NO151288B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE INDOLOKINOLIZINDINS - Google Patents

Description

This invention relates to the preparation of new indolo-(2,3-a)quinolizidines.

The new indolo(2,3-a)quinolizidines produced according to the invention have the general formulas (I) and (II)

where R means

where R' is

- one to C,. alkoxy radical; or

- a trimethoxy-substituted phenyl radical;

According to the invention, the acid addition salts of the above compounds are also produced.

The compounds produced according to the invention are of particular interest because of their effect on blood circulation in the brain. One or more of the compounds produced according to the invention can be incorporated into therapeutic preparations together with a therapeutically acceptable diluent or carrier.

The above compounds are prepared in accordance with the invention by condensing a corresponding compound where R means -CI^-NI^» with a compound of the formula R'COHal, where R' is as stated at the outset, and Hal is halogen. The starting material can be prepared by condensing 2-aminoethyl-3-indole with 1-chloro-4-cyano-4-chlorocarbonyl-hexane to form the corresponding amide; the amide is subjected to strongly basic conditions to eliminate HCl and produce ring formation at the nitrogen atom of the 3-indole substituent; quinolizidine cyclization of the product is produced by treating it with a dehydrating agent followed by a perchlorate salt; the resulting quinolizidinium perchlorate is hydrogenated to produce the corresponding 1-ethyl-1-cyano-indolo-(2,3-a)-quinolizidine isomeric mixture, and the isomers are separated. The aminomethyl starting material is then obtained.

In the following forms denotes:

Typical reaction conditions for each reaction step are as illustrated in the following examples. Other conditions for carrying out the same conversions will be obvious to those skilled in the art.

The following examples shall serve to illustrate the invention Example 1

(a) Preparation of 3-[2'-(2"-cyano-2"-ethyl-5"-chloro-valeroylamino)-ethyl]-indole

31 g (0.19 4 mol) of tryptamine, 500 ml of dichloromethane and 20 g (0.198 mol) of triethylamine were placed in a 1 liter flask. The mixture was cooled to 0°C over ice and it was added

40 g (0.192 mol) of 2-cyano-2-ethyl-5-chloro-valeroyl chloride dissolved in 150 ml of methyl dichloride. After 2 hours at room temperature, the mixture was washed with water, then with 10% hydrochloric acid and then with 10% sodium hydroxide. It was dried and the solvent was removed by evaporation. The product, recrystallized from isopropyl ether/petroleum ether, melted at 120°C (yield 40 g). The analysis results are as follows:

Calculated for C^H^t^ClO: C 65.0, H 6.64, N 12.65%

Found: C 64.03, H.6.78, N 12.60%.

(b) Preparation of 1-[(2'-indol-3"-yl-ethyl)-3-ethyl-3-cyano]-2- piperidone

22 g were placed in a 1 liter round-bottomed flask

(0.0665 mol) of the product from step (a) above, 200 ml of tetrahydrofuran and 300 ml of t-butanol. The mixture was cooled to 0°C over ice and 8.5 g (0.076 mol) potassium tert-butoxide was added in small amounts. After 2 hours at room temperature, the mixture was reduced in volume and hydrolysed. The organic phase was extracted with methylene dichloride, washed with water, dried and the solvent was removed by evaporation. The desired product, recrystallized from ethanol/ether 50/50 melted at 180°C (yield 15 g, 80%). The analysis results are as follows:

Calculated for ClgH23N30: C 73.2, H 7.1 N 14.2%

Found: C 72.46 H 7.15, N 14.01% (c) Preparation of l-ethyl-l-cyano-5,12b-didehydro-indolo-(2,3-a)quinolizidinium-perchlorate

50 g (0.169 mol) of the product from step (b) above and 700 ml of phosphoryl chloride were placed in a 1 liter flask with stirring. After heating under reflux cooling for 20 hours

the reaction mixture was concentrated and extracted 2 or 3 times with 500 ml of methylene dichloride which was then removed by evaporation. The product was taken up in 300 ml of methylene dichloride and cooled over ice, and 300 ml of a solution of lithium perchlorate (1 mol) was added

under vigorous stirring. A yellow precipitate was formed which, after recrystallization from methanol, melted at 260°C (yield 44 g, 70%). The analysis results are as follows:

IR 3400 cm<-1> NH indole

2260 cm"<1> C=N

1620 cm"<1> C=N<+ >(d) Preparation of 1- ethyl- 1- cyano- indolo( 2, 3- a) quinolizidine

(12b- H, l- C^H^ trans isomer)

200 ml of methanol, 100 ml of methylene dichloride and 13.5 g (0.036 mol) of the perchlorate product from step (c) above were placed in a 1 liter round bottom flask. The flask was cooled to approx. 5°C, and 5 g of sodium borohydrate were added in small amounts. The solution was then stirred for 2 hours at room temperature, concentrated, washed with water and extracted with methylene dichloride. After drying and removal of the solvent, 8 g of yellow crystals were obtained,

which after recrystallization from isopropyl ether melted at 160°C (yield 80%). The analysis results are as follows: IR 3420 cm"1 )

3440 cm"<1> )

2760 cm"<1>' )

2,800 cm ) NH and Bohlmann bands

2250 cm"<1> CN

NMR (dimethyl sulfoxide, dg, 80 MHz) 6

0.86, 3H in (t) (CH )

3.77, 1H (s) (H at Cn )

— 9a

9.66, 1H (s) (NH)

Calculated for c1sH21N3: C 77'7' K 7.2, N 15.2%

Found: C 77.55, H 7.32, N 15.10%.

(e) Preparation of 1-ethyl-1-cyano-indolo(2,3-a)quinolizidine

( 12b- H, 1- C2H5 cis- isomer)

19 g of the perchlorate product from step (c) above, 300 ml of 95% ethanol and 40 g of zinc powder were placed in a 1 liter flask. Then 100 ml of concentrated hydrochloric acid was added. Weak reflux could be observed during addition of the acid. The mixture was allowed to stand

at room temperature for 10 hours. It was then concentrated, washed with water and extracted with methylene dichloride. It was made alkaline with sodium hydroxide and filtered through Celite.

After decantation, drying and evaporation of the solvents, 6 g of a product, insoluble in ether, with a melting point of 250°C were obtained. The analysis results are as follows:

IR 3410 cm"<1> (NH)

2260 cm"<1> (CN)

Calculated for <C>18H21<N>3<*1/>4H20: C 76'5' H 7'60' N 14.85%

Found: C 76.59, H 7.80, N 14.55%.

The ether extracts were concentrated to give 4 g (total yield 71.5%) of the cis isomer of the same product as step (d) above.

NMR (dimethylsulfoxide d,, 80 MH_) 6:

and L

1.05, 3H (t) (CH3)

3.45, 1H (s) (H at CQ )

10.32, 1H (s) (NH)

(f) Preparation of 1-ethyl-1-aminomethyl-indolo(2,3-a)-quinolizidine (12b-H,1-C,,H5 trans-isomer II)

4 g of lithium aluminum hydride and 400 ml of dry ether were placed in a 1 liter flask. The flask was cooled to a temperature between 0 and 5°C and 8.9 g of the product from step (d) above was added, in small portions. After the flask had been allowed to stand

for 1 hour at room temperature, 60 ml of dry tetrahydrofuran was added. The mixture was heated for 2 hours under reflux. After cooling, 40 ml of water was added dropwise, followed by 200 ml of methylene dichloride. The mixture was stirred for 15 minutes. After filtration over "Celite", drying and concentration of the filtrate, 7.2 g of white crystals were obtained which after recrystallization from ether melted at 175°C (80% yield).

The analysis results are as follows:

IR 3280, 3190 cm"<1> NH--1

3350 cm NH indole

The CN peak at approx. 2250 cm 1 was absent.

Calculated for C^H^: C 76.4, H 8.85, N 14.8%

Found: C 75.85, H 8.90, N 15.52%.

g) 1- ethoxycarbonylaminomethyl- 1- ethyl- indolo( 2, 3- a) quinolizidine hydrochloride ( 12b- H, 1- C^H^ trans-isomer II)

To a solution of 2 g (0.00705 mol) of the trans-product II from (f) in 20 ml of dimethoxyethane, cooled to 0°C, were added alternately to keep the pH basic, portions of: 800 mg of ethyl chloroformate in solution in 5 ml of dimethoxyethane, and 750 mg of sodium carbonate in solution in 5 ml of water.

After the reaction mixture had been allowed to stand for 3 hours at ambient temperature, the product was extracted with dichloromethane, the dichloromethane extract was washed with water, dried and evaporated to dryness. The product was recrystallized from ethanol.

Weight: 2 g, yield: 80%, Melting point: 140°C.

The results of microanalysis are as follows: Calculated for c2iH29<N>3°2<:> C 71'0' H 8'17' N H/8% Found: C 70.94, H 8.16, N 11.54% .

The hydrochloride salt was formed from the above 2 g of product by the addition of 4N HCl in 20 ml of ethanol.

Weight: 2 g, yield: 90%, m.p.: 260°C.

Example 2

1-(3',4',5'-trimethoxybenzoylaminomethyl)-1-ethyl-indolo-(2,3-a)-quinolizidine hydrochloride (12b-H,l-C^H^ trans-isomer II)

Into a three-necked flask with a volume of 250 ml equipped

with a stirrer, a CaC₂ trap, a thermometer and a dropping funnel, 2.85 g of the transproduct II from example 2(f), 1.1 g of triethylamine and 50 ml of dichloromethane were introduced.

The mixture was stirred and cooled to 0.2°C. At this temperature, 2.31 g of 3,4,5-trimethoxybenzoyl chloride in 15 ml of dichloromethane were added slowly. The addition took place over a period of 15 to 20 minutes, after which the reaction mixture was stirred for 1 hour at 0°C and then for 15 hours at room temperature.

The reaction mixture was then washed several times with water, then with 10% aqueous sodium hydroxide and then again with water. It was dried over sodium sulfate and concentrated to form a non-crystalline mass with a meringue texture and melting point near 100°C.

TLC: methylene chloride/methanol: 90/10, Rf = 8/10

IR 3230 cm"1 NH

3190 cm"<1> NH

2,750 and 2,800 cm"<1>Bohlmann band

1640 cm <1> C=0 amide

Amount of base with HC104: 97%

The amount of base determined by an anhydro-titrimetric method using perchloric acid in glacial acetic acid.

To prepare the hydrochloride salt, the above product was dissolved in a 1:1 mixture of diisopropyl ether and isopropanol, and 4N hydrochloric acid was added. The hydrochloride salt crystallized while hot and was filtered hot and washed with ethanol to give 4.5 g (88% yield) of the product.

TLC: methylene chloride/methanol: 90/10, Rf = 8/10

Sm.p. : 210°C, Koffler)

Amount of hydrochloride: 100% (1 function).

Microanalysis gave the following results:

Calculated for C28<H>35N3°4'HC1: C 65'45' H 7'00' N 8.18%

Found: C 64.34, H 7.17, N 8.11%

C 64.15, H 7.16, N 7.96%.

Claims (1)

Analogy method for the production of therapeutically active indolo(2,3-a)quinolizidines of the general formulas (I) and (II) where R' is - a to C 1 - alkoxy radical; or - a trimethoxy-substituted phenyl radical; characterized in that a corresponding compound where R means -CI^-NH^/ is condensed with a compound of the formula R'COHal, where R' is as indicated at the outset, and Hal is halogen.