DE3323584A1 - 14-OXO-15-ALKOXYCARBONYL-E-HOMOEBURNANE, METHOD FOR PRODUCING THE SAME AND MEDICINAL PRODUCTS CONTAINING THE SAME - Google Patents

Description

Y 2 2 3 5 S 4

DR. STEPHAN G. BESZtDES PATENTA ^ aVΛLT

VM: 101265

AUTHORIZED REPRESENTATIVE AT THE EUROPEAN PATENT OFFICE

PROFESSIONAL REPRESENTATIVE ALSO BEFORE THE EUROPEAN PATENT OFFICE COGO DACHAU EEI MDNCHEN '

POST Γ ACH H 68

MDNCHENER STRASSE 8OA Federal Republic of Germany

TELEPHONE: DACHAU 08131/4371 TELEX: 527537 bepat d

PoeUichockkonto MOnchan CBLZ 700 100 60)

Account No. 1 368 71-801 Bank account no. 900 370 at the Sparkasse Dachau

(BLZ 700 515X0)

(VIA Bayerische Landesbank

Girozentrale, Munich)

P 1 771

Claims and description of the patent application

JUDGE GEDEON VEGIESZETI Glh. RT Budapest, Hungary

"concerning

14-Oxo-i ^ -alkoxycarbonyl-E-homoeburnanc, process for preparation; the same and medicinal products containing them

- 8 description;

The invention relates to new 14-0x0-15-alkoxycarbonyl- -E-homoeburnane and their acid addition salts including the epimeric forms and optically active antipodes, a process for their preparation and medicaments containing these compounds, in particular those with a Effect against depression or antidepressant effect and an effect against hypoxemia respectively Hypoxidosis or antihypoxive effect.

The invention is based on the object of superior pharmacological effects, in particular effects against Depression and hypoxemia, containing new e-homoeburnan derivatives, a process for their manufacture and medicaments containing them.

The above has surprisingly been achieved by the invention.

The invention relates to racemic and optically active ^/ 14-0xo-15-alkoxycarbonyl-E-homoeburnanes of the general formula

Q Q O O C Q /

ν w ζ. J J υ 4

IL and Ep »which can be the same or different, for alkyl radicals with 1 to 6 carbon atoms),

as well as their acid addition salts.

The alkyl groups for the E ^ and E ₂ ^st eken, may be straight or branched, for example methyl, ethyl, n-propyl, isopropyl, η-butyl, sec-butyl, tert-butyl, ητ-pentyl, isopentyl, n-hexyl or isohexyl radicals. They are preferably those with Λ to 4, in particular 1 or 2, carbon atom (s), very particularly ethyl radicals.

Particularly preferred compounds of the invention are (±) -cis-14-oxo-15-ethoxycarbonyl-E-homoeburnan (3i _<:) 17o6) and (i) -trans-14-0xo-15-ethoxycarbonyl-E-homoeburnan (3 / 2,17e <) as well as their hydrochlorides.

As acid addition salts according to the invention of the 14-0xo- -15-alkoxycarbonyl-E-homoeburnane of the general formula I. especially those with pharmaceutically acceptable acids, both inorganic and organic, come in Irage. Examples are those with inorganic acids, such as Hydrohalic acids, for example hydrochloric acid and hydrobromic acid, sulfuric acid, phosphoric acid and superhalogen acids, for example superchloric acid, organic carboxylic acids such as formic acid, acetic acid, propionic acid, Oxalic acid, glycolic acid, maleic acid, cinnamic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, Malic acid, salicylic acid, lactic acid, benzoic acid and alkyl sulfonic acids, such as methanesulfonic acid, cycloaliphatic

Sulfonic acids, such as cyclohexylsulfonic acid, arylsulfonic acids, such as p-toluenesulfonic acid, and amino acids such as aspartic acid, Glutamic acid, N-acetylaspartic acid and N-acetylglut amic acid.

The invention also provides a method for Preparation of the compounds according to the invention, which is characterized in that racemic or optically active 1-alkyl-1 - ({mono- or polyalkoxycarbonyl | -alkyl) - -1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines the general formula

T) 1 - O - C ( - σ
Il J - C Ii \ H ο Χ. ^E 5 - O

II

for hydrogen or a radical of the formulas

- -11 -

= Il

C-C

^H 2

C-O-R.

C-O-H,

respectively

3323534

III

C-O

C = O
0

C-C

B ₂

σ - ο -

IV,

in the soft latter E. is laid down as above,

stands,

E _{3 is} identical to E "or is hydrogen

and

- 12 -

and

Ep as stated above,

with the further; Provided that ₃ in the case that

E, hydrogen means

A also represents hydrogen,

or acid addition salts thereof are cyclized, whereupon in a manner known per se, if appropriate, the obtained 14-Oxo-i 5-alkoxycarbonyl-E-homoeburnane of the general Formula I can be converted into acid addition salts with acids or the optionally obtained acid addition salts of the 14-oxo-15-alkoxycarbonyl-E-homoeburnanes of the general Formula I can be converted into the corresponding free bases of the general formula I or into other salts and / or optionally a cleavage of the resulting racemic 14- -oxo-15-alkoxycarbonyl-E-homoeburnane of the general formula I in their optically active antipodes or an Eacemization of the corresponding optically active compounds is made.

The cyclization of the 1-ia ± yl-1 - ({Eox> - or poVal30xycarbai7l3-alkyl) -1,2,3, ^, 6,7,12,12b-octahydroindo-Io [2,3-a] quinolizine of the general formula II carried out in inert, organic aprotic non-polar solvents. Aromatic hydrocarbons are preferably used as solvents for this purpose.

Appropriately for the cyclization of the 1-J0k3'l-1 - (- [mar> - uC.ac aü'jcc- ^ caxbonyl} -alkyl) -1,2,3,4,6,7,12,12b ~ oct oh; "dr oindolo [2,3-a] chinolizine of the general formula II in which R ₅ is. and R. are the same, used strong bases. Preferably, to this cyclizing cues sfcaikc Bncen Alkdihydride, particularly liatriumhydrid UR4 / odar lisOiuinhydrid., or Alkali alcoholates, in particular potassium and / or sodium ethylate, and / or potassium tert-butylate, especially the latter, are used. This cyclization in aprotic organic solvents, preferably xylene, toluene and / or benzene, in particular the latter, is advantageous. This cyclization is expediently carried out at the boiling point of the reaction mixture. The reaction takes place within a short time, generally within 10 to 40 minutes, in advantageous cases within 15 "to 30 minutes.

It is useful to cyclize the 1 -ΑΠζ, .1-1 - ({πεωο-ο ±; ι · polyalkoxycarbonyl] -rl kyl) -1,2,3,4,6,7,12,12b-ocxahydroindo-Io [ 2,3-a] quinolizines of the general formula II, in which A and R- stand for hydrogen, dehydrating agents, in particular phosphorus oxychloride, are used. Another example of dehydrating agents is phosphorus pentoxide. This cyclization is advantageously carried out in inert organic solvents, preferably aromatic hydrocarbons, in particular benzene, or chlorinated hydrocarbons, in particular chloroform and / or carbon tetrachloride.

When using the starting compounds i-alkyl-1 - (^ aar) -od3? polyalkoxycarbonyl} -alkyl) -1,2,3,4,6,7, i2, i2b-octahydroindolo [2,3-a] quinolizines in the form of their acid addition salts, for example hydrohalides or perchlorates, expedient

er pafeTakoxycarboi; yl} -eU ^ / l) -1,2,5, / f, * ..-,?, *. 2.1? B- ^ -Slquinolizine bases of general

Formula II released from their salts prior to cyclization. The release of the 1-alkyl-1- (imono-or

can with aqueous solutions of inorganic bases, such as of Alkali carbonates, for example sodium carbonate and / or Potassium carbonate, or alkali hydroxides, for example sodium hydroxide and / or potassium hydroxide, in water-immiscible inert organic solvents such as halogenated hydrocarbons, for example dichloromethane and / or chloroform.

With the method according to the invention, the 14- -Oxo-15-alkoxycarbonyl-E-homoeburnane of the general formula I or ßäureadditionsalze be prepared both in the trans form and in the cis form. Which of the two is obtained depends on whether the starting compound 1-ATkyl-i- ({mono- cde-'polyalkoxycarbonylj-alkyl) - -1,2,3,4,6,7,12, i2b-octahydroindolo [2,3-a] quinolizine der general formula II or its acid addition salt was in the trans form or in the cis form.

The inventive method can racemic and optically active 14-Qxo-15-alkoxycarbonyl-E-homoeburnane of the general formula I or acid addition salts the same can be obtained. When using the output connections 1-Alkyl-i-Ctraio- or polyalkoxycarbonyl] -alkyl) - -1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines der general formula II or its acid addition salts as Eacemate are also the end products 14-0xo-15- -alkoxycarbonyl-E-homoeburnane of the general formula I or Acid addition salts of the same racemic. However, these can in a manner known per se in their

- 15 -

optical antipodes are split. To manufacture the optically active i4-0>: o-15- & lko:>: ycarbonyl-E-homoeburnane of the general formula I or their acid addition salts however, it can also be derived from optically active 1-alkyl-1 ~ - (CmOD- or polyalta-ycarbonyl} -alkyl) -1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formula II or their acid addition salts are assumed. In this case, optically active 14-oxo- -15-alkoxycarbonyl-E-homoeburnane of the general formula I. or get their acid addition salts.

The conversion of the inventive racemic or optically active 14-0xo-15-alkoxycarbonyl-E-homoeburnane der general formula I in their acid addition ε al ze is advantageous in inert organic solvents, preferably in alkanols with 1 to 6 carbon atom (s), in particular Methanol. The procedure is preferably as follows. The 14-oxo-15-alkoxycarbonyl-E-homoebur.-nanbase of the general formula .1 is dissolved in such a solvent and then becomes the solution as long as the appropriate acid is added until a weakly acidic pH is established (up to a pH of about 6). then is the acid addition salt of the I ^ Oxo-i ^ -alkoxycarbonyl- -E-homoeburnanes of the general formula I separated from the reaction mixture, expediently by precipitation with a Water-immiscible organic solvents, for example diethyl ether.

Optionally, the 14-0xo-15- according to the invention -alkoxycarbonyl-E-homoeburnane of the general formula I. or acid addition salts thereof in the form of acemates or optically active antipodes for example by recrystallization. The choice of solvent for recrystallization depends on the solvent

- 16 -

Liability and crystallization properties of the; 'eweiliperi umzukri rUnl glazed connections ob.

The 1- alky 1-1 - ({mono- or poly alkoxy carbonyl ¹ -alkyl) -1,2,?, 4,6,7,12,12b-octahydroindolo [2,3- a] quinolizines of the general formula II or acid addition salts thereof can have been prepared according to the process described in Belgian patent specification 883 576 in such a way that the corresponding hexahydroindolo [2,3-a] quinolizinium salts are alkylated electrophilically with dialkyl methylenemalonates and the products obtained are catalytically hydrogenated and optionally then also partially hydrolyzed.

Furthermore, according to the invention, medicaments which 1 or more of the compounds according to the invention as an active ingredient, respectively Active ingredients, if necessary together with 1 or more conventional pharmaceutical formulation (s), included, provided.

This is because, as already mentioned, the compounds according to the invention have valuable pharmacological effects, in particular those against depression and hypoxemia, some of them, especially cis-14-Oxo-15-alkoxycarbonyl-E- -homoeburnane, has a significant anti-depression effect, while another, especially trans-i4-0xo-15- -alkoxycarbonyl-E-homoeburnane. an effect against hypoxemia having.

The effect of the 14-oxo-15-alkoxycarbonyl-E-homoeburnans according to the invention against hypoxemia, which is particularly pronounced in the case of the trans-14-0xo-15-alkoxycarbonyl-E-homoeburnans (3 _; r, 17 ^) -s, was on Hand of the survival times of

- 17 -

-V-

Mice detected in the test experiment of normobaric hypoxemia. For this purpose, 5 male mice were placed in a 3 l beaker, which was flowed through by a gas mixture containing 96% by volume of nitrogen and 4% by volume of oxygen. The compound of the invention to be investigated and vincamine, the recognized effective comparison substance with the same direction of action, were per 10 animals for 30 minutes administered intraperitoneally in doses of 50 mg / kg body weight prior to placing in the beaker. It the time between the introduction of the mice and their death was measured. Those animals which after the Twice the time in which the untreated blind test animals died and were still alive were considered to be protected rated.

The results of these tests are given in the table below compiled.

Tabel

time of increase protection Survival there? duration at in of excess % link Minutes ifibeQS ^^ n— the T> irrhFsr * hrri Ήτ above that animals + ■ BÜndvexsich. scattering in (i) -trans-14-Oxo-i5- -ethoxycarbonyl-E-homo- 8.3 ± 1.1 +32 20th aburnan (3 'V'17 <) Vincamine (Comparison substance) 7.1 ± 1.30 +13 0 Blind test 6.3 i 1.45 - 0

- 18th

From the table above it can be seen that the duration of the survival of the animals is due to a reduction in the oxygen content the atmosphere of induced hypoxemia was significantly prolonged by the compound according to the invention, this extension was 32% of the survival time of the untreated blind test animals. The effect the compound according to the invention exceeded the effect of the vincamine successfully used in therapy, which under the same conditions and in the same doses, the survival time of the animals was only increased by an average of 13%, While no protection was achieved with vincamine in any animal, with the compound according to the invention in 20% the same achieved protection.

On the other hand, the cis-14-0xo-15 ~ -alkoxycarbonyl-E-homoeburnan (3 ^, i7 ^{v) -e in particular have} a valuable effect against depression.

The compounds according to the invention can be used as active ingredients together with non-toxic substances customary in pharmacy inert solid or liquid carriers, extenders and / or auxiliaries in the form of pharmaceutical preparations for parenteral or enteral transport are present. Examples of carrier substances are water, gelatine, milk sugar (lactose), starch, pectins, magnesium stearate, Stearic acid, talc and vegetable oils such as peanut oil and olive oil. The medicament preparations according to the invention can in the usual application forms, such as in solid application form, for example as round or square tablets, Dragees, capsules, such as hard gelatine capsules, pills or suppositories, or in liquid application form, for example as oily or aqueous solutions, suspensions, emulsions, syrups or injection solutions. The amount of solid carrier in a dose unit can be varied within wide limits and is preferably 25 mg to 1 g. The pharmaceutical preparations according to the invention can optionally a cn those in pharmacy

common auxiliaries, for example preservatives, Wetting agents, emulsifying agents, salts for adjusting the osmotic pressure, buffers and / or flavor and / or Flavorings included. The pharmaceutical preparations according to the invention are expediently prepared in dosage units which are suitable for the desired form of administration You can use customary known pharmacy procedures, for example by sieving, mixing, granulating, Pressing or loosening, are prepared and possibly also others, in the pharmaceutical industry usual operations, for example sterilization, are subjected.

The invention is explained in more detail with reference to the following examples.

example 1

(+) -ei s-14-0x0-15-3 thoxy ca rbonyl-E -homo- eburnan (3 ^, 17- ..

From 880 mg (1.90 mmol) (iO-lcc-ethyl-lß-te ', 2'-diethoxycarbonyl-ethyl) -l, 2,3,4,6,7,12bcc-octahydroindoloC2,3-aJquinolizine hydrochloride the base is liberated in 25 ml of dichloromethane with 10 ml of 10 % aqueous sodium carbonate solution. After separating the organic phase, the aqueous phase is neutralized with noei. 5 ml of dichloromethane are extracted. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo.

The remaining oil is in 15 ml of absolute Benzene dissolved, the solution is mixed with 258 mg (2.3 mmol) of potassium tert-butoxide and the mixture in a

- 20 -

Boiled under reflux in a nitrogen atmosphere for 20 minutes. After cooling, the pH of the mixture is adjusted to 6 with acetic acid while cooling with ice. The solvent is then distilled off in vacuo. The evaporation residue is dissolved in 20 ml of dichloromethane, the solution is adjusted to pH 9 with 10 ml of 5% ± ger aqueous sodium carbonate solution, and the phases are separated from one another. The aqueous phase is extracted with a further 5 ml of dichloromethane. The combined organic phases are dried over anhydrous magnesium sulfate and, after filtration, freed from the solvent in vacuo. 560 mg of oil are obtained. The oil is recrystallized from 1.5 ml of methanol, 480 mg of product being obtained. Yield: 66.5 %.

Γ \ ti

Melting point: / 143-144 C (ethanol)

IR (KBr): 1738 (ester). 1690 cm " ¹ (lactam). MS / m / e ^ V: 380 / M ⁺ . 100 /. 379/35 /, 363/20 /, 352/17 /. 351/26 /, 335/12 /, 323 / 9.1 /. 307/55 /. 252/35 /, 237/17 /.

¹ H-NMR (CDCl ₃ ): cf = 8.52-7.35 (4H. M, -aromatic), 4.31 (2H, q, J = 7.2 Hz, OCH ₂ ), 4.08 ( 1H, s, 3-H), 3.75 (/ LH, d, J = 11 Hz, 15-H), 1.34 (3H, t, J = 7.6 Hz, QCH ₂ CH ₃ ), 0.91 (3H ₁ t, O = 8.1 Ez ₁ CH ₂ CH _7>

Example 2

(+ _) - trans-14-Oxo-15-ethoxycarbonyl-E-homo-ebuman (34'T7 -, 400 mg (θ, 94 mmol) (+) -lcc-ethyl-1ß '- (2', 2 to obtain '-diäthoxycarbonyl-äthyI) -1,2, .4,6 3, 7, l2,12bß-octahydro [2,3-a3chinolizin (as a by-product of example 1 of the Hungarian Pa ^ entaareMung MIFC on Docket RI-713 ) wercbn in 'OML ^ cs ^ rSroiem benzene dissolved, and to the solution are added 125 mg (l, 11 mmol) of potassium tert-butoxide. Oas reaction mixture is gekocifc in a nitrogen atmosphere for 20 minutes under reflux.

/. C O G

- 21 -

The pH of the cooled reaction mixture is adjusted to 6 with acetic acid and while cooling with ice the solvent is distilled off in vacuo. The remaining substance is dissolved in 10 ml of dichloromethane. The solution is with 5% aqueous sodium carbonate, solution Made alkaline to pH 9 · After the phases have separated, the organic phase is mixed with 5 ml of dichloromethane extracted * The combined organic phases are dried over anhydrous magnesium sulfate

j and after filtering in vacuo from the solvent freed · The oil obtained (300 mg) is extracted from 2 ml

Ethanol crystallizes. 260 mg (73.0 %) of product are obtained, which melts at 173-175 ° C. (ethanol).

IR (KBr): 2750-2700 (ßohlmann), 1735 (ester), 1680 cm " ¹ ι (lactam)"

Ms / m / e, % / z 380 / M ⁺ , 100 /, 378/38 /, 363/14 /, 352/11 /, j 351/16 /, 335/11 /, 323 / 5.5 /, 307/34 /.

H-NMR (CDCl ₃ ): ei = * 8.56-7.24 (4H, m, aromatic proto-J. -. Nes), 4.32 (2H, q, J = 7.6 Hz, OCH ₂ ), 4.08 j (IH, dd, O ₁ = 13.6 Hz, D ₂ = 2.7 Hz, IS-Η) _r

¹ 3.41 (IH, s, 3-H), 1.35 (3H ₁ t, J = 7.6 Hz,

OCH ₂ CH ₃ ), 0.74 (3H, t, J = 6 Hz, CH ₂ CH ₃ ).

Example 3

Aua 634.5 mg (^ J-IGC-Ethyl-1ß-Ca ¹ , 2 ', 4', 4'-tetra-'3thoxycarbonyl-butyl) -. L, 2,3,4,6,7, l2, l2boi) -octahydroindoloC ^ .S-aJquinolizine hydrochloride or from 698.0 mg (1 mmol) of the corresponding hydroperchlorate, the base is liberated in 25 ml of dichloromethane with 10 ml of 10 ml of aqueous sodium carbonate solution. The base is extracted with dichloromethane. The combined extracts are dried over anhydrous magnesium sulfate, the solvent is distilled off in vacuo. - 22 -

The remaining oil is dissolved in 15 ml of anhydrous benzene, Ί45 mg ("1.3 mmol) of potassium tert-butoxide are added to the solution and the reaction mixture is refluxed for half an hour in a stick The cooled mixture is adjusted to 6 with acetic acid and the solvent is distilled off in vacuo. The residue is dissolved in 10 ml of dichloromethane and the solution is made alkaline to pH 9 with 10 ml of 5% aqueous sodium carbonate solution 5 ml dichloromethane extracted. The organic phases are combined, dried over anhydrous magnesium sulfate and, after filtration, freed from the solvent in vacuo. The remaining

ι *

oil is from 1 ml of ethanol, crystallized · 307 mg (80.8%) of product are obtained, which at 143-144 ⁰ C.

(Ethanol) melts.

Example 4

(+) -cis-'l4-Oxo-l5-ethoxycarbonyl-E-homo-ebuiXLfiin. (3c <, i7 ^) The assumption is made from 870 mg (1 mmol) (jO-lcc-Ethyl-lß- - (2 ' , 2 ', 4', 4 ', 6', 6'-hexaethoxycarbonyl-hexy1-1,2,3,4,6, 7,12,12bcc-oct ahydroindoloC2,3-a ich inolizin-hyd rope chlorate from and works as described in Example 3. 264 mg (69.5 %) of product are obtained, which melts at 142-143 ° C. (ethanol).

Example 5

(+) -eis-14-0XO-15-ethoxycarbony1-E-homo-eburnan- (3cc, l7cc) -hydrochloride

200 mg (+ _) - cis-l4- produced according to Example 1 -O: z> -15-eth oxy ca rbony 1-E-homo-ebur nan (3ccl7rc) v / earth

dissolved in a mixture of 3 ml of dichloroethane and 2 ml. The pa-Watfc the solution wild, with one? Solution of hydrogen chloride in ifchaiaL adjusted to 2. Then the reaction mixture is evaporated to dryness and the evaporation

Il

residue from Ί, 5 ml of ethanol crystallized · Ί65 mg (75.2 %) of product are obtained. Melting point: 204-207 ⁰ C (ethanol).

Example 6

(+ ^ - cis-l ^ -Oxo-lS-ethoxycarbonyl-E-hofno-eburnanOuC, 17a :) 300 mg (0.755 mmol) (jO-lcc-ethyl-lß - ^ '- carboxy-2'- -ätüioxycarbonyl.-ethyl) -Ί, 2,3,4,6,7, ^, - ^ bcc-octahydroindoloE2,3-a] quino] izine are suspended in 2 ml of anhydrous benzene and added to the suspension while cooling with ice Given 2 ml of phosphorus oxychloride. The reaction mixture .misch is refluxed for 8-9 hours while stirring

After cooling, the reaction mixture in _a V uum is evaporated to dryness. The residue is triturated with 2 ml of ice water. The pH is adjusted to 9 with 10% aqueous sodium carbonate solution and the mixture is extracted with 3 × 2 ml of dichloromethane. The combined organic phases are dried over anhydrous magnesium sulfate and, after filtration, freed from the solvent in vacuo. The back

Il

Permanent oil (226 mg) is crystallized from 0.5 ml of ethanol. 156 mg of product are obtained. Yield: 54.3 %. Melting point: 142-144 ° C (ethanol), IR (KBr): 1725 (ester-CO), 1680 cm " ¹ (lactam-CO).

Claims (1)

Claims Racemic and optically active 14-oxo-15-alkoxycarbonyl-E-homoeburnane the general formula wherein and which can be the same or different, for alkyl radicals with 1 to 6 carbon atom (s), as well as their acid addition salts. 2.) 14-0xo-15-alkoxycart) onyl-E-homoe "burnane according to claim 1, characterized in that the alkyl radicals for which R. and R stand, those with 1 to 4, in particular 1 or 2, carbon atom (s). - 3 - -Z. -y (±) -cis-14-Oxo-i 5-ethoxycarbonyl-E-honio and its hydrochloride id. (i) -trans-14-0xo-15-ethoxycarbonyl-E-homo its hydrochloride. "Process for the preparation of the compounds nacn Claim 1 to 4, characterized in that one racemic or optically active 1-alkyl-1-C [mono- or polyalkoxycarbonylj-alkyl) -1,2,3,4,6,7,12,12Ta- -octahydroindolo [2,3-a] quinolizine of the general formula - 4 - 3323534 worm A. for hydrogen or a radical of the formulas -C-O Il σ ο III respectively -C- C = O G --- C = O O C-C H ₂ , C-O-R, C-O-R. JOZOJO ^ -y-H. in whichever R ,, as in the claim 1 or 2 is set, stent, , with E _x . is identical or hydrogen "means and ^E 1 and R _{2 are} as defined in claim 1 or 2, with the further proviso that, in the event that R, means hydrogen, A also represents hydrogen, or acid addition salts thereof cyclized, whereupon in a manner known per se, if appropriate the obtained 14-0xo-15 ~ alkoxycarbonyl-E- -homoeburnane of the general formula I converted into acid addition salts with acids or the optionally obtained acid addition salts of 14-0xo- -15-2ilkoxycarbonyl-E-homoeburnane of the general Formula I converted into the corresponding free bases of the general formula I or into other salts and / or possibly a split of the obtained racemic i ^ -oxo-i ^ -alkoxycarbonyl- -E-homoeburnane of the general formula I in their optically active antipodes or a Carries out racemization of the corresponding optically active compounds. 6.) Process according to claim 5 »characterized in that the cyclization of the 1-alkyl-1 - ((mono- or polyalkoxycarbonyl} -alkyl) -1.2.3 _t 4,6,7,12, i2b- - octahydroindolo [2,3-a] quinolizine of the general formula II in inert organic aprotic apolar solvents carries out · 7.) Method according to claim 5 or 6, characterized in that that to cyclize the 1-alkyl-1- ({mono- or polyalkoxycarbonylj-alkyl) - -1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formula II used as solvent aromatic hydrocarbons. 8.) Method according to claim 5 to 7 »characterized in that that to cyclize the 1-alkyl-1- ({mono- or polyalkoxycarbonylj-alkyl) - -1,2,3, ^, 6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formula II, in which R, and Ej are identical, strong bases are used. 9.) Method according to claim 5 to 8, characterized in that that to cyclize the 1-alkyl-1- ({mono- or polyalkoxycarbonyl} - alkyl) - -1,2,3, ^, 6,7, i2,12b-octahydroindolo [2,3-a] quinolizines of the general formula II, in which R, and R ^ are identical, as strong bases alkali hydrides or alkali alcoholates are used. 10.) Process according to claim 5 »characterized in that one for cyclizing the I-alkyl-IC ^ mono- or polyalkoxycarbonyl ^ -alkyl) -1,2,3,4,6,7,12,12b-
-octahydroindolo [2,3-a] quinolizines of the general formula II, in which A and R _{7 represent} hydrogen
stand, dehydrating agents, in particular
Phosphorus oxychloride is used. 11.) Medicines, characterized by a content of 1 or more compound (s) according to claims 1 to 4 as active ingredient or active ingredients, optionally together with 1 or more customary pharmaceutical formulations. description