PYRIDOBENZODIAZEPINONES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICALS CONTAINING THESE COMPOUNDS

PYRIDOBENZODIAZEPINONES, PROCEDE POUR LEUR PREPARATION ET PRODUITS PHARMACEUTIQUES EN CONTENANT

English 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.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing compounds of general formula I,
<IMG> (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,
<IMG> (II)
(wherein M represents an alkali metal atom) with a compound of formula III
(III)
<IMG>
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(wherein X represents a halogen or tosyl group); (b) reacting a compound of
fromula IV,
<IMG> (IV)
(wherein Y represents a halogen or tosyl group) with a compound of formula V,
<IMG> (V)
or (c) thermally decarboxylating a compound of formula VI,
<IMG> (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.

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.
56

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-
57

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.
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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.
59

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.
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.
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.
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.
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.
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
61

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.
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-,
62

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.
63

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.
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.
64

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.
66

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.
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.
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]
67

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.
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]-
68

[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-
69

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.
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.
71

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
72

to claim 131, 132 or 133 or an obvious chemical equivalent thereof.
73

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
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).
- 4
. ": ' .
. . . .
, . . . . .

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,
0 CH3
~ I r' ~
R2
(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,
-- ,
NH2
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,
H 0
. ~
~ 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
.
- 13 -

~.~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 `~
- 16
; , . ~

:`
: ::
~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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. ... . . I , I . . , ~ i
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rl p, ~.
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:-

5~286
~ . _._ , . _ , ~., .
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.~: ~ ~ ~ ~ : ~:
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~-rl . ~ CO
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'`: cd ~ rl ~ ~ ~ ~ ~ ~ C~J ~ ~ ~ '
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- ' ~d ~ ~0 , ~
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aJ o o o o o o o o o o ~ : ~:
.,1 o ~ In ~ In ~ ~ In u~ ~ In In ~ ~;t c~
.~ ~ fc~ i,~
'1: ~ . . . :
. . ~: U) ~ t) ~ ~rl
: ~
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. ~ ~o ~ ~ ~i ~ : :
~0 ~ . ~
~ -.P ~ . . : :, ,:. .
,- V U~ - U~
~ . .
~ rl ~ I~ O ~ O ~ ~ u~ O ~ ~D .. ~
o ~1 ~ ~d ~ ~ o ~ c~ ~ o o~~ 1~ ~ :
.- .,~,~ ~1 ~0 ~ ) C~ l ~ ~ ~ : :~
,~ . t~ 9. ~ . ~ . ~ -',~; '
o ' ~)O . .
,d ~ .~ ~n ~ . : .
gv ~ 3, .. _
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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
, . . '`' ;~: '
""
' ~'`~ : ''
- 23
., ' ' ' ' , - ' '
., ' ' ' " .
,,.. ~ . ~, , , , :
:;, , , , ., :

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. ;~
- 26
'.
.
'.,',' '',
'.
-~
~ .
.. . . .. . . . . . . .

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
28
,
. ., . -

.
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 -
- 33
`
.'~
. ,~ , , , , ~

~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.
- 34
. , .: :
"~ ,.
'" .,~,..

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
- 36
.-, ~ . .
. ~ ~
. ~ , .
-.
~, '' ' . ' .
`: ~, : : . , . , . :
. .:: , , . :
:, , ' :
'' ' ': .. :' ' 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
- 39
'' ~' ':
' ':
.. . : . .. .

~ ~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-
- 40 -
,
,
. , .
: - . ~

~.
~ ~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
~'~
,~ .
. .
-46-
,~ .

:
- ~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 - `
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~ 57~6 :
,~
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. 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
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