CA1108146A - Octahydro-indolo [2,3-a] quinolizine compounds - Google Patents

Abstract

Abstract of the Disclosure New pharmacologically active octahydro-indolo[2,3-a]?ui-nolisine derivative of the formula:
wherein Q in hydrogen or an A-CH2-CH2- group and A is cyano or -COOR, wherein R is C1-6 alkyl, are prepared by reacting 2,3,4,6,7,12-hexahydro-indolo[2,3-a]quinolizine with a compound of the formula CH2=CH-A, wherein A has the same meaning as above, and reducing the obtained hexahydro--indolo[2,3-a] quinolizine derivative of the formula

Description

llQ8~4~i The invention relates to pharmaceutically active new indoloquinolizine-monoesters, diesters or nitriles and phar-maceutical compositions containing the same, as well as to a process for the preparation thereof.
The new octahydro-indolo[2,3-a] quinolizine derivatives according to the invention, which contain one or two cyanoethyl group/s/ or one or two alkoxycarbonylethyl group/s/ in position 1, correspond to the general formulae /Ia/ and /Ib/, ~ ~ .

, ~ /I a/

H

CH

A
wherein A represents a cyano group or a group of the formula -COOR, and R is a Cl 6 alkyl group. The pharmaceutically acceptable acid addition salts of the above compounds are also ' within the scope of the invention.
The alkyl group represented by symbol R is a straight-chained or hranched Cl 6 alkyl group, such as methyl, ethyl, , ~.

:

08~6 n-propyl, isopropyl, n-butyl~ isobutyl, tert.-butyl, amyl, isoamyl, n-hexyl or isohexyl group.
The most preferred representatives of the compounds having the gen-eral formula /Ia/ are those wherein A represents cyano group, methoxycarbonyl group or ethoxycarbonyl group. Of the compounds having the general formula /Ib/ the derivative wherein A is methoxycarbonyl group is the most preferred one. The pharmaceutically acceptable acid addition salts of the above com-pounds are equally preferred.
The compounds of the general formulae /Ia/ and /Ib/ are asymmetric in structure, thus they can be resolved in a manner known per se to obtain the respective optically active compounds. Both the racemic and the optical-ly active compounds of the general formulae /Ia/ and /Ib/ are within the scope of the invention.
The compounds of the general formulae /Ia/ and /Ib/ and the pharm-aceutically acceptable acid addition salts thereof possess vasodilating ef-fects and can be applied in the therapy in the form of pharmaceutical compo-sitions.
The novel compounds of formula Ia or Ib can be prepared by reducing a compound of the formula IIa or IIb :
~o I ~ J ~, H

N(3 Ilb ~ ~-CH2-CH2 .'..................................... gH2 .
~ - 2 -.~

or an acid addition salt thereof, to obtain a compound of formula Ia or Ib, or an acid addition salt thereof, and, if required converting one ester to another ester by transesterification or hydrolysing a nitrile compound to an ester or converting an acid addition salt to the corresponding free base or converting a free base to a pharmaceutically acceptable acid addition salt.
Hexahydro intermediates of the general formulae /IIa/ and /IIb/
above, wherein A represents cyano group, have already been described in the United States patent specification No. 3,536,721. These compounds have no pharmaceutical effect. According to the process described in the cited reference the products obtained should always be subjected to chromatographi-cal purification, thus yields exceeding 30% cannot be attained. On the contrary, the known hexahydro intermediates of the general formulae /IIa/ and /IIb/, wherein A is cyano group, can be prepared with a yield of 86% by the process of the invention. Those compounds of the general formulae /IIa/ and /IIb/, wherein A is a -COOR group and R is a Cl 6 alkyl group, are novel sub-stances.
The compound of formula IIa or IIb can be obtained by reacting a compound of formula III
::`

~rl 111 ~

~': \/
; 20 with a compound of formula IV
H2=cH-A IV
wherein A is as defined above.
Thus, the new compounds of the generalformulae /Ia/ and /Ib/, wherein A is cyano group or a group of the formula -COOR and R is a Cl 6 alkyl group, or the pharaceutically acceptable acid addition salts of these compounds can be prepared according to the invention as follows:

,~

-

2,3,~,6,7,12-he~ahydro-indolo[2,3-a]quinolizine of the formula /III/
- above is reacted with a compound of the general formula /IV/, above wherein A
is as defined above, the resulting compound of the general formula /IIa/
and/or /IIb/ is, optionally after converting it into an acid addition salt, reduced, the resulting compounds of the general formulae /Ia/ and /Ib/, wherein A is as defined above, are optionally separated from each ' :

''' .

~1, h ~ - 3a -1~6 other, and, if desired, a thus-obtained ester is transesterified or a thus~obtained nitril is converted into ester in a manner known per se, and, if desired, a compound of the general formula /Ia/ or ~Ib/, wherein A is as defined above, is converted into its pharmaceutically acceptable acid addition salt.
The starting substance of the formula /III/ can be prepared as described in J. Heterocycl. Chem. 3, 101 /1966/.
The formula /III/ compound is reacted with a compound of the general formula /IV/, wherein A is as defined above, prefer-ably in an inert organic solvent, e.g. a halogenated hydrocarbon,such as dichloromethane. When a compound of the general formula /IV/, wherein A is a group of the formula -COOR, is applied as reactant, the reaction is performed preferably in a mixture of an inert organic solvent as defined above and an alcohol of the general formula R-OH, wherein R corresponds to substituent R of the reactant. The reaction temperature is not critical, it is -preferred, however, to perform the reaction under mild conditions at room temperature. The reaction time is not critical, too, it may vary, however, between 0.5 and 3 days depending on the reaction temperature. The reaction can be performed optionally in an inert gas atmosphere, such as nitrogen or argon atmosphere.
The reaction mixture is processed in a manner known per se, e.g. by evaporating the solvent or solvent mixture and optionally removing the excess of the reactant of the general formula /IV/ by treating the residue with an appropriate solvent, such as petroleum ether. If desired, the resulting compound/s/
of the general formula/e/ /IIa/ and/or /IIb/, obtained most frequently as crystalline substances, can be converted into acid addition salts. The acid addition salts are prepared e.g. by dissolving the base in an inert organic solvent, preferably in an :

~108~

aliphatic alcohol, and adding the appropriate acid to the resulting solution. As acid preferably a mineral acid, such as a hydrogen halide or a perhaloacid / e.g. perchloric acid/
is applied.
The compound/s/ of the general formula/e/ /IIa/ and/or /IIb/ can be reduced with a chemical reducing agent or with catalytically activated hydrogen. In this step the free basis or the acid addition salts, furthermore the pure mono- or disubstituted compounds or mixtures thereof can equally be applied as starting substances.
The reducing agent and the reaction conditions are selected so that the indoloquinolisine ring is saturated without the simultaneous reduction of the cyano group optionally present.
When a chemical reducing agent is applied in the reaction, it is preferable to apply a complex metal hydride, particularly a ' borohydride, such as lithium, sodium or potassium borohydride.
The borohydride reduction is performed in the presence of a solvent or suspending agent inert towards the reaction. As reaction medium preferably an aliphatic alcohol, such as methanol, or an aqueous alcohol, such as aqueous methanol is applied.
The borohydride is added to the reaction mixture in excess, preferably in a 1.5 to 7-fold molar excess. The reaction temperature and reaction time are not decisive factors; they depend primarily on the reactivities of the starting substances.
The reaction is performed generally at a temperature of about QC, and the mixture is stirred for about 0.25 to 3 hours after admix-ing the reactants with each other.
When the reduction is performed with catalytically activated hydrogen, preferably a metal, such as palladium, platinum, nickel, iron, copper, cobalt, chromium, zinc, molybdenum, 4~

tungsten, etc., or an oxide or sulfide of such metals is applied as catalyst. Supported catalysts can be applied as well, decreasing thereby the amount of expensive noble metal necessary to the reduction. As support e.g. carbon /particularly charcoal/, silicon dioxide, aluminum oxide or sulfates or carbonates of alkaline earth metals can be applied.
When the reduction is performed with catalytically activated hydrogen, it is p^e ferred to apply palladium/par-ticularly palladium-on-charcoal/ or Raney-nickel as catalyst;
the catalyst is selected, however, always by taking into account the properties of the substance to be reduced and the reaction conditions.
Catalytic hydrogenation is performed in a solvent inert towards the reaction, such as an alcohol, a halogenated hydro-carbon, ethyl acetate, glacial acetic acid, etc., or mixtures ` thereof. Aliphatic alcohols, such as methanol and ethanol, furthermore halogenated hydrocarbons, such as dichloromethane and dichloroethane, and mixtures of such solvents proved to be particularly preferable. When platinum oxide is applied as catalyst, it is perferred to perform the reaction in a neutral or -~ slightly acidic medium, whereas when Raney-nickel is applied as catalyst, preferably a neutral or alkaline medium is used.
The temperature, pressure and time of the catalytic reduçtion step may vary within wide limits depending on the starting substances, it is preferred, however, to perform the reaction at room temperature under atmospheric pressure until hydrogen uptake ceases. Hydrogen uptake ceases generally within a period of 10 minutes to 5 hours.
According to a preferred method of the invention the catalytic hydrogenation is performed so that the catalyst, :

' ' ., ' :~Q8~

preferably palladium-on~charcoal, is washed with water and the solvent applied in the hydrogenation step, preferably methanol, then the catalyst is prehydrogenated, thereafter a solution of the starting substance [compound/s/ of the general formula/e/
/IIa/ and/or /IIb/ or acid addition salts thereof] in the above solvent is admixed with the catalyst, and the mixture is hydro-genated preferably at room temperature under stmospheric pressure until the hydrogen uptake ceases.
When a mixture of the compounds of the general formulae /Ia/ and /Ib/ is obtained in the reduction, the individual components can be separated from the mixture according to known techniques. One of these techniques is preparative layer chroma-tography; in this instance separation is based on the fact that the Rf value of the disubstituted compound of the general formula /Ib/ is higher than that of the monosubstituted derivative of the general formula /Ia/.
As adsorbent preferably silica gel Merck PF254_366 is applied. Various solvent mixtures can be applied as eluting agent; mixtures of benzene and methanol, particularly a 14:2 mixture, are preferred [Halpaap, H.: Chemie-Ing.-Techn. 35, 488 /1963/].
The end-products of the general formulae /Ia/ and /Ib/
were subjected to I.R. analysis. The Bohlmann bands appearing in the I.R. spectra of both compound types indicate that the hydrogen atoms in positions 12b and 1, furthermore the hydrogen atom in position 12b and the -CH2-CH2-A group in position 1 are of 3 conformation, i.e. the compounds of the general formulae /Ia/ and /Ib/ are of trans configuration.
Those compounds of the general formula /Ia/ or /Ib/, 3Q wherein A is a -COQR group and R is Cl 6 alkyl, can be subjected to transesterification in a manner known per se. Thus if one of ''- X

the esters has already been prepared, this compound can be con-verted easily into any desired other ester. Transesterification can be performed by boiling a compound of the general formula /Ia/
or /Ib/, wherein A is a -COOR group and R is Cl 6 alkyl, in an alcohol corresponding to the new ester group to be introduced into the molecule in the presence of an alkali metal alcoholate, preferably sodium alcoholate, corresponding to this alcohol. If desired and possible, the alcohol liberated in the transesterifi-cation process, the boiling point of which is lower than that of the alcohol applied as solvent, is continuously removed from the mixture by distillation.
Those compounds of the general formula /Ia/ or /Ib/, wherein A represents cyano group, can be converted into the respective esters, i.e. to compounds wherein A is a -COOR group and R is a Cl 6 alkyl group. In this instance one can proceed e.g. by boiling a compound of the general formula /Ia/ or /Ib/, wherein A is cyano group, in a dilute aqueous solution of a mineral acid /such as hydrochloric or sulfuric acid/ or of an ; inorganic base /such as sodium hydroxide, potassium hydroxide, etc./, and esterifying the resulting carboxylic acid in a manner known per se. In this latter step the carboxylic acid can be boiled in an alcohol corresponding to the ester group to be introduced into the molecule. According to another method the carboxylic acid is converted e.g. into its silver salt and this salt is reacted with an alkyl halide, preferably iodide, corres-ponding to substituent R *o be introduced into the molecule. In a still further method the carboxylic acid is converted first into a reactive derivative, preferably an acid halide or anhydride, and ; the resulting reactive derivative is reacted with an alcohol of 3Q the general formula R~OH, wherein R is a Cl 6 alkyl group, corresponding to the R substituent to be introduced into the molecule. The cyano compounds can also be converted into esters by reacting them with an excess of an alcohol corresponding to the ester group to be introduced in the presence of hydrochloric acid; in this instance the desired ester is obtained through an iminoether derivative.
If desired, the compounds of the general formulae /Ia/
and /Ib/, whereln A is as defined above, can be purified e.g. by recrystallization. As solvent e.g. aliphatic alcohols, such as methanol, ethanol or isopropanol, aliphatic ethers, such as diethyl ether, etc. can be applied.
The compounds prepared according to the invention can also be purified by preparative layer chromatography. In this instance preferably silica gel Merck PF254 366 is applied as adsorbent, and various solvent combinations, such as mixtures of benzene and methanol /preferably a 14:2 or 14:3 mixture/ can be applied as developing solvents. As eluting agent preferably an aliphatic ether, such as diethyl ether, or an aliphatic ketone, such as acetone, is applied.
If desired, the compounds of the general formulae /Ia/
and /Ib/ can be converted into their pharmaceutically acceptable acid addition salts. In the salt formation e.g. the following acids can be applied: mineral acids, such as hydrogen halides /e.g. hydrochloric acid, hydrobromic acid/, sulfuric acid, phosphoric acid, etc., organic carboxylic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, lactic ;~ acid, benzoic acid or cynnamic acid; alkylsulfonic acids, such as methanesulfonic acid; cyclohexylsulfonic acids; aspartic acid, glutamic acid, N-acetyl~aspartic acid, N~acetyl-glutamic acid, etc.
X

11~8~

The salt-formation is performed preferably in an inert solvent, particularly in an aliphatic alcohol, such as methanol, by dissolving the free base of the general formula /Ia/ or /Ib/
in said solvent and adding the appropriate acid thereto until the pH of the mixture becomes slightly acidic /about 6/. Thereafter the salt is separated from the reaction mixture, preferably by precipitating it with a water-immiscible organic solvent, such as diethyl ether.
If the compounds of the general formulae /Ia/ and /Ib/
are obtained in the form of their acid addition salts, they can be treated with a base in an appropriate solvent to convert them into the free bases. In this instance e.g. the salt is dissolved in an appropriate solvent or solvent mixture, such as in aqueous ; acetone, and the calculated amount of the base, such as concen-trated aqueous ammonia, is added to this solution.
The compounds of the general formulae /Ia/ and /Ib/ are obtained by the process of the invention with high yields and in easily identifiable forms. The elementary analysis date of the new compounds are in good agreement with the calculated values.
The positions of the characteristic I.R. bands, the values of the NMR signals and the data of mass spectra prove unambi~uously that the products of the general formulae /Ia/ and /Ib/ correspond to the expected structures.
The pharmaceological examinations have shown that the compounds of the general formulae /Ia/ and /Ib/, wherein A is as defined above, exert significant vasodilating effects, which appear primarily in connection with the significant increase of blood flow in the cerebrum and limbs.
The pharmacological tests were performed on dogs narcotized with chloralose-urethan. The blood flow of the limbs ~' ~Q~

was measured at the arteria femoralis, whereas the cerebral blood flow was measured at the arteria carotis interna and arteria vertebralis. The vascular resistances at circulation were calculated from the appropriate values of blood pressure and blood flow.
The substances to be tested were administered intra-venously in dosages of 1 mg/kg. The percentage changes were calculated and averaged over the test group consisting of 6 animals. The average values are listed in Table 1, along with the respective data of apovincaminic acid ethyl ester, used to advantage in the therapy.
Remarks to Table 1:
1: blood pressure 2: pulse rate

3: cerebral blood flow ; 4: cerebral vascular resistance ~: blood flow in the limbs 6: vascular resistance in the limbs A: 1-/2'-methoxycarbonyl~ethyl/-1,2,3,4,6,7,12,12b-octahydro-,: .
indolo[2,3-a]quinolizine B: 1,1-di-/2'-methoxycarbonyl-ethyl/-1,2,3,4,6,7,12,12b-octa-hydro-indo~X2,3-a]quinolizine C: 1-/2'-ethoxycarbonyl-ethyl/-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine D: 1-/2'-cyano-ethyl/-1,2,3,4,6,7,12,12b~c tahydro-indolo-[2,3-a] quinolizine Ref.: aprovincaminic acid ethyl ester /reference substance/

~' 11981~6 Tabl . .
Substance tested 1 2 3 4 5 6 A -8 +12 0 -3 +148 -65 B -52 -5 +2 -7 +140 -65 C -25 +35 +78 -54 +93 -61 D -18 +27 +41 -43 +120 -54 ref~ -28 +14 +16 -20 +58 -35 The data of Table 1 clearly indicate that compounds A
and B markedly increase the blood flow of the limbs; in this respect they are about 2.5 times more active than the reference substance. Compounds C and D significantly increase the cerebral blood flow; they are 2.5 times and, resp., 5 times more active than the reference substance.
The prospective dosages of the new compounds according to the invention, when administered enterally in the human therapy, may range from some tenth mg/kg to 1 mg/kg. Of course, the actual dosage is selected always on the basis of the require-ments of the patient and the experiences of the physician, by taking into account the relevant factors of the disorder to be treated. It should be stressed that the above dosage range is only informative in nature and cannot be interpreted as a limit- -ation of the scope of the invention.
.~ :
- The compounds of the general formulae /Ia/ and /Ib/ can ~be converted into pharmaceutical compositions by admixing them ;with non-toxic, inert, solid or liquid pharmaceutical carriers and/or diluents usable in the preparation of enteral or parenteral compositions. As carrier or diluent e.g. water, gelatine, lactose, starch, pectine, magnesium stearate, stearic acid, talc, vegetable oils /such as sunflower oil, olive oil, peanut oil, etc./, - 12 ~

1~81~16 gum arabic, polyalkylene glycols, vaseline, etc. can be applied.
The pharmaceutical compositions may be e.g. solid compositions /such as round or edged tablets, dragees, capsules, pills, suppositories, etc / or liquid compositions /such as oily or aqueous solutions, suspensions, emulsions, syrups, soft gelatine capsules, injectable oily or aqueous solutions or suspensions, etc./. The amount of solid carrier may vary within wide limits;
a dosage unit contains preferably about 25 mg to 1 g of solid carrier. If desired or necessary, the compositions may also contain conventional pharmaceutical auxiliary agents, such as preservatives, stabilizing agents, wetting agents, emulsifying agents, salts for adjusting the osmotic pressure, buffers, , flavouring agents, odouring agents, etc. The eompositions may eontain more than one eompound of the invention and optionally i also other pharmaeeutically valuable substances. The compositions are prepared preferably in the form of unit dosages corresponding ; to the desired manner of administration. The pharmaeeutieal eompositions ean be prepared by methods known in the art, such as sieving, mixing, granulating, pressing, dissolving, ete. If desired, the eompositions ean be subjeeted to further eonventional pharmaeeutieal operations /e.g. sterilization/.
The invention is elucidated in detail by the aid of the following non-limiting Examples.
Example Mixture of 1-/2'-methoxyearbonyl-ethyl/-2,3,4,6,7,12-hexahydro-lH-indolo[2,3-a]quinolizinium-perehlorate and l,l-di--/2'-methoxyearbonyl-ethyl/-2,3,4,6,7,12-hexahydro-lH-indolo-[2,3-a]quinolizinium-perchlorate 2.24 g /10.0 mmoles/ or 2,3,4,6,7,12-hexahydroindolo-~2,3-a]quinolizine are dissolved in 100 ml of dichloromethane, ,' ~ - 13 -l~Q~

and Q~2 ml of methanol and 2.10 g ~24~4 mmoles/ of methylacrylate are added to the solution. The reaction mixture is allowed to stand at room temperature for 2 days. The solvent is evaporated in vacuo and the residue is triturated with petroleum ether in order to remove the excess of methyl acrylate. The solid residue is dissolved in 15 ml of methanol, the solution is acidified to pH 6 with 70% perchloric acid, the separated salt is filtered off, and washed with ether.

4.0 g of the title mixture are obtained; m.p.:
135-160C.
I.R. spectrum /KBr/: 3200 /indole NH/, 1735, 1718 /COOCH3/, 1630 and 1550 /C=N/ cm Example 2 `~
1-/2'-Methoxycarbonyl-ethyl/-1,2,3,4,6,7,12,12b-octa-hydro-indolo[2,3-a]quinolizine and 1,1-di-/2'-methoxycarbonyl-ethyl/-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine 4.0 g of the mixture obtained as described in Example 1 are hydrogenated in 100 ml of methanol in the presence of 2.0 g of palladium-on-charcoal. When the hydrogen uptake ceases the catalyst is filtered off, the filtrate is evaporated to dryness, and the residue is dissolved in aqueous methanol. The solution is rendered alkaline with 5% aqueous sodium carbonate solution and extracted with dichloromethane. The dichloromethane solutions are combined, dried, filtered, and the filtrate is evaporated to dryness. The components of the resulting mixture are separated from each other by preparative layer chromatography /adsorbent: silica gel Merck PF254+366, developing solvent: 14:2 mixture of benzene and methanol, eluting agent: acetone/. The Rf value of the l,l-disubstituted compound is greater than that 3Q of the l~monosubstituted derivative.

1.

~81~l~

1.6 g /4Q %~ of 1,l~di-~2~-methoxycarbonyl-ethyl/-1,2,3,4,6,7,12,12b-octahydro~indolo~2,3~a] quinolizine are obtained; m.p.: 226C /recrystallized from methanol/.
I.R. spectrum /KBr/: 3300 /NH/, 2790, 2740 /Bohlmann bands/, 1732, 1720 /COOCH3/ cm 1 Mass spectrum m/e %: 398 /16,M/; 397/llk 383/1~; 339/2/;
325/100/; 311/4/; 237/15/; 197/50/; 185/35/; 170/50/; 169/75/.
NMR-spectrum /CDC13/: ~ = 9.00 /lH, s, indole NH/, 7.30 /4H, m, aromatic protons/, 3.80 /eH, s, COOCH3/, 3.56 /3H, s, COOCH3/ ppm-In the separation process 0.8 g /25 %/ of 1-/2'-methoxy-carbonyl-ethyl/-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]-quinolizine are obtained. The hydrochloride of the product melts at 245C under decomposition.
I.R. spectrum /KBr/: 2780 /Bohlmann band/, 1725 /COOCH3/ cm Mass spectrum m/e /%/: 312/90,M/; 311/100/; 297/3/;
281/10/; 253/2/; 239/70/; 225/10/; 197/40/; 170/22/; 169/23/.
Example 3 1-/2'-Ethoxycarbonyl-ethyl/-2,3,4,6,7,12-hexahydro-lH-indolo[2,3-a]quinolizinium-perchlorate 10.1 g /45 mmoles/ of 2,3,4,6,7,12-hexahydro-indolo-[2,3-a]~uinolizine are dissolved in 230 ml of dichloromethane, 4.5 ml of ethanol and 5.1 g /50 mmoles/ of ethyl acrylate are added to the solution, and the reaction mixture is allowed to stand at room temperature for 2 days. The solvent is evaporated in vacuo, the residue is admixed with 70 ml of ethanol, and the solution is acidified to pH 6 with 70% perchloric acid. The separated substance is filtered off and washed with ethanol and ether.

81~6 12.5 g ~65 %/ of the title compound are obtained;
m.p.: 166C.
I.R. spectrum /KBr/: 3240 /indole NH/, 1725 /COOC2H5/, 1630, 1550 /C=N/ cm Example 4 1-/2 ~ -Ethoxycarbonyl-ethyl/-1,2,3,4,6, 7 l 12 ~12b-octa-hydro-indolo [2l 3-a]quinolizine hydrochloride 6.0 g /14 mmoles/ of the product of Example 3 are dissolved in a mixture of 90 ml of ethanol and 30 ml of di-chloromethane, and the mixture is hydrogenated in the presence of 10 g of palladium-on-charcoal. After the uptake of the calculated amount of hydrogen /about 1 hour/ the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is admixed with 50 ml of water, the mixture is rendered alkaline with 5% aqueous sodium carbonate solution, and the alkaline mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated.
The oily residue is dissolved in 20 ml of ethanol, the solution is acidified to pH 6 with ethanolic hydrochloric acid, the separated substance is filtered off, and washed with a small amount of alcohol and ether.
3.4 g /68 %/ of the title compound are obtained;
m.p.: 244C / after recrystallization from ethanol/.
I.R. spectrum /KBr/: 3145 /indole NH/, 2790l 2730 /Bohlmann bands/, 1724 /COOC2H5/ cm ; NMR spectrum /CDC13/: ~ = 8.80 /lH~ s/ indole NH/, 7. 30 /4H~ m, aromatic protons/, 4.18 /2H~ q, COOC_ 2CH3/~ 1.25 /3H~ t, COOCH2C_ 3/ ppm.
Mass spectrum m/e /%/: 326/85,M/; 325/95/r 296/17/;
3Q 281~18/; 253/3/i 239/lOQ/; 225/14/; 137/40/; 185/13/; 170/35/;

~ 16 .. ~1 ~:

Example 5 1-/2l-Ethoxycarbonyl~ethyl/-2,3!4,6,7,12-hexahydro--lH-indolo[2,3-a]quinolizine 2.2g /10 mmoles/ of 2,3,4,6,7,12-hexahydroindolo-[2,3-a]quinolisine are dissolved in 100 ml of dichloromethane, 0.5 ml of ethanol and 2.3 g /25 mmoles/ of ethyl acrylate are added to the solution, and the mixture is allowed to stand at room temperature for 2 days under argon atmosphere. The solvent is evaporated in vacuo, the residue is triturated with 3x3 ml of petroleum ether, the liquid is decanted, and the solid is dried.
2.75 g /86 %/ of the title compound are obtained;
m.p.: 72-74C.
Example 6 1-/2'-Ethoxycarbonyl-ethyl/-1,2,3,4,6,7,12,12b-octa-hydro-indolo[2,3-a]quinolizine hydrochloride 2.5 g /7.7 mmoles/ of the product of Example 5 are dissolved in 150 ml of ethanol, and the solution is hydrogenated in the presence of 2 g of palladium-on-charcoal. After the uptake of the calculated amount of hydrogen /about 30 minutes/ the catalyst is filtered off, and the solvent is evaporated in vacuo.
The residue is dissolved in 10 ml of ethanol, the pH of the solution is adjusted to 5 with methanolic hydrochloric acid, the separated precipitate is filtered off, washed with ethanol and ether, and dried.
1.2 g /50 %/ of the title compound are obtained. The physical constants of the product are identical with those of the compound prepared according to Example 4.

:

~1 Example 7 l-~?'Ethoxycarbonyl~ethyl/-1,2,3,4,6,7,12,12b-octa-hydro-indolo[2,3-a]quinolizine hydrochloride 0.35 g /1 mmole/ of 1-/2'-methoxycarbonyl-ethyl/-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine hydro-chloride are partitioned between 10 ml of dichloromethane and 3 ml of 5~ aqueous sodium carbonate solution, and the aqueous phase is extracted with 2x3 ml of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated. The oily residue is dissolved in 15 ml of absolute ethanol, 50 mg of sodium ethoxide are added to the solution, and the mixture is boiled for 2 hours. Thereafter the mixture is cooled, the sodium ethoxide is decomposed with glacial acetic acid, and the solution is evaporated to dryness in vacuo.
The residue is admixed with 10 ml of 5~ aqueous sodium carbonate solution, and the mixture is extracted with 20 ml of dichloro-methane. The organic phase is filtered, the filtrate is dried over magnesium sulfate, filtered again, and then evaporated in vacuo to dryness. The obtained 0.30 g of oily residue are dissolved in 2 ml of ethanol, the solution is acidified to pH 6 with ethanolic hydrochloric acid, the separated salt is filtered off, washed with ethanol and ether, and dried.
0.25 g /78 ~/ of the title compound are obtained;
m.p.: 244C.
Example 8 1-/2'-Cyano-ethyl/-2,3,4,6,7,12-hexahydro-lH-indolo-[2,3-a]~uinolizinium-perchlorate 2.24 g /10 mmoles/ of 2,3,4,6,7,12-hexahydro-indolo-[2,3-a] quinolizine are dissolved in 100 ml of dichloromethane, ::
3Q 1.25 g /23 mmoles~ of acrylonitrile are added to the solution, and the reaction mixture is allowed to stand at room temperature for 2 days. The solvent is evaporated in vacuo, the residue is dissolved in 20 ml of methanol, and the solution is acidified to p~6 with 70% perchloric acid. The separated crystalline substance is filtered off and washed with ether.
3.2 g /86 %/ of the title compound are obtained;
m.p.: 210C /decomposition/.
I.R. spectrum /KBr/: 3~80 /indole NH/, 2280 /CN/, 1625, 1550 /C-N/ cm Example 9 1-/2'-Cyano-eth~ 2~3~4~6,7~12~12b-octahydro-ind [2,3-a~ quinolizine hydrochloride 2.50 g /6.6 mmoles/ of the product of Example 8 are hydrogenated in 120 ml of methanol in the presence of 2.0 g of palladium-on-charcoal. After the uptake of the calculated amount ; of hydrogen /about 25 minutes/ the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is admixed with 30 ml of water, the mixture is rendered alkaline with aqueous sodium carbonate solution, and extracted with dichloromethane.
The dichloromethane solutions are combined, dried, filtered, and the filtrate is evaporated. The oily residue is dissolved in 10 ml of methanol, and the solution is acidified to pH 6 with methanolic hydrochloric acid. The separated substance is filtered off, washed with ether and dried.
1.5 g /72 ~/ of the title compound are obtained;
m.p.: 178C /decomposition/.
I.R. spectrum /KBr/: 1610 /aromatic vibration/, 2235 /CN/ cm Mass spectrum m/e /~/: 279/45,M/; 272/38/; 239/100/;
3Q 197/14/; 170/11/; 169~13~
`:

Example lQ
Tablets containing 1-/2'~ethoxycarbonyl-ethyl/-1,2,3,4,6,7,12,12b-octahydro~indolo[2,3-a] quinolizine hydro-chloride Composition of one tablet:
1-/2'-ethoxycarbonyl-ethyl/-1,2,3,4,6,7,12,12b-octahydro-indolo-[2,3-a] quinolizine hydrochloride /active principle/ 5 mg gelatine 3 mg magnesium stearate 2 mg talc 5 mg potato starch 40 mg lactose 95 mg The active principle is admixed with the lactose and 75% of the potato starch. The resulting homogeneous mixture is kneaded with an a~ueous solution of the gelatine, the wet mass is granulated, and the granules are dried. The granules are admixed with the talc, the magnesium stearate and the remaining 25% of the potato stearch, and the mixture is compressed into tablets. If desired, the tablet can be provided with a dividing line in order to facilitate dosage.

"', ~

' ~

~ - 20 -xi .

Claims (29)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing an octahydro-indolo[2,3-a]
quinolizine of formula Ia or Ib, Ia Ib wherein A represents a cyano group or a group of the formula -COOR and R is a C1-6 alkyl group, or a pharmaceutically accept-able acid addition salt thereof, which process comprises reducing a compound of the formula IIa or IIb IIa IIb or an acid addition salt thereof, to obtain a compound of formula Ia or Ib, or an acid addition salt thereof, and, if required con-verting one ester to another ester by transesterification or hydrolysing a nitrile compound to an ester or converting an acid addition salt to the corresponding free base or converting a free base to a pharmaceutically acceptable acid addition salt.

2. A process as claimed in claim 1 wherein the compound of formula IIa or IIb is obtained by reacting a compound of formula III

III

with a compound of formula IV
CH2=CH-A IV
wherein A is as defined in claim 1.

3. A process as claimed in claim 2, wherein the compound of formula IV is reacted with the compound of formula III in an inert organic solvent or solvent mixture,

4. A process as claimed in claim 3, wherein a halogenated hydrocarbon or a mixture of a halogenated hydrocarbon and an ali-phatic alcohol is used as solvent.

5. A process as claimed in claim 1, 2 or 3 wherein the compound of formula IIa or IIb is converted into acid addition salts before reduction.

6. A process as claimed in claim 1, 2 or 3 wherein the reduction of the compound of formula IIa or IIb is carried out on the free base.

7. A process as claimed in claim 1, 2 or 3 wherein the reduction is carried out with catalytically activated hydrogen.

8. A process as claimed in claim 1, 2 or 3, wherein the reduction is carried out with catalytically activated hydrogen and palladium-on-charcoal is used as catalyst.

9. A process as claimed in claim 1, 2 or 3 wherein the reduction is carried out in a solvent or solvent mixture with catalytically activated hydrogen and palladium on charcoal as catalyst.

10. A process as claimed in claim 1, 2 or 3, wherein the reduction is carried out with an aliphatic alcohol or a mixture of an aliphatic alcohol and a halogenated hydrocarbon as solvent, with catalytically activated hydrogen and palladium on charcoal as catalyst.

11. A process as claimed in claim 1, 2 or 3 which includes the further step that compounds of formula Ia and Ib are sepa-rated from each other by preparative layer chromatography.

12. A process as claimed in claim 1, 2 or 3 which includes the step that a compound of formula Ia or Ib is converted into its pharmaceutically acceptable acid addition salt.

13. A process as claimed in claim 1, 2 or 3 wherein a com-pound of formula IIa in which A is methoxycarbonyl, is converted into a compound of formula Ia in which A is methoxycarbonyl.

14. A process as claimed in claim 1, 2 or 3 wherein a compound of formula IIa, in which A is ethoxycarbonyl is con-verted into a compound of formula Ia in which A is ethoxycarbonyl.

15. A process as claimed in claim 1, 2 or 3 wherein a compound of formula IIa in which A is cyano, is converted into a compound of formula Ia in which A is cyano.

16. A process as claimed in claim 1, 2 or 3, wherein a compound of formula IIb in which A is methoxycarbonyl, is con-verted into a compound of formula Ib in which A is methoxy-carbonyl.

17. A compound of formula Ia or Ib, as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, when prepared by a process as claimed in claim 1 or an obvious chemi-cal equivalent thereof.

18. A process for preparing 1-(2'-methoxycarbonyl-ethyl) 1,2,3,4,6,7,12,12b- octahydro[2,3-a]quinolizine and 1,1-di-(2'-methoxycarbonyl-ethyl)-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]
quinolizine and their hydrochloride salts which comprises reduc-ing a mixture of 1-(2'-methoxycarbonyl-ethyl)-2,3,4,6,7,12-hexa-hydro-1H-indolo[2,3-a]quinolizinium perchlorate and 1,1-di-(2'-methoxycarbonyl-ethyl)-2,3,4,6,7,12-hexahydro-1H-indolo[2,3-a]
quinolizinium perchlorate by hydrogenation in methanol and in the presence of palladium on charcoal catalyst, followed by separat-ing the product of reduction by preparative layer chromatography to obtain the desired compounds and further followed, if required, by reaction with hydrogen chloride,

19. A process as claimed in claim 18 wherein the mixture 1-(2'-methoxycarbonyl-ethyl)-2,3,4,6,7,12-hexahydro-1H-indolo [2,3-a]quinolizinium perchlorate and 1,1-di-(2'-methoxycarbonyl-ethyl)-2,3,4,6,7,12-hexahydro-1H-indolo[2,3-a]quinolizinium per-chlorate is obtained by reacting 2,3,4,6,7,12-hexahydro-indolo [2,3-a]quinolizine with methyl methacrylate, followed by acidifi-cation with perchloric acid.

20. 1-(2'-Methoxycarbonyl-ethyl)-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine or 1,1-di(2'-methoxycarbonyl-ethyl)-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine or their hydrochloride salts when prepared by a process according to claim 18 or 19 or an obvious chemical equivalent thereof.

21. A process for preparing 1-(2'-ethoxycarbonyl-ethyl)-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine and its hydrochloride salt which comprises reducing 1-(2'-ethoxycarbonyl-ethyl)-2,3,4,6,7,12-hexahydro-lH-indolo[2,3-a]quinolizinium per-chlorate by hydrogenation in ethanol and in the presence of a palladium on charcoal catalyst followed, if required, by reaction with hydrogen chloride.

22. A process as claimed in claim 21 wherein the 1-(2'-ethoxycarbonyl-ethyl)-2,3,4,6,7,12-hexahydro-1H-indolo[2,3-a]
quinolizinium perchlorate is obtained by reacting 2,3,4,6,7,12-hexahydro-indolo[,3-a]quinolizine with ethyl acrylate, followed by acidification with perchloric acid.

23. 1-(2'-Ethoxycarbonyl-ethyl)-1,2,3,4,6,7,12,12b-octa-hydro-indolo[2,3-a]quinolizine and its hydrochloride salt when prepared by a process according to claim 21 or 22 or an obvious chemical equivalent thereof.

24. A process for preparing 1-(2'-ethoxycarbonyl-ethyl)-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine and its hydrochloride salt which comprises reducing 1-(2'-ethoxycarbonyl-ethyl)-2,3,4,6,7,12-hexahydro-1H-indolo[2,3-a]quinolizine by hydrogenation in ethanol and in the presence of a palladium on charcoal catalyst followed, if required, by reaction with hydro-gen chloride.

25. A process as claimed in claim 24 wherein the 1-(2'-ethoxycarbonyl-ethyl)-2,3,4,6,7,12-hexahydro-1H-indolo[2,3-a]
quinolizine is obtained by reacting 2,3,4,6,7,12-hexahydro-indolo[2,3-a]quinolizine with ethyl acrylate.

26. 1-(2'-Ethoxycarbonyl-ethyl)-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine and its hydrochloride salt when prepared by a process according to claim 24 or 25 or an obvious chemical equivalent thereof.

27. A process for preparing 1-(2'-ethoxycarbonyl-ethyl)-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine and its hydrochloride salt which comprises reacting 1-(2'-methoxycarbonyl-ethyl)-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine with sodium ethoxide in ethanol followed, if required, by reaction with hydrogen chloride.

28. A process as claimed in claim 27 wherein the 1-(2'-methoxycarbonyl-ethyl)-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]
quinolizine is obtained by a process according to claim 18 or an obvious chemical equivalent thereof.

29. 1-(2'-Ethoxycarbonyl-ethyl)-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine and its hydrochloride salt when prepared by a process according to claim 27 or 28 or an obvious chemical equivalent thereof.