NO754239L - - Google Patents

Description

"Procedure for the production of new

organic compounds".

The present invention relates to a method for the production of new organic compounds with formula I:

in which

R, means hydrogen or alkyl with 1-5 carbon atoms,

1*2 stands for a group~^CH2^n

in which

n means an integer from 0-3/

Rcog and Rg either independently stand for hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or halogen with an atomic weight below 80, or together stand for the 3,4-methylenedioxy group,

R^means hydrogen or;, if R5 and Rg both stand for alkoxy with 1-4 carbon atoms, also alkoxy with 1-4 carbon atoms,

R^means hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or halogen with an atomic weight below 80,

R^ stands for hydrogen or alkoxy with 1-4 carbon atoms.

As can be seen from formula I, the hydrogen atoms in the 7- and 12a-positions of the 1,2,3,4,5,7,12,12a-octahydro-1,4-diazepino[l/7-bj disoquinoline skeleton can be cis or trans to each other.

R^ preferably stands for alkyl, R^ and R^ for hydrogen, halogen or alkoxy. In particular, R^ stands for hydrogen and R^ is in the p-position.

R^ and R^ are in the 9- or 10-positions of the skeleton and preferably both mean hydrogen or alkoxy, especially hydrogen. Halogen is especially chlorine, and the alkyl and alkoxy residues preferably contain 1 or 2 carbon atoms.

n preferably means the number 0 or 1.

The peculiarity of the method according to the invention is that compounds of formula II

in which

R£, R3 and R^ have the above meaning and

either X means carbonyl, Y means carbonyl or methylene and Z has the meaning indicated for R1,

or X and Y stand for methylene and Z stands for alkanoyl with 1-5 carbon atoms or alkoxycarbonyl with 2-5 carbon atoms,

is reduced.

Y preferably stands for methylene. If R1 means methyl, Z. preferably stands for alkoxycarbonyl, especially ethoxycarbonyl or for methyl. If R1 contains more than 1 carbon atom, X preferably means carbonyl.

The method according to the invention constitutes a reduction

to the amine. It can be carried out analogously to known methods.

One goes, e.g. under such conditions where an Nfe-substituted amide is converted into a secondary or tertiary amine.

One uses e.g. metal hydrides such as aluminum hydride, dialkyl aluminum hydrides but also complex hydrides, especially complex aluminum hydrides such as lithium aluminum hydride, lithium aluminum hydride/aluminium hydride or disodium (2-methoxyethoxy) aluminum hydride in an inert solvent under reaction conditions,

as reactant. When using complex aluminum hydrides as a reducing agent, possible chlorine or bromine atoms on aryl residues can be replaced with hydrogen atoms. Disodium (2-methoxyethoxy)aluminum hydride is particularly suitable for the reduction of an alkoxycarbonyl group.

Usually, but with advantage, <lt to 4 moles of reducing agent are used, based on 1 mole of compound of formula II.

The reaction temperature can vary between room temperature and approximately 100°C. When choosing the reaction temperature, among other things, the nature of the substituents on the compounds of formula II must be taken into account. For the reduction of a possible alkoxycarbonyl group, it is appropriate to work at the reflux temperature for the reaction solution.

The compounds of formula I can be present in f±± form as a base

or in the form of addition salts with acids. From the free bases, acid addition salts can be prepared in a known manner, e.g. maleates or fumarates are produced and vice versa.

The compounds of formula II are new. They can be manufactured

analogously to for the preparation of N-substituted amides resp. urethanes known methods, e.g. as explained in the following examples, by proceeding u£ from the corresponding ^*-phenylacetacetic acid ethyl ester.

If the production of the starting compounds is not described, these are known or can be produced according to methods known per se or analogous to those described here or analogous to

per se known methods.

The compounds of formula I, in free form or in the form of their physiologically tolerable addition salts with acids, in the following termed the substances obtainable by the method according to the invention, have interesting pharmacodynamic properties. They can therefore be used as medicines.

They exhibit a sleep-promoting and sleep-farming effect.

Because of this effect, they are suitable for use as sleeping aids.

In addition to this, the substances exhibit an anti-aggressive effect. Because of this effect, they are suitable for use as anti-aggressive agents, e.g. for dampening the aggressive behavior of psychopaths and the feeble-minded.

For the above applications, substances in which R^ means methyl or ethyl, especially methyl, and those substances where R^ means a phenyl or benzyl group optionally monosubstituted with halogen, especially chlorine or methoxy, preferably in the p-position, are particularly suitable.

The substances in which the hydrogen atoms in the 7- and 12a-positions are in cis-configuration display a particularly interesting activity.

Medicines that contain one of the aforementioned substances and may be available in the form of e.g. a solution or a tablet can be prepared according to known methods using usual auxiliary and carrier substances.

In the following examples, all temperature indications are

in degrees Celsius and is uncorrected.

Example 1: (3RS, 12aRS)-1, 2, 3, 4, 5, 7, 12, 12a- octahydro- 7- p-methyloxv envl- 3- metvl- 1, 4- diazepino H, 7- bliso-quinoline

12, 5g (7RS,12aRS)-1,4,5,7,12,12a-hexahydro-7-p-methoxyphenyl-3-methyl-1,4-diazepino\l,7-b)isoshinoline-2 (3H )-one is dissolved in 210 ml of tetrahydrofuran and 1.41 g of lithium aluminum hydride is added in portions, the temperature rising to approximately 50°C. It is heated for 30 minutes under reflux, stirred for a further 2 hours and the reaction mixture is split by carefully dropping in 10 ml of methanol and 15 ml of saturated sodium sulphate solution. After filtering off the precipitate, the filtrate is evaporated to dryness. As evaporation residue, the compound mentioned in the title is obtained (melting point of the malinate 163-164°C - from methanol/ether).

The output connection can be produced in the following way:

a) ^Jp-f-enylacetoacetic acid ester is transferred into the 3-amino-4-phenylbutyric acid ethyl ester (melting point of the hydrogen oxalate 151-153°C).

From this is obtained with p-anisic acid chloride 3-p-methoxybenzamido-4-phenylbutyric acid ethyl ester (melting point 102-104°C). By boiling with phosphorus oxychloride according to Bischler-Napieralski, 3,4-dihydro-1-p-methoxyphenyl-3-isoquinolineacetic acid ethyl ester is obtained. Subsequent reduction with hydrogen gas in the presence of palladium 10% on charcoal gives the cis-1,2,3,4-tetrahydro-1-p-methoxyphenyl-3-isoquinoline-acetic acid ethyl ester. b) This ester is transferred with paraformaldehyde and potassium cyanide into the cis-2-cyanomethyl-1,2,3,4-tetrahydro-1-p-methoxyphenyl-3-isoquinoline-acetic acid ethyl ester and from this crude ester is further processed with hydrogen gas in the presence of nickel nickel to cis The -2-(2-aminoethyl)-1,2,3,4-tetrahydro-1-p-methoxyphenyl-3-isoquinolineacetic acid ethyl ester, which is directly cyclized to (?RS,12aRS)-1,4,5,7,12, 12α-hexahydro-7-p-methoxyphenyl-1,4-diazepino[1,7-bl isoquinolin-2(3H)-one (m.p. 196-198°). c) (7RS,12aRS)-1,4,5,7,12,12a~hexahydro-7-p-methoxyphenyl-1,4-diazepino [1, 7rb] isochinoylin-2 (3H)-one is alkylated with methyl iodide and thereby obtain (7RS,12aRS)-1,4,5,7,12,12a-hexahydro-7-p-methoxy-phenyl-3-methyl-1,4-diazepinoyl,7-b]isoquinoline-2( 3H)-one. (melting point 170-172°).

Example 2: (7RS, 12aRS)-1,2,3,4,5,7,12,12a,-octahdro-3-methyl-7-phenyl-1,4-diazepino [1,7-b| isoquinoline

The procedure is analogous to example 1 by starting from (7RS,12aRS)-1,7,12,12a-tetrahydro-3-methyl-7-phenyl-1,4-diazepino pL,7-b)isoquinoline-2 , 5 (3H, 4H )-dione and the compound mentioned in the title are obtained (melting point of the malinate 184-186°C - from methanol/ether).

The starting material is obtained in the following manner: Cis-1, 2,3, 4,-tetrahydro-1-phenyl-3-isoquinolineddloxyethyl ester (melting point of the hydrochloride 219-222°C) is prepared analogously to example 1, step a) using benzoyl chloride and is transferred with bromoacetyl chloride at -10°C in the presence of triethylamine in the cis-2-bromoacetyl-1,2,3,4Ttetrahydro-1-phenyl-3-isoquinolineacetic acid ethyl ester (melting point 107-109°C). This ester is converted with methylamine in tetrahydrofuran in an autoclave at 50°C to (7RS,12aRS)-1,7,12,12a-tetrahydro-3-methyl-7-phenyl-1,4-diazepino [1,7-b ] isoquinoline-2, 5(3H,4H)-dione (melting point 208-211°C).

Example 3: ( 7RS, 12aRS )- 3- efcvJr£l, 2, 3, 4, 5, 7, 12, 12a- octahvdro-7- f enyl- 1, 4- diazepino- fl, 7- b3 isoquinoline

6.0 g (7RS,12aRS)-3-acetyl-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepiono£1,7-b) isoquinoline in 100 ml of dioxane and the solution is then added dropwise to a boiling suspension of 3.14 g of lithium aluminum hydride in 75 ml of dioxane. It is boiled for a further hour under reflux, cooled to 0°C and the reaction mixture is decomposed by carefully dropping in 50 ml of methanol and 50 ml of saturated sodium sulphate solution. After filtering off the precipitate, the filtrate is evaporated to dryness. As evaporation residue, the compound mentioned in the title is obtained (melting point of the malinate 156-158° - from methanol/

ether).

Output the product. can be obtained in a folding way:

a) (7RS,12aRS)-1,4,5,7,12,12a-hexahydro-7-phenyl-1,4-diazepino 7-b) isoquinolin-2 (3H)-one (melting point 232-234°C ) is prepared analogously to example 1, steps a) and b) using benzoyl chloride and then reduced analogously to example 1 1 to (7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7 -phenyl-1,4-diazepino 1,7-b isoquinoline (melting point of the malinate 204-205°C). b) In a solution ay 9.9 g of (7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-bl isoquinoline 3.08 g of acetyl chloride are added dropwise at room temperature to 100 ml of methylene chloride, diluted with 10 ml of methylene chloride and, after the instillation has finished, it is stirred for a further hour at room temperature. The reaction solution is shaken twice with water, dried with magnesium sulphate and evaporated. As a residue (7RS,12aRS)-3-acetyl-1,2,3,4,5,12,12a-octahydro-7-phenyl-1,4-diazepino [I,7-b]isoquinoline is obtained (melting point 145-147° ).

Example 4: ( 7RS,! 2aRS )- 1, 2, 3, 4, 5, 7, 12, 12a- octahvdro- 3- metvl-7- phenyl- 1, 4- 7- diazepino 1, 7- b isoequinoline .

6.8 g (HRS, 12aRS)-1, 2, 3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-bj isoquinoline-3-carboxylic acid ethyl ester are dissolved in toluene and slowly dropwise with stirring into a boiling solution of 21.6 ml of disodium (2-methoxyethoxy) aluminum hydride 70% in benzene and 200 ml of toluene. After completion of instillation, boil for 30 minutes under reflux, cool to 0°C and the complex and excess reducing agent are decomposed by slowly instilling 60 ml of 20% sodium hydroxide solution. The organic phase is separated, shaken repeatedly with 100 ml of 20% sodium hydroxide solution and three times with water, magnesium sulfate is added and then evaporated to dryness. As evaporation residue, (^RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-3-methyl-7-phenyl-1,4-diazepino[1,7-b) isoquinoline is obtained ( melting point of the malinate 184-186°C - from methanol/ether).

The starting product is obtained in the following way:

5.4 g of (7RS,12aRS)-1,2,3,475,7,12/12a-octahydro-7-phenyl-1,4-diazepino|_1, 7-b] isoequinoline ISsed in 75 ml of chloroform and poured over with 30 ml of water. For this, add in drops at a temperature of 0-5°C

4.3 g of chloroformic acid ethyl ester and then a solution of 1.58 g of sodium hydroxide in 30 ml of water. The reaction mixture is stirred without cooling for a further 1 hour. The layers are now separated and the organic phase is decanted twice more with water. After filtration and evaporation of the filtered chloroform solution, (7RS,12aRS)-1, 2, 3, 4, 5, 7,12,12a-octahydro-7-genyl-1, 4-diazepinoj., 7-b] isoquinoline- 3-carboxylic acid ethyl ester (crude).

The following compound of formula I is obtained in an analogous manner

a) Starting from the corresponding compound with formula II,

in which X means carbonyl and Y the methylene and Z has therein' for an-

given meaning.

(3) Starting from the corresponding compound of formula II,

in which X and Y mean carbonyl and Z has the meaning given for R-j^

Starting from the corresponding compound of formula II,

wherein X and Y are methylene and Z is formyl

£) Starting from the corresponding compound with formula II,

wherein X and Y are methylene and Z is an ethoxycarbonyl.

The equivalent for the production of the output product

necessary, substituted cis- or trans-1,2,3,4-tetrahydro-3-, isoquinoline acetic acid ethyl ester is prepared analogously to example 1, step a). The reduction of the corresponding, substituted 3,4-dihydro~3-isoquinolineacetic acid ethyl ester, however, takes place with sodium borohydride in methanol instead of with hydrogen gas in close

be of palladium and gives a cis/trans mixture which can be separated by chromatography on the 50-fold amount of alumina/ activity basic II with absolute methylene chloride.

The conditions stated under £) can also be applied.

Claims (4)

1. Process for the preparation of new compounds of formula I in which R^ means hydrogen or alkyl with 1-5 carbon atoms. R2 stands for a group -(CB^ )n in which n means an integer from 0-3, Ri- and Rg either independently stand for hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or halogen with an atomic weight below 80, or together stand for the 3,4-methylenedioxy group R7 means hydrogen or if R5 and Rg both stand for alkyloxy with 1-4 carbon atoms, also alkyloxy with 1-4 carbon atoms R^ means hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or halogen with an atomic weight below 80, R4 stands for hydrogen or alkoxy with 1-4 carbon atoms, and acid addition salts thereof, characterized in that compounds of formula II, in which R 2 , R^/O and R^ have the above meaning and either X means carbonyl, Y carbonyl or methylene and X has the meaning indicated above. or X and Y stand for methylene and Z for alkanoyl with 1-5 carbon atoms or alkoxycarbonyl with 2-5 carbon atoms, is reduced, and the thus obtained compounds of formula I are recovered in the form of a base or as acid addition salts. 2. Procedure as stated in claim 1, characterized by preparing (7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-p-methoxyphenyl-3-methyl-1,4-diazepino [1,7-^ isoquinoline. 3. Procedure as stated in claim 1, characterized by at(7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-3-methyl-7-phenyl-1,4-diazepiono [1,7-b] isoquinoline is produced. 4. Procedure as stated in claim 1, characterized in that one prepares (7RS,12aRS) 7-p-chlorobenzyl-1,2,3,4,5,7,12,12a-octahydro-3-methyl-1,4-diazepino jj., 7-b] isoquinoline.