DE1620523C3 - - Google Patents

Description

(D

CO - CH, - N

with an amine of the general formula
NH

lets react and optionally then the base obtained in this way with a physiologically compatible one inorganic or organic acid converted into a salt.

in which R ₁ and R _{2 are} hydrogen atoms or methyl groups, R ₃ and "R _{4 are} identical straight-chain or branched alkyl radicals with 1 to 4 carbon atoms or allyl radicals or, together with the nitrogen atom in between, the pyrrolidino, piperidino or 4-methyl or 4- ( 2'-hydroxyethyl) piperazino group, as well as their salts with physiologically compatible inorganic or organic acids.

2. 11 - Dipropylaminoacetyl - 11 H - pyrido- [2,3-b] [1,5] benzodiazepine-5 (6 H) -on.

3. 11 - [4 '- (2 "-Hydroxyethyl) -piperazinoacely]] - 11 H-pyrido [2,3-b] [1,5] benzodiazepin-5 (6 H) -one.

4.8,9 - dimethyl - 11 - (4 '- methylpiperazinoacetyl) - HH - pyrido [2,3-b] [1,5] benzodiazepin-5 (6 H) -one.

5. Process for the preparation of the compounds according to claim 1, characterized in that a 11 H-pyrido [2,3-b] [l, 5] benzodiazepin-5 (6H) -one is used in a manner known per se the general formula

The invention relates to new 11 H-pyrido [2,3-b] [1.5] -benzodiazepin-5 (6H) -ones the general formula

O H

R ₁

CO - CH, - N

O H

C-N

R,

with a compound of the general formula
Hal '—CO —CH ₂ -Hai (III)

in which Hai and Hai 'be the same or different can and mean chlorine, bromine or iodine atoms, converts the halogen compound obtained the general formula

in which R ₁ and R _{2 are} hydrogen atoms or methyl groups, R ₃ and R _{4 are} identical straight-chain or branched alkyl radicals with 1 to 4 carbon atoms or allyl radicals or, together with the nitrogen atom in between, the pyrrolidino, piperidino or 4-methyl or 4- (2 '-Hydroxyäthyl) piperazino group, and their salts with physiologically (II) 45 compatible inorganic or organic acids and a process for their preparation.

The new compounds are obtained by using a 11 H-pyrido- [2,3-b] [I, 5] benzodiazepin-5 (6H) -one in a manner known per se the general formula

60

(IV) with a compound of the general formula

Hal '—CO —CH ₂ -Hai (III)

in which Hai and Hai 'be the same or different can and mean chlorine, bromine or iodine atoms,

converts the halogen compound obtained of the general formula

(IV)

with an amine of the general formula

NH

(V)

lets react and optionally then the base obtained in this way with a physiologically compatible one inorganic or organic acid converted into a salt.

The reaction of the compounds of general formula II with the haloacetic acid halides of General formula III is preferably carried out in an inert solvent in the presence of a hydrogen halide binding agent Means at elevated temperatures, preferably at the boiling point of the solvent used. Aromatic hydrocarbons such as benzene, Toluene or xylene, ethers such as diethyl ether, dipropyl ether or, preferably, cyclic ethers such as dioxane, be used; Tertiary organic bases, such as triethylamine, are suitable as hydrogen halide binding agents or pyridine or inorganic bases, such as alkali or alkaline earth metal carbonates or -hydrogen carbonates. The reaction mixture is worked up in the customary manner, and the yields are up to 80% of theory. The haloacetyl compounds of the general formula formed IV are mostly easily crystallizable substances that can be used as raw products without further purification Door can be used for further implementation.

The reaction of the haloacetyl compounds of the general formula IV with an amine of the general Formula V is advantageously carried out in an inert solvent, advantageously in the presence an acid-binding agent at elevated temperatures, preferably at the boiling point of the solvent used. The solvents used are preferably ethanol or acetone, but it can also aromatic hydrocarbons, such as benzene or toluene, or chlorinated hydrocarbons, such as methylene chloride can be used. The amine of the general formula V is expedient used in a sufficient excess to bind the liberated hydrogen halide, man but can also use other hydrogen halide binding agents such as pyridine, diethylaniline, alkali metal carbonates or add alkali hydrogen carbonates. If highly volatile amines are used, work may be carried out if necessary in a closed vessel.

In some cases it is used to shorten the reaction time and lower the reaction temperature In cases it is advisable to start from compounds of the general formula IV in which Hai means an iodine atom.

The end products of the general formula I are worked up and purified in the customary manner Way, there are yields of up to 85% of theory of recrystallized pure product.

If desired, the bases obtained can be physiologically tolerated by reaction with them inorganic or organic acids converted into their salts by methods known per se will. As acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Tartaric acid, citric acid, maleic acid, succinic acid and oxalic acid have been found to be suitable.

The preparation of the compounds of the general formula II required as starting materials can, for example be carried out according to the method described in German Patent 238,479. If the benzene ring of these compounds contains a methyl radical as a substituent, could in some Cases, the position of which has not yet been determined exactly, as referred to in the exemplary embodiments will.

The new compounds and their salts have valuable therapeutic properties, in particular they have a very good antitussive effect with low toxicity.

The substances

11-dimethylaminoacetyl

11 H-pyrido [2,3-b] [l, 5] benzo-

diazepin-5 (6 H) -one (Example 2) = A

11-di-n-propylaminoacetyl-

11 H-pyrido [2,3-b] [l, 5] benzo-

diazepin-5 (6 H) -one (Example 5) = B

-Di-n-butylaminoacetyl-8 (9) methyl-11 H-pyrido [2,3-b] [l, 5] benzo-

diazepin-5 (6 H) -one (Example 8) = C

11-di-isobutylaminoacetyl-

11 H-pyrido [2,3-b] [l, 5] benzo-

diazepin-5 (6 H) -one (Example 10) = D.

11-di-isobutylaminoacetyl-

8,9-dimethyl-l 1 H-pyrido [2,3-b] [l, 5] -

benzodiazepin-5 (6 H) -one (Example 11) = E 11-di-allylaminoacetyl-

11 H-pyrido [2,3-b] [l, 5] benzo-

diazepin-5 (6H) -one (Example 13) .... = F 11-pyrrolidinoacetyl

11 H-pyrido [2,3-b] [l, 5] benzo-

diazepin-5 (6 H) -one (Example 14) = G.

11-piperidinoacetyl

11 H-pyrido [2,3-b] [l, 5] benzo-

diazepin-5 (6 H) -one (Example 15) = H

1- (4'-MethylpiperazinoacetyI) -11 H-pyrido [2,3-b] [1,5] benzodiazepine-5 (6 H) -one (Example 16) .... = I 8,9-dimethyl-11 - ^ '- methylpiperazinoacetyl) -l 1 H-pyrido [2,3-b] [1,5] -benzodiazepine-5 (6 H) -one (Example 18) = J - [4- (2-hydroxyethyl) -piperazinoacetyl] -l 1 H -pyrido [2,3-b] [1,5] -benzodiazepin-5 (6H) -one (Example 19) = K

and

8,9-dimethyl-1 l- [4 '- (2 "-hydroxyethyl) -piperazinoacetyl]
11 H-pvrido [2,3-b] [1,5] benzodiazepin-5 (6 H) -one (Example 20) = L

were examined with regard to their antitussive effect and acute toxicity and compared with codeine

The experiments were carried out on conscious, white rats by inhaling a 7.5% citric acid spray according to Engelhorn and Püschmann in Arzneimittelforschung 13, 474 to 480 (1963), described methodology. The substances were previously in a dosage of 50 mg / kg administered orally. At the same time, experiments were carried out on groups of animals that had previously received the same dose of codeine. 5 animals were used per dose.

The acute toxicity was determined on white mice; 5 animals were used per dose. The substance was administered orally. The LD ₅₀ was calculated using the Litchfield and WiI co x on method.

The table below shows the average percentage decrease in the number of coughs 30 minutes after substance application, in each case in comparison to codeine:

Percentage decrease in 30 minutes substance Coughs, "Application after peroral of codeine the substance 42 A. 37 60 B. 86 67 C. 65 61 D. 71 44 E. 50 72 F. 30th 59 G 50 42 H 36 54 I. 53 60 J 81 75 K 86 44 L. 69 Codeine

LD ₅₀ mg / kg mouse
ρ. ο.

1900

100O ¹ )

5000 ² )

IOOO ³ )

500O ⁴ )

2725

1550

980
3OOO ⁵ )
lOOO ⁶ )
2000 ⁷ )
lOOO ⁸ )

535

') At 1000 mg / kg 0 of

² ) At 5000 mg / kg 0 of

³ ) At 1000 mg / kg 1 of

⁴ ) At 5000 mg / kg 0 of

⁵ ) At 3000 mg / kg 4 of

⁶ ) At 1000 mg / kg 0 of

⁷ ) At 2000 mg / kg 1 of

⁸ ) At 1000 mg / kg 0 of

10 animals died.
10 animals died.
10 animals died.
10 animals died.
10 animals died.
10 animals died.
5 animals died.
5 animals died.

Some of Substances A through L are better than codeine in terms of effects, but all substances are less toxic than codeine and therefore safer to use.

The compounds according to the invention can be incorporated into the customary pharmaceutical preparations will. The mean single dose of the substances is 5 to 50 mg.

The following examples serve to explain the invention in more detail.

example 1

a) I l-chloroacetyl-UH-pyrido [2,3-b] [l, 5] benzodiazepine-6 (5 H) -On

21 g (0.1 mol) of IIH-pyrido [2,3-b] [l, 5] benzodiazepine-6 (5th H) -one are dissolved in 300 ml of absolute dioxane with heating. To the boiling solution a solution of 15.8 g (0.14 mol) of chloroacetyl chloride, dissolved in 40 ml of absolute dioxane, and at the same time a solution of 14.4 g (0.14 mol) of triethylamine, dissolved in 30 ml absolute dioxane, too. After refluxing for eight hours, the mixture is filtered hot. The filtrate will evaporated in vacuo, the residue is recrystallized from isopropanol or from acetonitrile; ίο F. 223 to 225 ° C (decomposition); Yield 80% of the Theory.

C ₁₄ H ₁₀ ClN ₃ O ₂ (287.7):

Calculated: C 58.45, H 3.51, N 14.61, Cl 12.32%;
■ 5 found: C 58.50, H 3.59, N 14.67, CI 12.12%.

In the same way, the following compounds were obtained:

a,) 8- (or 9) -methyl-l 1-chloroacetyl-11 H-pyrido [2,3-b] [1,5] benzodiazepin-6 (5 H) -one

From 8- (or 9) -methyl-IIH-pyrido [2,3-b] [1,5] -C benzodiazepin-6 (5H) -one and chloroacetyl chloride; F. 215 ° C (decomposed from methanol); Yield 70% the theory.

C ₁₅ H ₁₂ ClN ₃ O ₂ (301.7):
Calculated ... Cl 11.78%;
found Cl 11.50%.

a ₂ ) 8,9-Dimethyl-II-chloroacetyl-11H-pyrido [2,3-b] [1,5] benzodiazepin-6 (5H) -one

From 8,9-dimethyl-II H-pyrido [2,3-b] [1,5] benzodiazepin-6 (5H) -one and chloroacetyl chloride; F. 242 to 245 ⁰ C (decomposition; from isopropanol or acetonitrile); Yield 52% of theory.

C ₁₆ H ₁₄ ClN ₃ O ₂

Calculated ..
found ...

(315.6):

. Cl 11.23%;
. Cl 11.25%.

b) 11-Diethylaminoacetyl-l 1 H-pyrido [2,3-b] [l, 5] -benzodiazepine-5 (6 H) -on

5.8 g (0.02 mol) of the 11-chloroacetyl -11 H -pyrido [2,3-b] [1,5] benzodiazepin-5 (6H) -one obtained in step a) and 3.65 g (0.05 mol) of diethylamine are dissolved in 300 ml of absolute ethanol and Heated under reflux for 18 hours. The hot solution is filtered and the filtrate is evaporated in vacuo and recrystallizes the residue from isopropanol; 172-174 ° C; Yield 85% of theory.

Q ₈ H ₂₀ N ₄ O ₂ (324.4):

Calculated ... C 66.65, H 6.21, N 17.27%;
found .... C 66.40, H 6.50, N 17.51%.

Example 2

11-Dimethylaminoacetyl-11 H-pyrido [2,3-b] [1,5] -benzodiazepine-5 (6 H) -on

In a 500 ml autoclave, 2.9 g of the after Example la) obtained 11 -chloroacetyl-11 H-pyrido-

in 200 ml

suspended in solid ethanol. To the on 0 ^c C ab- C ₁₆ H ₁₆ N ₄ O ₂ (296.3):

10 ml of dimethylamine are added to the cooled suspension. Calculated ... C 64.85, H 5.44, N 18.91%;

and closes the autoclave. The mixture is heated for 18 hours found ... C 64.90, H 5.62, N 18.68%.

to 70 to 80 ° C, cools and evaporates the obtained

Reaction solution in a vacuum. The residue 5 Using the same methods, the in

is recrystallized from isopropanol; F. 212 to the compounds listed below

213 ° C; Yield 60% of theory. of the general formula I:

example

CH,

- N

- N

- N

CH,, C ₂ H ₅

CH ₂ -CH ₂ -CH,

CH ₂ -CH, -

- N

-N

- N

-N

-N

CH ₂ -CH ₂ -

CH ₂ - ^ H ₂ -

^X CH ₂ -CH, -

CH ₂ -CH ₂ -

CH ₂ -CH ₂ -

- N

- N

-N

CH ₂ -CH ₂ -

CH ₂ -CH ₂ -

-CH ₂ -CH, -CH ₂ -CH,

-CH ₂ -CH, - (CH ₂ J ₂ -CH,

- (CH ₂ J ₂ -CH ₃ - (CH ₂ J ₂ -CH ₃

- (CH ₂ J ₂ -CH ₃ - (CH ₂ J ₂ -CH,

- (CH ₂ J ₂ -CH ₃ -CH (CH ₃ J ₂

-CH (CH ₃ J ₂ -CH (CH ₃ ),

-CH (CH ₃ J ₂ - (CHj) ₃ -CH ₃

- (CH ₂ J ₃ -CH, -CH = CH ₂

CH ₂ -CH = CH ₂

R ₁ 9-CH, The end-
) today 8-CH, 9-CH, 27 8-CH, H .15 H 9-CH, 27 H-CH, H 45 H H
or
9-CH, 25th 8-CH,
or
H 9-CH, 74 8-CH, H 45 H 9-CH, 38 NS, H 66 H H 46 H H 65 H 69

Melting point

F. = 235-236 ° C from acetonitrile

F. = 199-200 "C; ius isopropanol

F. = 171-172 ° C from isopropanol / ether

K = 151-153 ⁰ C from isopropanol

M.p. = 153-154 ° C from 50% ethanol

M.p. = 162-163 ° C from CH, OH / H ₂ O

M.p. = 182-183 ° C from methanol

F. = 176-177 "C from ethanol

F. = 174-175 "C from isopropanol / H ₂ O

K = 118-12O ⁰ C from isopropanol /

F. = 135-136 "C from methanol / Η, Ο

K = 230-231 ° C Zcrs. the end
Isopropanol

Summer formula

C ₁₈ H ₂₀ N ₄ O ₂

C ₂₀ H ₂₄ N ₄ O ₂

C ₂₀ H ₂₄ N ₄ O ₂

C ₂₂ H ₂₈ N ₄ O ₂

C ₂₂ H ₂₈ N ₄ O ₂

C ₂₃ H ₃₀ N ₄ O ₂

C ₂₄ H ₃₂ N ₄ O ₂

C ₂₂ H ₂₈ N ₄ O ₂

C ₂₄ H ₃₂ N ₄ O ₂

Q ₁ H ₃₂ N ₄ O ₂

C ₂₀ H ₂₀ N ₄ O ₂

C ₁₈ H ₁₈ N ₁ O ₂

Molge
weight

324.4

352.4

352.4

380.5

380.5

394.5

408.5

380.5

408.5

408.5

348.4

322.4

Analysis calculated found

C 66.65
H 6.22
N 17.27

C 68.16
H 6.86
N 15.90

C 68.16
H 6.86
N 15.90

C 69.45
H 7.42
N 14.72

C 69.45
H 7.42
N 14.72

C 70.02
H 7.66
N 14.20

C 70.56
H 7.90
N 13.71

C 69.45
H 7.42
N 14.72

C 70.56
H 7.90
N 13.71

C 70.56
H 7.90
N 13.71

C 68.95
H 5.79
N 16.08

C 67.07
H 5.63

N 17.38

C 66.40 H 6.13

N 17.45

C 68.40 H 6.92 N 16.30

C 68.20 H 6.94

N 15.75

C 69.30 H 7.54 N 14.95

C 69.75 H 7.47 N 14.73

C 69.80 H 7.78 N 14.00

C 70.60 H 7.82 N 13.89

C 69.40 H 7.42 N 14.77

C 70.60 H 7.86 N 17.79

C 70.60 H 8.03 N 13.70

C 68.80 H 5.97 N 15.85

C 66.90 H 5.74 N 17.35

409 520/439

continuation

10

example

- Ν - Ν - Ν -N

- Ν

N-CH ₃

N-CH,

N-CH ₃

N-CH ₂ -CH ₂ OH

- Ν

N-CH ₂ -CH ₂ OH

R, R ₂ the end
prey
1%) H H 58 H H 55 8-CHj
or
H H
or
9-CH ₃ 65 NS., 9-CH ₃ 36 H H 37 S-CH ₃ 9-CH ₃ 66

Melting point

M.p. = 257 ° C dec. from ethanol

F. = 216-218 ⁿ C from isopropanol

F. = 222 ° C from acetonitrile / ethanol

F. = 230-231 ¹ C from acetonitrile

Mp = 200-201 ⁰ C from isopropanol / ether

Dihydrochloride m.p. = 215-216 ° C (Decomp.)

F. = 232-234 ° C from isopropanol

Molecular formula

C ₁₉ H ₂₀ N ₄ O,
C ₁₉ H ₂₁ N ₅ O ₂
C ₂₀ H ₂₃ N ₅ O,
C ₂₁ H ₂₅ N ₅ O ₂

QoH ₂₃ N ₅ O ₃

C ₂₀ H ₂₅ Cl ₂ N ₅ O ₃
C ₂₂ H ₂₇ N ₅ O ₃

Molge
weight

336.4

351.4

365.5

379.5

381.4

454.3

409.5

Analysis calculated found

C 67.84
H 5.99
N 16.65

C 64.94
H 6.02
N 19.93

C 65.74
H 6.34
N 19.16

C 66.47
H 6.64

N 18.45

C 62.98
H 6.08
N 18.36

Cl 15.61

C 64.53
H 6.65
N 17.10

C 68.00 H 6.05 N 16.90

C 64.70 H 6.19 N 19.83

C 65.40 H 6.31 N 19.33

C 66.40 H 6.67 N 18.65

C 62.60 H 6.04 N 18.63

Cl 16.00

C 64.70 H 6.84 N 17.33

Claims (1)

Patent claims: 1.11 H-pyrido [2,3-b] [l, 5] benzodiazepin-5 (6H) -ones of the general formula O H C-N R,