Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Patent
1979-07-20
1982-10-12
Springer, David B.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
546 70, 546 71, A61K 31475, C07D40102
Patent
active
043539114
DESCRIPTION:
BRIEF SUMMARY
The invention relates to indolo(2,3-a)quinolizidines, to methods for their preparation and to therapeutic compositions containing them.
The new indolo(2,3-a)quinolizidines according to the invention have the general formulae (I) and (II) ##STR2## wherein R stands for --COOC.sub.2 H.sub.5 --, COOH--, CN, a primary or secondary methylenamino group, a methylenamido group, or wherein R, together with the ring nitrogen of the indole ring, represents one of the groups N--CO--NH--CH.sub.2 or N--CO--; the latter derivatives are D-homo-azaeburnamonines or D-eburnamonines.
The invention also relates to acid addition salts of the above compounds, when applicable.
R may be, for example, a methylenaminocarbalkoxy group, a methylenaminoaryloxycarbonyl group, a methylenaminoalkanoyl group, a methylenaminoalkyl group or a substituted methylenureido group.
Preferred identities of R according to this invention are COOH, NH.sub.2, methylenaminocarbethoxy, methylenamino-(3,4,5-trimethoxy)benzoyl, methylenaminophenoxycarbonyl, methylenureidodiethylaminoethyl, methylenaminopentanoyl, methylenaminopentyl and amidopiperonyl.
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 in admixture with a therapeutically acceptable diluent or carrier.
The above compounds may be prepared according to the invention by condensing 3-(2'-aminoethyl)indole with 1-chloro-4-(A)-4-chlorocarbonyl-hexane, wherein A stands for --COOC.sub.2 H.sub.5 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-substituent of the indole; 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 --COOC.sub.2 H.sub.5 or --CN (2 isomeric forms in each case, i.e., 4 compounds).
All the other derivatives are obtained from these compounds the schemes "Specific Reactions" A=--COOC.sub.2 H.sub.5), or the methylenamino derivative from the nitriles, by reduction with lithium aluminium hydride (see same schemes when A=--CN),
In the following schemes: starting material is the 4-ethoxycarbonyl derivative and the final products are acids or derivatives thereof and starting material is the 4-cyano derivative and the final products are methylamino derivatives thereof. ##STR3##
The invention is illustrated by the following Examples.
EXAMPLE 1
(a) Preparation of
3-[2'-(2"-ethoxycarbonyl-2"-ethyl-5"-chloro-valeroylamino)-ethyl]-indole
To a suspension of 2.5 g (0.0184 mole) of 3-(2'-aminoethyl)indole (tryptamine) in 50 ml dry chloroform containing 2 g (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 product which, recrystallized from a mixture of petroleum ether/isopropyl ether, melted at 76.degree. C. and had a yield of 95%. The results of analysis were as follows:
IR (KBr) 3350 and 3300 cm.sup.-1, NH; 1735 cm.sup.-1, CO ester; 1640 cm.sup.-1, CO amide. Calculated for C.sub.20 H.sub.27 N.sub.2 O.sub.3 Cl: C=63.40%; H=7.18%; N=7.40% Found: C=63.39%; H=7.05%; N=7.51%.
(b) Preparation of
1-[(2'-indol-3"-ylethyl)-3-ethyl-3-ethoxycarbonyl]-2-piperidone
To a suspension of 34.4 g (0.0908 mole) of the above compound in 150 ml of a 1:1 mixture of dry benzene and hexamethylphosphoric/triamide cooled in an ic
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