NO163597B - CONTROL DEVICE FOR A ONE OR TWO TRACKED VEHICLE. - Google Patents

Description

Process for the preparation of 11-substituted 8-chloro-1,2,3,11,12,12a-hexahydro (4H,6H)pyrido[2,1-cJ/JL,4]benzodiazepine-12-ones or salts or quaternary ammonium compounds or N-oxides thereof.

The present invention relates to a process for the production of hitherto unknown 11-substituted 8-chloro-1,2,3,11,12,12a-"hexahydro (4H,6H)pyrido [2,1-c] [1,4]benzodiazepine -l 2-ones with the general formula

where R means alkyl, alkenyl or benzyl,

or salts thereof with inorganic or organic acids or

quaternary ammonium compounds or N-oxides thereof.

These compounds have been shown to have valuable pharmacological properties.

The term "alkyl" means saturated, monovalent, aliphatic groups with the general formula ~cmH2m+l' ^lwhere m is a whole number from 1 - 10, and includes both straight and branched groups, such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-amyl, n-hexyl, n-octyl, isooctyl, nonyl and decyl. The term "alkenyl" includes ethylenically unsaturated, monovalent, aliphatic groups of 3-6 carbon atoms, such as e.g. allyl, methallyl and butenyl.

The compounds with the general formula I are prepared according to the invention by reacting 8-chloro-1,2,3,11,12,12a-hexa-hydro(4H,6H)pyrido[2,1-c][1,4jbenzodiazepine- l2-on with the formula

with a halide or a sulfate of an alcohol of the general formula

where R has the above meaning,

in the presence of an acid-binding agent and in an inert solvent and, if desired, converting a compound of the general formula I into an acid addition salt with an inorganic or organic acid or converting a compound of the general formula I into a quaternary ammonium salt by treatment with a usual quaternizing agent or to an N-oxide by treating the free base with hydrogen peroxide or with a per-acid.

As acid-binding agents and suitable inert solvents, the following should be mentioned: 1. alkali metal alcoholates, such as sodium or potassium methylate, -ethylate, -propylate or -n- or -tert. butylate, with sodium methylate or potassium tert.butylate as preferred agents, and in dimethyl sulfoxide} or 2. alkali metal hydrides, such as lithium, sodium or potassium hydride, where sodium hydride is preferred in ether-like solvents, such as e.g. in tetrahydrofuran, dioxane and diethylene glycol dimethyl ether; or 3. alkali metal amides, such as e.g. lithium, sodium or potassium amide, with sodium amide being preferred, in inert organic solvents, such as e.g. benzene, toluene, xylene$ or finally 4. alkyl or aryllithium, such as e.g. lower alkyllithium and especially butyllithium or phenyllithium, in inert organic solvents, such as e.g. in benzene, toluene, xylene and hexane.

Compounds of formula II are known from French patent document No. 1,389,526.

The compound of formula II is prepared from pipecolic acid alkyl esters and correspondingly substituted o-nitrobenzyl halides in inert solvents, such as benzene, toluene, xylene, in the presence of an excess of acid binding agent, such as e.g. potassium carbonate, sodium carbonate. The o-nitrobenzyl-pipecolic acid esters can be reduced in a manner known per se with hydrogen in the presence of Raney nickel at atmospheric pressure and room temperature, whereby the corresponding o-amino-benzyl-pipecolic acid esters arise as intermediate products. In order to avoid debenzylation during the hydrogenation, this must be stopped immediately after absorption of the theoretical amount of hydrogen. The formed o-aminobenzyl-pipecolic acid esters can be hydrolyzed and simultaneously condensed to the desired pyridobenzodiazepine by treatment with mineral acids,

like for example. hydrochloric acid, hydrogen bromide, sulfuric acid.

The 11-substituted pyridobenzodiazepines in question are racemates, as they have an asymmetric carbon atom in the 12a position.

They can be split into their d- and l-forms in a known manner. But it is also possible to proceed from optically active isomers with the formula II. The turnover according to the invention can then be carried out without affecting the center of asymmetry.

The 11-substituted pyridobenzodiazepines of the general formula I can be transferred to their N-oxides in the 5-position. This transformation can be carried out by reaction between the 11-substituted pyridobenzodiazepines and hydrogen peroxide in glacial acetic acid or by treatment with peracids, such as e.g. peracetic acid, perbenzoic acid, perphthalic acid, m-chloroperbenzoic acid. The N-oxides formed are stereoisomer mixtures consisting of 2 racemates, which, on the other hand, can be cleaved in a known manner into their corresponding optically active forms.

As mentioned, the present invention also includes the preparation

of pharmaceutically acceptable, non-toxic acid addition salts which can be prepared in a manner known per se using suitable inorganic or organic acids, such as e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, lactic acid, succinic acid, maleic acid, aconitic acid, phthalic acid, tartaric acid.

The quaternary ammonium salts of compounds with the general formula I are obtained by addition of alkyl or aralkyl esters of inorganic acids or organic sulphonic acids, such as e.g. methyl chloride, methyl bromide, methyl iodide, ethyl bromide, propyl bromide, benzyl chloride, benzyl bromide, methyl sulfate, methyl benzoesulfonate and methyl p-toluenesulfonate, to the corresponding free bases.

As already mentioned, the compounds of the general formula I in question have valuable pharmacological properties. In particular, they exhibit an analgesic, sedative or local anesthetic effect or several of these effects, which can be demonstrated by normal pharmacological tests. They know the procedure

compounds produced according to the invention can be used orally or parenterally in usual dosage forms, such as e.g. tablets, capsules or injection solutions, according to usual pharmaceutical administration practice.

The examples below illustrate the method according to the invention in more detail, as the following nomenclature is used in the examples below:

1,2,3,11,12,12a-Hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12(11H)-one.

The temperatures are indicated in degrees Celsius.

EXAMPLE 1.

8-chloro-11-methyl-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido [2,1-c]

[l,4]benzodiazepine-l2-one

6.27 g of 8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-cJ[1,4]benzodiazepine-12-one (m.p. 224 - 225°) in 50 ml of absolute dimethyl sulfoxide, add 1.5 g of sodium methylate and stir at room temperature for 30 minutes. 5.3 g of methyl iodide are then added all at once to this solution, and stirring is continued for 1 hour. The reaction solution is then poured under stirring

500 ml cold water. The reaction mixture is made alkaline by the addition of 2-n sodium hydroxide solution and allowed to stand in a refrigerator for 16 hours. A crystalline precipitate is precipitated, which is filtered off, dried and recrystallized from hexane, m.p. 107 - 108°.

This substance can be produced in the following way:

a) 10 g of 8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12-one and 4,5 g tart. of potassium butylate in 80 ml of absolute dimethylsulfoxide until a clear solution occurs. 2.5 g of dimethylsulphate is then added all at once and the solution is stirred for 20 hours. The reaction solution is then poured onto ice water and the precipitated, rubber-like mass is extracted with chloroform. The organic extract is washed with water, dried over sodium sulphate, filtered and finally evaporated under reduced pressure. The partially solid residue is taken up in boiling hexane, and the hexane solution is evaporated to a small volume. The crystallized 8-chloro-11-methyl-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12-one is filtered from and recrystallized from hexane. Melting point 107 - 108°. b) 50 g of 8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c]

[1,4]benzodiazepine and 22.4 g of tert. potassium butylate is mixed in

250 ml of absolute dimethylsulfoxide, until a clear solution occurs. 31 g of methyl iodide is then added thereto and the solution is stirred for 20 hours. The reaction mixture is then poured

in ice water, and the precipitated gum-like mass is extracted with chloroform. The organic extract is washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is taken up in boiling hexane. The hexane solution is evaporated to dryness, and the residue is recrystallized from hexane. Melting point 107 - 108°.

The 8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12-one used above as starting material can be prepared as follows: a) N-(2-nitro-5-chloro-benzyl)-pipecolic acid ethyl ester 33.3 g of pipecolic acid ethyl ester are dissolved in 200 ml of anhydrous toluene, to which are added 34 g of potassium carbonate, and to this is added dropwise while stirring a solution of 44.54 g of 2-nitro-5-chloro-benzyl chloride in 300 ml of anhydrous toluene. After the addition is complete, the mixture is boiled for 12 hours with reflux. After cooling, it is made acidic, and the reaction mixture is extracted to exhaustion with 3-n hydrochloric acid. The combined acidic extracts are washed

with ethyl acetate and then made strongly basic. The separated oil is extracted with ether; the ether extract is washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. By vacuum distillation of the residue, the desired product is obtained in the form of a yellow viscous oil with bp. 153 - 154°. b) N-(2-amino-5-chloro-benzyl)-pipecolic acid ethyl ester 7.5 g of N-(2-nitro-5-chloro-benzyl)-pipecolic acid ethyl ester are dissolved in 100 ml of ethanol and hydrated at room temperature and atmospheric pressure over Raney nickel. 1670 ml of hydrogen is taken up. The catalyst is removed by filtration, and the filtrate is evaporated to dryness under reduced pressure. By distillation of the residue, the desired intermediate product is obtained in the form of an oil with bp. 154° at 0.3 mm Hg pressure. c) 8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c]

[l,4]benzodiazepine-l2-one

20.0 g of N-(2-amino-5-chloro-benzyl)-pipecolic acid ethyl ester and 350 ml of 3-n hydrochloric acid are boiled for 5 hours under reflux. After cooling, the solution is adjusted to a pH value of 10 and extracted exhaustively with chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed in vacuo. A white crystalline residue remains, which is recrystallized from ethanol. The product melts at 224 - 225°.

EXAMPLE 2

8-chloro-11-methyl-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c]

[1,4]benzodiazepine-12-one-5-oxide

5 g of 8-chloro-11-methyl-1,2,3,11-12,12a-hexahydro (4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12-one and 9 g of m-chloroperbenzoic acid in 50 ml of chloroform and boil for 4 hours under reflux. It is then cooled and the reaction solution is washed first with saturated sodium carbonate solution, then with water. The residue is evaporated and recrystallized twice from acetone, whereby it is treated with animal charcoal. The N-oxide is obtained as white crystals with a melting point of 197 - 198° (decomposition).

From the mother liquors the second isomer can be isolated.

EXAMPLE 3

8-chloro-5,11-dimethyl-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido [2,1-c][1,4]benzodiazepine-12-one-iodide 5 g 8-chloro-11-methyl-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12-one is dissolved at room temperature in 25 ml methyl iodide. After 15 hours, the methyl iodide is evaporated under reduced pressure, and the residue is washed with acetone.

The product, a white crystalline substance, is recrystallized from water with the addition of animal charcoal. Melting point 283 - 284°

(fission).

EXAMPLE 4

(+) 8-chloro-11-methyl-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12-one

16.1 g of racemic 8-chloro-11-methyl-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12- on and 22.9 g of dibenzoyl-l-tartaric acid in 700 ml of hot isopropanol. Water is then carefully added until the solution starts to become cloudy and the mixture is allowed to stand for 2 days at 5°. A salt is precipitated, which is filtered off. The salt is suspended in ethanol to remove some oil-like material, filtered once more and recrystallized from isopropanol. One thus obtains the product with a melting point of 154 - 155° (cleavage); [<x]p = +292 , (c = 1.665 in dimethyl sulfoxide; 10 cm).

This salt (5 g) is split with 1-1 sodium hydroxide solution and the free base is extracted with chloroform. The chloroform extract is dried over sodium sulphate, filtered and concentrated under reduced pressure. The remaining oil is crystallized from hexane and recrystallized. Melting point 109 - 110°; [a]^7 = +385° (c = 1.8 in ethanol; 10 cm).

EXAMPLE 5

(-) 8-chloro-11-methyl-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido [2,1-c][1,4]benzodiazepine-12-one

24.9 g of racemic 8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12-one are used at using 33.5 g of dibenzoyl-d-tartaric acid ([cc]D 2 4^ = -69.8 o c = 1.81 in ethanol; 10 cm) in 150 ml of absolute ethanol to dibenzoyltartaric acid salt. The ethanol is then removed, and the residue is dissolved in a boiling ethanol-water mixture (consisting of approx. 1000 ml of water and 500 ml of ethanol). On standing, a partially crystalline precipitate precipitates. The excess solution is decanted off, and the gum-like residue is washed with hot ethanol and filtered. The salt thus obtained is recrystallized from isopropanol, m.p. 181 - 182°; [cc]p<5>° = -225° (c = 1.185 in dimethylsulfoxide;

10 cm). This salt is split with l-n sodium hydroxide solution and extracted

with chloroform. The chloroform extract is dried over sodium sulfate and concentrated under reduced pressure. The remaining oil is crystallized from hexane and recrystallized. The pure product with a melting point of 110 - 111 o is obtained; [ajj2j 5^ =

-368° (c = 2.16 in ethanol; 10 cm).

EXAMPLE 6

8-chloro-11-ethyl-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido [2,1-c][1,4]benzodiazepine-12-one

25.1 g of 8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,lc][1,4]benzodiazepine-12-one and 5.4 g of sodium methylate are added to 500 ml of absolute dimethyl sulfoxide and stir the mixture for 30 minutes at 50°. To the solution thus obtained, 15.6 g of ethyl iodide are added slowly at the same temperature and the reaction solution is further heated for 5 hours. The cooled reaction mixture is then poured into approx. 1000 ml of ice water, and the mixture is made alkaline with potassium carbonate. The aqueous layer is then decanted from the rubber-like precipitate. The precipitate is dissolved in chloroform, the chloroform solution is washed with water, treated with animal charcoal, filtered and concentrated under reduced pressure. The oil thus obtained is distilled in high vacuum, bp. 152 - 154°/0.015 mm Hg pressure. It

yellow oil is crystallized from hexane and recrystallized from

the same solvent, melting point 58 - 59°.

EXAMPLE. 7

11-allyl-8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido [2,1-c][1,4]benzodiazepine-12-one hydrochloride

5.0 g of 8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12-one and 1,2 g of sodium methylate in 60 ml of absolute dimethyl sulfoxide and stir the mixture for 18 hours. The reaction solution is then poured into 500 ml of ice-cold water, and the precipitated product is extracted with vinegar. The organic solution is treated with 2-n hydrochloric acid, and the aqueous-acidic solution is made alkaline with solid potassium carbonate at 0°, and the precipitated reaction product is finally extracted with acetic acid. The organic phase is now washed with saturated sodium chloride solution, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. A yellowish, viscous oil remains. This dissolves in a little ethanolic hydrochloric acid. The solvent and the excess acid are evaporated under reduced pressure, the residue is taken up in a little absolute ethanol and diluted with ether. The hydrochloride precipitates when this solution is allowed to stand overnight at 20°. By sublimation at 160°/0.001 mm Hg pressure and a further recrystallization from ethanol/ether, the product is purified; melting point 214° (decomposition).

EXAMPLE 8

8-chloro-11-isopropyl-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido [2,1-c][1,4]benzodiazepine-12-one maleate

25.0 g of 8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12-one and 5.97 g of sodium methylate in 100 ml of absolute dimethyl sulphoxide, heat the mixture to 100° and stir at this temperature for 30 minutes.

A clear solution is finally obtained, to which a solution of 18.3 g of isopropyl bromide in 50 ml of absolute dimethyl sulphoxide is added dropwise at 100°. The reaction mixture is further stirred for 15 hours at 100°.

Allow it to cool, pour it into 500 ml of ice water and make it alkaline by adding solid potassium carbonate. The aqueous layer is decanted, and the gummy residue is taken up in chloroform, treated with animal charcoal, dried over sodium sulfate, filtered, and the solvent is removed under reduced pressure. The remaining oil is dissolved in 2-N hydrochloric acid, treated with charcoal, filtered, and the filtrate is made alkaline and extracted with chloroform. After evaporation of the solvent, a viscous oil remains, which is distilled under high vacuum.

Kp. 150 - 155° at 0.065 mm Hg pressure.

The maleate salt is prepared by combining 6.4 g of the free base and 2.54 g of maleic acid in ethanol and evaporating the solvent. The remaining glass-like mass is crystallized from isopropanol and recrystallized; melting point 157 - 158°.

EXAMPLE 9

11-butyl-8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12-one- maleate

25.8 g of 8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12-one are suspended in 100 ml of absolute dimethyl sulfoxide and add 6.0 g of sodium methylate. It is then heated to 100° and stirred for 30 minutes at this temperature. Finally, a solution of 20.4 g of butyl bromide in 50 ml of absolute dimethylsulfoxide is added dropwise and stirred and heated for a further 6 hours. The cooled reaction solution is poured into ice water, after which a rubber-like precipitate precipitates out. The aqueous layer is decanted and extracted with chloroform. The sticky precipitate is taken up in chloroform, and the two chloroform solutions are combined, dried over sodium sulfate, treated with animal charcoal, filtered, and the solvent is removed by evaporation under reduced pressure. There will be an oil back,

which distills in high vacuum, whereupon an almost colorless oil is obtained; kp. 154 - 157°/0.1 mm Hg pressure. 9.5 g of the free base is converted in ethanol with 3.97 g of maleic acid to maleate. The ethanol is evaporated under reduced pressure and the residue is crystallized from isopropanol; melting point 137 - 138°.

EXAMPLE 10

11-benzyl-8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido [2,1-c][1,4]benzodiazepine-12-one hydrochloride

25 g of 8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c]

[1,4]benzodiazepine-12-one, 6 g of sodium methylate and 100 ml of absolute dimethyl sulphoxide are stirred together at 100° for approx. 30 minutes, in-

until a clear solution occurs. A solution is then dripped

ning of 18.9 g of benzyl chloride in 50 ml of absolute dimethylsulfoxide at 100°, and the solution is further heated for 5 hours with stirring. It is cooled, and the reaction solution is poured for approx.

500 ml of ice water. The gum-like precipitate is extracted with chloro-

form, the chloroform extract is washed with water, treated with animal

charcoal, filtered and dried over sodium sulfate. dissolution

the agent is then removed under reduced pressure, and the

remaining oil is distilled under high vacuum; kp. 180°/0.008 mm Hg pressure. The oil obtained is converted with ethanolic hydrochloric acid

to hydrochloride and recrystallized from ethanol. Melting point 200 - 20 2° (decomposition) .

Claims (1)

Process for the preparation of 11-substituted 8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiazepine-12-ones with the general formula where R means alkyl, alkenyl or benzyl", or salts thereof with inorganic or organic acids or quaternary ammonium compounds or N-oxides thereof, characterized by reacting an 8-chloro-1,2,3,11,12,12a-hexahydro(4H,6H)pyrido[2,1-c][1,4]benzodiaze pin-12-on with the formula in the presence of an acid scavenger and in an inert solvent agent with a halide or a sulfate of an alcohol of the general formula where R has the above meaning, and if desired converts a compound of the general formula I into an acid addition salt with an inorganic or organic acid or converts a compound of the general formula I into a quaternary ammonium salt by treatment with a common quaternizing agent or into an N-oxide by treatment of the free base with hydrogen peroxide or with a per acid.