment of bronchial asthma.
The new compotmds may, for example, be prepared according to~
the following processes, which processes constitute further : features of the present invention. ~ -,. ~
. a) Reaction of a compound of formula II, : 0 C~3 ~ f ~ r M
herein A and B are as hereinbefore defined and M represents `~
an alkali metal atom), with a compound of formula III, R : . ;~:-: X ~ (CEI2)n-N \ (III) : 2 (wherein Rl, R2:and n are as hereinbefore defined and X . .~`
represents a leaving group, for example a halogen atom or a ;~
tos~l group). The reaction is conveniently performed in an ` ~`~
. :
inert organic solvent at temperatures of from 20 to 250C. ~-: - 3 -'`~
~1~57~8~?
,. i` :
As inert solvents for example xylene, toluene, dioxan, -~
dimethyl ormamide or acetone may be used.
- The compound o~ ~ormula II is advantageously produced in situ ~n the reaction mixture, for example by reaction o sodium hydroxide, potassium hydroxide, liLhium hydroxide, sodium hydride~ potassium hydride or s~damide with a corresponding pyridobenzodiazepinone of ~ormula II, wherein M
represents a hydrogen atom.
~ b) Reaction of a compound of formula IV, ',' ' ' .. :, -~. , .
O CH
ti , 3
This invention relates to new pyridobenzodiazepinones as well ~`.;.~., AS to processes for their preparation and to pharmaceutical compositions containing them.
~ccording to one feature of the present in~ention there are pr~vided compounds of general formula I~
(CH2)n ~
wherein~
.~ ~ either R1 represents a hydrogen atom~ a straigh-t chain or branched alkyl group containing from 1 to 3 carbon atoms or a ~ ~ :
benzyl ~roup and R2 represents a straight chain or branched ~ ?'' ' alkyl~group containing from 1 to 3 carbon atoms, or ~ ;6, "' ~"
: Rl and R2, together with the nitrogen atom to which they are attached7 form a pyrrolidino, piperidino or hexamethyleneimino , gro~p;
;~ . n is 2 or 3;
either A represents a nitrogen atom and B represents the ~roup ,~
.~ -CH-, or ç B represents a nitrogen atom and A represents the~group =CH~ ?'`.:~
and acid addition salts thereof.
: ~, .: , -... " ,. . . ..
~S~286 ~ ~
:. ~
~ :, The compounds of general formula I and the physiologicall~
compatible acid addition salts thereo~, in general possess : useful pharmacological properties, particularly in the treat~
ment of bronchial asthma.
The new compotmds may, for example, be prepared according to~
the following processes, which processes constitute further : features of the present invention. ~ -,. ~
. a) Reaction of a compound of formula II, : 0 C~3 ~ f ~ r M
herein A and B are as hereinbefore defined and M represents `~
an alkali metal atom), with a compound of formula III, R : . ;~:-: X ~ (CEI2)n-N \ (III) : 2 (wherein Rl, R2:and n are as hereinbefore defined and X . .~`
represents a leaving group, for example a halogen atom or a ;~
tos~l group). The reaction is conveniently performed in an ` ~`~
. :
inert organic solvent at temperatures of from 20 to 250C. ~-: - 3 -'`~
~1~57~8~?
,. i` :
As inert solvents for example xylene, toluene, dioxan, -~
dimethyl ormamide or acetone may be used.
- The compound o~ ~ormula II is advantageously produced in situ ~n the reaction mixture, for example by reaction o sodium hydroxide, potassium hydroxide, liLhium hydroxide, sodium hydride~ potassium hydride or s~damide with a corresponding pyridobenzodiazepinone of ~ormula II, wherein M
represents a hydrogen atom.
~ b) Reaction of a compound of formula IV, ',' ' ' .. :, -~. , .
O CH
ti , 3
2 n ~ -~
, , , ~,- -. .
~ ~ 10 -~(wherein A,- B and n are as hereinbefore defined and Y ~
:, .,. ~.
- represents a leaving group such as a halogen atom, preerably~
a chlorine atom, or a tosyl group),with a compound o~ ;
~. .
formula V, H N ~ R~ (V) R2 ""
(wherein Rl and R2 are as hereinbe~ore defined).
. ": ' .
. . . .
, . . . . .
57æ~
The reaction is conveniently carried out in an inert organic solvent at temperatures of from -20 to +20C. As inert solvents for example xylene, toluene, dioxan, dimethyl ; formamide or acetone may be used.
; ,. ~
~5 c) Thermal decarboxylation of a compound of formula VI, ~ I r' ~
(wherein A, B, Rl, R2 and n are as hereinbefore defined).
The decarboxylation is conveniently carried out at temperQ~
; tures of from~150C to 250C9 optionally~in the presence of an inert~so1vent such as diethylene glycol, sulfolane, 10 ; o-dichlorobenzene or tetraethylene glycol dimethy1 ether.
Compounds o general formula I wherein RL represents a benzyl ;
group, may be converted into compounds of general ~ormula I, wherein Rl represents a hydrogen atom, by splitting o~ the benzy1 group hydrogenolytically. The hydrogenolytic removal ~5 lS o the benzyl group may be effected using catalytically ~ 5 . . . . .: - ......................... , -. . ,. . , ~ . , ,: . . , , . : , 5~ il6 ....
activated hydrogen at temperakures of from 20 to 100C and at a hydrogen pressure of from 1 to 100 atm. As catalysts ~ ;
noble metal catalysts,such as palladium on charcoal,have proved to be particularly suitableO
The compounds of general formula I may, if desired, be converted into their physiologically compatible acid addition ` salts with inorganic or organic acids. Particularl~ preferred acids include hydrochloric acid, hydrobromic acid, sulfuric acid~ phosphoric acid7 maleic acid, fumaric acid, citric acid~ -tartaric acid and malic acid. :
The compounds of general formula II, ~herein A represents the group =CH-) B represents a nitrogen atom and M represents ~ ^~
a hydrogen atom, used as starting materials, may be prepared ~ ~`
by reaction of a 2-halo-3-amino-pyridine of formula VIIa, -- , N ~ Hal (VIIa) ~ ,. . . .
, ~, . .
- 6 - - ~
,.
:
.,,. :
.. ~ .
~ ,' ` ' - ~572~
j,: , -:
` (wherein Hal represents a halogen atom), with an acid halide ~:~
of o-nitrobenzoic acid of formula VIIb, ..
.'-' ,' .
~ HOOC _ ~ (VIIb3 .~: 02N ~ I
The rea¢tion is conveniently carried out in an inert solvent, ~ such as benzene or toluene, in the presence of a hydrohalic ~ .
. 5 acid bindirlg agenk, e.g. an alkali carbonate~ trialkylamine or pyridine, at temperatures up to the boiling point of the reaction mixture. An amide of formula VIII, ,~ H 0 is first obtained, which is subsequently reduced,with : catalyticall~ activated hydrogen,at a temperature of fro~ 20 : 10 to 100C,with a metal chloride, such as~tin chlorideg in the presence of c~n inorganic acid. The compound o formula IX, H 0 .i~
N - C ~ (IX) N Hal H2N
- 7 - :~
".. . . ..
- , ~ , ~5~;~8~ ~
'~ :
~ thus obtained is then cyclized by heating up to a . .
~emperature of 200C or more. ~:
The reduction of the compound.of formula VIII is performed in an inert solvent such as methanol, ethanol or dioxan, -: . . . ,~.
preferably by means of hydrogen in the presence of Raney- :
nickel at a temperature of 50C and under pressure.
The ring closure of the compound of formula IX to the . ;~
5, ll-dihydro~6H-pyrido~2~3-b~1,4~ben2Odiazepine-6-one of ~: formula X, . ~
~ IJ \~ ~ ~x~ ~
~ N ~ \ / : ~ : ~
. .
~ may, if desired, be carried out~in the presence~ of a high ~
-~boiling~solventj such as paraffin oil or decalin7 optioDally in thepresence of a basic catalyst such as potassium carbonate~
or in the presence of copper powder. . : :~
The compound o formula X may be con~erted into the lS corresponding starting compound of formula II, wherein M
represents a hydrogen atom~ b~ treatment with methyl iodide :: ..~ ~ `
- - 8 ~
~ ~ .
. ., , ~ ~ .
,: . . . . , , , :
, . . . ., .. . . . . . . . ~
~572~
in hot ethanol in the presence of sodium hydroxide solution (see also German Patent Specifications No. 191791943 and ~ -~
.' 19~04J680~
~:~ The compounds o general formula LI~ wherein A represents . ~ . a nitrogen atom~ B represents the group =CH- and M represents ~ a hydrogen atom, used as starting compounds? may be obtained -~
: ~ by reaction of a 2-halo-nicotinic acid of formula XI
: . . . .
'; ~ COOh ~(XI) ~ N Hal ; ` ~ (where`in Hal represents a halogen atom), with o-phenylen.ediamine of ormula XII, H2N ~
H2N ~ ~ ~ (XII) The reaction is conveniently effected~at temperatures~above~
150C, optionally in the presence of an inert, high boiling solvent such as tetrahydronaphthalene~ dichloro- or ; ~ trichlorobenzene or glycol and in an inert gas atmosphere~
, i ~ .
6,11-dihydro~5H-pyrido~2,3-b~El,5~benzodiazepine-5~one o~
L5 formula XIII~ -_ 9 _ :
, ,"'''` ~, ~:
7286 ~ -- : -O H
(XIII) t 1 n is first obtained and is subsequently converted to the corresponding compound of formula II, wherein M represents - ~'.
a hydrogen atom, by means of methyl iodide in ethanol in the presence of sodium hydroxide solution by refluxing for 4 hours ~see also German Pa~ent Specifications No. 19~.38,479 and 1,251,767), The compounds of general formula IV may be obtained by reaction of a corresponding compound of formula II, in the fonm of its alkali metal salt (i.e. for example in the ~ . r.
presence of sodi~un hydride or sodium hydroxide) with ~ -dihaloalkanes~ e~g. with l~bromo-3-chloro~propane, preferably in the presence of an inert solvent and at room temperature.
The starting compounds of general formulae III and V are known ` ~--from the literature or may be prepared according to methods . ~.
known from the literature. ~-, .
~ The starting compounds of general formula VI may be prepared as follows ~ lo -: , . ,~, ' ~,, ',1 , ~L~S~2~
A compound of formula XIV, ~-i , 3 . - `:
(XIV) ~: H
(wherein A and B are as hereinbefore deined), is reacted . ~.
with phosgene, in toluene or diethyl ketone, at temperatures.
;
~ . of from 50 to 110 ~; the carboxylic acid chloride thus obtained is then reacted with an amino alcohol of formula X~
H0 - (CH ) N~ R~
(wherein ~1~ R2 and n are as hereinbefore defined), in the presence of an inert organic solvent at temperatures of from ~ ~ :
.
100 to 150C.
: As already mentioned above, the compounds of general fonmula T and their physiologically compatible acid addition salts possess useful pharmacological properties. The compounds according to the invention which we have tested have proved~
.
to be therapeutically active in the treatment of ~ronchial ., ~;' ', ~
. .j. . . , j , , ~L~5~2~6 ; ~ `
;
.,, `
asthma and they have shown decided advantages over the ~mimetics usually employed in this field in that they did not show the side effect of enhancing the heart frequenc~
exhibited by ~-mimetics. With ~-mimetics this side effect leads to unpleasant subjective grievances (e~g. pronounced `-~tachycardia) even when applying the effective dosage units.
In the case of an over-dose, they can cause severe compli~
cations (e.g. necrosis of the heart muscles).
~, .
In distinction to the ~-mime~cs, some of the new compounds of general formula I are not only capable of relaxing the spastically reacting bronchial muscular system of the asthma~`
patient, but are also able ~o liquefy the tenacious mucus, ~
which is an addltional impediment of the réspiratory ~unction.
For example the following substances have been tested with regard to their biological activities~
A ~ (3-Diethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido E2 ~ 3-b ] ~17 5 3ben~odiazepine-5-one hydrochloride ~ :~
B = 6,11-Dihydro~ (2-dimethylaminoethyl)-6-methyl-5H- `
pyrido~2,3-b~ 5~benzodiazepine-5-one hydrochloride C = 6,11-Dihydro-11-(3-dimethylaminopropyl)-6-methyl-5H-; pyrido[2,3-b3~1,5~benzodiazepîne-5-one hydrochloride ~ ~ :
12 -- ^
- , , . . , " ....... :, , : . . . .
57~
D = 6,1].-Dihydro-6-methyl~ (3-methylaminopropyl)-5H~
pyrido[2,3-b][1,5~benzodia~epine-5-one hydrochloride E = 11-~3-Ethylaminopropyl)-6,11-dihydro-6 methyl-5H-pyrido- ~.
~2,3-b~[1,5~benzodiazepine-S-one hydrochloride . ~-5.F = 6,11-Dihydro-11-(3-isopropylaminopropyl)-6~methyl-SH~
pyrido[293-b~C1,5]benzodiazepine~5-one hydrochloride G = 11-(2-Diethylami.noethyl)-6,11-dihydro-6-methyl-5rI-pyrido-: [2,3-b]~l~S]benzodiazepine-S-one h~drochloride . ~ `
I-I = 6,11-Dih~7dro-11-(3-di-n-propylaminopropyl)-6-methyl-SH- ~:
10pyri.do[2,3-b][195]benzodiazepine-5-one hydrochloride I = 6911-Dihydro~ (2-diisopropylaminoethyl)-6~methyl-SH- -~ pyridoC2~3-b3[13 5]benzodiazepine-5-one hydrochloride : ~ J = 5,11~Dihyrdo-11-(3-diisopropylaminopropyl)-6-methyl~
5H-py.rido~2,3-b][1,5]benzodiazepine-5-one hydrochloride : 15 K - 11-[3-(N-ethyl-N~isopropylamino)-propyl]-6911-dihydro-6~
~ . :
methyl-5H-pyr}do[2,3-b]C1,5]benzodiazepine-5-one ~ :
hydrochloride L - 6,11-Dihydro-6-methyl-11-(3-pyrrolidinopropyl-5H-pyrido~
[2,3-b]~1,5]benzodiazepine~5-one hydrochloride M - 6,11-Dihydro-6-methyl-11-(3-piperidinopropyl)-5H-pyrido .
[2,3-b~Ll,5]benzodiazepine-5-one hydrochloride .
~.~57;2 !3~ ~
.
N = 6 7 11 - Dihydro-11-(3-hexamethyleneiminopropyl)-6-methyl-5H-~- pyrido[2,3-b~195]benzodiazepine-S-one hydrochloride 0 = 6711-Dihydro-6-methyl-11-(2-pyrrolidinoethyl)~5H-pyrido~
~2,3-b] L 1,5]benzodiazepine-5-one hydrochloride P 11-(2-Diethylaminoethyl)-5,11-dihydro-5-methyl-6H-pyrido~
~2~3-b][1~4]benzodiazepine-6-one hydrochloride . . . ~
Q = 5,11-Dihydro-11 (2-diisopropylaminoethyl)-5-methyl-6H ~ :
pyrido[2?3-b3C1,4]benzodiazepine-6-one hydrochloride R = 5,11-~ih~dro-11-(3-dlmethyla~ninop.opyl)-5-methyl-6H - ''~
pyrido-~2,3~b][1,4~ben.odiazepine~5 one S = 5,11-Dihydro-11-(3 diethylaminopropyl)-5-methyl-6H- .~
~ pyrido~[2,3-b][1,4]benzodiazepine-6-one hydrochloride ~ ~ :
: . T ~ S,ll-Dîhydro~ (3-diisopropylaminop~opyl)-5-methyl-6H~
: pyridot2,3~b]~1,4]benzodiazepine-6-one hydrochloride U = 5,11-Dihydro-5-methyl-11-(3-pyrrolidinopropyl)-6H-pyrido-~2,3-bJ~1,4]benzodiazepine-6-one hydrochloride .. . .
= 5~ Dihydro-5-methyl-11-(3-piperidinopropyl)-6H~pyrido-[2,3~b3[1,4]~enzodiazepine-6~one hydrochloride ~ -~
. ;.
W = S,ll-Dihydro-ll (3-hexamethyleneiminopropyl)-5-methyl-6H~
pyrido[2g3-b~[1,4]benzodiazepine-6-one hydrochloride The broncholytic activity tests were carried out on ..;
narcotized guinea pigs, the intravenous acute toxicity tests , . . . . .
.; . . . ~, ~. .
.. , . ~ , .. . .. .
, , , ~,- -. .
~ ~ 10 -~(wherein A,- B and n are as hereinbefore defined and Y ~
:, .,. ~.
- represents a leaving group such as a halogen atom, preerably~
a chlorine atom, or a tosyl group),with a compound o~ ;
~. .
formula V, H N ~ R~ (V) R2 ""
(wherein Rl and R2 are as hereinbe~ore defined).
. ": ' .
. . . .
, . . . . .
57æ~
The reaction is conveniently carried out in an inert organic solvent at temperatures of from -20 to +20C. As inert solvents for example xylene, toluene, dioxan, dimethyl ; formamide or acetone may be used.
; ,. ~
~5 c) Thermal decarboxylation of a compound of formula VI, ~ I r' ~
(wherein A, B, Rl, R2 and n are as hereinbefore defined).
The decarboxylation is conveniently carried out at temperQ~
; tures of from~150C to 250C9 optionally~in the presence of an inert~so1vent such as diethylene glycol, sulfolane, 10 ; o-dichlorobenzene or tetraethylene glycol dimethy1 ether.
Compounds o general formula I wherein RL represents a benzyl ;
group, may be converted into compounds of general ~ormula I, wherein Rl represents a hydrogen atom, by splitting o~ the benzy1 group hydrogenolytically. The hydrogenolytic removal ~5 lS o the benzyl group may be effected using catalytically ~ 5 . . . . .: - ......................... , -. . ,. . , ~ . , ,: . . , , . : , 5~ il6 ....
activated hydrogen at temperakures of from 20 to 100C and at a hydrogen pressure of from 1 to 100 atm. As catalysts ~ ;
noble metal catalysts,such as palladium on charcoal,have proved to be particularly suitableO
The compounds of general formula I may, if desired, be converted into their physiologically compatible acid addition ` salts with inorganic or organic acids. Particularl~ preferred acids include hydrochloric acid, hydrobromic acid, sulfuric acid~ phosphoric acid7 maleic acid, fumaric acid, citric acid~ -tartaric acid and malic acid. :
The compounds of general formula II, ~herein A represents the group =CH-) B represents a nitrogen atom and M represents ~ ^~
a hydrogen atom, used as starting materials, may be prepared ~ ~`
by reaction of a 2-halo-3-amino-pyridine of formula VIIa, -- , N ~ Hal (VIIa) ~ ,. . . .
, ~, . .
- 6 - - ~
,.
:
.,,. :
.. ~ .
~ ,' ` ' - ~572~
j,: , -:
` (wherein Hal represents a halogen atom), with an acid halide ~:~
of o-nitrobenzoic acid of formula VIIb, ..
.'-' ,' .
~ HOOC _ ~ (VIIb3 .~: 02N ~ I
The rea¢tion is conveniently carried out in an inert solvent, ~ such as benzene or toluene, in the presence of a hydrohalic ~ .
. 5 acid bindirlg agenk, e.g. an alkali carbonate~ trialkylamine or pyridine, at temperatures up to the boiling point of the reaction mixture. An amide of formula VIII, ,~ H 0 is first obtained, which is subsequently reduced,with : catalyticall~ activated hydrogen,at a temperature of fro~ 20 : 10 to 100C,with a metal chloride, such as~tin chlorideg in the presence of c~n inorganic acid. The compound o formula IX, H 0 .i~
N - C ~ (IX) N Hal H2N
- 7 - :~
".. . . ..
- , ~ , ~5~;~8~ ~
'~ :
~ thus obtained is then cyclized by heating up to a . .
~emperature of 200C or more. ~:
The reduction of the compound.of formula VIII is performed in an inert solvent such as methanol, ethanol or dioxan, -: . . . ,~.
preferably by means of hydrogen in the presence of Raney- :
nickel at a temperature of 50C and under pressure.
The ring closure of the compound of formula IX to the . ;~
5, ll-dihydro~6H-pyrido~2~3-b~1,4~ben2Odiazepine-6-one of ~: formula X, . ~
~ IJ \~ ~ ~x~ ~
~ N ~ \ / : ~ : ~
. .
~ may, if desired, be carried out~in the presence~ of a high ~
-~boiling~solventj such as paraffin oil or decalin7 optioDally in thepresence of a basic catalyst such as potassium carbonate~
or in the presence of copper powder. . : :~
The compound o formula X may be con~erted into the lS corresponding starting compound of formula II, wherein M
represents a hydrogen atom~ b~ treatment with methyl iodide :: ..~ ~ `
- - 8 ~
~ ~ .
. ., , ~ ~ .
,: . . . . , , , :
, . . . ., .. . . . . . . . ~
~572~
in hot ethanol in the presence of sodium hydroxide solution (see also German Patent Specifications No. 191791943 and ~ -~
.' 19~04J680~
~:~ The compounds o general formula LI~ wherein A represents . ~ . a nitrogen atom~ B represents the group =CH- and M represents ~ a hydrogen atom, used as starting compounds? may be obtained -~
: ~ by reaction of a 2-halo-nicotinic acid of formula XI
: . . . .
'; ~ COOh ~(XI) ~ N Hal ; ` ~ (where`in Hal represents a halogen atom), with o-phenylen.ediamine of ormula XII, H2N ~
H2N ~ ~ ~ (XII) The reaction is conveniently effected~at temperatures~above~
150C, optionally in the presence of an inert, high boiling solvent such as tetrahydronaphthalene~ dichloro- or ; ~ trichlorobenzene or glycol and in an inert gas atmosphere~
, i ~ .
6,11-dihydro~5H-pyrido~2,3-b~El,5~benzodiazepine-5~one o~
L5 formula XIII~ -_ 9 _ :
, ,"'''` ~, ~:
7286 ~ -- : -O H
(XIII) t 1 n is first obtained and is subsequently converted to the corresponding compound of formula II, wherein M represents - ~'.
a hydrogen atom, by means of methyl iodide in ethanol in the presence of sodium hydroxide solution by refluxing for 4 hours ~see also German Pa~ent Specifications No. 19~.38,479 and 1,251,767), The compounds of general formula IV may be obtained by reaction of a corresponding compound of formula II, in the fonm of its alkali metal salt (i.e. for example in the ~ . r.
presence of sodi~un hydride or sodium hydroxide) with ~ -dihaloalkanes~ e~g. with l~bromo-3-chloro~propane, preferably in the presence of an inert solvent and at room temperature.
The starting compounds of general formulae III and V are known ` ~--from the literature or may be prepared according to methods . ~.
known from the literature. ~-, .
~ The starting compounds of general formula VI may be prepared as follows ~ lo -: , . ,~, ' ~,, ',1 , ~L~S~2~
A compound of formula XIV, ~-i , 3 . - `:
(XIV) ~: H
(wherein A and B are as hereinbefore deined), is reacted . ~.
with phosgene, in toluene or diethyl ketone, at temperatures.
;
~ . of from 50 to 110 ~; the carboxylic acid chloride thus obtained is then reacted with an amino alcohol of formula X~
H0 - (CH ) N~ R~
(wherein ~1~ R2 and n are as hereinbefore defined), in the presence of an inert organic solvent at temperatures of from ~ ~ :
.
100 to 150C.
: As already mentioned above, the compounds of general fonmula T and their physiologically compatible acid addition salts possess useful pharmacological properties. The compounds according to the invention which we have tested have proved~
.
to be therapeutically active in the treatment of ~ronchial ., ~;' ', ~
. .j. . . , j , , ~L~5~2~6 ; ~ `
;
.,, `
asthma and they have shown decided advantages over the ~mimetics usually employed in this field in that they did not show the side effect of enhancing the heart frequenc~
exhibited by ~-mimetics. With ~-mimetics this side effect leads to unpleasant subjective grievances (e~g. pronounced `-~tachycardia) even when applying the effective dosage units.
In the case of an over-dose, they can cause severe compli~
cations (e.g. necrosis of the heart muscles).
~, .
In distinction to the ~-mime~cs, some of the new compounds of general formula I are not only capable of relaxing the spastically reacting bronchial muscular system of the asthma~`
patient, but are also able ~o liquefy the tenacious mucus, ~
which is an addltional impediment of the réspiratory ~unction.
For example the following substances have been tested with regard to their biological activities~
A ~ (3-Diethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido E2 ~ 3-b ] ~17 5 3ben~odiazepine-5-one hydrochloride ~ :~
B = 6,11-Dihydro~ (2-dimethylaminoethyl)-6-methyl-5H- `
pyrido~2,3-b~ 5~benzodiazepine-5-one hydrochloride C = 6,11-Dihydro-11-(3-dimethylaminopropyl)-6-methyl-5H-; pyrido[2,3-b3~1,5~benzodiazepîne-5-one hydrochloride ~ ~ :
12 -- ^
- , , . . , " ....... :, , : . . . .
57~
D = 6,1].-Dihydro-6-methyl~ (3-methylaminopropyl)-5H~
pyrido[2,3-b][1,5~benzodia~epine-5-one hydrochloride E = 11-~3-Ethylaminopropyl)-6,11-dihydro-6 methyl-5H-pyrido- ~.
~2,3-b~[1,5~benzodiazepine-S-one hydrochloride . ~-5.F = 6,11-Dihydro-11-(3-isopropylaminopropyl)-6~methyl-SH~
pyrido[293-b~C1,5]benzodiazepine~5-one hydrochloride G = 11-(2-Diethylami.noethyl)-6,11-dihydro-6-methyl-5rI-pyrido-: [2,3-b]~l~S]benzodiazepine-S-one h~drochloride . ~ `
I-I = 6,11-Dih~7dro-11-(3-di-n-propylaminopropyl)-6-methyl-SH- ~:
10pyri.do[2,3-b][195]benzodiazepine-5-one hydrochloride I = 6911-Dihydro~ (2-diisopropylaminoethyl)-6~methyl-SH- -~ pyridoC2~3-b3[13 5]benzodiazepine-5-one hydrochloride : ~ J = 5,11~Dihyrdo-11-(3-diisopropylaminopropyl)-6-methyl~
5H-py.rido~2,3-b][1,5]benzodiazepine-5-one hydrochloride : 15 K - 11-[3-(N-ethyl-N~isopropylamino)-propyl]-6911-dihydro-6~
~ . :
methyl-5H-pyr}do[2,3-b]C1,5]benzodiazepine-5-one ~ :
hydrochloride L - 6,11-Dihydro-6-methyl-11-(3-pyrrolidinopropyl-5H-pyrido~
[2,3-b]~1,5]benzodiazepine~5-one hydrochloride M - 6,11-Dihydro-6-methyl-11-(3-piperidinopropyl)-5H-pyrido .
[2,3-b~Ll,5]benzodiazepine-5-one hydrochloride .
~.~57;2 !3~ ~
.
N = 6 7 11 - Dihydro-11-(3-hexamethyleneiminopropyl)-6-methyl-5H-~- pyrido[2,3-b~195]benzodiazepine-S-one hydrochloride 0 = 6711-Dihydro-6-methyl-11-(2-pyrrolidinoethyl)~5H-pyrido~
~2,3-b] L 1,5]benzodiazepine-5-one hydrochloride P 11-(2-Diethylaminoethyl)-5,11-dihydro-5-methyl-6H-pyrido~
~2~3-b][1~4]benzodiazepine-6-one hydrochloride . . . ~
Q = 5,11-Dihydro-11 (2-diisopropylaminoethyl)-5-methyl-6H ~ :
pyrido[2?3-b3C1,4]benzodiazepine-6-one hydrochloride R = 5,11-~ih~dro-11-(3-dlmethyla~ninop.opyl)-5-methyl-6H - ''~
pyrido-~2,3~b][1,4~ben.odiazepine~5 one S = 5,11-Dihydro-11-(3 diethylaminopropyl)-5-methyl-6H- .~
~ pyrido~[2,3-b][1,4]benzodiazepine-6-one hydrochloride ~ ~ :
: . T ~ S,ll-Dîhydro~ (3-diisopropylaminop~opyl)-5-methyl-6H~
: pyridot2,3~b]~1,4]benzodiazepine-6-one hydrochloride U = 5,11-Dihydro-5-methyl-11-(3-pyrrolidinopropyl)-6H-pyrido-~2,3-bJ~1,4]benzodiazepine-6-one hydrochloride .. . .
= 5~ Dihydro-5-methyl-11-(3-piperidinopropyl)-6H~pyrido-[2,3~b3[1,4]~enzodiazepine-6~one hydrochloride ~ -~
. ;.
W = S,ll-Dihydro-ll (3-hexamethyleneiminopropyl)-5-methyl-6H~
pyrido[2g3-b~[1,4]benzodiazepine-6-one hydrochloride The broncholytic activity tests were carried out on ..;
narcotized guinea pigs, the intravenous acute toxicity tests , . . . . .
.; . . . ~, ~. .
.. , . ~ , .. . .. .
3 ~57;2~
on mice and the activity on heart frequency tests on narcotized cats. Some of the above compounds were also tested for their secretolytic effect and in this respect they ;
were compared with the known broncholytic Meta-pro~erenol, also known as Orciprenaline or 3,5-dihydroxy-a-isopropylamirlo-,~
~- methyl-benzyl alcohol (sulfate).
The an~ bm~ ff-rt was tested as the antagonism to ~ronchospasm provoked by intravenous application of 20 ~g of .:
` ~ acetylcholine per kg of body weighi: in narcotized guinea pigs 10 - (according to the method of KON~ETT and ROSSLEP~). From thè
average percentage decrease of the bronchospasm produced by~
administering various doses of the compounds~of the present invention, an ED50 was dete~nined by graphical extrapolation.
- ., `~ The compounds were administered intravenously.
~ The acute toxicity was tested with NMRI mice~of male and female sex (body weight 20 g) after intravenous application -~
of the substances. O.l ml of a 0~9~/0 sodium chloride solution :
per lO g of animal were used as a vehicle. The LD50 was ;~
calculat~d from the pércentage of animals which died within ~0 a period of l4 days after administration of various doses, ~ ~`
according to the method of LITCHFIELD and WILCOXON
.
The influ~nce on heart freq~ency was tested on cats of male , , :
-;7~
~; ~
.`,;', ~
and'female sex (body weight between 2.3 and 3.5 kg) under ' chloralose-urethane narcosis. The heart frequency was con~
tinuously registered by means of a G-rass tachograph 7P4, directed by the R-wave of an electrocardiogram. The test substances were injected via a catheter introduced into the vena femoralis.
The expectoration tests were carried out according to the ~, method of PERRY, W. and BOYD, E.M.: J. Phanmacol7 exp. Therap.
73, 65 (1941~, modified by ENGELHORN, R. and PUSCHMANN, SO~
Arzneîm. Forsch. 21, 1045 (1971), on male guinea pigs (body- ;
~ -w ight from 450 to 550 ~)5 which had been narcotized by intraperitoneal application of a 25% urethane-solution ~ `
(1.0 g/kg)~ The substances were adminis~ered orally in the indicated dosage units, each in 2 ml of distilled watPr7 by "means of ~n oesophageal tube. 5 tests were carried out per dose. The increase in secretion was calculated f~om the ;
quantity of fluic~ secreted in a period of 2 hours a~ter application of the substance compared wi~h the quantity- ~ ' secreted without any applica-tion of substance. -The results obtained are recorded in Tables 1 to 3. Table 1- ~;
contains the values for the activity against acetylcholine- ' induced asthma in guinea pigs and the acute~toxicit~ in mi'ce `~
; , . ~
:`
: ::
~57;;~86 ~ ~
~ . after intravenous application. Table 2 contains the values , or the activity on heart ~requency in narcotized cats after , :
;ntravenous application and Table 3 contains the values for :
the percentage change in the quantity of secretion in guinea pigs as dependent on the dosage applied.
.
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on mice and the activity on heart frequency tests on narcotized cats. Some of the above compounds were also tested for their secretolytic effect and in this respect they ;
were compared with the known broncholytic Meta-pro~erenol, also known as Orciprenaline or 3,5-dihydroxy-a-isopropylamirlo-,~
~- methyl-benzyl alcohol (sulfate).
The an~ bm~ ff-rt was tested as the antagonism to ~ronchospasm provoked by intravenous application of 20 ~g of .:
` ~ acetylcholine per kg of body weighi: in narcotized guinea pigs 10 - (according to the method of KON~ETT and ROSSLEP~). From thè
average percentage decrease of the bronchospasm produced by~
administering various doses of the compounds~of the present invention, an ED50 was dete~nined by graphical extrapolation.
- ., `~ The compounds were administered intravenously.
~ The acute toxicity was tested with NMRI mice~of male and female sex (body weight 20 g) after intravenous application -~
of the substances. O.l ml of a 0~9~/0 sodium chloride solution :
per lO g of animal were used as a vehicle. The LD50 was ;~
calculat~d from the pércentage of animals which died within ~0 a period of l4 days after administration of various doses, ~ ~`
according to the method of LITCHFIELD and WILCOXON
.
The influ~nce on heart freq~ency was tested on cats of male , , :
-;7~
~; ~
.`,;', ~
and'female sex (body weight between 2.3 and 3.5 kg) under ' chloralose-urethane narcosis. The heart frequency was con~
tinuously registered by means of a G-rass tachograph 7P4, directed by the R-wave of an electrocardiogram. The test substances were injected via a catheter introduced into the vena femoralis.
The expectoration tests were carried out according to the ~, method of PERRY, W. and BOYD, E.M.: J. Phanmacol7 exp. Therap.
73, 65 (1941~, modified by ENGELHORN, R. and PUSCHMANN, SO~
Arzneîm. Forsch. 21, 1045 (1971), on male guinea pigs (body- ;
~ -w ight from 450 to 550 ~)5 which had been narcotized by intraperitoneal application of a 25% urethane-solution ~ `
(1.0 g/kg)~ The substances were adminis~ered orally in the indicated dosage units, each in 2 ml of distilled watPr7 by "means of ~n oesophageal tube. 5 tests were carried out per dose. The increase in secretion was calculated f~om the ;
quantity of fluic~ secreted in a period of 2 hours a~ter application of the substance compared wi~h the quantity- ~ ' secreted without any applica-tion of substance. -The results obtained are recorded in Tables 1 to 3. Table 1- ~;
contains the values for the activity against acetylcholine- ' induced asthma in guinea pigs and the acute~toxicit~ in mi'ce `~
; , . ~
:`
: ::
~57;;~86 ~ ~
~ . after intravenous application. Table 2 contains the values , or the activity on heart ~requency in narcotized cats after , :
;ntravenous application and Table 3 contains the values for :
the percentage change in the quantity of secretion in guinea pigs as dependent on the dosage applied.
.
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-- 1 9 - .,, :
, , . . . . . . . . ~ . , S7Z~6 : ~ -Ta~le 2 Activity on heart frequency o~ narcotized cats after intravenous application : . Sobo~onco tested dosage rangé type of the "ED10"++ `~0~7"+~
~ ~g/kg i.v. reaction ~ ~g/kg ~g/kg ~.
. ~ . - . .,. ~ ~-- ';"'' ~:' :~: A 12.5 - 16 000 _ 2 100 ~16 000 ~
250 - 4 000 _~ 4 000 ~: :~-E 250 - 4 000 _1 050 ~ 4 000 ;
` I 250 - 4 000 _1 300 > 4 000 ~ :~
: : . J 250 - 4 000 ~1 9SO ~ 4 000 ~-~
~ ~ - K 250 - 4 000 _1 350 ~ 4 000 ~ ?~
.~ L 250 - 4 000 _1 900 : 3 950 ~`
~; M 250 - 4 000 _1 400 ~ 4 000 . ~ o 250 - 4 000 _ ~ 4 000 - :` : ~ ~i-:: ~ T 250 ~ 4 000 _ 1 400 : 3 600~ ;
U 250 - 4 ooo _ 2 300 ~ 4 ~00 250 - 4 ooo ~ l lQO > 4 000 :~
W 125 - 4 000 : L 200 > 4 000 ;~
Orcipre- 0.4.~ - 8 ~ 0.7 2.2 naline _ . .... . -~
_ , .. _ . ~ ~ : ,.
= decrease o~ heart fre~uency = increase of heart frequency ~) dose leading to a 10 or 25% change in heart freq~ency de~ermined by graphical extrapolation - ."."
- 20 ~
::, :, , ;. :
'' ' .:
.,"" . . ., ,. .. . ., . , ~ , . . .
~72i36 Teble 3 : . ~. . .... - - - - --- ----- ... . . . . _~
Substance Dose 0 percentage alteration in ~g/kg the ~uantity of secretion ` ~-,. __ __... - .. __ _ .... ~ .. _ .
+ 114 0.5 + 80 _ . .. _ __ .. , ... _ _ . ~ ~ ~
0.5 ~ 113 .; . _ ~ . . . _ _ . __ . _ J 1 0.5 1 ~ 108 : _ .. , .. . . . . ,., " , _ ..... _._ . ~
As may~be seen from Table 1~ the compounds of general formula I
tested po~sess a broncholytic activity which is dependent on the dosage applied on an experimentally started asthma attack in guinea~pigs~ the broncholytic activity being as high as that ~-of orciprenal-ine or even higher. The duration of activity ~ `~
of the single dose of the new compounds significantly surpasses that of the known orciprenaline.
A somewhat increased acute toxicity results from the prolonged -d~ration of activity compared with orciprenaline, but this is of no importance because of the absolute therapeutic breadth. ~ ~-The claimed compounds dif~er from orciprenaline fundamentally -in their side effect on the heart. While, as may be seen from - 21 - -~
.
,,, . . . , , ~ .
. , .; , ,~., . -. .
7~
~.
, Table 2, orciprenaline, being a typical ~-mimetic, shows a - - .
positive chronotropic effect on heart frequency, even when ~ applied in very low dosages, the compounds of general formula ; I show no such effect on the heart in the preferred dosage range. Only in high dosages do they cause a moderate ~radycardia~ (i.e. exactly the opposite activity of . ... .
orciprenaline~. ;
Some o~ the compounds of general formula I surprisingly posséss distinct secretolytic properties in addition to their ..
broncholytic acti~ity, even when applied in lower dosages, ;
~ which cannot be found with orciprenaline.
. . .
According to a still further feature of the present invention - -there are provided pharmaceutical ~ompositions comprising7 as ..
active ingredient~ at least one compound of formula I or a 15~ physiologically compatible acid addition salt thereof, in .,-association with a pharmaceutical carrier or excip~ent.
For pharmaceu~ical administration the compounds o~general formula I or their physiologically compatible acid addition ;,: , salts may be incorporated into the conventional pharmaceutical preparations, optionally in combination with other acti~e :
ingredients.
... . .
The compositions may, for example, be presented in a form - 22 - - ~
:;,. ..
'' ' .
~57286 ... . ',~ .
suitable for oral, rectal or parenteral administration.
PrPferred forms include tablets, coated tablets? gelatine capsules, suppositories~syrups or aerosols.
Advantageously the compo~iLions may be formulated as dosage~
units, each ~mit being ~dapted to supply a fixed dose of ~ctive ingredient. Suitable dosage units for adults contain from 5 to 5000 ~g., preferably from 50 to 500 ~g o active ingredient. For adults3 a suitable daily dose of a tive ingredient according to the invention3 is ~rom 0.015 to 15~mg, lU preferably from 0.15 to 1.5 mg.
The following no~-limiting examples serve to illustrate ~he~
invention.
:` J
, . . '`' ;~: ' ""
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11-(3-Diethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-~:: r 2,3-bl ~1,5~benzodiaze~ 5-one _ __ _ _ .. . .
; - 4.52 g (0.02 mol) of 6,11-dihydro-6-methyl-5H- ?
~ 5 pyrido[2~3-b]~l95~-benzodiazepine-s-one~7.o g ~0.175 mol) ".~: ' , ., o~ finely divided sodium hydroxide, 50 ml o acetone and 12 ml of 3-diethylaminopropyl chloride were refluxed ~ ;
.. ..
.. ::. ...
for 2 hours. After that time, the hot mixture was filtered with suction and the iltrate was evaporated under vacuum. The residue was shaken in a mixture of ,~ , .. .
; ~ acetic acid and ether. The acidic aqueous layer was made ~
` alkaline with a concentrated ammonia solution and the oil -which precipitated was extracted with ether. After evaporation of the ether, the oily residue was distllled.
Yield: 76% of theory of 11-(3-diethylaminopropyl)-6,11 dihydro-6-methyl-5H-pyridoC2,3-b][1,53benzodiazepine~
one of b~p~o 14 198-200C
The hydrochloride, obtained from the base dissol~ed in dioxan~together with concentrated h~drochloric acid, melted at 206-208C after recrystalliæation from iso-";,~' -, . .
propanol.
The same compound was obtained by using potassium `~
- 24 - ~
:~ :
. , , . ;, .
~s hydroxide or potassium methoxide instead of sodium ' hydroxide.
Example 2 The compound of Ex~mple 1 was also prepared as '~ `
follows:
a) 22.6 g of''6,11-dihydro-6-methyl-5H-pyrido[2,3-b]-,. :
' [1,5~benzodiazepine-5-one were dissolved in 225 ml of :'~ dimethyl formamide. 5025 g of 80% sodium hydride in ~
mineral oil were add~d and the mixture was stirred at ;
; lO ` 60C for b~5 minutes. After cooling to 20C, 17.1 ml of trimet~ylene bromochloride were added and the mixture ~ '''- `
was~ stirred for a further 30 minutes at 20C. 1 ltr. ~
, of methylene chloride was added and the mixture was washed thrice with lO0 ml aliquots of water. The organic 15 ~ ~ layer was evaporated under vacuum without heating the ' - ' 1as~. The oily residue was purified by'~olumn ~hromato~
graphy (silica gel, eluant: chloroform + ethyl acetate '~
+1) and recrystallized from 9~l% ethanol.
Yield: 10.5 g of 11-(3-chloropropyl)6911-dihydro~6 methyl-5H-pyrido[2,3-b][l,5~benzodiazepine-5-o~e of m.p.
102 - 103.5C. ~" ' - 25 - ~
:: , : , ' . ''`' '-' , '~' ` ' .
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-; b) 10.0 g of this chloropropyl compound were stirred, at room temperature, with 20 ml of diethylamine in 100 ml .~ .,.
of dimethyl formamide for 16 hours. The solvent was -~ ~
distilled off under vacuum. The residue was dissolved ~-~; 5 in ether and extracted with dilute acetic acid. The ` ~``
acidic, aqueous layer was made alkaline w;th a concentrated i. -aqueous ammonia solution and the base, precipitated as an oil, was extracted with ether. After clistillation, :. ~
1.1 g of 11-(3-diethylaminopropyl)-6,11-di~ydro-6-methyl~
~ 5H-pyrido[2,3-b][1,5]benzodiazepine-5-one of b.p.o 12 ; 196 - 199C. were obtained. ' .~ . ~.,.
The following compounds were also prepared in the ;`~
, . . ~ ~ , .
same way~
[3-(N-Ethyl-isopropyl~mino)propyl~-6,11-dihydro-6 .: .
~15~ ~ methyl-5H-pyr;do[2,3-b]~1,5]benzodiazepine-5-one of o.os 185 ~ 187 C.
11-(3-Diisopropylaminopropyl)-6,11-dihydro-6-methyl-5H~
~ pyrido-[2,3-b][1,5]benzodiazepine-5-one of b~.p.~ 08 ; 200 - 203C
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-- 1 9 - .,, :
, , . . . . . . . . ~ . , S7Z~6 : ~ -Ta~le 2 Activity on heart frequency o~ narcotized cats after intravenous application : . Sobo~onco tested dosage rangé type of the "ED10"++ `~0~7"+~
~ ~g/kg i.v. reaction ~ ~g/kg ~g/kg ~.
. ~ . - . .,. ~ ~-- ';"'' ~:' :~: A 12.5 - 16 000 _ 2 100 ~16 000 ~
250 - 4 000 _~ 4 000 ~: :~-E 250 - 4 000 _1 050 ~ 4 000 ;
` I 250 - 4 000 _1 300 > 4 000 ~ :~
: : . J 250 - 4 000 ~1 9SO ~ 4 000 ~-~
~ ~ - K 250 - 4 000 _1 350 ~ 4 000 ~ ?~
.~ L 250 - 4 000 _1 900 : 3 950 ~`
~; M 250 - 4 000 _1 400 ~ 4 000 . ~ o 250 - 4 000 _ ~ 4 000 - :` : ~ ~i-:: ~ T 250 ~ 4 000 _ 1 400 : 3 600~ ;
U 250 - 4 ooo _ 2 300 ~ 4 ~00 250 - 4 ooo ~ l lQO > 4 000 :~
W 125 - 4 000 : L 200 > 4 000 ;~
Orcipre- 0.4.~ - 8 ~ 0.7 2.2 naline _ . .... . -~
_ , .. _ . ~ ~ : ,.
= decrease o~ heart fre~uency = increase of heart frequency ~) dose leading to a 10 or 25% change in heart freq~ency de~ermined by graphical extrapolation - ."."
- 20 ~
::, :, , ;. :
'' ' .:
.,"" . . ., ,. .. . ., . , ~ , . . .
~72i36 Teble 3 : . ~. . .... - - - - --- ----- ... . . . . _~
Substance Dose 0 percentage alteration in ~g/kg the ~uantity of secretion ` ~-,. __ __... - .. __ _ .... ~ .. _ .
+ 114 0.5 + 80 _ . .. _ __ .. , ... _ _ . ~ ~ ~
0.5 ~ 113 .; . _ ~ . . . _ _ . __ . _ J 1 0.5 1 ~ 108 : _ .. , .. . . . . ,., " , _ ..... _._ . ~
As may~be seen from Table 1~ the compounds of general formula I
tested po~sess a broncholytic activity which is dependent on the dosage applied on an experimentally started asthma attack in guinea~pigs~ the broncholytic activity being as high as that ~-of orciprenal-ine or even higher. The duration of activity ~ `~
of the single dose of the new compounds significantly surpasses that of the known orciprenaline.
A somewhat increased acute toxicity results from the prolonged -d~ration of activity compared with orciprenaline, but this is of no importance because of the absolute therapeutic breadth. ~ ~-The claimed compounds dif~er from orciprenaline fundamentally -in their side effect on the heart. While, as may be seen from - 21 - -~
.
,,, . . . , , ~ .
. , .; , ,~., . -. .
7~
~.
, Table 2, orciprenaline, being a typical ~-mimetic, shows a - - .
positive chronotropic effect on heart frequency, even when ~ applied in very low dosages, the compounds of general formula ; I show no such effect on the heart in the preferred dosage range. Only in high dosages do they cause a moderate ~radycardia~ (i.e. exactly the opposite activity of . ... .
orciprenaline~. ;
Some o~ the compounds of general formula I surprisingly posséss distinct secretolytic properties in addition to their ..
broncholytic acti~ity, even when applied in lower dosages, ;
~ which cannot be found with orciprenaline.
. . .
According to a still further feature of the present invention - -there are provided pharmaceutical ~ompositions comprising7 as ..
active ingredient~ at least one compound of formula I or a 15~ physiologically compatible acid addition salt thereof, in .,-association with a pharmaceutical carrier or excip~ent.
For pharmaceu~ical administration the compounds o~general formula I or their physiologically compatible acid addition ;,: , salts may be incorporated into the conventional pharmaceutical preparations, optionally in combination with other acti~e :
ingredients.
... . .
The compositions may, for example, be presented in a form - 22 - - ~
:;,. ..
'' ' .
~57286 ... . ',~ .
suitable for oral, rectal or parenteral administration.
PrPferred forms include tablets, coated tablets? gelatine capsules, suppositories~syrups or aerosols.
Advantageously the compo~iLions may be formulated as dosage~
units, each ~mit being ~dapted to supply a fixed dose of ~ctive ingredient. Suitable dosage units for adults contain from 5 to 5000 ~g., preferably from 50 to 500 ~g o active ingredient. For adults3 a suitable daily dose of a tive ingredient according to the invention3 is ~rom 0.015 to 15~mg, lU preferably from 0.15 to 1.5 mg.
The following no~-limiting examples serve to illustrate ~he~
invention.
:` J
, . . '`' ;~: ' ""
' ~'`~ : '' ., ' ' ' ' , - ' ' ., ' ' ' " .
,,.. ~ . ~, , , , :
:;, , , , ., :
11-(3-Diethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-~:: r 2,3-bl ~1,5~benzodiaze~ 5-one _ __ _ _ .. . .
; - 4.52 g (0.02 mol) of 6,11-dihydro-6-methyl-5H- ?
~ 5 pyrido[2~3-b]~l95~-benzodiazepine-s-one~7.o g ~0.175 mol) ".~: ' , ., o~ finely divided sodium hydroxide, 50 ml o acetone and 12 ml of 3-diethylaminopropyl chloride were refluxed ~ ;
.. ..
.. ::. ...
for 2 hours. After that time, the hot mixture was filtered with suction and the iltrate was evaporated under vacuum. The residue was shaken in a mixture of ,~ , .. .
; ~ acetic acid and ether. The acidic aqueous layer was made ~
` alkaline with a concentrated ammonia solution and the oil -which precipitated was extracted with ether. After evaporation of the ether, the oily residue was distllled.
Yield: 76% of theory of 11-(3-diethylaminopropyl)-6,11 dihydro-6-methyl-5H-pyridoC2,3-b][1,53benzodiazepine~
one of b~p~o 14 198-200C
The hydrochloride, obtained from the base dissol~ed in dioxan~together with concentrated h~drochloric acid, melted at 206-208C after recrystalliæation from iso-";,~' -, . .
propanol.
The same compound was obtained by using potassium `~
- 24 - ~
:~ :
. , , . ;, .
~s hydroxide or potassium methoxide instead of sodium ' hydroxide.
Example 2 The compound of Ex~mple 1 was also prepared as '~ `
follows:
a) 22.6 g of''6,11-dihydro-6-methyl-5H-pyrido[2,3-b]-,. :
' [1,5~benzodiazepine-5-one were dissolved in 225 ml of :'~ dimethyl formamide. 5025 g of 80% sodium hydride in ~
mineral oil were add~d and the mixture was stirred at ;
; lO ` 60C for b~5 minutes. After cooling to 20C, 17.1 ml of trimet~ylene bromochloride were added and the mixture ~ '''- `
was~ stirred for a further 30 minutes at 20C. 1 ltr. ~
, of methylene chloride was added and the mixture was washed thrice with lO0 ml aliquots of water. The organic 15 ~ ~ layer was evaporated under vacuum without heating the ' - ' 1as~. The oily residue was purified by'~olumn ~hromato~
graphy (silica gel, eluant: chloroform + ethyl acetate '~
+1) and recrystallized from 9~l% ethanol.
Yield: 10.5 g of 11-(3-chloropropyl)6911-dihydro~6 methyl-5H-pyrido[2,3-b][l,5~benzodiazepine-5-o~e of m.p.
102 - 103.5C. ~" ' - 25 - ~
:: , : , ' . ''`' '-' , '~' ` ' .
,: -.': ,, :
, ~ .
:. ., , . , :, 1.... . . . .
: :
~i7;~
,~
-; b) 10.0 g of this chloropropyl compound were stirred, at room temperature, with 20 ml of diethylamine in 100 ml .~ .,.
of dimethyl formamide for 16 hours. The solvent was -~ ~
distilled off under vacuum. The residue was dissolved ~-~; 5 in ether and extracted with dilute acetic acid. The ` ~``
acidic, aqueous layer was made alkaline w;th a concentrated i. -aqueous ammonia solution and the base, precipitated as an oil, was extracted with ether. After clistillation, :. ~
1.1 g of 11-(3-diethylaminopropyl)-6,11-di~ydro-6-methyl~
~ 5H-pyrido[2,3-b][1,5]benzodiazepine-5-one of b.p.o 12 ; 196 - 199C. were obtained. ' .~ . ~.,.
The following compounds were also prepared in the ;`~
, . . ~ ~ , .
same way~
[3-(N-Ethyl-isopropyl~mino)propyl~-6,11-dihydro-6 .: .
~15~ ~ methyl-5H-pyr;do[2,3-b]~1,5]benzodiazepine-5-one of o.os 185 ~ 187 C.
11-(3-Diisopropylaminopropyl)-6,11-dihydro-6-methyl-5H~
~ pyrido-[2,3-b][1,5]benzodiazepine-5-one of b~.p.~ 08 ; 200 - 203C
-...... .
6,11-Dihydro~ (2-dimethylaminoethylj-6-methyl-5H-pyrido-~ ~
.
2,3-b][1,5]benzodiazepine-5-one of b.p.o ol 163 - 16~.C. ;~
'.
.
'.,',' '', '.
-~
~ .
.. . . .. . . . . . . .
57 ~ ~ ~
6,11-Dihydro-11-(3-dimethylaminopropyl)-6-methyl-SH-pyrido-[2,3-b][1,5]-benzodiazepine-5-one of b.p.o o3 180-183C.
6J11-Dihydro-6-methyl-11-(3-methylaminopropyl)-5H-pyrido-.~ [2,3-b~C1,5]benzodiazepine-5-one of b.p.o 05 182C
~ (3-Ethylaminopropyl) 6~11-dihydro-6-methyl-5H-pyrido~
~ ~ .
[2,3-b]C1,5~benzodiazepine-5-one of b~p~o 12 193-195C
6,11-~ihydro-11-(3-isopropylaminopropyl)-6-methyl-5H-pyrido- ~.
C2,3-b]~1,5]benzodiazepine-5-one of b.p.o 05 183-185C
11-(2-Diethylaminoeth~1)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b~C1,5]benzodiazepine-5-one of b~p~o 06 183-186C
6~11-Dihydro-11-(3-di-n-propyl~inopropyl)-6-methyl-5H~
pyrido[2,3-b3[1,5~benzodiazepine-5-one of b~p~o 04 192-195C ~ -6,11-Dihydro-11-(2-diisopropylamînoethyl~-6-methyl-5H- W rido-2,3-bj~l,S]benzodiazepine-5-one of b~p~o 07 188-191C .
6,11-Dihydro-6-methyl-11-(3-pyrrolidinopropyl)-5H-pyrido~
[2,3-b][195~benzodiazepine-5-one of b.p.o l5 203-206C
6~11-Dihydro-6-methyl~ 3-piperidinopro W l)-SH-pyrido-[2,3-b~[l,S]benzodiazepine-5-one of b~p~o o9 200-202C
6tll-Dihydro-ll-(3-hexamethyIeneiminopropyl)-6-methyl-5H
pyrido[2,3-b][1,5]benzodiazepine-S-one of b~p~o o5 238-2~2C ;
6,11-Dihydro-6-methyl-11-(2-pyrrolidinoethyl)-SH-pyrido-[2,3 b][l,5~benzodiazepine-5-one of b.P.
~' .. ''.
:
- ~57;~8~i :
~ (2-Diethylaminoethyl)-5,11-dihydro-5-methyl-6H-pyrido- ~-, . , [2,3-b][l,L]benzodiazepine-6-one of b.p~o o7 197-19gC
~; 5,11-Dihydro-11-(2-diisopropylaminoethyl)-S-methyl-6H-pyrido- ;~
2,3-b]~ benzodiazepine-6-one of brp.o 07 196-199C
5,11-Dihydro-11-(3-dimethylaminopropyl)-5-methyl-6H-pyrido-- [2,3-b][l,~l~benzodiazepine-6-one of b.P.2 5 202-205C
5,11-Dihydro-11-(3-diethylaminopropyl)-5-methyl-6H-pyrido- `
~2,3-b][l~]benzodiazepine-6-one of bop.o 2 212-214C ` ~
~ 5711-Dihydro~ (3-diisopropylaminopropyl)-5-methyl-6H- ~`-- -;~ ~ pyrido-[2J3-b][1,~13benzodiazepine-6-one of b.p.o 1 217 ` 220C `-5,11-Dihydro-5-methyl-11-(3-pyrrolidinopropyl)~6H-pyrido-~ 2,3-b][l,~l~benzodiazepine 6-one, m.p. 119-121C
- ~ ~ 5,11-Dihydro-5-methyl-11-~3-piperidinopropyl)-6H-pyrido- -~
~ [2,3-b][l,~,]benzodiazepine-6-one of b.p.o 06 198-2oooc ; ~ 5,11-Dihydro-11-(3-hexamethyleneiminopropyl)-5-methyl-6H-pyrido[2,3-b~[19~c~benzodiazepine-6-one of b.p.o 06 195 Y 198C.
Example 3 ~ -, . . -." ~ ~
11-(2-Dimethylaminoethyl)-6,11-dihydro-6-methyl-5H-pyrido~
- L 2,3-b~[195]benzodiazepine-5 _ne~
, j l . . .
g~0 g of 6,11-dihydro-6-methyl-5H-pyrido~2,3~b][1,5]~
benzodiazepine-5-one were dissolved in 200 ml of hot , . ., . -.
.
2,3-b][1,5]benzodiazepine-5-one of b.p.o ol 163 - 16~.C. ;~
'.
.
'.,',' '', '.
-~
~ .
.. . . .. . . . . . . .
57 ~ ~ ~
6,11-Dihydro-11-(3-dimethylaminopropyl)-6-methyl-SH-pyrido-[2,3-b][1,5]-benzodiazepine-5-one of b.p.o o3 180-183C.
6J11-Dihydro-6-methyl-11-(3-methylaminopropyl)-5H-pyrido-.~ [2,3-b~C1,5]benzodiazepine-5-one of b.p.o 05 182C
~ (3-Ethylaminopropyl) 6~11-dihydro-6-methyl-5H-pyrido~
~ ~ .
[2,3-b]C1,5~benzodiazepine-5-one of b~p~o 12 193-195C
6,11-~ihydro-11-(3-isopropylaminopropyl)-6-methyl-5H-pyrido- ~.
C2,3-b]~1,5]benzodiazepine-5-one of b.p.o 05 183-185C
11-(2-Diethylaminoeth~1)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b~C1,5]benzodiazepine-5-one of b~p~o 06 183-186C
6~11-Dihydro-11-(3-di-n-propyl~inopropyl)-6-methyl-5H~
pyrido[2,3-b3[1,5~benzodiazepine-5-one of b~p~o 04 192-195C ~ -6,11-Dihydro-11-(2-diisopropylamînoethyl~-6-methyl-5H- W rido-2,3-bj~l,S]benzodiazepine-5-one of b~p~o 07 188-191C .
6,11-Dihydro-6-methyl-11-(3-pyrrolidinopropyl)-5H-pyrido~
[2,3-b][195~benzodiazepine-5-one of b.p.o l5 203-206C
6~11-Dihydro-6-methyl~ 3-piperidinopro W l)-SH-pyrido-[2,3-b~[l,S]benzodiazepine-5-one of b~p~o o9 200-202C
6tll-Dihydro-ll-(3-hexamethyIeneiminopropyl)-6-methyl-5H
pyrido[2,3-b][1,5]benzodiazepine-S-one of b~p~o o5 238-2~2C ;
6,11-Dihydro-6-methyl-11-(2-pyrrolidinoethyl)-SH-pyrido-[2,3 b][l,5~benzodiazepine-5-one of b.P.
~' .. ''.
:
- ~57;~8~i :
~ (2-Diethylaminoethyl)-5,11-dihydro-5-methyl-6H-pyrido- ~-, . , [2,3-b][l,L]benzodiazepine-6-one of b.p~o o7 197-19gC
~; 5,11-Dihydro-11-(2-diisopropylaminoethyl)-S-methyl-6H-pyrido- ;~
2,3-b]~ benzodiazepine-6-one of brp.o 07 196-199C
5,11-Dihydro-11-(3-dimethylaminopropyl)-5-methyl-6H-pyrido-- [2,3-b][l,~l~benzodiazepine-6-one of b.P.2 5 202-205C
5,11-Dihydro-11-(3-diethylaminopropyl)-5-methyl-6H-pyrido- `
~2,3-b][l~]benzodiazepine-6-one of bop.o 2 212-214C ` ~
~ 5711-Dihydro~ (3-diisopropylaminopropyl)-5-methyl-6H- ~`-- -;~ ~ pyrido-[2J3-b][1,~13benzodiazepine-6-one of b.p.o 1 217 ` 220C `-5,11-Dihydro-5-methyl-11-(3-pyrrolidinopropyl)~6H-pyrido-~ 2,3-b][l,~l~benzodiazepine 6-one, m.p. 119-121C
- ~ ~ 5,11-Dihydro-5-methyl-11-~3-piperidinopropyl)-6H-pyrido- -~
~ [2,3-b][l,~,]benzodiazepine-6-one of b.p.o 06 198-2oooc ; ~ 5,11-Dihydro-11-(3-hexamethyleneiminopropyl)-5-methyl-6H-pyrido[2,3-b~[19~c~benzodiazepine-6-one of b.p.o 06 195 Y 198C.
Example 3 ~ -, . . -." ~ ~
11-(2-Dimethylaminoethyl)-6,11-dihydro-6-methyl-5H-pyrido~
- L 2,3-b~[195]benzodiazepine-5 _ne~
, j l . . .
g~0 g of 6,11-dihydro-6-methyl-5H-pyrido~2,3~b][1,5]~
benzodiazepine-5-one were dissolved in 200 ml of hot , . ., . -.
7;~
:~:
absolute xylene. 2.1 g of 50% sodium hydride in mineral oil were added and the mixture was refluxed for 2 hours. ;~
5.3 g of 2-dimethylaminoethyl chloride were then ~dded ~ dropwise and the mixture was refluxed or a further 16 ; hours. The cooled reaction mixture was agitated with ether and water. The organic layer was separated and ~ . ~
extracted with dilute acetic acid. The acidic aqueous layer was subsequently made alkaline with a concentrated -~
:: -ammonia solution and the precipitated oil was extracted .~ .. :. . .
with ether. After evaporation of the ekher, the residue ~
.~ ~
was distilled. Yield: 7.0 g (59% of theory) of 11-(2-dimethylaminoethyl)-6,11-dihydro-6-meth~1-5H-pyrido[2,3-b]-[1,5~benzodiazepine-5-one of b.p.o ol 163-164C.
Example 4 . . .
(3-~imethylaminopropyl)-6,11-dihydro-6-metnyl-5H-pyrido-: r 2,3- ~ benæodi~ pîne-5-one _ ~L~ 5 g of 6,11-dihydro-6-methyl-5H-pyridor2~3-b~ 5~
benzodiazep;ne-5-one were refluxed with 0.83 g of 55% sodium :. .;: . .
hydride in mineral oil in 100 ml of absolute xylene for ,A
2 hours. 7 g of 3-dimeth~laminopropyl p-toluenesulfonate~
~ ., .
were added and the mixture was refluxed for a further 1 hours. After cooling9 the mixture was filtered with suction ~ , .~ .
'~
',~
.
~57Z86 and the filtrate was extracted with dilute acetic acid. ;~
From the acidic layer9 the base was precipitated as an oil with a concentrated ammonia solution and then taken up in ether. After evaporation of the ether9 the residue was distilled. Yield: 2.4 g of 11-(3-dimethylaminopropyl)~
6,11-dihydro-6-methyl-5H-pyridot2,3-b][1,5]-benzodiazepine~
5-one of b~p~o 03 180-183C, which melted at 98.5 - 100C
after crystallization from cyclohexane and recrystallization from petroleum ether. ' ~;~
Example 5 (2-Methylaminoethyl)-6,11-dihydro-6-methyl-5H-pyrido-~[2,~3-b~rl,5~benzodiazepine-5-one a) 18.1 g (0.08 mol) o~ 6,11-dihydro-6-methyl-5H
pyrido~2,3-b]C1,53benzodiazepine-5-one were dissolved in 180~ml of~dimethyl formamide at room temperature. 2.88 g ` -(0.096 mol) of 80% sodium hydride in mineral oil were added and the mixture was stirred at 60C for /15 minutes.
17.7 g (0.096 mo~) of 2-(N-benzyl-methylamino)-ethylchloride ' ~`
were then added dropwise and the mixture was stirred at ~-~
I20C for 30 minutes. After evaporation under vacuum 9 ': .'~
the residue was dissolved in a mixture of chloro~orm and dilute acetic acid. The aqueous layer was separated and `;
- 30 - ~ ' :~' ",'' ,, , , . - ~
~5~72~6 :
made alkaline with a concentrated am~onia solution. The base, precipitated as an oil, was taken up in chloroform.
The solvent was then distilled off under vacuum and the , oily residue was d:istilled. Yield: 22.~l g ~75% of theory) of 11 [2-(N-benzyl-methylamino)-ethyl~-6,11-dihydro 6 mPthyl-5H- pyrido~2,3-b][1,5~benzodiazepine-5-one of b~p.o oS 212-216C.
b) 13.5 g of this substance were dissolved in 175 ml of -methanol and hydrogenated with palladium on charcoal :
at 50G and 50 atm. After separating the catalyst, the `
reaction mixture was evaporated under vacuum and the oily residue was purified by column chromatography (silica . .
-~ gel, eluant: chloroform ~ methanol ~ n-pentane + a concen-~; trated ammonia solution = 68+15+15+2). After distillation of the evaporated eluate (b.p. o 07 18h-186C) 9 6 . 5 g of (2-methylaminoethyl)-6911-dihydro-6-methyl-5H-pyrido~
[2,3-b~[1,5]benzodîazepine-5-one were obtained.
Yield: 22% of theory. ;~
.
11-(3-Methylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-r 2,3-b~ r 1,5~benzodiaze ine-5-one ' ; - 31 -`'" :.
.
.
~ 572~
a) 22.5 g of 6,11-dihydro-6-methyl-5H-pyrido~2,3-b][1,5]-benzodiazepine-5-one ~ere dissolved in 500 ml of hot ab- ;
solute ~ylene. 5.25 g of 50% sodium hydride in mi.~eral ;' oil were added and the mixture was refluxed for 2 hours. '~ ' 18 g of 3-(N-benzyl~methylamino)-prOpyll chloride were then added dropwise and the mixture was refluxed for a furbher 16 hours. The cooled reaction mixture was shaken with ' ' ''~
ether and water. The organic layer was then separated `~ ~ ' and extracted with dilute acetic acid. The acidic aqueous layeF waB made alkaline with a concentrated ammonia ^
solution and the base, precipitated as an oil, was "
extracted with ether. 'After evaporation of the eth~r, '' the residue was distilled. "' YieId: 20 g of 11-~3-(N-benzyl-methylamino)propyl]-6,11- ~' dihydro-6-methyl-5H-pyridoC2,3-b][1,5]benzodiazepine-5-one ' -of b-p-o 05 225-230C. ~ ' b) 16.4 g of this substance were debenzylated w;th '`
palladium on charcoal in methanol and processed according~
to Example 5b~ ''' Yield: ~..8 g (38% of theory~ of 11-(3-methylaminopropyl)~
6,11-dihydro-6-meth-yl-5H-pyrido[2,3-b][l,5]b'e'n'zodiazep'ine- ~
5-one of b.p~o.o5 182 C. 32 '' ~' ~ . . ' . !
~S72~3~
. ~ ":
., ~,: .~~ Example 7 .~ .-11-(3-Ethylaminopropy~)-6,11-dihydro-6-methyl-5H-pyrido- ~`
~ ~ .
[2,3-b]rl,5~benæodiaze~ine-5-one _ _ _ ' . :~ -a) 18.0 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b~- ;
[1,5]benzodiazepine-5-one, 400 ml of absolute xylene, ~ -~
2 g of 50% .sodium hydride in mineral oil and 16.8 g of 3-(N-benzyl-ethylamino)-propyl chloride were reacted and processed analogously to Example 6a.
Yield: 18 g (56% of theory) of 11-~3-(N-benzyl-ethylamino)-. ~ ~
; ~ propyl]~6,11-dihydro-6-methyl 5H-pyrido[2,3-b][1,5]benzo~
diazepine-5-one of b.p.o 12 235-238C.
~b) 18 g of this compound were debenzylated and processed -~
analogously to Example 5b~ ~-,,~ , . .
Yield: 3.2 g (23% of theory) of 11-(3~ethylaminopropyl)-6,11-dihydro-6~methyl-SH-pyrido[2,3-b~[1,5~-benzodiazepine~
5-one of b.p.o.l2 193-195 C.
Example 8 11-(3-Isopropylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-a) 18 g of 6911-dihydro-6-methyl-5H-pyrido[2,3-b~[1,5]- ;
benzodiazepine-5~one, 180 ml of dimethyl formamide, 3.0 g -`
.'~
. ,~ , , , , ~
~10 S7;~6 ~ .
.. . .
of 80% sodium hydride in mineral oil and 22.4 g of 3-(N- ~ ~
benzyl-isopropylamino,-propyl chloride were reacted and ;~ `
. .: .
processed analogously to Example 5a.
- Yield: 17 g of 11-[3-~N-benzyl-isopropylamino)propyl]- -6,1l-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepine~
5-one of b-p-o 06 222-227C. `~
b) 15.3 g of this compound were debenzylated and proc-~ . .
essed analogously to Example 5b. ~
. .; .
Yield: ~I.5 g (35% of theo~y) of 11-(3-isopropylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5~-benzodiazepine- `
., ~
5-one of b.p.o 05 183~185C.
Example 9 (2-Diethylaminoethyl)--6,11-dihydro-6-methyl-5H-pyrido~
. 1 ~ .
; 9.0 g of 6,11-dihydro-6-methyl-5H-pyrido~2,3-b~1,5]~
~benzodiazepLne-S-one, 200 ml of absolute xylene, 1.32 g of 80% sodium hydride in mineral oil and 6.8 g of 2-diethyl~
aminoethyl chloride were reacted and processed analogously to Example 3.
.1,. ... ~ . .
Bcp.0 06 183~186C. Yield: 52% of theory.
. , .: :
"~ ,.
'" .,~,..
i7Z86 ' 11-(3-Di-n-propylaminopropyl)-6,11-dihydro-6-methyl-5H- ;
pyrido~2,3-b~[1,5~benzodia~ine-5-; 12.2 g of 6,11-dihydro-6-methyl-5H-pyrido~2,3-b][1,5]-benzo~iazepine-5-one, 220 ml of absolute xylene, 2.36 g of 50% sodium hydride in mineraI oil and 7.3 g of 3-di-n-propylaminopropyl chloride were reacted and processed `-~
analogously to Exam21e 3.
B~p~o 0~ 192-195C. Yield: 65a/o of theory.
11-(2-Diisopropylaminoethyl)-6,11-dihydro-6-methyl-5H-ine-5-one ': : . :.
:~:
absolute xylene. 2.1 g of 50% sodium hydride in mineral oil were added and the mixture was refluxed for 2 hours. ;~
5.3 g of 2-dimethylaminoethyl chloride were then ~dded ~ dropwise and the mixture was refluxed or a further 16 ; hours. The cooled reaction mixture was agitated with ether and water. The organic layer was separated and ~ . ~
extracted with dilute acetic acid. The acidic aqueous layer was subsequently made alkaline with a concentrated -~
:: -ammonia solution and the precipitated oil was extracted .~ .. :. . .
with ether. After evaporation of the ekher, the residue ~
.~ ~
was distilled. Yield: 7.0 g (59% of theory) of 11-(2-dimethylaminoethyl)-6,11-dihydro-6-meth~1-5H-pyrido[2,3-b]-[1,5~benzodiazepine-5-one of b.p.o ol 163-164C.
Example 4 . . .
(3-~imethylaminopropyl)-6,11-dihydro-6-metnyl-5H-pyrido-: r 2,3- ~ benæodi~ pîne-5-one _ ~L~ 5 g of 6,11-dihydro-6-methyl-5H-pyridor2~3-b~ 5~
benzodiazep;ne-5-one were refluxed with 0.83 g of 55% sodium :. .;: . .
hydride in mineral oil in 100 ml of absolute xylene for ,A
2 hours. 7 g of 3-dimeth~laminopropyl p-toluenesulfonate~
~ ., .
were added and the mixture was refluxed for a further 1 hours. After cooling9 the mixture was filtered with suction ~ , .~ .
'~
',~
.
~57Z86 and the filtrate was extracted with dilute acetic acid. ;~
From the acidic layer9 the base was precipitated as an oil with a concentrated ammonia solution and then taken up in ether. After evaporation of the ether9 the residue was distilled. Yield: 2.4 g of 11-(3-dimethylaminopropyl)~
6,11-dihydro-6-methyl-5H-pyridot2,3-b][1,5]-benzodiazepine~
5-one of b~p~o 03 180-183C, which melted at 98.5 - 100C
after crystallization from cyclohexane and recrystallization from petroleum ether. ' ~;~
Example 5 (2-Methylaminoethyl)-6,11-dihydro-6-methyl-5H-pyrido-~[2,~3-b~rl,5~benzodiazepine-5-one a) 18.1 g (0.08 mol) o~ 6,11-dihydro-6-methyl-5H
pyrido~2,3-b]C1,53benzodiazepine-5-one were dissolved in 180~ml of~dimethyl formamide at room temperature. 2.88 g ` -(0.096 mol) of 80% sodium hydride in mineral oil were added and the mixture was stirred at 60C for /15 minutes.
17.7 g (0.096 mo~) of 2-(N-benzyl-methylamino)-ethylchloride ' ~`
were then added dropwise and the mixture was stirred at ~-~
I20C for 30 minutes. After evaporation under vacuum 9 ': .'~
the residue was dissolved in a mixture of chloro~orm and dilute acetic acid. The aqueous layer was separated and `;
- 30 - ~ ' :~' ",'' ,, , , . - ~
~5~72~6 :
made alkaline with a concentrated am~onia solution. The base, precipitated as an oil, was taken up in chloroform.
The solvent was then distilled off under vacuum and the , oily residue was d:istilled. Yield: 22.~l g ~75% of theory) of 11 [2-(N-benzyl-methylamino)-ethyl~-6,11-dihydro 6 mPthyl-5H- pyrido~2,3-b][1,5~benzodiazepine-5-one of b~p.o oS 212-216C.
b) 13.5 g of this substance were dissolved in 175 ml of -methanol and hydrogenated with palladium on charcoal :
at 50G and 50 atm. After separating the catalyst, the `
reaction mixture was evaporated under vacuum and the oily residue was purified by column chromatography (silica . .
-~ gel, eluant: chloroform ~ methanol ~ n-pentane + a concen-~; trated ammonia solution = 68+15+15+2). After distillation of the evaporated eluate (b.p. o 07 18h-186C) 9 6 . 5 g of (2-methylaminoethyl)-6911-dihydro-6-methyl-5H-pyrido~
[2,3-b~[1,5]benzodîazepine-5-one were obtained.
Yield: 22% of theory. ;~
.
11-(3-Methylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-r 2,3-b~ r 1,5~benzodiaze ine-5-one ' ; - 31 -`'" :.
.
.
~ 572~
a) 22.5 g of 6,11-dihydro-6-methyl-5H-pyrido~2,3-b][1,5]-benzodiazepine-5-one ~ere dissolved in 500 ml of hot ab- ;
solute ~ylene. 5.25 g of 50% sodium hydride in mi.~eral ;' oil were added and the mixture was refluxed for 2 hours. '~ ' 18 g of 3-(N-benzyl~methylamino)-prOpyll chloride were then added dropwise and the mixture was refluxed for a furbher 16 hours. The cooled reaction mixture was shaken with ' ' ''~
ether and water. The organic layer was then separated `~ ~ ' and extracted with dilute acetic acid. The acidic aqueous layeF waB made alkaline with a concentrated ammonia ^
solution and the base, precipitated as an oil, was "
extracted with ether. 'After evaporation of the eth~r, '' the residue was distilled. "' YieId: 20 g of 11-~3-(N-benzyl-methylamino)propyl]-6,11- ~' dihydro-6-methyl-5H-pyridoC2,3-b][1,5]benzodiazepine-5-one ' -of b-p-o 05 225-230C. ~ ' b) 16.4 g of this substance were debenzylated w;th '`
palladium on charcoal in methanol and processed according~
to Example 5b~ ''' Yield: ~..8 g (38% of theory~ of 11-(3-methylaminopropyl)~
6,11-dihydro-6-meth-yl-5H-pyrido[2,3-b][l,5]b'e'n'zodiazep'ine- ~
5-one of b.p~o.o5 182 C. 32 '' ~' ~ . . ' . !
~S72~3~
. ~ ":
., ~,: .~~ Example 7 .~ .-11-(3-Ethylaminopropy~)-6,11-dihydro-6-methyl-5H-pyrido- ~`
~ ~ .
[2,3-b]rl,5~benæodiaze~ine-5-one _ _ _ ' . :~ -a) 18.0 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b~- ;
[1,5]benzodiazepine-5-one, 400 ml of absolute xylene, ~ -~
2 g of 50% .sodium hydride in mineral oil and 16.8 g of 3-(N-benzyl-ethylamino)-propyl chloride were reacted and processed analogously to Example 6a.
Yield: 18 g (56% of theory) of 11-~3-(N-benzyl-ethylamino)-. ~ ~
; ~ propyl]~6,11-dihydro-6-methyl 5H-pyrido[2,3-b][1,5]benzo~
diazepine-5-one of b.p.o 12 235-238C.
~b) 18 g of this compound were debenzylated and processed -~
analogously to Example 5b~ ~-,,~ , . .
Yield: 3.2 g (23% of theory) of 11-(3~ethylaminopropyl)-6,11-dihydro-6~methyl-SH-pyrido[2,3-b~[1,5~-benzodiazepine~
5-one of b.p.o.l2 193-195 C.
Example 8 11-(3-Isopropylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-a) 18 g of 6911-dihydro-6-methyl-5H-pyrido[2,3-b~[1,5]- ;
benzodiazepine-5~one, 180 ml of dimethyl formamide, 3.0 g -`
.'~
. ,~ , , , , ~
~10 S7;~6 ~ .
.. . .
of 80% sodium hydride in mineral oil and 22.4 g of 3-(N- ~ ~
benzyl-isopropylamino,-propyl chloride were reacted and ;~ `
. .: .
processed analogously to Example 5a.
- Yield: 17 g of 11-[3-~N-benzyl-isopropylamino)propyl]- -6,1l-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepine~
5-one of b-p-o 06 222-227C. `~
b) 15.3 g of this compound were debenzylated and proc-~ . .
essed analogously to Example 5b. ~
. .; .
Yield: ~I.5 g (35% of theo~y) of 11-(3-isopropylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5~-benzodiazepine- `
., ~
5-one of b.p.o 05 183~185C.
Example 9 (2-Diethylaminoethyl)--6,11-dihydro-6-methyl-5H-pyrido~
. 1 ~ .
; 9.0 g of 6,11-dihydro-6-methyl-5H-pyrido~2,3-b~1,5]~
~benzodiazepLne-S-one, 200 ml of absolute xylene, 1.32 g of 80% sodium hydride in mineral oil and 6.8 g of 2-diethyl~
aminoethyl chloride were reacted and processed analogously to Example 3.
.1,. ... ~ . .
Bcp.0 06 183~186C. Yield: 52% of theory.
. , .: :
"~ ,.
'" .,~,..
i7Z86 ' 11-(3-Di-n-propylaminopropyl)-6,11-dihydro-6-methyl-5H- ;
pyrido~2,3-b~[1,5~benzodia~ine-5-; 12.2 g of 6,11-dihydro-6-methyl-5H-pyrido~2,3-b][1,5]-benzo~iazepine-5-one, 220 ml of absolute xylene, 2.36 g of 50% sodium hydride in mineraI oil and 7.3 g of 3-di-n-propylaminopropyl chloride were reacted and processed `-~
analogously to Exam21e 3.
B~p~o 0~ 192-195C. Yield: 65a/o of theory.
11-(2-Diisopropylaminoethyl)-6,11-dihydro-6-methyl-5H-ine-5-one ': : . :.
8.9 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b~1,5]-: , benzodiazepinew5-one, 180 ml~of absolute xylene, 1.95 g of 50% sodium hydride in mineral oil and 7.75 g of 2-diisopropylaminoethyl chloride were reacted and processed analogously to Example 3.
Bop.0 07 188-191C. Yield: 71% of theory.
Example 12 ~, .
11-(3-Diisopropylaminopropyl)-6,11-dihydro-6-methyl-5H- ' P,y~[~--~C 1~ 5~bensodiazepinew 5-one ~ . .
_ 35 ~;
,. .. .
, ....... . . : ;~
~L~57;~8~
- ~-~ /l.75 g of 6,11~dihydro-6-methyl-5H-pyrido~2,3-b]~ ~.,.. , :-:
[l,s~benzodiazepine 5-one, 0.63 g of 80% sodium hydride ~r,'~, in mineral oil, ~.7 ml of dimethyl formamide and 3.5 g ` of 3-diisopropylaminopropyl chloride were reacted and processed analogously to Example 5a. B.p. o 08 200-203C.
Yield: 79% of theory).
!~ E~ample 13 ~ [3-(N-Ethyl-isopropylamino)propyl]~6,11-dihydro-6- ~;~
- ~ methyl-5H-pyrido~2,3-b][1,5~benzodiazepine-5-on-e ''1 ~ - ~
6.8 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b~
[1~5~benzodiazepine-5-one~ 150 ml of absolute xyIene, ;
i ~ ~ 1.5 g of 50/O sodium hydride in mineral oil and L.0 g o~ 3-(N-ethyl-isopropylamino~-propyl chloride were r~acted and processed analogously to Example 3.
B~p~o 05 185-187C. Yield 51% of theory.
Example lt 11-(3-Pyrrolidinopropyl)-6,11-dihydro-6-methyl-5H~
~ 7.9 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b~[1,5]-j~ benzodiazepine-5-one and 1.57 g of 55~O sodium hydri~de in mineral oil were stirred in 100 ml of absolute``dioxan ~; at 80C for ~5 minutes. Subsequent]y 5.6 g of 3-pyrrolidino .-, ~ . .
. ~ ~
. ~ , .
-.
~, '' ' . ' .
`: ~, : : . , . , . :
. .:: , , . :
:, , ' :
'' ' ': .. :' ' i ; ~ , , 1~57;~l5 6 -propyl chloride weFe added dropwise and the mixture was - refluxed for 1 hour. The solvent was distilled off under `
~ . .
vacuum and the residue was dissolved in a mixture of ether ~ ~ `
.
and water. The further procedure is as described in:
Example 3- B.p.o 15 203-206C. Yield: 63% of theory.
(3-Piperidinopropyl)-6,11-dihydro-6-methyl-5H-pyrido-:
,3-b~1,5]b nzodiazeE~e-5-one
Bop.0 07 188-191C. Yield: 71% of theory.
Example 12 ~, .
11-(3-Diisopropylaminopropyl)-6,11-dihydro-6-methyl-5H- ' P,y~[~--~C 1~ 5~bensodiazepinew 5-one ~ . .
_ 35 ~;
,. .. .
, ....... . . : ;~
~L~57;~8~
- ~-~ /l.75 g of 6,11~dihydro-6-methyl-5H-pyrido~2,3-b]~ ~.,.. , :-:
[l,s~benzodiazepine 5-one, 0.63 g of 80% sodium hydride ~r,'~, in mineral oil, ~.7 ml of dimethyl formamide and 3.5 g ` of 3-diisopropylaminopropyl chloride were reacted and processed analogously to Example 5a. B.p. o 08 200-203C.
Yield: 79% of theory).
!~ E~ample 13 ~ [3-(N-Ethyl-isopropylamino)propyl]~6,11-dihydro-6- ~;~
- ~ methyl-5H-pyrido~2,3-b][1,5~benzodiazepine-5-on-e ''1 ~ - ~
6.8 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b~
[1~5~benzodiazepine-5-one~ 150 ml of absolute xyIene, ;
i ~ ~ 1.5 g of 50/O sodium hydride in mineral oil and L.0 g o~ 3-(N-ethyl-isopropylamino~-propyl chloride were r~acted and processed analogously to Example 3.
B~p~o 05 185-187C. Yield 51% of theory.
Example lt 11-(3-Pyrrolidinopropyl)-6,11-dihydro-6-methyl-5H~
~ 7.9 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b~[1,5]-j~ benzodiazepine-5-one and 1.57 g of 55~O sodium hydri~de in mineral oil were stirred in 100 ml of absolute``dioxan ~; at 80C for ~5 minutes. Subsequent]y 5.6 g of 3-pyrrolidino .-, ~ . .
. ~ ~
. ~ , .
-.
~, '' ' . ' .
`: ~, : : . , . , . :
. .:: , , . :
:, , ' :
'' ' ': .. :' ' i ; ~ , , 1~57;~l5 6 -propyl chloride weFe added dropwise and the mixture was - refluxed for 1 hour. The solvent was distilled off under `
~ . .
vacuum and the residue was dissolved in a mixture of ether ~ ~ `
.
and water. The further procedure is as described in:
Example 3- B.p.o 15 203-206C. Yield: 63% of theory.
(3-Piperidinopropyl)-6,11-dihydro-6-methyl-5H-pyrido-:
,3-b~1,5]b nzodiazeE~e-5-one
9.0 g of 6,11-dihydro-6-methyl-5H-pyridor2,3-b][1,5]-`benzodiazepine-5-one~ 180 ml of absolute xylene, 1.92 g of 50% sodium hydride in mineral oil and 6.5 g of 3-piperidinopropyl chloride were reacted~and processed as descri~ed in Example 3.
B.~p.~ 09 200-202C. Yield: 63% of theory.
, :
Exæmple 16 - 11-(3-Hexamethyleneiminopropyl)-6,11-dihydro-6~methyl-i5H- -~ ;
, 7.9 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b~f- `~
[1,5]benæodiazepine~5 one9 100 ml of absolute dioxan, 1.57 g of 55% sodi~m hydride in mineral oil and 6.7 g of 3-hexamethyleneiminopropyl chloride were reacted and . - ~ .
processed as described in Example 14. B~p~o ~ 37 _ .. : . . . ~ , ~, .
~S7;~86 `:
:, .
238-2~12C, yield: 62% of theoryO
__7 11-(2-Pyrrolidinoethyl)-6~ dihydro-h-methyl-5H-pyrido-[2,3- ~ 1,5~benzodiazepine-5-one 7.9 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b]-~1,5~benzodiazepine~5-one, 100 ml o absolute dioxan, 1.57 g of~55% sodium hydride in mineral oil and 5.1 g of 2 , pyrrolidinoethyl chloride w re reacted and processed as described in Example 1~.
B~p~o 06 183-185C. Yield: 72% of theory.
Exam~
11-(2-Dimethylaminoethyl)-5,11-dihydro~5-methyl-6H-pyrido~
[2,3-b][l~lbenzodiazeE~ine-6-onP
T~ 9.0 g of 5,11-dihydro-5-methyl-6H-pyridoC2,3'b][1~h] ~ ~ It benzodiazepine-6-one were dissolved in 200 ml o~ hot absolute xylene~ 2.1 g of 50% sodium h~dride in mineral ~oil were added and the mixture was refluxed for 2 hours.
:~ ... .-; 5.3 g of 2-dimethylaminoethyl chloride were then added dropwise and the mixture was refluxed for a further 16 -~
', : .
hours. The cooled reaction mixture was distributed between ether and water. The organic layer was separated ; ~ - 38 - ~
- .
:
~i7Zl36 and extracted with dilute acetic acid. The acidic aqueous layer was made alkaline with a concentrated aqueous ammonia solution and the precipitated oil was extracted with ether~
After evaporation of the ether~ the residue was distilled.
5 . L g of 11-(2-dimethylaminoethyl-5,11-dihydro-5-methyl-6H-pyrido[2,3-b]Cl,f~]benzodiazepine-6-one were obtained of b.p.o 006 171-173C
After cry~tallization and recrystallization from ' ~ :
petroleum ether, 3.2 g of substance of m.p. 109 - 110C ~ `
were obtained. -Example 19 ~ `~
11-(2-Diethylaminoethyl)-5,11-dihydro-5 methyl-6H-pyrido~
9.05 g of S,ll-dihydro-5-methyl-6H-pyrido[2s3-b]~l,L]-benzodiazepine-6-one were dissolved in 90 ml of dimethyl formamide at 20C. 1.2 g of 80% sodium hydride in mineral oil were added and the mixture was stirred at 60C for `~ -.
~5 minutes. 6.55 ml of 2-diethylaminoethyl chloride - were then added dropwise and the mixture was stirred at ~-120C for 30 minutesO After evaporation under vacuum, ~ ~
' ..
the residue was agitated with a mixture of chloroform and dilute acetic acid~ The aqueous layer was separated '' ~' ':
' ':
.. . : . .. .
~ ~5~ 6 and made alkaline with a concentrated ammonia solution.
The base, precipitated as an oil, ~as taken up in chloroorm. The solvent was distilled off under vacuum and the oily residue was distilled.
Yield: 5.6 g (42.8% of theory~ of 11-(2-diethylaminoethyl)~
5,11-dihydro-5-methyl-6H-pyridoC2,3-b][1,4]benzodiazepine~
6-one of b.poo 07 197-199C ~;
11-(2-Diisopropylaminoethyl)-5Jll-dihydro-5-methyl-6H~
py,~,ido~2~3-bJ[1,4]benzodiazepine-6-one 4.52 g of 5,11-dihydro-5-rnethyl-6H-pyrido~2,3-b][1,4]-benzodiazepine-6-one9 45 ml of dimethyl formamide, 0.75 g of ~ ;
80Yo sodium ~ydride in mineral oil and 4.85 g of 2-diiso-propylaminoethyl chloride were reacted and processed analogously to Example l9.~
B.p.0~07 196-199C. Yield:~58% of theory.
Exam (3-Dimethylaminopropyl)-5,11-dihydro 5-methyl-6H-.
~ 9.0 g of 5,11-dihydro-5-methyl-6H-pyrido[2,3-b][1,4]- -`
..~ .
benzodiazepine-6-one, 200 ml of absolute xylenej 2.1 g ; of 50% sodium hydride in mineral oil and 5.3 g of 3-, , . , .
: - . ~
~.
~ ~5~ZI!36 ~` dimethylaminopropyl chloride were reacted and processed analogously to Example 18.
B.P.2 5 202-205C. M.p.: 85.5 - 86.5C (recrystallized ` from petroleum ether). Yield~. 30% of theory. ~ -~
22 `
11-(3-Diethylaminopropyl)-5,11-dihydro-S-methyl-6H-pyrido- -~2,3-b]~1,4]benzodiazepine-6-one ~
- ~ ~
` ~ 5.0 g of 5,11-dihydro-5-methyl-6H-pyrido[2,3-b][l,~]~
benzodiazepine-6-one, 100 ml of absolute xylene, 1.06 g ; of 50% sodi~m hydride and 3.0 g of 3-diethylaminopropyl chloride were reacted and processed as described in ~` -Example 18.
B~p~o 2 212-214G. Yield: 52% of theory.
(3-Diisopropylaminopropyl)-5,11-dihydro-5-methyl-6H~
:::: ~ ; , 4.75 g of 5,11-dihydro-5-methyl-6H-pyrido[2,3-b][1,4~ ;?
benzodiazepine-6-one, ~7 ml of dimethyl formamide, 0.63 g~ ~
, . ~ , - ~ .
of 80% sodium hydride and 3.5 g of 3-diisopropylaminopropyl `
;~ ~ chlorlde were reacted and processed as described in Example 19.
B~p~o 1 217-220C. Yield: 42% of theory. `
- 41 - ;?
., .' `.
,: , . . .
157;~6 (3-Pyrrolidinopropyl)-S,ll-dihydro-5-methyl-6H-pyrido~
.:. ~, .
.~ L 2,3-b~[1,4~benzodiazepine-6-one 7.9 g of 5,11-dihydro-5~methyl-6H-pyrido[293-b]C1,4]- -benzodiazepine-6 one and 1.57 g of 55% sodium hydride in mineral oil were stirred in 100 ml of absolute dioxan at . - . , ~ .
;~ 80C for ~5 minutes. 5.6 g of 3-pyrrolidinopropyl chloride ~ ;;
, ~ .-~; were then added dropwise and the mixture was refluxed ~! ~ for l hour. The solvent was distilled off under vacuum and the residue was dissolved in a mixture of ether and water. The further procedure was carried out~as described -., ~ . ~ , , ; ~ in ExamplQ 18. M.p-.: 119-121C (from cyclohexane). -~
-Yield: 57~0 of theory.
Hydrochloride: From the base with ethereal hydrochloric acid;in~dioxan. N.p.: 218-221C ~from isopropanol).
(3 Piperidinopropyl)-S,ll-dihydro-5-methyl-6H-pyrido~
[2~3-b ~ enzodiazepine-6-one ~ ~ 7.9 g of 5,11-dihydro-5-methyl-6H-pyrldo[2,3-b][1,4 ;; ~ benzodiazepine-6-one7 100 ml of absolute dioxan, 1.57 g of 55% sodium hydride in mineral oil and 6.15 g of 3 piperidinopropyl chloride were reacted and processed ~ - 42 '' :,.
. :
~115~728~
..
as described in Example 24.
! B~p~o 06 198-200C. Yield: 62% of theory.
Example 26 11-(3-Hexamethyleneiminopropyl)-5,11-dihydro-5-methyl-6H~
rldo r 2,3-b~ r 1 3 4~benzodiazepine-6-one _ _ PY ~ ~:
7.9 g of 5,11-dihydro-5-methyl-6H-pyrido[2,3-b~[l,h~
benzodiazepine-6-one, 100 ml of absolute dioxan, 1.57 g of 55% sodi~lm hydride in mineral oil and 6.8 g of 3-hexa-methyleneiminopropyl chloride were reacted and processed as described in Example 24.
B~p~o 06 195-198C. Yield: 54% of theory.
Example 27 (3-Diethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-~2,3-b][~5~benzodiazepine~5-one 11.3 g (0.05 mol~ of 6,11-dihydro-6-methyl-5H-pyrido~
: , :
[2,3-b][l,5]benzodiazepine-5-one were dissolved in 100 ml of dimethyl formamide. O.b4 g (0.055 mol) of lithium hydride were added under nitrogen and the mixture was ~ -stirred for 30 mlnutes at 50C. A solution of 9~0 g (0.06 mol) of 3 diethylaminopropyl chloride in 20 ml of dimethyl forrnamide was added dropwise and the mixture was heated up to about 100C. The solvent was distilled ~ 43 -''; '"`' ' .
, ~
,.. . . . . .
. , , , . . , .: , , . , , . . , . .. ~
: ` :
:
~57286 , :`.
off under vacuum. The residue was mixed with amZmonia `, and extracted with ether. The residue of the ether extract was distilled. Yield: 71% of theory of 11-(3-; diethylaminopropyl) 6,11-dihydro-6-methyl-5H-pyrido-, ` C2,3-blZ[1,5]benzodiazepine-5-one of b.p.o 13 197-198C.
:
Example 28 11-(3-Diethylaminopropyl~-6,11-dihydro-6-methyl-SH-pyrido-CZ,3-b~l 9 5]benzodiazepine~5-on~
a) 20.0 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]-benzodiazepine-5-one were dissolved in 170 ml of diethyl `;
;`Z
i~ ketone and 11 ml of pyridine at 40C~ Within 15 minutes 100 ml of a 20% solution o~ phosgene in toluene were ~ ~ , added dropwise and the mixture was heated at 60C for 2 hours, at 80C for a further 2 hours and finally at 110C for 1 hour. After cooling to room temperature, ~ ;~
200 ml of water were added and the mixture was filtered The organic layer was dried over sodium sulfate and a ~ . , quantity of the solvent was distilled off to leave a ~olume of about 50 ml. After cooling, the mixture was ;~
filtered with suction and washed with cold diethyl ketone.
Yield: 15.5 g of 11-chloroformyl-6,11-dihydro-6-methyl-; SH pyrido[2,3-b][l,S~benzodiazepine-5-one of m.p. 184-186C.
i - 44 -!
:
.
: ..
3L~5~
b) 8.8 g oE this chloroformyl compound were boiled with `~
12 g of 3-diethylamino-propan-1-ol in 88 ml of chlorobenze~e `
for L hours. The cooled solution was washed with an aqueous `
bicarbonate solution and then extracted with dilute aqueous - ;~
hydrochloric acid. The hydrochloric acid solution was made alkaline with bicarbonate and the base was extracted with chloroform. The chloroform solution, having been treated with charcoal and sodium sulfate, was evaporated under Z
vacuum. The residue was recrystallized from a mixture ,.
of one part of ethyl acetate to 10 parts of cyclohexane. ~
,. . . .
Yield: 8.2 g of 6,11-dihydro-6--methyl~ (3~diethylamino~
propoxycarbonyl3-5H-pyrido[2,3~b~[1,5]benzodiazepine-5-one ~Z
of m.p. 92-93C.
c~ 3.0 g of this basic ester were heated in an oil-bath -` at 220C for 1 hour. The carbon dioxide evolution~ which~
; ~ commenced at 180C, was complete after about 1 hour. After cooling to about 100C~ 32 ml of dioxan were added followed ~ , by 0.66 ml of concentrated aqueous hydrochloric acid.
After standing for several hours, the hydrochloride ;~ of 11-(3-diethylaminopropyl)-6,11-dlhydro-6-methyl-5H~
pyridoC293-b~C1,5~benzodiazepine-5-one crystallized out ~ -, . . .
` from this solution in a yield of 82% of theory. The ,, :~ .
~ .
1(~57~1~6 hydrochloride melted at 205-208C af~er recrystallization from isopropanol.
~e same compound could also be obtained in about the same yield, when the ~ ,?
decarboxyla~ion was effec~ed in diethylene glycol, sulfolane, o-dichloro-benzene o~ tetraethylene glycol dimethyl ether.
Example 29 11-(2-Dime~hylaminoethyl)-5,11-dihydro-5-methyl-6H-pyrido~2,3-b~1,4~benzo-diazepine-6-one 2.7 g of 5,11-dihydro-5-methyl-11-(2-dimethylaminoethoxycarbonyl) 6H-pyridof2,3-bJ~1~4~benzodia7epine-6-one, of m.p. 65-70C, (obtained by esterification of the 11-chloroformyl-5,11-dihydro-5-methyl-6H-pyrido~2,3-b~-~1,4~benzodiazepine-6-one, of m.p. 166-168C, with 3-dimethylaminoethanol analogously to Example 28b were decarboxylated as described in Example 28c. ;
The compound was obtained of m.p. 108.5-111C in a yield of 58~ of theory.
Example 30 11-(3-Dimethylaminopropyl)-5~11-dihydro-5-methyl-6H-pyrido[2,3-bJ[1,4Jbenzo~
diazep me-6-one 3.2 g of 5,11-dihyd~o-5-methyl-11-(3-dimethylaminopropoxycarbonyl)-6H-pyrido~2,3-bJ[1,4~benzodia7epine-6-' , ., .
f ~'~
,~ .
. .
,~ .
:
- ~57i2~6 ' ' -one of m.p. 92-94C were decarboxylated as described ; in Example 28c. The compound was obtained of m.p. 84 ~ 86C in a yield of 54% of theory.
:'-~ . ' .
Example I
- ~ ,.
Tablets containing 50 ~g of 11-(3-diethylaminopropyl)-6 dihydro-6-methyl-5H-pyrido[2,3-b3~1,5]benzodiazepine-5 one hydrochloride Composition:
~ 1 tablet contains: -'~ Active ingredient 0.05 mg . . : ,.
corn starch 75.00 mg `
`~ lactose 49.95 mg ~ polyvinyl pyrrolidone 4.00 mg ,? . ' '' magneslum stearate 1.00 mg 130.00 mg i ;~
. ' . . ~ .-A mixture of the corn starch and lactose was homogen~
eously moistened with an aqueous solution containing the ;
active ingredient and the polyvinyl pyrrolidone. The mass ~
: ~''':; ~:' was granulated through a screen of l.s mm mesh-size, dried at 45C and again passed through the said screen. ;
~ 67 : . ,' ~, ' .
, . . . ' , . , ,, , ' . ' ' ' . ' , ': . . . " ., ' ~ ! -957;~1~6 The granulate thus obtain~d was mixed with the magnesium stearate and pressed into tablets~
Weight of tablet: 130 mg Punch: 7 mm, flat, faceted on both sides Exam~le II
Coated tablets containing S00 ~g of 11-(3-diethylamino-propyl)-6,11-dihydro-6-methyl-5H-pyrido[2,3-b]~1,5]-Composition:
1 coated tablet core contains~
Active ingredient 0.5 mg ;, , ~
calcium hydrogen phosphate9anhydrous 34O0 mg corn starch 9.5 mg gelatine~ : 2.0 mg :J ,' ~ talcum 4.0 mg ., - .
. 50.0 mg t~2s~sL~
. .
::
A mixture of the active ingredient with the corn ~ ;
starch and calcium hydrogen phosphate was moistened with a solution of the gelatine in water and granulated through a screen o~ l.S mm mesh-size, dried at 45C and again .
passed through the said screen. The granulate thus obtained ~ ~
- 48 - : ~i ;
::, - , : - --. .
~9s7~
was mixed with talculn and pressed into coated tablet cores.
Weight of core: 50.0 n.g Punch: 5 mm, arcuat~.
The coated tablet cores were covered according to known processes with a coating consisting~essentially of sugar and talcum. The finished coated tablets were polished with beeswax. ;
Weight of coated tablet: 80 mg.
Example III
&elatine capsules containing 20 ~g of 11-(3-dieth~lamino-;
~ propyl)-6,11-dihydro-6-methyl-5H-pyridoC2,3-b][1,5]~benzo- ~ ~. . ...
diaze~_ne-5-one hydrochloride _ Composition:
,, .
;~ ~1 gelatine capsule contains: ;~
Active ingredient 0.020 mg ' ~ corn starch 79.989 mg - - ;
Aerosil 200 3.000 mg ~ ~
- . ,:
magnesium stearate 2.000 m~
85.000 mg Method of preparation~
After the aqueous solution of the active ingredient had been adsorbed by the Aerosil and the product had dried, : . . :
- 49 - - ~
T~ade~ar k ~;
,. . .. . . . . . . .
,, ,, .. .. , ~- . . , ~57;~36 the components were intimately mixed and filled into gelatine capsules.
Content of capsule: 85 mg Example IV
Tablets containing 5 ~g of 11-~3-diethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido[2,3-b][l,S]benzodiazepine-6-.-:
one hydrochloride _ _ _ Composition:
f Active ingredient 0O005 mg :t ~ ~-ethoxy-acetanilide 200.000 mg lactose 75.000 mg corn starch 99.995 mg polyvlnyl pyrrolidone ~20.000 mg ~ ~ ~ magnesium stearate 5dO00 mg - 400.000 mg ~ ~ Method of preparation-., ~ .. ' The active ingredient and the polyvinyl pyrrolidone were dissolved in ethanol and the mixture o~ ~-ethoxy-; : :
acetanilide, lactose and corn starch was moistened with this~solution. The mass was granulated through a screen `~
of 1.5 mm mesh-size, dried at 45C and passed through a `
; screen of 1.0 mm mesh~size. The finished granulate was - 50 ~ -,.,. ' : ;' . . . .
~;i7~
mixed with the magnesium stearate and pressed into tablets. , Weight of tablet: 400 mg ~ ;~
Punch. 11 mm, flat.
Example V
Suppositories containing 200 ~g of 11-(3-diethylamino~
propyl)-6,11-dihydro-6-methyl-5H-pyrido~2,3-b][lj53- -benzodiazepine-5-one hydrochloride `~
1 suppository contains~
Active ingredient 0.2 mg suppository mass (e.g. Witepsol H 19 and W 45) 1 699.8 mg 1 700.0 mg io~.
The supporitory mass was melted. The finely divided active ingredient was homogeneously dispersed in the melt at 38C. The mass was cooled to 35C and poured into pre-cooled supposîtory moulds. `~
Weight of suppository: 1.7 g Example VI
Syrup containing 10 ~g/ml of 11-(3-diethylaminopropyl)-6,11 dih~dro-6-methyl-5H-pyridoC2,3-b][1~53benzodiazepine-5-one hydrochloride .
72~
~ .
100 ml of syrup contain:
Active ingredient 0.001 g carboxymethylcellulose 0.1 g me~hyl p-hydroxyb~nzoate 0.05 g propyl ~-hydroxybenzoate 0.01 g cane sugar 10.0 g glycerine 5 0 g sorbit solution 70% 20.0 g fla~ouring 0.3 g distilled water ad 100.0 ml Method of preparation:
;
The distilled water was heated to 70C and the methyl ~and propyl ~-hydroxybenzoates, the glycerine and carboxy :
methylcellulose were disgolved therein whilst stirring.
:.,'. - ` ' The solution was cooled to room temperature and the active ingredient was added whilst stirring and dissolved. After .
~ addition of the sugar~ sorbit solution and flavouring, the l, ~
syrup was placed under vacuum for de-aeration w~ilst stirring.
5 ml o syrup contai~l 0.05 mg of 11-(3-diethyl-aminopropyl)-6,11-dihydro-6-methyl-5H-pyrido- `
2,3-b3[1,5~benzodiazepine-5-one hydrochloride .- 52 - `
'`"' :' , `: :
~ 57~6 :
,~
, , . Dosed aerosol conkaining 50 ~g/dose of 11~(3-diethylamino-~ - propyl')-6,11-dihydro-6-methyl-SH~pyrido[2,3-b][1,5]- ~ ~:
-'' benzodiaze~ine-S-one hvdrochloride j~ ' l.pressurized package (150 strokes) contains~
` Active ingredient 7~5 mg .
~ ; ~
~: ethanol - 997.5 mg ;~
propellant 12/14 (60:40)8,895.0 mg - 9 900~0 mg .
The active ingredient was dissolved ;n ethanol. The ,~ ~: ; solution was cooled to -30C and filled .into a pre-cooled ~ .. . . .
aluminium package. The dosed propellant mixture9 cooled ~
to -50C, was'subsequently added and the valve was . '~ ~ ' tightly fitted in.
1 s~trok~ contains 0.05 mg of 11-(3-diethylamino-propyl~-6,1.1-dihydro-6-methyl-5H-pyrido[2,3-b]
1,5~ben~ e e~9 one hydrochloride "
i 53 ~ ~ ~:
,i - , ' 'i ~ ~ ' ,, . ~ .~
. . ~ ., .
.
, , ~
B.~p.~ 09 200-202C. Yield: 63% of theory.
, :
Exæmple 16 - 11-(3-Hexamethyleneiminopropyl)-6,11-dihydro-6~methyl-i5H- -~ ;
, 7.9 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b~f- `~
[1,5]benæodiazepine~5 one9 100 ml of absolute dioxan, 1.57 g of 55% sodi~m hydride in mineral oil and 6.7 g of 3-hexamethyleneiminopropyl chloride were reacted and . - ~ .
processed as described in Example 14. B~p~o ~ 37 _ .. : . . . ~ , ~, .
~S7;~86 `:
:, .
238-2~12C, yield: 62% of theoryO
__7 11-(2-Pyrrolidinoethyl)-6~ dihydro-h-methyl-5H-pyrido-[2,3- ~ 1,5~benzodiazepine-5-one 7.9 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b]-~1,5~benzodiazepine~5-one, 100 ml o absolute dioxan, 1.57 g of~55% sodium hydride in mineral oil and 5.1 g of 2 , pyrrolidinoethyl chloride w re reacted and processed as described in Example 1~.
B~p~o 06 183-185C. Yield: 72% of theory.
Exam~
11-(2-Dimethylaminoethyl)-5,11-dihydro~5-methyl-6H-pyrido~
[2,3-b][l~lbenzodiazeE~ine-6-onP
T~ 9.0 g of 5,11-dihydro-5-methyl-6H-pyridoC2,3'b][1~h] ~ ~ It benzodiazepine-6-one were dissolved in 200 ml o~ hot absolute xylene~ 2.1 g of 50% sodium h~dride in mineral ~oil were added and the mixture was refluxed for 2 hours.
:~ ... .-; 5.3 g of 2-dimethylaminoethyl chloride were then added dropwise and the mixture was refluxed for a further 16 -~
', : .
hours. The cooled reaction mixture was distributed between ether and water. The organic layer was separated ; ~ - 38 - ~
- .
:
~i7Zl36 and extracted with dilute acetic acid. The acidic aqueous layer was made alkaline with a concentrated aqueous ammonia solution and the precipitated oil was extracted with ether~
After evaporation of the ether~ the residue was distilled.
5 . L g of 11-(2-dimethylaminoethyl-5,11-dihydro-5-methyl-6H-pyrido[2,3-b]Cl,f~]benzodiazepine-6-one were obtained of b.p.o 006 171-173C
After cry~tallization and recrystallization from ' ~ :
petroleum ether, 3.2 g of substance of m.p. 109 - 110C ~ `
were obtained. -Example 19 ~ `~
11-(2-Diethylaminoethyl)-5,11-dihydro-5 methyl-6H-pyrido~
9.05 g of S,ll-dihydro-5-methyl-6H-pyrido[2s3-b]~l,L]-benzodiazepine-6-one were dissolved in 90 ml of dimethyl formamide at 20C. 1.2 g of 80% sodium hydride in mineral oil were added and the mixture was stirred at 60C for `~ -.
~5 minutes. 6.55 ml of 2-diethylaminoethyl chloride - were then added dropwise and the mixture was stirred at ~-120C for 30 minutesO After evaporation under vacuum, ~ ~
' ..
the residue was agitated with a mixture of chloroform and dilute acetic acid~ The aqueous layer was separated '' ~' ':
' ':
.. . : . .. .
~ ~5~ 6 and made alkaline with a concentrated ammonia solution.
The base, precipitated as an oil, ~as taken up in chloroorm. The solvent was distilled off under vacuum and the oily residue was distilled.
Yield: 5.6 g (42.8% of theory~ of 11-(2-diethylaminoethyl)~
5,11-dihydro-5-methyl-6H-pyridoC2,3-b][1,4]benzodiazepine~
6-one of b.poo 07 197-199C ~;
11-(2-Diisopropylaminoethyl)-5Jll-dihydro-5-methyl-6H~
py,~,ido~2~3-bJ[1,4]benzodiazepine-6-one 4.52 g of 5,11-dihydro-5-rnethyl-6H-pyrido~2,3-b][1,4]-benzodiazepine-6-one9 45 ml of dimethyl formamide, 0.75 g of ~ ;
80Yo sodium ~ydride in mineral oil and 4.85 g of 2-diiso-propylaminoethyl chloride were reacted and processed analogously to Example l9.~
B.p.0~07 196-199C. Yield:~58% of theory.
Exam (3-Dimethylaminopropyl)-5,11-dihydro 5-methyl-6H-.
~ 9.0 g of 5,11-dihydro-5-methyl-6H-pyrido[2,3-b][1,4]- -`
..~ .
benzodiazepine-6-one, 200 ml of absolute xylenej 2.1 g ; of 50% sodium hydride in mineral oil and 5.3 g of 3-, , . , .
: - . ~
~.
~ ~5~ZI!36 ~` dimethylaminopropyl chloride were reacted and processed analogously to Example 18.
B.P.2 5 202-205C. M.p.: 85.5 - 86.5C (recrystallized ` from petroleum ether). Yield~. 30% of theory. ~ -~
22 `
11-(3-Diethylaminopropyl)-5,11-dihydro-S-methyl-6H-pyrido- -~2,3-b]~1,4]benzodiazepine-6-one ~
- ~ ~
` ~ 5.0 g of 5,11-dihydro-5-methyl-6H-pyrido[2,3-b][l,~]~
benzodiazepine-6-one, 100 ml of absolute xylene, 1.06 g ; of 50% sodi~m hydride and 3.0 g of 3-diethylaminopropyl chloride were reacted and processed as described in ~` -Example 18.
B~p~o 2 212-214G. Yield: 52% of theory.
(3-Diisopropylaminopropyl)-5,11-dihydro-5-methyl-6H~
:::: ~ ; , 4.75 g of 5,11-dihydro-5-methyl-6H-pyrido[2,3-b][1,4~ ;?
benzodiazepine-6-one, ~7 ml of dimethyl formamide, 0.63 g~ ~
, . ~ , - ~ .
of 80% sodium hydride and 3.5 g of 3-diisopropylaminopropyl `
;~ ~ chlorlde were reacted and processed as described in Example 19.
B~p~o 1 217-220C. Yield: 42% of theory. `
- 41 - ;?
., .' `.
,: , . . .
157;~6 (3-Pyrrolidinopropyl)-S,ll-dihydro-5-methyl-6H-pyrido~
.:. ~, .
.~ L 2,3-b~[1,4~benzodiazepine-6-one 7.9 g of 5,11-dihydro-5~methyl-6H-pyrido[293-b]C1,4]- -benzodiazepine-6 one and 1.57 g of 55% sodium hydride in mineral oil were stirred in 100 ml of absolute dioxan at . - . , ~ .
;~ 80C for ~5 minutes. 5.6 g of 3-pyrrolidinopropyl chloride ~ ;;
, ~ .-~; were then added dropwise and the mixture was refluxed ~! ~ for l hour. The solvent was distilled off under vacuum and the residue was dissolved in a mixture of ether and water. The further procedure was carried out~as described -., ~ . ~ , , ; ~ in ExamplQ 18. M.p-.: 119-121C (from cyclohexane). -~
-Yield: 57~0 of theory.
Hydrochloride: From the base with ethereal hydrochloric acid;in~dioxan. N.p.: 218-221C ~from isopropanol).
(3 Piperidinopropyl)-S,ll-dihydro-5-methyl-6H-pyrido~
[2~3-b ~ enzodiazepine-6-one ~ ~ 7.9 g of 5,11-dihydro-5-methyl-6H-pyrldo[2,3-b][1,4 ;; ~ benzodiazepine-6-one7 100 ml of absolute dioxan, 1.57 g of 55% sodium hydride in mineral oil and 6.15 g of 3 piperidinopropyl chloride were reacted and processed ~ - 42 '' :,.
. :
~115~728~
..
as described in Example 24.
! B~p~o 06 198-200C. Yield: 62% of theory.
Example 26 11-(3-Hexamethyleneiminopropyl)-5,11-dihydro-5-methyl-6H~
rldo r 2,3-b~ r 1 3 4~benzodiazepine-6-one _ _ PY ~ ~:
7.9 g of 5,11-dihydro-5-methyl-6H-pyrido[2,3-b~[l,h~
benzodiazepine-6-one, 100 ml of absolute dioxan, 1.57 g of 55% sodi~lm hydride in mineral oil and 6.8 g of 3-hexa-methyleneiminopropyl chloride were reacted and processed as described in Example 24.
B~p~o 06 195-198C. Yield: 54% of theory.
Example 27 (3-Diethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-~2,3-b][~5~benzodiazepine~5-one 11.3 g (0.05 mol~ of 6,11-dihydro-6-methyl-5H-pyrido~
: , :
[2,3-b][l,5]benzodiazepine-5-one were dissolved in 100 ml of dimethyl formamide. O.b4 g (0.055 mol) of lithium hydride were added under nitrogen and the mixture was ~ -stirred for 30 mlnutes at 50C. A solution of 9~0 g (0.06 mol) of 3 diethylaminopropyl chloride in 20 ml of dimethyl forrnamide was added dropwise and the mixture was heated up to about 100C. The solvent was distilled ~ 43 -''; '"`' ' .
, ~
,.. . . . . .
. , , , . . , .: , , . , , . . , . .. ~
: ` :
:
~57286 , :`.
off under vacuum. The residue was mixed with amZmonia `, and extracted with ether. The residue of the ether extract was distilled. Yield: 71% of theory of 11-(3-; diethylaminopropyl) 6,11-dihydro-6-methyl-5H-pyrido-, ` C2,3-blZ[1,5]benzodiazepine-5-one of b.p.o 13 197-198C.
:
Example 28 11-(3-Diethylaminopropyl~-6,11-dihydro-6-methyl-SH-pyrido-CZ,3-b~l 9 5]benzodiazepine~5-on~
a) 20.0 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]-benzodiazepine-5-one were dissolved in 170 ml of diethyl `;
;`Z
i~ ketone and 11 ml of pyridine at 40C~ Within 15 minutes 100 ml of a 20% solution o~ phosgene in toluene were ~ ~ , added dropwise and the mixture was heated at 60C for 2 hours, at 80C for a further 2 hours and finally at 110C for 1 hour. After cooling to room temperature, ~ ;~
200 ml of water were added and the mixture was filtered The organic layer was dried over sodium sulfate and a ~ . , quantity of the solvent was distilled off to leave a ~olume of about 50 ml. After cooling, the mixture was ;~
filtered with suction and washed with cold diethyl ketone.
Yield: 15.5 g of 11-chloroformyl-6,11-dihydro-6-methyl-; SH pyrido[2,3-b][l,S~benzodiazepine-5-one of m.p. 184-186C.
i - 44 -!
:
.
: ..
3L~5~
b) 8.8 g oE this chloroformyl compound were boiled with `~
12 g of 3-diethylamino-propan-1-ol in 88 ml of chlorobenze~e `
for L hours. The cooled solution was washed with an aqueous `
bicarbonate solution and then extracted with dilute aqueous - ;~
hydrochloric acid. The hydrochloric acid solution was made alkaline with bicarbonate and the base was extracted with chloroform. The chloroform solution, having been treated with charcoal and sodium sulfate, was evaporated under Z
vacuum. The residue was recrystallized from a mixture ,.
of one part of ethyl acetate to 10 parts of cyclohexane. ~
,. . . .
Yield: 8.2 g of 6,11-dihydro-6--methyl~ (3~diethylamino~
propoxycarbonyl3-5H-pyrido[2,3~b~[1,5]benzodiazepine-5-one ~Z
of m.p. 92-93C.
c~ 3.0 g of this basic ester were heated in an oil-bath -` at 220C for 1 hour. The carbon dioxide evolution~ which~
; ~ commenced at 180C, was complete after about 1 hour. After cooling to about 100C~ 32 ml of dioxan were added followed ~ , by 0.66 ml of concentrated aqueous hydrochloric acid.
After standing for several hours, the hydrochloride ;~ of 11-(3-diethylaminopropyl)-6,11-dlhydro-6-methyl-5H~
pyridoC293-b~C1,5~benzodiazepine-5-one crystallized out ~ -, . . .
` from this solution in a yield of 82% of theory. The ,, :~ .
~ .
1(~57~1~6 hydrochloride melted at 205-208C af~er recrystallization from isopropanol.
~e same compound could also be obtained in about the same yield, when the ~ ,?
decarboxyla~ion was effec~ed in diethylene glycol, sulfolane, o-dichloro-benzene o~ tetraethylene glycol dimethyl ether.
Example 29 11-(2-Dime~hylaminoethyl)-5,11-dihydro-5-methyl-6H-pyrido~2,3-b~1,4~benzo-diazepine-6-one 2.7 g of 5,11-dihydro-5-methyl-11-(2-dimethylaminoethoxycarbonyl) 6H-pyridof2,3-bJ~1~4~benzodia7epine-6-one, of m.p. 65-70C, (obtained by esterification of the 11-chloroformyl-5,11-dihydro-5-methyl-6H-pyrido~2,3-b~-~1,4~benzodiazepine-6-one, of m.p. 166-168C, with 3-dimethylaminoethanol analogously to Example 28b were decarboxylated as described in Example 28c. ;
The compound was obtained of m.p. 108.5-111C in a yield of 58~ of theory.
Example 30 11-(3-Dimethylaminopropyl)-5~11-dihydro-5-methyl-6H-pyrido[2,3-bJ[1,4Jbenzo~
diazep me-6-one 3.2 g of 5,11-dihyd~o-5-methyl-11-(3-dimethylaminopropoxycarbonyl)-6H-pyrido~2,3-bJ[1,4~benzodia7epine-6-' , ., .
f ~'~
,~ .
. .
,~ .
:
- ~57i2~6 ' ' -one of m.p. 92-94C were decarboxylated as described ; in Example 28c. The compound was obtained of m.p. 84 ~ 86C in a yield of 54% of theory.
:'-~ . ' .
Example I
- ~ ,.
Tablets containing 50 ~g of 11-(3-diethylaminopropyl)-6 dihydro-6-methyl-5H-pyrido[2,3-b3~1,5]benzodiazepine-5 one hydrochloride Composition:
~ 1 tablet contains: -'~ Active ingredient 0.05 mg . . : ,.
corn starch 75.00 mg `
`~ lactose 49.95 mg ~ polyvinyl pyrrolidone 4.00 mg ,? . ' '' magneslum stearate 1.00 mg 130.00 mg i ;~
. ' . . ~ .-A mixture of the corn starch and lactose was homogen~
eously moistened with an aqueous solution containing the ;
active ingredient and the polyvinyl pyrrolidone. The mass ~
: ~''':; ~:' was granulated through a screen of l.s mm mesh-size, dried at 45C and again passed through the said screen. ;
~ 67 : . ,' ~, ' .
, . . . ' , . , ,, , ' . ' ' ' . ' , ': . . . " ., ' ~ ! -957;~1~6 The granulate thus obtain~d was mixed with the magnesium stearate and pressed into tablets~
Weight of tablet: 130 mg Punch: 7 mm, flat, faceted on both sides Exam~le II
Coated tablets containing S00 ~g of 11-(3-diethylamino-propyl)-6,11-dihydro-6-methyl-5H-pyrido[2,3-b]~1,5]-Composition:
1 coated tablet core contains~
Active ingredient 0.5 mg ;, , ~
calcium hydrogen phosphate9anhydrous 34O0 mg corn starch 9.5 mg gelatine~ : 2.0 mg :J ,' ~ talcum 4.0 mg ., - .
. 50.0 mg t~2s~sL~
. .
::
A mixture of the active ingredient with the corn ~ ;
starch and calcium hydrogen phosphate was moistened with a solution of the gelatine in water and granulated through a screen o~ l.S mm mesh-size, dried at 45C and again .
passed through the said screen. The granulate thus obtained ~ ~
- 48 - : ~i ;
::, - , : - --. .
~9s7~
was mixed with talculn and pressed into coated tablet cores.
Weight of core: 50.0 n.g Punch: 5 mm, arcuat~.
The coated tablet cores were covered according to known processes with a coating consisting~essentially of sugar and talcum. The finished coated tablets were polished with beeswax. ;
Weight of coated tablet: 80 mg.
Example III
&elatine capsules containing 20 ~g of 11-(3-dieth~lamino-;
~ propyl)-6,11-dihydro-6-methyl-5H-pyridoC2,3-b][1,5]~benzo- ~ ~. . ...
diaze~_ne-5-one hydrochloride _ Composition:
,, .
;~ ~1 gelatine capsule contains: ;~
Active ingredient 0.020 mg ' ~ corn starch 79.989 mg - - ;
Aerosil 200 3.000 mg ~ ~
- . ,:
magnesium stearate 2.000 m~
85.000 mg Method of preparation~
After the aqueous solution of the active ingredient had been adsorbed by the Aerosil and the product had dried, : . . :
- 49 - - ~
T~ade~ar k ~;
,. . .. . . . . . . .
,, ,, .. .. , ~- . . , ~57;~36 the components were intimately mixed and filled into gelatine capsules.
Content of capsule: 85 mg Example IV
Tablets containing 5 ~g of 11-~3-diethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido[2,3-b][l,S]benzodiazepine-6-.-:
one hydrochloride _ _ _ Composition:
f Active ingredient 0O005 mg :t ~ ~-ethoxy-acetanilide 200.000 mg lactose 75.000 mg corn starch 99.995 mg polyvlnyl pyrrolidone ~20.000 mg ~ ~ ~ magnesium stearate 5dO00 mg - 400.000 mg ~ ~ Method of preparation-., ~ .. ' The active ingredient and the polyvinyl pyrrolidone were dissolved in ethanol and the mixture o~ ~-ethoxy-; : :
acetanilide, lactose and corn starch was moistened with this~solution. The mass was granulated through a screen `~
of 1.5 mm mesh-size, dried at 45C and passed through a `
; screen of 1.0 mm mesh~size. The finished granulate was - 50 ~ -,.,. ' : ;' . . . .
~;i7~
mixed with the magnesium stearate and pressed into tablets. , Weight of tablet: 400 mg ~ ;~
Punch. 11 mm, flat.
Example V
Suppositories containing 200 ~g of 11-(3-diethylamino~
propyl)-6,11-dihydro-6-methyl-5H-pyrido~2,3-b][lj53- -benzodiazepine-5-one hydrochloride `~
1 suppository contains~
Active ingredient 0.2 mg suppository mass (e.g. Witepsol H 19 and W 45) 1 699.8 mg 1 700.0 mg io~.
The supporitory mass was melted. The finely divided active ingredient was homogeneously dispersed in the melt at 38C. The mass was cooled to 35C and poured into pre-cooled supposîtory moulds. `~
Weight of suppository: 1.7 g Example VI
Syrup containing 10 ~g/ml of 11-(3-diethylaminopropyl)-6,11 dih~dro-6-methyl-5H-pyridoC2,3-b][1~53benzodiazepine-5-one hydrochloride .
72~
~ .
100 ml of syrup contain:
Active ingredient 0.001 g carboxymethylcellulose 0.1 g me~hyl p-hydroxyb~nzoate 0.05 g propyl ~-hydroxybenzoate 0.01 g cane sugar 10.0 g glycerine 5 0 g sorbit solution 70% 20.0 g fla~ouring 0.3 g distilled water ad 100.0 ml Method of preparation:
;
The distilled water was heated to 70C and the methyl ~and propyl ~-hydroxybenzoates, the glycerine and carboxy :
methylcellulose were disgolved therein whilst stirring.
:.,'. - ` ' The solution was cooled to room temperature and the active ingredient was added whilst stirring and dissolved. After .
~ addition of the sugar~ sorbit solution and flavouring, the l, ~
syrup was placed under vacuum for de-aeration w~ilst stirring.
5 ml o syrup contai~l 0.05 mg of 11-(3-diethyl-aminopropyl)-6,11-dihydro-6-methyl-5H-pyrido- `
2,3-b3[1,5~benzodiazepine-5-one hydrochloride .- 52 - `
'`"' :' , `: :
~ 57~6 :
,~
, , . Dosed aerosol conkaining 50 ~g/dose of 11~(3-diethylamino-~ - propyl')-6,11-dihydro-6-methyl-SH~pyrido[2,3-b][1,5]- ~ ~:
-'' benzodiaze~ine-S-one hvdrochloride j~ ' l.pressurized package (150 strokes) contains~
` Active ingredient 7~5 mg .
~ ; ~
~: ethanol - 997.5 mg ;~
propellant 12/14 (60:40)8,895.0 mg - 9 900~0 mg .
The active ingredient was dissolved ;n ethanol. The ,~ ~: ; solution was cooled to -30C and filled .into a pre-cooled ~ .. . . .
aluminium package. The dosed propellant mixture9 cooled ~
to -50C, was'subsequently added and the valve was . '~ ~ ' tightly fitted in.
1 s~trok~ contains 0.05 mg of 11-(3-diethylamino-propyl~-6,1.1-dihydro-6-methyl-5H-pyrido[2,3-b]
1,5~ben~ e e~9 one hydrochloride "
i 53 ~ ~ ~:
,i - , ' 'i ~ ~ ' ,, . ~ .~
. . ~ ., .
.
, , ~
Claims (134)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing compounds of general formula I, (I) wherein either R1 represents a hydrogen atom, a straight chain or branched alkyl group containing from 1 to 3 carbon atoms or a benzyl group and R2 represents a straight chain or branched alkyl group containing from 1 to 3 carbon atoms, or R1 and R2, together with the nitrogen atom to which they are attached, form a pyrrolidino, piperidino or hexamethyleneimino group, n is 2 or 3;
either A represents a nitrogen atom and B represents the group =CH-, or B
represents a nitrogen atom and A represents the group =CH-; and pharmaceuti-cally acceptable acid addition salts thereof, which process comprises: (a) reacting a compound of formula II, (II) (wherein M represents an alkali metal atom) with a compound of formula III
(III) (wherein X represents a halogen or tosyl group); (b) reacting a compound of fromula IV, (IV) (wherein Y represents a halogen or tosyl group) with a compound of formula V, (V) or (c) thermally decarboxylating a compound of formula VI, (VI) (d) when R1 represents a hydrogen atom, subjecting a compound of formula I
in which R1 represents a benzyl group to hydrogenolysis; and, if a pharm-aceutically acceptable acid addition salt is required, reacting the compound of formula I with a suitable acid.
either A represents a nitrogen atom and B represents the group =CH-, or B
represents a nitrogen atom and A represents the group =CH-; and pharmaceuti-cally acceptable acid addition salts thereof, which process comprises: (a) reacting a compound of formula II, (II) (wherein M represents an alkali metal atom) with a compound of formula III
(III) (wherein X represents a halogen or tosyl group); (b) reacting a compound of fromula IV, (IV) (wherein Y represents a halogen or tosyl group) with a compound of formula V, (V) or (c) thermally decarboxylating a compound of formula VI, (VI) (d) when R1 represents a hydrogen atom, subjecting a compound of formula I
in which R1 represents a benzyl group to hydrogenolysis; and, if a pharm-aceutically acceptable acid addition salt is required, reacting the compound of formula I with a suitable acid.
2. A process according to claim 1 wherein process (a) is used and the compound of formula II is produced in situ by reaction of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride or sodamide with a corresponding pyridobenzodiazepinone of formula II in which M
represents a hydrogen atom.
represents a hydrogen atom.
3. A process according to claim 1 wherein process (d) is used and the compound of formula I in which R1 is a benzyl group which is subjected to hydrogenolysis is obtained by process (a), (b) or (c) of claim 1.
4. A process according to claim 1 wherein A is nitrogen, B is =CH-.
5. A process according to claim 4 wherein n is 3.
6. A process according to claim 4 wherein n is 2.
7. A process according to claim 4, 5 or 6 wherein R1 and R2 are each the same alkyl group of 1 to 3 carbon atoms or, together with the nitrogen atom to which they are attached, form a pyrrolidino, piperidino or hexa-methyleneimino group.
8. A process according to claim 1 wherein A is =CH- and B is nitrogen.
9. A process according to claim 8 wherein n is 3.
10. A process according to claim 8 wherein n is 2.
11. A process according to claim 8, 9 or 10 wherein R1 and R2 are each the same alkyl group of 1 to 3 carbon atoms or, together with the nitrogen atom to which they are attached, form a pyrrolidino, piperidino or hexa-methyleneimino group.
12. A process according to claim 1 wherein A is nitrogen, B is =CH-, one of R1 and R2 is hydrogen and the other of R1 and R2 is methyl, ethyl or isopropyl.
13. Compounds of formula I as defined in claim 1 and their pharmaceuti-cally acceptable acid addition salts when made by a process according to claim 1 or by an obvious chemical equivalent thereof.
14. A process according to claim 1 wherein A is nitrogen, B is =CH-, n is 3 and R1 and R2 are both ethyl groups.
15. A process which comprises reacting the sodium or potassium salt of 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with 3-diethylaminopropyl chloride to produce 11-(3-diethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one and, if the hydrochloride salt is required reacting the product with hydrogen chloride.
16. A process according to claim 15 wherein the sodium or potassium salt of 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one is pre-pared in situ by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] diazepin-5-one with sodium hydroxide, potassium hydroxide or potassium methoxide.
17. A process which comprises reacting 11-(3-chloropropyl)-6,11-dihydro-6-methyl-5H-pyrido [2,3-b][1,5] benzodiazepin-5-one with diethylamine to produce 11-(3-diethylaminopropyl)-6,11-dihydro-6-methyl-pyrido [2,3-b]-[1,5] benzodiazepin-5-one.
18. A process which comprises reacting the lithium salt of 6,11-di-hydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with 3-dithylamino-propyl chloride to produce 11-(3-diethyleminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
19. A process according to claim 18 wherein the lithium salt is prepared in situ by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5]-benzodiazepin-5-one with lithium hydride.
20. A process which comprises heating in an inert solvent 6,11-dihydro-6-methyl-11-(3-diethylaminopropoxycarbonyl)-5H-pyrido-[2,3-b][1,5] benzodiaz-epin-5-one to produce 11-(3-diethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one and, if the hydrochloride salt is required reacting the product with hydrogen chloride.
21. 11-(3-Diethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one and its hydrochloride salt whenever pre-pared by a process according to claim 15, 16 or 20 or an obvious chemical equivalent thereof.
22. 11-(3-Diethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one whenever prepared by a process according to claim 17, 18 or 19 or an obvious chemical equivalent thereof.
23. A process according to claim 1 wherein A is nitrogen, B is =CH-, n is 2 and R1 and R2 are both methyl groups.
24. A process which comprises reacting 11-(2-chloroethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one with-dimethylamine to produce 6,11-dihydro-11-(2-dimethylaminoethyl)-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
25. A process which comprises reacting the sodium salt of 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one with 2-dimethylaminoethyl chloride to produce 11-(2-dimethylaminoethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
26. A process according to claim 25 wherein the sodium salt is prepared in situ by reaction between sodium hydride and 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one.
27. 11-(2-Dimethylaminoethyl)-6,11-dihydro-5-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one whenever prepared by a process according to claim 24, 25 or 26 or an obvious chemical equivalent thereof.
28. A process according to claim 1 wherein A is nitrogen, B is =CH-, n is 3 and R1 and R2 are both methyl groups.
29. A process which comprises reacting 11-(2-chloropropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one with dimethylamine to produce 6,11-dihydro-11-(3-dimethylaminopropyl)-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one.
30. A process which comprises reacting the sodium salt of 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with 3-dimethylamino-propyl p-toluenesulfonate to produce 6,11-dihydro-11-(3-dimethylaminopropyl)-6-methyl-5H-pyrido [2,3-b][1,5] benzodiazepin-5-one.
31. A process according to claim 30 wherein the sodium salt is prepar-ed in situ by reaction between sodium hydride and 6,11-dihydro-11-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
32. 6,11-dihydro-11-(3-dimethylaminopropyl)-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one whenever prepared by a process according to claim 29, 30 or 31 or an obvious chemical equivalent thereof.
33. A process according to claim 1 wherein A is nitrogen, B is =CH-, n is 3, R1 is methyl and R2 is hydrogen.
34. A process which comprises reacting 11-(3-chloropropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with methylamine to produce 11-(3-methylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
35. A process which comprises debenzylating by hydrogenolysis 11-[3-(N-benzyl-methylamino)-propyl]-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5]
benzodiazepin-5-one to produce 11-(3-methylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
benzodiazepin-5-one to produce 11-(3-methylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
36. A process according to claim 35 wherein the 11-[3-(N-benzyl-methylamino)-propyl]-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] is prepared by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one and 3-(N-benzyl-methylamino)-propyl chloride in the presence of sodium hydride.
37. 11-(3-Methylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]
[1,5] benzodiazepin-5-one when prepared by a process according to claim 34, 35 or 36 or an obvious chemical equivalent thereof.
[1,5] benzodiazepin-5-one when prepared by a process according to claim 34, 35 or 36 or an obvious chemical equivalent thereof.
38. A process according to claim 1 wherein A is nitrogen, B is =CH-, n is 3, R1 is ethyl and R2 is hydrogen.
39. A process which comprises reacting 11-(3-chloropropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,4] benzodiazepin-5-one with ethylamine to produce 11-(3-ethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]
[1,5] benzodiazepin-5-one.
[1,5] benzodiazepin-5-one.
40. A process which comprises debenzylating by hydrogenolysis 11-[3-(N-benzyl-ethylamino)-propyl]-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5]
benzodiazepin-5-one to produce 11-(3-ethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
benzodiazepin-5-one to produce 11-(3-ethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
41. A process according to claim 40 wherein the 11-[3-(N-benzyl-ethylamino)-propyl]-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,4] benzodiazepin-5-one is prepared by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one and 3-(N-benzyl-ethylamino)-propyl chloride in the presence of sodium hydride.
42. 11-(3-Ethylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one whenever prepared by a process according to claim 39, 40 or 41 or an obvious chemical equivalent thereof.
43. A process according to claim 1 wherein A is nitrogen, B is =CH-, n is 3, R1 is isopropyl and R2 is hydrogen.
44. A process which comprises reacting 11-(3-chloropropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with isopropyl-amine to produce 11-(3-isopropylaminopropyl)-6,11-dihydro 6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
45. A process which comprises debenzylating by hydrogenolysis 11-[3-(N-benzyl-isopropylamino)-propyl]-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one to produce 11-(3-isopropylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
46. A process according to claim 45 wherein the 11-[3-(N-benzyl-isopropylamino)-propyl]-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5]
benzodiazepin-5-one is produced by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one and 3-(N-benzyl-isopropylamino)-propyl chloride.
benzodiazepin-5-one is produced by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one and 3-(N-benzyl-isopropylamino)-propyl chloride.
47. 11-(3-Isopropylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one whenever prepared by a process according to claim 44, 45 or 46 or an obvious chemical equivalent thereof.
48. A process according to claim 1 wherein A is nitrogen, B is =CH?
n is 2 and R1 and R2 are both ethyl groups.
n is 2 and R1 and R2 are both ethyl groups.
49. A process which comprises reacting 11-(2-chloroethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with diethylamine to produce 11-(2-diethylaminoethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one.
50. A process which comprises reacting the sodium salt of 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with 2-diethylaminoethyl chloride to produce 11-(2-diethylaminoethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
51. A process according to claim 50 wherein the sodium salt is prepar-ed in situ by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5]
benzodiazepin-5-one and sodium hydride.
benzodiazepin-5-one and sodium hydride.
52. 11,(2-Diethylaminoethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one whenever prepared by a process according to claim 49, 50 or 51 or an obvious chemical equivalent thereof.
53. A process according to claim 1 wherein A is nitrogen, B is =CH-, n is 3 and R1 and R2 are both n-propyl groups.
54. A process which comprises reacting 11-(3-chloropropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with di-n-propylamine to produce 11-(3-di-n-propylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
55. A process which comprises reacting the sodium salt of 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with 3-di-n-propylaminopropyl chloride to produce 11-(3-di-n-propylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one.
56. A process according to claim 55 wherein the sodium salt is pre-pared in situ by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one.
57. 11-(3-Di-n-propylaminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one whenever prepared by a process according to claim 54, 55 or 56 or an obvious chemical equivalent thereof.
58. A process according to claim 1 wherein A is nitrogen, B is =CH-, n is 2 and R1 and R2 are both isopropyl groups.
59. A process which comprises reacting 11-(2-chloroethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with diisopropyl-amine to produce 11-(2-diisopropylaminoethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one.
60. A process which comprises reacting the sodium salt of 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one with 2-diisopropylaminoethyl chloride to produce 11-(3-diisopropylaminoethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one to produce 11-(2-diisopropylaminoethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] diazepin-5-one.
61. A process according to claim 60 wherein the sodium salt is pre-pared in situ by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] diazepin-5-one and sodium hydride.
62. 11-(2-Diisopropylaminoethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one whenever prepared by a process according to claim 59, 60 or 61 or an obvious chemical equivalent thereof.
63. A process according to claim 1 wherein A is nitrogen, B is =CH-, n is 3 and R1 and R2 are both isopropyl groups.
64. A process which comprises reacting 11-(3-chloropropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with diisopropyl-amine to produce 11-(3-diisopropylaminopropyl)-6,11-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5 one.
65. A process which comprises reacting the sodium salt of 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with 3-diisopropylamine-propyl chloride to produce 11-(3-diisopropylaminopropyl)-6,11-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
66. A process according to claim 65 wharein the sodium salt is prepared in situ by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5]
benzodiazepin-5-one and sodium hydride.
benzodiazepin-5-one and sodium hydride.
67. 11-(3-diisopropylaminopropyl)-6,11-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one whenever prepared by a process according to claim 54, 65 or 66 or an obvious chemical equivalent thereof.
68. A process according to claim 1 wherein A is nitrogen, B is =CH-, n is 3, R1 is an ethyl group and R2 is an isopropyl group.
69. A process which comprises reacting 11-(3-chloropropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with N-ethyl-N-isopropyl-amine to produce 11-[3-(N-ethyl-N-isopropylamino)-propyl]-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
70. A process which comprises reacting the sodium salt of 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with 3-(N-ethyl-N-iso-propylamino)-propyl chloride to produce 11-[3-(N-ethyl-N isopropylamino)-propyl]-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
71. A process according to claim 70 wherein the sodium salt is pre-pared in situ by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one and sodium hydride.
72 11-[3-(N-ethyl-N-isopropylamino)-propyl]-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one whenever prepared by a process according to claim 69, 70 or 71 or an obvious chemical equivalent thereof.
73. A process according to claim 1 wherein A is nitrogen, B is =CH-, n is 3 and R1 and R2 together with the nitrogen atom to which they are at-tached form a pyrrolidine ring.
74. A process which comprises reacting 11-(3-chloropropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with pyrrolidine to produce 11-(3-pyrrolidinopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one.
75. A process which comprises reacting the sodium salt of 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with 3-pyrroli-dinopropyl chloride to produce 11-(3-pyrrolidinopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
76. A process according to claim 75 wherein the sodium salt is pre-pared in situ by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one and sodium hydride.
77. 11-(3-pyrrolidinopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one whenever prepared by a process according to claim 74, 75 or 76 or an obvious chemical equivalent thereof.
78. A process according to claim 1 wherein A is nitrogen, B is =C -, n is 3 and R1 and R2 together with the nitrogen atom to which they are attached form a piperidine ring.
79. A process which comprises reacting 11-(3-chloropropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,4] benzodiazepin-5-one with piperidine to produce 11-(3-piperidinopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one.
80. A process which comprises reacting the sodium salt of 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with 3-piperidinopropyl chloride to produce 11-(3-piperidinopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
81. A process according to claim 80 wherein the sodium salt is pre-pared in situ by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one and sodium hydride.
82. 11-(3-Piperidinopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one whenever prepared by a process according to claim 79, 80 or 81 or an obvious chemical equivalent thereof.
83. A process according to claim 1 wherein A is nitrogen, B is =CH-, n is 3 and R1 and R2 together with the nitrogen atom to which they are at-tached form a hexamethyleneimine ring.
84. A process which comprises reacting 11-(3-chloropropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with hexamethy-leneimine to produce 11-(3-hexamethyleneiminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
85. A process which comprises reacting the sodium salt of 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with 3-hexamethyleneiminopropyl chloride to produce 11-(3-hexamethyleneiminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
86. A process according to claim 85 wherein the sodium salt is pre-pared in situ by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one and sodium hydride.
87. 11-(3-Hexamethyleneiminopropyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one whenever prepared by a process according to claim 84, 85 or 86 or an obvious chemical equivalent thereof.
88. A process according to claim 1 wherein A is nitrogen, B is =CH-, n is 2 and R1 and R2 together with the nitrogen atom to which they are at-tached form a pyrrolidine ring.
89. A process which comprises reacting 11-(2-chloroethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with pyrrolidine to pro-duce 11-(3-pyrrolidinoethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5]
benzodiazepin-5-one.
benzodiazepin-5-one.
90. A process which comprises reacting the sodium salt of 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one with 2-pyrrolidinoethyl chloride to produce 11-(3-pyrrolidinoethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5] benzodiazepin-5-one.
91. A process according to claim 90 wherein the sodium salt is prepar-ed in situ by reaction between 6,11-dihydro-6-methyl-5H-pyrido-[2,3-b][1,5]
benzodiazepin-5-one and sodium hydride.
benzodiazepin-5-one and sodium hydride.
92. 11-(3-Pyrrolidinoethyl)-6,11-dihydro-6-methyl-5H-pyrido-[2,3-b]-[1,5] benzodiazepin-5-one whenever prepared by a process according to claim 89, 90 or 91 or an obvious chemical equivalent thereof..
93. A process according to claim 1 wherein A is =CH-, B is nitrogen, n is 2 and R1 and R2 are both ethyl groups.
94. A process which comprises reacting 11-(2-chloroethyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with diethylamine to produce 11-(2-diethylaminoethyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one.
95. A process which comprises reacting the sodium salt of 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with 2-diethylaminoethyl chloride to produce 11-(2-diethylaminoethyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one.
96. A process according to claim 95 wherein the sodium salt is prepared in situ by reaction between 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4]
benzodiazepin-6-one and sodium hydride.
benzodiazepin-6-one and sodium hydride.
97. 11-(2-Diethylaminoethyl)-5,11-dihydro-5-methyl-6H pyrido-[2,3-b]-[1,4] benzodiazepin-6-one whenever prepared by a process according to claim 94, 95 or 96 or an obvious chemical equivalent thereof.
98. A process according to claim 1 wherein A is =CH-, B is nitrogen, n is 2 and R1 and R2 are both isopropyl groups.
99. A process which comprises reacting 11-(2-chloroethyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with diisopropylamine to produce 11-(2-diisopropylaminoethyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one.
100. A process which comprises reacting the sodium salt of 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with 2-diisopropylamino-ethyl chloride to produce 11-(2-diisopropylaminoethyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one.
101. A process according to claim 100 wherein the sodium salt is prepared in situ by reaction between 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4]
benzodiazepin-6-one and sodium hydride.
benzodiazepin-6-one and sodium hydride.
102. 11-(2-Diisopropylaminoethyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one whenever prepared by a process according to claim 99, 100 or 101 or an obvious chemical equivalent thereof.
103. A process according to claim 1 wherein A is =CH-, B is nitrogen, n is 3 and both R1 and R2 are methyl groups.
104. A process which comprises reacting 11-(3-chloropropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with dimethylamine to produce 11-(3-dimethylaminopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one.
105. A process which comprises reacting the sodium salt of 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with 3-dimethylamino-propyl chloride to produce 11-(3-dimethylaminopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one.
106. A process according to claim 105 wherein the sodium salt is pre-pared in situ by reaction between 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one and sodium hydride.
107. A process which comprises heating in an inert solvent 5,11-dihydro-5-methyl-11-(3-dimethylaminopropoxycarbonyl)-6H-pyrido-[2,3-b][1,4] benzo-diazepin-6-one to produce 11-(3-dimethylaminopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one.
108. 11-(3-Dimethylaminopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one whenever prepared by a process according to claim 104, 105 or 106 or an obvious chemical equivalent thereof.
109. 11-(3-Dimethylaminopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one whenever prepared by a process according to claim 107 or an obvious chemical equivalent thereof.
110. A process according to claim 1 wherein A is =CH-, B is nitrogen, n is 3 and R1 and R2 are both ethyl groups.
111. A process which comprises reacting 11-(3-chloropropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with diethylamine to produce 11-(3-diethylaminopropyl)-5,11-dihydro-5-methyl-6H-pyrido [2,3-b]-[1,4] benzodiazepin-6-one.
112. A process which comprises reacting the sodium salt of 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with 3-diethylaminopropyl chloride to produce 11-(3-diethylaminopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one.
113. A process according to claim 112 wherein the sodium salt is pre-pared in situ by reaction between 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one and sodium hydride.
114. 11-(3-Diethylaminopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one whenever prepared by a process according to claim 111, 112 or 113 or an obvious chemical equivalent thereof.
115. A process according to claim 1 wherein A is =CH-, B is nitrogen, n is 3 and R1 and R2 are both isopropyl groups.
116. A process which comprises reacting 11-(3-chloropropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with diisopropyl-amine to produce 11-(3-diisopropylaminopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one.
117. A process which comprises reacting the sodium salt of 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with 3-diiso-propylaminopropyl chloride to produce 11-(3-diisopropylaminopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one.
118. A process according to claim 117 wherein the sodium salt is pre-pared by reaction between 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4]
benzodiazepin-6-one and sodium hydride.
benzodiazepin-6-one and sodium hydride.
119. 11-(3-diisopropylaminopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one whenever prepared by a process according to claim 116, 117 or 118 or an obvious chemical equivalent thereof.
120. A process according to claim 1 wherein A is =CH-, B is nitrogen, n is 3 and R1 and R2 together with the nitrogen atom to which they are attach-ed form a pyrrolidine ring.
121. A process which comprises reacting 11-(3-chloropropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with pyrrolidine to produce 11-(3-pyrrolidinopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one.
122. A process which comprises reacting the sodium salt of 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with 3-pyrrolidino-propyl chloride to produce 11-(3-pyrrolidinopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one and, if the hydrochloride salt is required, reacting the product with hydrogen chloride.
123. A process according to claim 122 wherein the sodium salt is pre-pared in situ by reaction between 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one and sodium hydride.
124. 11-(3-pyrrolidinopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one and its hydrochloride salt whenever prepared by a process according to claim 121, 122 or 123 or an obvious chemical equivalent thereof.
125. A process according to claim 1 wherein A is =CH-, B is nitrogen, n is 3 and R1 and R2 together with the nitrogen atom to which they are at-tached form a piperidine ring.
126. A process which comprises reacting 11-(3-chloropropyl)-5,11-dihydro-5-methyl-6H pyrido-[2,3-b][1,4] benzodiazepin-6-one with piperidine to produce 11-(3-piperidinopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one.
127. A process which comprises reacting the sodium salt of 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with 3-piperidinopropyl to produce 11-(3-piperidinopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one.
128. A process according to claim 127 wherein the sodium salt is pre-pared in situ by reaction between 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one and sodium hydride.
129. 11-(3-Piperidinopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one whenever prepared by a process according to claim 126, 127 or 128 or an obvious chemical equivalent thereof.
130. A process according to claim 1 wherein A is =CH-, B is nitrogen, n is 3 and R1 and R2 together with the nitrogen atom to which they are at-tached form a hexamethyleneimine ring.
131. A process which comprises reacting 11-(3 chloropropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with hexamethylene-imine to produce 11-(3-hexamethyleneiminopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one.
132. A process which comprises reacting the sodium salt of 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one with 3-hexamethylene-iminopropyl chloride to produce 11-(3-hexamethyleneiminopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one.
133. A process according to claim 132 wherein the sodium salt is pre-pared in situ by reaction between 5,11-dihydro-5-methyl-6H-pyrido-[2,3-b]-[1,4] benzodiazepin-6-one and sodium hydride.
134. 11-(3-hexamethyleneiminopropyl)-5,11-dihydro-5-methyl-6H-pyrido-[2,3-b][1,4] benzodiazepin-6-one whenever prepared by a process according to claim 131, 132 or 133 or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742408111 DE2408111C3 (en) | 1973-02-20 | 1974-02-20 | Facsimile receiver |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1057286A true CA1057286A (en) | 1979-06-26 |
Family
ID=5907942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA227,479A Expired CA1057286A (en) | 1974-02-20 | 1975-05-21 | Pyridobenzodiazepinones, processes for their preparation and pharmaceuticals containing these compounds |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1057286A (en) |
-
1975
- 1975-05-21 CA CA227,479A patent/CA1057286A/en not_active Expired
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