NO831034L - PROCEDURE FOR THE PREPARATION OF NEW DERIVATIVES OF INDOLIZINO (8,7-B) INDOLES. - Google Patents

Description

The invention relates to a process for the preparation of new derivatives of indolizino[8,7-b]indoles with the formula

in which R a is the group ~(CH2^m~' in which m zero or 1, R, b denotes the group -CH(R^)-, in which R^ means hydrogen, lower alkyl, optionally esterified or etherified hydroxy, lower alkylthio or optionally substituted amino , R2 means optionally esterified or etherified hydroxymethyl or optionally functionally converted carboxy, R^ and R^ each means hydrogen or lower alkyl, or instead of the group -(R, .D -R cl)- the group -CH=CH-, and in which the carbocyclic ring A is unsubstituted or contains unsubstituted or substituted lower alkyl, optionally esterified or etherified hydroxy, nitro and/or optionally substituted amino as substituents, with the proviso that in compounds of formula I, in which R& denotes the group of the formula ~(CH2 ^m-'in which m stands for 1, R^ denotes the group of formula -CH(R^)-, in which R^ is hydrogen, R2 is hydroxymethyl, or benzyloxymethyl, R^ is the ethyl group and R^ is hydrogen, is the carbocyclic ring A unsubstituted, and with the further proviso that in compounds of formula I, in which Ra means the group of the formula -(CH2)m-, in which m stands for 1, R^ denotes the group of formula -CH(R^)-, in which R^ means ethyl , R2 means hydroxymethyl or benzyloxymethyl, and R^ and R^ are each hydrogen, the carbocyclic ring A is unsubstituted, and with the further proviso that in compounds of formula I, in which R 3. means the group of the formula -(CH2)m-, in which m stands for 1, Rfa denotes the group of formula -CH(R^)-, in which R is hydrogen, R2 denotes the carboxymethoxy group or the cyano group and R^ and R4 are each hydrogen,

is the carbocyclic ring A unsubstituted, such as epimer mixtures, pure epimers, racemate mixtures, racemates, optical antipodes, mixtures of cis and trans isomers, pure cis or trans isomers, N-oxides or salts thereof.

Functionally converted carboxy is esterified, such as aliphatic, cycloaliphatic or aromatically esterified carboxy and denotes primarily lower alkoxycarbonyl, lower alkylthiocarbonyl or substituted lower alkoxycarbonyl, as optionally etherified or esterified hydroxy or optionally substituted amino, containing lower alkoxycarbonyl, in which the substituents are preferably separated by at least two carbon atoms from oxy-oxygen, e.g. hydroxyl lower real oxycarbonyl, amino lower real oxycarbonyl, lower alkylamino lower real oxycarbonyl, lower alkoxy lower real oxycarbonyl, dilower alkylamino lower real oxycarbonyl, lower alkyleneamino lower real oxycarbonyl, oxalaverealkyleneamino lower real oxycarbonyl, thialaverealkyleneamino lower real oxycarbonyl or aza lower alkyleneamino lower real oxycarbonyl, in which the azanite nitrogen atom can be unsubstituted or substituted, e.g. with lower alkyl, further optionally with lower alkyl or lower alkoxy substituted cycloalkyloxycarbonyl, whereby the substituents can be present several times, especially 1 to 3 times, further optionally partially hydrogenated benzofuranyloxycarbonyl such as 1,3-dihydro-1-oxo-isobenzofuranyloxycarbonyl.

Functionally converted carboxy can also be amidated carboxy, such as carbamoyl, N-lower alkylcarbamoyl, N,N-dilower alkylcarbamoyl, optionally substituted in the phenyl part, e.g. with lower alkyl, lower alkoxy, halogen and/or nitro substituted N-phenyl lower alkyl carbamoyl, lower alkylene aminocarbonyl, oxala lower alkylene amino carbonyl, thial lower alkylene amino carbonyl or aza lower alkylene amino carbonyl, in which the azanite nitrogen atom may be unsubstituted or substituted, e.g. with lower alkyl, further the cyano group. Amidated carboxy can also be hydrazinocarbonyl or N<1->substituted, such as N'-lower alkylated or N-acylated hydrazinocarbonyl, e.g. N,N'-lower alkylhydrazinocarbonyl, N,N1-lower alkanoyl-hydrazinocarbonyl or N,N<1->aroyl-hydrazinocarbonyl, whereby aroyl in particular indicates in the phenyl part optionally with lower alkyl, lower alkoxy, halogen and/or nitro substituted benzoyl or nicotinoyl.

Etherated hydroxy is e.g. lower alkoxy, however, can also stand for phenyl lower hydroxy, and, as a substituent of the carbocyclic ring A, stand for lower alkylidene or lower alkylene dioxy, while esterified hydroxy can be acylated hydroxy, e.g. halogen or with an aliphatic or aromatic carboxylic acid or sulphonic acid esterified hydroxy, e.g. aroyloxy, such as benzoyloxy, or benzenesulfonyloxy,

whose aromatic part can each be unsubstituted or e.g. substituted with lower alkyl, lower alkoxy, halogen and/or nitro, whereby substituents of the aforementioned kind may be the same or different and each may be present several times, especially 1 to 3 times, or may be lower alkanoyloxy, e.g. pivaloyloxy.

Substituted amino is e.g. lower alkylamino, dilower alkylamino, lower alkyleneamino, oxalaverealkylenamino, thialaverealkylenamino, or azaloweralkylenamino, in which the azanite nitrogen atom can be unsubstituted or substituted, e.g. with lower alkyl, further acylated amino, such as lower alkanoylamino or lower alkoxycarbonylamino.

Substituted lower alkyl primarily contains halogen, further hydroxy, lower alkoxy or phenyl lower oxy as substituents.

Esterified hydroxymethyl is e.g. such, in which the esterified hydroxy group has the meaning stated above - and indicates e.g. halogen or optionally, e.g. as indicated substituted aroyloxy, such as benzoyloxy or benzenesulfonyloxy, further

lower alkanoyloxy.

Ethered hydroxymethyl is e.g. such, in which the etherified hydroxy group is, for example, lower alkoxy.

The substituents mentioned for the ring A can therein be

present several times, preferably up to 4 times.

The meanings given above can have the following meanings, whereby "lower" designated substituents and compounds contain up to and including 7, especially up to and including 4 carbon atoms and/or substituted groups can contain one or more substituents.

Lower oxycarbonyl is e.g. methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl or tert-butyloxycarbonyl.

Cycloalkyloxycarbonyl has 3-7, especially 5-6, ring members in the cycloalkyl part and is e.g. cyclohexyloxycarbonyl or trimethylcyclohexyloxycarbonyl.

Lower oxylower oxycarbonyl is e.g. 2-methoxyethoxycarbonyl or methoxymethoxycarbonyl.

In substituted lower alkoxycarbonyl groups, the substituents are preferably separated by more than one carbon atom from the oxy-oxygen atom and mean e.g. 2-hydroxyethyloxycarbonyl, 2-methoxyethyloxycarbonyl, 2-ethoxyethyloxycarbonyl, 2-chloroethyloxycarbonyl, 2-aminoethyloxycarbonyl, 2-methylaminoethyloxycarbonyl, 2-dimethylaminoethyloxycarbonyl, 2-diethylaminoethyloxycarbonyl, 3-dimethylaminopropyloxycarbonyl, 2-pyrrolidinoethyloxycarbonyl, 2-(4-morpholino)ethyloxycarbonyl, 2-(4-thiamorpholino)ethyloxycarbonyl or 2-(4-methylpiperazino)ethyloxycarbonyl.

Lower alkylthiocarbonyl is e.g. methylthiocarbonyl, ethylthiocarbonyl, n-propylthiocarbonyl, isopropylthiocarbonyl, n-butylthiocarbonyl or tert-butylthiocarbonyl.

Low-area coke is e.g. methoxy, ethoxy, n-propyloxy, iso-propyloxy or n-butyloxy, and phenyl lower oxy, e.g. benzyloxy, while lower alkylidenedioxy or lower alkylenedioxy e.g. is methylenedioxy or 1,1-ethylidenedioxy.

Phenylaveral oxy is e.g. benzyloxy.

Halogen is e.g. fluorine, chlorine or bromine, i.e. halogen with

an atomic number up to 35, however, can also be iodine.

Aroyloksy is e.g. optionally 1-3 times with lower alkyl

or lower alkoxy, such as methyl or methoxy, substituted benzoyloxy, such as 3,4,5-trimethoxybenzoyloxy or 4-methylbenzenesulfonyloxy.

Lower alkanoyloxy is e.g. acetyloxy, propionyloxy, pivaloyloxy or butyryloxy.

Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, further n-pentyl, neopentyl, n-hexyl or n-heptyl.

Phenyl lower alkyl is e.g. benzyl or 2-phenylethyl.

Phenoxy lower alkyl is e.g. phenoxymethyl or 2-phenoxyethyl.

Phenylthiolower alkyl is e.g. phenylthiomethyl or 2-phenylthioethyl.

Lower alkylthio is e.g. methylthio or ethylthio.

Lower alkylamino is e.g. methylamino or ethylamino, while dilaverealkylamino is e.g. dimethylamino, N-ethyl-N-methylamino or diethylamino, and lower alkyleneamino are e.g. pyrrolidino

or piperidino.

In oxalaverealkylenamino, thialaverealkylenamino and azalaverealkylenamino, the heteroatom is separated from the amino nitrogen atom by at least two carbon atoms, the residues can e.g. mean 4-morpho-

lino, 4-thiamorpholino, 4-piperazino or 4-lower alkylpiperazino.

Halogen-lower alkyl is primarily trifluoromethyl, while hydroxyl-lower alkyl can be e.g. hydroxymethyl, and lower alkyl veralkyl can be e.g. 2-Methoxyethyl.

Acylated amino is e.g. aroylamino, such as benzoylamino, whose aromatic part may be unsubstituted or the substituents indicated by aryloxy, e.g. lower alkyl, lower alkoxy, halogen or functionally converted carboxy, can be present one or more times, especially 1-3 times, and can therefore be e.g. benzoyl- or 3,4,5-trimethyloxybenzoyl-amino.

Lower alkanoylamino is e.g. acetylamino, propionylamino

or pivaloylamino.

1,3-dihydro-1-oxo-isobenzofuranyloxycarbonyl is e.g. 1,3-dihydro-1-oxo-3-isobenzofuranyloxycarbonyl.

N-phenyl lower alkylcarbamoyl is e.g. N-(2-phenylethyl)-carbamoyl.

N,N'-lower alkylhydrazinocarbonyl is e.g. N,NA methylhydrazinocarbonyl or N,N<1>,N<1->dimethylhydrazinocarbonyl.

N,N'-aroylhydrazinocarbonyl is e.g. N,N'-(4-methoxy-benzoyl)-hydrazinocarbonyl or N,N'-(2-nicotinoyl)-hydrazinocarbonyl.

The compounds of formula I can exist as epimer mixtures, pure epimers, racemate mixtures, racemates, optical antipodes, mixtures of cis and trans isomers, pure cis or trans isomers, N-oxides or salts, especially acid addition salts, above all pharmaceutically usable, non-toxic acid addition salts, as well as existing as quaternary ammonium compounds or their salts.

Quaternary ammonium compounds optionally contain as quaternary substituents e.g. as indicated, substituted lower alkyl, e.g. lower alkyl, hydroxy- or halo-lower alkyl, phenyl lower alkyl, phenoxy lower alkyl or phenylthio lower alkyl, in which the phenyl moiety may each be unsubstituted or substituted with lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or nitro. Salts of quaternary ammonium compounds corresponding to the following defined, especially those as pharmaceutically usable, non-toxic acid addition salts which are individually indicated, especially those formed with hydrohalic acids, sulfuric or phosphoric acids.

The new compounds may exist in the form of their salts

as their acid addition salts and primarily present as their pharmaceutically usable, non-toxic acid addition salts. Suitable salts are e.g. those of inorganic acids, such as halogen hydrogen acids, e.g. hydrochloric acid or hydrobromic acids, sulfuric acid or phosphoric acid, or those of organic acids, such as aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic acids or sulphonic acids, e.g. ant, vinegar, propion, amber, glycol, milk, apple, wine, lemon, maleic, hydroxymaleic, pyrrhotite, fumar, benzo, 4-aminobenzo, anthralin, 4-hydroxybenzo-, 2,4-, 2,5-, 2,6- or 3,5-dihydroxybenzoic acid, salicylic, acetylsalicylic or embonic acid, 4-acetamidobutyric acid, furan-2-carboxylic acid, 3- (theophylline-7-yl)-propanesulfonic acid, theophylline-7-acetic acid, nicotinic acid, 5-bromonicotinic acid, indole-3-acetic acid, methanesulfone, ethanesulfone, 2-hydroxyethanesulfone, ethylenesulfone, toluenesulfone, naphthalenesulfone -,

camphorsulfonic, sulfanilic acid or N-cyclohexylsulfamic acid or with other acidic organic substances, such as alginic, ascorbic or tannic acid, acidic esters of phosphoric acid, such as glucose-1- or 6-phosphate, 5-pyridoxal phosphate, saccharin, acidic groups, e.g. e.g. carboxylic acid and/or especially sulfonic acid group containing cation exchange resins, e.g. sulfonation products of copolymers of possibly indifferent substituted styrenes and smaller amounts of divinylbenzene as cross-linking agent or condensation products of phenols or phenol ethers with formaldehyde and optionally substituted benzenesulfonic acids.

The new compounds of formula I have valuable pharmacological properties. In particular, they act on the central nervous system.

For example, they provide protection against the amnesiogenic effect of cerebral electroshock and an improvement in memory ability. Results of the aforementioned nature can be determined by the following learning test:

Test:

The test device consists of a large box (35 x 20 x 10 cm),

which is connected by a sliding door with a smaller box (10 x 10 x 18 cm). While the smaller box is illuminated from above by a 100 W lamp, the large box is in the dark. The bottom of the two compartments consists of an electrically conductive grid. For practice, individual groups of 10 male mice (20-22 g) are placed in the smaller box that is illuminated. Since mice have a spontaneous preference for the dark, most go to the dark compartment within 30 s. Once they have completely arrived there, the sliding door is closed and the animals are given a foot shock (ImA, 5 s). The animals are then immediately removed from the experimental apparatus.

To test the learning effect (retest), the mice are individually inserted after 24 hours again into the light compartment and the time course until all the animals are in the dark compartment is measured. Usually, most of the animals now stay in the bright compartment for the entire observation time of 150 seconds. The learning effect is essentially canceled or the memory of the foot shock is at least obliterated when, as an amnesiogenic treatment immediately after the foot shock in the training program, a temporal electroshock treatment is associated. Parameter for the electroshocks: 50 mA, 0.4 seconds, 50 Hz., 0.6 seconds (pulse time).

For the test and for comparison of their protective effect against the amnesiogenic effect of the electric shocks, the test substances are administered intraperitoneally 30 minutes before the training in doses of 0.1 mg/kg, 1 mg/kg, 10 mg/kg and 100 mg/kg (for each dose use 10 mice) depending on solubility as a solution in physiological NaCl solution or as a 0.5% solution of methylcellulose in water and after the training the animals are immediately subjected to the electroshock treatment. 24 hours later, the result of the learning effect that is still present is measured on the basis of the residence time in the illuminated box, and compared with the effect obtained from the other test substances, as well as from the control animals that have only been administered the relevant solvent used and which have not been subjected to dressage, such as those with subsequent electroshock treatment.

The above-mentioned effects can be demonstrated on the new compounds of formula I, for example erythrocis-g-hydroxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7- The b]indole-1-propionic acid methyl ester or the cis-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester, in a dose range from approx. 0.1 mg/kg to 100 mg/kg.

For the immediate measurement of the improvement of the memory ability, the following test methodology is used: The test device consists of a box (50 x 50 x 50) normally illuminated by daylight with an electrically conductive grid, whose grid rods (6 mm diameter) are arranged at a distance of 13 mm. A wooden platform (10 mm height, 67 mm diameter) is arranged in the middle of the grating, which is surrounded by a plastic tube (20 cm high, 68 mm inner diameter). For the implementation of the dressage, groups are used each time

30 male mice (20 - 25 g), each of the animals being put on

the platform surrounded by the plastic tube, after 10 seconds the plastic tube is removed and the time required for the animal to descend and touch the grating with all 4 paws is measured. When all 4 paws touch the grating, a foot shock (1 mA, 50 Hz) is administered. Within 10 seconds after the administration of the foot shock, the test substances are administered intraperitoneally in doses of 0.1 mg/kg, 1 mg/kg and 10 mg/kg (for each dose 30 mice are used) according to solubility as a solution in physiological NaCl solution, or as a 0.5% solution of methylcellulose in water. 24 hours later, due to the residence time of each individual animal on the platform, the result of the improvement or reduction of the learning effect is determined in comparison with the animals which, as a control, had been applied only the solvent. Thus, the new compounds of formula I can be demonstrated, for example after i.p. administration of 1 mg/kg erythro-cis-α-hydroxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H -indolizino[8,7-b]indole-1-propionic acid methyl ester or cis-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indole-rzino[8,7-b]indole-1 -propionic acid methyl ester in mice an improvement of memory ability.

Due to these properties, new compounds appear

with formula I suitable for the treatment of vigilance disorders and cerebral performance insufficiency, especially of memory disorders of various kinds, such as senile dementia, multi-infarct dementia or dementia of the Alzheimer's type, further of secondary conditions of brain dreams or apoplexy.

The invention relates in particular to a process for the preparation of compounds of formula I, in which R a is the group -(CH z _) m-, in which m is zero or 1, R^ denotes the group -CH(R^-)-, in which R 1 means hydrogen , lower alkyl, optionally esterified or etherified hydroxy, lower alkylthio, or optionally substituted amino, R2 means optionally esterified or etherified hydroxymethyl or optionally functionally converted carboxy, and R^ means each hydrogen or lower alkyl or instead of the group --(R, O - R 3.)- stands the group

-CH=CH-, and in which the carbocyclic ring A is unsubstituted or contains unsubstituted or substituted lower alkyl, optionally esterified or etherified hydroxy, nitro and/or optionally substituted amino as substituents, with the proviso that in compounds m■ e• d formula I , ' in which R

means the group with the formula ~(CH2^m-' stands for 1, R^ stands for the group with the formula -CH(R^)-, in which R^ is hydrogen,

R2 is hydroxymethyl, R^ is the ethyl group and R^ is hydrogen,

the carbocyclic ring A is unsubstituted, and with the further proviso that in compounds of formula I, in which R^ denotes the group of formula -(CH2)m-, in which m stands for 1, R^ denotes the group of formula -CH(R^) -, in which R^ means ethyl, R2 means hydroxymethyl and R^ and R^ each means hydrogen, the carbocyclic ring A is unsubstituted, and with the further proviso that in compounds of formula I, in which R means the group of formula -(CH2)m ~, in which m stands for 1, R^ denotes the group of formula -CH(R^)-, in which R^ is hydrogen, R2 means the carbomethoxy group or the cyano group and R^ and R^ are each hydrogen the carbocyclic rin- A unsubstituted, which epimer mixtures, pure epimers, racemate mixtures, racemates, optical antipodes, mixtures of cis and trans isomers, pure cis or trans isomers, N-oxides or salts, especially acid addition salts, above all pharmaceutically usable non-toxic acid addition salts thereof, or such compounds as quaternary ammonium compounds or their salts.

The invention relates in particular to methods for the preparation of compounds of formula .1, in which R , R 1 and m , as well as the group of formula -(R, -R )- have the indicated meanings,

then

R^indicates hydrogen, lower alkyl, hydroxy, halogen, aroyloxy, lower alkanoyloxy, lower alkoxy, phenyl lower alkyl, lower alkylthio, amino, N-lower alkylamino, N,N-dilower alkylamino, lower alkyleneamino, oxalaverealkylenamino, thialaverealkylenamino, azaloweralkylenamino, in which the azanite nitrogen atom may be unsubstituted or substituted with laverealkyl, eller angir laverealkanoylamino, R2står for hydroksymetyl, aroyloksymetyl, benzensulfonyloksymetyl, karboksy, laverealkoksykarbonyl, hydroksylaverealkoksykarbonyl, laverealkoksy-laverealkoksykarbonyl, halogenlaverealkoksykarbonyl, aminolaverealkoksykarbonyl, laverealkylamino-laverealkoksykarbonyl, dilaverealkylaminolaverealkoksykarbonyl, laverealkylenamino-laverealkoksykarbonyl, oksalaverealkylenamino-laverealkoksykarbonyl, tialaverealkylenamino-laverealkoksykarbonyl, eller azalaverealkylenamino-laverealkoksykarbonyl , in which the azanitrogen atom can be unsubstituted or substituted with lower alkyl, lower alkylthiocarbonyl, optionally with la loweralkyl or lower alkoxy 1 to 3 times substituted cycloalkyloxycarbonyl, benzofuranyloxycarbonyl, 1,3-dihydro-1-oxo-3-isobenzofuranylcarbonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-diloweralkylcarbamoyl, loweralkyleneaminocarbonyl, oxalaverealkyleneaminocarbonyl, thialaverealkyleneaminocarbonyl or azalaverealkyleneaminocarbonyl, in which the azanite nitrogen atom can be unsubstituted or substituted with lower alkyl, hydrazinocarbonyl, N,N<1->lower alkylhydrazinocarbonyl, N,N<1->lower alkanoylhydrazinocarbonyl, optionally in the phenyl part with lower alkyl, lower alkoxy, halogen and/or nitro substituted N,N'-benzoylhydrazinocarbonyl, N,N'-nicotinoylhydrazinocarbonyl, or the cyano group, and R^ is each hydrogen or lower alkyl, and wherein the carbocyclic ring A is unsubstituted or contains lower alkyl, halo-lower alkyl, hydroxy lower alkyl, lower hydroxy lower alkyl, hydroxy, lower alkoxy, phenyl lower alkyl, lower alkylidene or lower alkylene dioxy, halogen, lower alk anoyloxy, nitro, amino, N-lower alkylamino, N,N-dilower alkylamino, lower alkyleneamino, oxalaverealkylenamino, thialaverealkylenamino, azalaverealkylenamino, in which the azanite nitrogen atom can be unsubstituted or substituted with lower alkyl and/or lower alkanoylamino as substituents each 1-3 times with the proviso that in compounds with formula I, ' in which Ra means the group of formula -(CH2)m~, in which m stands for 1, R denotes the group of formula -CH(R^)-, in which R^ is hydrogen,

R2 is hydroxymethyl, R^ is the ethyl group and R^ is hydrogen,

the carbocyclic ring A is unsubstituted, and with the further proviso that in compounds of formula I, in which RSl means the group of formula -(CH2)m-, in which m stands for 1, R^ denotes the group of formula -CH(R1)-, wherein R1 is ethyl,

R 2 is hydroxymethyl and R 1 and R 2 are each hydrogen,

the carbocyclic ring A is unsubstituted, and with the further proviso that in compounds of formula I, in which Ra means the group of formula ~(CH2^m~'^lvor:'- m st^r f°r 1'

R represents the group of formula -CH(R^)-, in which R^ is hydrogen,

R 2 means the carbomethoxy group or the cyano group, and R 1 and

R^ is each hydrogen, the carbocyclic ring A is unsubstituted, such as epimer mixtures, pure epimers, racemate mixtures, racemates, optical antipodes, mixtures of cis and trans isomers, pure cis or trans isomers, N-oxides or salts, especially acid addition salts, especially pharmaceutically usable, non-toxic acid addition salts thereof or such compounds as quaternary ammonium compounds or their salts.

The invention relates in particular to a process for the preparation of compounds of formula I, in which R&, R^ and m as well as the group of formula -(R, ■D -R cl)- have the indicated meanings,

R1 means hydrogen, hydroxy, lower alkoxy, aroyloxy, lower alkanoyloxy, amino, N-lower alkylamino, N,N-dilower alkylamino or lower alkanoylamino, R2 denotes hydroxymethyl, royloxymethyl, carboxy, lower alkoxycarbonyl, lower alkoxy-lower oxycarbonyl, lower alkylthiocarbonyl, dilower alkylaminolower oxycarbonyl, carbamoyi, N-lower alkylcarbamoyl, hydrazinocarbonyl, N,N 1 -benzoylhydrazinocarbonyl, N,N*-nicotinoylhydrazinocarbonyl, N,N-dilaverealkylcarbamoyl or the cyano group, ;R^ and R^ are each hydrogen or lower alkyl, and wherein the carbocyclic ring A is unsubstituted or is each 1 - 3 times substituted with lower alkyl, trifluoromethyl, hydroxy, lower alkoxy, f phenyl lower alkyl, lower alkylenedioxy, halogen, lower alkanoyloxy, nitro, amino and/or lower alkanoylamino, whereby lower alkoxy, lower alkyl, lower alkanoyl and lower alkanoylamino can each contain up to 4 carbon atoms, with the proviso that in compounds of formula I, in which R a means the group with formula -CH to _) m-, in which m stands for 1, R represents the group of formula - CH(R^)-in which R^ is hydrogen, R2 is hydroxymethyl, R^ is the ethyl group and R^ is hydrogen, the carbocyclic ring A unsubstituted, and with the further proviso that in compounds of formula I, in which R a means the group of formula -(CH0) - in which m stands for 1, R^ denotes a group of formula -CH(R^)-, ; in which R ^ is hydrogen, R2 is the carboxymethoxy group or the cyano group, and R^ and R^ are each hydrogen, the carbocyclic ring A is unsubstituted, such as epimer mixtures, pure epimers, racemate mixtures, racemates, optical antipodes, mixtures of cis and trans isomers, pure cis - or trans-isomers, N-oxides or salts, especially acid addition salts, especially pharmaceutically usable, non-toxic acid addition salts thereof, or such compounds as quaternary ammonium compounds, in which the quaternary group is lower alkyl, hydroxyl lower alkyl, halogen lower alkyl, phenyl lower alkyl or phenoxy lower alkyl, or their so lter. The invention relates in particular to a process for the preparation of compounds of formula I, in which R&, R^ and m as well as the group of formula -(Rrjd -R a)- have the indicated meanings, ;R^ means hydrogen, hydroxy, benzoyloxy, lower alkanoyloxy or amino . hydrazinocarbonyl or stands for the cyano group, R_ and R^ are each hydrogen or lower alkyl, and in which the carbocyclic ring A is unsubstituted or substituted, preferably in positions 8 and/or 9, with lower alkyl, e.g. methyl, hydroxy, lower alkoxy, e.g. methoxy, phenyl lower alkyl, e.g. benzyloxy, lower alkylenedioxy, e.g. methylenedioxy, and/or halogen, e.g. bromine, wherein lower alkyl and lower alkoxy each contain up to 4 carbon atoms, with the proviso that in compounds of formula I, in which R& represents the group of formula ~^CH2^m~'wherein m stands for 1, R^ denotes a group of formula -VH(R^)-, in which R^ is hydrogen, R2 is hydroxymethyl, R^ is the ethyl group and R^ is hydrogen, the carbocyclic ring A is unsubstituted, and with the further proviso that in compounds of formula I, in which R 3.means the group of formula~(CH2^m~wherein m stands for 1, R^denotes a group of formula -CH(R^)-, in which R^is hydrogen, R2means the carbomethoxy group or the cyano group, R^and R^ is each hydrogen, the carbocyclic ring A is unsubstituted, such as epimer mixtures, pure epimers, racemate mixtures, racemates, optical antipodes, mixtures of cis and trans isomers, pure cis or trans isomers, N-oxides or salts, especially acid addition salts, especially pharmaceutically usable, non-toxic acid addition salts thereof, or such compounds as quaternary ammonium um compounds, in which the quaternary group is lower alkyl or phenyl lower alkyl, or their salts. The invention relates in particular to a process for the preparation of compounds of formula I, in which R denotes the group of formula ~^^ 2^ m~' ^vorve(^ m stands for 1, R^ denotes the group of formula -CH(R^)-, whereby R^ is hydrogen or hydroxy, benzoyloxy or acetyloxy, R2 means hydroxymethyl, optionally with lower alkyl, such as methyl, or lower alkoxy, such as methoxy, or carboxy substituted benzoylmethyl, e.g. 3,4,5-trimethoxybenzoylmethyl, carboxy, lower alkoxycarbonyl, in particular methoxycarbonyl or ethoxycarbonyl, lower alkoxy-lower oxycarbonyl such as methoxy-;methoxycarbonyl, lower alkylthiocarbonyl, such as ethylthiocarbonyl, carbamoyl or the cyano group, R_ means hydrogen or lower alkyl and R^ means hydrogen, and in which the carbocyclic ring A is unsubstituted or substituted in 8- and/or in-position with hydroxy or lower alkoxy, e.g. methoxy, or methylenedioxy and/or halogen, such as bromine, whereby in these compounds the hydrogen atom is in the llb position and the residue R^, especially e tyl, are in the trans or preferably in the cis configuration to each other, with the proviso that in compounds of formula I, in which R denotes the group of formula -(CH2) in which m stands for 1, R^indicates the group of formula -CH(R ^)-, in which R^ is hydrogen, R2 is hydroxymethyl, R^ is the ethylene group and R^ is hydrogen, the carbocyclic ring A is unsubstituted, and with the further proviso that in compounds of formula I, in which Rcl is the group of formula ~(CH2 ^m~'where m is greater than 1'^ indicates the group of formula -CH(R^)-, in which R^ is hydrogen, R2 means methoxycarbonyl or the cyano group, R^ and R^ are each hydrogen is the carbocyclic ring A unsubstituted, such as epimer mixtures, pure epimers, racemate mixtures, racemates, optical antipodes, mixtures of cis and trans isomers, pure cis or trans isomers, N-oxides or salts, especially acid addition salts, especially pharmaceutically usable, non-toxic acid addition salts thereof , or such compounds as quaternary ammonium compounds, in which the quat ernary group is lower alkyl, e.g. methyl, or their salts. The invention relates in particular to a process for the preparation of compounds of formula I, in which R denotes the group of formula ~(CH2^m-'in which m stands for 1, R^denotes the group of formula -CH(R^)-, whereby R^er hydrogen, hydroxy, lower alkanoyloxy, such as acetyloxy, or aroyloxy, such as benzoyloxy, R2 is carbamoyl, carboxy or lower alkoxycarbonyl, such as methoxycarbonyl, R^ denotes lower alkyl such as ethyl, and R4 denotes hydrogen, and wherein the carbocyclic ring A is unsubstituted or substituted in 8- and/or 9-position with halogen, such as bromine, whereby in these compounds the hydrogen atom is in the llb-position and the residue, especially ethyl, is in the trans-configuration, preferably however in the cis-configuration to each other, and a hydroxy group R^is in threo-form, preferably in erythro-form, referred to the cis-configuration formed by the hydrogen atom in position llb and the lower alkyl group R^, especially ethyl, such as epimer mixtures, pure epimers, racemate mixtures, racemates, optical antipodes or are salts, especially acid addition salts, especially pharmaceutically usable non-toxic acid addition salts thereof. The invention primarily relates to a process for the preparation of the new compounds of formula I or salts described in the examples, especially acid addition salts, especially pharmaceutically usable, non-toxic acid addition salts thereof. The new compounds of formula I are prepared in a manner known per se. You can get these e.g. as one in a connection with formula ; ; in which means hydrogen or a cleavable and hydrogen-replaceable substituent or lower alkyl and optionally hydroxy and/or amino groups are substituted with a cleavable and hydrogen-replaceable r-residue with the proviso that at least X^ means a cleavable and hydrogen-replaceable substituent, or at least hydroxy - and/or amino groups are substituted with a cleavable and hydrogen-replaceable substituents, or in a salt thereof, it cleaves from hydrogen various groups X^ and/or hydroxy and/or amino groups substituting, cleavable and hydrogen-replaceable substituents and replaces with hydrogen, and if desired, converts a prepared compound of formula I into another compound I, and/or, if desired, separates a prepared racemate mixture into the racemates or separates a prepared racemate into the optical antipodes, or separates a prepared mixture of cis- and trans isomers into the pure cis and trans isomers or separates a prepared epimer mixture into the pure e pimers, and/or if desired, transfers a prepared compound of formula I in a salt or transfers a prepared salt in a free compound or in another salt. The removal of the group X^ or of the substituents of the hydroxy and/or amino groups, whereby such hydroxy and/or amino groups can also be substituted together with a divalent substituent, takes place by means of solvolysis, such as hydrolysis, alcoholysis or acidolysis, or by by means of reduction including hydrogenolysis. A particularly suitable cleavable group X^ or a hydroxy and/or amino protecting group is primarily a hydrogenolytically cleavable α-aryl lower alkyl group, such as an optionally substituted 1-polyphenyl lower alkyl or 1-phenyl lower alkyl group, in which substituents, especially for the phenyl part, e.g. e.g. can be lower alkyl as well as methyl, or lower alkoxy such as methoxy, or halogen, such as chlorine or trifluoromethyl, and primarily benzyl. Hydroxy and/or amino protecting groups can also be a solvolytic, such as hydrolytic or acidolytic further a reductive, including hydrogenolytic, cleavable residue, especially a corresponding acyl residue, such as the acyl residue of an organic carboxylic acid, e.g. lower alkanoyl, such as acetyl", or aroyl, such as benzoyl, can further be the acyl residue of a half-ester of the carboxylic acid, such as lower alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, 2-halo lower oxycarbonyl, e.g. 2,2 ,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, optionally substituted 1-phenyl lower oxycarbonyl, e.g. benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, e.g. phenacyloxycarbonyl, further an optionally substituted 1-polyphenyl lower alkyl group, wherein substituents, primarily to the phenyl part, e.g. can have the above meaning, and can primarily be trityl, while as solvolytically, as hydrolytically or acidolytically cleavable residue means the residue of a half-ester or the carboxylic acid, e.g. lower alkoxycarbonyl, methoxy- or ethoxycarbonyl , or means the residue of an organic sulfonic acid, such as an arylsulfonyl residue, such as benzene or p-toluenesulfony1 residue. A 2-valent residue which together may substituting hydroxy and/or amino groups is primarily a hydrogenolytically cleavable group, such as optionally substituted 1-phenyl-lower alkylidene, in which the substituent, especially for the phenyl part, can be e.g. lower alkyl or lower alkoxy and are especially benzylidene, as well as solvolytic, especially hydrolytic cleavable groups, such as lower alkylidene, e.g. methylene or isopropylidene, or 1-phenyl-lower alkylidene, whose phenyl part is optionally substituted with lower alkyl, such as methyl or lower alkoxy such as methoxy, especially benzylidene, or cycloalkylidene, e.g. cyclopentylidene or cyclohexylidene. Starting materials usable in the form of salts are primarily used in the form of acid addition salts, e.g. of mineral acids, as well as of organic acids. ;Hydrogenolytically cleavable residues X^as well as in this case hydroxy and/or amino group substituting residues of this kind, especially substituted 1-phenyl lower alkyl groups, further also suitable acyl groups, such as optionally substituted 1-phenyl lower oxycarbonyl, as well as hydroxy and/or amino groups standing together optionally substituted 1-phenyl lower alkylidene groups can also be split off by treatment with catalytically activated hydrogen, e.g. with hydrogen in the presence of a nickel catalyst, such as Raney nickel, or in the presence of a suitable noble metal catalyst. ;Hydrolytically cleavable groups X, and in this case also hydroxy and/or amino group substituting groups of this kind, such as acyl residues of organic carboxylic acids, e.g. lower alkoxycarbonyl, further e.g. trityl residues as well as lower alkylidene, 1-phenyl-lower alkylidene or cyclo-alkylidene groups which together can substitute hydroxy and/or amino groups, depending on the nature of such residues, can be split off by treatment with water under acidic or basic conditions, e.g. in the presence of a mineral acid, such as hydrochloric or sulfuric acid, or in the presence of an alkali metal or alkaline earth metal hydroxide or carbonate or an amine, such as isopropylamine. ;Acidolytically cleaved residues X^as well as hydrosky- and/or amino group-substituting residues of this kind are particularly specific acyl residues of half-residues of the carbonic acid, e.g. tert.-lower oxycarbonyl, or, as substituents for amino and/or hydroxy groups, optionally substituted diphenylmethoxycarbonyl residues, furthermore also a tert.-lower alkyl residue, e.g. tert.butyl, whereby such residues can be cleaved off by treatment with suitable strong organic carboxylic acids, such as optionally with halogen, especially fluorine, substituted lower alkylcarbonyl acids, primarily with trifluoroacetic acid (when necessary, in the presence of an activating agent, such as anisole), as well as with formic acid. Reductively cleavable, hydroxy- and/or amino group-substituting residues of this kind shall also be understood to mean such groups which are cleaved off by treatment with a chemical reducing agent (especially with a reducing metal or a reducing metal compound). Such residues are especially 2-halogen lower oxycarbonyl or arylmethoxycarbonyl, such as e.g. by treatment with a reducing heavy metal, such as zinc, or with a reducing heavy metal salt, such as a chromium (II) salt, e.g. -chloride or -acetate, usually in the presence of an organic carboxylic acid, such as formic acid or acetic acid, and of water can be split off. ;Protective groups for hydroxy and/or amino groups correspond to the above-mentioned groups that can be split off using the described methods and are exchangeable with hydrogen, whereby such groups are split off at the same time as other groups or subsequently in a separate process step during the execution of the described method. The above-mentioned reactions are usually carried out in the presence of a solvent or solvent mixture, whereby suitable reaction participants can simultaneously also function as such, and, if necessary, during cooling or heating, e.g. in an open or closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen. Starting substances with formula II can be prepared in a manner known per se. Starting substances of formula II, in which instead of the group~(Rj3_Ra)~is the residue of formula -CH=CH-, can be formed in the usual way, reacting a compound of formula; with an aldehyde with the formula or a reactive derivative thereof, such as one in which the aldehyde group is in silylated form and consequently the group corresponds to e.g. wherein R- is lower alkyl, e.g. methyl, and the hydroxy group is preferably present in reactive, esterified form, e.g. as an ester of an inorganic acid, such as a hydrohalic acid, or of an organic acid, e.g. p-toluenesulfonic acid, and consequently there is e.g. as bromine or as p-tolublsulphonyoxy, in the presence of a basic agent, such as an amine, such as e.g. ethyl diisopropylamine, in a suitable solvent, such as one of a strongly polar and aprotic character, such as dimethylformamide, to a compound of formula and reacting such a compound formed with a compound of formula v- in which Hal stands for halogen, e.g. . chlorine, and R2 1 optionally means esterified or amidated carboxy, e.g. lower alkoxycarbonyl, carbamoyl or cyano, in the presence of a base, e.g. an alkali metal tetraalkanolate or hydride, such as potassium tert.butylate or sodium hydride, under the conditions of the Wittig reaction of a compound of formula II, in which the group ~(Rj-,-Ra)- is replaced by the residue of formula -CH= CH- and wherein RI has the indicated meaning. But one can also work so that one reacts an aldehyde of formula Ild with a compound of formula in which Hal stands for halogen, especially for bromine, under the conditions of the Reformatsky reaction in the presence of zinc in a suitable inert solvent, e.g. benzene or tetrahydrofuran, hydrolyzes the reaction product to a compound of formula ; and from this a compound of formula II is produced during water elimination, in which instead of the group -Rb-Ra~ the residue -CH=CH- and R^ has the indicated meaning. Starting substances with formula II, in which R& and Rj^ have the stated meanings with the exception of the group -CH=CH-, can be formed by e.g. in a compound of formula wherein M 0 is the anion of an acid, e.g. to the perchloric acid, X has the above-mentioned meaning, and regarding the hydroxy and/or amino groups present, the specified substituents and caveats apply, it reduces the common double bond of the rings C and D to a carbon-nitrogen single bond, e.g. by means of hydrogen in the presence of a hydrogenation catalyst, such as a palladium-on-charcoal catalyst, or by means of a hydride, such as diborane or sodium borohydride, or a dilate metal hydride, such as lithium-tri-tert.butoxy-aluminum hydride, Hereby care is taken that other double bonds present are not attacked, for example by volumetric control of the hydrogen consumption or corresponding dosage of one of the mentioned reducing agents and timely interruption of the reduction. On the other hand, starting materials with formula III can, for example, be produced by the following reactions: A compound of formula e.g. is reduced in the usual way. by means of catalytically activated hydrogen, such as hydrogen in the presence of a nickel catalyst, such as Raney nickel, preferably in the presence of ammonia, to a tryptamine derivative of formula reacts this with a compound of formula or a reactive derivative thereof, for example with that of a in the 2-position optionally lower alkylated, such as ethylated, Y-butyrolactone of formula and thionyl chloride in the presence of a suitable condensing agent, such as anhydrous zinc chloride, converts in the usual way similarly producible 4-chlorobutyryl chloride of formula into a compound of formula converts such a compound on usual way, e.g. in the presence of a condensing agent, such as one of an acidic nature such as phosphorus oxychloride, by ring-closing condensation in a compound of the formula prepares therefrom by treatment with a base, such as an alkali hydroxide, such as sodium hydroxide, a compound of the formula and reacts such compound with an acrylic compound of formula ; to a compound of formula III, in which R denotes the group ;- CE^-, R^ and R^ have the indicated meanings. ;These turnovers are carried out in a manner known per se. The new compounds of formula I can also be formed when, in a compound of formula; where M is the anion of an acid, e.g. to the perchloric acid, the group stands for the group or R^ has the meaning of R^, or stands for one of a protecting group protected, by means of reduction in a free hydroxy group convertible hydroxy group, or R| is a lower alkenyl residue, or optionally instead of the group with formula (IVa), in which R" ; the residue is hydrogen or ; a lower alkyl residue that has one less carbon atom, or instead of the group -CI H-R a- the group -CH=CH- (IVb) stands, and ;Ri ;R ^ means hydrogen or a lower alkenyl residue, they reduce the common double bond of rings C and D to a carbon-nitrogen single bond, reduce an optionally present lower alkenyl residue R| and/or R^ to the lower alkylene group respectively and/or optionally reduce the group IVa to the group ; to the group ; and/or optionally reduces the group IVb CH^-Cr^- (IVc), and/or reduces a possibly present double bond in the ring C to a carbon-carbon single bond and/or reduces an optionally present group to the group ; and off cleaves ;txl hydroxy and/or amino groups optionally substituted, cleavable under the reduction conditions and hydrogen exchangeable protective groups, and replaces with hydrogen, and, if desired, carries out the method steps described in connection with the first method. ;A lower alkenyl residue R| respectively R^ has up to 7, preferably up to 4 carbon atoms and is e.g. a vinyl, 2-methylvinyl, allyl or 2-methylallyl residue. For hydroxy and/or amino groups optionally substituted and, under the conditions of this reduction procedure, groups that can be split off and are exchangeable with hydrogen are e.g. the reductive cleavable and hydrogen-replaceable groups mentioned for and before the hydroxy and/or amino group, e.g. an α-aryl lower alkyl group, e.g. a 1-phenyl lower alkyl group, such as the benzyl group, while commonly substituted residues for hydroxy and/or amino groups, such as phenylidene residues of the described kind are e.g. the benzylidene residue. ;The reduction of the double bond common to rings C and D and/or a lower alkenyl group R| and/or R^ respectively. a group IVa or IVb as well as a double bond possibly present in ring C, and/or the removal of any protective groups to hydroxy and/or amino groups including protective groups to the indole nitrogen atom in the case that the group ; indicates the group ; can happen in and of itself; known way, e.g. when treated with catalytic. activated hydrogen, such as nitrogen in the presence of a suitable hydrogenation catalyst, e.g. a nickel, platinum or palladium catalyst, whereby any hydrogenolytically cleavable protective groups present are simultaneously cleaved off and replaced with hydrogen, or one works with a suitable hydride reducing agent, such as e.g. diborane, or an alkali metal borohydride, e.g. sodium borohydride. For the reduction of the common ;double bond to rings C and D, whereby the group ;stands for the group ; comes further into consideration ; ]dilate metal hydrides, such as lithium aluminum hydride, especially lithium tri-tert.-butoxyaluminum hydride. ;When using a hydride reducing agent, acyl residues of carboxylic acids bound to oxygen can also be split off, such as e.g. that of the acetic acid, by the same working operation. When carrying out this, especially the catalytic reduction, care must be taken that other groups are not attacked, e.g. by volumetric control of the hydrogen consumption and timely interruption of the reduction, or by corresponding dosing of the reducing agent. ;For the case that in starting substances with formula IV the group ; stands for the group, their reductive transformation takes place in the group; as well as the simultaneous reduction of the double bond common to rings C and D to a carbon-nitrogen single bond and optionally present groups IVa or IVb as well as an optionally present lower alkylene group ;R| and/or and 'a possibly present double bond in the ring C in the usual way by means of hydrogen in the presence of a catalyst with both hydrating and desulfurizing effects, such as Raney nickel. This reduction is carried out in the usual way, e.g. in the presence of a suitable solvent and in a temperature range from approx. -10°C to approx. + 100°C in an open or closed vessel, possibly in an inert gas atmosphere, e.g. under nitrogen. Starting substances with formula IV can be prepared in a manner known per se. Thus, one can 'e.g. analogously to the reaction steps IIIb-IIIh described for the preparation of compounds of formula III, whereby the group ; work as follows: stands for the group One reacts, for example, a tryptamine compound with the formula in which X2 is lower alkyl or a suitable group that can be split off by means of solvolysis, such as hydrolysis, which derives from an organic sulfonic acid and is e.g. arylsulfonyl, such as p-toluenesulfonyl, or denotes a residue of a half-ester of the carboxylic acid, e.g. lower alkoxycarbonyl, such as e.g. tert-butoxycarbonyl, e.g. with the corresponding 4-chlorobutyryl chloride of the formula to a compound of the formula being prepared from an optionally lower alkylated in the 2-position, such as ethylated, γ-butyrolactn of formula III and thionyl chloride in the presence of anhydrous zinc chloride in the usual way to a compound of the formula subject such a compound to the ring-closing, on usual way e.g. in the presence of a condensing agent, e.g. such an acidic character as phosphorus oxychloride, carrying out condensation to a compound of formula converts such a compound especially of a base, such as an alkali hydroxide, such as sodium hydroxide, into a compound of formula and reacts such a compound, possibly after splitting off the group X2, e.g. using water in basic media, e.g. in the presence of an alkali hydroxide, such as sodium hydroxide, with a compound of formula and optionally carrying out subsequent cleavage of the group X2, e.g. as indicated, and its replacement by hydrogen, to a compound of formula IV. When treating such a compound with a dehydrating agent, such as in buffered aqueous solution, e.g. with air oxygen, one can, after removal of any present cleavable and hydrogen-replaceable group X2, as indicated, obtain a compound of formula IV with a further double bond in ring C. A process variant for the production of starting substances of formula IV consists in in the usual way transfers a compound of formula in which the optionally substituting hydroxy and/or amino groups of the carbocyclic ring A are suitably present in protected, e.g. aralkylated, such as 1-phenyl lower alkylated, e.g. benzylated, form, in a corresponding dianion-present compound with formula, for example by reaction with a suitable organometallic compound, such as an organic alkali metal amide, e.g. lithium diisopropylamide, converts such a compound with a compound of formula IVi into a compound of formula and then converts such a compound by ring-closing condensation with the aid of a suitable condensing agent, such as one described above, e.g. one of an acidic nature, such as e.g. phosphorus oxychloride, and subsequent cleavage of any protective group present, e.g. by hydrolysis, in a compound of formula IV. This reaction is carried out in a manner known per se. Starting substances with formula IV, which contain the group IVa, can be formed by reacting e.g. a compound of formula in which the primary hydroxy group is preferably present in reactive esterified form, e.g. as an ester of an inorganic or organic acid, such as a hydrohalic acid or an organic sulphonic acid, such as p-toluenesulphonic acid, and consequently, for example, denotes p-tosyloxy or especially bromine, with a compound of formula IVh in the usual way, e.g. in slightly acidic buffered solution, approximately at a pH of 6.0-6.8. Starting substances of formula IV, in which the group denotes the group can be prepared in a manner known per se, by reacting, for example, a tryptamine compound of formula IVd with a carboxylic acid of formula ~ or a reactive derivative thereof, such as an ester of a lower alkanol, f .ex. methanol, to a compound of formula ; The reaction is carried out in a manner known per se, usually in the presence of a suitable solvent, e.g. in a temperature range from approx. -10° to approx. + 100°C in an open or closed vessel. A compound of formula IVo, in which hydroxy and/or amino groups are optionally present in a protected form, is then converted, e.g. as described above, in acylated, such as lower alkanoylated, e.g. acylated, or aralkylated, e.g. benzylated, form by oxidation in a compound of formula ; ; or a salt thereof and any protective groups present are cleaved off hydrolytically, e.g. as described. Suitable oxidizing agents are, for example, Hg(II) salts, e.g. Hg(II)-acetate, further hypochlorous acid, suitably in the form of a suitable derivative, such as tert-butyl hypochlorite. A thus formed compound of formula IVp is then converted by treatment with a base, e.g. with an alkali metal hydroxide, such as sodium hydroxide, in a compound of formula; This is followed by the reaction of a compound thus formed with a compound of formula IVi, e.g. analogously as described above, to a compound of formula which then converts by reaction with a suitable sulfur compound, e.g. 2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (Lawesson's reagent) in a compound of formula IV, in which the group stands for the group By changing this reaction order, one also works so that one converts a compound of formula IVq with a suitable sulfur compound, as described, e.g. with the Lawesson reagent defined above, in a compound of formula and forms from such a compound by reaction with a compound of formula IVi, e.g. analogously to that described above, a compound of formula IV, in which the group denotes the group Starting substances of formula IV, which contain a group IVb, can in the usual way, e.g. by reacting a tryptamine compound of formula IVd, in which hydroxy and/or amino groups are conveniently present in protected form, as described, e.g. protected with α-aryl lower alkyl, such as benzyl, with a compound of formula in which the aldehyde group is conveniently present in protected, such as e.g. acetalized form, e.g. as dilave alkyl, as dimethyl acetal, the carboxyl group is present in esterified form, e.g. as an ester, such as of a lower alkanol, e.g. ethanol, and the primary hydroxyl group is present in reactive esterified form, e.g. as an ester of an inorganic acid, e.g. hydrochloric acid, or of an organic acid, such as of p-toluenesulfonic acid, and consequently means e.g. chlorine or p-tosyloxy, is converted into a compound of formula which is then subjected to the cyclizing condensation to a compound of formula; The reaction conveniently takes place in the presence of a condensing agent, e.g. a base, such as a heterocyclic nitrogen base, such as imidazole, at elevated temperature. The possibly protected, such as acetalized, aldehyde group is then converted in an acidic medium, such as in acetic acid, into the free aldehyde group. A thus formed compound of formula IVv is then reacted with a compound of formula in which Hal stands for halogen, e.g. chlorine, and R'2 means optionally esterified or amidated carboxy, e.g. lower alkoxycarbonyl or carbamoyl, in the presence of a base, e.g. an alkali metal avereal alkanolate, such as potassium tert.-butylate, under the conditions of the Witting reaction to a compound of formula a compound thus formed becomes by means of cyclizing condensation, such as in the presence of a suitable condensing agent, e.g. one of such a sour character, as e.g. phosphorus oxychloride, and cleavage of the group X^ as well as optionally present hydroxy and/or amino protecting groups and their exchange with hydrogen, as described, is converted into a compound of formula IV which contains a group IVb. These reactions are usually carried out in a suitable solvent and in a temperature range from approx. -10 to approx. +150°C, possibly in an inert gas atmosphere, e.g. ;under nitrogen. Starting substances of formula IV, in which m in the group R cler zero, can be formed in the usual way, by reacting a compound of formula with a compound of formula ; to a compound of formula IV. The hydroxy group in a compound of formula (IVz) is conveniently present in a reactive, esterified form, e.g. as an ester of a strong organic sulphonic acid, as of an aliphatic or aromatic sulphonic acid, or of a halohydrogen acid and consequently means e.g. the methanesulfonyloxy or p-tosyloxy group, further halogen, especially bromine and especially iodine. A group R2 is in particular an esterified carboxy group of the type indicated, e.g. one with a lower alkanol, e.g. methanol, esterified carboxy group. The reaction is carried out in the usual way in a suitable solvent, e.g. in an inert and possibly aprotic solvent, e.g. dimethylsulfoxide, optionally in a further solvent of an inert nature, e.g. an aromatic solvent such as toluene, at an elevated temperature, such as in a range from +30 - +180°C, preferably approx. +70 - + 150°C and suitably in an inert gas atmosphere, such as under nitrogen. Starting substances of formula IVy are obtained, for example, from a compound of formula IVh by cleavage of the group X2, e.g. by hydrolysis, and their yield with hydrogen. These transactions are carried out in a manner known per se. The new compounds of formula I can also be obtained by reacting a compound of formula; in which X means lower alkyl or means a group that can be split off under the process conditions and is replaceable with hydrogen, and hydroxy and/or amino groups are optionally present in protected, e.g. by solvolysis, such as hydrolysis, cleavable form, with a compound of formula in which X o means* the residue of formula or the residue of formula that exists in quaternary form, e.g. as quaternary halide, e.g. as chloride, or X denotes the residue by formula

wherein Rc- is lower alkyl, e.g. ethyl, or

XX means halogen, and R^ denotes optionally esterified or amidated carboxy, and converts a compound formed by simultaneous or subsequent cleavage of the cleavable and hydrogen-replaceable group X^ and optionally present hydroxy and/or amino protecting group into a corresponding compound of formula I, in which instead of the group -(R^-R^- the residue -CH=CH- stands, and if desired, they carry out the aforementioned method step in connection with the first method.

A cleavable group X^ under the starting method conditions

is e.g. a group cleavable with water in basic or acidic media and indicates e.g. the residue of an organic sulfonic acid,

such as arylsulfonyl, e.g. p-toluenesulfonyl, or the residue of a half-ester of the carboxylic acid, such as lower alkoxycarbonyl, e.g. tert.-butoxycarbonyl.

The hydroxy and/or amino protecting group is e.g. acyl residues of organic carboxylic acids, e.g. lower alkanoyl, such as acetyl, or half-esters of carboxylic acids, e.g. lower alkoxycarbonyl, further, for example, trityl or silyl residues, such as e.g. trimethylsilyl. Such protective groups are split off with the help of water, possibly in the presence of basic agents or weak acids.

Esterified carboxy is e.g. one with a lower alkanol, e.g. methanol or ethanol, or a lower alkanethiol, such as ethyl mercaptan, esterified carboxy, and consequently indicates e.g. lower alkoxycarbonyl, such as methoxy or ethoxycarbonyl or lower alkylthiocarbonyl, e.g. ethylthiocarbonyl.

Amidated carboxy, in which the nitrogen atom is bonded to two

from hydrogen different residues, corresponds to the formula _CONRgR^ (Ve), in which Rg and R^ are each e.g. lower alkyl, such as methyl, or Rg and R^ together mean e.g. lower alkylene, oxa-,

thia-, optionally N<1->substituted, as N-lower alkylated azalower alkylene and consequently forms together with the N atom, for example, pyrrolidino, morpholino, piperazino or N'-methylpiperazino. The reaction with a compound of formula Va, in which Xq means a group Vb, Vc or Vd,

usually occurs in the presence of a basic agent, e.g. an alkali metal avereal alkanolate, such as potassium tert.butylate, or in the presence of an alkali metal hydride, such as sodium hydride.

The reaction of a compound of formula V with a compound of formula Va, in which Xq stands for halogen, for example bromine, and

R^' preferably stands for esterified carboxy, and the simultaneous or subsequent cleavage of the group X^ and possibly present hydroxy and/or amino protecting groups takes place in the usual way, e.g. under the conditions of the Reformatsky reaction in the presence of zinc in a suitable inert solvent such as an aromatic solvent such as benzene or an ethereal liquid such as diethyl ether. In this way, a corresponding compound with formula I is obtained during water elimination, in which instead of the group

-(Rj^-R^)- the remainder stands -CH=CH-.

This reaction is usually carried out, e.g. in the presence of a solvent or solvent mixture, if necessary, during cooling or heating, e.g. in an open or closed vessel and/or in an inert gas atmosphere, e.g. nitrogen.

Starting substances with formula V can be prepared in a manner known per se.

Thus, one can convert e.g. a compound with formula

with an aldehyde of formula IIb or a reactive derivative thereof, such as one in which the aldehyde group is present in a protected form, e.g. silylated form, and consequently corresponds to e.g. the group lic, and the hydroxy group is present in a reactive, esterified form, to a compound of formula V, and then cleave off an optionally present aldehyde protecting group.

A reactive esterified hydroxy group is in one with a strong acid, especially a strong inorganic acid, such as a hydrohalic acid, especially hydrochloric, bromic or hydroiodic acid or sulfuric acid, or a strong organic acid, especially a strong organic sulfonic acid, such as an aliphatic or aromatic sulphonic acid, e.g. methanesulfonic acid, 4-methyl-phenylsulfonic acid or 4-bromophenylsulfonic acid, esterified hydroxy group, and denotes primarily halogen, e.g.

bromine or aliphatic or aromatically substituted sulphonyloxy, e.g. methylsulfonyloxy or 4-methylphenylsulfonyloxy.

The above-mentioned reaction is carried out in a manner known per se, whereby one works, in particular by using a starting material with a reactive esterified hydroxy group, preferably in the presence of a basic agent, such as an organic basic agent, such as an amine, e.g. e.g. ethyldiisopropylamine, usually in a suitable solvent, such as one of a strongly polar, aprotic character, e.g. dimethylformamide in a temperature range from approx. -5°C to +150°C, preferably from +10°C to +100°C, in an open or closed vessel and/or in an inert gas atmosphere, e.g. nitrogen.

Starting substances of formula Va are known or can be prepared by conventional methods. Then you can e.g. to prepare a starting material of formula Va, in which Xq stands for the group Vc, react triphenylphosphine with a compound of formula Va, in which Xq stands for halogen, such as chlorine. Starting substances of formula Va, in which Xq stands for the group Vd, can be obtained by reacting a trialkyl phosphite of formula III

with a compound of formula Va, wherein X is halogen, such as chlorine.

These sales are carried out in the usual way.

The new compounds of formula I can likewise be obtained by using a compound of formula

in which X^ means lower alkyl or a group that can be split off under the process conditions and is replaceable with hydrogen,

and X^ means halogen or a hydroxy group esterified with an organic sulfonic acid, cleaves off the group X^ and in the sense of R^, substitutes corresponding, optionally substituted amino, optionally esterified or etherified hydroxy or lower alkylthio and simultaneously or subsequently cleaves off a cleavable and hydrogen exchangeable group X^ and replace with hydrogen, and, if desired, carry out the method steps described in connection with the first method. A cleavable under the process conditions and replaceable with hydrogen group X^ is a group cleavable with water in basic or acidic media or with ammonolysis and indicates e.g. the residue of an organic sulphonic acid, e.g. p-toluenesulfonyl or the residue of a half-ester of the carboxylic acid, e.g. ethoxycarbonyl or tert-butoxycarbonyl.

The cleavage of the group X^ and its yield, e.g. towards the optionally substituted amino group takes place by reaction with a compound which allows the introduction of such an amino group. Thus, one can convert e.g. a compound of formula VI, wherein X^ is, for example, halogen, such as chlorine, with hexamethylenetetramine in the usual manner, e.g. in a suitable inert solvent, such as chloroform, and converting the formed adduct in acidic media, e.g. in the presence of a halogen hydrogen acid, such as aqueous hydrochloric acid, in a compound of formula VI, in which the primary amino group is substituted for, and at the same time cleaving a protecting group X^, e.g. tert.-butoxy group, and replace with hydrogen. But it is also possible to work in such a way that the exchange of the group X^ against amino is carried out with the help of ammonia, e.g. as a solution in a suitable solvent, such as such an inert, e.g. of an aromatic character, as benzene, or an ethereal liquid,

such as dioxane, or by means of a primary or secondary amine, optionally in the presence of an acid-binding agent, then

as a basic agent, e.g. potassium carbonate, or an excess of the amine which is to introduce the amino group, whereby, at the same time, a suitable protecting group X^ is cleaved off, e.g. the said tert.-butoxy group.

The exchange of a group X^, for example chlorine, with the corresponding hydroxy in the sense of R, can be carried out in the usual way, e.g. by means of water, possibly in the presence of an acid or a base, e.g. a hydroxide or carbonate of an alkali metal or alkaline earth metal, e.g. sodium hydroxide, sodium carbonate or magnesium carbonate, or in the presence of aqueous mineral acids, e.g. aqueous sulfur

acid during simultaneous cleavage of a protecting group X^, e.g. ethoxycarbonyl or n-butoxycarbonyl.

The substitution of a group X^ for esterified hydroxy, for example aroyloxy, benzenesulfonyloxy or lower alkanoyl-

oxy, can e.g. happen by reaction with a suitable salt, such as an alkali metal salt, e.g. sodium or potassium salt of an acid corresponding to the hydroxy group to be esterified, such as an optionally, as indicated, substituted aromatic carboxylic or sulphonic acid or a lower alkane carboxylic acid, suitably in a suitable solvent, such as one of such polar character much like alcohol, like a lower alkanol, e.g. ethanol, or a carboxylic acid amide, such as N-methylacetamide, N,N-dimethylacetamide, N,N,N',N'-tetramethylurea or sulfolane.

The removal of a group X^, such as chlorine, and its replacement with in the sense of the corresponding etherified hydroxy, e.g. lower alkoxy, or lower alkylthio occurs in the usual way by reaction with one to the etherified hydroxy group or lower alkylthio group corresponding to alkanol or lower alkanethiol, conveniently in the form of a metal compound. Thus, for example, an alkali metal compound can be converted from a lower alkanol, or lower alkanethiol, such as that of ethanol, as sodium ethoxide, or that of ethyl mercaptan, as its sodium compound, with a compound of formula VI, in which X^ is, for example, halogen, such as chlorine, or methanesulfonyloxy, whereby the group X^ is replaced by a corresponding lower alkoxy or lower alkylthio and a protecting group X^, for example benzenesulfonyl or ethoxycarbonyl, are split off and replaced with hydrogen.

These reactions are usually carried out in the presence of a solvent under cooling or heating in a temperature range from approx. -20 to approx. + 120°, possibly in a protective gas atmosphere, such as under nitrogen.

Starting substances with formula VI can, if these are new, be obtained in a manner known per se, by converting e.g. a compound with formula

with a compound of formula

and associated salt formation, e.g. with perchloric acid, to

a compound with formula

This reaction is usually carried out in the presence of a suitable solvent of an inert nature, e.g. a halogenated hydrocarbon, so methylene chloride.

This is followed by the reduction of the double bond common to rings C and D to a compound of formula VI, which can take place in the usual way, e.g. using lithium-tri-tert.butoxy-aluminum hydride.

Starting substances with formula Via can also be obtained analogously to it

for the preparation of a compound of formula Ille described reaction sequence Illa-IIIe sorted the following:

One reacts a tryptamine compound with formula

for example with a compound of formula to a compound of formula which is then converted in the usual way by ring-closing condensation, e.g. in the presence of a suitable condensing agent, such as one of an acidic nature, such as an acid halide, e.g. phosphorus oxychloride, to a compound of formula

from which is obtained by treatment with a basic agent, e.g. an inorganic base, such as an alkali hydroxide such as sodium hydroxide, a starting material of formula Via. Starting substances of formula Vie can again be obtained in the usual way by reaction of an optionally lower alkylated in the 2-position, e.g. ethylated, Y-butyrolacetone of formula Uld with thionyl chloride in the presence of a suitable condensing agent, such as anhydrous zinc chloride.

The new compounds of formula I, in which R stands for amino, can also be obtained when, in a compound of formula

in which Xj. means lower alkyl, lower alkenyl or a group cleavable under the reduction conditions and exchangeable with hydrogen, the group reduces to the group

and reduces a possibly present

being a common double bond to rings C and D, whereby in such a case the common N atom of rings C and D carries a positive charge and the anion M has the indicated meaning, to a carbon-nitrogen single bond, and/or reduces a possibly present lower alkenyl group X^ to a lower alkyl group, and/or reduces an optionally present, cleavable under the reduction conditions and hydrogen-replaceable group Xj., and cleaves any cleavable and replaceable protecting groups to hydroxy and/or amino groups under the reduction conditions and replaces with hydrogen and, if desired , they carry out the method steps described in connection with the first method.

A particularly suitable cleavable group X, as well as protective groups optionally bound to hydroxy and/or amino groups is primarily a hydrogenolytically cleavable α-aryl lower alkyl group, such as an optionally substituted 1-polyphenyl lower alkyl or 1-phenyl lower alkyl group, in which substituents, especially for the phenyl part, can be e.g. lower alkyl, such as methyl, or lower alkoxy, such as methoxy, and is primarily benzyl.

In addition, suitable acyl groups are taken into consideration, which in the phenyl part, if necessary, e.g. as above, substituted 1-phenyl lower oxycarbonyl.

The reduction is carried out in the usual way, for example by treatment with catalytically activated hydrogen, such as hydrogen in the presence of a hydrogenation catalyst, e.g. in the presence of a nickel catalyst, such as Raney nickel, or a noble metal catalyst, such as platinum or palladium, whereby the double bond common to rings C and D is reduced to a carbon-nitrogen single bond, the group Vila is reduced to the group Vllb, a lower alkenyl group X,- is reduced protective groups bound to a lower alkyl group or a cleavable protective group X^ and optionally to hydroxy and/or amino groups are cleaved off and replaced with hydrogen. The reduction can also be carried out step by step, as

the double bond common to rings C and D reduces to a carbon-nitrogen single bond and in a compound thus formed, analogous to formula VII, reduces the group Vila to group Vllb, reduces a lower alkenyl group X,, to a lower alkyl group or splits off a cleavable and hydrogen exchangeable protective group X, as well as any protective groups bound to hydroxy and/or amino groups and substituted with hydrogen. The reduction of the double bond common to the rings C and D can take place e.g. by means of a suitable hydride reducing agent, such as a dilate metal hydride reducing agent, e.g. lithium-tri-tert.butoxyaluminium hydride, while the associated reduction of the group Vila to the group Vllb and the removal of the protecting groups, e.g. by means of activated hydrogen, as indicated, or by means of an alkali metal, such as sodium, in an alcohol, such as a lower alkanol, such as ethanol, can be carried out.

Starting substances with formula VII can be prepared in a manner known per se. These can be produced, e.g. by reacting a compound of formula in which Xg stands for hydrogen or is a suitable cleavable group, e.g. chlorine, bromine or iodine, with a nitrosating agent. As such, one can use e.g. nitric acid which is conveniently formed in situ from a salt of nitric acid, for example an alkali metal salt, e.g. the sodium salt, in an acidic medium, such as in acetic acid.

Starting substances with formula VIIc can further be prepared,

by reacting a tryptamine compound of formula

e.g. with a 4-chlorobutyryl chloride of formula to a compound of formula and from this prepare by ring-closing condensation, e.g. in the presence of a suitable condensing agent, such as one of an acidic nature, e.g. an acid halide, such as phosphorus oxychloride, a compound of formula which is obtained by treatment with a basic agent, e.g. an inorganic base, such as an alkali hydroxide, such as sodium hydroxide, a compound of formula By reaction of such a compound e.g. with a compound of formula

in the presence of a suitable solvent, such as a halogenated hydrocarbon, such as dichloromethane,' and subsequent salt formation, e.g. with perchloric acid, a compound of formula VIIc can be obtained

where m is the group R a1, These transactions are carried out in a manner known per se.

The new compounds of formula I, in which R 2 stands for possibly esterified or amidated carboxy and R 4 stands for hydrogen, can also be obtained when, in a compound of formula

opens the ring E by means of alcoholysis, aminolysis including ammonolysis or hydrolysis to form an optionally esterified or amidated carboxy group R2 and, if desired, carries out the method steps described in connection with the first method. The alcoholysis can be carried out in the absence or presence of accelerating agents, e.g. basic substances. Appropriately, however, the turnover is carried out in basic media, e.g. in the presence of a suitable base,

such as a metal compound of the alcohol in question, the latter also serving as a solvent. Metal compounds of this kind are e.g. such of alkaline earth numbers, but especially of alkali metals and consequently indicates, for example, a magnesium lower alcohol alkoxide, such as magnesium ethylate, or an alkali metal lower alcoholate, such as sodium methoxide.

The aminolysis, including ammonolysis, is suitably carried out in a suitable, for example inert, solvent.- These are e.g. liquids of an ethereal nature, such as diethyl or di-n-butyl ether, tetrahydrofuran or dioxane, or that. concerns aromatic solvents, such as e.g. benzene, toluene or xylol. For the ammonolysis, a solution of ammonia in one of the mentioned solvents can be used, but also an aqueous solution.

The hydrolysis is carried out using water, appropriately

in acidic, but preferably in basic media. As acids come into consideration e.g. mineral acid, such as sulfuric acid, or organic acids, e.g. acetic acid or trifluoroacetic acid, while basic agents are, for example, inorganic bases, such as hydroxides of iodo-alkali or alkali metals, e.g. magnesium hydroxide or sodium hydroxide.

The above-mentioned reactions are carried out in a manner known per se and usually in the presence of a solvent, e.g. in the presence of one of the aforementioned, or a solvent mixture, and, if necessary, during cooling or heating, e.g. in a temperature range from approx. -20°C to approx. +150°C in an open or closed vessel and/or in an inert gas atmosphere, e.g. in a nitrogen atmosphere.

Starting substances with formula VIII can be prepared in a manner known per se. Thus, one can e.g. in a connection with formula

wherein Xg has the above-mentioned meaning as hydrogen or a suitable cleavable group, e.g. chlorine, bromine or iodine, but also denotes a hydroxy group esterified with a sulphonic acid, e.g. methanesulfonyl group, replace the group Xg by in the sense of in that of the group R^ corresponding where applicable

esterified hydroxy, lower alkylthio or optionally substituted amino or lower alkyl. Thus, one can substitute a compound of formula VHIb, in which X fi is different from hydrogen and means e.g. chlorine or bromine, with etherified hydroxy, for example lower alkoxy or phenyl lower alkylthio, or with lower alkylthio, reacting an alcohol or lower alkene thiol corresponding to these groups, suitably in the presence of a basic agent, e.g. a metal lower alkanolate, such as sodium lower alkanolate, with such a compound of formula VHIb and optionally cleaves off present hydroxy and/or amino protecting groups, which under the reaction conditions can be cleaved, and replaces with hydrogen. Or one uses the alcohol used or the corresponding lower alkanethiol as a metal compound, e.g. as such with an alkali metal, e.g. sodium, for this reaction, which is usually carried out in a suitable solvent, such as a lower alkanol, such as ethanol.

For the introduction of optionally substituted, such as lower alkylene amino, further lower alkylene amino, oxolave alkyleneamino, thialave alkyleneamino or aza lower alkyleneamino, one can react a compound of formula VHIb, in which XD is different from hydrogen, e.g. with ammonia or a compound which emits ammonia, such as hexamethylenetetramine, or a phthalimide compound, e.g. phthalimide potassium, or a primary or secondary amine containing the aforementioned substituents, in the usual manner, in the absence or presence of a suitable solvent, and/or in the presence of an acid-binding agent, e.g. a basic agent, such as potassium carbonate, or in an excess of the corresponding amine containing the amino group to be introduced, optionally at elevated or lowered temperature, in an open or closed vessel. If the reaction takes place with hexamethylenetetramine, this is followed by the addition of the intermediately formed adduct in the acidic medium, such as with the help of dilute hydrochloric acid, while by reaction e.g. with the help of the intermediate product formed by phthalimide potassium, the phthaloyl group must be split off, e.g. using hydrazine hydrate. In the latter case, the primary amino group is introduced in the described manner and any hydroxy and/or amino protecting groups that may be present, which can be removed under the reaction conditions described, are removed and replaced with hydrogen.

The introduction of a primary amino group can also take place by reacting a compound of formula VHIb, in which X has the indicated meaning, and in which amino groups in particular are protected by the protecting group, for example those that are cleavable by reduction, such as hydrogen oleic acid, and exchangeable with hydrogen , like for example. α-aralkyl groups such as 1-phenyl lower alkyl groups, e.g. benzyl, with a nitrosating agent, such as nitric acid, which is conveniently formed in situ in the reaction mixture, such as from a salt, e.g. alkali metal salt such as sodium nitrite, or an ester, e.g. tert.-butyl nitrite, in the presence of an acid to a compound of formula VHIb, in which the group -CHXg- corresponds to the group -C(=NOH)-, whereby the formed hydroxyimino group can be present in syn or anti form or as a mixture of these two forms, and reduces the hydroxyimino group to the primary amino group. The reduction of the hydroxyimino group to a primary amino group can, for example, take place with activated hydrogen, e.g. hydrogen in the presence of a hydrogenation catalyst, such as Raney nickel, or in the presence of a noble metal catalyst, such as platinum or palladium, whereby any protective groups present, which can be split off under these reaction conditions, to the hydroxy group and especially to the amino group, e.g. α-aryl lower alkyl-, e.g. 1-phenyl lower alkyl groups,

such as benzyl, is split off and replaced with hydrogen, or one reduces, for example, by means of nascent hydrogen, e.g. by means of an acid, such as a mineral acid, such as sulfuric acid, in the presence of a suitable metal, such as zinc, or by means of an amalgam, e.g. an alkali metal amalgam, such as sodium amalgam, in water, or by means of an alkali metal, e.g. sodium in a lower alkanol, such as ethanol, whereby any protecting groups to hydroxy- and/or amino-

groups and can be split off under the reaction conditions, for example silyl groups, such as trimethylsilyl groups, or a lower alkoxycarbonyl group, such as tert.-butoxycarbonyl, are split off and replaced with hydrogen.

The yield of a group Xg , e.g. chlorine, against in the meaning corresponding to hydroxy can take place in the usual way by means of hydrolysis, optionally in the presence of an acid or base, e.g. in the presence of a hydroxide or carbonate of an alkali or alkaline earth metal, e.g. potassium hydroxide, sodium bicarbonate or magnesium carbonate, whereby under these conditions any hydroxy and/or amino protecting groups that may be cleavable, which may be present, are cleaved off and replaced with hydrogen.

Hydroxy or amino groups introduced in the manner described above can be transferred into esterified hydroxy or acylated amino. For example, a formed compound of formula VHIb, in which Xg is replaced by hydroxy, is reacted with an aromatic carboxylic or sulfonic acid or a lower alkane carboxylic acid, or a reactive derivative thereof,

such as an anhydride, mixed anhydride, such as a halide, such as acid chloride, or a reactive ester, for example such, whose alcoholic component is activated with suitable groups or substituents, in the usual way. Analogously, a free amino group can be converted into acylated amino, such as lower alkanoylamino, e.g. by reaction with a corresponding acid anhydride. By introducing the above-described optionally etherified hydroxy groups or optionally substituted amino groups in a compound of formula VHIb, the described opening of ring E can be effected at the same time, which then leads to compounds of formula I, in which R2 optionally denotes esterified or amidated carboxy.

The exchange of a group Xg as hydrogen against the value of R1 corresponding to lower alkyl can e.g. happen in such a way that a compound of formula VHIb, in which Xg is hydrogen, replaces this hydrogen atom with a suitable metal, e.g. an alkali metal, which in turn is available for further reactions, possibly by reaction with a reactive alkali metal compound such as lithium isopropyl amide, and reacting the resulting compound with a reactive ester of a lower alkanol, for example a halide, such as chloride, bromide or iodide, or a sulfonic acid ester,

such as one of aliphatic or aromatic character, such as a methanesulfonic or p-toluenesulfonic acid. These transactions are carried out in the usual way in a suitable, e.g. inert. solvent during cooling or heating in open or closed vessels, possibly in a protective gas atmosphere, such as nitrogen.

Starting substance f is of formula VHIb, in which R is the group

-Cf^-, can also be obtained by e.g. reacts a tryptamine compound of formula

which in turn is available e.g. analogously to that for the conversion of a compound of formula IIIa in a method described with formula IIIb, in which X denotes lower alkyl or the residue of an organic sulphonic acid, e.g. The p-tosyl residue, or residues of a half-ester of the carboxylic acid, e.g. a lower alkoxycarbonyl, such as methoxy or ethoxycarbonyl, e.g. with a 4-calorbutyryl chloride of the above-described formula Ille to a compound of formula and from this by ring-closing condensation, e.g. in the presence of a suitable condensing agent, such as one of an acidic nature, e.g. an acid halide, such as phosphorus oxychloride, produces a compound of the formula of which on treatment with a basic agent, e.g. an inorganic base, such as an alkali hydroxide, such as sodium hydroxide, and simultaneous or subsequent cleavage of a cleavable and hydrogen-replaceable group X_ and their replacement with hydrogen can be obtained a compound of formula

In the case of associated sales of such a connection, e.g. with an acrylic compound of formula

and subsequent reduction of the common double bond present in rings C and D to a carbon-nitrogen single bond, e.g. using hydrogen in the presence of a hydrogenation catalyst, such as a palladium-on-charcoal catalyst, gives a compound of formula

of which, especially when R 2 denotes an esterified carboxy group, e.g. lower alkoxycarbonyl, and X, is hydrogen, can be obtained by ring-closing condensation in the usual way, e.g. in basic medium, such as in the presence of an alkali metal avereal alkanolate, e.g. potassium tert.butylate, preferably in the presence of a substance suitable for enolate formation, for example a carbonyl compound, to which a mobile hydrogen atom suitable for enol formation is bound to a carbon atom adjacent to the carbonyl group, e.g. an aryl lower alkyl ketone, such as acetophenone,

or a 1,3-diketone, e.g. an acylacetone, such as a lower alkanoylacetone such as acetylacetone, a compound of formula VHIb can be obtained, wherein Xg is hydrogen.

These transactions are carried out in the usual way.

Starting material f is of formula VHIb, in which m in the group R is 0, and Xg means hydrogen, can be obtained in the usual way, e.g. by reacting a compound of formula VIHf with a compound of the above-mentioned formula IVz in the manner described there and associated cyclization of a compound thus formed, e.g. as described above.

In the starting substances with formula VHIb, in which X,, means hydrogen, a hydrogen atom which is bound to a carbon atom which is adjacent to the carbonyl group, can be replaced with e.g. to the group Xg corresponding to halogen, such as chlorine, bromine or iodine, converting one, e.g. as described above, formed compound of formula VHIb, in which Xg is hydrogen, in a corresponding compound containing a carbanion, e.g. by reacting with lithium diisopropylamide in a suitable solvent, such as tetrahydrofuran, then reacting the reaction product with a carbon tetrahalide, such as tetrachloro- or tetrabromomethane or a solution of iodine in tetrahydrofuran, and hydrolyzing by means of acidic agents, such as aqueous hydrochloric acid. (Cf. to this: R.T.Arnold et al.: J.Org. Chem. 4_3, 3687-89 (1978). But the exchange of a group Xg as hydrogen in a compound of formula VHIb for corresponding hydroxy can also be carried out by converting for example a reaction product with lithium diisopropylamide, for example such as described above, by reaction with trimethylchlorosilane in a compound of formula prepared from such a compound by means of a suitable oxidizing agent, such as a peroxide, such as m-chloroperbenzo- acid, a corresponding epoxide and produces from this in close

be of acid reacting agents, e.g. triethylammonium fluoride, a compound of formula VHIb, in which the group Xg as hydrogen is replaced by a hydroxy group.

A modification of the transformation of the group Xg as hydrogen

in corresponding hydroxy consists in oxidizing the above-described reaction product of a compound of formula VHIb with lithium diisopropylamide by means of the complex MOj. vpyridine-hexamethylphosphoric acid triamide in analogy with the method of Vedejs et al.: J.Org. Chem. 4J3, 188 (1978).

The hydroxy group thus formed can then be converted, e.g. with a halohydrogen acid corresponding to Xg or a sulphonic acid, such as methanesulphonic acid, or a reactive derivative thereof, e.g. the halide,

in a corresponding esterified hydroxy group Xg. The conversion of the hydroxy group into halogen can also take place by the action of a halogenating agent, such as phosphorus oxychloride, in the usual way, e.g. in a suitable solvent, such as chlorobenzene. The above-described oxidation and esterification resp. halogenation methods take place in the usual way and appropriately in such compounds of formula Hlb, in which the hydroxy and/or amino groups bound to the carbocyclic ring A are protected in a suitable manner, whereby the removal of such protective groups, if appropriate and desired, can take place in the course of the described conversions of the compounds of formula VHIb.

The new compounds of formula I can likewise be obtained by using a compound of formula

in which, by means of reduction in a lower alkyl group, R^ denotes a transferable group and R^ denotes hydrogen or lower alkenyl, optionally a double bond is common to rings C and D, and in this case the associated N atom carries a positive charge and such a connection exists as a salt, and hydroxy and/or amino groups are optionally protected by groups that can be split off by reduction and replaceable with hydrogen, reduces groups R^ to the lower alkyl group R^, reduces a possibly present lower alkenyl group R^ to a lower alkyl group, reduces a possibly present common double bond to rings C and D to carbon-nitrogen single bond, and cleaves any protective groups to hydroxy and/or amino groups, which groups are cleavable under the reducing conditions and exchangeable with hydrogen, and replaces with hydrogen, and, if desired, they carry out in connection to the first method described method step.

A lower alkenyl group R| has up to 7, preferably up to

4 carbon atoms and indicates e.g. vinyl, 2-methylvinyl or allyl residue.

R^ is e.g. an unsaturated aliphatic hydrocarbon residue with

up to 7, preferably up to 4 carbon atoms, and -contains double or triple bonds and consequently denotes, for example, vinyl-, 2-methyl-vinyl-, allyl-, 2-methallyl-,

3,3-dimethylallyl, 1-butenyl, ethynyl or propargyl residue. RI are further remnants of an eventual, e.g. with an organic sulfonic acid esterified primary lower alkanol, e.g. a p-toluenesulfonyloxylave alkane or a corresponding lower alkylcarboxaldehyde with up to 7, preferably 4 carbon atoms and consequently indicates, for example, 2-hydroxyethyl, 3-hydroxypropyl, 2-(p-toluenesulfonyloxy)-ethyl, or the rest of the acetaldehyde or the 3-propionaldehyde.

A protective group bound to hydroxy and/or amino groups, which can be removed under reducing conditions and which can be replaced by hydrogen, is primarily a hydrogenolytically removable α-aryl lower alkyl group, such as an optionally substituted 1-polyphenyl lower alkyl or 1-phenyl lower alkyl group, in which substituents, especially for the phenyl part,

can be e.g. lower alkyl such as methyl, or lower alkoxy such as methoxy, or halogen, such as chlorine, or trifluoromethyl,

and is primarily benzyl. A hydrogenolytically cleavable residue is furthermore a corresponding acyl residue, such as the acyl residue of an organic carboxylic acid, e.g. lower alkanoyl, such as acetyl, or aroyl, such as benzoyl, further the acyl residue of a half-ester of the carboxylic acid, such as lower alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, 2-halo-lower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, optionally substituted 1-phenyllower oxycarbonyl, e.g. benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, e.g. phenacyloxycarbonyl, further an optionally substituted 1-polyphenyl-lower alkyl group, in which substituents, primarily the phenyl part, can have e.g. the meaning given above, and is primarily trityl. A divalent residue which together can substitute a hydroxy and/or amino group is primarily a hydrogenolytically cleavable group, such as optionally substituted 1-phenyl-lower alkylidene, in which substituents, especially for the phenyl part, can be, for example, lower alkyl or lower alkoxy and is especially the benzylidene.

The reduction of an unsaturated hydrocarbon residue R^ to a corresponding lower alkyl residue R^ as well as a possibly present lower alkenyl group R^ to a lower alkyl group and the possibly present double bond common to rings C and D to a carbon-nitrogen single bond and the cleavage of any protective group present to hydroxy and/or amino groups can be carried out in a known manner, e.g. by treatment with catalytically activated hydrogen, such as hydrogen in the presence of a suitable hydrogenation catalyst, e.g. a nickel, platinum or palladium catalyst, whereby present hydrogenolytic cleavable protecting groups are simultaneously cleaved off and replaced with hydrogen, or one works with a suitable hydride reducing agent, such as e.g. diborane, or an alkali metal borohydride, e.g. sodium borohydride.

The reduction can also take place in stages, as one e.g. first reduces a possibly present double bond common to rings C and D to a carbon-nitrogen single bond, e.g. using lithium-tri-tert.-butoxyaluminum hydride, and then reductively converting the unsaturated residue R^,

e.g. as indicated by a lower alkyl residue R 1 .

When using hydride reducing agents, acyl residues of carboxylic acid can also be bound to oxygen, such as e.g.

that of acetic acid, is split off in the same work operation. The reduction of a to the group R^ corresponding residue of a primary lower alkanol, e.g. 2-hydroxyethyl, which conveniently exists in a reactive esterified form, e.g. such as 2-p-toluenesulfonyloxyethyl, can be carried out in a conventional manner using a dilate metal hydride such as lithium aluminum hydride in a suitable solvent such as tetrahydrofuran. The reduction of a lower alkylcarboxaldehyde corresponding to the residue R^ can e.g. is carried out using hydrazine hydrate in the presence of a suitable solvent, e.g. diethylene glycol. When carrying out this, especially the catalytic, reduction, it must be ensured that

other groups are not attacked, e.g. by volumetric control of the hydrogen consumption and timely interruption of the reduction or by corresponding dosing of the reducing agent. These reductions are usually carried out in the presence of a solvent or solvent mixture, whereby suitable reaction participants can simultaneously also function as such, and, if necessary, during cooling or heating, e.g. in an open or closed vessel and/or in the atmosphere of an inert gas.

Starting substances of formula IX can be obtained in the usual way, e.g. as the following:

One reacts a tryptamine compound with formula

in which Xg denotes hydrogen, lower alkenyl or a group by means of reduction comprising hydrolysis or solvolysis, which can be split off by hydrolysis and is exchangeable with hydrogen, e.g. an α-aryl lower alkyl group, such as an optionally substituted 1-phenyl lower alkyl group, in which substituents in the phenyl part can be e.g. lower alkyl, such as methyl or lower alkoxy, such as methoxy, or halogen, such as chlorine, or trifluoromethyl, and is especially benzyl, or a group that can be split off and replaced with hydrogen by solvolysis, such as hydrolysis, e.g. a sulfonyl, such as p-toluenesulfonyl or methanesulfonyl residue, or denotes the residue of a half-ester of carboxylic acid, for example lower alkoxycarbonyl, such as tert.-butoxycarbonyl, with a compound of formula

or a reactive derivative thereof, for example that of a in the 2-position with a residue, e.g. vinyl or allyl

the remainder, substituted γ-butyrolactone of formula

and thionyl chloride in the presence of a condensing agent, such as anhydrous zinc chloride, obtainable corresponding to 4-chlorobutyryl chloride with formula to a compound of formula From this one prepares by means of ring-closing condensation, suitably in the presence of a suitable condensing agent, such as one of an acidic nature, as phosphorus oxychloride, a compound of formula wherein M is the anion of an acid, e.g. that of the perchloric acid, obtained from this by treatment with a base such as an alkali hydroxide, e.g. sodium hydroxide, a compound of formula and reacts such a compound with a compound of the above formula and obtains after associated salt formation, e.g. with perchloric acid, a compound of formula IX, in which R represents the group -CH2-, and R1 and R2 have the indicated meanings, in a double bond to the rings C and D are common and the associated N atom carries a positive charge. For the preparation of starting substances of formula IX, in which m in the group R 3.is 0, a compound of the formula IXg given above can be reacted with a compound of formula

The hydroxy group in a compound of formula IXh is conveniently present in reactive, esterified form, e.g.

as an ester of a strong, organic sulphonic acid, as an aliphatic or aromatic sulphonic acid, or a halohydrogen acid,

and therefore means e.g. the methanesulfonyloxy or p-tosyloxy group, further halogen, especially bromine and especially iodine. A group R^ is in particular an esterified carboxy group of the type indicated, e.g. one with a lower alkanol, e.g. methanol, esterified carboxy group.

The reaction is carried out in the usual way in a suitable solvent, e.g. an inert and possibly aprotic solvent, e.g. dimethylsulfoxide, optionally with a further solvent of an inert nature, e.g. an aromatic solvent such as toluene at elevated temperature, so

as in a range from +30 - + 180°C, preferably approx. +70 - +150°C and suitably in an inert gas atmosphere, such as under nitrogen.

A variant for the preparation of starting substances with formula IX consists in carrying out the corresponding reaction sequences described for formulas IXa-IXg with such compounds in which the group Ri is replaced by a hydrogen atom, and reacting a compound finally formed in this way with formula

with a compound of formula Uli or formula IXh and associated salt formation, e.g. with perchloric acid, to a compound of formula

wherein R a means the group -CH c0. -, respectively m in the group R a is 0.

When treating such a compound with a base, such as

an alkali hydroxide such as sodium hydroxide, a compound of formula is obtained

in which 1-position the group is then introduced, e.g. by reaction with a reactive derivative which allows the introduction of the group R^, such as with a compound of formula

in which the hydroxy group is suitably present in a reactive form, e.g. as described for compounds of formula IXh, and consequently can mean e.g. halogen, such as bromine. After associated salt formation, e.g. with perchloric acid,

a compound of formula IX is obtained, in which rings C and D have a common double bond. These reactions are carried out in the usual way, such as in the presence of a suitable solvent and possibly at elevated temperature in an open or closed vessel and in a protective gas atmosphere, e.g. nitrogen.

After cleavage of a present cleavable and hydrogen-replaceable group Xg, which, if it is a reductive, as hydrogenolytically cleavable group,

e.g. as described, and which can be split off in the subsequent reduction, a compound of formula IX is obtained, in which rings C and D have a common double bond. This can be reduced, e.g. by means of lithium tri-tert.-butoxyaluminum hydride to the carbon-nitrogen single bond corresponding to a compound of formula IX.

The new compounds of formula I, in which the group~^R]3~Ra)~stands for the group -CH=CH-, can likewise be obtained when in a compound of formula

in which Xg is hydrogen, lower alkyl or a group cleavable under the process conditions and exchangeable with hydrogen, the group converts with formula

of water cleavage in the group -CH=CH-, cleaves off a possibly present under the process conditions cleavable if hydrogen exchangeable group Xg and replaces with hydrogen, cleaves any hydroxy and/or amino protecting groups present and replaces with hydrogen, and if desired, they carry out in connection with the first method described method steps.

A group Xg that can be split off under the process conditions and is exchangeable with hydrogen is a group that can be split off by means of solvolysis, such as hydrolysis, alcoholysis or acidolysis,

which derives e.g. from an organic sulphonic acid, e.g. an arylsulfonic acid, and is, for example, p-toluenesulfonyl or means the residue of a half-ester to the carboxylic acid and consequently indicates e.g. lower alkoxycarbonyl, such as tert-butoxycarbonyl.

Hydroxy and/or amino protecting groups are those which, under the process conditions, are split off by means of hydrolysis, alcoholysis or acidolysis, and are replaced by hydrogen. Consequently, a protecting group of this kind denotes a solvolytically, hydrolytically or acidolytically cleavable residue, especially a corresponding acyl residue, such as the acyl residue of an organic carboxylic acid, e.g. lower alkanoyl, such as acetyl, or aroyl, such as benzoyl, further the acyl residue of a half-ester to the carboxylic acid, such as lower alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, 2-halo-lower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, optionally substituted 1-phenyllower oxycarbonyl, e.g. benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, e.g. phenacyloxycarbonyl, further an optionally substituted 1-polyphenyl-lower alkyl group, in which substituents, primarily in the phenyl part, have e.g. the meaning given above and is primarily trityl.

A divalent residue which can simultaneously substitute hydroxy and/or amino groups is a solvolytic, especially hydrolytically cleavable group, such as the lower alkylidene, e.g. methylene or isopropylidene, or 1-phenyl-lower alkylidene, whose phenyl part is optionally substituted with lower alkyl, such as methyl or lower alkoxy, such as methoxy, branched benzylidene or cycloalkylidene, e.g. cyclopentylidene or cyclohexylidene.

The water separation according to the invention takes place on

conventional manner in the presence of acidic substances, optionally in the presence of a solvent and at elevated temperature in an open or closed vessel if desired in a protective gas atmosphere, such as under nitrogen.

Acidic substances are e.g. acids, such as mineral acids or carboxylic acids or their acid-reactive functional derivatives or acid salts thereof, for example sulfuric acid, potassium bisulphate, thionyl chloride, possibly in the presence of a nitrogen base, such as pyridine, further phosphoric acid, phosphorous oxychloride, formic acid, acetic acid or their halides, such as acetyl chloride, or their anhydride, further sulphonic acids such as e.g. methanesulfonic acid or p-toluenesulfonic acid.

Hydroxy and/or amino protecting groups of the aforementioned

species is split off under the water splitting conditions or during subsequent processing and is replaced by hydrogen. These reactions are carried out in a manner known per se.

Starting substances of formula X can be formed in the usual way and can be prepared, e.g. in the following way:

One reacts a compound with a formula

with an aldehyde of formula or a reactive derivative thereof, e.g. one in which the aldehyde group is present in silylated form and therefore corresponds to e.g. the group in which is lower alkyl, e.g. methyl, and the hydroxy group is preferably present in reactive, esterified form, e.g. as an ester of an inorganic acid, e.g. a hydrohalic acid, or of an organic acid, e.g. p-toluenesulfonic acid, and consequently there is e.g. as bromine or as p-toluenesulfonyloxy, in the presence of a basic agent, such as an amine, such as e.g. ethyl diisopropylamine, in a suitable solvent, such as one of a strongly polar and aprotic character, such as dimethylformamide, to a compound of formula and prepares from such a compound formed by reaction with a compound of formula in which Hal stands for halogen, especially bromine, under the conditions of the Reformatsky reaction a compound of formula X. These reactions are carried out in the usual way. The new compounds of formula I, in which R^ means the cyano group and R^ in the group R^ means hydroxy, can likewise be obtained by making a compound of formula

deposits hydrogen cyanide or a similarly reacting cyano compound giving secondary hydroxy group R^

optionally in protected form, and converts the secondary hydroxy group formed, optionally present in protected form, into the free hydroxy group, and, if desired, carries out the method steps described in connection with the first method. This transaction is carried out in a manner known in and of itself

manner, possibly during cooling or heating in an open or closed vessel, e.g. under pressure and/or in an inert gas atmosphere, such as under nitrogen.

A compound that reacts in the same way as hydrogen cyanide and is suitable for forming a secondary hydroxy group, possibly in protected form, is e.g. a suitable silyl cyanide compound, such as trimethylsilyl cyanide, which adds to a starting material of formula XI in the usual way,

e.g. in an inert solvent, such as one of such an aromatic or ethereal character, such as toluene or tetrahydrofuran at elevated or lowered temperature with the formation of a secondary hydroxy group protected by the trimethylsilyl group, in which the protective groups are cleaved off with acidic agents, e.g. hydrogen chloride, and is replaced by hydrogen to form a corresponding end product of formula I, in which R^ is hydroxy. In the course of this reaction, the formed hydroxy group R^ can be split off with a hydrogen atom bound to the neighboring methyl group with the formation of water, whereby a compound of formula I is formed, in which the group -(Rb-Ra)- stands for the group -CH=CH- .

Starting substances of formula XI, in which R^ denotes the group ~(CH2)m can be further prepared by reacting compounds of formula

in which Xg has the above-mentioned meaning and in particular has a meaning different from hydrogen, with a compound of the above-explained formula IXh and associated salt formation, e.g. with perchloric acid, to a compound of formula and its associated reduction, e.g. using lithium aluminum hydride in tetrahydrofuran, to a compound of formula

of which can be produced by oxidation using a suitable oxidizing agent, e.g. pyridinium chlorochromate, optionally after cleavage of protective groups bound to hydroxy and/or amino groups as well as an optionally present protective group Xg, aldehydes of formula XI. These transactions are carried out in the usual way.

Starting substances of formula XI, in which R& denotes the group ~^CH2^m-whose value m stands for 0, denotes analogues of the above-explained starting substances of formula V, whose preparation starting from compounds of formula Vf, as indicated is described.

When choosing the suitable methods described above for the preparation of compounds of formula I, it must be ensured that the substituents present are not converted or 'cleaved off', if such conversions or spin-offs are not desired. Thus, especially esterified or amidated carboxyl groups can participate and be converted during the solvolysis, especially the hydrolysis, and also during the reduction reactions. On the other hand, simultaneous conversions of substituents may be desired, e.g. can the group -CH=CH- under the conditions of a reduction method used according to the invention to the group

-CH 2 -CH 2 .

In formed compounds, in the framework of the definition of the compounds of formula I, compounds formed in the usual way can transfer the other end products, e.g. while converting, introducing or cleaving off suitable substituents.

Furthermore, in compounds formed with an aromatically bound halogen in the carbocyclic ring A, e.g. by treatment with hydrogen in the presence of a common hydrogenation catalyst, such as Raney nickel or palladium on charcoal, split off such halogen and replace it with hydrogen.

In the compounds formed, on the other hand, halogen atoms can be introduced into the carbocyclic ring A. This can happen in the usual way, especially at a non-elevated temperature, respectively during cooling and in the presence of a catalyst such as iron, iodine, iron III chloride, aluminum chloride or the corresponding bromides.

In compounds formed, in which R. is hydrogen, by reaction with a lower alkanol, whose hydroxy group is preferably present in a reactive, esterified form, e.g.

as an ester of an organic sulphonic acid, or of a halohydrogen acid, and which thus exists as e.g. methanesulfonyloxy or p-toluenesulfonyloxy group or as chlorine, bromine or especially iodine, in the usual way, e.g. in the presence of a basic condensing agent, such as an alkali carbonate, bicarbonate or hydroxide, such as sodium carbonate or bicarbonate, or sodium hydroxide, introduce a lower alkyl group R 1 .

A free carboxyl group can be esterified in the usual way, for example by reaction with a corresponding alcohol, preferably in the presence of an acid, such as a mineral acid, e.g. sulfuric acid or hydrochloric acid, or in the presence of a water-binding agent, such as dicyclohexylcarbodiimide, or by reaction with a corresponding diazo compound, e.g. diazomethane. The esterification can also be carried out by reacting a salt, preferably an alkali metal salt, of the acid with a reactive esterified alcohol, e.g. a corresponding halide, such as chloride.

A free carboxyl group can be amidated in the usual way, for example by reaction with ammonia, or with a primary or secondary amine, preferably in the presence of a water-binding agent, such as dicyclohexylcarbodiimide, or by transferring the carboxyl group into a halocarbonyl, e.g. . chlorocarbonyl group, and associated reaction with ammonia or with a primary or secondary amine.

In compounds containing an esterified carboxyl group, this can be in the usual way, e.g. by hydrolysis, preferably in the presence of strong bases, such as an alkali metal hydroxide,

e.g. sodium or potassium hydroxide, or in the presence of strong acids, e.g. a strong mineral acid, such as a hydrohalic acid, e.g. hydrochloric acid, or sulfuric acid, transfer in a free carboxyl group.

In compounds with an esterified carboxyl group as substituents, these can be used in the usual way, e.g. by ammonolysis or aminolysis with ammonia or a primary or secondary amine is transferred in the corresponding carbamoyl group.

In compounds with an esterified carboxyl group, this can be converted by transesterification into other esterified carboxyl groups, e.g. by reaction with an alcohol, whose boiling point is clearly above that of the alcohol in the esterified compound whose carboxyl group is to be converted and carries out the reaction e.g. in an excess of the alcohol used and/or in an inert organic solvent whose boiling point is clearly above that of the alcohol in the esterified compound to be transesterified, preferably in the presence of a catalyst, e.g. an alkali metal low-alkaline anolate,

at an elevated temperature and usually by distilling off the liberated alcohol.

In compounds with a carbamoyl group, this can be converted

in a nitrile group, e.g. by means of suitable water splitting agents, such as N,N'-dicyclohexylcarbodiimide.

In compounds with an esterified carboxyl group, this can be converted in the usual way by reduction, e.g. by means of an alkali metal in a lower alkanol, such as sodium in ethanol, i.a hydroxymethyl group.

In compounds with a hydroxy group, this can be converted in the usual way into an acyloxy group, e.g. by reaction with a carboxylic acid or sulphonic acid corresponding to the acyl residue, or a reactive derivative thereof, e.g. an acid halide, or an ester, optionally in the presence of an acid binding agent or condensing agent.

In compounds containing an acyloxy group, this can be converted in the usual way, e.g. by hydrolysis, preferably in the presence of a strong base, such as an alkali metal hydroxide,

such as sodium hydroxide, or a strong acid, such as a mineral acid, such as a hydrohalic acid or sulfuric acid,

in the free hydroxy group.

In compounds with an amino group, this can be converted in the usual way into an acylamino group, e.g. by reaction with a carboxylic acid corresponding to the acyl residue or a reactive derivative thereof, e.g. an acid halide, or an ester optionally in the presence of an acid binding agent or condensing agent.

In compounds containing an acylamino group, this can be converted in the usual way, e.g. by hydrolysis, preferably in the presence of a strong base, such as an alkali metal hydroxide, such as sodium hydroxide, or a strong acid, such as a mineral acid, such as a hydrohalic acid or sulfuric acid in the free amino group.

In compounds with a cyano group, this can be converted by means of hydrolysis, e.g. using water in acidic or basic media, e.g. in the presence of a mineral acid, such as sulfuric acid or an alkali or alkaline earth hydroxide, such as sodium or calcium hydroxide, in a carboxy group.

In compounds with a cyano group, this can be converted by means of partial hydrolysis, e.g. using water in acidic or basic media, e.g. with a hydroxide or bicarbonate of an alkali metal, optionally in the presence of a peroxide, such as hydrogen peroxide, in the carbamoyl group.

In compounds with a cyano group, this can be converted by reaction with an alcohol, such as a lower alkanol, e.g. in acidic media, such as hydrogen chloride, in the corresponding iminoether and from this is converted by hydrolytic cleavage of the imino group into an esterified carboxy group.

In compounds with a group R a, in which m is 1 and a group is Rtø, in which R^ is hydroxy, by splitting off water in the usual way, e.g. by heating in the presence of a suitable solvent, such as one of an aromatic nature such as e.g. toluene, preferably in the presence of an agent which accelerates the splitting off of water, e.g. an acidic catalyst, e.g. p-toluenesulfonic acid, a compound is obtained in which the group -(R, JD -R cl)- is replaced by the group -CH=CH-.

Non-N-oxidized compounds of formula I can be converted

by the influence of suitable oxidizing agents, e.g. a peroxy compound, e.g. a peroxycarboxylic acid such as m-chloro-perbenzoic acid, or peracetic acid, or of hydrogen peroxide, in the corresponding N-oxidized compound.

N-oxidized compounds can be converted using suitable reducing agents, e.g. activated hydrogen, such as hydrogen in the presence of a hydrogenation catalyst, such as a nickel, platinum or palladium catalyst, or by sulfur acidification of the non-N-oxidized compounds.

Non-quaternized compounds of formula I can be converted

in the corresponding quaternized groups by reaction with a compound corresponding to the aforementioned quaternary groups, e.g. optionally substituted lower alkyl, such as methyl, which is present as a reactive, esterified derivative of the appropriate quaternary group corresponding to alcohol, e.g. as halide, as chloride, bromide or iodide or as ester of sulfuric acid or an organic sulphonic acid, e.g. an aliphatic or aromatic sulfonic acid, such as methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, in the absence or presence of a suitable solvent, possibly under cooling or heating in an open or closed vessel.

As with the production methods, care must also be taken when carrying out additional steps that unwanted side reactions do not occur, which may result in the transformation of further groupings.

The reactions described above can possibly be carried out simultaneously or one after the other, further in any order. If necessary, these take place in the presence of diluents, condensation agents and/or catalytic agents, at a lowered or elevated temperature, in a closed vessel under pressure and/or in an inert gas atmosphere.

Epimer mixtures, which are also mixtures of cis- and trans-isomers, can usually be separated by fractional crystallization of suitable solvents and/or chromatography using suitable materials that effect chromatographic separation, e.g. silica gel or starch, using suitable solvents or their mixtures in the pure epimers or pure cis or trans isomers. Preferably, one isolates the most active of the epimers or the cis or trans isomers.

Formed racemate mixtures can be separated due to the physico-chemical differences of the diastereomers in a known manner, e.g. by chromatography and/or fractional crystallization, in the two stereoisomeric (diastereomeric) racemates.

Formed racemates can be split according to known methods in the antipodes, e.g. by recrystallization of an optically active solvent, by treatment with suitable microorganisms or by reaction with an optically active substance, especially acid, with which the racemic compound forms salts, and separation of the salt mixtures formed in this way, e.g. due to different solubility in the diastereomeric salts,

of which the free antipodes can be released by the action of certain agents. Particularly applicable, optically active acids are e.g. The D and L forms of Tartaric acid, Di-0-0'-(p-toluoyl)-tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Preferably, the most effective of the two antipodes is isolated.

Depending on the process conditions and starting materials, the new compounds are obtained in free form or in the form of their salts, which is also covered by the invention, whereby new compounds or salts thereof can also be present as hemi-, mono-, sesqui- or polyhydrates. Acid addition ion salts of the new compounds can be transferred in a manner known per se in the free compounds, e.g. when treated with basic agents, such as alkali metal hydroxides,

-carbonates or hydrogen carbonates or ion exchangers.

On the other hand, free bases formed with organic or inorganic acids, e.g. with the aforementioned acids, form acid addition salts, whereby for their preparation such acids are used in particular which are suitable for the formation of pharmaceutically usable, non-toxic salts.

These or other salts, especially acid addition salts of the new compounds, such as e.g. oxalates or perchlorates, can also serve to purify the free bases formed, as one transfers the free bases into salts, separates and purifies these, and releases the bases again from the salts.

Depending on the choice of starting materials and working methods, the new compounds can exist as epimer mixtures, pure epimers, racemate mixtures, racemates, optical antipodes, mixtures of cis- or trans-isomers, or as pure cis- or trans-isomers, the starting materials can also be used as pure epimers, pure cis- or trans-isomers or as specific optical antipodes, or if it is a question of oximes also used as such in syn or anti form.

The invention also relates to such embodiments of the method, from which one starts from a compound that can be obtained as an intermediate product at any stage of the process and carries out the missing process steps, or interrupts the process at any stage, or in which a starting material is formed under the reaction conditions, or in which a reaction component is possibly present in the form of their salts.

Expediently, such starting materials are used for carrying out the reactions according to the invention, which lead to the groups of end products specifically mentioned above and especially to the end products specifically described or highlighted.

The starting materials are known or can be obtained, if they are new, according to known methods, e.g. as described above and analogously as illustrated in the examples. New starting substances, especially those with the formulas II, III, IV, V, VI, VII, VIII, IX, X and XI have been especially developed for carrying out the above-described methods and likewise constitute a method for their preparation an object of the invention. The invention also relates to obtainable new intermediate products as well as methods for their production.

The invention likewise relates to the use of the compounds of formula I or of pharmaceutically usable, non-toxic acid addition salts of such compounds, in particular as pharmacologically usable compounds which primarily act on the central nervous system. Hereby one can use these, preferably in the form of pharmaceutical preparations, in a method for prophylactic and/or therapeutic treatment of animals or humans, especially for the treatment of Vigilanz disorders and cerebral performance insufficiency, especially of memory disorders of varying degrees and of sequelae of brain dreams or apoplexy.

The invention further relates to pharmaceutical preparations,

which contain compounds of formula I or pharmaceutically usable, non-toxic acid addition salts of such compounds as active substances, as well as methods for their preparation.

The new compounds can be used as e.g. in the form of pharmaceutical preparations, which contain a pharmacologically effective amount of active substance, possibly together with pharmaceutically usable carriers, which are suitable for enteral administration, e.g. oral, or parenteral administration, and can be inorganic or organic, solid or liquid. Thus, tablets or gelatin capsules are used, which contain active substances together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerin and/or lubricant, - e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets may also contain a binder, e.g. magnesium aluminum silicate, starch, such as corn, wheat, rice or arrowroot starch, gelatins, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, explosives, e.g. starch, agar, alginic acid or salts thereof, such as sodium alginate, and/or fizzy mixes, or adsorbents, dyes, flavorings and sweeteners. Furthermore, the new pharmacologically active compounds can be used in the form of parenterally administrable preparations or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, whereby these e.g. in the case of lyophilized preparations, which contain the active substance alone or together with a carrier material, e.g. mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilizers, wetting agents and/or emulsifiers, solubility enhancers, salts for regulating osmotic pressures and/or buffers. The present pharmaceutical preparations, which, if desired, may contain additional pharmacologically active substances, are produced in a manner known per se, e.g. by conventional mixing, granulating, coating, dissolving or lyophilization methods, and contains from approx. 0.1% to 100%, especially from approx. 1% to approx. 50%, lyophilisates up to 100% of the active substance.

The dosage of the active substance, which is administered alone or together with usual carriers and excipients, can depend on various factors, such as method of application, species, age and/or individual condition. Thus, the total daily dose that can be administered, of one or more, preferably at most 4 single doses for warm-blooded beings of approx. 70 kg body weight and lie in an area from approx. 10 mg to 500 mg, preferably from approx. 25 mg to 250 mg.

The following examples serve to illustrate the invention;

Temperatures are in degrees Celsius.

Example 1

A solution of 384 g (1 mol) according to the mixture formed in example 2 of the stereomers α-acetoxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b] indole-1-propionic acid methyl ester in 10 liters of methanol, chlorine hydrogen gas is introduced at reflux temperature for 3 hours. After evaporation of reaction mixtures, the residue is dissolved in 4 liters of ice/water mixture, neutralized with sodium bicarbonate, extracted three times with 2 liters of methylene chloride each time,

wash the combined organic phases with water, dry over sodium sulphate and evaporate the filtrate in vacuo. The foam formed is dissolved in 3 liters of methanol and added with 3 liters of ether. After cooling, the racemate of threo-cis-a-h<y>droxy-l-et<y>l-2,3,5,6,11,Hb-hexahydro-lH-indolizino[8,7-b]indole-l crystallized -propionic acid methyl ester, whose optical antipodes correspond to the formula

Melting point 219-220°C, Melting point of the hydrochloride 230-233°C (from methanol/ether).

The volume of the mother liquor is reduced in vacuum to 2 liters and made acidic to pH 5 with methanolic hydrochloric acid solution, evaporated in vacuum and the residue is dissolved in 3 liters of acetone. On cooling, the hydrochloride of the racemate crystallized in the erythro form of the above-mentioned cis compound, whose optical antipodes correspond to the formula

melting point 232-234°C, melting point of the free base: 183-185°C (of methylene chloride/ether).

The mother liquor thus formed is evaporated, the residue is dissolved

in 1 liter of ice/water mixture, the solution is made alkaline with 25% aqueous ammonia solution, extracted three times with 1.5 liters of methylene chloride each time, the combined organic phases are washed with 1 liter of water, dried over sodium sulfate and the filtrate is evaporated in vacuo. The resulting mixture of the 3 stereoisomeric forms of the compound with the indicated formula is chromatographed over 4 kg of silica gel 60 (70-230 mesh, Merck) using a mixture of toluene/ethyl acetate with increasing amounts of ethyl acetate. In this way, both a further quantity of the threo isomer of the cis compound and a further quantity of the erythro isomer of the cis compound with a melting point of 183-185°C are isolated. In addition, an isomer of the trans-α-hydroxy-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester is obtained with the formula

melting point 153-154 C, melting point of the acidic oxalate: 132-134°C (from acetone), melting point of the acidic sulfate as hemihydrate 220-221° (from methanol/acetone).

A variant of this method can be described as follows: One uses as starting material 384 g (1 mol) of the

according to example 2 by reduction using sodium borohydride mixture of the stereoisomers a-acetoxy-1-ethyl-2,3,5,6,11,Hb-tetrahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester . After the work-up, as described, and separation of the formed threo-cis-α-hydroxy-l-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-1 -propionic acid methyl ester gives a mother liquor which is reduced in vacuum to a volume of 1 liter and added while stirring with a solution of 75 g of anhydrous oxalic acid in 250 ml of methanol. After evaporation in a vacuum, the residue is dissolved in 1.5 liters of acetone, from which, on cooling, the acidic oxalate of trans-α-hydroxy-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[ 8,7-b]indole-1-propionic acid methyl ester of the stated formula with melting point 132-134°C. Melting point of the free base: 153-154° (from ether), melting point of the acid sulfate (as hemihydrate): 220-221° (from methanol/acetone).

Example 2

A mixture of 300 g (1.25 mol) of 1-ethyl-2,3,6,11-tetrahydro-5H-indolizino[8,7-b]-indole, 4 liters of methylene chloride, 460 g 2-acetoxyacrylic acid methyl ester (prepared according to: J.Wolinski, R.Novak: ■ J.Org. Chem. 29_, 3596 (1964)) and 50 ml of methanol at room temperature. After 65 hours, the solution is evaporated under vacuum, the oily residue is stirred to remove excess 2-acetoxyacrylic acid methyl ester three times with each time 500 ml of n-hexane, the residue is dissolved in 6 liters of methanol and a 70% aqueous perchloric acid solution is added dropwise under ice cooling until pH 6.5 is reached. The resulting solution of α-acetoxy-1-ethyl-1,2,3,5,6,11-hexahydro-indolizino [8,7-b]indol-4-ium-1-propionic acid methyl ester perchlorate is hydrated in the presence of 150 g of palladium-on-charcoal catalyst (10%) for 24 hours at normal pressure, the reaction mixture is filtered, the filtrate is evaporated in vacuo, the residue is dissolved in 2 liters of methylene chloride and 2-n sodium hydroxide solution is added until pH 7.5. The organic phase is separated, dried over sodium sulphate, filtered and evaporated in vacuo, after which a mixture of the stereoisomers a-acetoxy-1-ethyl-2 , 3 , 5 , 6 ,11, Hb-hexahydro-lH-indolizino is obtained [8 , 7-b] the indole-1-propionic acid methyl ester of the formula

A variant of this method is described as

following:

That by reaction of 300 g (1.25 mol) 1-ethyl-2,3,6,11-tetra-hydro-5H-indolizino[8,7-b]indole and 460 g of 2-acetoxyacrylic acid methyl ester and subsequent 3 times treatment with 500 ml of n-hexane, as described above, formed crude amorphous reaction product with melting point 76-80°C, can also be reduced as follows:

The reaction product formed is dissolved in 10 liters of methanol

and adds 53 g of sodium borohydride in portions to the solution while stirring at room temperature. After the addition is complete, the mixture is stirred for a further 30 minutes, the solution is acidified with glacial acetic acid to pH 6 and evaporated completely in vacuo. The residue is neutralized with 5% aqueous sodium bicarbonate solution and extracted four times with 3 liters of ether each time. The combined organic phases are washed with water, dried over sodium sulfate and the filtrate evaporated in vacuo, whereupon a mixture of the stereoisomers a-acetoxy-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino is obtained The [8,7-b] indole-1-propionic acid methyl ester of the above formula as a yellow foam.

The starting material can also be produced in the following way:

a) 1.14 kg (10 mol) 2-ethyl-γ-butyrolactone (prepared according to: R.F. Borne, H.Y. Aboul-Enein, I.W. Waters, J. Hicks: J.Med.Chem. 16, (3), 245, (1973) is introduced during 30 minutes at 40°C into a well-stirred solution of 162 g of anhydrous zinc chloride in 2.5 liters of thionyl chloride and the mixture is boiled for 18 hours under reflux. After distilling off the solvent under normal pressure, the black residue is distilled over a Vigreuz column under water jet vacuum, after which the 2-ethyl-4-chloro-butyryl chloride with boiling point 105-110°/20 mm is obtained.

b) 900 g of a 55% sodium hydride suspension in paraffin

oil is washed to remove the paraffin oil with 1.5 litres

n-hexane and the residue is suspended in 4 liters of tetrahydrofuran. Under nitrogen and cooling at 0 to 5°, a solution of 800 g (5 mol) tryptamine in 4 liters of tetrahydrofuran is dripped in over 1 hour, the dark green suspension is cooled to -10°C and added over 3 hours with a solution of 850 g 2 -ethyl-4-chloro-butyryl chloride in 1 liter of tetrahydrofuran. After further stirring the reaction mixture for 18 hours at room temperature, cool to 0 to 5°C, excess sodium hydride is decomposed by slow addition

of 2 liters of water and diluted with 15 liters of toluene. • It is extracted twice with each time 2 liters of hydrochloric acid, three times with each time 20 liters of water and once with 4 liters of saturated aqueous sodium chloride solution, the organic phase is dried over sodium sulfate and evaporated after filtration to a volume of 3 liters. After adding 200 g of activated charcoal, heat to boiling temperature, filter over Celite^ AND wash the filter residue with 2 liters of hot toluene, whereby after cooling the 3-ethyl-N-[2-(3'-indolyl)-ethyl]-2-pyrrolidone crystallizes out , melting point 9 8-100°C.

c) A mixture of 6 40 g (2.5 mol) of the formed 3-ethyl-N-[2-(3'-indolyl)-ethyl]-2-pyrrolidone and 2 liters of phosphorus oxychloride is stirred for 4 hours under reflux, then cooled, poured onto 15 liters of ice/water mixture, diluted with a further 10 liters of water and cooled to 3°C. While stirring, 875 g of sodium perchlorate are introduced over 30 minutes and stirred for a further 5 hours at room temperature. After the filtration, the filter residue was recrystallized from methanol, after which 1-ethyl-1,2,3,5,6,11-hexahydro-indolizino[8,7-b]indol-4-ium perchlorate is obtained with the formula

melting point 168 - 171°C.

d) In a solution of 510 g (1.5 mol) of the compound formed in 1.5 liters of dimethyl sulfoxide and 3 liters of toluene

introduced under nitrogen with good stirring 2 liters l-n. baking soda. After dilution with 6 liters of toluene, the organic phase is separated, washed with 1 liter of water, dried over pot ash, filtered and the solvent is evaporated under vacuum, after which 1-ethyl-2,3,6,11-tetrahydro-5H-

indolizino[8,7-b]indole as an orange-red oil.

Example 3

A solution of 320 g (0.75 mol) of 1-ethyl-1,2,3,5,6,11-hexahydro-indolizino[8,7-b]indol-4-ium-1-propionic acid methyl ester perchlorate and 75 g of anhydrous potassium acetate in 6 liters of methanol is hydrated in the presence of 30 g of palladium-on-charcoal catalyst (5%) for 3 hours at normal pressure. The reaction mixture is filtered, the filtrate is evaporated in vacuo, the residue is dissolved in 4.5 liters of methylene chloride and 1.5 liters of sodium hydroxide solution are added. The organic phase is separated, washed twice with 500 ml of water each time, dried over sodium sulphate, filtered and evaporated in vacuo. The residue is dissolved in 1.5 liters of hot toluene, 1.5 liters of n-hexane are added, after which, after cooling, cis-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7 -b]indole-1-propionic acid methyl ester with the formula

melting point 162 - 163°C.

For transfer into the methanesulfonate, 32.6 g (0.1 mol) of the compound formed is dissolved in 250 methanol and 9.6 g of methanesulfonic acid is added with stirring. After addition of 1.5 liters of ether and cooling, the methanesulfonate of the cis-compound crystallized out, m.p. 218-219°C.

The mother liquor formed during the preparation of the base is completely evaporated in a vacuum, the residue is suspended in 12 liters of n-hexane and stirred for 30 minutes at room temperature. After filtering off, the solution is evaporated in vacuo, dissolved in 500 ml of ether and added with 1 liter of n-hexane. After cooling, the trans-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester crystallized out, melting point 118-121°C.

For transfer into the methanesulfonate, 32.6 g (0.1 mol) of this compound are dissolved in 1 liter of acetone and 9.6 g of methanesulfonic acid are added to the solution while stirring. After cooling, the methanesulfonate crystallized out of the t trans compound, melting point 147-148°C.

The starting material can also be obtained as follows:

a) A mixture of 300 g (1.25 mol) of the l-ethyl-2,3,6,11-tetrahydro-5H-indolizino[8,7-b] formed according to example 2d) is stirred under a nitrogen atmosphere the indole and 300 g of acrylic acid methyl ester in 4.5 liters of methylene chloride for 65 hours at room temperature, then evaporate the solution in vacuo, stir the red oily residue to remove excess acrylic acid methyl ester 3 times with each time 500 ml of n-hexane, after which l-ethyl- The 2,3,5,6-tetrahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester of the formula

crystallized, Melting point 129-132°. For transfer into the perchlorate, a solution of 324 g (1 mol) of this compound in 5 liters of methanol is added at 0 to 5°C with stirring during 30 minutes with 150 ml of erf 70% aqueous perchloric acid solution and 500 ml ether. After cooling, 1-ethyl-1,2,3,5,6,11-hexahydro-indolizino crystallized

The [8,7-b]indol-4-ium-1-propionic acid methyl ester perchlorate of the formula

melting point 144-145°C.

From the hexane mother liquor, the 1-ethyl-2,3-dihydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester can be obtained by working up with the formula

which after several recrystallizations from ether shows a melting point of 159-160°C. The methanesulfonate of this compound with the formula

shows melting point 164-165°, (of acetone).

Example 4

A solution of 13.1 g (0.04 mol) of the cis-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b ]indole-1-propionic acid methyl ester in 200 ml of ethyl alcohol (95%) with a solution of 3.2 g of sodium hydroxide in 200 ml of ethyl alcohol (95%) and boil for 2 hours under reflux. After cooling, the solvent is evaporated in vacuo, the residue is dissolved in 400 ml of water and the solution is neutralized with 2-n.aqueous acetic acid, after which, after cooling, cis-1-ethyl-2,3,5,6,11,11b-hexahydro- The 1H-indolizino[8,7-b]indole-1-propionic acid with melting point 251-254°C crystallized out.

A solution of 9.4 g (0.03 mol) of the formed cis-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indol- l-propionic acid in 50 ml of ethyl alcohol (95%) with a solution of 1.2 g of sodium hydroxide in 100 ml of ethyl alcohol (95%). After evaporation in vacuo, the residue dissolves

in 100 ml of methyl ethyl ketone, the solution is cooled to 0 to 5°C and added with good stirring over 15 minutes with 3.75 g of bromomethyl methyl ether. This solution is stirred for 2 hours at room temperature and then evaporated in a vacuum. The residue is taken up in 300 ml of methylene chloride and 200 ml of water, the organic phase is separated and washed twice with 100 ml of water each time, dried over sodium sulphate, filtered and evaporated. After filtration over 50 g of silica gel 60 (0.063 to 0.200 mm, Merck) in acetic acid ethyl ester, cis-l-ethyl-2, 3 , 5 , 6 , 11, Hb-hexahydro-lH-indolizino [8 , 7-b] indole is obtained -1-propionic acid methoxymethyl ester with melting point 104-105°C.

Example 5

A solution of 11.2 g (0.04 mol) of cis-D-Nor-Vincamone (prepared according to M. Mailand et al., Chem. Ber. 114, 1926 (1981)) in 350 ml of methanol is added with 30 ml 2-n.sodium lye and boil under reflux for an hour. After cooling, the solvent is evaporated in vacuo, the residue is taken up in 200 ml of water and the solution is neutralized with 2-n-acetic acid, whereupon on cooling cis-1-ethyl-2,3,5,6,11,11b-hexahydro-1H The -indolizino[8,7-b]indole-1-acetic acid with melting point 243-245°C (decomposition) crystallized out.

A suspension of 7.45 g (0.025 mol) of the formed cis-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino [8,7-b]indole-1- acetic acid in 400 ml of methanol while stirring dropwise with 125 ml of a 1% ethereal diazomethane solution (prepared according to T.J. de Boer, H.J. Backer: Org. Synth.Coll. Vol. IV,250 (1963)). The yellow solution formed is decolorized by adding a few drops of acetic acid, evaporated in vacuo to 70 ml, made slightly acidic with 6 ml of a 4.5-n. methanolic hydrogen chloride solution, after which, after adding 250 ml of ether on cooling, the cis-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-acetic acid methyl ester hydrochloride with melting point 238-240° (decomposition) crystallizes. Melting point of the free base (monohydrate): 108-109°C, (of ether/n-hexane).

The described conversion corresponds to the following reaction equation:

Example 6

In a suspension of 3.8 g of lithium aluminum hydride in 250 ml of tetrahydrofuran, a solution of 34.2 g (0.1 mol) of the raw material of threo- The cis-α-hydroxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester with melting point 219-220°C in 750 ml of tetrahydrofuran .

After 2 hours, carefully add 4 ml of water, then

4 ml of a 15% aqueous sodium hydroxide solution and then a further 12 ml of water, filter off the white precipitate and evaporate the solvent in vacuo. The residue is dissolved in 250 ml of methylene chloride, extracted twice with 50 ml of water each time, the organic phase is dried over sodium sulphate, filtered and evaporated in vacuo. The residue is dissolved in 250 ml of methanol, after which after cooling threo-cis-<3>'-[l-et<y>l-2,3,5,6,11,Hb-hexahydro-1H-indolizino [8,7- The b]indole-1]-propane-1<1>,2'-diol with 1 mol of crystal methanol with a melting point of 224-225°C crystallizes out.

For transfer into the cyclamate, 15.7 g (0.05 mol) of this compound are suspended in 50 ml of methanol and added while stirring with a solution of 9 g of N-cyclohexylsulfamic acid in 100 ml of methanol. 300 ml of ether is added to the solution formed, after which, after cooling, threo-cis-3'-[1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino-[8,7-b]- The indole-1]-propane-1<1>,2<1->diol cyclamate with melting point 177-179°C crystallizes out.

The described reaction corresponds to the following reaction equation

Example 7

In a suspension of 3.8 g of lithium aluminum hydride in 250 ml of tetrahydrofuran, a solution of 34.2 g (0.1 mol) of the erythrocis-a- hydroxy-l-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-l-propionic acid methyl ester with melting point 183-185°C

in 750 ml of tetrahydrofuran.

After 2 hours, carefully add 4 ml of water, then

4 ml of a 15% aqueous sodium hydroxide solution and then a further 12 ml of water, filter off the white precipitate and evaporate the solvent in vacuo. The residue is dissolved in 250 ml of methylene chloride, extracted twice with 50 ml of water each time, the organic phase is dried over sodium sulphate, filtered and evaporated in vacuo. The residue is dissolved in 200 ml of methanol, after which, after cooling, erythro-cis- The b]indole-1]-1',2'-diol with a melting point of 206-208°C crystallizes out.

For transfer in the methanesulfonate, dissolve 15.7 g

(0.05 mol) of this compound in 150 ml of methanol and add the stirred solution with 4.8 g of methanesulfonic acid. After evaporation of the solvent in vacuum, the residue is dissolved in 400 ml of acetone, after which, after cooling, the methanesulfonate of the above-mentioned erythrocis compound with a melting point of 220-222°C crystallizes out.

The reaction described corresponds to the reaction equation given in example 6.

Example 8

In a suspension of 3.8 g of lithium aluminum hydride in 250 ml of tetrahydrofuran, a solution of 34.2 g (0.1 mol) of the one isomer of trans-a formed according to example 1 is dripped in a nitrogen atmosphere with stirring over the course of 40 minutes -hydroxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester with melting point 153-154°C in 750 ml of tetrahydrofuran. After 2 hours, 4 ml of water are carefully added dropwise, then 4 ml of a 15% aqueous sodium hydroxide solution and then a further 12 ml of water, the white precipitate is filtered off and the solvent is evaporated in vacuo. The residue is dissolved in 250 ml of methylene chloride, extracted twice with 50 ml of water each time, the organic phase is dried over sodium sulphate, filtered and evaporated in vacuo. The residue is dissolved in 150 ml of ether and 250 ml of n-hexane is added, after which, after cooling, trans-3'-[l-ethyl-2 , 3 , 5, 6 ,11, Hb-hexahydro-lH-indolizino[8,7-b ]indole-1]propane-1',2'-diol with melting point 167-169°C crystallizes out.

For transfer in the cyclamate, dissolve 15.7 g (0.05 mol)

of this compound in 100 ml of methanol and adds to the resulting solution with stirring a solution of 9 g of N-cyclohexylsulfamic acid in 100 ml of methanol. The solvent is evaporated in vacuo and the residue is dissolved in 350 ml of acetone, after which, after cooling, trans-3'-[1-ethyl-2,3,5,6,11, Hb-hexahydro-1H-indolizino[8,7-b] indole-1]-propane-11,21-diol cyclamate with melting point 158-160°C crystallizes.

The described conversion corresponds to the following reaction equation:

Example 9

A solution of 15.45 g (0.05 mol) of one isomer of cis-a-amino-D-nor-E-homo-vincamone of melting point 139-140°C is boiled in 500 ml of methanol and 55 ml of l-n .sodium lye under reflux for 1 hour, allow to cool, add while cooling and stirring with 55 ml l-n.hydrochloric acid and evaporate in vacuum. The residue is suspended in 300 ml methylene chloride, filtered, evaporated and the residue redissolved in 200 ml methanol. While stirring, this solution is added with 2 30 ml of a 1% ethereal diazomethane solution (pre-

styled according to: T.J. de Boer and H.J. Backer: Org. Synth. Coll. Vol. IV, 250 (1963)). The yellow solution formed is decolorized by adding a few drops of acetic acid and evaporated in vacuo. After filtration over 250 g of silica gel 60 (70-230 mesh, Merck) and crystallization from ether, one isomer is obtained

of the cis-α-amino-l-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-l-propionic acid methyl ester of the formula

with melting point 143-146°, melting point of the dihydrochloride (as sesquihydrate): 227-230°, (from methanol/ether).

The isomer of cis-α-amino-D-nor-E-homo-vincamone with melting point 139-140°G used as starting material can be prepared as follows: a) A solution of 29.4 g (0.1 mol) is added cis-D-nor-E-homo-Vincamone (prepared according to E.Bølsing et al., Chem.Ber. 114, 1932 (1981)) in 600 ml of toluene in a nitrogen atmosphere while stirring with 100 ml of 90% tert. -butyl nitrite and then portionwise with 29 g of potassium tertiary butylate, whereby the solution is heated to 45°C. One stirs for a further hour, then adds 1.5 liters of a 5.4% aqueous ammonium chloride solution, stirs for a further hour at room temperature, after which α-hydroxyimino-cis-D-nor-E-homo-vincamone with melting point 225-228° crystallizes (from methanol).

The turnover corresponds to the following reaction equation:

For transfer into the hydrochloride, 16.1 g (0.05 mol) of the compound formed is suspended in 200 ml of methanol and added with stirring with 15 ml of a 3.5-n methanolic hydrogen chloride solution. After adding 400 ml of ether, anti-α-hydroxyimino-cis-D-nor-E-homo-vincamone hydrochloride with a melting point of 255-265°C (decomposition) crystallizes out on cooling.

b) A solution of 14.4 g (0.04 mol) of the formed anti-g<->hydroxymino-cis-D-nor-E-homo-vincamone hydrochloride in

1.5 liters of methanol are hydrated in the presence of 5 g of palladium-on-charcoal catalyst (5%) for 40 hours at normal pressure. The reaction mixture is filtered, the filtrate is evaporated in vacuo, the residue is dissolved in 300 ml of water and made alkaline with conc. aqueous ammonia solution. After 3 times of extraction with 300 ml of methylene chloride each time, the combined organic phases are washed once with 150 ml of water, dried over sodium sulphate, filtered and evaporated in vacuo. The residue is dissolved in 300 ml of water and made alkaline with conc. aqueous ammonia solution. After 3 times of extraction with 300 ml of methylene chloride each time, the combined organic phases are washed once with 150 ml of water, dried over sodium sulphate, filtered and evaporated in vacuo. The residue is dissolved in 30 ml of ether, after which, after cooling, one isomer of cis-g-amino-D-nor-E-homo-vincamone with the formula

with melting point 139-140°C crystallizes, melting point of the dihydrochloride: 290-293°C (decomposition).

Example 10

A solution of 15.45 g (0.05 mol) of one isomer of trans-g<->amino-D-nor-E-homo-vincamone with a melting point of 125-127°C is boiled in 500 ml of methanol and 55 ml l-n. caustic soda for 1 hour under reflux, allow to cool, add while cooling and stirring with 55 ml l-n. hydrochloric acid and evaporate the reaction mixture in vacuo. The residue is suspended in 300 ml of methylene chloride, filtered, the filtrate is evaporated and the residue is redissolved in 200 ml of methanol. While stirring, 230 ml of a 1% ethereal diazomethane solution is added to this solution, the resulting yellow solution is decoloured by the addition of a few drops of acetic acid and evaporated in vacuo. The residue is dissolved in 200 ml of methanol, the solution is added while cooling and stirring with 30 ml of a 3.5-n. methanolic hydrogen chloride solution, after which, after adding 150 ml of ether on cooling, trans-α-amino-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole- The l-propionic acid methyl ester dihydrochloride with melting point 235-238° (decomposition) crystallizes out. The free base formed therefrom in the usual way is an amorphous white powder.

The turnover corresponds to the following reaction equation:

the starting material can be produced in the following way:

a) A mixture of 49 g (0.15 mol) of the trans-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino formed according to example 3

[8,7b]indole-1-propionic acid methyl ester, 55 g of acetophenone and 8.5 g of potassium tert-butylate in 6 liters of toluene are boiled in a nitrogen atmosphere for 6 hours with stirring and reflux, then cooled to 0 to 5° and added 1 liter of 0.5 n hydrochloric acid. The toluene phase is separated, washed twice each time

300 ml of water, the combined aqueous phases are sublayered with 2 liters of methylene chloride and adjusted with concentrated aqueous ammonia solution to pH 8. After phase separation, the aqueous phase is extracted a further three times with each time 750 ml of methylene chloride, the combined organic phases are washed twice with each time 500 ml of water, dried over sodium sulphate, filtered and evaporated under vacuum. The residue is dissolved in

200 ml of methanol and 100 ml of ether are added, after which, after cooling, trans-D-nor-E-homo-vincamone with a melting point of 131-132° crystallizes out.

The turnover corresponds to the following reaction equation:

b) A solution of 29.4 g (0.1 mol) of the formed trans-D-nor-E-homo-Vincamone in toluene is added in a nitrogen atmosphere while stirring with 100 ml of 90% tert-butyl nitrite and then portionwise with 29 g of potassium tert.-butylate, whereby the solution heats up to 45°C. The mixture is stirred for a further 1 hour, then 1.5 liters of a 5.4% aqueous ammonium chloride solution is added and stirred for a further 1 hour at room temperature. After phase separation, the aqueous phase is extracted 3 times with 300 ml of methylene chloride each time. The combined organic phases are washed a further 2 times with each time 250 ml of water, dried over sodium sulphate, filtered and the solvent evaporated in vacuo. The residue is dissolved in 300 ml of hot methanol, after which, on cooling, a-anti-hydroxyimino-trans-D-nor-E-homo-vincamone with a melting point of 212-214°C crystallizes out.

The turnover corresponds to the following reaction equation:

For transfer in the hydrochloride, 16.1 g are suspended

(0.05 mol) of the compound formed in 100 ml of methanol and add, with stirring, 15 ml of a 3.5-n methanolic chlorine-hydrogen solution. After adding 200 ml of ether, α-anti-hydroxymino-trans-D-nor-E-homo-vincamone hydrochloride with melting point 213-217°C (decomposition) crystallizes out on cooling.

c) A solution of 14.4 g (0.0 mol) of the formed α-anti-hydro-imino-trans-D-nor-E-homo-vincamone hydrochloride in

500 ml of glacial acetic acid is hydrated in the presence of 5 g of palladium-on-charcoal catalyst (5%) for 90 hours at 25°C at normal pressure. The reaction mixture is filtered, the filtrate is evaporated in vacuo, the residue is dissolved in 300 ml of water and made alkaline with conc. aqueous ammonia solution. After 3 extractions with 300 ml of methylene chloride each time, the combined organic phases are washed once with 150 ml of water, dried over sodium sulphate, filtered and the filtrate evaporated in vacuo. The residue is dissolved in 80 ml of ether, after which, on cooling, one isomer of trans-α-amino-D-nor-E-homo-vincamone with a melting point of 125-127° crystallizes out.

The turnover corresponds to the following reaction equation:

Example 11

A solution of 386 g (0.75 mol) of 1-ethyl-11-benzyl-1,2,3,5,6,11-hexahydro-indolizino[8,7-b]indol-4-ium-1-propionic acid methyl ester perchlorate and 75 g anhydrous potassium acetate in 6.5 1 methanol are hydrogenated analogously to the method described in example 3 until uptake of 2 molar equivalents of hydrogen and the hydration solution, as described there, is worked up, after which one obtains cis-l-ethyl-2 , 3, 5 , 6 , 11, Hb-hexahydro-lH-indolizino [8 , 7-b] indole-l-propionic acid methyl ester with the formula stated there with melting point 162-163°C. The processing of the mother liquor gives the trans-l-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester described in example 3 with a melting point of 118-121° C.

The starting material can be obtained as follows:

a) Analogous to the working method described in example 2 b), 250 g (1 mol) of N-benzyl-tryptamine (J.Med.Chem.9^,

793-94 (1966)) with 170 g of 2-ethyl-4-chloro-butyryl chloride.

After working up, 3-ethyl-N-[2-(3'-N-benzylindolyl)-ethyl(-2-pyrrolidone) is obtained, which is further processed as such.

b) A mixture of 346 g (1 mol) of the compound formed and 800 ml of phosphorus oxychloride is reacted analogously to the method described in example 2 c), after which, after working up, 1-ethyl-1-benzyl-1,2,3 ,5,6,11-hexahydro-indolizino [8, 7-b] indol-4-ium perchlorate, which as such is further processed.

c) A solution of 214.3 g (0.15 mol) of the product formed in 500 ml of dimethyl sulfoxide and 1 liter of toluene

treated analogously to example 2 d) with 670 ml sodium hydroxide solution.

After work-up, 1-ethyl-11-benzyl-2,3,6,11-tetrahydro-5H-indolizino[8,7-b]indole is obtained as a crude product. d) Under a nitrogen atmosphere, a mixture of 41.0 g (0.125 mol) of the crude product formed according to example c), 400 ml of methylene chloride, 30 g of acrylic acid methyl ester and 5 ml of methanol is stirred for 65 hours at room temperature, then the reaction mixture is evaporated in vacuo and treat the oily residue to remove excess acrylic acid methyl ester 3 times with each time 50 ml of n-hexane, decant the hexane solution, dissolve the residue at a temperature of 0 to 5°C in 500 ml of methanol and add with stirring over the course of 10 minutes 15 ml of a 70% aqueous perchloric acid solution and then 50 ml of ether. After cooling the reaction mixture to 0°C, 1-ethyl-11-benzyl-1,2,3,5,6,11-hexahydro-indolizino[8,7-b]indol-4-ium-1 crystallizes out after a longer period of time -propionic acid methyl ester perchlorate.

Example 12

A solution of 334 g (0.75 mol) α-hydroxyimino-cis-1-ethyl-11-benzyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b] indole -1-propionic acid methyl ester in 3 liters of methanol is hydrogenated in the presence of 30 g of palladium-on-charcoal catalyst until complete hydrogen absorption. After filtering off the catalyst and evaporating the filtrate under reduced pressure, one filters over 1250 g of silica gel 60 (70-230 mesh, Merck) and recrystallizes the filter residue from ether, after which one isomer of cis-g-amino-l-ethyl is obtained The -2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester with melting point 14 3-146°.

The α-hydroxyimino-cis-1-ethyl-11-benzyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b] indole-1-propionic acid methyl ester used as starting material can be prepared as following:

a) A solution of 51.5 g (0.1 mol) of the 1-ethyl-11-benzyl-1,2,3,5,6,11-hexahydro-indolizino[8,7 -b]indol-4-ium-1-propionic acid methyl ester perchlorate in 550 ml of tetrahydrofuran is cooled to 0°C and added under a nitrogen atmosphere with 76.3 g (0.3 mol) of lithium tri-tert-butoxy aluminum hydride. After stirring the reaction mixture for 4 hours at 0° under a nitrogen atmosphere, it is evaporated under reduced pressure to a volume of approx. 150 ml and the solution is poured into 2 liters of ice water. After suction, the filter residue is boiled off with 400 ml of tetrahydrofuran, filtered off and the filtrate evaporated under reduced pressure to dryness, after which cis-1-ethyl-11-benzyl-2,3,5,6,11, Hb-hexahydro-1H- indolizino[8,7-b]indole-1-propionic acid methyl ester as crude product. b) A solution of 41.6 g (0.1 mol) of the crude product formed in 600 ml of toluene is added in a nitrogen atmosphere

while stirring with 100 ml of 90% tert-butyl nitrite and then portionwise with .29 g of potassium tert-butylate. After further stirring for 1 hour, 1.5 liters of a 5.4% aqueous ammonium chloride solution are added, stirred for a further 1 hour at room temperature and the reaction mixture essentially evaporated, the residue is added with 300 ml of water and the precipitated α-hydroxyimino- cis-1-ethyl-11-benzyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-propionic acid methyl ester.

Example 13

To a solution of 48.0 g (0.1 mol) cis-1-ethyl-11-(p-tosyl)-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7- b]indole-1-propionic acid methyl ester in 1 liter of ethanol, 240 ml of a 2-n aqueous sodium hydroxide solution is added and the mixture is boiled for 60 hours under a nitrogen atmosphere under reflux. After cooling, the resulting solution is evaporated under reduced pressure, the residue is dissolved in 1200 ml of water and the solution is neutralized with 2-n aqueous acetic acid, after which after cooling cis-1-ethyl-2,3,5,6,11,Hb-hexahydro- 1H-indolizino [8,7-b] indole-1-propionic acid with a melting point of 251-254°C crystallizes out.

The starting material can be obtained as follows:

a) A solution of 156 g (1 mol) of indole-2-acetonitrile in 2 liters of methylene chloride is added at 0-5° with stirring

in a nitrogen atmosphere with 2 liters of a 2-n.aqueous sodium hydroxide solution and 5 g of tetra-n-butylammonium hydrogen sulfate and then portionwise with 210 g of p-tosyl chloride.

After further stirring of the reaction mixture for 3 hours at 0-5°, it is allowed to warm to room temperature and stirred for a further 22 hours at a temperature of 22°C, the two layers are separated, the organic phase is washed 3 times with 500 ml of water each time, dried over sodium sulfate and evaporate the solution in vacuo. The foam formed is dissolved in 750 ml of methylene chloride and 3 liters of ether are added to the solution, after which, after cooling, 1-(p-tosyl-indole)-3-acetonitrile with a melting point of 162-163°C crystallizes out.

b) A solution of 190 g (0.61 mol) 1-(p-tosyl-indole)-3-acetonitrile in 2 liters of a 10% solution of ammonia gas

in absolute ethanol is hydrated in the presence of 50 g of a rhodium (0.5%)-on-alumina catalyst at room temperature and a pressure of 4 bar for 24 hours. After filtration under vacuum, the foam formed is dissolved in 1.5 liters of ether, after which, after cooling, 1-(p-tosylindole)-3-(2-ethylamine) with a melting point of 122-124°C crystallizes out, melting point of the hydrochloride

1/3 hydrate : 205-207°C (from acetone/ether).

c) Analogous to the method described in example 2 b), 31.4 g (0.1 mol) of 1-(p-tosyl-indole)-3-(2-ethylamine) are reacted

with 17 g of 2-ethyl-4-chloro-butyryl chloride. After the work-up, 3-ethyl-N-[2-(3'-p-rtosyl-indole)-ethyl]-2-pyrrolidone is obtained, which is further processed as a crude product.

d) 41 g (0.1 mol) of the compound formed is reacted analogously to the method described in example 2 c) with 80 ml

phosphorus oxychloride, after which, after work-up and reaction with sodium perchlorate, 1-ethyl-1-(p-tosyl)-1,2,3,5,6,11-hexahydro-indolizino[8,7-b]indol-4-ium is obtained -perchlorate as a raw product, which is further processed as such.

e) A solution of 49.3 g (0.1 mol) of the crude compound formed is dissolved in 100 ml of dimethylsulfoxide and 250 ml

toluene and adding under a nitrogen atmosphere 134 ml l-n. aqueous sodium hydroxide solution. After diluting the solution with 400 ml of toluene, the organic phase is separated, washed with water, dried over potassium carbonate and the filtrate evaporated in vacuo, after which 1-ethyl-11-(p-tosyl)-2,3,6,11-tetrahydro is obtained -5H-indolizino[8,7-b]indole as crude product.

f) A mixture of 39.2 g (0.1 mol) of that according to example

c) crude product formed, 325 ml of methylene chloride, 30 g of acrylic acid methyl ester and 5 ml of methanol are stirred in a nitrogen atmosphere for 70 hours at room temperature and then the reaction mixture is essentially evaporated in vacuo. To remove excess acrylic acid methyl ester, the residue is treated 3 times with 70 ml of n-hexane each time, the hexane solution is decanted, the residue is dissolved in 450 ml of methanol and, with stirring at a temperature of 0 to 5°C, 12 ml of a 70% aqueous perchloric acid solution and then 50 ml of ether. After cooling to 0°C, 1-ethyl-11-(p-tosyl)-1,2,3,5,6,11-hexahydro-indolizino[8,7-b]indol-4-ium crystallizes out after a longer period of time -1-propionic acid methyl ester perchlorate. g) A solution of 434 g (0.75 mol) of the compound formed is reduced exactly analogously to the method described in example 11, after which the preparation of the hydration solution gives cis-1-ethyl-11-(p-tosyl)-2 ,3,5,6,11, Hb-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester. After working up the formed mother liquor, the corresponding trans-compound is obtained, namely trans-l-ethy1-11-(p-tosyl)-2 , 3 , 5 , 6 ,11, Hb-hexahydro-lH-indolizino [8 , 7 -b] indole-1-propionic acid methyl ester.

Example 14

To a solution of 51.5 g (0.1 mol) of cis-1-ethyl-11-(p-tosyl)-2,3,5,6,11,1lb-hexahydro-1H-indolizino[8,7- b]indole-1-[a-chloro)-propionic acid methyl ester in 240 ml of ethanol, 110 ml of 3-n sodium hydroxide solution is added and the mixture is boiled under a nitrogen atmosphere for 60 hours under reflux.

After cooling, the resulting solution is evaporated to dryness, the residue is dissolved in 1100 ml of water and neutralized with 2-n-acetic acid, after which, after cooling, cis-α-hydroxy-1-ethyl-2,3,5,6,11 is precipitated, Hb-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid as a mixture of the threo and erythro forms.

To separate this mixture, the compound formed is transferred by means of diazomethane in ethereal solution to the corresponding methyl ester, the ethereal solution is evaporated to dryness, the residue is dissolved in 300 ml of methanol and 300 ml of ether is added. After cooling, as described in example 1, the racemate of threo-cis-a-hydroxy-l-ethyl-2,3,5,6,11,Hb-hexahydro-lH-indolizino[8,7-b]indol- The 1-propionic acid methyl ester with melting point 219-220°C.

From the mother liquor, as described in example 1, the racemate of the erythrocis form of this compound is isolated as hydrochloride with a melting point of 232-235°C. By hydrolysis of these two compounds using 2-n. aqueous sodium hydroxide solution in ethanolic solution is always obtained the racemate of threo- or erythro-cis-α-hydroxy-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid.

The starting material can be obtained as follows:

a) 39.2 g (0.1 mol) of the 1-ethyl-11-(p-tosyl)-2,3,6,11-tetrahydro-5H-indolizino[8,7- b] indole is reacted analogously to the procedure described in example 13 f) with 42 g of hydroquinone-stabilized α-chloroacrylic acid methyl ester (C.S. Marvel, J.C. Cowan: JACS 61, 3156-59 (1939)). After the work-up and the reaction described in example 13 f) with 12 ml of a 70% aqueous perchloric acid solution, 1-ethyl-11-(p-tosyl)-1,2,3,5,6,11 is finally obtained -hexahydro-indolizino[8,7-b]indol-4-ium-1-(α-chloro)-propionic acid methyl ester perchlorate. b) 61.3 g (0.1 mol) of the crude compound formed is reduced corresponding to the working method described in example 12 a), after which one obtains after corresponding work-up cis-1-ethyl-11-(p-tosyl)-2, 3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-1-(a-chloro)-propionic acid methyl ester, which is further processed as such.

Example 15

A solution of 317 g (0.75 mol) of 1-vinyl-1,2,3,5,6,11-hexahydro-indolizino[8,7-b]indol-4-ium-1-propionic acid methyl ester perchlorate and 75 g of anhydrous potassium acetate is hydrated corresponding to the procedure described in example 3 and worked up, after which the cis-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b] described there is obtained Indole-1-propionic acid methyl ester with melting point 16 2-16 3°C. After working up the formed mother liquor, trans-1-ethyl-2,3,5,6,11, Hb-hexahydro-1H-indolizino [8 , 7-b] indole-1-propionic acid methyl ester with melting point 118-121°C is obtained .

The starting material can be obtained as follows:

a) 800 g (5.mol) of tryptamine is reacted according to the method described in example 2 b) with 710 g of 4-chlorobutyryl chloride. After the work-up of the reaction mixture described there, N-[2-(3<1->indole)-ethyl]-2-pyrrolidone is obtained as crude product. b) A mixture of 114 g (0.5 mol) of the compound formed and 400 ml of phosphorus oxychloride is reacted analogously to example 2 c)

and worked up, after which 1,2,3,5,6,11-hexahydro-indolizino[8,7-b]indol-4-ium perchlorate is obtained analogously to the formula given in example 2 c).

c) In a solution of 155.2 g (0.5 mol) of the compound formed according to b) in 500 ml of dimethyl sulphoxide and 1 liter

toluene, 635 ml of sodium hydroxide solution are introduced under a nitrogen atmosphere. After diluting the reaction mixture with 2 liters of toluene, the organic phase is separated, washed with 350 ml of water, dried over sodium carbonate and the solution evaporated in vacuo, after which 2,3,6,11-tetrahydro-indolizino[8,7-b ]indole as residue.

d) A mixture of 21 g (0.1 mol) of the compound formed is reacted according to the one described in example 3 a)

working method with 30 g of acrylic acid methyl ester and the reaction mixture is worked up, as indicated. After the described reaction with 12 ml of a 70% aqueous perchloric acid solution, 1,2,3,5,6,11-hexahydroindolizino[8,7-b] indol-4-ium-1-propionic acid methyl ester perchlorate is finally obtained .

e) According to t-1 the working method described under c) 198.2 g (0.5 mol) of the formed compound is converted into

The 2,3,6,11-tetrahydro-inolizino[8,7-b]indole-1-propionic acid methyl ester, which is obtained as a raw product and further processed as such.

f) 12 g vinyl bromide, 5 g potassium iodide and 29.6 g (0.1 mol)

of the compound formed according to e) is held together with

50 ml of methylene chloride in the bomb tube for 60 hours at a temperature of 55-60°C. After complete reaction, the volatile parts are evaporated, the residue is dissolved in 150 ml of methanol and added with stirring at a temperature of 0-5°C during 10 minutes with 12 ml of a 70% aqueous perchloric acid solution. After adding 60 ml of ether, 1-vinyl-1,2,3,5,6,11-hexahydro-indolizino [8,7-b]indol-4-ium-1-propionic acid methyl ester perchlorate crystallizes out on cooling.

Example 16

To a solution of 34.2 g (0.1 mol) threo-cis-ct-hydroxy-l-ethyl-2 , 3 , 5 , 6 , 11, Hb-hexahydro-lH-indolizino [8 , 7-b] Indole-l-propionic acid methyl ester in 300 ml methylene chloride and 25 ml pyridine is added dropwise with stirring in a nitrogen atmosphere at a temperature of 0-5°C a solution of 16.9 g benzoyl chloride in 150 ml methylene chloride over the course of 30 minutes.

After a further 2 hours, the solution is poured into 300 ml of ice water and 100 ml of 10% aqueous sodium bicarbonate solution, the organic phase is washed three times with 50 ml of water each time, dried over sodium sulphate and the solution is evaporated in vacuo. After the recrystallization of the residue from acetic acid ethyl ester, threo-cis-α-benzoyloxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester is obtained with melting point 128-130°C, melting point of the salt with benzoic acid: 142-144°C (from acetic acid ethyl ester).

Example 17

Corresponding to the procedure described in example 16, 32.2 g (0.1 mol) of erythro-cis-hydroxy-1-ethyl-2,3,5,6,11, Hb-hexahydro-1H-indolizino[8,7 -b]indole-1-propionic acid methyl ester with 16.9 g of benzoyl chloride. After the work-up, the residue formed after evaporation of the organic phase is recrystallized from acetone ether, after which erythro-cis-α-benzoyloxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[ 8,7-b]indole-1-propionic acid methyl ester with melting point 158-160°C.

Example 18

A solution of 32.6 (0.1 mol) cis-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester in 200 ml of a 6-n. methanolic ammonia solution is heated in the bomb tube for 24 hours at 100°C. After evaporation of the reaction mixture in vacuo, the residue is dissolved in 100 ml of methanol, after which, after cooling, cis-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-1- propionic acid amide with melting point 202-204°C crystallizes.

Example 19

A solution of 34.1 g (0.1 mol) cis-o-amino-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-1 -propionic acid methyl ester in 200 ml of a 6-n methanolic ammonia solution is heated in the bomb tube for 24 hours at 80°C.

After evaporation in a vacuum, the residue is dissolved in 150

ml methanol, whereupon after cooling cis-α-amino-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H.indolizino[8,7-b]indole-1-propionic acid amide with melting point 208-210 °C crystallizes.

Example 20

A solution of 56.7 g (0.1 mol) of cis-1-ethyl-11-(p-tosyl)-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b ]indole-1-(α-ethoxycarbonylamino)-propionic acid methyl ester in 260 ml of ethanol is hydrolyzed analogously to the method described in example 14. After work-up, one isomer of cis-a-amino-l-ethyl-2,3,5,6,11,Hb-hexahydro-lH-indolizino[8,7-b]indole-l-propionic acid, whose methyl ester ,

which are obtained by reacting the carboxylic acid formed with diazomethane in ethereal solution, shows a melting point of 143-146°C.

The starting material can be obtained as follows:

To a solution of 51.5 g (0.1 mol) of the acc

example 14 b) formed cis-1-ethyl-11-(p-tosyl)-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-1-(ct- chlorine) -propionic acid methyl ester in 120 ml anhydrous dimethylformamide to-

12.2 g of potassium cyanate and 22 ml of methanol are added and the mixture is heated for 2 hours with vigorous stirring at 100°C, the salts precipitated after cooling are filtered off, removed

the dimethylformamide under reduced pressure, dissolve the residue in 120 ml of acetone, filter off the precipitated salts and evaporate the filtrate in vacuo, after which one obtains cis-1-ethyl-11-(p-tos<y>1)-2,3,5, 6,11,Hb-hexahydro-1H-indolizino[8,7-b] indole-1-(α-ethoxycarbonylamino)-propionic acid methyl ester.

Example 21

Analogous to the methods described in the general description and illustrated in the examples given above, the following compounds of formula 1, their N-oxides or salts can also be prepared, using the corresponding starting materials and/or methods: a) cis-a- methylthio-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino-[8,7-b]indole-1-propionic acid methyl ester; b) cis-8-bromo-α-hydroxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester; c) cis-9-amino-g<->hydroxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester; d) trans-2'-amino-3 1 -[1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole]-propane-1<1- >cl; e) 3'-(8,9-methylenedioxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole)-acrylic acid methyl ester; f) 1-n-propyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester; g) 1-n-butyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b] indole-1-propionic acid methyl ester; h) cis-8-bromo-g<->hydroxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid dimethylamide; i) cis-8-bromo-g<->hydroxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid morpholide; j) trans-2'-amino-3'-[8-bromo-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole]-propane- 1'-ol; k) cis-α-benzoylamino-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid thioethyl ester; 1) cis-g-ethoxy-2,3,5,6,11,Hb-hexahydro-1H-indolizino [8,7-b]indole-1-propionic acid-3-phthalidyl ester;

m) cis-7-ethoxycarbonylamino-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-acetic acid-(2-hydroxypropyl)-ester;

n) trans-g<->pivaloyloxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid-(3,3,5 -trimethylcyclohexyl) ester;

o) cis-g<->hydroxy-1-ethyl-11-methyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid-4- N-oxide;

p) cis-g<->dimethylamino-1-ethyl-10-methoxy-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid--( 2'-piperidinoethyl) ester;

q) cis-1-n-propyl-8-acetoxy-11-methyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid-(N1 - nicotinoyl )-hydrazide;

r) trans-9-nitro-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid-(2-phenylethyl)-amide;

s) cis-3<1->[1-ethyl-8-trifluoromethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indol-yl]-propan-1 '-ol-3,4,5-trimethoxybenzoic acid ester;

t) cis-g-p-toluenesulfonyloxy-1-ethyl-8-benzyloxymethylene-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid- [2-( 4-methylpiperazino)ethyl]ester;

u) trans-2'-ethylthio-3'-[1-ethyl-8-methyl-9-dimethylamino-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole -yl]-propan-1-ol;

v) cis-g-methyl-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]-indole-1-propionic acid amide;

w) cis-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]-indole-1-propionic acid methyl ester-N 4 -ammonium methoiodide;

x) trans-3'-[1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]-indol-yl]-propan-1<1->ol -2-trimethylammonium chloride;

y) cis-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-1-propionitrile;

z) trans-8-bromo-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-1-propionitrile;

z') erythro-cis-α-hydroxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid morpholide;

z") erythro-cis-g-hydroxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid-(4-methyl) -piperazide

Example 22

Tablets containing 20 mg of active substance are prepared with the following composition in the usual way:

Composition:

Preparation: cis-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b] indole-1-propionic acid methyl ester methanesulfonate is mixed with part of the wheat starch, with milk sugar and colloidal silicic acid and the mixture is passed through a sieve. A further part of the wheat starch is mixed with 5 times the amount of water in the water bath and the powder mixture is crushed with this paste until a weak plastic mass is formed. The plastic mass is pressed through a sieve with approx. 3 mm mesh size,

is dried and the dry granules formed are passed once more through a sieve. Then the rest of the wheat starch, the talc and magnesium stearate are mixed in and the mixture is pressed

fissured tablets with a weight of 145 mg.

Example 2 3

Capsules containing 10 mg of active substance are prepared as follows in the usual way:

Composition:

Manufacturing

The active substance is mixed well with talc and colloidal silicic acid, the mixture is pressed through a sieve with a mesh size of 0.5 mm and this is filled in portions of 11 mg each in

hard gelatin capsules of a suitable size.

Example 24

Dissolve 50.0 g of cis-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino [8,7-b]indole-1-propionic acid methyl ester methanesulfonate in distilled water, the solution is made up to 5,000 ml and the sterilized solution is filled into ampoules of 5 ml containing 1 ml of 10 mg of active substance.

Example 25

Instead of the compounds used as active substance in examples 22 to 24, the following compounds of formula I, their N-oxides or pharmaceutically acceptable non-toxic acid addition salts can also be used as active substances in tablets, dragees, capsules, ampoule solutions, etc.: threo- cis-a-hydroxy-l-et<y>l-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-l-propionic acid methyl ester,

erythro-cis-g-hydroxy-l-et<y>l-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-l-propionic acid methyl ester,

g<->acetoxy-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino [8,7-b]indole-1-propionic acid methyl ester,

trans-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b] indole-1-propionic acid methyl ester,

cls-l-ethyl-2 ,3,5,6 ,11,Hb-hexahydro-1H-indolizino [8 ,7-b]indole-l-propionic acid,

cis-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b] indole-1-acetic acid methyl ester,

cis-3 • - [l-ethyl-2 ,3,5,6,11, Hb-hexahydro-1H-indolizino [8 , 7-b] indole-1]-propane-1<1>,2<1- >diol with melting point 224-225 C.

cis-3<1>-[l-et<y>1-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b] indole-1]-propane-1<1 >,2<1->diol with melting point 206-208°,

trans-3<1>-[l-et<y>1-2,3,5,6,11,Hb-hexahydro-1H-indolizino [8,7-b]indole-1]-propane-1<1 >,2'-diol,

trans-α-hydroxy-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]-indole-1-propionic acid methyl ester,

trans-α-amino-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]-indole-1-propionic acid methyl ester,

cis-g-amino-l-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino [8,7-b]indole-l-propionic acid methyl ester,

threo-cis-2-benzo<y>loxy-l-et<y>l-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-l-propionic acid methyl ester,

erythro-cis-g-benzoyloxy-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-1-propionic acid methyl ester,

cis-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b] indole-1-propionic acid amide,

cis-g-amino-l-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino[8,7-b]indole-l-propionic acid amide,

as well as the compounds mentioned in example 21 or their N-oxides or pharmaceutically acceptable, non-toxic acid addition salts.

Claims (4)

1. Process for the preparation of new derivatives of indolizino[8,7-b]indoles with the formula in which Ra is the group ~ (CH2 )m"' in which m 0 or 1, Rfa denotes the group -CH(R1 )-, in which R1 means hydrogen, lower alkyl, optionally esterified or etherified hydroxy, lower alkylthio or optionally substituted amino, R2 means optionally esterified or etherified hydroxymethyl or optionally functionally converted carboxy, R^ and R4 each mean hydrogen or lower alkyl, or instead of the group -(Rj^-R )-is the group -CH=CH-, and in which the carbocyclic ring A is unsubstituted, or contains as substituents unsubstituted or substituted lower alkyl, optionally esterified or etherified hydroxy, nitro and/or optionally substituted amino, with the proviso that in compounds of formula I, in which R& denotes the group of formula -(CH2) -, in which m stands for 1, R^ denotes the group of formula -CrHR^ )-, in which R^ is hydrogen, R2 is hydroxymethyl or benzyloxymethyl, R3 is the ethyl group and R4 is hydrogen, the carbocyclic ring A is unsubstituted, and with the further proviso that in compounds of formula I, in which Rcl means the group of formula ~ (CH2 ) m""' in which m stands for 1, Rk denotes the group of formula -CH(R1 )-, in which R1 means ethyl, R2 means hydroxymethyl or benzyloxymethyl, and R^ and R^ each means hydrogen, the carbocyclic ring A is unsubstituted r tued, and with the further proviso that in compounds of formula I, in which R means- the group of formula ~ (CH2 ^m -' in which m stands for 1, R^ denotes the group of formula -CH(R^ )-, in which is hydrogen, R^ means the carbomethoxy group or the cyano group, and R^ and R^ are each hydrogen, the carbocyclic ring A is unsubstituted, such as epimer mixtures, pure epimers, racemate mixtures, racemates, optical antipodes, mixtures of cis and trans isomers, pure cis- or trans-isomers, N-oxides or salts thereof, characterized in that mana) in a compound with formula in which means hydrogen or a cleavable and hydrogen-replaceable substituent or lower alkyl and optionally hydroxy and/or amino groups are substituted with a cleavable and hydrogen-replaceable res, with the proviso that at least X^ means a cleavable and hydrogen-replaceable substituent, or at least hydroxy and/or amino groups are substituted with a cleavable and hydrogen-replaceable substituent, or in a salt thereof, it cleaves from hydrogen various groups X^ and/or in cleavable and hydrogen-replaceable substituents which are substituted with hydroxy and/or amino groups, and replace with hydrogen, or b) in a compound of formula where M 0 is the anion of an acid, e.g. that of the perchloric acid, the group stands for the group or has the meaning of R^,. or stands for a with a protecting group protected, by reduction in a free hydroxy group convertible hydroxy group, or R| denotes a lower alkenyl residue, or possibly instead of the group ■ the rest stand by formula C=CHR£ (IVa), in which R^ means hydrogen or a lower alkyl radical containing one less carbon atom, or instead of the group stands the group -CH=CH- (IVb), and R^ means hydrogen or a lower alkenyl residue, reduces the common double bond of rings C and D to a carbon-nitrogen single bond, reduces an optionally present lower alkenyl residue R| and/or R^ to the lower alkyl group R1 or R4 and/or optionally the group IVa to the group and/or optionally reduces the group IVb to the group -CF^ -Cr^ - (IVc), and/or reduces a possibly present double bond in ring C to a carbon-carbon single bond and/or reduces a possibly present being group to group and cleaves to hydroxy and/or amino groups optionally bound under the reduction conditions cleavable and hydrogen exchangeable protective groups and yields with hydrogen, or, c) reacts a compound with the formula in which X^ means lower alkyl or a group that can be split off under the process conditions and is replaceable with hydrogen, and hydroxy and/or amino groups are optionally present in protected, e.g. by solvolysis, as hydrolysis, cleavable form, with a compound of formula where Xq means the remainder with formula or the remainder by formula which exists in quaternary form, or Xq denotes the remainder by formula (Vd) , in which Rj. is lower alkyl, e.g. ethyl, or Xq means halogen, and R^ denotes optionally esterified or amidated carboxy, converts a compound formed by simultaneous or subsequent cleavage of the cleavable and hydrogen-replaceable group X^ and optionally present hydroxy and/or amino protecting groups into a corresponding compound of formula I, wherein instead of the group -(Rt)-Ra)- the remainder stands -CH=CH-, or d) in a connection with formula in which X^ means lower alkyl or a group that can be split off under the process conditions and is replaceable with hydrogen and X^ means halogen or a hydroxy group esterified with an organic sulfonic acid, the group X^ is split off and replaced by in the sense of corresponding, optionally substituted amino, optionally esterified or esterified hydroxy or lower alkylthio and simultaneously or subsequently cleaves off a cleavable and hydrogen-replaceable group X^ and replaces with hydrogen, or) reduces a compound of formula where Xj . means lower alkyl, lower alkenyl or one which is cleavable under the reduction conditions and exchangeable with hydrogen group, the group to the group and an optionally present common double bond to rings C and D, whereby in such a case the N atom common to rings C and D carries a positive charge and the anion M has the indicated meaning, to carbon-nitrogen single bond, and/or a optionally present lower alkenyl group X,, to a lower alkyl group, and/or cleaves off an optionally present, cleavable under the reduction conditions and hydrogen-replaceable group X^ , and to the hydroxy and/or amino group optionally bound under the reduction conditions cleavable and hydrogen-replaceable protecting groups and replaces with hydrogen , orf) in a connection with formula opens the ring E by means of alcoholysis, aminolysis including ammonolysis or hydrolysis, forming an optionally esterified or amidated carboxyl group R2 r org) in a compound of formula in which a by reduction in a lower alkyl group R^ denotes a transferable group and R^ denotes hydrogen or lower alkenyl, optionally the rings C and D have a common double bond and in this case the associated N atom carries a positive charge and such a compound exists as a salt and hydroxy and/or amino groups are optionally protected by reduction-cleavable and hydrogen-replaceable groups, reduces the group to a lower alkyl group R^ , reduces an optionally present lower alkenyl group R| to a lower alkyl group, reduce any double bond common to rings C and D to a carbon-nitrogen single bond and optionally cleave to hydroxy and/or amino groups bound, cleavable and hydrogen-replaceable protective groups under the reduction conditions and replace with hydrogen, orh) in a compound with formula in which Xg is hydrogen, lower alkyl or one which can be split off under the process conditions and is replaceable with hydrogen group, transforms the group with formula using water cleavage in the group -CH=CH-, cleaves off any group Xg that is cleavable and exchangeable with hydrogen under the process conditions and replaces with hydrogen, cleaves any hydroxy and/or amino protecting groups present and replaces with hydrogen, or i) to a compound with_ formula adds hydrogen cyanide or 'a similarly reacting compound which forms secondary hydroxy group R^ , optionally in protected form, and converts the secondary hydroxy group formed, optionally present in protected form, into the free hydroxy group, and, if desired, converts a formed compound of formula I in another compound of formula I, and/or if desired, separates a formed racemate mixture into the racemates, or separates a formed racemate into the optical antipodes, or separates a formed mixture of cis- and trans-isomers into the pure cis- and trans-isomers, or separates a formed epimer mixture in the pure epimers, and/or if desired, transfer a formed compound of formula I in a salt or transfer a formed salt in a free compound or in another salt or N-oxide. 2. Process according to claim 1, characterized in that erythro-cis-α-hydroxy-1-ethyl-2,3,5,6,11,Hb-hexahydro-1H-indolizino-[8,7-b ]indole-1-propionic acid methyl ester. 3. Method according to claim 1, characterized in that cis-1-ethyl-2,3,5,6,11,11b-hexahydro-1H-inolizino[8,7-b]indole-1-propionic acid methyl ester is prepared. 4. Method according to one of claims 1-3, characterized in that a formed compound of formula I is transferred into a pharmaceutically usable, non-toxic acid addition salt.