CA1100959A - Indolo (2,3-a) quinolizidines, preparation and therapeutic use - Google Patents
Indolo (2,3-a) quinolizidines, preparation and therapeutic useInfo
- Publication number
- CA1100959A CA1100959A CA316,809A CA316809A CA1100959A CA 1100959 A CA1100959 A CA 1100959A CA 316809 A CA316809 A CA 316809A CA 1100959 A CA1100959 A CA 1100959A
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- Prior art keywords
- indolo
- ethyl
- product
- quinolizidine
- preparation
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- Indole Compounds (AREA)
Abstract
A B S T R A C T
The invention relates to a multistep preparation process of new indolo(2,3-a)quinolizidines of the general formulae (I) and (II):
The invention relates to a multistep preparation process of new indolo(2,3-a)quinolizidines of the general formulae (I) and (II):
Description
The invention relates to indolo(2,3~a)quinolizidines, to methods For their preparation and to therapeutic compo-sitions containing them.
The new indolo(2,3-a)quinolizidines according to the invention have the general formulae (I) and (II);
(I) (II) wherein R stands for -COOC2H5, - COOH, - CN, a primary or ~
secondary methylenamino group, a methylenamido group, or : :
wherein R, together with the ring nitrogen of the indolo ring, -represents one of the groupings N-CO-NH-CH2 or N-CO-; the latter derivatives are D homo azaeburnamonines or D ebur-namonines. More specifically R may be, for example, a methyl-enaminocarbalkoxy, a methylenaminoaryloxycarbonyl, a methylen-aminoalkanoyl, a methylenaminoalkyl or a substituted methylen-ureido group.
Preferred identities of R according to this invention ~ ~
are COOH, NH2, methylenaminocarbethoxy, methylenamino (3,4,5- ::
trimethoxy) benzoyl, methylenaminophenoxycarbonyl, methylen-ureidodiethylaminoethyl, methylenaminopentanoyl, methylenamino-pentyl and amidopiperonyl.
The invention also provides acid addition salts of the above compounds, when applicable.
The compounds according to this invention are especially interesting for their activity in the field of blood circulation in the brain. The invention accordingly provides therapeutic compositions comprising one or more such compounds 1 _ ~
5 ~
in admixture with a therapeutically acceptable diluent or carrler.
The above compounds may be prepared according to the invention by condensing together 2-aminoethyl-3-indole and l-chloro-4-(A)-4-chlorocarbonyl-hexane, wherein A stands for -COnC2H5 or -CN, to form the corresponding amide; subjecting the amide to strongly basic conditions to eliminate HCl and effect ring formation at the nitrogen atom on the 3-indole substituent; effecting quinolizidine ring formation of the product by treating it with a dehydrating agent followed by a perchlorate salt; hydrogenating the resulting quinolizidinium perchlorate to produce the corresponding indolo(2,3-a)-quinolizidine isomer mixture and separating the isomers, the corresponding reaction schemes are represented hereafter under the heading "Initial Common Routes" and lead only to the compounds wherein R is -COOC2H5 or -CN (2 isomer forms in each case, i.e., ~ compounds).
All the other derivatives derive from these compounds - either directly, e.g. the acids, from the esters, by saponi-fication (see the schemes "Specific Routes" A = -COOC2H5), or the methylenamino from the nitriles, by reduction with lithium aluminium hydride (see same schemes when A = -CN), - or from the acids or methylamino derivatives, by well known reactions.
In the following schemes:
- I is a reference to cis-isomers - II a reference to trans-isomers - 1 (a) to 1 (i), references of the various steps of example 1 wherein the starting material is the 4-ethoxycarbonyl deriva-tive and the fir,al products, acids or derivatives thereof and- 2 (a) to 2 (g), references to the various steps of example 2 11~0959 wherein the starting material is the 4-cyano derivative and the final products methylenamino compounds or derivatives thereof.
, :
'~
ll~U95~ `
Initial ColTunon routes 1 (a) or 2 (a) ~CH2CH2NH2 A ~/
~\N~ +C2HS C (C 2 3 ~\
1 (b~
or t But O K
The new indolo(2,3-a)quinolizidines according to the invention have the general formulae (I) and (II);
(I) (II) wherein R stands for -COOC2H5, - COOH, - CN, a primary or ~
secondary methylenamino group, a methylenamido group, or : :
wherein R, together with the ring nitrogen of the indolo ring, -represents one of the groupings N-CO-NH-CH2 or N-CO-; the latter derivatives are D homo azaeburnamonines or D ebur-namonines. More specifically R may be, for example, a methyl-enaminocarbalkoxy, a methylenaminoaryloxycarbonyl, a methylen-aminoalkanoyl, a methylenaminoalkyl or a substituted methylen-ureido group.
Preferred identities of R according to this invention ~ ~
are COOH, NH2, methylenaminocarbethoxy, methylenamino (3,4,5- ::
trimethoxy) benzoyl, methylenaminophenoxycarbonyl, methylen-ureidodiethylaminoethyl, methylenaminopentanoyl, methylenamino-pentyl and amidopiperonyl.
The invention also provides acid addition salts of the above compounds, when applicable.
The compounds according to this invention are especially interesting for their activity in the field of blood circulation in the brain. The invention accordingly provides therapeutic compositions comprising one or more such compounds 1 _ ~
5 ~
in admixture with a therapeutically acceptable diluent or carrler.
The above compounds may be prepared according to the invention by condensing together 2-aminoethyl-3-indole and l-chloro-4-(A)-4-chlorocarbonyl-hexane, wherein A stands for -COnC2H5 or -CN, to form the corresponding amide; subjecting the amide to strongly basic conditions to eliminate HCl and effect ring formation at the nitrogen atom on the 3-indole substituent; effecting quinolizidine ring formation of the product by treating it with a dehydrating agent followed by a perchlorate salt; hydrogenating the resulting quinolizidinium perchlorate to produce the corresponding indolo(2,3-a)-quinolizidine isomer mixture and separating the isomers, the corresponding reaction schemes are represented hereafter under the heading "Initial Common Routes" and lead only to the compounds wherein R is -COOC2H5 or -CN (2 isomer forms in each case, i.e., ~ compounds).
All the other derivatives derive from these compounds - either directly, e.g. the acids, from the esters, by saponi-fication (see the schemes "Specific Routes" A = -COOC2H5), or the methylenamino from the nitriles, by reduction with lithium aluminium hydride (see same schemes when A = -CN), - or from the acids or methylamino derivatives, by well known reactions.
In the following schemes:
- I is a reference to cis-isomers - II a reference to trans-isomers - 1 (a) to 1 (i), references of the various steps of example 1 wherein the starting material is the 4-ethoxycarbonyl deriva-tive and the fir,al products, acids or derivatives thereof and- 2 (a) to 2 (g), references to the various steps of example 2 11~0959 wherein the starting material is the 4-cyano derivative and the final products methylenamino compounds or derivatives thereof.
, :
'~
ll~U95~ `
Initial ColTunon routes 1 (a) or 2 (a) ~CH2CH2NH2 A ~/
~\N~ +C2HS C (C 2 3 ~\
1 (b~
or t But O K
2 tb) ~ / .~ ~
1 (c) or 2 (c) \>\ H2/Pt 1 (d)/ \ 1 (d) 2 (d)k~ 2 (e) r,~
Q~
Specific routes A= -COOC2H5 C2~15-l(h) KOH l(e) KOH
~ 3 ~
HO-l~J HO-~
(I~ - (II) A = -CN
.
I!C ,~ NC ~ ~:
~(g) " 2(f) ¦ L,AlH4 ~ LiAlH4 (I) ~II) .
. .
~l~U9S9 ..
The compounds according to the invention in which R
is a secondary amino or amido yroup, or E homo azaeburnamonines according to the invention, may be prepared from the above ;
products in which R is OH or NH2 by methods known per se for the interconversion of substituent groups.
Typical reaction conditions for each rea~tion step sequence are as illustrated in the Following Examples. Other conditions for effecting the same conversions will be readily apparent to those skilled in the art.
The invention is illustrated by the following Examples.
(a) Preparation of 3~ (2"-ethoxycarbonyl-2"-ethyl-5"-chloro-valeroylamino)ethy ~-indole To a suspension of 2.5 9 (0.0184 mole~ of 3-(2'-aminoethyl)indole (tryptamine) in 50 ml dry chloroform con-taining 2 9 (0.02 mole) of triethylamine cooled in an ice bath there were added drop by drop 4.7 g (0.0184 mole~ of 2-ethyl-2-ethoxycarbonyl-5-chloro-valeroyl chloride. After stirring for 2 hours at room temperature, the solution was washed with dilute aqueous hydrochloric acid. After drying the organic ~
phase and evaporating it under reduced pressure there was ~ ~;
obtained 6.6 g of the above produc~ which, recrystallized from petroleum ether/isopropyl ether melted at 76C and had a yield of 95%. The results of analysis were as follows:
IR (KBr~ 3350 and 3300 cm NH
1735 cm~l CO ester 1640 cm 1 CO amide Calculated for C20H27N203Cl : C=63.40%; H=7.18%i N=7.40%
Found : C=63.39%; H=7.05%; N=7.51%.
- . ~ ,. . .. . . .
s9 (b) Preparation of 1- ~2'-indol-3"-ylethyl~-3-ethyl-3-ethoxycarbony ~-2-piperidone To a suspension of 34.4 9 (0.0~08 mole~ of the above compound in 150 ml of a 1:1 mixture of dry benzene and hèxa-methylphosphoric/triamide cooled in an ice bath there was added, in small quantities and in a nitrogen atmosphere, 10.6 9 (0.0946 mole) of potassium t-butoxide. After stirr;ng for 8 hours at room temperature, the solution was poured into a cold dilute aqueous solution of hydrochloric acid. The aqueous phase, after decantation, was extracted two times with benzene.
The resulting organic phase was washed twice with water and dried. After evaporating under reduced pressure there was obtained 30 9 of the desired product which, recrystallized from isopropyl ether, melted at 84F and had a yield of 96%, the results of analysis were as follows:
IR (KBr) 3250 cm 1 NH indole 1730 cm~l C0 ester 1620 cm 1 C0 amide r C20H26N203 : C=70.15%, H-7 65%; N 8 1 Found : C=6g.97%, H-7.65%; N~8.20%.
(c) Preparation of l-ethyl-l-ethoxycarbonyl-5,12b-didehydro-indolo(2,3-a)quinolizidinium perchlorate Into a solution of 30 9 (Q.0876 mole) of the above compound in 480 ml of dry toluene there were poured 240 ml of distilled phosphoryl chloride. This solution was heated under reflux for 9 hours with a moisture guard. Excess phosphoryl chloride and toluene were then removed by evaporation under reduced pressure. The residue was taken up with methylene dichloride and the solution was washed with water, dried over sodium sulphate and evaporated under reduced pressure. A part of the solution was agitated with a lM aqueous solution of lithium perchlorate. After decanting the aqueous phase, washing with water, drying over sodium sulphate and evaporating the solvent under reduced pressure there was obtained a yellow powder which was recrystallized from ethanol. The resulting product melted at 191F. The results of analysis were as follows:
IR (KBr) 3340 cm 1 NH
17~0 cm~l CO ester 1625 cm 1 C-N~ ~3 (d) Preparation of l-ethyl-l-ethoxycarbonyl-indolo(2,3-a)-quinolizidine (12b-H; l-C2H5 trans and cis isomer) , A solution of 6.25 g (0.0147 mole) of the above per-chlorate salt in 80 mls ethanol was hydrogenated for 12 hours in the presence of 0.3 9 of platinum oxide. After filtration, the ethanol was evaporated under reduced pressure and the residue taken up with methylene dichloride and agitated with 5%
sodium hydroxide. The organic phase was decanted and washed with distilled water. ;~
On chromatography of a solution of the product with ;
methylene dichloride over 100 grams of silica, and elution with the same solvent, there ~as separated 1.12 g of a first fraction (yield 25%) which was the 12b-H, l-C2H~ trans isomer of the product and melted at 112C (recrystallized from petroleum ether/isopropyl ether). The results of analysis were as follows:
IR (KBr) 3410 cm 1 NH
2770, 2805, 2825 cm 1 Bohlmann bands 1710 cm~l CO ester NMR (CDC13 90 MHz) :
among other signals : 8.5 ~ OH (s) (NH indole) 4.35~ 2H (q) (O-CH2-CH3)
1 (c) or 2 (c) \>\ H2/Pt 1 (d)/ \ 1 (d) 2 (d)k~ 2 (e) r,~
Q~
Specific routes A= -COOC2H5 C2~15-l(h) KOH l(e) KOH
~ 3 ~
HO-l~J HO-~
(I~ - (II) A = -CN
.
I!C ,~ NC ~ ~:
~(g) " 2(f) ¦ L,AlH4 ~ LiAlH4 (I) ~II) .
. .
~l~U9S9 ..
The compounds according to the invention in which R
is a secondary amino or amido yroup, or E homo azaeburnamonines according to the invention, may be prepared from the above ;
products in which R is OH or NH2 by methods known per se for the interconversion of substituent groups.
Typical reaction conditions for each rea~tion step sequence are as illustrated in the Following Examples. Other conditions for effecting the same conversions will be readily apparent to those skilled in the art.
The invention is illustrated by the following Examples.
(a) Preparation of 3~ (2"-ethoxycarbonyl-2"-ethyl-5"-chloro-valeroylamino)ethy ~-indole To a suspension of 2.5 9 (0.0184 mole~ of 3-(2'-aminoethyl)indole (tryptamine) in 50 ml dry chloroform con-taining 2 9 (0.02 mole) of triethylamine cooled in an ice bath there were added drop by drop 4.7 g (0.0184 mole~ of 2-ethyl-2-ethoxycarbonyl-5-chloro-valeroyl chloride. After stirring for 2 hours at room temperature, the solution was washed with dilute aqueous hydrochloric acid. After drying the organic ~
phase and evaporating it under reduced pressure there was ~ ~;
obtained 6.6 g of the above produc~ which, recrystallized from petroleum ether/isopropyl ether melted at 76C and had a yield of 95%. The results of analysis were as follows:
IR (KBr~ 3350 and 3300 cm NH
1735 cm~l CO ester 1640 cm 1 CO amide Calculated for C20H27N203Cl : C=63.40%; H=7.18%i N=7.40%
Found : C=63.39%; H=7.05%; N=7.51%.
- . ~ ,. . .. . . .
s9 (b) Preparation of 1- ~2'-indol-3"-ylethyl~-3-ethyl-3-ethoxycarbony ~-2-piperidone To a suspension of 34.4 9 (0.0~08 mole~ of the above compound in 150 ml of a 1:1 mixture of dry benzene and hèxa-methylphosphoric/triamide cooled in an ice bath there was added, in small quantities and in a nitrogen atmosphere, 10.6 9 (0.0946 mole) of potassium t-butoxide. After stirr;ng for 8 hours at room temperature, the solution was poured into a cold dilute aqueous solution of hydrochloric acid. The aqueous phase, after decantation, was extracted two times with benzene.
The resulting organic phase was washed twice with water and dried. After evaporating under reduced pressure there was obtained 30 9 of the desired product which, recrystallized from isopropyl ether, melted at 84F and had a yield of 96%, the results of analysis were as follows:
IR (KBr) 3250 cm 1 NH indole 1730 cm~l C0 ester 1620 cm 1 C0 amide r C20H26N203 : C=70.15%, H-7 65%; N 8 1 Found : C=6g.97%, H-7.65%; N~8.20%.
(c) Preparation of l-ethyl-l-ethoxycarbonyl-5,12b-didehydro-indolo(2,3-a)quinolizidinium perchlorate Into a solution of 30 9 (Q.0876 mole) of the above compound in 480 ml of dry toluene there were poured 240 ml of distilled phosphoryl chloride. This solution was heated under reflux for 9 hours with a moisture guard. Excess phosphoryl chloride and toluene were then removed by evaporation under reduced pressure. The residue was taken up with methylene dichloride and the solution was washed with water, dried over sodium sulphate and evaporated under reduced pressure. A part of the solution was agitated with a lM aqueous solution of lithium perchlorate. After decanting the aqueous phase, washing with water, drying over sodium sulphate and evaporating the solvent under reduced pressure there was obtained a yellow powder which was recrystallized from ethanol. The resulting product melted at 191F. The results of analysis were as follows:
IR (KBr) 3340 cm 1 NH
17~0 cm~l CO ester 1625 cm 1 C-N~ ~3 (d) Preparation of l-ethyl-l-ethoxycarbonyl-indolo(2,3-a)-quinolizidine (12b-H; l-C2H5 trans and cis isomer) , A solution of 6.25 g (0.0147 mole) of the above per-chlorate salt in 80 mls ethanol was hydrogenated for 12 hours in the presence of 0.3 9 of platinum oxide. After filtration, the ethanol was evaporated under reduced pressure and the residue taken up with methylene dichloride and agitated with 5%
sodium hydroxide. The organic phase was decanted and washed with distilled water. ;~
On chromatography of a solution of the product with ;
methylene dichloride over 100 grams of silica, and elution with the same solvent, there ~as separated 1.12 g of a first fraction (yield 25%) which was the 12b-H, l-C2H~ trans isomer of the product and melted at 112C (recrystallized from petroleum ether/isopropyl ether). The results of analysis were as follows:
IR (KBr) 3410 cm 1 NH
2770, 2805, 2825 cm 1 Bohlmann bands 1710 cm~l CO ester NMR (CDC13 90 MHz) :
among other signals : 8.5 ~ OH (s) (NH indole) 4.35~ 2H (q) (O-CH2-CH3)
3.85~ lH (s) ~H on Cga) ! - 8 -i1~3C~9~9 1.35~ 3H (t) (CH3-CH2-0-) 0.75~ 3H (t) (CH3 CH2) r C20H26N202 : C-73.59%; H-8 03% N 8 Found : C=73.47%i H=8.12%; N~8.33%.
The later fractions of chromatography gave 1.8 9 o~
an oil which was the 12b-H; l-C2H5 cis isomers oF the desired product.
The results of analysis were as follows:
IR (KBr) 3420 cm 1 NH
3750, 3800 cm I Bohlmann bands 1705 cm 1 CO ester NMR (CC14 90 MHz) among other signals : 7.78~ lH (s) (NH indole)
The later fractions of chromatography gave 1.8 9 o~
an oil which was the 12b-H; l-C2H5 cis isomers oF the desired product.
The results of analysis were as follows:
IR (KBr) 3420 cm 1 NH
3750, 3800 cm I Bohlmann bands 1705 cm 1 CO ester NMR (CC14 90 MHz) among other signals : 7.78~ lH (s) (NH indole)
4.15~ 2H ~q) (-OCH2-CH3) 3.93~ lH (s) (H on Cga) ~ ~-1.09~ 3H (t) (CH3-CH2-0) ~-0.9 ~ 3H (t) (CH3-CH2) The hydrochloride, recrystallized from isopropanol, ~ ~-melted at above 260C.
Calculated for C2oH26N2o2.Hcl.l.5 H2C :
C=61.57%; H=7.75%; N=7.18%
Found : C-61.51%i H=7.33%; N-7.35%.
(e) Preparation of l-ethyl-l-carboxy-indolo(2,3-a)-quinolizidine (12b-H; l-C2H5 trans isomer), hydrochloride -~
: ',, f ~ .HCl HOOC-To a solution of 8.8 9 of the ester obtained in step (d) above, in 100 ml of ethanol are added 8.8 9 of KOH and the .
g , ., .. .. . ~ , .
s9 mixture is refluxed for 12 hours. The solvent is evacuated under reduced pressure and the residue retreated by iced water, acidified by concentrated hydrochloric acid until acid pH is reached; hydrochloride precipitates, is separated, washed and dried. Yield 9.5 9 (100%) of the product crystallized with l mole of H20. M.P. : > 260C.
Analysis Formula Cl~H22N202'HC1~l2 M.W. : 353.
C H N
Calculated 61.20% 7.08% 7.93%
Found : 61.01% 6.75% 7.72%
IR (KBr) 3340 cm l NH
1705 cm l (-~-OH) o (f) Preparation of l-ethyl-l-piperonylpiperazidocarbonyl-indolo(2,3-a)quinolizidine (12b-H; l-C2H5 trans isomer), dihydrochloride ~ N .2 HCl L ~
6 g of hydrochloride of step (e) above are suspended in 50 ml of benzene and there are added, while cooling, 40 ml of oxalyle chloride. After stirring for 24 hours at 40C, excess of oxalyle chloride is evacuated by distillation under reduced pressure and the residue is retreated four times by dry benzene. The dry residue is thus suspended in 50 ml of methyl-ene chloride and cooled at 0C. A solution of 3.6 g of piper-onylpiperazine and 3.4 g of triethylamine in 20 ml of methylene chloride are added and the mixture is stirred for 6 hours at ... ... . : .
room temperature. After filtration of the insolubles and evacuation of methylene chloride, the residue is treated on a silica gel column (eluent CHzCl2). 4.9 g (yield : 60%) of an oily product are obtained.
IR (film) 3360 cm 1 (NH); 1640 cm 1 (CO) NMR (COC13, internal TM~) ~in 10 6 9.2 ls (lH) NH indole
Calculated for C2oH26N2o2.Hcl.l.5 H2C :
C=61.57%; H=7.75%; N=7.18%
Found : C-61.51%i H=7.33%; N-7.35%.
(e) Preparation of l-ethyl-l-carboxy-indolo(2,3-a)-quinolizidine (12b-H; l-C2H5 trans isomer), hydrochloride -~
: ',, f ~ .HCl HOOC-To a solution of 8.8 9 of the ester obtained in step (d) above, in 100 ml of ethanol are added 8.8 9 of KOH and the .
g , ., .. .. . ~ , .
s9 mixture is refluxed for 12 hours. The solvent is evacuated under reduced pressure and the residue retreated by iced water, acidified by concentrated hydrochloric acid until acid pH is reached; hydrochloride precipitates, is separated, washed and dried. Yield 9.5 9 (100%) of the product crystallized with l mole of H20. M.P. : > 260C.
Analysis Formula Cl~H22N202'HC1~l2 M.W. : 353.
C H N
Calculated 61.20% 7.08% 7.93%
Found : 61.01% 6.75% 7.72%
IR (KBr) 3340 cm l NH
1705 cm l (-~-OH) o (f) Preparation of l-ethyl-l-piperonylpiperazidocarbonyl-indolo(2,3-a)quinolizidine (12b-H; l-C2H5 trans isomer), dihydrochloride ~ N .2 HCl L ~
6 g of hydrochloride of step (e) above are suspended in 50 ml of benzene and there are added, while cooling, 40 ml of oxalyle chloride. After stirring for 24 hours at 40C, excess of oxalyle chloride is evacuated by distillation under reduced pressure and the residue is retreated four times by dry benzene. The dry residue is thus suspended in 50 ml of methyl-ene chloride and cooled at 0C. A solution of 3.6 g of piper-onylpiperazine and 3.4 g of triethylamine in 20 ml of methylene chloride are added and the mixture is stirred for 6 hours at ... ... . : .
room temperature. After filtration of the insolubles and evacuation of methylene chloride, the residue is treated on a silica gel column (eluent CHzCl2). 4.9 g (yield : 60%) of an oily product are obtained.
IR (film) 3360 cm 1 (NH); 1640 cm 1 (CO) NMR (COC13, internal TM~) ~in 10 6 9.2 ls (lH) NH indole
5.9 Is (2H) O-CH2-0 ! ~-05 ls (lH) H ~C12b) 0.3 lt ~3H) CH3-CH2 Dihydrochloride is obtained by treatment with aqueous HCl, in ethanol; crystallization with 3H20. Melting point 242C. ~'~
Analysis C30H36N403~2Hc1~3H2o M.W. : 627.6 C H N
,. ~,.
Calculated 57.40% 7.01% 8.92%
Found : 57.82% 6.55% 8.64%
(g) Preparation of l-ethyl-l ~trimethoxybenzamido-4)piper-azinocarbony ~indolo(2,3-a)quinolizidine (12b-H; l-C2H
trans isomer), hydrochloride ~ .HCl CH30 N ~ / N
~ H
CH30~c NH N ~ 5 - \ ~
5 g of hydrochloride of step (e) above are treated by oxalyle chloride as described in step (f) above. 5.3 g of dry residue are obtained, to which there are added 50 ml of methyl-ene chloride and the mixture is cooled at 0C. A solution of 3 9 of triethylamine and 3 9 of trimethoxy benzoyl-4-amino-1 ~ 0~59 piperazine in 20 ml of methylene chloride. The mixture is st;rred for 24 hours at room temperature, then washed with a 10% aqueous soda solution, then with water, dried and the excess solvent is evacuated. 7.2 g of an oily product are obtained.
IR (film) 3380 cm 1 and 3240 cm 1 (NH) 1650 cm 1 and 1620 cm 1 (CO) Hydrochloride is obtained by treatment with aqueous HCl, in ethanol. M.P. : 225C.
Analysis C32H41NS5'~l~l M.W. : 611 C H N
Calculat~d 62.87~ 6.92% 11.46%
Found : 62.24% 6.95% 11.18%
(h) Preparation of l-ethyl-l-carboxy-indolo(2,3-a)-quinolizidine (12b-H; l-C2H5 cis isomer) HOC
O
Into a solution of 6.8 9 of l-ethyl-ethoxycarbonyl-indolo(2,3-a)quinolizidine (12b-H; l-C2H5 cis isomer) obtained in the preceding example (d), in 100 ml of ethanol at 95%, ~ ~`
there are added 6.8 9 of potassium hydroxide. The mixture is refluxed for 12 hours, the solvent evaporated under reduced pressure and the residue retreated with iced water and acidi-fied with HCl up to pH = 4.5. The product crystallizes, is separated, washed and dried. 4.1 9 of acid are thus obtained.
Analysis C18H22N22 M-298.37 .. .. .
~10~59 C H N
Calculated 72.45% 7.43% 9.37%
Found : 72.61% 7.49% 9.20%
IR 1620 cm~l v CO, OH associated.
(i) Preparation of -~ D nor eburna!nonine ~ 1 ) (COC1 )2 ~ 2) NaOH aq.
HOOC O
~ ~ ., .
There are added, dropwise, to a suspension of 6 9 (0.0179 mole) of 1-ethyl-1-carboxy-indolo(2,3-a)quinolizidine (12b-H; l-C2H5 cis isomer) of previous step ~h), in 60 ml of dry benzene, 30 ml of oxalyle chloride. The suspension is stirred for 2 hours at room temperature, then refluxed for 9 hours. The solvents are evacuated under reduced pressure and the residue retreated with methylene chloride, is stirred in the presence of diluted soda. The organic solution, washed with water, dried on sodium sulphate, evaporated under reduced vacuum, gives 4.25 g of the researched product. Yield 83%.
After washing on alumina column, 3.25 g of beige `~ ;
crystalline product are obtained. M.P. = 136C (diisopropylic oxide).
IR (KBr) : 2805, 2845, 1735, 1660 cm 1 C18H20N20 = 280~96 Calculated % : C=77.11% H-7.19% N= 9.99%
Found : C=77.54% H-7.78% N-10.09%
HlRMN (COC13) reference int. TMS ~TMS ~ 7-9~7 7 (m) aromatic; 7.5-7.05 (m) 3H aromatic; 4.3 (m) lHi 1.1 (t~
CH3-CH2.
9S~3 Hydrochloride The necessary amount of aqueous HCl 7N is added to a solution of 3.25 9 of base in 30 ml of absolute alcohol. The solvents are evaporated under reduced vacuum, at 30C and the residue, retreated with acetone, gives 3.32 g of a white crystalline product. M.P. : 264C.
IR (KBr) : 3400, 2470, 2320, 1740, 1680 cm 1 C13RMN (D20) reference dioxan ~ ppm 107.426 C = 0, -13.712 CHi -82.162 CH3.
EXAMPLE 2 ;
(a) Preparation of 3- ~'-(2"-cyano-2"-ethy1-5"-chloro-valeroylamino)ethy ~-indole In a 1 litre flask there 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 0C over ice and there were added 40 g (0.192 mole) 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, then with 10% sodium hydroxide. It was then dried and the solvent removed by evaporation. The product, recrystallized from `
isopropyl ether/petroleum ether, melted at 120C (yield 40 g). ;~
The results of analysis are as follows: ~ -IR (KBr) 3400 cm 1 NH indole 3340 cm 1 NH amide 2860 cm~l CN
1660 cm 1 C-N
O
Calculated for C18H22N3C10 : C=65.0 %; H=6.64%; N=12.65%
Found : C=64.03%; H=6.78%; N=12.60%.
- - . . ., ,. .. . . - :
9s9 (b) Prepar~tion of 1- ~2'-indol-3"-yl-ethyl~-3~ethyl-3-cyan ~-2-piperidone In a 1 litre round-bottomed flask there were placed 22 9 ~0.0665 mole) of the product of step (a) above, 200 ml of tetrahydrofuran, and 300 ml of t-butanol. The m~xture was cooled to 0C over ice and there were added, in small quanti-~ies, 8.5 9 (0.076 mole) of potassium tert.butoxide. 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 removed by evaporation. The desired product, recrystallized from ethanol/
ether 50/50 melted at 180C (yield 15 9, 80%). The results of analysis are as follows:
IR 3400 cm 1 NH indole 2260 cm~l CN
1635 cm~l ICl-N ~ ~
O -,:
Calculated for C18H23N30 : C-73.2 %j H-7.1 %i 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 In a 1 litre flask there were placed, with stirring, 50 9 (0.169 mole) of the product of step (b) above and 700 ml of phosphoryl chloride. After heating under reflux 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 then taken up with 300 ml of methylene dichloride and cooled over ice, and 300 ml of a solution of lithium perchlorate ~1 mole) was added with vigorous stirring. There was produced a yellow precipitate which, recrystallized from methanol melted at 260C (yield 44 9, 70%). The results of analysis are as follows:
-9~9 IR 3400 cm 1 NH indole 2260 cm 1 C_N
1620 cm 1 C=N~3 (d) Preparation of l-ethyl-l-cyano-indolo(2,3-a)quinolizidine (12b-H; l-C2H5 trans isomer) In a l-litre round-bottomed Flask there were placed 200 ml methanol, 100 ml methylene dichloride and 13.5 g (0.036 mole) of the perchlorate product oF s-tep (c) above. The flask was cooled to about 5C and 5 g oF sodium borohydrate were added in small quantities. The solution was then stirred for 2 hours at room temperature, concentrated, washed with water and extracted with methylene dichloride. After drying and removing the solvent, there were obtained 8 g of yellow crystals, recrystallized from isopropyl ether melting at 160C (yield 80%). The results of analysis are as follows:
IR 3420 cm 1 3440 cm~l 2760 cm 1 ) NH and Bohlmann bands 2800 cm~l 2250 cm 1 CN
NMR (dimethylsulphoxide d6, 80 MHz) 0.86~ 3H (t) (CH3) 3.77~ lH (s) (H at Cga) 9.66~ lH (s) (NH) Calculated for C18H21N3 : C=77.7 %; H=7.2 %; N=15.2 %
Found : C=77.55%; H=7.32%; N=15.10%.
(e) Preparation of l-ethyl-l-cyano-indolo(2,3-a)quinolizidine (12b-H; l-C2H5 cis isorrler) In a l-litre flask there were placed 19 g of the per-chlorate product Gf step (c) above, 300 cc of 95% ethanol and 40 9 zinc powder. There was added in an ampoule 100 mls concentrated hydrochloric acid. Mild reflux could be observed during the addition of the acid. The mixture was allowed to stand at room temperature for 10 hours. It was then concen-trated, washed with water and extracted with methylene dichlor;de. It was made alkaline with sodium hydroxide and filtered through Celite ~Trade Mark). After decanting, drying and evaporating off the solvents there were obtained 6 9 of a product, insoluble in ether, melting at 250C. The results of analysis are as follows:
IR 3~10 cm 1 (NH) 2260 cm~l (CN) Calculated for C18H21N3.1/4H20 : C
Found : C-76.59%; H=7.80%; N=14.55%. ~ -The ether extracts were concentrated to provide 4 g (total yield 71.5%) of the cis isomer of the same product as step (d) above.
NMR (dimethylsulphoxide d6, 80 MHz) 1.05~ 3H (t) (CH3) 3.458 lH (s) (H at Cga) 10.32~ lH (s) (NH) (f) Preparation of l-ethyl-l-aminomethyl-indolo(2,3-a)-quinolizidine (12b-H; l-C2H5 trans isomer II) :
In a l-litre flask there were placed 4 g of lithium aluminium hydride and 400 ml of dry ether. The flask was cooled to from O to 5C, and there were added, in small quanti-ties, 8.9 g of the product of step (d) above. After leaving the flask to stand for 1 hour at room temperature, there were added 60 ml dry tetrahydrofuran. The mixture was heated for 2 hours under reflux. After cooling there were added, drop by drop, 40 ml water~ followed by 200 ml of methylene dichloride.
The mixture was stirred for 15 minutes. On filtering over llO~S~
Celite, drying and concentrating the filtrate there was obtained 7.2 g of white crystals which, recrystallized from ether, melted at 175C ~8Q% yield). The results of analysis are as follows:
IR 3280, 3190 cm 1 NH2 3350 cm 1 NH indole The CN peak at about 2250 cm 1 was a~sent.
Calculated for C18H25N3 : C=76.4 %; H=8.85%; N=14.8 %
Found : C=75.85%; H-8.90%; N~15.52%.
(g) Preparation of l-ethyl-l-aminomethyl-indolo~2,3-a)-quinolizidine (12b-H; l-C2H5 cis isomer I) To a 500 ml flask there were added 3.4 9 of lithium aluminium hydride, 200 ml of ether and 100 ml of tetrahydro-furan. While cooling over ice there were added, in small quantities, 6.9 g of the cis isomer of step (e) above. After allowing the mixture to stand for 15 hours at room temperature, `~ the product was isolated as in step (f) above. On recrystalli-zation from diethyl ether/petroleum ether 50/50 there was obtained 5 g of a product melting at 125F (yield 71%).
Calculated for Cl8H25N3 : C=76.4 %; H-8.85%; N=14.8 %
Found : C=76.25%i H=8.61%; N=14.43%.
l-ethoxycarbonylaminomethyl-l-ethyl-indolo(2,3-a)quinolizidine hydrochloride (12b-H; l-C2H5 trans isomer II) ~, .HCl CH "
C2H50.CO.NH
To a solution of 2 g (0.00705 mol) of the trans product II of Example 2 (f) in 20 ml in dimethoxyethane, cooled i .
to 0C, there were alternately added, so as to maintain 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 allowing the reaction mixture to stand for 3 hours at ambient temperature, the product was extracted ~ith dichloromethane, the dichloromethane extract was ~ashed with water, dried and evaporated to dryness. The product was recrystallized from ethanol. ~:
Weight : 2 9 Yield : 80% M.P. : 140C.
IR 3210 cm 1 amide NH
3400 cm 1 indole NH
2760 and 2800 cm 1 Bohlmann bands 1690 cm 1 carbamate C = 0.
The results of microanalysis are as follows:
C21H29N302 : C=71.0 %; H-8 17%; N=ll 8 %
Found : C=70.94%; H=8.16%~ N=11.54%.
~ 20 The hydrochloride salt was formed from the above 2 g :~ of product by adding 4N HCl in 20 ml of ethanol.
Weight : 2 9 Yield : 90% M.P. : 260C.
E homo azaepieburnamonine hydrochloride .HCl NH
First l-phenoxycarbonylaminomethyl-l-ethyl-indolo-.. .... . . .
Sg (2,3-a)quinolizidine (12b-H; l-C2H5 trans isomer) was prepared by repeating the procedure of Example 3, but replacing the ethyl chloroformate with phenyl chloroformate.
To a solution of 8 g (0.02 mol) of the product in 250 ml of tetrahydrofuran there were added 2 9 of sodium hydride to 50%. After stirring for 90 minutes, the reaction product was extracted with diethyl ether, washed with water and dried. The diethyl ether was removed by evaporation to leave 5 g of an oil, analysis of which gave the following data:
IR 3200 cm 1 amide NH
1670 cm 1 amide C = 0 NMR (CC14; internal TMS) 0.65~ (3H, t, CH3-CH2) -~
1 to 3.2 ~ (solid 15 protons) 3.3 ~ (lH, s, angular proton 12b-H) 7.2 ~ (solid 3H aromatics) 3.1 ~ (solid lH aromatic) The hydrochloride salt was prepared by treating the above oil with 4N hydrochloric acid in 20 ml of ethanol, followed by centrifuging. The yield was 60~, calculated on the starting amine (II). M.P.: 260C. The yroduct crystallized with 1/2 mol of water of crystallization. The results of microanalysis are as follows:
Calculated for ClgH23N30.HC1Ø5 H20 :
C=64.5 %; H=7.05%; N=11.8 %
Found : C-64.38%; H=7.11%; N=11.62%.
1-(3',4',5'-trimethoxybenzoylaminomethyl)-1-ethyl-indolo-(2,3-a)quinolizidine hydrochloride (12b-H; l-C2H5 trans isomer II) .;
' 9S~ ' In a three-necked bottle of 250 ml capacity fitted with a stirrer, a CaC12 guard, a thermometer and a dropping funnel there were added 2.85 g of the trans product II of Example 2 (f), 1.1 9 of triethylamine and 50 ml of dichloro-methane.
The mixture was stirred and cooled to 0.2C. At this temperature there were slowly added 2.31 9 of 3,4,5-trimethoxy-benzoyl chloride in 15 ml of dichloromethane. The addition took place over a period of 15 to 20 minutes, after which time the reaction mixture was stirred for 1 hour at 0C then for 15 hours at ambient 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 sulphate and concentrated to form a non-crystalline mass, having the texture `
of meringue and melting towards 100C.
CCM : 90/10 8/10 IR 3230 cm 1 NH
3190 cm 1 NH
2750 and 2800 cm 1 Bohlmann bands 1640 cm 1 C = 0 amide Dosage of the base with HC104 : 97%. -To prepare the hydrochloride salt, the above product was dissolved in a 1:1 mixture of di-isopropyl ether and iso-propanol, and 4N hydrochloric acid was added. The hydro-chloride salt crystallized when hot, and was filtered while hot and washed with ethanol to produce 4.5 9 (8~ yield) of the product.
CCM : 90/10 8/10 M.P. : 210C bond on the plate Dosage of hydrochloride : 100% (1 function).
Microanalysis gave the following results:
28H35N304,HCl C=65.45%; H-7 00~ N ~
10 Found : C-64.34%; H-7.17%i N-8.11%
C-64.15%; H=7.16%; N=7.96%.
l-(N'- ~iethylaminoethy~7-N-ureidomethyl)-l-ethyl-indolo-(2,3-a)quinolizidine (12b-H; l-C2H5 trans isomer II) (C2H5)2N-CH2CH2-NH-CONHCH2"
There was first prepared the corresponding l-phenoxy-carbonylaminomethyl-l-ethyl derivative, 7 g of the trans product II of Example 2 (f) and 100 ml of tetrahydrofuran were placed in a three-necked flask of 500 ml capacity, having a stirrer and two dropping funnels. The flask was cooled to between 0C and 5C and at this temperature, there were simul-taneously added 4.25 9 of phenyl chloroformate in 50 ml of tetrahydrofuran and 2.9 g of sodium carbonate in 50 ml of - water. The rates of addition were such as to maintain the pH
at from 6 to 7. The flask 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 ~o~gsg and the extract was washed several times with water before being dried with sodium sulphate, and concentrated by evapo-ration. There were obtained 11 9 of the product, which was an oil .
IR 3270 cm 1 NH
1710 cm~l C = 0 The l-ureidomethyl product was prepared as follows:
into a 500 ml flask provided with a cooler, there were placed 11 g of the above oil 3.5 9 of dimethylaminoethyl amine and 180 ml o~ methanol. The amoun~ of dimethylaminoethyl amine used corresponded to a 20% excess. The mixture was heated under 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 then with water.
After drying over sodium sulphate it was concentrated to provide a yellowish crystalline product. The product was taken up in two stages in diethyl ether and centriFuged. The first stage yielded 4.6 g of crystalline product melting at 202C, and the second stage yielded 0.8 g of crystalline product melting at 198C. The combined products were then recrystal-lized From benzene to provide 4.65 g of the final product.
M.P. : 204C Yield : 45% based on the am;ne (II) ~ :
CCM : 90/10 5/10 Dosage of the base with HC104 : 100% (2 functions) IR 3360 cm 1 NH
3250 cm 1 NH
1620 cm~l C = 0 urea Microanalysis gave the fol lowing results:
r C25H39N50 : C=70.6 %; H=9 17%; N=1645%
30Found : C=70.58%; H-9.20%; N=16.67%
~ 9 S 9 l-pentanoylaminomethyl-l-ethyl-indolo(2,3-a~quinoliz;dine (12b-H; l-C2H5 trans isomer II) CH3~(CH2)3-Co NH~C~l2 Using reaction conditions and technlques identical to those of Example 5, there were reacted a solution of 5.7 g of the trans product II of Example 2 (f) and 2.1 g of triethyl-amine in 120 ml of dichloromethane and a solution of 2.45 9 pentanoyl chloride in 20 ml of dichloromethane.
There were thus obtained 7.& 9 of an oll containing a little residual triethylamine.
IR 3180-3380 cm 1 NH
1630-1650 cm~l C = 0 From the oil it was possible to obtain crystals of the product, melting at 110C.
l-pentylaminomethyl-l-ethyl-indolo(2,3-a~quinolizidine (12b-H; l-C2H~ trans isomer II) CH3-(CH2)4-NH-cH2 - 20 In a three-necked flask of 500 ml capacity having a stirrer, a condenser, a thermometer, and a dropping funnel there were placed 100 ml of anhydrous diethyl ether. When this had been cooled over an ice bath there was added 4 9 of lithium ~ 24 ~
195g hydride, and the contents of the flask were stirred for 15 minutes. There was then added very slowly a solution of 7.4 g of the product of Example 7 in 50 ml of anhydrous diethyl ether. The mixture was then heated under reflux for 2 hours and stirred for a further 15 hours at ambient temperature. It was then cooled over an ice bath and there were added dropwise 20 ml of water followed by 150 ml of dichloromethane. The reaction mixture was then filtered over Celite, dried over sodium sulphate and concentrated by evaporation. There ~lere obtained 7 g of an oil which could be crystallized to a product melting at 80C.
Recrystallization ~rom the minimum amount of iso-propanol gave 4.3 9 of a crystalline product melting at 97C.
Dosage of the base with HC104 : 100% (2 functions). ;~
Microanalysis gave the following results: ~ -Calculated for C23H35N3 C=78.20%; H=9.92%; N-11.90%
Found : C-78.18%; H~9.81%; N=12.00%.
IR basic : 3310 cm 1 NH
1620 cm 1 C = 0 Dimaleate An acid addition salt with maleic acid was prepared, working in solution in a mixture of isopropanol and di-isopropyl ether. Initially the salt formed as an oil, but was recrystallized from ethyl acetate to give 6.7 9 of the di-maleate, melting at ln5C. `~
Dosage of the dimaleate with HC104 : 99.6% (2 functions).
Rf : 90/10 9/10.
l-guanidinocarbonylaminomethyl-l-ethyl-indolo(2,3-a)-quinolizidine dimaleate (12b-H; l-C2H5 trans isomer) ~)1)959 dlmaleate ~C-NHCONH-- ' Into a 250 ml ~lask, 9 9 of the compound prepared in Example 3, 2.2 9 of base guanidine (liberated ~rom 3 g of chlorohydrate by the couple ethylate-ethanol) are put into 120 ; ml of ethanol. The mixture is refluxed for 48 hours and the solvent evaporated to dryness. The residue is retreated by a water-methylene chloride mixture, filtered on Celite and decanted, the organic phase washed again with water. The methylene chloride phase is then washed twice by a 5% acetic acid solution and the acid waters are alkalinized with sodium bicarbonate in the presence of ether; the ethereal phases are dried and evaporated.
Analysis C30H36N403~2Hc1~3H2o M.W. : 627.6 C H N
,. ~,.
Calculated 57.40% 7.01% 8.92%
Found : 57.82% 6.55% 8.64%
(g) Preparation of l-ethyl-l ~trimethoxybenzamido-4)piper-azinocarbony ~indolo(2,3-a)quinolizidine (12b-H; l-C2H
trans isomer), hydrochloride ~ .HCl CH30 N ~ / N
~ H
CH30~c NH N ~ 5 - \ ~
5 g of hydrochloride of step (e) above are treated by oxalyle chloride as described in step (f) above. 5.3 g of dry residue are obtained, to which there are added 50 ml of methyl-ene chloride and the mixture is cooled at 0C. A solution of 3 9 of triethylamine and 3 9 of trimethoxy benzoyl-4-amino-1 ~ 0~59 piperazine in 20 ml of methylene chloride. The mixture is st;rred for 24 hours at room temperature, then washed with a 10% aqueous soda solution, then with water, dried and the excess solvent is evacuated. 7.2 g of an oily product are obtained.
IR (film) 3380 cm 1 and 3240 cm 1 (NH) 1650 cm 1 and 1620 cm 1 (CO) Hydrochloride is obtained by treatment with aqueous HCl, in ethanol. M.P. : 225C.
Analysis C32H41NS5'~l~l M.W. : 611 C H N
Calculat~d 62.87~ 6.92% 11.46%
Found : 62.24% 6.95% 11.18%
(h) Preparation of l-ethyl-l-carboxy-indolo(2,3-a)-quinolizidine (12b-H; l-C2H5 cis isomer) HOC
O
Into a solution of 6.8 9 of l-ethyl-ethoxycarbonyl-indolo(2,3-a)quinolizidine (12b-H; l-C2H5 cis isomer) obtained in the preceding example (d), in 100 ml of ethanol at 95%, ~ ~`
there are added 6.8 9 of potassium hydroxide. The mixture is refluxed for 12 hours, the solvent evaporated under reduced pressure and the residue retreated with iced water and acidi-fied with HCl up to pH = 4.5. The product crystallizes, is separated, washed and dried. 4.1 9 of acid are thus obtained.
Analysis C18H22N22 M-298.37 .. .. .
~10~59 C H N
Calculated 72.45% 7.43% 9.37%
Found : 72.61% 7.49% 9.20%
IR 1620 cm~l v CO, OH associated.
(i) Preparation of -~ D nor eburna!nonine ~ 1 ) (COC1 )2 ~ 2) NaOH aq.
HOOC O
~ ~ ., .
There are added, dropwise, to a suspension of 6 9 (0.0179 mole) of 1-ethyl-1-carboxy-indolo(2,3-a)quinolizidine (12b-H; l-C2H5 cis isomer) of previous step ~h), in 60 ml of dry benzene, 30 ml of oxalyle chloride. The suspension is stirred for 2 hours at room temperature, then refluxed for 9 hours. The solvents are evacuated under reduced pressure and the residue retreated with methylene chloride, is stirred in the presence of diluted soda. The organic solution, washed with water, dried on sodium sulphate, evaporated under reduced vacuum, gives 4.25 g of the researched product. Yield 83%.
After washing on alumina column, 3.25 g of beige `~ ;
crystalline product are obtained. M.P. = 136C (diisopropylic oxide).
IR (KBr) : 2805, 2845, 1735, 1660 cm 1 C18H20N20 = 280~96 Calculated % : C=77.11% H-7.19% N= 9.99%
Found : C=77.54% H-7.78% N-10.09%
HlRMN (COC13) reference int. TMS ~TMS ~ 7-9~7 7 (m) aromatic; 7.5-7.05 (m) 3H aromatic; 4.3 (m) lHi 1.1 (t~
CH3-CH2.
9S~3 Hydrochloride The necessary amount of aqueous HCl 7N is added to a solution of 3.25 9 of base in 30 ml of absolute alcohol. The solvents are evaporated under reduced vacuum, at 30C and the residue, retreated with acetone, gives 3.32 g of a white crystalline product. M.P. : 264C.
IR (KBr) : 3400, 2470, 2320, 1740, 1680 cm 1 C13RMN (D20) reference dioxan ~ ppm 107.426 C = 0, -13.712 CHi -82.162 CH3.
EXAMPLE 2 ;
(a) Preparation of 3- ~'-(2"-cyano-2"-ethy1-5"-chloro-valeroylamino)ethy ~-indole In a 1 litre flask there 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 0C over ice and there were added 40 g (0.192 mole) 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, then with 10% sodium hydroxide. It was then dried and the solvent removed by evaporation. The product, recrystallized from `
isopropyl ether/petroleum ether, melted at 120C (yield 40 g). ;~
The results of analysis are as follows: ~ -IR (KBr) 3400 cm 1 NH indole 3340 cm 1 NH amide 2860 cm~l CN
1660 cm 1 C-N
O
Calculated for C18H22N3C10 : C=65.0 %; H=6.64%; N=12.65%
Found : C=64.03%; H=6.78%; N=12.60%.
- - . . ., ,. .. . . - :
9s9 (b) Prepar~tion of 1- ~2'-indol-3"-yl-ethyl~-3~ethyl-3-cyan ~-2-piperidone In a 1 litre round-bottomed flask there were placed 22 9 ~0.0665 mole) of the product of step (a) above, 200 ml of tetrahydrofuran, and 300 ml of t-butanol. The m~xture was cooled to 0C over ice and there were added, in small quanti-~ies, 8.5 9 (0.076 mole) of potassium tert.butoxide. 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 removed by evaporation. The desired product, recrystallized from ethanol/
ether 50/50 melted at 180C (yield 15 9, 80%). The results of analysis are as follows:
IR 3400 cm 1 NH indole 2260 cm~l CN
1635 cm~l ICl-N ~ ~
O -,:
Calculated for C18H23N30 : C-73.2 %j H-7.1 %i 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 In a 1 litre flask there were placed, with stirring, 50 9 (0.169 mole) of the product of step (b) above and 700 ml of phosphoryl chloride. After heating under reflux 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 then taken up with 300 ml of methylene dichloride and cooled over ice, and 300 ml of a solution of lithium perchlorate ~1 mole) was added with vigorous stirring. There was produced a yellow precipitate which, recrystallized from methanol melted at 260C (yield 44 9, 70%). The results of analysis are as follows:
-9~9 IR 3400 cm 1 NH indole 2260 cm 1 C_N
1620 cm 1 C=N~3 (d) Preparation of l-ethyl-l-cyano-indolo(2,3-a)quinolizidine (12b-H; l-C2H5 trans isomer) In a l-litre round-bottomed Flask there were placed 200 ml methanol, 100 ml methylene dichloride and 13.5 g (0.036 mole) of the perchlorate product oF s-tep (c) above. The flask was cooled to about 5C and 5 g oF sodium borohydrate were added in small quantities. The solution was then stirred for 2 hours at room temperature, concentrated, washed with water and extracted with methylene dichloride. After drying and removing the solvent, there were obtained 8 g of yellow crystals, recrystallized from isopropyl ether melting at 160C (yield 80%). The results of analysis are as follows:
IR 3420 cm 1 3440 cm~l 2760 cm 1 ) NH and Bohlmann bands 2800 cm~l 2250 cm 1 CN
NMR (dimethylsulphoxide d6, 80 MHz) 0.86~ 3H (t) (CH3) 3.77~ lH (s) (H at Cga) 9.66~ lH (s) (NH) Calculated for C18H21N3 : C=77.7 %; H=7.2 %; N=15.2 %
Found : C=77.55%; H=7.32%; N=15.10%.
(e) Preparation of l-ethyl-l-cyano-indolo(2,3-a)quinolizidine (12b-H; l-C2H5 cis isorrler) In a l-litre flask there were placed 19 g of the per-chlorate product Gf step (c) above, 300 cc of 95% ethanol and 40 9 zinc powder. There was added in an ampoule 100 mls concentrated hydrochloric acid. Mild reflux could be observed during the addition of the acid. The mixture was allowed to stand at room temperature for 10 hours. It was then concen-trated, washed with water and extracted with methylene dichlor;de. It was made alkaline with sodium hydroxide and filtered through Celite ~Trade Mark). After decanting, drying and evaporating off the solvents there were obtained 6 9 of a product, insoluble in ether, melting at 250C. The results of analysis are as follows:
IR 3~10 cm 1 (NH) 2260 cm~l (CN) Calculated for C18H21N3.1/4H20 : C
Found : C-76.59%; H=7.80%; N=14.55%. ~ -The ether extracts were concentrated to provide 4 g (total yield 71.5%) of the cis isomer of the same product as step (d) above.
NMR (dimethylsulphoxide d6, 80 MHz) 1.05~ 3H (t) (CH3) 3.458 lH (s) (H at Cga) 10.32~ lH (s) (NH) (f) Preparation of l-ethyl-l-aminomethyl-indolo(2,3-a)-quinolizidine (12b-H; l-C2H5 trans isomer II) :
In a l-litre flask there were placed 4 g of lithium aluminium hydride and 400 ml of dry ether. The flask was cooled to from O to 5C, and there were added, in small quanti-ties, 8.9 g of the product of step (d) above. After leaving the flask to stand for 1 hour at room temperature, there were added 60 ml dry tetrahydrofuran. The mixture was heated for 2 hours under reflux. After cooling there were added, drop by drop, 40 ml water~ followed by 200 ml of methylene dichloride.
The mixture was stirred for 15 minutes. On filtering over llO~S~
Celite, drying and concentrating the filtrate there was obtained 7.2 g of white crystals which, recrystallized from ether, melted at 175C ~8Q% yield). The results of analysis are as follows:
IR 3280, 3190 cm 1 NH2 3350 cm 1 NH indole The CN peak at about 2250 cm 1 was a~sent.
Calculated for C18H25N3 : C=76.4 %; H=8.85%; N=14.8 %
Found : C=75.85%; H-8.90%; N~15.52%.
(g) Preparation of l-ethyl-l-aminomethyl-indolo~2,3-a)-quinolizidine (12b-H; l-C2H5 cis isomer I) To a 500 ml flask there were added 3.4 9 of lithium aluminium hydride, 200 ml of ether and 100 ml of tetrahydro-furan. While cooling over ice there were added, in small quantities, 6.9 g of the cis isomer of step (e) above. After allowing the mixture to stand for 15 hours at room temperature, `~ the product was isolated as in step (f) above. On recrystalli-zation from diethyl ether/petroleum ether 50/50 there was obtained 5 g of a product melting at 125F (yield 71%).
Calculated for Cl8H25N3 : C=76.4 %; H-8.85%; N=14.8 %
Found : C=76.25%i H=8.61%; N=14.43%.
l-ethoxycarbonylaminomethyl-l-ethyl-indolo(2,3-a)quinolizidine hydrochloride (12b-H; l-C2H5 trans isomer II) ~, .HCl CH "
C2H50.CO.NH
To a solution of 2 g (0.00705 mol) of the trans product II of Example 2 (f) in 20 ml in dimethoxyethane, cooled i .
to 0C, there were alternately added, so as to maintain 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 allowing the reaction mixture to stand for 3 hours at ambient temperature, the product was extracted ~ith dichloromethane, the dichloromethane extract was ~ashed with water, dried and evaporated to dryness. The product was recrystallized from ethanol. ~:
Weight : 2 9 Yield : 80% M.P. : 140C.
IR 3210 cm 1 amide NH
3400 cm 1 indole NH
2760 and 2800 cm 1 Bohlmann bands 1690 cm 1 carbamate C = 0.
The results of microanalysis are as follows:
C21H29N302 : C=71.0 %; H-8 17%; N=ll 8 %
Found : C=70.94%; H=8.16%~ N=11.54%.
~ 20 The hydrochloride salt was formed from the above 2 g :~ of product by adding 4N HCl in 20 ml of ethanol.
Weight : 2 9 Yield : 90% M.P. : 260C.
E homo azaepieburnamonine hydrochloride .HCl NH
First l-phenoxycarbonylaminomethyl-l-ethyl-indolo-.. .... . . .
Sg (2,3-a)quinolizidine (12b-H; l-C2H5 trans isomer) was prepared by repeating the procedure of Example 3, but replacing the ethyl chloroformate with phenyl chloroformate.
To a solution of 8 g (0.02 mol) of the product in 250 ml of tetrahydrofuran there were added 2 9 of sodium hydride to 50%. After stirring for 90 minutes, the reaction product was extracted with diethyl ether, washed with water and dried. The diethyl ether was removed by evaporation to leave 5 g of an oil, analysis of which gave the following data:
IR 3200 cm 1 amide NH
1670 cm 1 amide C = 0 NMR (CC14; internal TMS) 0.65~ (3H, t, CH3-CH2) -~
1 to 3.2 ~ (solid 15 protons) 3.3 ~ (lH, s, angular proton 12b-H) 7.2 ~ (solid 3H aromatics) 3.1 ~ (solid lH aromatic) The hydrochloride salt was prepared by treating the above oil with 4N hydrochloric acid in 20 ml of ethanol, followed by centrifuging. The yield was 60~, calculated on the starting amine (II). M.P.: 260C. The yroduct crystallized with 1/2 mol of water of crystallization. The results of microanalysis are as follows:
Calculated for ClgH23N30.HC1Ø5 H20 :
C=64.5 %; H=7.05%; N=11.8 %
Found : C-64.38%; H=7.11%; N=11.62%.
1-(3',4',5'-trimethoxybenzoylaminomethyl)-1-ethyl-indolo-(2,3-a)quinolizidine hydrochloride (12b-H; l-C2H5 trans isomer II) .;
' 9S~ ' In a three-necked bottle of 250 ml capacity fitted with a stirrer, a CaC12 guard, a thermometer and a dropping funnel there were added 2.85 g of the trans product II of Example 2 (f), 1.1 9 of triethylamine and 50 ml of dichloro-methane.
The mixture was stirred and cooled to 0.2C. At this temperature there were slowly added 2.31 9 of 3,4,5-trimethoxy-benzoyl chloride in 15 ml of dichloromethane. The addition took place over a period of 15 to 20 minutes, after which time the reaction mixture was stirred for 1 hour at 0C then for 15 hours at ambient 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 sulphate and concentrated to form a non-crystalline mass, having the texture `
of meringue and melting towards 100C.
CCM : 90/10 8/10 IR 3230 cm 1 NH
3190 cm 1 NH
2750 and 2800 cm 1 Bohlmann bands 1640 cm 1 C = 0 amide Dosage of the base with HC104 : 97%. -To prepare the hydrochloride salt, the above product was dissolved in a 1:1 mixture of di-isopropyl ether and iso-propanol, and 4N hydrochloric acid was added. The hydro-chloride salt crystallized when hot, and was filtered while hot and washed with ethanol to produce 4.5 9 (8~ yield) of the product.
CCM : 90/10 8/10 M.P. : 210C bond on the plate Dosage of hydrochloride : 100% (1 function).
Microanalysis gave the following results:
28H35N304,HCl C=65.45%; H-7 00~ N ~
10 Found : C-64.34%; H-7.17%i N-8.11%
C-64.15%; H=7.16%; N=7.96%.
l-(N'- ~iethylaminoethy~7-N-ureidomethyl)-l-ethyl-indolo-(2,3-a)quinolizidine (12b-H; l-C2H5 trans isomer II) (C2H5)2N-CH2CH2-NH-CONHCH2"
There was first prepared the corresponding l-phenoxy-carbonylaminomethyl-l-ethyl derivative, 7 g of the trans product II of Example 2 (f) and 100 ml of tetrahydrofuran were placed in a three-necked flask of 500 ml capacity, having a stirrer and two dropping funnels. The flask was cooled to between 0C and 5C and at this temperature, there were simul-taneously added 4.25 9 of phenyl chloroformate in 50 ml of tetrahydrofuran and 2.9 g of sodium carbonate in 50 ml of - water. The rates of addition were such as to maintain the pH
at from 6 to 7. The flask 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 ~o~gsg and the extract was washed several times with water before being dried with sodium sulphate, and concentrated by evapo-ration. There were obtained 11 9 of the product, which was an oil .
IR 3270 cm 1 NH
1710 cm~l C = 0 The l-ureidomethyl product was prepared as follows:
into a 500 ml flask provided with a cooler, there were placed 11 g of the above oil 3.5 9 of dimethylaminoethyl amine and 180 ml o~ methanol. The amoun~ of dimethylaminoethyl amine used corresponded to a 20% excess. The mixture was heated under 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 then with water.
After drying over sodium sulphate it was concentrated to provide a yellowish crystalline product. The product was taken up in two stages in diethyl ether and centriFuged. The first stage yielded 4.6 g of crystalline product melting at 202C, and the second stage yielded 0.8 g of crystalline product melting at 198C. The combined products were then recrystal-lized From benzene to provide 4.65 g of the final product.
M.P. : 204C Yield : 45% based on the am;ne (II) ~ :
CCM : 90/10 5/10 Dosage of the base with HC104 : 100% (2 functions) IR 3360 cm 1 NH
3250 cm 1 NH
1620 cm~l C = 0 urea Microanalysis gave the fol lowing results:
r C25H39N50 : C=70.6 %; H=9 17%; N=1645%
30Found : C=70.58%; H-9.20%; N=16.67%
~ 9 S 9 l-pentanoylaminomethyl-l-ethyl-indolo(2,3-a~quinoliz;dine (12b-H; l-C2H5 trans isomer II) CH3~(CH2)3-Co NH~C~l2 Using reaction conditions and technlques identical to those of Example 5, there were reacted a solution of 5.7 g of the trans product II of Example 2 (f) and 2.1 g of triethyl-amine in 120 ml of dichloromethane and a solution of 2.45 9 pentanoyl chloride in 20 ml of dichloromethane.
There were thus obtained 7.& 9 of an oll containing a little residual triethylamine.
IR 3180-3380 cm 1 NH
1630-1650 cm~l C = 0 From the oil it was possible to obtain crystals of the product, melting at 110C.
l-pentylaminomethyl-l-ethyl-indolo(2,3-a~quinolizidine (12b-H; l-C2H~ trans isomer II) CH3-(CH2)4-NH-cH2 - 20 In a three-necked flask of 500 ml capacity having a stirrer, a condenser, a thermometer, and a dropping funnel there were placed 100 ml of anhydrous diethyl ether. When this had been cooled over an ice bath there was added 4 9 of lithium ~ 24 ~
195g hydride, and the contents of the flask were stirred for 15 minutes. There was then added very slowly a solution of 7.4 g of the product of Example 7 in 50 ml of anhydrous diethyl ether. The mixture was then heated under reflux for 2 hours and stirred for a further 15 hours at ambient temperature. It was then cooled over an ice bath and there were added dropwise 20 ml of water followed by 150 ml of dichloromethane. The reaction mixture was then filtered over Celite, dried over sodium sulphate and concentrated by evaporation. There ~lere obtained 7 g of an oil which could be crystallized to a product melting at 80C.
Recrystallization ~rom the minimum amount of iso-propanol gave 4.3 9 of a crystalline product melting at 97C.
Dosage of the base with HC104 : 100% (2 functions). ;~
Microanalysis gave the following results: ~ -Calculated for C23H35N3 C=78.20%; H=9.92%; N-11.90%
Found : C-78.18%; H~9.81%; N=12.00%.
IR basic : 3310 cm 1 NH
1620 cm 1 C = 0 Dimaleate An acid addition salt with maleic acid was prepared, working in solution in a mixture of isopropanol and di-isopropyl ether. Initially the salt formed as an oil, but was recrystallized from ethyl acetate to give 6.7 9 of the di-maleate, melting at ln5C. `~
Dosage of the dimaleate with HC104 : 99.6% (2 functions).
Rf : 90/10 9/10.
l-guanidinocarbonylaminomethyl-l-ethyl-indolo(2,3-a)-quinolizidine dimaleate (12b-H; l-C2H5 trans isomer) ~)1)959 dlmaleate ~C-NHCONH-- ' Into a 250 ml ~lask, 9 9 of the compound prepared in Example 3, 2.2 9 of base guanidine (liberated ~rom 3 g of chlorohydrate by the couple ethylate-ethanol) are put into 120 ; ml of ethanol. The mixture is refluxed for 48 hours and the solvent evaporated to dryness. The residue is retreated by a water-methylene chloride mixture, filtered on Celite and decanted, the organic phase washed again with water. The methylene chloride phase is then washed twice by a 5% acetic acid solution and the acid waters are alkalinized with sodium bicarbonate in the presence of ether; the ethereal phases are dried and evaporated.
6.4 9 of a porous mass are obtained and chromato-graphied on silica (60 9 of silica : eluent CH2C12-MeOH 80-20).
After separating 0.7 9 of a first product, a second one is isolated and crystallized in ether. Yield: 3.5 9.
M.P. = 150C.
IR (KBr) 3200-3400 cm 1 strong and broad bands (v NH) 1600 cm 1 broad band (v C = O) The dimaleate is prepared in isopropanol.
CCM Merck plate MP 254 :
eluent acetone, CHC13, n butanol, NH~OH 25%
Rf ~ 0.4 1 spot Microanalysis C20H28N60 + C8H808 ~, , :
``` l~lLOU9S9 Calculated % C-56.00% H-6.00% N=14.00%
Found : C=56.07% H=6.46% N=12.59%
E homo 14 azaeburnamonine (12b-H; 1-C2H5 cis ~somer I) ¦ .HCl ~ H
Example 4 was repeated except that the cis product (I) of Example 2 (9) was used in place of the trans product ~ :
(II) of Example 2 (f). There was obtained 5.7 9 of product ~ (yield 69%). M.P. : 190C.
: 10 IR 3260 cm 1 NH ~ `~
1690 cm~l C = 0 Microanalysis gave the following results~
Calculated for ClgH23N30 : C=73.B %i H=7.45%i N-13-6 % --;
Found : C~73.48%; H=7.35%; N=12.99%.
. , .
The hydrochloride was obtained by adding 4 N HCl to - ~:
a solution of the base in a 1:1 mixture of ethanol and diethyl ether.
EXAMPLE 11 `~:
l-ethoxycarbonylaminomethyl-l-ethyl-indolo(2,3-a)quinolizidine hydrochloride (12b-H; l-C2H5 cis isomer I) -~ ~ .2 HCl 52H50-Co-NH-cH
The procedure of Example 3 was repeated except that the cis product ~I) of Example 2 (g) was used instead of the trans product (II) of Exa~ple 2 (f). There was obtained 2.1 9 of the free base (84% yield). M.P. : 210C.
IR 3400 cm 1 indole NH
3210 cm 1 amide NH
2790 and 2810 cm~l Bohlmann bands 1690 cm 1 carbamate C = 0 Microanalysis gave the following results:
C21H29N302 : C=71.0 %; H=8 17%i N=ll 82%
Found : C=70.85%; H=8.22%i N=11.94%
NMR (CDC13i internal TMS) 1.1 ~ (6H, t, CH3 ethyl and ethyl ester) 1.5 to 3.5 ~ (15H, solid) 3.9 ~ ~2H, q, CH20) 5.65~ (lH, m, NH-amide)
After separating 0.7 9 of a first product, a second one is isolated and crystallized in ether. Yield: 3.5 9.
M.P. = 150C.
IR (KBr) 3200-3400 cm 1 strong and broad bands (v NH) 1600 cm 1 broad band (v C = O) The dimaleate is prepared in isopropanol.
CCM Merck plate MP 254 :
eluent acetone, CHC13, n butanol, NH~OH 25%
Rf ~ 0.4 1 spot Microanalysis C20H28N60 + C8H808 ~, , :
``` l~lLOU9S9 Calculated % C-56.00% H-6.00% N=14.00%
Found : C=56.07% H=6.46% N=12.59%
E homo 14 azaeburnamonine (12b-H; 1-C2H5 cis ~somer I) ¦ .HCl ~ H
Example 4 was repeated except that the cis product (I) of Example 2 (9) was used in place of the trans product ~ :
(II) of Example 2 (f). There was obtained 5.7 9 of product ~ (yield 69%). M.P. : 190C.
: 10 IR 3260 cm 1 NH ~ `~
1690 cm~l C = 0 Microanalysis gave the following results~
Calculated for ClgH23N30 : C=73.B %i H=7.45%i N-13-6 % --;
Found : C~73.48%; H=7.35%; N=12.99%.
. , .
The hydrochloride was obtained by adding 4 N HCl to - ~:
a solution of the base in a 1:1 mixture of ethanol and diethyl ether.
EXAMPLE 11 `~:
l-ethoxycarbonylaminomethyl-l-ethyl-indolo(2,3-a)quinolizidine hydrochloride (12b-H; l-C2H5 cis isomer I) -~ ~ .2 HCl 52H50-Co-NH-cH
The procedure of Example 3 was repeated except that the cis product ~I) of Example 2 (g) was used instead of the trans product (II) of Exa~ple 2 (f). There was obtained 2.1 9 of the free base (84% yield). M.P. : 210C.
IR 3400 cm 1 indole NH
3210 cm 1 amide NH
2790 and 2810 cm~l Bohlmann bands 1690 cm 1 carbamate C = 0 Microanalysis gave the following results:
C21H29N302 : C=71.0 %; H=8 17%i N=ll 82%
Found : C=70.85%; H=8.22%i N=11.94%
NMR (CDC13i internal TMS) 1.1 ~ (6H, t, CH3 ethyl and ethyl ester) 1.5 to 3.5 ~ (15H, solid) 3.9 ~ ~2H, q, CH20) 5.65~ (lH, m, NH-amide)
7.25~ (4H, solid, aromatics) 7.9 ~ (lH, s, NH - indole) The hydrochloride salt was prepared using 4N hydro-chloric acid in acetone.
~- 20 Yield : 90%. M.P. : 250C.
~ EXAMPLE 12 -~ l-(N'- ~iethylaminoethy ~-N-ureidomethyl~-l-ethyl-indolo-(2,3-a)quinolizidine (12b-H; l-C2H5 cis isomer I) (c2H5)2NcH2cH2NH-co-NH-cH
The first part of Example 6 was repeated using the cis product I of Example 2 (9) instead of the trans product II
of Example 2 (f). The second part of Example 6 was then .
5~
repeated on a smaller scale, using 3 g of the l-phenoxy carbonylaminomethyl derivative, 1.2 g of diethylaminoethyl amine and 50 ml of methanol. There was thus produced 2.8 g of the above product which ~as an oil.
The di-hydrochloride salt was obtained by treatment with 4N hydrochloric acid in acetone. The salt was isolated by concentrating the acetone solution and recrystallizing from a 1:1 mixture of ethyl acetate and ethanol.
There were obtained 1.8 g of product, melting at 250C. Yield: 48.5% based on the weight of amine base.
IR 3300 cm 1 1640 cm~l Microanalysis gave the following results assuming 1 mole of water of crystallization.
Calculated for C25H39N50. 2HCl. H20 :
C=58.30%; H-8.35%; N=13.74%
Found : C=58.56%; H=8.25%, N=13.60%.
Toxicity LD 50 has been determined per os on mice. The compounds of the invention present a toxicity comparable to that one of vincamine or a lower one. The more toxic (LD 50 :
400 m~/kg; vincamine 450 mg/kg) are those of Examples 2 (f), 3 and 4, the less toxic are those of Examples 5, 10 and 12 where-- as the remaining compounds present an intermediate toxicity. Pharmacology The activity of the compounds of the invention has been researched in the field of femoral and vertebral flows, arterial pressure and cardiac rhythm. Comparison was made with vincamine and with compounds described in French patent publi-cations n 2,285,377 and 2,292,475. The experimentationconducted as still known for vincamine, has shown that the Q~59 compounds of the invention, and more particularly these of Examples 3 and 5;
a) induce an increase of the femoral flow; French patent publications compounds present a similar action but vincamine reduces this flow;
b) induce a strong increase of the vertebral flow; French patent publications compounds do not act at all or induce a moderate increase whereas vincamine reduces this Flow, c) do not affect significantly arterial blood pressure whereas the comparison compounds lower it, d) induce a slight increase of cardiac rhythm whereas French patent publications compounds generally induce a more important increase and vincamine lowers this factor.
From these results the compounds of the invention appear to have a very favourable action in the field of cerebral irrigation, which was confirmed clinically.
Posology . ~
The compounds of the invention may be administered , i.v. or pe~ ss, at doses comparable to those used for vincamine, (dosage units for S to 40 mg).
;' ,,,~
.
, ' .
- ; . , ", ' :~
,,
~- 20 Yield : 90%. M.P. : 250C.
~ EXAMPLE 12 -~ l-(N'- ~iethylaminoethy ~-N-ureidomethyl~-l-ethyl-indolo-(2,3-a)quinolizidine (12b-H; l-C2H5 cis isomer I) (c2H5)2NcH2cH2NH-co-NH-cH
The first part of Example 6 was repeated using the cis product I of Example 2 (9) instead of the trans product II
of Example 2 (f). The second part of Example 6 was then .
5~
repeated on a smaller scale, using 3 g of the l-phenoxy carbonylaminomethyl derivative, 1.2 g of diethylaminoethyl amine and 50 ml of methanol. There was thus produced 2.8 g of the above product which ~as an oil.
The di-hydrochloride salt was obtained by treatment with 4N hydrochloric acid in acetone. The salt was isolated by concentrating the acetone solution and recrystallizing from a 1:1 mixture of ethyl acetate and ethanol.
There were obtained 1.8 g of product, melting at 250C. Yield: 48.5% based on the weight of amine base.
IR 3300 cm 1 1640 cm~l Microanalysis gave the following results assuming 1 mole of water of crystallization.
Calculated for C25H39N50. 2HCl. H20 :
C=58.30%; H-8.35%; N=13.74%
Found : C=58.56%; H=8.25%, N=13.60%.
Toxicity LD 50 has been determined per os on mice. The compounds of the invention present a toxicity comparable to that one of vincamine or a lower one. The more toxic (LD 50 :
400 m~/kg; vincamine 450 mg/kg) are those of Examples 2 (f), 3 and 4, the less toxic are those of Examples 5, 10 and 12 where-- as the remaining compounds present an intermediate toxicity. Pharmacology The activity of the compounds of the invention has been researched in the field of femoral and vertebral flows, arterial pressure and cardiac rhythm. Comparison was made with vincamine and with compounds described in French patent publi-cations n 2,285,377 and 2,292,475. The experimentationconducted as still known for vincamine, has shown that the Q~59 compounds of the invention, and more particularly these of Examples 3 and 5;
a) induce an increase of the femoral flow; French patent publications compounds present a similar action but vincamine reduces this flow;
b) induce a strong increase of the vertebral flow; French patent publications compounds do not act at all or induce a moderate increase whereas vincamine reduces this Flow, c) do not affect significantly arterial blood pressure whereas the comparison compounds lower it, d) induce a slight increase of cardiac rhythm whereas French patent publications compounds generally induce a more important increase and vincamine lowers this factor.
From these results the compounds of the invention appear to have a very favourable action in the field of cerebral irrigation, which was confirmed clinically.
Posology . ~
The compounds of the invention may be administered , i.v. or pe~ ss, at doses comparable to those used for vincamine, (dosage units for S to 40 mg).
;' ,,,~
.
, ' .
- ; . , ", ' :~
,,
Claims (6)
1. Process for the preparation of a compound of the general formula I or II:
(I) (II) wherein R stands for -COOC2H5 or 3',4',5'-trimethoxybenzoylaminomethyl, which comprises reacting the 1-ethyl-1-aminomethyl-indolo-(2,3-a)quinolizidine with ethylchloroformate when R is to be -COOC2H5 and with 3',4',5'-trimethoxybenzoylchloride when R is to be 3',4',5'-trimethoxybenzoylaminomethyl.
(I) (II) wherein R stands for -COOC2H5 or 3',4',5'-trimethoxybenzoylaminomethyl, which comprises reacting the 1-ethyl-1-aminomethyl-indolo-(2,3-a)quinolizidine with ethylchloroformate when R is to be -COOC2H5 and with 3',4',5'-trimethoxybenzoylchloride when R is to be 3',4',5'-trimethoxybenzoylaminomethyl.
2. Process for the preparation of 1-ethoxycarbonyl-aminomethyl-1-ethyl-indolo(2,3-a)quinolizidine (12b-H; 1-C2H5 trans isomer) which comprises reacting 1-ethyl-1-aminomethyl-indolo(2,3-a)quinolizidine (12b-H; 1-C2H5 trans isomer) with ethylchloroformate.
3. Process for the preparation of 1-(3',4',5'-trimethoxybenzoylaminomethyl)-1-ethyl-indolo(2,3-a)quinol-izidine (12b-H, 1-C2H5 trans isomer) which comprises reacting 1-ethyl-1-aminomethyl-indolo(2,3-a)quinolizidine (12b-H, 1-C2H5 trans isomer) with 3,4,5-trimethoxybenzoylchloride.
4. A compound of the general formula I or II:
(I) (II) wherein R is -COOC2H5 or 3',4',5'-trimethoxybenzoylaminomethyl, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
(I) (II) wherein R is -COOC2H5 or 3',4',5'-trimethoxybenzoylaminomethyl, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
5. The 1-ethoxycarbonylaminomethyl-1-ethyl-indolo-(2,3-a)quinolizidine (12b-H; 1-C2H5 trans isomer), when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.
6. The 1-(3',4',5'-trimethoxybenzoylaminomethyl)-1-ethyl-indolo(2,3-a)quinolizidine (12b-H; 1-C2H5 trans isomer), when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB49201 | 1977-11-25 | ||
| GB4920177 | 1977-11-25 |
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| DE (1) | DE2851028A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0079411B1 (en) * | 1981-11-18 | 1987-02-04 | Thal, Claude | Indoloquinolizine derivatives, process for their preparation and their therapeutic use |
| FR2529552B1 (en) * | 1982-07-05 | 1985-09-27 | Centre Nat Rech Scient | NOVEL PROCESS FOR THE PREPARATION OF VINDOLINE SYNTHESIS INTERMEDIATES AND SYNTHESIS INTERMEDIATES |
| HU191454B (en) * | 1984-10-05 | 1987-02-27 | Richter Gedeon Vegyeszeti Gyar Rt.,Hu | Process for producing amides of oktahydro-indolo/2,3-a/quinolyzin-1-yl-alkanecarboxylic acids and pharmaceutically acceptable acid additional salts thereof |
| HU194220B (en) * | 1985-04-19 | 1988-01-28 | Richter Gedeon Vegyeszet | Process for production of derivatives of 1,12 b disubstituated-octahydro-indolo /2,3-a/ quinolisine and medical compounds containing thereof |
| HU195214B (en) * | 1985-04-19 | 1988-04-28 | Richter Gedeon Vegyeszet | Process for producing 12b-substituted-1-(hydroxymethyl)-octahydro-indolo /2,3-a/ quinolizine derivatives and pharmaceutical preparations comprising these compounds |
| FI95572C (en) | 1987-06-22 | 1996-02-26 | Eisai Co Ltd | Process for the preparation of a medicament useful as a piperidine derivative or its pharmaceutical salt |
| PT704439E (en) * | 1993-06-18 | 2001-12-28 | Fujisawa Pharmaceutical Co | A NEW INTERMEDIARY FOR SYNTHETIC USE AND PROCESS FOR THE PREPARATION OF AMINOPIPERAZINE DERIVATIVES |
| FR2713643B1 (en) * | 1993-12-14 | 1996-06-07 | Adir | New analogs of eburnane, process for their preparation and pharmaceutical compositions containing them. |
| FR2713644B1 (en) * | 1993-12-14 | 1996-02-09 | Adir | New analogs of eburnane, process for their preparation and pharmaceutical compositions containing them. |
| CA2490055C (en) † | 2002-06-24 | 2011-10-18 | Saint-Gobain Isover | Insulation panel for supply duct |
| FR2911141B1 (en) * | 2007-01-05 | 2009-02-20 | Servier Lab | NOVEL TRIAZABENZO [A] NAPHTHO [2,1,8-CDE] AZULENE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2911142A1 (en) * | 2007-01-05 | 2008-07-11 | Servier Lab | New amino-pyrroloindole and amino-pyridazinoindole derivatives, are tyrosine hydroxylase inducers, useful e.g. for treating anxiety, depression or memory loss |
| FR2911143A1 (en) * | 2007-01-05 | 2008-07-11 | Servier Lab | Use of neuroprotective compounds to prepare medicaments for treating neurodegenerative diseases |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU167366B (en) * | 1972-09-06 | 1975-09-27 | ||
| BE802387A (en) * | 1973-07-16 | 1973-11-16 | Omnium Chimique Sa | PROCESS FOR PREPARING VINCAMONE AND EPI-21 VINCAMONE FROM TABERSONIN AND NEW INDOLIC DERIVATIVES. |
| HU169916B (en) * | 1974-09-27 | 1977-02-28 | ||
| HU171165B (en) * | 1974-11-26 | 1977-11-28 | Richter Gedeon Vegyeszet | Process for producing oktahydro-indolo-bracket-2,3-a-bracket closed-quinolizine derivatives |
| FR2315277A1 (en) * | 1975-06-25 | 1977-01-21 | Anvar | NEW PENTACYCLIC DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM |
-
1978
- 1978-11-15 ZA ZA00786426A patent/ZA786426B/en unknown
- 1978-11-20 BE BE191824A patent/BE872134A/en not_active IP Right Cessation
- 1978-11-22 NZ NZ188974A patent/NZ188974A/en unknown
- 1978-11-23 PT PT68825A patent/PT68825A/en unknown
- 1978-11-23 AR AR274552A patent/AR218514A1/en active
- 1978-11-23 ES ES475328A patent/ES475328A1/en not_active Expired
- 1978-11-23 AU AU41874/78A patent/AU529108B2/en not_active Expired
- 1978-11-23 AT AT0837478A patent/AT372384B/en active
- 1978-11-23 FI FI783581A patent/FI64372C/en not_active IP Right Cessation
- 1978-11-23 NO NO783958A patent/NO151288C/en unknown
- 1978-11-24 IT IT30171/78A patent/IT1160263B/en active
- 1978-11-24 IN IN851/DEL/78A patent/IN151146B/en unknown
- 1978-11-24 LU LU80576A patent/LU80576A1/en unknown
- 1978-11-24 MX MX787557U patent/MX5529E/en unknown
- 1978-11-24 CA CA316,809A patent/CA1100959A/en not_active Expired
- 1978-11-24 IE IE2328/78A patent/IE47518B1/en unknown
- 1978-11-24 FR FR7833175A patent/FR2423492A1/en active Granted
- 1978-11-24 WO PCT/FR1978/000043 patent/WO1979000319A1/en unknown
- 1978-11-24 NL NL7811562A patent/NL7811562A/en not_active Application Discontinuation
- 1978-11-24 DE DE19782851028 patent/DE2851028A1/en active Granted
- 1978-11-24 FR FR7833176A patent/FR2409755A1/en active Granted
- 1978-11-24 DK DK524978A patent/DK154430C/en not_active IP Right Cessation
- 1978-11-24 JP JP54500118A patent/JPS6147838B2/ja not_active Expired
- 1978-11-24 CH CH683579A patent/CH641181A5/en not_active IP Right Cessation
- 1978-11-25 EG EG669/78A patent/EG13683A/en active
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1979
- 1979-07-23 SE SE7906287A patent/SE431650B/en not_active IP Right Cessation
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1980
- 1980-11-07 SE SE8007845A patent/SE435622B/en not_active IP Right Cessation
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1982
- 1982-12-03 SG SG611/82A patent/SG61182G/en unknown
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1984
- 1984-08-02 HK HK608/84A patent/HK60884A/en unknown
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1985
- 1985-12-30 MY MY29/85A patent/MY8500029A/en unknown
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