FI64372B - EXTERNAL PROTECTION OF THERAPEUTIC ACID 1-SUBSTITUTE DAMINOMETHYL-1-ETHYL-INDOLO- (2,3-A) -QUINOLIZIDINE - Google Patents

Description

____ Γ-Λ Γο,. KU U LUTU SJ ULKAISU, λ ΎΠ η ^ ^ UTLÄGGNINGSSKRIFT 643/2 • SVgj (4S): L ι. :. l · i, - / (51) Kr.iJt.?int.C!.3 C 07 D 471/14 SUOMI FINLAND (21) P ™ en «'h * kemu' - Pitentansöknlng 783581 (22) Hekemlipilvt - Ansökntngcdag 23 Ij. . 78 (23) ALkupSIvi— Gfltlghetsdag 23.-i.78 (41) Made public - Bliv't ofTentllg 26.05.79

Patent * and Registry Managed Nihanksipanon). monthM ^^ and date. - 29 - 07.83

Patent and registration authorities Ansekan utlagd och ut! .Skrlften pubilcertd (32) (33) (31) Requested privilege — Begird prlorltet 25-11.77

English-English.d (GB) U9201 (71) Societe de Conseils de Recherches et d'Applications Sciennifiques SCRAS, 2Gb, rue du Faubourg Saint-Honore, 75008 Paris, France-France (FR) (72) Andre Buzas, Bievres, France-Frankrike (FR) (71) Leitzinger Oy (5 ^) Method for the preparation of therapeutically active 1-substituted-aminomethyl-1-ethyl-indolo- (2,3-a) -quinolizidines -Förfarande för framställning av therapeutiskt activa 1-substati -tueradamino methyl-1-ethyl-indolo- (2,3-a) -quinolyside

The invention relates to a process for the preparation of therapeutically active 1-substituted-aminomethyl-1-ethyl-indolo- (2,3-a) -quinolizidines of the general formulas (I) and (II)

Coe. cr? ·.

HJ "R'-C-NH-CFL · R'-C-NH-CH2" <1 ^ 11 ^ 10% (I) (II) wherein R 'represents an alkyl group having 1 to 6 carbon atoms, or optionally a phenyl group substituted with one or more alkoxy groups having 1 to 6 carbon atoms, an alkyloxy group having 64 to 372 carbon atoms, a dialkylamino or alkylamino group having 1 to 6 carbon atoms, or to prepare acid addition salts of these compounds.

The compounds of this invention are of particular interest because they are active in the cerebral circulation.

These compounds can be prepared according to the invention by condensing 2-aminoethyl-3-indole and 1-chloro-4-CN-4-chlorocarbonylhexane together to form the corresponding amide, which is subjected to strongly basic conditions to remove hydrogen chloride, whereby the 3-substituent of the indole A piperidine ring is formed around the N atom, this compound is treated with a dihydrating agent followed by a perchlorate salt to form a quinolizidine ring, which quinolizine perchlorate is hydrogenated to the corresponding cis- or trans-1-ethyl-1-cyano-indolo- (2,3-a) -quinolizidine to form a mixture of isomers which is hydrogenated with lithium aluminum hydride to give 1-ethyl-1-aminomethyl-indolo- (2,3-a) quinolizide, which is reacted with a carboxylic acid chloride or amide of formula R'COOH, wherein R 'is as defined above, and thus the mixture obtained is optionally divided into isomers, whereby the compound of formula (T) or (II) obtained is converted, if necessary, into acid addition salts si.

3 6 4 3 7 2

General initial routes 1 (a) CH-CH-NH- _ Λ il JJ + c H - C - (CH) Cl_ »\ IL! r, ^ C0Cl |

A

1 ^ t But O K

jTXq.cioG O

A ^ A-t ^ \ Hj / Pt 1 (d) 1 (d) fX — ϊΓΧ OnC ^ 1

"Ι'Ί; XJ

a k k

OF

OF

4 64372

OcXjX.

ä .L; -O

NC ^ ^ NC

1 (g) l LiAlH4 1 (f) l LiAlH4 o5d, Otxx * 00 h O1 ^ R'OOCl or R'GONH2 ^ R'COCl or R'CCNH.,

oJo OnO

H J H T

R 1 is -C-NH-CH 2 O 2 R 2 -C-NH-CH 2 O 0

Pharmacology (I) is cis-isane (II) is trans-isane

The activity of the compounds according to the invention has been studied in relation to femotal and vertebral flows, arterial pressure and heart rate. The activity was compared with that of vincamine and the compounds described in French Patents 2,285,377 and 2,292,475. In a manner similar to experiments performed on vincamine, the compounds of the invention, and in particular the compounds of Example 2, a) increase femoral flow; the compounds of the French patents have a similar effect but vincamine reduces this effect; b) greatly increase vertebral flow; the compounds of the French patent publication have no or only moderate effect, whereas vincamine reduces this flow; (c) do not significantly affect arterial blood pressure, whereas reference compounds reduce it; / 1 5 64372 d) slightly increase the heart rate, whereas the compounds of the French patent generally increase more and vincamine reduces this factor.

The results show that the compounds of the invention appear to have a very beneficial effect on blood circulation in the brain, which was also confirmed clinically.

Toxicity LD 50 was determined per os in mice. The toxicity of the compounds of the invention is comparable to or lower than that of vincamine. More toxic (LD 50: 400 mg / kg; vincamine 450 mg / kg) are the compounds of Examples 1 (f) and 2; the compounds of Example & are less toxic and the toxicities of the other compounds are in between.

Dosage

The compounds of the invention may be administered i.v. or orally in doses comparable to those of vincamine (dosage units 5-40 mg).

The following examples illustrate the reaction conditions typical of each reaction step.

Example 1 (a) Preparation of 3- [2 "- (2" -cyano-2 "-ethyl-5" -chlorovaleroylamino) ethyl] indole _______ 31 g (0.194 moles) of tryptamine, 500 ml of dichloromethane and 20 g ( 0.198 moles) of triethylamine was placed in a 1 liter vessel.

The mixture was cooled to 0 ° C with ice, and then 40 g (0.192 mol) of 2-cyano-2-ethyl-5-chlorovaloryl chloride dissolved in 150 ml of methyl dichloride was added. The mixture was kept at room temperature for 2 hours, then washed with water, 10% hydrochloric acid and 10% sodium hydroxide. The mixture was then dried and the solvent was removed / .....

6 64372 by evaporation. The melting point of the iso-ethyl ether / petroleum ether recycle was 120 ° C (yield 40 g). The results of the analysis were as follows: (KBr) 3400 cm -1 NH indole 3340 cm -1 NM amide

2860 cm'1 CN

1660 cm-1 C-M

B

0

Calculated for C 18 H 22 N 3 Cl 10: Cr 65.0%; H = 6.64% No. 12.65%

Result: C = 6 4.0 3; Hr 6.78%; N = 12.60 S

(b) Preparation of 1 - [(2'-indol-3 "yl-ethyl) -3-ethyl-3-sysno [2-piperidinone] 22 g (0.0665 moles) of the product of the previous step (a), 200 ml of letrahydrofuran and 300 ml of t-butanol were placed in a 1 liter round-bottomed flask, the mixture was cooled to 0 ° C with ice, and then 8.5 g (0.076 mol) of potassium tert-butoxide a was added in small portions. The organic phase was extracted with methylene chloride 11a, washed with water, dried and the solvent removed by evaporation, the melting point of the product recrystallized from a 50/50 mixture of ethanol and ether was 180 ° C (yield 15 g, 80%). The analysis results were as follows: IR 3400 cm-1 NH indole

2260 cm -1 CN

16 5 5 cm-1 Π -N

u

U

calculated for C18H2N3O: Γ = 73.2%; Hr 7.1 S; N = 14.2%

Tujps: C r 72.46? I; Hr 7.15 »; Nsl4,02 »

II

Preparation of 50 g (0.169 moles) of step (b) was added to a 1 liter flask with stirring, 7 64372 ie)] -ethyl i-cyano-5,12b-didehydro-indolo- (2,3-a) -quinolizidinium perchlorate. product and 700 ml f'os foryy 1 i kl or idi a. The reaction mixture was heated at reflux for 20 hours, after which it was already extracted 2 or 3 times with 500 ml of methylene chloride, which was later removed by evaporation. The product was taken up in 300 ml of methylene chloride and cooled in ice, after which 300 ml of a solution of lithium percorate (1 mol) were added with vigorous stirring. A yellow precipitate was formed which had a melting point of 260 ° C after recrystallization from methanol (yields 44 g, 70%). The results of the analysis were as follows: R 3400 cm-1 NH indole

2260 cm-1 C N

Preparation of 1620 cm-1 C = (d) 1-ethyl-1-cyano-indolo- (2,3-a) -quinolithicidine (12-H; 1-CpH 2 trans isomer) ml of methylene dichloride and 13.5 g (0.036 moles) of the product from the previous step (c) were placed in a 1 liter round bottom flask. The wood was cooled to about 5 ° C and 5 g of sodium borohydride 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 removal of the solvent, 8 g of yellow crystals with a melting point of 160 DEG C. after recovery of the isopropyl ether were obtained (yield 80%). The analysis results were as follows: IR 3420 cm-1 34 40 cm 1) 2760 cm'1) NH Rohlm3nn peaks 2800 cm-1) 2250 cm "'ΓΝ 64372 \' MR (di met yy 1 i su .1 f nks i di, 80 M

Calculated, C, H 2 O 3: C = 77.7 S; H = 7.2 »; N = 15.2% ru] os. Γ = 77.59%; Hr 7.32%; Preparation of No. 11,10 (i) 1-ethyl-1-cyano-indo-1- (2,3-a) -quinolizidine (12b-H; cis-isomer) 19 g of the previous step (c) perchlorate product, 300 ml of 95% ethyl ethanol and 40 g of zinc powder were placed in a 1 liter flask. 100 ml of concentrated hydrochloric acid was added in an ampoule. During the addition of acid, a slight regression was observed.

The mixture was allowed to stand at room temperature for 10 hours. It was then concentrated, washed with water and extracted with ethylene chloride. The mixture was made alkaline with sodium hydroxide and filtered through Celite (trademark). After decantation, drying and evaporation of the solvents, 6 g of an ether-insoluble product with a melting point of 250 [deg.] C. were obtained. The results of the analysis were as follows: IR 3410 cm -1 (MH) 2260 cm -1 (CM) calculated: c 18 H 21 N 3 * 1 M 2 O 2: c- 76.5%; H = 7.60%; Mr 14.85% T u ^ os: C r 7 6.5 9%; H = 7.80%; N = 14.55 S.

The extracts were concentrated to give 4 g (total yield 71.5%) of the same product as in step (d) of the 5-isomer.

MMR (dimethylsulfoxide d, 80 MH 2) 1.05 δ 3H (t) (CH) 3.45 δ 1H (s) (H in C 6) 10.32 δ 1H (s) (NH) δ 64372 (f) 1-ethyl-1-aminomet. yl-indolo- (2,3-a) -kino !. preparation of itsidine (i 2 b - H ·, i - C ^ H trans isomer II) 4 (lithium a lumi inhydride and 40 ml of dry ether were placed in a J liter flask. The flask was cooled to 0-5 ° C and its 8.9 g of the product of the previous step (d) were then added in small amounts, the flask was allowed to stand for 1 hour at room temperature, then 60 ml of dry tetrahydrofuran was added, the solution was heated at reflux for 2 hours, and after cooling, 40 ml of water were added dropwise. After stirring through Celite, drying and concentrating the filtrate, 7.2 g / l of initial crystals with a melting point of 17 DEG C. after re-crystallization from ether were obtained (yield 80%).

The analysis results were as follows: 1H 3280, 3190 cm-1 NH ^ 3330 cm ^ NH indole CN .: no peak at about 2250 cm *

Calculated, C = 76.4 H = 8.85 S; N.- 1.48%

Result: C = 75.8%: H = 8.90%; N = 15.52¾.

(d) Preparation of 1-ethyl-1-aminomethyl-indolo- (2,3-a) -quinolizidine (12b-H; 1-C 2 H 2 cis-isomer I) 3.4 g of lithium lumine yridi ä, 200 mj ether and J nt) m! tetrahydrofuran in a 500 m 1 flask. Under ice-cooling, 6.9 g of the cis-innmeer of step (c) were added in small amounts. The mixture was allowed to stand for 15 hours at room temperature, after which the product was isolated as in the previous step (f). Recrystallization from diethyl ether / Petro 1 ether 50 / in gave 5 g of product with a melting point of 52 ° C (yield 71%},

Calculated, λ max 25 25: 3: 76.4% H- 8.85% N = 14.8% Result: Cr 76.25%; Hr 8.16%: N-14.43¾ 10 64372

Example 2 i - et, oxycarbamoyl larninonet yy Jyl-ethyl-indolio- (2,3-a) -quinolite - <- '1 i rt i-hydrochloride (12b-H; 1C ^ H,. Tran s -isomer II) rrt ^ 1 -HCl CH2 / 2

C2H O.CO.NH

To a solution cooled to 0 ° C containing 2 g (0.00703 moles) of the trans product of Example 1 (f) II in 20 ml of dimethoxyethane was added alternately and so that the pH remained basic: 800 mg of ethyl acetate. chloro rma a 11 ia as a solution in 3 Oil d dimethoxyethane;

JS

730 mg of sodium carbonate as a solution in 5 ml of water.

The reaction mixture was allowed to stand for 3 hours at ambient temperature, after which the product was extracted with dichloromethane, the dichloromethane extract was washed with water, dried and evaporated to dryness.

The residue was recrystallized from ethanol.

Weight: 2g Yield: 80% S p. : 140 ° C

3210 cm -1 amide NH

3400 cm-1 indole NH

2760 and 2800 cm "1 Bohlnann peaks 1690 cm" 1 carbamate ti Γ = 0.

The results of the microanalysis were:

calculated, i: 21H29N3 ° ?: Γ = 7 · 1Π: H = 8.17 Nr U * H

'out: Cr 70.94 58 Hr 8.16%; Mr 11.34¾ 11 64372

The hydrochloride salt was prepared by adding 2 .mu.l of product. hydrochloric acid 20 in them ethanol.

Weight; 2 q S a an to: 90% M.p .: 260 ^ 0.

Example 3 1- (3 ', 4', 5'-Trimethoxybenzoylaminomethyl) -1-ethyl-indolo- (2,3-a) -quinolizidine dihydrochloride (12b-H; 1C, trans trans isomer ( II) ----------------- 1 .HCl

2.25 g of the trans-product II of Example 1 (f), 1.1 g of triethylamine and 50 ml of dichloromethane were placed in a 250 ml vol. was equipped with a stirrer, CaCl 2 tube 11a, a thermometer and a dropping funnel.

The mixture was stirred and cooled to 0.2 ° C. At this temperature, 2.31 g of 3,4,5-trimethoxybenzoyl oride in 15 ml of dichloromethane were slowly added. The addition was carried out for 15 to 20 minutes, after which the mixture was stirred for 1 hour at 0 ° C and then for 15 hours at ambient temperature.

The reaction mixture was then washed several times with water, then with 10% aqueous sodium hydroxide 11a and again with water. The mixture was dried over sodium sulfate and concentrated to give crystals; k s i. jo 1 ·. a was ma r en k i ma i n en structure 12 64372. i o having a melting point of about 100 C.

CCM: 90/10 8/10

IR 3230 cm -1 MH

3190 cm -1 MH

2730 and 2800 cm 'Bohl man n peaks 16 * 0 cm -1' C = 0 amide 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 hydrochloride was crystallized hot, the salt was filtered hot and washed with ethanol to give 4.3 g (yield 88%) of product.

CCM: 90/10 8/10

Sp. : 210 ° C bound amount of hydrochloride on the plate: 100% (1 function).

Microanalysis gave: calculated, C 28 H 35 N 3 O α-HCl: 0 = 63.0 S; H = 7.00 S; Mr 8.18%

Result: Cr 6 *, 34 S; H = 7.17 δ; M- 8.11%

C = 64.13 S; H = 7.16 S; Mr 7.96 S

Example 4 i_ (N '(diethylaminoethyl) -M-ureidomethyl) -1-ethylindolo- (2,3-a) -quinolizidine (12b-H; Ι-Ο ,, Η ,.t. an s-iso me different II) I f

B

(C2H5} 2NN * ~ i ^ H2CH2 "'lslll ~ C0 ^ HCH2 *" li 64372

First, the corresponding 1-phenoxycarbonyl 1-ethylmethyl-1-ethyl derivative was selected by adding 7 g of the trans product of Example 1 (f) and ICO ml of tetrahydrofuran. and 500 ml of a 1 ml tube equipped with a stirrer and two dropping soups.

Pij Ilo was cooled to 0-5 ° 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 added simultaneously. The addition rates were such that the pH was maintained between 6 and 7. The vessel was then allowed to warm to 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, the sodium sulfate was filtered off and the concentrate was evaporated.

11 g of an oily product were obtained.

IR 3270 cm-1 NH

1710 cm-1 C = O 1-ureido methyl product was prepared as follows: 11 g of the above oil, 3.5 g of dimethylaminoethylamine and 180 ml of methanol were placed in a 500 ml flask equipped with a condenser. The amount of dimethylaminoethylamine filled corresponded to an excess of 20? Ό. The mixture was heated at reflux for 2.5 hours and then the methanol was removed by evaporation. The residue was taken up in dichloromethane and washed with 10% aqueous sodium hydroxide followed by water. After drying over sodium sulfate, the mixture was concentrated to give a yellowish crystalline product. The product was taken up in two steps in diethyl ether and centrifuged. In the first step, 4.6 g of a crystalline product with a melting point of 202 ° C was obtained, and in the second step, 0.8 g of a crystalline product with a melting point of 198 ° C was obtained. The combined products were then recrystallized from benzene to give 4.65 g of final product.

5p .: 204of Yield: 45 based on the amine T1.

0: 90/10 5 / I h

Amount of base with HC ΙΠ: 100% (2 functions).

14 64372 'R: 3360 cd "1 \ Ή

3230 cm -1

162Q cm x C r 0 urea.

Microanalysis gave the following results: calculated. C Π N 0: C = 70.6 S; H = 9.17 No. 16.45% 'out: Or 7 0.5 8? Ό; Hr 9.20%; N = 16.67% Example 5 1-Pentanoylaminomethyl-1-ethyl-indolo- (2,3-a) -quinolizidine (12b-H: trans-isomer II;

»· M

Cl1- (CH 2) 2 -CO-NH-CH 2 Using the reaction conditions and methods of Example 5, a solution of 5.7 g of the trans product of Example 1 (f) II and 2.1 g of triethylamine in 120 ml was reacted: in dichloromethane, and a solution of 2.45 g of pentanoyl chloride in 20 ml of dichloromethane.

This gave 7.8 g of an oil containing a little residual f nrt vy 1 inmin.

f R r 3180-3380 cm-1 MH

.16 3Π - 1 6 50 cm-1 C r 0 ij 1 i y s t a n 1 s possible crystals of the product, melting point! 10 ° C.

Claims (1)

64372 A process for the preparation of therapeutically active 1-substituted-aminomethyl-1-ethyl-indolo- (2,3-a) -quinolizidines of the general formulas (I) and (II) Coo. coa H Ϊ 1 1 R'-O-NH-CH, I R'-C-NH-CH '' • i ^ ^ ri Z S. O ox (I) (II) wherein R * represents an alkyl group having 1 -6 carbon atoms, or a phenyl group optionally substituted by one or more alkoxy groups having 1 to 6 carbon atoms, an alkyloxy group having 1 to 6 carbon atoms, a dialkylamino or alkylamino group having 1 to 6 carbon atoms, or acid addition salts of these compounds, characterized in that 2-Aminoethyl-3-indole and 1-chloro-4-CN-4-chlorocarbonylhexane are condensed together to form the corresponding amide, which is subjected to strongly basic conditions to remove hydrogen chloride to form a piperidine ring around the N atom of the 3-substituent of indole. this compound is treated with a dihydrating agent followed by a perchlorate salt to form a quinolizidine ring, which quinolizine perchlorate is hydrogenated to form the corresponding cis- or trans-1-ethyl-1-cyano-indolo- (2,3-a) -quinolizidine isomer mixture. hydrogenated with lithium aluminum hydride to give 1-ethyl-1-aminomethyl-indolo- (2,3-a) -quinolizide which is reacted with a carboxylic acid chloride or amide of formula R'COOH, wherein R 'is as defined above, and thus obtained the mixture is optionally divided into isomers, whereby the compound of formula (I) or (II) obtained is converted, if necessary, into an acid addition salt. 64372 16 For the preparation of a therapeutically active 1-substituted-aminomethyl: i-1-ethyl-indolo- (2,3-a) -quinolizidine with a formulation of (I) and (II) Oc. HJHIJ R'-C-NH-CH2 R'-c-NH-ay ' an alkoxy group having 1 to 6 colatomers substituted with a phenyl group, and an alkyloxy group having 1 to 6 colatomers, and a dialkylamino or alkylamino group having 1 to 6 colatomers, and a derivative of the cyanide, -4-CN-4-chlorocarbonylhexane is a condenser having the same image as the parent compound in which the starting material is chlorinated, the color being indolent 3-substituents of the N-atom in which the piperidine is used to give for the preparation of quinolizidine rings, which are quinolizidine perchlorate hydrates for the preparation of cis-ethyl-1-ethyl-1-cyano-indolo- (2,3-a) -quinolizidine isomers, with hydrolyses of lithium aluminum hydride or 1-ethyl- 1-Aminomethyl-indolo- (2,3-a) -quinolizide, with carboxylic acid In the case of formula R'COOH, R 'is defined, syrachloride or amide, and in which case it is possible to carry out the mixture of isomers, the colors of which may be used in the form of formula (I) or (II) to give a solution. Il