CH630904A5 - Process for preparing novel derivatives of 1,2,3,4,4a,10b-hexahydrobenzo(f)isoquinoline. - Google Patents

Abstract

The invention relates to a process for preparing compounds of the formula I, <IMAGE> in which R1, R2 and R3 have the meaning given in the description, by introducing the R3 group into corresponding compounds which are unsubstituted in the 3 position. The compounds of the formula I possess the properties of inhibiting aggression and depressing the central nervous system.

Description

The invention relates to a process for the preparation of new 1,2,3,4,4a, 10b-hexahydro-benz [f] isoquinoline derivatives of the general formula

15 where

Rj denotes hydrogen, halogen with an atomic number of 9 to 35 or an alkyl or alkoxy group with 1-4 carbon atoms,

R2 represents hydrogen, alkyl having 1-4 carbon atoms or 20 a phenyl group which is mono- or disubstituted by halogen with an atomic number of 9 to 35, alkyl having 1-4 carbon atoms or alkoxy having 1-4 carbon atoms and Rs is an alkyl group having 1 -4 carbon atoms, an alkene-25 nyl or alkynyl group with 3-6 carbon atoms, the multiple bond of which is not adjacent to the nitrogen atom of the tricyclic ring structure, a cycloalkylalkyl group with 4-10 carbon atoms, a cycloalkyl group with 3-7 carbon atoms, a given-3o if in the phenyl ring by halogen with an atomic number of 9 to 35, alkyl with 1-4 carbon atoms or alkoxy with 1-4 carbon atoms mono- or disubstituted phenylalkyl group with 7-10 carbon atoms or an alkanoylalkyl group with 3-5 carbon atoms, whose 35 oxygen atom is separated from the nitrogen atom of the tricyclic ring structure by at least 2 carbon atoms,

in the form of their ice and trans isomers and of their mixtures and their acid addition salts.

40 The most obvious, but structurally different, previously known compounds of the compounds of the formula I are 1,2,3,4,5,6-hexahydro-3,6-dimethylbenz [f] isoquinoline [Iorio et al., J. Med. Chem. 16, No. 6, 592 (1973)], 1,2,3,4,4a, 5,6,10b-0ctahydrobenz [f] isoquinoline [Tetrahedron 45 Letters No. 12,1001 (1974) ] and 1,2,3,4-tetrahydro-benz [f] isoquinoline (Indian J. of Chem. 12,113, (1974)]. No use is specified for these compounds. Furthermore, US Pat. No. 3,931,188 the 1,2,3,4,5,6-hexahydro-3-methylbenz [f] isoquinoline is known as an intermediate for the preparation of anesthetic agonists / antagonists 50.

If the compounds of formula I contain alkyl or alkoxy groups defined above, these preferably have 1 or 2 carbon atoms and in particular represent methyl or methoxy. If a substituent represents halogen defined above, it preferably represents chlorine.

In the compounds of the formula I, the substituent R 1 is preferably hydrogen. Another substituent 60 Ri is preferably arranged in the 8-position of the ring structure. The substituent R2 is preferably hydrogen, methyl or phenyl. The alkenyl or alkynyl groups symbolized above by R3 preferably contain 3 or 4 carbon atoms. A phenylalkyl group R3 defined above preferably represents an optionally substituted phenethyl group. If R3 represents an alkanoylalkyl group, this preferably contains an acetyl radical and in particular represents acetonyl.

NO.

10th

(I)

3rd

630904

According to the invention, the new compounds of the formula I and their acid addition salts are obtained by using compounds of the formula

N-H

and then proceed as described in Examples lf) and lg).

b) Compounds of the formula IV can be obtained, for example, by reducing compounds of the formula

(II) 10

(V)

15

wherein Rj and R2 are as defined above, alkylated and, if desired, a resulting mixture of isomers of a compound of the formula I is separated and / or a compound of the formula I obtained is converted into its acid addition salts.

The alkylation of the compounds of formula II can be carried out in a manner known per se for the alkylation of secondary amines, e.g. by reaction with compounds of the formula

Ra X

CH2OH

where Rt has the above meaning. To prepare compounds of the formula II in which R2 has the meaning given above with the exception of hydrogen, the procedure is, for example, as described in Example 1a) to Ig). To prepare compounds of the formula II in which R 2 is hydrogen, the procedure described in Example la) to ld) can be carried out, the ketone obtained in a manner known per se, e.g. reduce with lithium aluminum hydride

20th

where Rt is as defined above and R4 is lower alkyl. The reduction can be carried out, for example, using complex metal hydrides such as lithium aluminum hydride in a manner known per se.

c) Compounds of the formula V can be obtained, for example, by using compounds of the formula

COOR

(HI) 25

where R3 has the above meaning and X stands for the acid residue of a reactive ester.

Compounds of the formula III in which X represents halogen or an organic sulfonic acid radical are preferably used.

The compounds of the formula I obtained according to the invention may be in the form of the free bases or their acid addition salts. The free bases can be converted into their acid addition salts in a manner known per se. Thus, the compounds of the formula I according to the invention can form acid addition salts with inorganic acids such as hydrogen chloride or with organic acids such as maleic acid.

The compounds of the formula I have 2 asymmetric carbon atoms in positions 4a and 10b in their tricyclic ring structure. Two isomer groups are therefore possible, namely compounds in which the rings B and C are cis-linked and compounds in which the rings B and C are trans-linked. In the process according to the invention, the linkage of the rings in the tricyclic ring structure of the respective starting compounds is retained. The starting products can be obtained as follows: a) Compounds of the formula II can be prepared from compounds of the formula by methods known per se

(IV)

30th

(VI)

wherein R4 has the above meaning, with a Grignard connection of the formula

35

40

Mg-X

(VII)

where Rt has the above meaning and X1 represents chlorine, bromine or iodine. The reaction can be carried out, for example, using the method described in J. Org. Chem. 22, 261 (1957).

Insofar as the preparation of the starting compounds is not described, they are known or can be prepared by processes known per se or analogously to the 50 described here or analogously to processes known per se.

The compounds of the formula I and their pharmacologically tolerated acid addition salts have not hitherto been described in the literature. They are characterized by interesting pharmacodynamic properties 55 and can therefore be used as a remedy. In particular, the compounds show anti-aggressive properties.

Due to their anti-aggression properties, the substances can be used to treat aggressive arousal states, for example to dampen the aggressive behavior of psychopaths and the insane.

In addition, the substances in higher doses also have central depressant properties and can therefore be used in psychiatry for the treatment of arousal states.

The compounds of the formula I or their physiologically tolerable acid addition salts can be used as medicinal products.

630904

alone or in a suitable pharmaceutical form with pharmacologically indifferent excipients.

In the following examples, which explain the invention in more detail but are not intended to restrict its scope in any way, all the temperatures are given in degrees Celsius.

example 1

trans-1,2,3,4,4a, 10b-hexahydro-3-isopropyl-6-methylbenz [f] -isoquinoline

A mixture of 7.0 g of trans-1,2,3,4,4a, 10b-hexahydro-6-methylbenz [f] isoquinoline and 8.0 g of anhydrous sodium carbonate in 70 ml of dimethylformamide is preheated to 50 °. At this temperature, a solution of 6.5 g of isopropyl bromide in 20 ml of dimethylformamide is slowly added dropwise, the reaction mixture is stirred for a further 6 hours at the same temperature, cooled to 20 ° and poured onto 300 ml of water and 200 ml of chloroform. The organic solution is separated off, the aqueous phase is further extracted with chloroform. The combined organic solutions are washed with water, dried over sodium sulfate and evaporated. The title compound is isolated as the hydrochloride from methanol / ethanol. M.p .: dec. over 300 °.

The starting material can be produced as follows:

a) A solution of 39 g of thionyl chloride in 300 ml of anhydrous chloroform is slowly added dropwise at 0-5 ° to a solution of 82 g of l-methyl-4-phenylpiperidine-3-ylmethanol in 1500 ml of anhydrous chloroform. The reaction mixture is now stirred for 1 hour at room temperature, 1 hour at 40 ° and then 3 hours at boiling temperature, evaporated to dryness and triturated with a lot of ether. The solid 3-chloromethyl-1-methyl-4-phenylpiperidine hydrochloride is suction filtered and dried in vacuo. M.p .: 203 to 211 °.

b) The above product is converted into the base with sodium hydroxide solution, which is extracted with methylene chloride. After drying over sodium sulfate, the organic phase is evaporated to dryness. 51 g of the evaporation residue and 13.4 g of sodium cyanide are suspended in 40 ml of dimethylformamide and heated to boiling for 2 hours with vigorous stirring. After cooling to room temperature, the reaction mixture is diluted with 200 ml of water, extracted with chloroform and the chloroform phase washed with water, dried over sodium sulfate and concentrated. The 1-methyl-4-phenylpiperidin-3-ylacetonitrile (mp of the naphthalene-1,5-disulfonic acid salt: 292-296 ° and decomp.) Remaining as a viscous oil is used without special cleaning.

c) A solution of 85 g of the above product in 150 ml of absolute ethanol is saturated at 10 ° with hydrogen chloride. The dark reaction solution is then stirred at boiling temperature for 24 hours, concentrated significantly, mixed with 200 ml of anhydrous benzene and evaporated to dryness. The evaporation residue is taken up in 290 ml of absolute ethanol, mixed with 7.2 ml of water and heated to boiling for 2 hours. After evaporation, the residue is dissolved in chloroform, water is added and the mixture is made alkaline with sodium bicarbonate. After the chloroform solution has been separated off, the aqueous solution is shaken out again with chloroform, the extracts are washed with 10% sodium bicarbonate and with water, dried over sodium sulfate and evaporated to dryness. The residue is distilled in a high vacuum, the 1-methyl-4-phenylpiperidin-3-yl-ethyl acetate passing over at 118-123 ° / 0.08 torr. nD20: 1.5220.

d) A solution of 16.8 g of l-methyl-4- is added to a mixture of 85 g of polyphosphoric acid and 25 ml of anhydrous xylene, preheated to 90 °.

-phenylpiperidin-3-ylacetic acid ethyl ester in 10 ml of anhydrous xylene is added dropwise within 15 minutes, the reaction mixture is stirred for a further 2 hours at 120-125 °, cooled to approx. 80 ° and poured onto 300 ml of water. The aqueous solution thus obtained is washed with ether, made alkaline with 20% sodium hydroxide solution and extracted with chloroform. The chloroform solution is washed neutral with water, dried over sodium sulfate, evaporated, the residue dissolved in a mixture of methylene chloride / methanol 9/1, filtered through aluminum oxide and evaporated to dryness. The 1,2,3,4,4a, 10b-hexahydro-3-methylbenz [f] isoquinolin-6- (5H) -one (mixture of isomers) remaining as an oil distilled at 106-III ° / 0.08-0 , 1 torr.

Isomer separation: The trans form crystallizes from the mixture of isomers from ether / petroleum ether. Mp 84-85 ° (ether / petroleum ether). (Hydrochloride, m.p .: 300-302 ° dec., From methanol).

The cis form is isolated from the mother liquors as a hydrogen fumarate. M.p .: 175-177 °, sint. 172 ° (from ethanol / ether).

e) To dissolve 115 ml of 2 M methyl lithium in ether and 400 ml of anhydrous ether, a solution of 20.0 g of trans-1,2,3,4,4a, 10b-hexahydro-3 is left in with stirring and in a nitrogen atmosphere -methylbenz [f] isoquinolin-6 (5H) - one drop in 400 ml of anhydrous benzene within 45 minutes at room temperature. The reaction mixture is stirred for a further 2 hours at room temperature, poured onto 11 20% ammonium chloride solution, the organic phase is separated off and the aqueous solution is extracted with methylene chloride. The various organic solutions are washed with water, dried over sodium sulfate and evaporated together. The remaining trans-1,2,3,4,4a, 5,6,10b - octahydro-3,6-dimethylbenz [f] isoquinolin-6-ol is recrystallized from benzene / hexane. Sint. 130 °, mp 148-153 °.

f) A mixture of 14.6 g of trans-l, 2,3,4,4a, 5,6,10b-0cta-hydro-3,6-dimethylbenz [f] isoquinolin-6-ol in 20 ml of isopropanol and 30 ml of 5N isopropanolic hydrogen chloride solution is heated to boiling under nitrogen for 30 minutes. The suspension obtained is cooled to 10 ° and the crystallized hydrochloride of trans-1,2,3,4,4a, 10b-hexahydro-3,6-dimethylbenz [ f] isoquinoline filtered, washed with ether and recrystallized from ethanol / isopropanol. M.p .: dec.

from 302-303 °.

g) A solution of 12.2 g of ethyl chloroformate is left to dissolve 7.0 g of trans-1,2,3,4,4a-10b-hexahydro-3,6-dimethylbenz [f] isoquinoline in 70 ml of anhydrous benzene dropwise in 50 ml of benzene at room temperature within 1 hour. The reaction mixture is now stirred for 1 hour at room temperature and 3 hours at the boiling temperature, cooled to room temperature and washed with water, with 1N hydrochloric acid and again with water, dried over magnesium sulfate and evaporated to dryness. The crude trans-3-ethoxycarbonyl-l, 2,3,4,4a, 10b - hexahydro-6-methylbenz [f] isoquinoline obtained is taken up in 34 ml of n-butanol, mixed with 4.5 g of potassium hydroxide and Stirred at 100 ° for 18 hours. After cooling, the reaction mixture is diluted with 300 ml of benzene, washed neutral with water and extracted with 2 N tartaric acid. The tartaric acid extract is made alkaline with sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solutions are washed with water, dried over sodium sulfate and evaporated. The one remaining as an oily residue. The title compound is taken up in ethanol and converted into the hydrogen maleinate. M.p .: 169-170 ° (from ethanol / ether).

Analogously to Example 1, the following compounds of the formula I are also obtained by alkylating the corresponding compounds of the formula II:

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

630904

Example No.

line

Rx

Ra

Rs

Salt form

M.p.

2nd

3rd

trans trans trans trans trans trans trans trans

H H

H

8-ch3

H

H

H H

-ch3

-ch3 -ch3

-ch3

h h

-ch3

-CH,

-C2H5 -CH (CH3) 2

- <CH2> 2

-ch-O

- (ch2)

-ch2c = ch -ch2coch3

Hydrochloride hydrochloride

Hydrochloride

Hydrochloride hydrochloride

Hydrochloride

Hydrochloride hydrochloride

278-280 °

over 300 ° (dec.)

264-265 °

276-278 ° 252-253 °

240-241 °

242-243 ° 215-216 °

Claims (2)

630904 2nd PATENT CLAIMS 1. Process for the preparation of new 1,2,3,4,4a, 10b - hexahydrobenz [f] isoquinoline derivatives of the general formula wherein Rj denotes hydrogen, halogen with an atomic number of 9 to 35 or an alkyl or alkoxy group with 1-4 carbon atoms, R2 represents hydrogen, alkyl having 1-4 carbon atoms or a phenyl group which is mono- or disubstituted by halogen with an atomic number of 9 to 35, alkyl having 1-4 carbon atoms or alkoxy having 1-4 carbon atoms and R3 is an alkyl group having 1 -4 carbon atoms, an alkenyl or alkynyl group with 3-6 carbon atoms, the multiple bond of which is not adjacent to the nitrogen atom of the tricyclic ring structure, a cycloalkylalkyl group with 4-10 carbon atoms, a cycloalkyl group with 3-7 carbon atoms, one optionally in the phenyl ring by halogen with an atomic number of 9 to 35, alkyl with 1-4 carbon atoms or alkoxy with 1-4 carbon atoms mono- or disubstituted phenylalkyl group with 7-10 carbon atoms or an alkanoylalkyl group with 3-5 carbon atoms, the oxygen atom of which at least 2 carbon atoms are separated from the nitrogen atom of the tricyclic ring structure, in the form of their cis and trans isomers and of their mixtures and their acid addition salts, characterized in that compounds of the formula in which R 1 and R 2 have the above meaning are alkylated and, if desired, a compound of the formula I obtained is converted into its acid addition salts. 2. The method according to claim 1, characterized in that the cis and trans isomers are separated from the isomer mixture obtained.