DK154430B - METHOD OF ANALOGUE FOR THE PREPARATION OF INDOLO (2,3-A) QUINOLIZIDIN OR ACID ADDITION SALTS - Google Patents

Description

in

DK 154430 B

The present invention relates to an analogous process for the preparation of novel indolo (2,3-a) quinolizidines or pharmaceutically acceptable acid addition salts thereof, and the process according to the invention is characterized by the characterizing part of the claim.

The indolo (2,3-a) quinolizidines of the invention have the general formulas (I) and (II): no Cn

Wherein R represents -COOC 2 H 5, -COOH, -CN, an aminomethyl group or a substituted aminomethyl group of the formula R'-NH-Cl 2 - wherein R 'represents alkyl, acanoyl or alkoxy -carbonyl having up to 5 C atoms, phenyloxycarbonyl, diethylaminoethylaminocarbonyl, trimethoxybenzoyl or guanidinocarbonyl, or wherein R together with the nitrogen atom of the indole ring represents ^ N-CO-NH-CE ^ - or ^ N-CO-. These latter derivatives are D homo azaeburnamonines or D eburnamonines.

Preferred compounds of the invention are those wherein R represents COOH, methyleneamocarbethoxy, methyleneamino (3,4,5-trimethoxy) benzoyl, methyleneaminophenoxycarbonyl, methylenureidodiethylaminoethyl, methylenaminopentanoyl, or methylenaminopentyl.

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2

The compounds of the invention are remarkable because of their effect on the blood circulation of the brain. Thus, the compounds may be formulated as therapeutic agents containing one or more of the subject compounds in combination with a therapeutically acceptable diluent or carrier.

FR-A-2,285,877 and 2,292,475 disclose compounds which are closely related to the compounds of the invention. However, the compounds thus known have a significantly less effective effect on blood circulation than the present compounds of formulas I and II, which will be elaborated below.

The process of the invention consists in condensing 2-aminoethyl-3-indole with 1-chloro-4- (A) -4-chlorocarbonyl-hexane, where A represents -COCX or -CN, to form the corresponding amide. Subsequently, the amide is subjected to strong alkaline action, whereby HCl is expelled while a cyclization occurs at the nitrogen atom of the 3-indole substituent. By treating the thus obtained product with dehydrating agent and then with a perchloirate salt, a quinolizidine ring formation is obtained and the resulting quinolizidinium perchlorate is hydrogenated to form a mixture of isomers of the corresponding indolo (2,3-a) quinolizidine. Eventually, the isomers separate. The reaction schemes are listed below ("general reaction") and these only lead to compounds in which R represents -CCKX 3 Hg or -CN (in each of these cases 2 isomers are formed, i.e., a total of 4 compounds are obtained). All other derivatives are derived from these compounds: - either directly, ie. the acids are obtained by saponification of the esters (see the "special reaction procedures" diagrams,

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3 where Å is -COOCgHjj) and the methylenamino compounds are obtained from the nitriles by reduction with lithium aluminum hydride (the same reaction schemes where A is -CN) - or from the acids or methylenamino compounds by well known methods.

In the reaction schemes, the following terms are used: (I) denotes cis isomers and (II) denotes trans isomers.

1 (a) to 1 (i) denote the various steps of Example 1 wherein the starting material is the 4-ethoxycarbonyl derivative and the final products are acids or acid derivatives.

2 (a) to 2 (g) indicate the various steps of Example 2 wherein the starting material is 4-cyano derivatives and the end products are methylenamino compounds or derivatives thereof.

4 DK 154430 B

General Reaction Programs 1 (a) or 2 (a) * · yy— TJ ♦ C2H5 - C - (CH2) 3 Cl >> Lk J π / C1 coci 'jj H Sv'av ^ 1 (b) or 2 (b) ) called tert-butoxide

1 (cl V

or

I Λ. C104 ® * -3 I I

/ Vn t, cl0, vv VS

A ^

k \ S

\ Hj / Pt 1 (d) \ 1 (d) 2 W XN. 2 (e)

SnCO OoS

vss vss V v 5

Special reaction steps 1 54430 B

A = -C00C2H5 A Al

Wi i .W-f o '' o ^

1 (h) KOH x (e) KOH

/ VXA

li i * CJOLii

Mjf) ΊΠΤ "V <0 ^ ϋ (I) (Π)

A = -CN

ΦοΦ (XX &

A A

toilet v 2 (g) 2 (f) \

LiAlH4 LiAlH4

Cell ¢ 1¾

A A

H 2 h2n --- ''

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6

Compounds of formula (I) or (II), in which R is a substituted aminomethyl group, as well as E homoazae burnamonines, can be prepared from the above products wherein R is COOH or Cl 2 NE 2 by methods known per se to internal conversion of substituent groups.

The process of the invention is further illustrated by the following examples.

Example 1 (a) Preparation of 3- / 21 - (2,2-Ethoxycarbonyl-2 "-ethyl-5" -chloro-valerovlamino) -ethyl-indole

To a suspension of 2.5 g (0.0184 mol) of 3- (2 * -aminoethyl) -indole (tryptamine) in 50 ml of dry chloroform containing 2 g (0.02) of triethylamine cooled in an ice bath was added dropwise 4.7 g (0.0184 mol) of 2-ethyl-2-ethoxycarbonyl-5-chloro-valeroyl chloride. After stirring for 2 hours at room temperature, the solution was washed with dilute hydrochloric acid. The organic phase was dried and evaporated under reduced pressure to give 6.6 g of the above product, which after recrystallization from petroleum ether / isopropyl ether gave a yield of 95% Melting point: 76 ° C. Analytical results:

IR (KBr) 3350 and 3300 cnf1 NH

1735 cm ^ CO ester 1640 cm- · * · CO amide.

Calculated for C 20 H 27 N 2 O 3 Cl: C = 63.40%, H = 7.18%, N = 7.40% Found: C = 63.39%, H = 7.05%, N = 7.51%

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7 (b) Preparation of 1- [(2, -indole-3, - ylethyl) -3-ethyl-3-ethoxycarbonyl] -2-piperidone

To a suspension of 34.4 g (0.0908 mol) of the above compound in 150 ml of a 1: 1 mixture of benzene and hexamethylphosphor triamide, cooled in an ice bath, was added slowly and in nitrogen atmosphere 10.6 g (0.0946 mole) potassium tert-butoxide. After stirring for 8 hours at room temperature, the solution was poured into cold dilute hydrochloric acid. After decanting, the aqueous phase was extracted twice with benzene, after which the resulting organic phase was washed twice with water, dried and evaporated under reduced pressure to give 30 g of the desired product. This was recrystallized from isopropyl ether to yield 96%. Melting point: 29 ° C. Analysis results: IR (KBr) 3250 cm ”1 1 NH indole 1730 cm" 1 CO ester 1620 cm ”1 CO amide

Calculated for C 20 H 26 W 2 ° C: C = 70.15%, H = 7.65%, N = 8.13%

Found: C = 69.97%, H = 7.65%, N = 8.20% (c) Preparation of 1-ethyl-1-ethoxycarbonyl-5,12b-didehydro-indolo- (2,3-a) auinolizidinium chloride 240 ml of distilled phosphonyl chloride was poured into a solution of 30 g (0.0876 mol) of the above compound in 480 ml of dry toluene. This solution was refluxed for 9 hours in the presence of a water-soaking agent. Excess phosphoryl chloride and toluene were then removed by evaporation under reduced pressure. The residue was collected with methylene dichloride and the solution was washed with water, dried

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8 over sodium sulfate and evaporated under reduced pressure.

Part of the solution was shaken with a 1 M aqueous solution of lithium perchlorate, and after decanting the aqueous phase, washing out with water, drying over sodium sulfate and evaporation of the solvent under reduced pressure, a yellow powder which was recrystallized from ethanol was obtained. Melting point of the resulting product: 71 ° C. Analytical results:

IR (KBr) 3340 cm -1 NH

1740 cm "1 CO ester 1625 cm" 1 C = NC & (d) Preparation of 1-ethyl-1-ethoxycarbonyl-indolo (2,3-a) -quinolizidine (I2b-H, 1C i s omere)

A solution of 6.25 g (0.0147 mol) of the above perchlorate salt in 80 ml of ethanol was hydrogenated for 12 hours in the presence of 0.3 g of platinum oxide. After filtration, the ethanol was evaporated under reduced pressure and the residue was collected with methylene dichloride and shaken with 5% sodium hydroxide. The organic phase was then decanted off and washed with distilled water. A solution of the product was chromatographed with methylene dichloride over 100 g of silica and eluted with the same solvent. Hereby, 1.12 g (yield 25%) of a first fraction which was the 12b-H, 1-C ^ H ^ trans isomer of the product is replaced. Melting point: 112 ° C (recrystallized from petroleum ether / isopropyl ether). Analysis results: e

IR (KBr) 3410 cm -1 NH

2770, 2805, 2825 cm "1 Bohlmann band 1710 cm" 1 CO ester

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9 NMR (CDCl 3, 90 MHz): among other signals: 8.5 S OH (s) (NH indole) 4.35 & 2H (q) (O-CH 2 -CH 3) 3.85 M 1.35 C 3H (t) (CH 3 -CH 2 -O-) 0.75 3 H (t) (CH 3 -CH

Calcd for C20 N2 O2: C = 73.59%, H = 8.03%, N = 8.58%

Pound: 0 = 73.47%, H = 8.12%, N = 8.33%.

Later fractions from the chromatography afforded 1.8 g of an oil which was the 12b-H, 1-C2H3 cis isomer of the desired product.

Analytical results:

IR (KBr) 3420 cm -1 NH

3750, 3800 cm "1 Bohlmann band 1705 cm" CO CO ester NMR (CCl ^, 90 MHz)

Among other signals: 7.78 S 1H (s) (NH indole) 4.15 S 2H (q) (-0CH 2 -CH 3) 3.93 S 1H (s) (H on C9a) 1.09 S 3H (t (CH3-CH2-O) 0.9 S 3H (t) (CH3-CH2-)

The hydrochloride, recrystallized from isopropanol, had a melting point above 260 ° C.

Calculated for C20 H20 N2 O2 .HCl.1.5 H2 O: C = 6.1, 57%, H = 7.75%, N = 7.18%

Pound C = 6.1, 51%, H = 7.33%, N = 7.35%

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(E) Preparation of 1-ethyl-1-carboxy-indolo (2,3-a) quinolizidine (12b-H, 102 ^ trans-isomer), hydrochloride -ΤΤΤH in HCl. H! HOOC '\

To a solution of 8.8 g of the ester obtained in step (d) in 100 ml of ethanol was added 8.8 g of Η0Η, after which the mixture was heated under reflux for 12 hours. The solvent was evacuated under reduced pressure, after which the residue was treated with ice water and acidified with concentrated hydrochloric acid. The hydrochloride, which was separated, precipitated, washed and dried. The yield was crystallized 9.5 g (100%) with 1 mole of crystal water. Melting point:> 260 ° C. Analytical results:

Formula Ο - ^^ ϊ ^ ί ^ ίΗΟΙ, ^ Ο Molecular Weight: 355 ·

C Η N

Calculated 61.20% 7.08% 7.93%

Found: 61.01% 6.75% 7.72%

IR (KBr) 3340 cm -1 NH

1705 cm -1 (-C-OH) u 0

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(F) Preparation of 1-ethyl-carboxy-indolo- (2,3-a) -quinolizidine (12b-H. 1-CoHr-cis isomer) O-

V H0CxvN / ^ 8 - ·,

To a solution of 6.8 g of 1-ethyl-1-ethoxycarboxyl-indolo (2,3-a) quinolizidine (I2b-H, 1C ^ H ^ cis isomer), obtained in step (d), in 100 ml of 95 % ethanol was added 6.8 g of potassium hydroxide. The mixture was heated under reflux for 12 hours, the solvent evaporated under reduced pressure, and the residue was treated with ice water and acidified with HCl to pH 4.5. The crystallized product was separated, washed and dried to give 4.1 g of acid.

Analysis: ^ 18 ^ 22 ^ 2 ^ 2 M = 298.37

C Η N

Calculated 72.45% 7.43% 9.37%

Found: 72.61% 7.49% 9.20% IR 1620 cm -1 V CO, OH attached

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12 (g) Preparation of - D nor eburnamonin iim, u ΠτΤ ^

Cn. .JL Jv [> 11 2) NaOH vandi ^^ / '' '^ \ ViL ^^ H J_'

moc'i ^ 'L

To a suspension of 6 g (0.0179 mol) of 1-ethyl-1-carboxy-indolo (2,3-a) quinolizidine (I2b-H, 1-02Η cis isomer) from the previous step (f) in 60 ml of dry benzene were added dropwise 30 ml of oxalyl chloride. The suspension was stirred for 2 hours at room temperature and then refluxed for 9 hours. The solvents were evaporated under reduced pressure and the residue treated with methylene chloride and stirred in the presence of a dilute soda solution. The organic solution was washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give 4.25 g of the product sought (yield: 83%) ·

After washing out on an alumina column, 3.25 g of a beige crystalline product was obtained. Melting point: 136 ° C (diisopropyloxide).

IR (KBr): 2805, 2845, 1735, 1660 cm -1 C18 H20 N2 ° = 280.96.

Calculated%: C 77.11% H 7.19% N 9.99%

Found: 77.54% 7.78% 10.09%

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HjNMR (COCl4) reference int. IMS = 0 7.9-7.7 (m) aromatic, 7.5-7.05 (m) 3H aromatic, 4.3 (m) 1H, 1.1 (t) ch 3 -ch 2.

hydrochloride

The required amount of 7N hydrochloric acid was added to a solution of 3.25 g of base in 30 ml of absolute alcohol. The solvents were evaporated under reduced pressure at 30 ° C and the residue, after treatment with acetone, yielded 3.32 g of a white crystalline product, mp 264 ° C.

IR (KBr): 3400, 2470, 2320, 1740, 1680 cm ”1 C NMR (D₂O) reference dioxane S ppm 107.426 C = O, -13.712 CH, -82.162 CH 3

Example 2 (a) Preparation of 3- / 2, - (2, - cyano-2,1-ethyl-5 "-chloro-valerovlamino) -ethyl-indole.

Into a 1 liter flask were placed 31 g (0.194 mole) of tryptamine, 500 ml of dichloromethane and 20 g (0.198 mole) of triethylamine. The mixture was cooled to 0 ° C over ice and 40 g (0.192 mol) of 2-cyano-2-ethyl-5-chloro-valeroyl chloride dissolved in 150 ml of methyl dichloride was added. After 2 hours at room temperature, the mixture was washed with water and then with 10% hydrochloric acid and 10% sodium hydroxide. Then it was dried and the solvent evaporated. The product, recrystallized from isopropyl ether / petroleum ether, melted at 120 ° C (yield 40 g).

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14 IR (KBr) 3400 cm - NH NH indole 3340 cm- NH NH amide

2860 cm -1 CN

1660 cm -1 C-N

8

Calcd for c18 H22 N3 Cl2: 0 = 65.0%, H = 6.64%, N = 12.65%

Pound: 0 = 64.03%, H = 6.78%, N = 12.60% (b) Preparation of 1- (2-indol-3M-yl-ethyl) -3-ethyl-3-cyano-7 2-Piperidone Into a 1 liter round bottom flask was placed 22 g (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 mole) of potassium tert-butoxide was added slowly. After 2 hours at room temperature, the mixture was reduced in volume and hydrolyzed. The organic phase was extracted with methylene dichloride, washed with water and dried, then the solvent was evaporated. The desired product, recrystallized from a 1: 1 mixture of ethanol and ether, melted at 180 ° C (yield: 15 g, 80%). Analysis results: IR 3400 cm -1 NH indole

2260 cm "1 CN

1635 cm -1 C-N

II

0

Calcd for ^ 18 ^ 23 ^ 3 ^ C = 73.2%, H = 7.1%, N = 144.2%

Found: C = 72.46%, H = 7.15%, N = 4.01%

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(C) Preparation of 1-ethyl-1-cyano-5,12b-didehydroindolo (2,5-a) -auinolizidinium orochlorate In a 1 liter flask, 50 g (0.169 mol) of the product of step ( b) and 700 ml of phosphoryl chloride. After 20 hours of refluxing, 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 collected with 300 ml of methylene dichloride and cooled over ice, then 300 ml of a 1 molar solution of lithium perchlorate was added with vigorous stirring. A yellow precipitate formed which, after recrystallization from methanol, melted at 260 ° C (yield 44 g, 70%). Analysis results: IR 3400 cm -1 NH indole

2260 cm -1 C = N

1620 cm -1 C = N + (d) Preparation of 1-ethyl-1-cyano-indole (2,3-a) -quinolizidine (I2b-H. 1-CLE-trans isomer) In a 1 One liter round bottom flask was charged with 200 ml of methanol, 100 ml of methylene dichloride and 13.5 g (0.036 mol) of the perchlorate product of step (c). The flask was cooled to about 5 ° C and 5 g of sodium borohydrate was 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 evaporation of the solvent, 8 g of yellow crystals were obtained, which after crystallization from isopropyl ether melted at 160 ° C (yield: 80%). Analysis results:

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16 IR 3420 cm "1 ^ 3440 cm" 1 ^ 2760 cm "1 ^ NH and Bohlmann band 2800 cm" 1)

2250 cm "1 CN

NMR (dimethylsulfoxide dg, 80 MHz) 0.86 S 3H (t) (CH 3) 3.77 S 1 H (s) (H on Cga) 9.66 δ 1H (s) (NH)

Calculated for C = 77.7%, H = 7.2%, N = 15.2% O = 77.55%, H = 7.32%, N = 15.10% (e) Preparation of 1-ethyl -1-cyano-indolo (2,3-a) quinolizidine (l2b-H, l-C2Hc cis isomer) Into a 1 liter flask was placed 19 g of the perchlorate product from step (c), 300 ml of 95% ethanol and 40 g of zinc powder. 100 ml of concentrated hydrochloric acid was added to an ampoule and slight reflux was observed during the addition. The mixture was allowed to stand at room temperature for 10 hours, then concentrated, washed with water and extracted with methylene chloride. It was made basic with sodium hydroxide and filtered through Cel i tea®. After decanting, drying and evaporation of the solvents, 6 g of an ether-insoluble product were obtained, m.p. 250 ° C. Analysis results in IR 3410 cm -1 (NH) 2260 cm -1 (CN)

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17

Calculated for C C HHp-, N ^. 1 / 4HpO: 0 = 76.5%, H = 7.60%, N = 144.85% 0 = 76.59%, H = 7.80%, N = 144.55%

The ether extracts were concentrated to give 4 g (total yield 71.5%) of the c1 isomer of the same product as in step (d) above. NMR (dimethylsulfoxide d6, 80 MHz) 1.05 S 3 H (t) (CH 3) 3.45 S 1 H (s) (H on C 9a) 10.32 S 1 H (s) (NH) (f) Ethyl 1-aminomethyl-indolo (2-, 3-a) quinolizidine (1,2b-H, 1-CpH 4 trans-isomer II) Into a 1 liter flask was placed 4 g of lithium aluminum hydride and 400 ml of dry ether. The flask was cooled to 0-5 ° C and in small portions 8.9 g of the product of step (d) was added. After standing for 1 hour at room temperature, 60 ml of dry tetrahydrofuran was added and the mixture was heated under reflux for 2 hours. After cooling, 40 ml of water and then 200 ml of methylene dichloride were added dropwise, and the mixture was stirred for 15 minutes. Filtration over CelitiP, drying and concentration of the filtrate gave 7.2 g of white crystals which, after recrystallization from ether, melted at 175 ° C (yield: 80%). Analysis results: IR 3280, 3190 cm -1 NH 3333 cm 1 NH indole CN band at approx. 2250 cm ”1 was missing

Calculated for C- HH ^New O = 76.4%, H = 8.85%, N = 144.8%

Found: C = 75r, 85%, H = 8.90%, N = 15.52%

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(G) Preparation of 1-ethyl-1-aminomethyl-indolo (2,3-a) quinolizidine (12b-H, 1-CgH 2 -cis isomer i) 3.4 g of lithium aluminum hydride, 200 ml of ether and 100 ml of tetrahydrofuran was transferred to a 500 ml flask and, under cooling over ice, 6.9 g of the cis isomer of step (e) was added in small portions. After standing for 15 hours at room temperature, the product was isolated as indicated in step (f). Recrystallization from 1: 1 diethyl ether / petroleum ether gave 5 g of a product, mp 42 ° C (yield 71%). Analysis:

Calculated for 0 = 76.4%, H = 8.85%, N = 14.8%

Found: 0-76.25%, H = 8.61%, N = 144.43%

EXAMPLE 3 1-Ethoxycarbonylaminomethyl-1-ethyl-indolo (2,3-a) quinolizidine hydrochloride (I2b-H, 1-O-trans-isomer II) - R

^ CH2 L

c2h5o.co.nh ^

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

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After standing at ambient temperature for 3 hours, the product was extracted with dichloromethane and 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

IR 3210 cm -1 amide NH

3400 cm -1 NH indole

2760 and 2800 cm "1 Bohlmann band 1690 cm" 1 carbamate C = 0.

Microanalysis results:

Calculated for C ^H ^N₂: 0 = 71.0%, H = 8.17%, N = 11.8%

Found: 0 = 70.94%, H = 8, 16%, N = 11, 54%

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

Weight: 2 g Yield: 90% Melting point: 260 ° C.

Example 4 1- (3 *, 4 ', 5' - trimethoxybenzoylaminomethyl) -1-ethylindolo (2,3-a) quinolizidine hydrochloride (I2b-H, 1-Ctrans isomer II)

_R / N

H + .MCI

CH3 ° / 1

\ - \ H

CK30- / c0-NH-CH / -CH3 °

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In a 250 ml three-necked flask equipped with a stirrer, humidifier of CaCl 2, thermometer and separatory funnel were placed 2.85 g of the trans product of Example 2 (f), 1.1 g of triethylamine and 50 ml of dichloromethane. The mixture was stirred and cooled to 0.2 ° C. At this temperature, 2.31 g of 3,4,5-trimethoxybenzoyl chloride was slowly added in 15 ml of dichloromethane. The addition took place over a period of 15-20 minutes, after which the reaction mixture was stirred for 1 hour at 0 ° C and then for 15 hours at ambient temperature. The reaction mixture was washed several times with water, with 1096 aqueous sodium hydroxide and again with water. Then it was dried over sodium sulfate and concentrated to a non-crystalline meringue structure melting about 100 ° C.

TLC; 90/10 8/10

IR 3230 cm -1 NH

3190 cm ”1 NH

2750 and 2800 cm "1 Bohlmann band 1640 cm” 1 C = 0 amide dosing of base with HCl ^: 97%.

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 salt crystallized in the heat and was filtered off while warm. It was washed with ethanol to give 4.5 g (88% yield) of the product.

TLC: 90/10 8/10

Melting point: 210 ° bound to the plate hydrochloride dosing: 100% (1 function).

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21

Microanalysis yielded the following results:

Calculated for C ^HCl: 0 = 65.45%, H = 7.00%, N = 8.18% 0 = 64.34%, H = 7.17%, N = 8.1% Found: C = 64.15%, H = 7, 16%, N = 7.96%.

Example 5

1- (N '/ diethylamino ethyl7-N-ureidornethyl) -1-ethyl-indolo (2,3-a) quinolizidine (I2h-H, 1-02 ^ trans isomer II

ΓΊγγΤί

vVyN

Å (C2H5) 2N “CH2CH2-NH-CONHCHg First, the corresponding 1-phenoxy-carbonylaminomethyl-1-ethyl derivative was prepared. 7 g of the trans compound II of Example 2 (f) and 100 ml of tetrahydrofuran were placed in a three-necked 500 ml flask equipped with a stirrer and two separating funnels. The flask was cooled to between 0 ° C and 5 ° C, and at this temperature, 4.25 g of phenyl chloroformate in 50 ml of tetrahydrofuran and 2.9 g of sodium carbonate in 50 ml of water were simultaneously added. The additions occurred at such rates that a pH of 6-7 could be maintained. The flask was then allowed to reach ambient temperature and stirring was continued for 3 hours. The reaction product was extracted with 100 ml of dichloromethane and the extract was washed several times with water, dried over sodium sulfate and concentrated by evaporation. 11 g of an oil was thus obtained.

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22

IH 3270 cm -1 NH

1710 cm -1 C = 0

The 1-ureidomethyl compound was prepared as follows: Into a 500 ml flask with cooling was placed 11 g of the above oil, 3.5 g of dimethylaminoethylamine and 180 ml of methanol. The amount of dimethylaminoethylamine used was 20% excess. The mixture was heated at reflux for 2.5 hours, then the methanol was evaporated. The residue was collected in dichloromethane and washed with 10% aqueous NaOH and then with water. After drying over sodium sulfate, the substance was concentrated to give a yellow crystalline product? this was collected in diethyl ether in two steps and centrifuged. The first step yielded 4.6 g of a crystalline product of m.p. 202 ° C, and the second step yielded 0.8 g of crystalline product, mp 198 ° C. The combined products were then recrystallized from benzene to give 4.65 g of final product.

Melting point: 204 ° C Yield: 45% based on amine (II).

TLC: 90/10 5/10

Dosage of base with HClO ^: 10% (2 functions)

IR 3360 cm -1 NH

3250 cm -1 NH

1620 cm -1 C = 0 urea

Microanalysis yielded the following results:

Calculated for C₂ ^H ^N ^O: 0 = 70.6%, H = 9.17%, N = 16.45%

Found: 0 = 70.58%, H = 9.20:, N = 16.67%.

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23

Example pool 6 '1-pentanoylaminomethyl-1-ethyl-indolo (2,3-a) quinolizidine (I2b-H, 1-02¾ trans-isomer II) fTl

1 I

/ K / CH 3 - (CH 2) 3-CO-NH-CH

Using Hamme reaction conditions as in Example 4, a solution of 5.7 g of the trans compound of Example 2 (f) and 2.1 g of triethylamine in 120 ml of dichloromethane was reacted with a solution of 2.45 g of pentanoyl chloride in 20 ml of dichloromethane. . There was thus obtained 7.8 g of an oil containing a small residue of triethylamine.

From the oil it was possible to obtain crystals of the substance of melting point 110 ° C.

Example 7 1-Ethoxycarbonylaminomethyl-1-ethyl-indolo (2,3-a) -quinolizidine hydrochloride (I2b-H, 1-C

I H

i '1 j jj .2 HC1 viTT | C2H50-C 0-NH-CH 2

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24

The procedure of Example 3 was repeated with the change that the cis product (I) of Example 2 (g) was used instead of the trans product (II) of Example 2 (f). 2.1 g of the free base was obtained (84% yield). Melting point: 210 ° C.

IR 3400 cm -1 indole NH

3210 cm -1 amide NH

2790 and 2810 cm “^ Bohlmann band 1690 cm” · * · carbamate C = 0

Microanalysis yielded the following results:

Calcd for ^ 21 ^ 29 ^ 3 ^ 21 0 = 71.0%, H = 8.17%, N = ll, 82%

Found: 0 = 70.85%, H = 8.22%, N = 111, 94%.

NMR (CDCl 3, internal TMS) 1.1 in (6H, t, CH 2 ethyl and ethyl ester) 1.5 to 3.5 (15H, broad band) 3.9 ε (2H, q, CH 2 O) 5.65 (1H, m, NH-amide) 7.25 S (4H, broad band, aromatic) 7.9 S (1H, s, NH-indole)

The hydrochloride salt was prepared using 4N hydrochloric acid in acetone.

toxicity

Determined LD 50 per us in mice. The compounds of the invention exhibit a toxicity comparable to or less than the toxicity of vincamine. The most toxic compounds of the invention are those mentioned in Examples 2 (f) and 3 (LD 50: 400 mg "kg, vincamine 450

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25 mg / kg). The least toxic compound is that referred to in Example 4. The other compounds exhibit a toxicity which lies between the toxicities of these two groups.

pharmacology

The useful effect of the compounds of the invention has been demonstrated by comparing a representative range of compounds prepared according to the invention with the compound vincamine known from FR patent no. 2 285 877 and with compounds A and B of the formulas

OyQs cua

H and h XJ

NCCH2CH2 k H2NCH2CH2CH2 kT

(A) (B) known from FR Patent No. 2,292,475. The pharmacological tests were carried out as described in the former FR patent using anesthetized dogs treated with 3.5 mg / kg of vincamine or an equivalent thereof. amount of one of the other compounds. Percentage changes in femoral and vertebral blood flow, blood pressure and heart rate were measured. The results are shown in the following table, from which it is clearly seen that the compounds of the invention have remarkable properties in relation to the closely related reference compounds A, B and vincamine.

DK 154430 B

26

Femoral Vertebral 1 blood gene

Blind light flow flow Blood pressure Heart rate pressure frequency

Vincamin - 13.5 SS - 26.6% - 29.2 K - 23.8 ϋ A + 54.1 »+ 56.1% - 42% + 41.8 S! B +301.5% + 1% - 22.6% + 16.3% Γ c____________________________________ ______________________ ϋ Ex. 3 +67% +212.8% - 1.6S + 6.2 (U___________________________________________________________

Ex. 4 + 71.7% +194.8% + 1% +8.4% r-H U— £ g- Ex. 5 + 84.7% +204% + 4.8, ¾ + 9.7 / ¾ 4-1 -------------------------- -------------------------------- i di Ex. 6 + 57.8% +185.5% + 3.4% + 10.1% ----------------------------- ----------------------------- u.in Ex. 7 + 80.1 + 173.3% + 3.6 + 8.3%

Claims (1)

Patent Claims: Analogous Process for Preparation of Indolo (2,3-a) Quinolizidines of General Formulas (I) and (II): CcQ / iV / / \ s' R j R "d)" (Π) wherein R represents -COC 3 H-, -COOH, -CN, an aminomethyl group or a substituted aminomethyl group of the formula R'-Nil-el 2 - / wherein R 'represents alkyl, alkanoyl or alkoxy-carbonyl having up to 5 C , phenyloxycarbonyl, diethylaminoethylaminocarbonyl, trimethyloxybenzoyl or quanidinocarbonyl, or wherein R together with the nitrogen atom of the indole ring represents one of the groups ^ N-CO-NH-Cl 2 and ^ N-CO-, or pharmaceutically acceptable acid addition salts thereof, characterized by condensation 2-aminoethyl-3-indole with 1-chloro-4- (A) -4-chlorocarphonyl-hexane, where A represents -COCK 3 H,. or -CN, the amide obtained rings at the indole nitrogen atom by treatment with a strong base, cycles the compound obtained by treatment with a dehydrating agent and then with a perchlorate salt, hydrogenates the resulting quinolizidinium perchlorate to give a mixture of isomers of the corresponding indole (2,3-a) quinolizidine and separating the isomers, whereupon, if desired, DK 154430 B is desired to subject an obtained compound of formula (I) or (II) wherein R is COCK wherein R is -COOH and, if desired, converts a compound so obtained, wherein R is -COOH, to a compound wherein R together with the nitrogen atom of the indole ring represents -CO-NH-C desirably, a obtained compound of formula (I) or (II) wherein R is -CN undergoes a reduction to obtain a corresponding compound wherein R is -CH 2 -NH 2 followed by condensation of this aminomethylene compound with a suitable the halogenated group to give a compound wherein R is R'-NH-CH 2 -, where R 'is as defined above, and optionally transfer a obtained compound of formula (I) or (II) into a corresponding acid addition salt.