DE2321520A1 - CONDENSED HETEROCYCLIC AZAINDOLE COMPOUNDS - Google Patents

Description

Condensed heterocyclic azaindole compounds.

The invention relates to condensed heterocyclic azaindole compounds, in particular substituted 2,3,5,6,11,11b-hexahydro-IH-pyrido / 3 ¹ , 2 ': 4,57pyrrolo / 3,2-g7indolizine and 1,2, -3, 4,6,7,12,12b-octahydropyrido / 3 ', 2 ·: 4,57 ~ pyrrolo / 2,3- ^ 7-quinolizine, as well as processes for the preparation of the compounds and pharmaceutical agents.

The invention provides heterocyclic compounds of the general Formulas Ia and Ib:

RI (CHJ ₁

^l 2'n
(Ia) (Ib)

3 0 S 8 U 6/1 1 5 2

ORIGINAL INSPECTED

l AHP-574Q

2321S2Q

wherein X stands for two hydrogen atoms or an oxo group j

R is hydrogen, alkyl with 1 -. 5 carbon atoms or allyl means}

R is methyl, ethyl or n-propyl;

ρ
R represents alkyl of 1-5 carbon atoms or allyl; and

η stands for 1 or 2, as well as their pharmacologically acceptable ones Acid addition salts, when X is an oxo group, R preferably represents hydrogen or lower alkyl.

A preferred class of compounds of the general formula (la) is that of the formula (Ic):

^0H 2> n

(Io)

wherein R, R and η have the meanings given above, as well as their pharmacologically acceptable acid addition salts. Typical examples of compounds of the general formula (Ia) are:

2,3,5,6,11,11b-hexahydro-11,11b-dimethyl-1H-pyrido / 3 ', 2 ·: 4,57-pyrrolo / 3,2-g7indolizine

2,3,5,6,11, iib-hexahydro-iib-methyl-IH-pyrido / ¹ , 2 ": 4,57 pyrrolo- / 3,2-g7indolizine

11-ethyl-2,3,5,6,11,11 b-hexahydro-11 b-methyl-1H-pyrido / 3 ', 2 »: 4,57-pyrrolo / 3,2-g7indolizine

11 b-Ityl-2,3,5,6,11,11 b-hexahydro-IH-pyrido / 3 ', 2': 4,57 pyrrolo- / 3,2-g7indolizine

1 tb-ethyl-2,3,5,6,11,11b-hexahydro-11-methyl-iH-pyrido / 3 ·, 2 ·: 4,57 pyr ^ olo / 3, 2-g7indolizine

A .. ■ .: / '1 1 5

ί ΑΗΡ-5740

1,2,3,4,6,7,12,12b-Octahydro-12b-methylpyridoZ3 ^f , 2 ": 4,57-pyrrolo / 2,3-α7-quinolizine

1,2,3,4,6,7,12b-octahydro-12,12b-dimethylpyrido _/ T3 ', 2': 4,57-pyrrolo / 2,3-a7-quinolizine

11,11b-diethyl-2,3,5,6,11,11b-hexahydro-iH-pyrido / 3 ', 2': 4,5j pyrrolo / 3,2-g7indolizine

2,3,5,6,11,11 b-Hexahydro-11 b-methyl-1 1 -propyl-IH-pyridb- / 3 ¹ , 2 ¹ : 4,57 pyrrolo / 2, 2-g7indolizine

11-Allyl-2,3,5,6,11,11 b-hexyhydro-1 ib-methyl-1H-pyrido / 3 ¹ , 2 ": 4.57 · pyrrolo / 3.2-g7indolizine

/ 3 ¹ , 2 ': 4,5jpyrrolo / 2,3-a7phinolizine

12-allyl-1,2,3,4,6,7,12,12b-octahydro-12b-methyl-pyrido- / 3 ', 2 ': 4,57 pyrrolo / 2,3-a7cMnolizine

11-butyl-2,3,5,6,11,1 ib-b.exab.ydro-1 ib-methyl-1H-pyrido- / 3 ', 2 ■: 4,57pyrrOI0 / 3,2-g7indolizine

2,3,5,6,11,11b-hexahydro-11b-propyl-1H-pyrido- / 3 ', 2 ": 4,57-pyrrolo / 3,2-g_7indolizine

2,3,5,6,11,11b-Hexahydro-11-methyl-1ib-propyl-IH-pyrido-Z3 ¹ , ² ': 4,57pyrrolo / 3,2-g_7indolizine

2,3,5,6,11,11b-Hexahydro-11-isoamyl-i1b-methyl-1H-pyrido- / 3 ^f , 2 ': 4,57pyrr0I0 / 3,2-g7indolizine "

11-Amyl-2,3,5,6,11,11b-hexahydro-11b-methyl-IH-pyrido- / 3 ', 2': 4,57pyrrolo / 3,2-g7indolizine

Also preferred are the compounds of general portioning mel (Ib) are:

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12 "'

in which R, R and η have the meanings given above and their pharmacologically acceptable acid addition salts. A typical example of a compound of the general formula (Ib) is 2,3,5,6,11, Hb-hexahydro-11, Hb-dimethyl-IH-pyrido / 3 ¹ , 2 ': 4,5 / pyrrolo / 3.2 g / indolizine 4-oxide hydrochloride.

The compounds of the general formula (Ic) in the form of the free base are generally colorless oils or solids, which are essentially insoluble in water and in organic solvents such as benzene, methanol, chloroform and acetone,

j are generally soluble. In the form of their acid addition salts, they are generally white solid substances that are found in Water and methanol are appreciably soluble. In the connections

j of the general formula (Ib) are solid substances,

! which are essentially soluble in water and methanol. The infrared, ultraviolet and HMR spectrographic analysis of the compounds prepared in accordance with the method described below provides spectral data corresponding to those given above Confirm molecular structure. Consider the above physical characteristics together with the nature of the starting materials, the elemental analysis and the synthetic route, so here, too, there is agreement with the molecular structure given above. The connections of the general

J Formulas (Ib) and (Ic) practice analgesia in warm-blooded creatures Effects from what is revealed by standard pharmacological test procedures shows or they are intermediates for such compounds with pharmacological activity. .... "■■

A second class of compounds falling under the general formula (Ia) is that of the general formula (Id):

Vn

^R 1 (CH ₀ ),

(Id)

-4- 3 O H b ύ fi / 1 1 5? ·

ζ ΑΗΡ-3740

wherein R, R and η have the meanings given above and their acid addition salts.

Typical examples of compounds of the general formula (Id) are:

1,2,5,6,11,11b-Hexahydro-11b-methyl-3H-pyridoZ3 ', 2': 4,57-pyrrolo / 3,2-g / indolizin-3-one

1,2,5,6,11,11b-hexahydro-11,11b-dimethyl-3H-pyrido / 3 ·, 2 ·: 4.57 pyrrolo / 3,2-g_7indolizin-3-one

; 11b-ethyl-1,2,5,6,11,11b-hexahydro-3H-pyrido / 3 », 2 *: 4, S7pyrrolo- / 3,2-g7indolizin-3-one

11b-ithyl-1,2,5,6,11,11b-hexahydro-11-methyl-3H-pyrido / 3 ', 2': 4,5_7pyrrolo / 3,2-g7indolizin-3-one

2,3,6,7,12,12b-hexahydro-12b-methylpyrido / 3 ^I , 2 ·: 4,57pyrrolo- / 2,3-α7-quinolizin-4 (iH) -one

2,3,6,7,12,12b-hexahydro-12,12b-dimethylpyrido / 3 ', 2 ^I : 4,57-pyrrolo / 2,3-α7-quinolizin-4 (1H) -one

1,2,5,6,11,11b-hexahydro-11b-propyl-3H-pyrido / 3 ■, 2 ': 4,57-pyrrolo / 3,2-g _ ^. Ndolizin-3-one

1,2,5,6,11,11b-hexahydro-11b-methyl-11b-propyl-3H-pyrido- / 3 ', 2': 4,57pyrrolo / 3,2-g7indolizin-3-one

The compounds of the general formula (Id) are generally colorless oils or solids in the form of the free base, essentially insoluble in water and generally soluble in organic solvents such as chloroform and letrahydrofuran. In the form of their acid addition salts, they are generally white solid substances found in water and methanol are noticeably soluble.

The investigations of the compounds prepared according to the method described below with the help of infrared, ultraviolet and NMR spectrographic analysis gives spectral data,

309846/1152

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which confirm the molecular structure given above. Considered the aforementioned physical characteristics together with the nature of the starting materials, elemental analysis and the synthetic route, agreement with the structure given above is also found here.

The compounds of the general formula (Id) are useful as intermediates since they are prepared according to procedures described below can be converted into the analgesic compounds of the general formula (Ic).

The present invention also relates to pharmaceutical compositions, which are suitable for administration to warm-blooded living beings and a compound of the general Formula (Ic] J or the formula (Ib) or a pharmacologically acceptable one Acid addition salt thereof in connection with a pharmaceutically acceptable carrier.

The active one used in the pharmaceutical agent The constituent is preferably 2,3,5,6,11,11b-hexahydro-11,11b-dimethyl-1H-pyrido / ~ 3 ', 2 · : 4,57 pyrrolo / ~ 3,2-g_7-indolizine or one of its pharmacologically acceptable acid addition salts, especially the dihydrochloride.

The compounds of the general formula (Ia) and (Ib), at

1 2
where R, R, R, X and η have the meanings given above, and their pharmacologically acceptable acid addition salts can be prepared by the following processes:

(a) a compound of the general formula:

3 0 9 846/1152

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wherein R is hydrogen or alkyl; with 1-5 carbon atoms or means allyl; . -

R represents methyl, ethyl or n-propyl; η is 1 or 2;

Z and W independently represent oxygen, sulfur or two hydrogen atoms, one of the radicals Z or W must always represent oxo or sulfur,

is reduced in a known manner, for example if Z or W represent an oxo radical, with an alkali metal aluminum hydride, for example lithium aluminum hydride, or if Z or W represent sulfur, with Raney nickel; If desired, a compound in which R is hydrogen is alkylated (including allylated) on the indole nitrogen in a known manner, either before or after the reduction, in order to introduce the alkyl or allyl group (R), for example by adding the compound with a strong Base, such as an alkali metal alcoholate, alkali metal hydride or alkali metal amide, in particular treated with sodium hydride and then treated with an alkylating agent, e.g. an alkyl halide, alkyl sulfonate, e.g. an alkyl tosylate or a similar mineral acid ester, so that a compound of the general formula:

obtained in which R is hydrogen, alkyl having 1-5 carbon atoms or allyl and R and η have the meanings given above to have. Preferred starting materials are those in which Z is two hydrogen atoms and W is the oxo radical or represents sulfur.

(b) A compound of the general formula:

" ⁷ " 3 0 a B Λ Β / 1 1 5 2

9 AHP-5740

where R is methyl, ethyl or n-propyl,

Z and ¥ each independently represent oxo, sulfur or two hydrogen atoms stand and

η stands for 1 or 2, is in a known manner on the indole nitrogen alkylated (including allylated) to introduce the alkyl or allyl group (R) by e.g. B. with a strong base, such as an alkali metal alcoholate, alkali metal hydride or alkali metal amide, especially with sodium hydride, and then with one Alkylating agents, e.g. an alkyl halide, alkyl sulfonate, e.g. a tosylate or a similar mineral acid alkyl ester, and, if desired, either before or after the alkylation a compound in which Z or W is oxo or sulfur, reduced in a known manner, for example with an alkali metal all aluminum hydride when Z or W is oxo or with Raney nickel when Z or W is sulfur, so that one Connection of the general formula:

^l 2'n

obtained in which R denotes alkyl with 1-5 carbon atoms or allyl j and R, Z, W and η have the meanings given above. Preferred starting materials are those in which Z represents two hydrogen atoms and ¥ represents oxo or sulfur or j those in which each of the radicals Z and W represents two hydrogen atoms j.

ι - ■■ -

(c) a compound of the general formula:

3 0 9 8 A 6/1 1 5 2

AHP-5740

where R is hydrogen or alkyl with 1 - 5 carbon atoms, is made with a compound of the general formula:

where R is methyl, ethyl or n-propyl, X stands for oxo or two hydrogen atoms and η stands for 1 or 2,

implemented according to the Fischer indole process, if necessary in the presence of an acidic catalyst such as boron trifluoride, zinc chloride or polyphosphoric acid, and if desired a product in which X is oxo is reduced in a known manner, for example with an alkali metal aluminum hydride, and if a product in which R is hydrogen is desired to be alkylated on the indole nitrogen in a known manner (including allylated), either before or after the reduction, which may be carried out, to remove the alkyl »or allyl group (R) introduce, for example, by reaction with a strong base, such as an alkali metal alcoholate, alkali metal hydride or Alkali metal amide, especially sodium hydride, and then with an alkylating agent such as an alkyl halide, alkyl sulfonates e.g. losylate or a similar mineral acid alkyl ester, so that you get a compound of the general formula:

309846/1152

1Q AHI-5740

obtained in which R is hydrogen, alkyl having 1 - 5 carbon atoms or allyl and R, X and η have the meanings given above. Preferred starting materials are those at where X stands for two hydrogen atoms.

(d) A compound of the general formula:

where R is hydrogen or alkyl having 1-5 carbon atoms, is made with a keto acid of the general formula:

0 0
R-CCH ₂ (GH ₂ ) -GOH.

where R is methyl, ethyl or n-propyl and η is 1 or 2, or its functional derivative ^ & .B. an enollactone derivative ί

implemented and an open-chain intermediate product is cyclized, if desired, the product is "reduced" in a known manner, for example with an alkali metal aluminum hydride or by treatment with phosphorus pentasulfide and subsequent reduction with Raney nickel and, if desired, a product in the R denotes hydrogen on the indole nitrogen in a known manner alkylated (including allylated), either iror or post the possible reduction ^ around the alkyl or allyl group (R) to be introduced, for example by treatment with a strong base such as an alkali metal alcoholate alkali metal hydride or alkali metal amide, especially sodium hydride, and then with an alkylating agent such as an alkyl halide

" ¹⁰ " 309846/1152

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Alkyl sulfonate, e.g. tosylate or a similar mineral acid alkyl ester, so that you get a compound of the general formula:

; where R is hydrogen, alkyl with 1-5 carbon atoms

: or allyl and R, X and η have the abovementioned meaning

have services.

'> (e) A combination of the general formula:

.i where J ^ is a halide anion,
. η stands for 1 or 2 and

R is hydrogen, alkyl with 1-5 carbon atoms or allyl, is with a methyl, ethyl or n-propyl Grignard reagent (R MgX) or a methyl, ethyl or n-propyl methyl reagent (R Li) to a compound of the general formula:

• j

where R and η have the meanings given above and R is methyl, Means ethyl or n-propyl, implemented.

(f) A combination of the general formula:

" ¹¹ " 309846/1152

AHP-5740

where R is methyl, ethyl or n-propyl, η is 1 or 2 and R is an unsaturated alkyl group having 2-4 carbon atoms is reduced, e.g. with hydrogen and a noble metal catalyst, e.g. a catalyst from 10 ^ palladium on carbon, creating the unsaturated alkyl group is converted into the corresponding saturated alkyl group.

(g) A compound of the general formula:

& Ö

\ Wherein R is alkyl having 1-5 carbon atoms or allyl;

ί 1
R for methyl, ethyl, or n-propyl and

j η stand for 1 or 2, is oxidized e.g. with a peroxy acid,

i in particular with m-chloroperoxybenzoic acid, to a connec-

j formation of the general formula:

! 2 1

¹ in which R, R and η have the meanings given above. Before-

i 1. "

I preferably use a starting material in which R and R

j denotes methyl and η denotes 1.

ι (h) Sin racemic mixture of a compound of

I general formula:

- 12 -

30H846 / 1 152

wherein R is hydrogen, alkyl with 1-5 carbon atoms or Allyl means

R is methyl, ethyl or n-propyl and η is 1 or 2, is dismantled. A preferred compound for the decomposition is that in which R and R are methyl and η is 1.

(i) The products of processes (a) to (h) above are in the form of the free base with a pharmacologically acceptable one Treated acid so as to form the corresponding pharmacologically acceptable acid addition salt.

Specific examples of the methods described above can be found below, with further reference to the enclosed one

-j
Figure 1 received, where R and R have the meanings given above and which schematically shows the reaction sequence for the preparation of the 2,3,5,6,11,11 b-hexahydro-1H-pyrido / 3 ', 2': 4.5 / pyrrolo / 3,2-g_7-indolizine and the 1,2,5,6,11,11b-hexahydro-3H-pyrido / 3 ', 2': 4,57-pyrrolo / 3,2-g7indolizin-3-ones , that is to say the compounds of the general formula (Ia), where η is 1, illustrated.

Now to Figure 1. The connections are designated with Roman numerals. In Method A, 7-azatryptamine (II) is made with a keto acid of the formula:

0 0
R ¹ -C-CH ₂ CH ₂ -GOH

wherein R is lower alkyl to give the amino amide intermediate (IV). The methods used in this process correspond to those described by S. Wawzonek and JD Nordstrom in J. Med, Chem. 8, 265 (1965). The same intermediate (IV) can

- 13 -

309846/1152

on the other hand, are also prepared by process B in two stages, 7-azatryptamine (II) first with one Enollactone of the formula: -

is brought together and the ketoamide intermediate (III) is obtained and then the intermediate is cyclized. The first stage of procedure B is carried out according to a method corresponding to that of 3 ?. Shiroyan in arms. Khim. Zh., 20 , 649 (1967). The cyclization is achieved by heating the ketoamide intermediate (III) in the presence of a mineral acid, for example hydrogen chloride in isopropanol. '

The aminoamide intermediate (IV) is produced using the procedure C is converted into the amine (V) by removing the amide carbonyl group with a reducing agent such as lithium aluminum hydride. The reduction is carried out in a non-reactive solvent, such as tetrahydrofuran, carried out at reflux temperature. Alternatively, the reduction can also be carried out in such a way that the ketoamide is obtained by reaction with phosphorus penic sulfide converted into a thioamide in a non-reactive solvent and then the thioamide with Raney nickel according to the in U.S. Patent 3,454,583.

Alkylation of the amine (V) on the indole nitrogen gives the product (VII). The alkylation is achieved by bringing the amine (V) into contact with a base in a non-reactive solvent, for example sodium hydride in dimethylformamide, and then an alkylating agent, for example a lower alkyl halide or tosylate, at a temperature in the range of about O ⁰ C to about 100 ⁰ C adds. If R stands for a lower alkyl group, the product (VII) can also be prepared according to process D

" ^H " 309 8 46/1152

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by N ^ alkylation of the amino amide (IV) and subsequent Reduction of the amide carbonyl group using those described above Reduction methods are produced.

It will be understood that the indole nitrogen atom of the 7-azatryptamine can be substituted with an appropriate alkyl group (R). Such substituted compounds can be used as starting materials in process A of the method described above, so that the amino amide (VII) is obtained directly without an alkylation step (process D). ^>

The amine (V) can also be prepared according to Pischer's indole synthesis be prepared by adding a keto compound of formula (VIII):

(VIII)

wherein R is methyl, ethyl or n-propyl, with 2-hydrazinopyridine or an N- (alkyl) -IT- (2-pyridyl) hydrazine. The keto compound (VIII) can be synthesized by the following methods:

Bin 2- (alkyl) proline (IX) is first prepared using standard procedures, e.g. with thionyl chloride and methanol, converted into its methyl ester (X). Palis the ester as acid addition salt accrues (which is the case if the thionyl chloride-methanol method is used) »it must be neutralized with a strong base, e.g. with triethylamine, this is what you get free amine. The free amino ester (X) is then mixed with an appropriate one 4-halobutyric acid methyl ester alkylated on nitrogen, whereby a diester (Xl) is obtained which is then cyclized in the presence of a base such as sodium methylate and gives a (3-ketoester compound in situ, which in water is extracted. The water containing the intermediate

- 15 -

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extract is acidified to about pH 1 and heated, whereupon Hydrolysis and 'decarboxylation takes place and the keto compound (VIII) arises.

The 1,2,3,4,6,7 _f 12,12b-octahydropyrido / 5 ', 2': 4,57pyrrolo / 2,3-a7-quinolizine compounds of the formula (Ia) (these are the compounds at where η stands for 2) can.according to the previously described process A or process B from 7-azatryptamine or a N, - (alkyl) substituted 7-azatryptamine and a keto acid:

- 0 0
R ¹ -GCH ₂ CH ₂ CH ₂ COH

or an enol lactone:

! where R is methyl, ethyl or n-propyl, are prepared, ! The cyclic intermediate thus formed:

is converted into a compound of the formula (Ia) in which η is

ί 2, where the reduction and N .-, -

: - md

ί alkylation processes or equivalent modified processes j can be used.

■ The connection obtained by the methods described above gene of formula (la) or (Ic) and their corresponding intermediate

■ products can be isolated and cleaned in the usual way. Also in the various methods described above

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Factors such as solvents and temperatures are not decisive. In general, the solvent must be inert during the reaction, that is, it must not interfere with the course of the reaction and must be such that the reactants are soluble in it. If a compound of the formula (Ia) or (Ic) is used as Acid addition salt obtained, it can be converted into the free base in the usual way, e.g. by dissolving the salt and treated the solution with sodium hydroxide. If a compound of the formula (Ia) or (Ic) is obtained as a free base, it can they are converted into a suitable acid addition salt by dissolving the base and treating the solution with the desired acid will. ·

The starting materials for the synthetic procedures described above are described in the literature or they can be prepared by known processes. 7-azatryptamine was by M. Robinson and B. Robinson, J. Am. Chem. Soc, J8, 1247 (1956), see also French patent 1,261,179, British patent 897,988 and US patent 3,354,174. 2-methylproline was described by K. Kariyone, Chem. And Pharm. Bull. (Japan) 8, 1110 (1960) and in U.S. Patent 3,422,110.

The N-oxides of formula (Ib) where R, R and η are the above Have meanings are obtained by oxidation of a compound of the formula:

in which R denotes alkyl with 1 - 5 carbon atoms or allyl!

R represents methyl, ethyl or n-propyl and

η stands for 1 or 2, prepared with an organic peroxy acid. Suitable peroxy acids are peroxyformic acid, peroxy-

" ¹⁷ " 309846/1152

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acetic acid, peroxytrifluoroacetic acid, m-chloroperoxybenzoic acid, Peroxyphthalic acid and the like. However, m-chloroperoxybenzoic acid is preferably used. The peroxyacid can be either be prepared beforehand or in situ by reacting hydrogen peroxide with a suitable carboxylic acid, as by Fieser and Fieser in "Reagents for Organic Synthesis", John Wiley,. 1967, pages 457-465.

In general, the oxidation reaction is carried out in an inert organic solvent for the reaction at a temperature in the range of about -5 ° C to about 5O ⁰ C for a period of up to 2 hours. The preferred temperature range is from about -5 ⁰ C to about 5 ⁰ C and the preferred solvent is tetrahydrofuran. The Ek-Oxyd derivative forms an acid addition salt with the carboxylic acid formed during the decomposition of the selected peroxy acid. The salt thus formed can be recovered or converted into a salt which contains a different anion than that contained in the salt originally formed by bringing the salt into contact with an organic or mineral acid which has an acidic strength greater than that of the carboxylic acid to which the iL-Oxyd derivative was originally bound. If, for example, m-chloroperoxybenzoic acid is used as the oxidizing agent, the N, -oxide derivative combines with m-chlorobenzoic acid. The m-chlorobenzoic acid addition salt can be contacted with hydrogen chloride to give the hydrochloride salt.

If desired, the W ^ oxide derivative can be used as an acid addition salt be converted into the corresponding free N ^ -oxide derivative, by bringing the salt into contact with a suitable base. When neutralizing in a suitable pharmaceutical compatible solvent is carried out and if no toxic products are formed, the solution can be free IL-Oxydbase directly for the biological ones described here Purposes. For example, the salt can be in water

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dissolved and treated with enough sodium hydroxide that the base is generated.

Since the compounds according to the invention have an asymmetric carbon atom, optical enantiomorphs are possible and the compounds according to the invention can be the pure enantiomorphs or mixtures of such enantiomorphic compounds, such as the racemates. The products according to the invention can be obtained in the form of the pure enantiomorphs by either performing a separation at a suitable synthesis stage or by separating the desired products. The separation can be carried out in a known manner. For example, the pure right and left enantiomorphs of 2,3,5,6,11,11b-hexahydro-11,11b-dimethyl-1H-pyridoZ3 ', 2': 4,57pyrrolo / 3,2-g7indolizine are obtained by Treatment of the racemate with 2,3-dibenzoyl-2 (R): 3 (R) -tartaric acid. The salt of the 1-isomer is isolated by crystallization and the 1-isomer is obtained in the form of its free base by treating the salt with a suitable strong base. The d-isomer is isolated by removing the residue, which is obtained by evaporation of the mother liquor the crystallization stage has been obtained, treated with 2,3-dibenzoyl-2 (S): 3 (S) -tartaric acid, the salt formed thereby crystallizes and the. Salt treated with a suitable strong base. If desired, the separated bases can be converted into the corresponding acid salts in the usual way. The pure enantiomorphs can be subjected to oxidation with a peroxy acid, whereby the right or left form of 2,3,5,6,11,11b-hexahydro-11,1ib-dimethyl-iH-pyrido / 3 ¹ , 2 ': 4,57-pyrrolo / 3,2-g7indolizine-4-oxide dihydrochloride is obtained.

The analgesic effectiveness of the compounds of formula (la) or (Ib) was tested in rats by the method of D'Amour and Smith, J. Pharmacol., 22, 74 (1941) demonstrates details are given in Example 32. The compound 2,3,5,6,11,11b-Hexahydr0-11,11 b-dimethyl-1H-pyrido / 3, 2: 4, -57pyrrolo / 3,2-g_7-

~ ¹⁹ ~. 309846/1152

j indolizine has proven to be an extremely effective analgesic compound proven to be about 110 times more effective when administered orally and when administered interamuscularly

, about 17 times larger than that of morphine.

For producing a analgesia in warm-blooded animals \ varies the efficacy dose depending on the used specific ί-rush compound, the strength and nature of pain and the j subject to be treated.

In general, large warm-blooded creatures (about

70 kg body weight) good results = can be achieved if ^: the oral route doses of 0.1 to about 50 mg are given every 4 hours or as soon as required. When administered intramuscularly, good results can be obtained by administering doses from 0.5 to about 7.5 mg as soon as necessary.

Therapy should be started at lower doses i and then increased until the desired analgia j is achieved. Pur Z ^^^ JI ^ IIb-Hexahydro-ii ^ iib-dimethyl-IH-pyrido- · I / 3-Ί2 ¹ : 4,5J ^ pyrrolo / 3,2-g_7indolizine, a preferred compound, is the preferred range 0.1 to 1.0 for oral use and 0.5 to about 2.0 mg for intramuscular use.

I ■

i When used as an analgesic agent, the active sub-! punch alone or in combination with pharmaceutically ! tolerable carriers, their proportion and nature through the solubility and chemical properties of the chosen Verbinj administration, the chosen route of administration and standard pharmaceutical practice. The connection [ fertilizers of the formula (I) can e.g. orally in solid dosage forms, e.g. in the form of capsules, tablets or powders or in liquid Form, e.g. in the form of solutions or suspensions. The compounds can also be in the form of sterile Solutions or suspensions are injected parenterally. Festivals oral forms can use common diluents, e.g. lactose,

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ΑΗΡ-5740

Sucrose, magnesium stearate, resins and like materials contain. Liquid oral forms can contain various flavors, colors, preservatives, stabilizers, soli-dilizers or contain suspending agents. Parenteral preparations are sterile aqueous or non-aqueous solutions or suspensions containing various preserving, stabilizing, buffering, solubilizing or suspending agents contain. If desired, additives such as salt or Glucose can be added to make the solutions isotonic.

For parenteral administration it is expedient to use the compounds according to the invention in the form of their pharmacologically compatible acid addition salts that are water-soluble and can therefore easily be incorporated into preparations suitable for injection. The salts will made in a known way. Suitable salts are formed with inorganic and organic acids, e.g. with hydrogen chloride acid, hydrobromic acid, sulfuric acid, sulfonic acid, Phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, emboxylic acid, succinic acid, methanesulfonic acid, Acetic acid, propionic acid, tartaric acid, citric acid, lactic acid, malic acid, mandelic acid, cinnamic acid, palmitic acid, Itaconic acid and benzenesulfonic acid.

The following examples serve to further illustrate the invention without, however, restricting it. All temperatures are given in ⁰ C. ·

example 1

1,2,5,6,11,11 b-Hexahydro-11 b-methyl-3H-pyrido- / 3 ■, 2 »: 4,57- pyrrolo / 3« 2-g.7indolizin-5-one .. . «■■ --.- ·, - ·. .

Method 1:

Butylcellosoiv (70 ml), 2.9 g levulinic acid and 2.0 g 7-azatryptamine β & M, Robinson and BC Robinson, J. Am. Chem. Soc. 28: 1247 (1956); French patent 1 261 179 -CA, J57,

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• AHP-5740

2274b (1962), British Patent 897,988 - CA. JJ7, 12567d (1962) 7 'are _{refluxed for 20 hours (under N 0} ) and the solvent is removed in vacuo. The resin residue solidifies "on trituration with excess water, aqueous sodium hydroxide and the brown powdery substance is isolated, carefully washed with water and triturated with ether. Twice recrystallization of the crude product from acetone gives 0.7 g of the compound named in the title, decomposition at 253 - ^ -> 4 °; .λ. ^^ ^r ) ^: 3.31, 5.97 Ji; NMR (CDCl ₃ ): & 1.77 (singlet, 11b-methyl), 4.58 (multiplet, C- 5 proton) ppm.

Method 2:

j 7-Azatryptamine (4.6 g), 3.1 g of angelicalactone and 60 ml of dry tetrahydrofuran (THE ¹ ) are refluxed for one hour

boiled and the solution is cooled to + 5 ° for approx. 16 hours. The pest substance is isolated, washed with cold (approx. -70 °) THP, dried carefully and 4.6 g of N- / ~ 2- (7-aza-; indol-3-yl) ethyl7-4-oxovaleramide are obtained, Pp = 136-137 °; λ> _v (EBr):! 3.05, 5.86, 6.11 µ; NMR (CDCl ₅ ) S2.17 (singlet, COCH ₅ ),

6.49 (multiplet, amide-NH) ppm. ,

j ■

Isopropanol (80 ml), 3.9 g of N-Z2- (7-azaindol-3-yl) äthyi7-4-oxovaleramid and 5 ml of a 3.2 η HGl / isopropanol solution are refluxed for 3 hours and the Reaction mixture ί is then evaporated to dryness. Successive TJmj crystallization of the residue from isopropanol, chloroform / ither and isopropanol / methanol give 1.7 g of the compound named in the title as the hydrochloride salt, solvated with 0.2 molecules of isopropanol per molecule of salt, decomposition at 283-286 °; (S _ (KBr): 2.95, 4.05, 5.94 µ ', NMR (dDMSO): S 1.05 (doublet, J = 6H ^, isopropylmethyl), I ₉ 65 (singlet, 11b-methyl ), 4.27 (multiplet, C-5 proton) ppm.

The above hydrochloride (0.5 g, solvated with Isopropanol) is converted into the free base from acetone

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and is recrystallized from niiromethane. A 208 mg quantity of material is isolated and a 101 mg portion is made from acetone recrystallized, 64 mg of those mentioned in the title Maintains compound, decomposes at 255 - 256 °. Taken at the same time, the product of method 1 melts at 254 °, while a mixture of the two samples decomposes at 254 °.

The IR, HMR and UV spectra of the two samples are the same and show only very small differences that depend on the presence come from different trace amounts of solvent.

Example 2

2,3,5,6,11,11b-hexahydro-11b-methyl-1H-pyrido / 3 ', 2 ": 4,57- pyrrolo / 3, 2-g_7indolizine

Method 1;

3.2 ml of thionyl chloride and 5.2 g of dl-2-methylproline / K are added successively to 15 ml of methanol at -10 °. Kariyone, Chem. And Pharm. Bull. (Japan), 8, 1110 (1960); US Patent 3,422,1117, holds the solution at about 25 ° for 3 hours and then refluxes for two hours. The solvent is removed and the residue is recrystallized from acetone, giving 3.2 g of 2-methyl-2-pyrrolidine-carboxylic acid methyl ester hydrochloride, 2p = 95-96 °; f> _max (KBr): 3.68, 5.73 yes; NMR (dDMSO): S1.63 (singlet, 2-methyl), 3.79 (singlet, O-methyl) ppm.

A mixture of the salt prepared above (63.0 g) and 500 ml of triethylamine is stirred vigorously for 4 hours and then filtered. The filtrate is saved and the pest substance is triturated three times with triethylamine as before. The triethylamine is removed from the combined piltrates and 41.0 g of crude methyl 2-methyl-2-pyrrolidine-carboxylate are obtained; h (PiIm) i 3.00, 5.77 / i.

Acetone (300 ml), 17.1 g of methyl 2-methyl-2-pyrrolidine-carboxylate, 16.5 g anhydrous potassium carbonate, 18.0 g 4-chloro butter

" ²³ '3 0: -; H U 6/1 1 5 2

acid methyl ester and 19.5 g of anhydrous sodium iodide are stirred and refluxed for 48 hours. The reaction mixture is filtered and the filtrates are freed from solvent. Suspension of the residue in ether, filtration and evaporation of the ether from the piltrate gives a residue which is distilled and 14.0 g of 2-carboxy-2-methyl-1-pyrrolidine. butyric acid dimethyl ester gives, bp = 105-108 ° / 0.1 mm; Λ _v (film): 5.75 μ ', NMR (CDCl,): ⁶ 1.25 (singlet, 2-methyl), 3, 65 (singlet, O-methyl) ppm.

Analysis for C ₁₂ H ₂₁ NO ₄ : Calculated: C, 59.24; H, 8.70; N, $ 5.76

Found: C, 59.61; H, 8.62; N, 5.76 #.

Toluene (400 ml), 8.9 g sodium methoxide and 33.3 g 2-carboxy-2-methyl-i-pyrrolidine butyric acid dimethyl ester are refluxed for 4 hours. The reaction mixture is extracted with water and the combined aqueous extracts (approx. 300 ml) are made strongly acidic with concentrated HCl and then heated on the steam bath. After heating for 12 hours the ferric chloride test is negative.

One 20 ml serving of the above acidic solution (negative ferric chloride test) and 2.0 g of 2-hydrazinopyridine hydrochloride are refluxed for 2 hours and then evaporated to dryness. The residue and about 6 g of polyphosphoric acid are heated sequentially at 170 °, 200 ° and 250 ° for one hour periods. After cooling, the reaction mixture becomes mixed with ice, with aqueous sodium hydroxide made basic and extracted with ether. The essential extracts are washed with brine, dried (magnesium sulfate) and freed from solvent ^ whereby an oil is obtained, which is dissolved in dilute aqueous hydrochloric acid and washed with ether. The acidic solution becomes basic made, extracted with ether and the solvent is removed from the ethereal extracts, giving 1.5g

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oily base which is purified by chromatography on a column of neutral aluminum oxide of activity level III. A crystalline pest substance is isolated from the chloroform eluate, which is recrystallized from ether and gives 350 mg of the compound mentioned in the title, mp = 199-200 °; k max ( ^θΓ ) ^: 3.16 ^; EMR (CDClJ: δΐ, 65 (singlet, 11t-methyl) ppm., & (EtOH 95/0: 228 (£ 25,640), 291 (S 9 460) mu; ^ min ^{(95? Δ Et0H} ) ^{: 249} & ⁶⁹ °) ¹ V ¹ '

Analysis for C ₁₄ H ₁₇ N ₅ : Calculated: C, 73.97; H, 7.54; N, 18.49 ^

Found: C, 73.99; H, 7.45 * N, $ 18.41

Method 2:

A suspension of 2.0 g of lithium aluminum hydride in 100 ml of dry THF, which is refluxed with stirring under N ₂ , is slowly mixed with a solution of 4.0 g of 1,2,5,6,11, Hb-hexahydro-Hbmethyl-3H-pyrido / 3 ·, 2 ': 4,57pyrrolo / 3,2-g-jindolizin-3-one in 200 ml of dry THP. Refluxing and stirring is continued for 2 hours and the reaction mixture is cooled as soon as 10 ml of an η NaOH solution are carefully added with vigorous stirring. The mixture is filtered and the particulate matter is carefully washed with boiling THP. The solvent is removed from the combined THP units and a residue is obtained which is dissolved in methanol and acidified with excess isopropanolic hydrogen chloride. Dilution of the acidified methanolic solution with acetone and cooling results in a crystalline powder substance. Recrystallization of this material from methanol / acetone (three times) gives 1.7 g of the compound mentioned in the title as the dihydrochloride salt, Pp = 180-282 °; S _max (KBr): 2.99, 4.02ju; NMR (dDMSO): 6 2.02 (singlet, 11b-methyl) ppm; * max ^ ⁹⁵ ^ ^Et0H ) ^: 223. (6 27 200), 290 (S 10 080) mju; EtOH): 244 (£ 1,280)

An aqueous solution of approx. 100 mg of the dihydrochloride salt in water is mixed with excess aqueous sodium hydroxide

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made basic and the solution extracted with ether. Tray washing with saline will be the essential extracts; concentrated to a volume of approx. 5 ml and cooled, wherein; after drying, 60 mg of the compound mentioned in the title are obtained, Pp = 200 °. This product is due to the melting point of the mixed melting point, dünnschichtchromatoj .graphischer comparisons and the IR, MR and ^UV-spectral data identical to that obtained by Method 1 diamine. ι

! Example 3

· - ■ ■

2,3,5,6,11,11b-Hexahydro-11,11b-dimethyl-1H-pyrido / "3 ', 2 ·: 4, 5j-

pyrrolo / ~ 5 _t 2-g7indolizine

Method 1:

; To a solution of 8.1 g of 1,2,5,6,11,11 b-hexahydro-11 b-methyl-3H-pyrido / 3 ', ² ': 4,5jpyrrolo / ~ 3,2-g_7indolizine-3 One in 100 ml of dry dimethylformamide (DMP) is added 1.8 g of an approximately 50% sodium hydride mineral oil dispersion and the mixture is stirred for one hour. 4.76 g of methyl iodide in 10 ml of dry DMP are added, the mixture is stirred for a further 2 hours and then the mixture is freed from solvent (in vacuo). A solution of the residue in dilute aqueous hydrochloric acid is washed with ether and the acidic solution is then made strongly basic and extracted with chloroform. The chloroform extracts are washed with brine, dried over magnesium sulfate and then the solvent is evaporated off. The resin residue is dissolved in a small amount of methanol, an excess of isopropanolic hydrogen chloride and ether are added, whereby a salt is precipitated, which is recrystallized from methanol and 3.8 g of 1,2,5,6,11,11b-hexahydro -11,11b-dimethyl-3H-pyridoZ3 ', 2': 4,5jpyrido / 3,2-g7indolizin-3-one gives as the hydrochloride salt, which has 0.25 molecules of water per molecule of aminoamide hydrochloride, Pp = 272-275 °; ^ _ _βΫ (KBr): 2.96, 4.42, 5.91 µ; NMR (dDMSO): δ 1.62 (singlet, '11b-methyl), 3.90 (singlet, 11-methyl), 4.30 (multiple, ”C-5 proton) ppm.

' ^2ß "30 9 8Λ6 / 1 152

0.93 g of sodium methylate are added to a solution of 5 »0 g of 1,2,5,6,11,11 b-hexahydro-11,11 b-dimethyl-3H-pyrido / 3 ', 2 ·: 4.57 -pyrrolo / ~ 3.2-g3ndolizin-3-one hydrochloride, 0.25 hydrate, in 150 ml of hot methanol and frees the mixture from solvent and carefully dries the residue. The solid substance, suspended in 100 ml of dry THF, is slowly added to a stirred, refluxing suspension of 2.5 g of lithium aluminum hydride in 100 ml of dry THP. After refluxing for 2 hours, the reaction mixture is cooled, carefully treated with 12.5 ml of an η NaOH solution and filtered. The solid is carefully washed with boiling THP and the solvent is removed from the combined THP fractions. Dissolving the residue in ether and adding an excess of isopropanolic hydrogen chloride gives a precipitate which is isolated and recrystallized from methanol, giving 2.50 g of the compound named in the title as the dihydrochloride salt, decomposition at 305 °; £ _max (KBr): 4.17, 490/1; NMR (dDMSO): δ 1.98 (singlet, 11b-methyl), 3.87 (singlet, 11-methyl) ppm., & _MöY ($ 95 EtOH): 225.5 (£ 25,600), 290 (E. 8,970) mja; <S _min (95% EtOH): 248 (£ 660) mja.

Method 2:

To a solution of 1.4 g of 2,3,5,6,11, Hb-hexahydro-Hb-methyl, iH-pyrido / 3 ', 2 ¹ : 4,5jpyrroloZ3,2-g7indolizine (see Example 2) in 20 0.33 g of an approximately 5% sodium hydride mineral oil dispersion is added to ml of dry DMP and the reaction mixture is stirred for 1 hour (under N ₂ ). 0.96 g of methyl iodide is added and stirring is continued for an additional hour. A few drops of glacial acetic acid are added and the DMP is removed in vacuo. After dissolving in dilute aqueous HGl, the residue is washed with ether and the acidic solution is made strongly basic and extracted with ether. Washing the essential extracts with salt solution, drying (MgSO.) And removing the solvent gives 1.05 g of the compound named in the heading as a resin; NMR (CDCl3): θ 1.60 (singlet, 11b-methyl),

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3.85 (singlet, 11-methyl) ppm; ^ _ma _ (95 ^ EtOH): 230 (£ 24,850),

Max

max 292 (£ 8 610) VLJXIh _101n (95 $ EtOH): 250 (£ 900) mja.

A 0.9 g portion of the oMgen base is added to 50 ml of ether treated with an excess of isopropanolic HCl. That so formed salt is washed with ether and carefully dried, this gives 0.65 g of the compound mentioned in the title as the dihydrochloride salt, decomposition at 305 °. Based on IR, NMR and UV spectral comparisons, the product is the same as that prepared according to method 1 above Salt.

Example 4

; 11-ethyl-2,3,5,6,11,11b-hexahydro-11b-methyl-iH-pyrido / 3 ', 2': 4.57-.

! pyrrolo / 3.2 -g indolizine __

: '3.2 g 2,3,5,6,11,11b-hexahydro-11b-methyl-iH-pyrido / 3', 2 ^l : 4.57-

\ pyrrolo / 3.2-g_7indolizin are about 50% with 0.76 g

! Sodium hydride mineral oil dispersion and 2.44 g ethyl iodide

I ethylated as in Example 3, Method 2, described. the

i Benzene extracts of the basic aqueous fraction are mixed with

j brine, dried (magnesium sulfate) and on

j a 100 g column of neutral alumina of activity

j III given. The column 3/7 ether / benzene is eluted and

j holds 2.2 g of the compound named in the heading as

I resin; KMR (CDGl ₃ ) s 8 1.48 '(triplet, J = 7 Ha) and 1.59 (singlet),

^: Overlap (IT-CH ₂ CH ₃ and Hb-GH ₃ ), 4.33 (quartet, 3 = 7 Hz),

; N-CH--) ppm. ~ ™ "

■ A 2.0 g portion of the above base is mixed with isopropanolic

; Treated hydrogen chloride, recrystallization of the so formed

^: Salt from acetonitrile gives 0 ^ 65 g of the title compound as a di

I hydrochloride salt, decomposes at 244 - 246 °.

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Example 5

11 b-ethyl-1,2,5,6,11,11 b-hexahydro-3H-pyrido / 3 ', 2': 4,57pyrar.olo- /3.2-g7indolizin-3-one _ ■

Butylcellosolv (100 ml), 16.12 g of 7-azatryptamine, and $ 15.62 4-0xohexanoic acid become with removal of the volatile constituents heated to a distillation temperature of approx. 170 is reached and the solution is then refluxed for 19.5 hours. After removing the solvent (im Vacuum) remaining resin is dissolved in dilute aqueous HCl, washed with ether and with excess aqueous sodium hydroxide precipitated again. Extract the precipitate with methylene chloride, wash the organic solution with water, dry (sodium sulfate) and remove the solvent yields 24.75 g of brown foamy resin.

The aforementioned resin (24.55 g), 200 ml of isopropanol and 100 ml of an approximately 2.57 η isopropanolic hydrogen chloride solution are refluxed for 16 hours, the solvent is removed and the residue is dissolved in water. After washing with ether, the acidic aqueous solution is made basic with aqueous sodium hydroxide and with methylene chloride extracted. The organic extracts are washed with water, dried (sodium sulfate) and the solvent is removed removed. A leathery yellow pest substance, 21.05 g, remains, which is dissolved in chloroform and over a 600 g Column of neutral alumina of activity III is sent. Recrystallization (ethyl acetate) from the chloroform eluates isolated yellow powdery substance yields 14.02 g of crude product, Pp = 197-199 °. A 400 mg portion is made from ethyl acetate recrystallized, 326 mg of the title compound are obtained,

° _{max 3}

δ 1.08 (iriplet, J = 7 Hz, -CH ₂ CH ₃ ), 4.62 (multiplet, C-5 proton)

Pp = 198.0 - 200.5 °, * _max (KBr): 3.30, 5.99 μ \ NMR (CDCl ₃ ):

₂₃
ppm. '""""

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Treating 2.55 g of the above base (Pp = 197-199 °) in . 30 ml of dry THF with 1.J6 g of maleic acid in 15 ml of dry THP and dilute the resulting solution with 200 ml of ether, a salt is obtained in this way, which is crystallized twice (ethyl acetate) to give 2.30 g of the title compound as a 1: 1 maleate salt, Decomposition at 143 - 145 °.

Although the product named in the heading is from the original foamy resin can be isolated, the yield is determined by treating this material with isopropanolic Hydrogen chloride isopropanol increased.

Example 6

11 b-ethyl-2,3,5,6,11,11 b-hexahydro-1 H-pyrido / 3 ', 2: 4,57pyrrolo- / 3,2-gjlnaolizine -

A solution of 9.72 g of 11b-ethyl-1,2,5,6,11,11b-hexahydro-3H-pyrido / 3 is added to a refluxing suspension of 2.89 g of lithium aluminum hydride in 75 ml of dry THi ^{1 I} , 2 ': 4.5 / pyrrolo / 3.2-g / indol-3-one in 125 ml of dry THP. After stirring and refluxing for 2 hours, the reaction mixture is cooled and carefully decomposed with 15 ml of NaOH and filtered. The pest substance is carefully washed with warm THP and the organic fractions are freed from solvent. A residue remains, which is dissolved in dilute aqueous HGl, washed with ether and reprecipitated with excess aqueous sodium hydroxide. The precipitate is extracted into methylene chloride, washed with water and then dried (sodium sulfate). The solvent is removed and 8.73 g of gray-white pest substance are obtained. A 6.89 g portion of this material is purified by chromatography on a 150 g column of neutral aluminum oxide of activity level III. 5.97 g of crude product, pp = 208-211 °, are isolated from the 1/9, 1/4 and 1/1 chloroform / benzene eluates and the early Chldroform eluates. Two um-

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Si

A 3.0 g portion of the product is crystallized from ethyl acetate yields 2.53 g of the title compound, Pp = 209-211 °, ^h max ^{(KBr): 5 '30} ^

Analysis for C ₁₅ H ₁₉ IT ₅ ? Calculated: C, 74.65; H, 7.94; N, $ 17.41

Found: C, 74.52; H, 8.06; N, $ 17.74.

1 g of the above base (Pp «= 208-211 °) is treated in acetone with an excess of isopropanolic hydrogen chloride and then with ether. The white pest substance which separates out is recrystallized from methanol / acetone and represents a salt, decomposition at 218 - 248, which, based on the elementary analysis, 0.5 molecules "water and 1.9 molecules hydrogen chloride per molecule in de:
3.00, 4.08 / i.

B e is ρ iel

kül contains the base named in the heading. / S "(KBr):

Max

11b-ethyl-2,3,5,6,11,11b-hexahydro-11-methyl-iH-pyrido / 3 ', 2': 4,57pyrrolo / 3,2-g7indolizine

5.31 g of 11b ~ ethyl-2,3,5,6,11,11b-hexahydro-iH-pyridoZ3 ^l , 2 ^l : 4,57-pyrrolo / 3,2-g_7indolizine in 100 ml of dry DMP are mixed with 1, 06 g of an approximately 50% sodium hydride mineral oil dispersion and 3.44 g of methyl godide according to Example 3, Method 2, methylated, giving 5.26 g of crude base as a yellow oil from the methylene chloride extracts of the basic aqueous solution. Chromatographic purification of the amine on a 150 g column of neutral aluminum oxide of activity level III gives 4.81 g of the title compound as a pale pink oil from the benzene eluates, HMR (CDCl ₃ ): 8 0.99 (triplet, J = 7 Hz, -CH ₂ CH ₃ ), 3.85 (singlet, 11-methyl) ppm. "-"

A 4.38 g amount of the above base dissolved in 100 ml of acetone, is treated with an excess of isopropanolic hydrogen chloride. Three times recrystallization of the so formed

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sz

Salt from methanol / acetone gives 2.72 g of the title compound as Dihydrochloride salt, decomposes at 263 - 265 ° (softening at 250 °). '

Example 8

2,3,6,7,12,12b-hexahydro-12b-methyl-pyrido / ~ 3 », 2 ': 4,57pyrrolo- / 2,3-α7-quinolizin-4 (1H) -one

A solution of 7-azatryptamine (3.2 g), 2-0xo-6-methyl-2,3-dihydropyran / ~ 2.4 g, b.p. 50-54 ° / 1.5 mm, P. Shiroyan, et al., arm. Khim. Zh., 1967 , 649;: OA, £ 9, 987 (1968) 7 and 68 ml IHP is refluxed for 2 hours, concentrated to a volume of about 35 ml, cooled and diluted with 100 ml of ether. The powder substance which separates out is recrystallized from benzene and gives 2.4 g of 5-oxo-N- / 2- (1H-pyrrolo / 2,3-b / pyridin-3-yl) ethyl / hexanamide, melting point 114 °, ^ _mQY (KBr): 3.04, 3.27, 5.83, 6.12 µ.

λ ΧΩ. QA

NMR (CIXJl ₃ ): 0 2.02 (singlet, -CCJCH ₃ ), 6.30 (multiplet, amide-NH, exchangeable) ppm. ~ "~~

Isopropanol (450 ml), 35.0 g of 5-0xo-N- / 2- (1H-pyrrolo / 2,3-b7-pyridin-3-yl) ethyl7hexanamide and 70 ml of approx. 2.57 η isopropanolic hydrogen chloride are combined Refluxed for 4 hours. After concentration to a volume of approx. 270 ml and cooling to -10 ° overnight, the light brown powdery substance is isolated and dried, 30.3 g of crude salt being obtained, Pp => 300 °. A 3.5 g portion of this material is recrystallized from ethanol and thus gives 2.8 g of the title compound as the hydrochloride salt, Pp => 300 °, h _max (ICBr) % 3.33 sh, 3.72 br, 6.12ju; M (d _g DMSO and D ₂ O): S 1.80 (singlet, 12b-methyl), 5.02 (multiplet, C-6 proton) ppm.

A 300 mg serving of the above salt is added to excess water Sodium hydroxide made basic. The base is extracted into methylene chloride, washed with water, dried (Sodium sulfate) and the solvent is evaporated. A -

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AHP-5740

cream-colored residue * "remains, Pp = 222 - 224 °, er is recrystallized from ethyl acetate and gives 192 mg Title compound, m.p. 234-237 °.

Example- 9

1,2,3,4,6,7,12,12b-octahydro-12b-methylpyrido / 3 ', 2 ¹ : 4,57 pyrrolo ~ / 2,3-α7quinolizine

Reduction of 5.0 g 1,2,3,4,6,7,12,12b-0ctahydro-12b-methylpyrido / "3 ' , 2 ': 4.5 / pyrrolo / 2,3-a / quinolizin-4 (1H) -one at 2.0 g Lithium aluminum hydride in 350 ml dry THP according to the example 2, method 2, gives 5.1 g from the tetrahydrofuran fraction ($ 108) crude product, Pp = 156 - 158 °. A 4.5 g portion of the product is dissolved in methanol / ether with an excess of isopropanol Treated hydrogen chloride. Successive TJ crystallizations of the salt from isopropanol, methanol / ether, nitromethane and methanol / acetone (twice) give 1.2 g of the title compound as a dihydrochloride salt, which contains 0.5 molecules of water per molecule of dihydrochloride, melting range 215 - 245 °.

A 400 mg portion of the crude product (Pp = 1 (56-158 °) is recrystallized from ether and gives 0.25 g of the title compound, Pp = 161-162 °, X _max (KBr): 3.25 br u.

Analysis for C ₁₅ H ₁₉ N ₃ : Calculated: C, 74.65; H, 7.94; N, $ 17.41

Found: C, 74.57; H, 8.13; N, $ 17.22.

Example 10

1,2,3,4,6,7,12,12b-octahydrO-12,12b-dimethylpyrido / 3 ', 2': 4,57- pyrrolo / 2,3-a / quinolizine

The methylation of 2,4.g 2,3,6,7,12,12b-hexahydro-12bmethylpyrido / "3 ', ² ': 4,57pyrrolo / 2,3-a / quinolizine (2.4 g) in 40 ml of dry DMP with 0.53 g of an approximately 50% sodium hydride mineral oil dispersion and 1.44 g of methyl iodide is carried out according to Example 3, Method 2. The benzene extracts of the basic

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aqueous fraction are washed with salt solution and placed on a 75 g column of neutral aluminum oxide of activity level III. The column is eluted with 3/25 ether / benzene, this gives 2.0 g of the title compound as an oil, NMR ((IDCl ₃ ): (f 1.49 (singlet, 12b-methyl), 3.96 (12- Methyl) ppm.

A 1.9 g portion of the above base is treated with an excess of isopropanolic hydrogen chloride. Recrystallization of the ethanol salt thus formed gives 1.7 g of the title compound as the dihydrochloride salt, decomposition at 288 °.

Example 11

2,3,6,7,12,12b-hexahydro-12,12b-dimethylpyrido / 3 ', 2': 4,57- pyrrolo / 2,3-α7-quinolizin-4 (iH) -one

A solution of 2.5 g of 2,3,6,7,12,12b-hexahydro-12b-methylpyrido / f3 ^f , 2 '^^ pyrrolo / S, 3- ^ quinqlizin-4 (1H) -one in 36 ml dry DMF is methylated according to Example 3, Method 1, with 0.53 g of an approximately 50% strength sodium hydride mineral oil dispersion and 1.42 g of methyl iodide. The benzene extracts of the basic aqueous fraction are .man, after washing with salt and after drying with magnesium sulfate, on a 75 g column of aluminum oxide of activity level III. The column is developed with 3/20 ether / benzene and gives 1.2 g of the title compound, mp = 159-160 °.

If 1.1 g of the above base is treated in ether with an excess of isopropanolic hydrogen chloride, a salt is obtained which, recrystallized from Mtromethane, gives 0.7 g of the title compound as the dihydrochloride salt, mp = 253 °, ^ _max (KBr): 4, 54, 6.11 sh, 6.15 yes; MR (dDMSO): 8 1.78 (singlet, 12b-methyl), 4.11 (singlet, 12-methyl), 4.95 (multiplet, C-6 proton) ppm.

Example 12

1,2,3,6,7.8a-Hexahydr o-8a-methylindolizin-8 ("" 5H) -one

Toluene (200 ml), 4.1 g sodium methylate and 16.0 g 2-carboxy-2-methyl-1-pyrrolidine butyric acid dimethyl ester will be 3 hours

- 34 - -309846/1 152

■ AHP-'J74O

long reflux. · The mixture is extracted with water and the combined aqueous extracts are concentrated with HCl adjusted to pH 1. After 3 hours of heating at approx. 100 °, the acidic solution gives a positive iron (III) chloride test. The heating is therefore continued for a further 10 hours, after which the reading is negative. The solution becomes Ms. evaporated to a small volume and treated with an excess of sodium carbonate and ether. The ether phase becomes separated and the residue is carefully triturated with ether. After drying (MgSO.) The combined ethereal fractions are freed from solvent and the oil residue is distilled, giving 4.4 g of 1,2,3,6,7,8a-hexahydro-8a-methylindolizin-8 (5H) -one obtained, Kp - 115 - 119 ° / 22 mm; ^ (PiIm): 5.83 ju; EMR (CDCl,): So, 95 (singlet, 8a-methyl) ppm.

Example 13

2,3,5,6,11,11b-hexahydro-11b-methyl-11-propyl-IH-pyrido- / 3 '. 2 ': 4,57 pyrrolo / 3,2-g7 indolizine _; .

Propylation of 6.82 g of 2,3,5,6,11,11b-hexahydro-11b-methyl-1H-pyrido / T3 ', ² '! 4,57pyrrolo / 3,2-g7indolizine in approx. 100 ml of dry DMF with 1.59 g of 50% sodium hydride mineral oil dispersion and 7.07 g of n-propyl p-toluenesulfonate according to Example 3, Method 2, 7.2 g of crude product are obtained from the benzoil extracts of the basic aqueous fraction. Purification of the product on a 240 g aluminum oxide column (neutral, activity III), gives 4.99 g of the title compound as a pale pink resin from the benzene eluates, BMR (CDCl,): S 1.03 (! Triplet, J = 7 Hz, -CH ₂ CH ₃ ), 1.58 (singlet, 11b-methyl) and 4.17 (multiplet, 11-methylene) ppm.

The above base is dissolved in acetone with an excess of isopropanol Treated hydrogen chloride. Two recrystallizations of the salt thus formed from methanol / acetone give 2.99 g Title compound as the dihydrochloride salt, solvated with a

- 35 -

09H46 / 1152

AZP-5740

Third molecule of water per molecule of dihydrochloride, decomposition at 232.5 - 239.5 ° (softens at 227 °), A. (EBr): 2.95,

Max

4.22, 4.40, 6.15 ju.

Example 14

11-Allyl-2,3,5,6,11,11b-hexahydro-11b-methyl-iH -pyrido- [V , 2 '; 4,5 / pyrroloZ3,2-g7indolizine

Allylation of 2,3,5,6,11,11b-hexahydro-11b-methyl-1H-pyrido- / 3 ', 2': 4.57ρ7ΓΓθ1ο / 3.2 ^ 7ΐηάο1ίζίη (5.69 g) in approx. 100 ml dry DMF with 1.32 g of an approx. 50% sodium hydride mineral oil dispersion and 3.33 g of allyl bromide according to Example 3, Method 2, results from the methylene chloride extracts of the basic aqueous fraction 5.61 g resinous amine, which is purified on a 200 g aluminum oxide column (neutral, activity III) will. The 1: 1 benzene / hexane and benzene eluates become 3.03 g of title compound isolated as a resin, £ _, _ "(film): 6.13,

. Max

10.94 yes; NMR (CDGl ₃ ): -8 1.55 (singlet, 11b-methyl), 4.95 (multiplet, 11-1T-CH ₂ - and -CH = CH ₂ protons) and 6.05 (multiplet, 11-1T -CH ^ CH = CH ₂ ProTön) ppm.

If 2.83 g of the above base is treated in acetone with an excess of isopropanolic hydrogen chloride, a salt is obtained which, recrystallized twice from ethanol, gives 2.12 g of the title compound as the dihydrochloride salt, solvated with one third molecule of water per molecule of dihydrochloride, decomposition at 239 - 242 ° (er \ feicht at 230 °), ^ _max (KBr): 2.93, 6.11, 10.60 μ.

Beis piel 15

11.11 b-diethyl-2,3,5,6,11,11 brhexahydro-iH-pyr.ido- / 3 ', 2 ·.: 4,57-

pyrrole o ^ 3 _t 2-g7indolizine ___._ "__ __

Ethylation of 11-ethyl-2 ₉ 3 ₉ 5,6,11, Hb-hexahydro-1H-pyrido- / 3 ', 2': 4,57pyrrolo / 3,2-g7indolizine (5.31 g) in about 110 ml of dry DME with 1.16 g of an approx. 5% sodium hydride

309B46 / 1152

* ΑΗΡ-5740

Mineral oil dispersion and 3.77 g of ethyl iodide according to the method of Example 3, method 2, results from the benzene extracts of the basic aqueous fraction, a yellow oil, which on a 200 g aluminum oxide column, neutral, activity level III, purified will. 4.81 g of crude product are isolated from the benzene eluates as a pale pink pest substance. Pp = 80.0-83.5 °.

A 500 mg portion of the crude product is distilled at 92-99 ° / 10 "" mm and gives 438 mg of white title compound, Pp = 80.5-83.0 °, NMR (CDCl ₅ ): 60.98 (triplet, J = 7 Hz, Hb-CH ₂ CH ₅ ), 1.45 (triplet, J = 7 Hz, -N-CH ₂ CH ₅ protons) and 4.28 (multiplet, 11-methylene) ppm.

Treating 4.17 g of the crude product (Pp = 80.0-83.5 °) in Acetone with an excess of isopropanolic hydrogen chloride and the salt obtained is crystallized out twice Methanol / acetone in order to obtain 3.43 g of the title compound as Dihydrochloride, decomposes at 237-242 ° (softening at 215 °).

Example 16

11b-ethyl-1,2,5,6,11,11b-hexahydro-11-methyl-3H-pyrido / 3 ', 2': 4.57.pyrrolo / "3« 2-pL / indolizin-3-one

According to example 3, method 1, 11b-ethyl-1,2,5,6,11,11b-hexahydro-3H-pyrido / 3 ', 2': 4,5_7pyrrolo / ~ 3,2-g_7indolizin-3-one (2.04 g) in approx. 60 ml of dry DMP with 0.42 g of a 50% sodium hydride mineral oil dispersion and 1.25 g of methyl;) odide methylated. The benzene extracts of the basic aqueous fraction are washed with water and brine and dried over sodium sulfate. The solvent is removed and 2.00 g of yellow resin is obtained, which is purified on a 70 g aluminum oxide column (neutral, activity III). From the 1/4 and 1/1 chloroform / benzene eluates, 1.77 g of the title compound are isolated as a colorless glassy mass, ^ _max (KBr): 5.96 ju. NMR (CDCl ₅ ): 6 0.98 (triplet, J = 7 Hz, Hb-CH ₂ CH ₅ ), 3.83 (singlet, 11-methyl) and 4.50 (multiplet, C-5 proton) ppm .

- 37 -

3 Q y η 4 fi / 1 1 S 2

3 * AHP-5740

If the above base (1.63 g) is treated with an excess isopropanolic hydrogen chloride, then one obtains "with twice Recrystallization from methylene chloride / acetone 1.18 g Ϊ it elver connection as the hydrochloride salt, decomposition at 264 - 267 °

Example 17

12-ethyl-1,2,3,4,6,7,12,12b-octahydro-12b-methylpyrido / 3 ^! .2 '; 4, 5 / pyrrolo ^ "2 _t 3-a7ohinolizin

2.41 g of 1,2,3,4,6,7,12,12b-octahydro-12b-methylpyrido / 3 ', 2': 4,57-pyrrolo / 2,3-a7-quinolizine in 36 ml of dry DMP are mixed with 0.53 g of sodium hydride mineral oil dispersion and 1.7 g of ethyl iodide in 5 ml of dry DMi ¹ according to Example 3, Method 2, ethylated. The benzene extracts of the basic aqueous fraction are washed with salt solution and placed in an 80 g aluminum oxide column (neutral, activity III). 1.6 g of the title compound, mp = 80 °, HMR (CDGl ₅ ): S 1.45 (singlet, 12b-methyl) and 430 (multiplet, 12 N-CH ₂ -) ppm are isolated from the benzene eluates.

A 1.5g serving of the above base is added to the hydrochloride salt transferred, obtained after recrystallization from acetonitrile 0.8 g of the title compound as the dihydrochloride salt, pp = 232 234 °.

Example 18

12-allyl-1,2,3,4,6,7,12,12b-octahydro-12b-methylpyrido / 3 ', 2': 4,5-7pyrroloZ2,3-a7quinolizine

Following the procedure of Example 3, Method 2, 4.5 g 1,2,3,4,6,7,12,12b-octahydro-12-methylpyrido / 3 ', 2': 4,57pyrrolo- / 2,3-α7-quinolizine in 70 ml of dry DMP with 0.98 g of 50% sodium hydride mineral oil dispersion and 2.37 g of allyl bromide in 5 ml of dry DMP reacted. See the chloroform extracts of the basi- aqueous solution are washed with brine, dried (magnesium sulfate) and freed from solvent.

- 38 -

■ 30 il 846/1152

AHP-5740

Chromatographic purification of the residue on a 150 g aluminum oxide column (neutral, activity III) gives 2.9 g titanium compound as resin, MR (CDCl,) S 1.48 (singlet, 12b-methyl), 5 from the benzene eluates , 02 (multiplet, N-CH ₂ - and -CH = CH ₂ ), 6.02 (multiplet, N-CH ₂ CH = CH ₂ ) ppm.

Conversion of 2.8 g of the above base to the hydrochloride salt and recrystallization of the crude salt from methanol / acetone gives 1.6 g of T it el compound as dihydrochloride salt, solvated-with 1/4 molecule of water per molecule of salt, Pp = 233 - 235 ° k (KBr): 2.95, 6.13, 10.65 Ji.

Example 19

1,2,5,6,11,11b-hexahydro-11b-propyl-3H-pyrido / 3 ^! , 2 ·: 4.57- l ^ 327idlii3

Butylcellosolv (500 ml), 40.32 g 7-azatryptamine and 38.92 g 4-oxoheptanoic acid / cf. US Pat . No. 2,577,133 (CA 46, 6147h), also TM Patrick, J. Org. Chem., J ^, 1009 (Ί952) 7 are reacted and purified according to Example 5. The product isolated after the chromatography (47.9 g) is recrystallized from ethyl acetate and gives 47.55 g of the title compound, Pp = 180.5 to 184.0 °, (S _max (KBr): 3.12.5 , 98 ju, BMR. (CDCl ₃ ): 6 0.90 (triplet, J = 6 Hz, Hb-CH ₂ CH ₃ ), 4.55 (multiplet, C-5 proton) ppm.

A solution of 4.04 g of the above base in dry THP is added to 1.74 g of pumaric acid in the same solvent. Subsequent Addition of ether and cooling gives a salt which recrystallizes from ethyl acetate (twice) and from ethyl acetate / ether 1.11 g of the title compound is obtained as the monofumarate salt, decomposition at 164.5-167.0 °.

Example 20

1,2,5,6,11,11b-Hexahydro-11-methyl-11b-propyl-3H-pyrido / 3 ', 2':

4,5. / Pyrrolo / 3 »2-g7inolizin-3-one

According to Example 3, method 1, 1,2,5,6,11,11b-hexahydro-11bpropyl-3H-pyrido / 3 ^I , 2 ^l : 4,57pyrrolo / 3,2-g7indolizin-3-one (8, 08 g)

~ ³⁹ "3is ■ ·. ■■ U. Y 1 1 5 2

AHP-5740

232152Q

methylated in 75 ml of dry DMP with 1.58 g of a 50% sodium hydride mineral oil dispersion and 4.68 g of methyl iodide. The benzene extracts of the basic aqueous solution are washed with water and brine and dried (sodium sulfate). The resin (8.5 g) remaining after removal of the solvent is purified by chromatography on 250 g of neutral aluminum oxide (activity III). 6.70 g of the title compound are isolated as a colorless resin from the 1/4 chloroform / benzene and 1/1 chloroform / benzene eluates, ^ _max (CHCl. *): 6.02 ju; HMR (CDCl ₃ ): S 0.94 (triplet, J = 6 Hz, Hb-CH ₂ CH ₃ ), 3.85 (singlet, 11-methyl), 4.53 (multiplet, C-5 trotone) ppm .

If the above base (6.6 g) is treated in ether with an excess of isopropanolic hydrogen chloride, one obtains a salt which, when recrystallized twice from methylene chloride / acetone 5.11 g of the compound mentioned in the heading as HydroChloridsalζ results, decomposition at 253 - 256 ° (softens at 220 °).

Example 21

2,3,5,6,11,11b-hexahydro-11b-propyl-iH-pyrido / 3 ', 2 ·: 4,57- pyrroloZ "3,2-g7indolizine

The reduction of 21.55 g 1,2,5,6,11,11b-hexahydro-11b-propyl-3H-pyrido / 3 ', ^2I i4,57pyrroloZ3,2-g7indolizin-3-one with 6.07 g lithium aluminum hydride in 250 ml of dry THP is carried out as in Example 6. The pest substance isolated from the methylene chloride extracts is recrystallized from ethyl acetate and gives 16.8 g of the compound mentioned in the title, Pp = 146.0-148.5 °, MR (CDCl ₃ ) S 0.87 (! Triplet, J = 6 Hz, Hb-CH ₂ CH ₃ ) ppm.

A 5.11 g portion of the above base in dry THP is treated with an excess of isopropanolic hydrogen chloride and then treated with acetone. Two recrystallizations of the so formed

" ^40. " 3 0 ^ η α Β / 1 15 2

AHP-5740

Salt from methanol / acetone give those mentioned in the heading Compound as dihydrochloride, 1.55 g, decomposes at 251 - 261 ° (softening at 235 °) *

Example 22

2.3,5,6,11,11b-Hexahydro-11-methyl-11b-propyl-1H-pyrido- /3'.2 '; 4.5/pyrrolo/3,2-g7indolizine

The methylation of 2,3,5,6,11,11b-hexahydro-11b-propyl-1H-pyrido / 3 ¹ , 2 ': 4,57pyrrolo / 3,2-g7indolizine (7.66 g) in 125 ml of dry DMP with 1.59 g of 50% sodium hydride mineral oil dispersion and 4.68 g of methyl iodide is carried out as in Example 3, method 2. From the benzene extracts of the basic aqueous fraction, 6.65 g of brown resin are isolated, which is placed on a 350 g aluminum oxide column, neutral, activity III. Removal of the solvent from the 1: 1 benzene / chloroform eluate gives 6.22 g of the crude compound named in the heading as a colorless resin, NMR (GDCl ₃ ): S 0.87 (triplet, J = 6 Hz, Hb-CH ₂ CH ₃ ), 3.80 (singlet, 11-methyl) ppm.

A 6.12 g portion of the above base is dissolved in ether with a Treated excess of isopropanolic hydrogen chloride. The salt thus formed was recrystallized three times Methanol / acetone and from methanol / ether (addition of a small Amount of HCl gas to ensure complete salt formation) provides 2.28 of the compound named in the heading as dihydrochloride, decomposes at 247-252 ° (softening at 238 °).

Example 23

11-butyl-2,3,5,6,11,11b-hexahydro-11b-methyl-iH-pyrido / 3 ', 2': 4,57pyrroloZ3.2-gjindolizine

Butylation of 5.69 g 2,3,5,6,11,11b-hexahydro-11b-methyliH-pyrido / 3 ¹ ^ 2 ^f : 4,57pyrrolo / ~ 3,2-g_7indolizin in 100 ml dry DMP with 1, 32g of an approx. 50 $ strength sodium hydride mineral oil dispersion and 3.75 g of 1-bromobutane are carried out according to Example 3,

- 41 -

3 0 9 8 4 6/1152

AHP-5740

Method 2. A crude base (6.37 g) is isolated from the benzene extracts of the basic aqueous fraction and is purified on a 200 g aluminum oxide column, neutral, activity III. The resin eluted with benzene (3 * 41 g) is distilled, giving 2.7 "I g of the compound named in the heading as a viscous pale yellow oil, ^{b.p. 137-138 / 10 ~ 3} mm; KMR (GDCl ₅ ) : S 1.00 (triplet, J = 7 Hz, -CH ₂ CH ₃ ), 1.58 (singlet, 11b-methyl), 4.24 (multiplet, 11-methylene) "ppm.

A 2.14 g portion of the above base is made up with isopropanol in acetone Treated hydrogen chloride, then ether is added. Twice recrystallization of the so formed Salt of methylene chloride / acetone gives 0.63 g of the compound named in the title as the dihydrochloride salt, decomposition at 235 - 239 ° (softening at 210 °).

Example 24

2,3,5,6,11,1ib-hexahydro-11-isoamyl-i1b-methyl-iH-pyrido- / 3 ', 2'; 4,5 / pyrrolo / 5,2-g7indolizine

6.82 g 2,3,5,6,11, Hb-HexahydrO-Ib-methyl-IH-pyrido / 3 ¹ , 2 ': 4,57-pyrrolo / 3,2-g_7indolizine in 100 ml dry DMP with 1.59 g of 50% sodium hydride mineral oil dispersion and 6.54 g of 1-iodo-3-methylbutane according to Example 3, Method 2, alkylated. 8.4 g of crude base are obtained from the benzoil extracts of the basic aqueous fraction. Purification of this amine on a 250 g aluminum oxide column, neutral, activity III, yields 5.05 g of the compound named in the heading as a pink resin, IiMR (CDCl ₅ ) S 1.01 (doublet, J = 6Hz, - CH ^ § |), 1.59 (singlet, 11b-methyl), 4.23 (multiplet,

11-methylene) ppm. -— "---. ^ '· -.-- ■ ·· -

4.77 g of the above base are dissolved in acetone, and an excess of isopropanolic hydrogen chloride is added and then treated with ether, being a salt

- 42 -

309846/1152

AHP-5740

obtained, which is recrystallized twice from 2-propanol. A final recrystallization from acetonitrile gives 2.84 g of the compound named in the title as the dihydrochloride salt, solvated with 2/3 of a molecule of water per molecule of dihydrochloride, decomposition at 197 - 206 ° (softening at 182 °), Λ (KBr): 2.93, 4.01 u.

Iu cw * * *

Example 25

1-2,3,5,6,11,1ib-hexahydro-11,1ib-dimethyl-iH-pyrido / 3 ', 2 ·: 4,5 / pyrr οίο / 3,2-g_7indolizine dihydrochloride

A solution of 56.45 g of 2,3-dibenzoyl-2 (R): 3 (R) -tartaric acid monohydrate ff ° S7 ^ -114.7 ° (c = 1.028, methanol )] in 200 ml of warm (50 ° ) Methanol is mixed with a solution of 36.20 g of 2,3,5,6,11,11b-hexahydro-11,11b-dimethyl-1H-pyrido / 3 ^f , 2: 4.57pyrrolo / 3.2- treated g_7-indolizine in 100 ml of warm methanol (50 °). After inoculation, the mixture is kept at approx. 25 ° for 4 hours and at + 8 ° for 16 hours. The product is isolated and recrystallized three times from methanol, giving 29.59 g ($ 66) 1-2,3,5,6,11 ₁ , 11b-hexahydro-11,1 ib-dimethyl-iH-pyrido / 3 ¹ , 2 ": 4,57-pyrrolo / 3,2-; g7indolizine, 2,3-dibenzoyl-2 (R): 3 (R) -tartrate (1: 1), obtained, decomposition at 175.5-177, 0 °, M ^ -97.5 ° (c = 1.006, DMP).

The above-mentioned salt, 27.77 g, is suspended in 0.25 l of water, treated with 10 ml of a 50% (w / w) aqueous sodium hydroxide solution and the amine is extracted into ether. After washing in succession with water and with salt solution, the ethereal solution is dried over sodium sulfate and the solvent is removed, giving 10.67 g ($ 95) of 1-2,3,5,6,11,11b-hexahydro-11 , 11b-dimethyl-IH-pyrido / 3 ¹ , ²¹ : 4,57pyrrolo / ~ 3,2-g7indolizine as a black / ach yellow viscous oil, £ ocj ^ ⁶ = -115.8 ° (c = 0.9605, methanol ).

10.4-2 g of the aforementioned oily base are in 150 ml dissolved in absolute ethanol and with 40 ml 2.48 η isopropanoli-

- 43 -

3 (J ^f -! '^ B / .1 1 52

Schem hydrogen chloride is added, whereby a salt is obtained. The salt is recrystallized twice from methanol / acetone, giving 11.26 g ($ 83) of that mentioned in the title

Compound as a white residual substance, decomposes at 306.5 - 308.0 °, 26th

6 ₌ _82 _f 6 ° (c = 0.971, methanol).

Example 26

d-2,3,5,6,11,11b-hexahydro-11,1ib-dimethyl-iH-pyrido / 3 ¹ , 2 ': 4,57- pyrrolo / 3,2-g-7indolizine dihydrochloride

The residue isolated after evaporation of the methanolic mother liquor from which the crude left isomer has been separated off (see Example 25) is mixed with 400 ml of water - 20 ml of 50% w / w. aqueous sodium hydroxide - shaken and the released base is extracted into ether. After washing with water and brine and drying (sodium sulfate), the solvent is evaporated to give a brown oil. To remove non-basic impurities, the oil is dissolved in 200 ml η hydrochloric acid and the acidic solution is carefully washed with ether. The acidic solution is made basic and then extracted with ether, the ether extract is washed with water and with brine. After drying the ethereal solution (sodium sulfate) and removing the solvent, 17.84 g of crude right base are isolated as a brown resin, fccj ^ = + 89.00 ° (e = 1.002, methanol).

This resin (17.64 g) is added in 50 ml of methanol to a warm (^ 50 °) solution of 27.51 g of 2,3-dibenzoyl-2 (S): 3 (S) -tartaric acid monohydrate [βΰψ = + 115.7 ° (c = 1.025, methanol) 7 in 90 ml of methanol. After inoculation, the mixture is kept at + 5 ° for 22 hours. The salt is isolated and recrystallized three times from methanol, washing with small amounts of cold methanol and with ether after each recrystallization. 27.06 g ($ 60) of d.-2, 3, 5,6,11,11b-hexahydro-11,11b-dimethyl-1H-pyrido / 3 ', 2': 4, 57pyrrolo / 3, 2 are obtained -g7indolizine,

- 44 -

- '$ U ■ - ■'. ι 1 1 5 2

AHP-5740

2,3-Dibenzoyl-2 (S): 3 (S) -tartrate (1: 1), decomposition at 176-177 ° ¹ ^ ₊ 99.O ° (c = 1.026, DMF).

25.34 g of the above-mentioned salt are, as described for the left isomer, (see Example 25) converted into the free base, giving 9.74 g (96%) d-2,3,5,6, 11,11b-hexahydro-11,1ib-dimethyl-IH-pyrido / 3 ¹ , 2 ·: 4,57pyrrolo / 3,2-g_7-indolizine as a pale yellow viscous oil, [° ΰ · ^ = + 115.5 ° (c = 0.992, methanol).

A 9.49 g portion of the abovementioned base in 150 ml of absolute ethanol is treated with 35 ml of 2.48 η isopropanolic hydrogen chloride. The solid substance formed is isolated and recrystallized twice from methanol / acetone, giving 9.97 g (81%) of the compound mentioned in the title, decomposition at 306.5 ° -308.0 °, / ^ ⁶ = +82.4 ° (c = 1.061, methanol).

Example 27

2,3,5,6,11, Hb-hexahydro-11,1 ib-dimethyl-iH-pyrido / 3 ¹ , 2 ": 4,57- pyrrolo / 3 _t 2-g_7indolizine

(a) Methylhydrazine (36.8 g) and 12.8 g of 2-bromopyridine are refluxed for 6 hours, then the reaction solution is concentrated to an oil at 50 ° in vacuo, with. Ice mixed and basified with 50% (w / w) aqueous sodium hydroxide solution. The mixture is extracted with ether, the extract is washed with brine and dried (MgSO.). The ether is removed and the residue is distilled, giving 4.9 g of N-methyl-N- (2-pyridyl) hydrazine, boiling point 74-76 ° / 3 mm, HMR (CpCl ₃ ): S 3.25 (Singlet, N-CH ₅ ) ppm.

G. Palazzo and L. Baiocchi / Ann. Chim. (Rome), j55, 935 (1965); Approx. , 63, 16335h (196,517 prepared N-methyl-N- (2-pyridyl) hydrazine with methyl! Augmentation of 2-hydrazinopyridine with methyl iodide and sodium hydride forth Kp "68 ° / 0.5 mm. ■

- 45 -

309846/1152

AHP-5740

(b) 146.1 g of 2-carboxy-2-raethyl-1-pyrrolidine-butyric acid dimethyl ester and 35.7 g of sodium methylate are reacted in 1.5 1 of toluene by refluxing for 5 hours, as in Example 12. After 20 hours has heated at about 100 °, the acidic aqueous solution is evaporated to dryness and the residue is extracted with methanol and filtered to remove insoluble constituents. The extract is freed from solvent and the residue is redissolved in methanol (200 ml), it is filtered and the filtrate is concentrated to a volume of about 150 ml. 450 ml of acetone are added, the mixture is cooled (+ 5 °) and, after careful drying, 58.2 g of 1,2,3,6,7,8a-hexahydro-8a-methylindplizin-8 (5H) -one hydrochloride, pp = 199 - 201 °, * _max (KBr): 4.02, 5.77 yes; NMR (dg-DMSO): 81.64 (singlet, 8a-methyl) ppm.

(c) 25 ml of absolute ethanol, 2.5 g of N-methyl-N- (2-pyridyl) hydrazine (see part (a) above) and 3.8 g of 1,2,3,6,7,8a- Hexahydro-8a-methylindolizin-8 (5H) -one hydrochloride are heated on the steam bath and the solution is adjusted to a pH of approx. 1 with isopropanolic hydrogen chloride. The solution is then heated on the steam bath with evaporation of the solvent and the resinous residue is dissolved in water. The aqueous solution is made basic with aqueous sodium hydroxide, then the mixture is extracted with chloroform, the organic extracts are washed with brine, dried (MgSO,) and freed from solvent, a liquid residue is obtained. Distillation of this material at 158 ° / 3 «10 ~ ⁵ mm gives 3.8 g of 1 ^^^, ^, Sa-methylindolizin-8 (5H) -one, N-methyl-N- (2-pyr.idyl-) hydrazone, NMR (CDCl ₃ ): S 1.33 (singlet, C-Me), 3.17 (singlet, N-methyl) ppm.

(d) ... A solution of 0.5 gi ^^ ö methylindolizin-8 (5H) -one, N-methyl-N-pyridylhydrazone in 7 ml diphenyl ether is refluxed for 30 minutes, cooled, with ether vthilute and with dilute aqueous hydrogen chloride

- 46 -

309846/1152

acid extracted. The acidic extract is used after washing made basic with ether with concentrated sodium hydroxide and the mixture is extracted with chloroform. After washing with saline and drying (MgSO-) the Chloroform solution freed from solvent and the residue chromatographed on 12 g of neutral aluminum oxide, activity III. 108 mg of resin are isolated from the benzene eluates, which is dissolved in ether and treated with an excess of isopropanolic hydrogen chloride. The so-formed plague substance is triturated with ether and carefully dried, 85 mg of salt are obtained, decomposition at 301 - 304 ° (softening at 298 °). The melting point, mixed melting point, thin-layer chromatographic, IR and NMR spectrographic Comparison with the product of Example 3, Method 1, shows that it is the dihydrochloride of the compound named in the title.

Example 28

1,2,5,6,11,11 b-Hexahydro-11 b-methyl-3H-pyrido / ~ 3 ·, 2 ': 4,57-pyrrolo- ^ 2-g-7-indolizine-3-thione

100 ml dirnethoxyethane, 2.4 g phosphorus pentasulfide and 2.4 g 1,2,5,6,11,11b-hexahydro-11b-methyl-3H-pyrido / 3 ', 2': 4,57 pyrrolo / 3,2-g7indolizin-3-one are refluxed for 4 hours. After cooling, dilute aqueous ammonium hydroxide is added added, the reaction mixture extracted with chloroform and washed the organic solution with dilute aqueous ammonium hydroxide, with brine and then dry (MgSO.). The dried chloroform solution is passed through a 100 g aluminum oxide column, neutral, activity III, skilful and eluted with chloroform, .this gives 2.3 g of pest substance. Recrystallization this material from methylene chloride / acetone gives 0.8 g of the compound named in the title, decomposition at 299-300 °.

- 47 -

3 π '/ 115?

AHP-5740

Analysis for C ₁₄ H ₁₅ N ₅ S:

Calculated: C, 65.34, H, 5.88; N, 16.33; S, 12.46%

Found: C, 64.98; H, 6.09; N, 16.05; S, 12.51%

0.7 g of the above product are treated in methylene chloride with an excess of isopropanolic hydrogen chloride, then if ether is added and a salt is obtained, which is recrystallized from methanol / acetone and 0.6 g in the title named compound results as the hydrochloride salt, decomposition at 300 ° (softening at 285 °).

Example 29

2,3,5,6,11,11b-Hexahydro-1ib-methyl-IH-pyrido / 3 ¹ , 2 ': 4,57- pyrrolo / 3i 2-g_7indolizine

1,2g 1,2,5,6,11,11b-hexahydro-11b-methyl-3H-pyrido / ~ 3 ·, 2'14,57-pyrrolo / 3,2-g7indolizine-3-thione are in 150 ml of absolute ethanol with 15 g (wet weight) Raney nickel (Grace Co. No. 28, previously with distilled water and then slurried with absolute ethanol) refluxed for 2 hours, then is filtered and the insoluble material washed with 100 ml of hot ethanol. The Ethanol Piltrates and Wash Solutions are combined, freed from solvent, the residue is dissolved in dilute aqueous hydrochloric acid and washed with ether. The acidic solution becomes basic made, then extracted with ether, the extracts are washed with brine and dried with magnesium sulfate. Evaporation of the solvent gives 0.6 g of solid substance, which is neutralized with chloroform through a 20 g aluminum oxide column, Activity III, is sent. The third substance isolated from the chloroform eluates is recrystallized from methylene chloride / ether and gives 0.2 g of solid substance, mp = 290 °. distance of the solvent from the methylene chloride / ether crystallization mother liquor gives a solid which is recrystallized twice from ether. The so isolated

- 48 - "■

3Ü- ··, 'λ / 1 1 5 2

AHP-5740

Compound which melts at 196.5 ° proves to be more IR and NMR spectroscopic on the basis of the melting point, the mixed melting point and Compare with the product of Example 2, * Method 1, as the amine mentioned in the title. In the Conditions used in Examples 28 and 29 are as described in U.S. Patent 3,454,583.

Example 30

2,3,5,6,11,11 b-Hexahydro-11,1ib-dimethyl-IH-pyrido / 3 ¹ , 2 ·: 4,57- pyrrolo / 3,2-gJft.ndolizine - 4-oxide

A solution of 2.41 g 2,3,5,6,11, Hb-hexahydro-11,11b-dimethyl-1H-pyridoZ3 ', 2': 4,57pyrrolo / 3,2-g7indolizine in 25 ml dry THP becomes stirred and kept at 0 °, a solution of 1.73 g of m-chloroperoxybenzoic acid in 25 ml of dry THi ^{1 being} added dropwise (5 minutes). After stirring for 0.5 hours at 0 °, 9.0 ml of a 2.3 η isopropanoli see hydrogen chloride solution are added and the mixture is stirred for a further 0.5 hours. 20 ml of acetone are added in order to promote the piltrability, the product is isolated, washed with acetone and dried. Two recrystallizations of the product from methanol give 1.7 g of the compound named in the title as dihydrochloride, decomposition at 270-278 °.

Example 31

11-Amyl-2,3,5,6,11,11 b-hexahydro-11 b-methyl-IH-pyrido / 3 ', 2 ·: 4, 5j pyrroloZ "3,2-g7indolizine

According to Example 3, Method 2, 6.82 g of 2,3,5,6,11,11b-hexahydro-11 b-methyl-1H-pyrido / 3 ·, 2 *: 4 _f 57pyrrolo / ~ 3.2- gjindolizine in 100 ml of dry DMP reacted with 1.59 g of a 50 # strength sodium hydride mineral oil dispersion and 4.99 g of 1-bromopentane. 8.2 g of viscous yellow resin are isolated from the benzoil extracts of the basic aqueous solution, which is chromatographed on a 250 g column of neutral aluminum oxide of activity III

309846/1152

: 30 AHP-5740

is cleaned. The solvent is removed from the benzene eluates and 4 »75 g of the compound named in the title are obtained as a pale pink resin, NMR (CDCl,): 0.93 (triplet, -CH ₂ CH ₅ ), 1.63 (singlet, 11b- Methyl),. 4.25 (multiplet, 11-methylene) ppm.

If a solution of 4.60 g of the above base in acetone is treated with an excess of isopropanolic hydrogen chloride and then ether is added, a salt is obtained which recrystallizes 3.04 g of the title compound as dihydrochloride, solvated with 1/4 molecule of water per molecule of dihydrochloride, gives, decomposition at 194-199 °, ^ _max (KBr): 2.92, 4.15 μ.

Example 32

The analgesic effectiveness of the compounds of the formula I can be demonstrated in rats using the following procedure:

Groups of at least 5 rats are used. Each rat is placed in such a position that a beam of high intensity light shines on the tip of its tail 3-8 seconds their tail removed from the beam. The mean of three measurements taken 10 minutes apart serves as a control. The test compound is then administered and reaction times are measured every 30 minutes for a two hour period Reaction time after drug administration is compared to that of the control mean by statistical analysis. Analgesic activity is indicated by the ability of the compound to prolong reaction time. EDc ₀ is defined as the dose of test material sufficient to produce a positive in the test animal Cause reaction.

- 50 -

309846/1152

<# AHP-5740

If one uses 2,3,5,6,11, Hb-hexahydro-11, Hb-dimethyl-iH-pyrido / 3 ', 2 ·: 4,5_7pyrrolo / ~ 3,2-g_7indolizine as dihydrochloride in the process described above, so an ED ₁ -Q of 0.09 mg / kg (PO) and 0.12 mg / kg (IM) is obtained; 2,3,5,6,11,11b-Hexahydro-11b-methyl-.iH-pyrido / 3 ^f , 2 ': 4,57pyrrolo / 3,2-g_7indolizindihydrochlorid has an ED ₅₀ of 6 mg / kg (PO) and 4.75 mg / kg (IM). In this test, morphine has an ED ₁ -Q of 10 mg / kg (PO) and 2.0 mg / kg (IM).

The following compounds exhibit analgesic activity intraperitoneal administration (there are no! fatalities determined) at the following doses:

Connection (a)
of example - Dose (mg / kg)
IP Reaction (b) 2 12.5 3/5 3 0.032 6/10 4th 0.78 5/10 6th 6.25 4/5 7th 6.25 5/5 13th 6.25 5/5 9 3.12 • 5/10 10 3.12 8/10 14th 1.56 5/5 15th 6.25 5/5 17th 6.25 10/10 18th 3.12 9/10 21 12.5 2/6 22nd 25th 6/6 23 6.25 5/5 24 ■ 6.25 5/6 26th 0.078 · ■ "■ 4/6" ■ "" " 25th 6.25 3/6, 4/6 30th 1.56
0.39 10/10
8/10 31 6.25 2/6 - 51 - 3 U y ^ n η / 1 1 5 2

: Remarks:

. ' (a) The compounds were prepared as salts which are described in the above ', examples tested.

. (b) number of rats showing positive reaction ; , Total number of rats in the 2nd group

■ When administered IP, morphine has an ED ₅₀ of 3.5 mg / kg

■ on.

Example 33

: An injectable solution is made up of the following formulation j made:

¹ 2,3,5,6,11,11b-hexahydro-11,11b-dimethyl-iH-pyrido 50 mg ^1/3 ', 2': 4,5vpyrroloZ3,2-g7indolizin dihydrochloride

; Sodium Acetate, Anhydrous 60.15 mg

! Phenol 50 mg

; Glacial acetic acid so much that pH 5

! Water for the injection so much that 50 ml

The phenol and the sodium acetate are dissolved in 40 ml of Viasser. Then the active ingredient is dissolved in the solution. The pH of the solution is adjusted with glacial acetic acid. After all, one gives so-

; add plenty of water for injection so that 50 ml of solution are obtained.

^! The solution containing 1 mg / ml drug is sterile filtered

■ and aseptically filled into sterile vials or ampoules.

Example 34

Tablets for oral use are made with the following formulation;

0.5 mg

: ^^, ejtiJib-Hexahydro-I ^ Ub-dimethyl-iH-pyrid / 3 ', 2': 4.5 / pyrrolo / ~ 3.2-g_7indolizine dihydrochloride

Microcrystalline cellulose, N.F. 30.0 mg

- 52 -

3 0 - ° -; ■ '. R / 1 1 5 2

SS

ÄHP-5740

Magnesium stearate, U.S.P. Amlaerlite, IRP 88 lactose

0.3 mg

1.0 mg

68.2 mg

100.0 mg

The components are mixed, ground, mixed again and pressed for iDabletten, which contain 0.5 mg of active ingredient.

- 53 -

309846/1 152

Claims (1)

OASE: AHP-5740 PAIEH CLAIMS Connections of the general formulas: and OH ₀ ) 2'n wherein X represents two hydrogen atoms or an oxo group; R is hydrogen, alkyl of 1-5 carbon atoms or allyl; R is methyl, ethyl or n-propyl; R denotes alkyl with 1-5 carbon atoms or allyl and η is 1 or 2; as well as their pharmacologically acceptable Acid addition salts. ....... Compounds according to claim 1 of the general formula: ~ ⁵⁴ ~ 309846/1152 AHP-5740 wherein R is hydrogen, alkyl with 1-5 carbon atoms or Allyl "means; R is methyl, ithyl or n-propyl and η stands for 1 or 2, as well as their pharmacologically acceptable ones Acid addition salts. 3. Compound according to claim 2, namely 2,3,5,6,11,11b-hexahydr0-11,11b-dimethyl-IH-pyrido / 3 ', 2 ·: 4,57pyrrolo / 3, 2-gI- indolizine as well as their pharmacologically acceptable acid addition salts. 4. Compound according to claim 3, namely d.-2,3,5,6,11,11b-hexahydro-11,11 b-dimethyl-IH-pyrido / 3 ·, 2 ·: 4,57pyrrolo / 3, 2- gJ- indolizine. 5. Compound according to claim 3, namely 3.-2,3,5,6,11,11b-hexahydro-11,1 ib-dimethyl-iH-pyrido / 3 ¹ , 2 ': 4,57pyrrolo / 3,2- g7 indolizine. 6. Compound according to claim 2, namely 2,3,5,6,11,11b-hexahydro-1 ib-methyl-iH-pyrido / 3 ¹ , 2 ¹ : 4,57pyrrolo - / * 3,2-g7indolizine. 7. Compound according to claim 2, namely 11-ethyl-2,3,5,6, -. 11,11 b-hexahydro-11 b-methyl-1H-pyrido / "3 ', 2': 4,57 pyrrolo / 3,2-g7-indolizine. 8. Compound according to claim 2, namely 11b-ethyl-2,3,5,6, -11,1 ib-hexahydro-IH-pyrido / 3 ¹ , 2 ·: 4,57pyrrolo / 3,2-g ^ .ndolizine . - 55 - 3 ü U : ^} / ß / 1 1 5 2 ■ AHP-5740 232152Q 9. A compound according to claim 2 which is 11b-ethyl-2,3,5, -6,11,11 b-hexahydro-11 -methyl-IH-pyrido / 3 ', 2': 4,57pyrrolo / ~ 3,2-g7-indolizine. 10. Compound according to claim 2, namely 1,2,3,4,6,7,12,12b-octahydro-12b-methylpyrido / 3 ', 2 · : 4,57 pyrrolo- / 2,3-a / quinolizine. 11. Compound according to claim 2, namely 1,2,3,4,6,7,12,12b-octahydro-12,12b-dimethylpyrido / 3 ^f , 2 ^f : 4-, 5jpyrroloZ2,3-a7quinolizine. 12. Compound according to claim 2, namely 11, 11b-diethyl-2,3,5,6,11,11b ~ hexahydro-iH-pyridoZ3 ', 2 ·: 4,57 pyrrolo- / 3,2-g_7-indolizine. ; 13. The compound of claim 2 which is 2,3,5,6,11,11b-hexahydro-11 b-methyl-11-propyl-iH-pyrido / 3 ', 2': 4, S / py ^ irolo- / 3,2-g7indolizine. ; 14. Compound according to claim 2, namely 11-allyl-2,3,5, -, 6,11,11 b-hexahydro-11 b-methyl-1 H -pyrido / 3 ', 2': 4,5-7 pyrrolo- / 3,2-g-jindolizine. ^: 15. Compound according to claim 2, namely 12-Ä-fchyl-i, 2,3, -; 4,6,7, .12,12b-octahydro-12b-methylpyridoZ3 ^l, 2 ': ^{4,5jpyrrolo-;} / 2,3-a / quinolizine. 16. Compound according to claim 2, namely 12-allyl-1,2,3, -4,6,7,12,12b-octahydro-12b-methylpyrido / 3 ', 2 ·: 4,57 pyrrolo- / 2,3-a7-quinolizine. 17. The compound of claim 2 which is 2,3,5,6,11,11b-hexahydro-1 ib-propyl-iH-pyrido / 3 ', 2': 4,5_7pyrrolo / 3,2-g_7indolizine. 18. Compound according to claim 2, namely 2,3,5,6,11,11b-hexahydro-11-methyl-1ib-propyl-iH-pyrido / 3 ', 2': 4, / 3,2-g7indolizine. " ⁵⁶ "'3098 46/1 1 5 2 19. The compound of claim 2 which is 11-butyl-2,3,5, -6,11,1 ib-hexahydro-11b-methyl-1H-pyrido / 3 ', 2': 4,57pyrr.olo- / 3,2-g7indolizine. 20. A compound according to claim 2 which is 2,3,5,6,11,11b-hexahydro-11-isoamyl-i1b-methyl-1H-pyrido / 3 ', 2 ¹ : 4,57 pyrrolo / 3,2-g-jindolizine . 21. Compound according to claim 2, namely 1 i-amyl-2,3,5,6, -11,1ib-hexahydro-11b-methyl-1H-pyrido / 3 ', 2': 4,57pyrrolo- / 3,2-g7indolizine. 22. Compounds of the general formula: wherein R is hydrogen or lower alkyl and B. is lower alkyl and η stands for 1 or 2, as well as their acid addition salts. 23. Compounds according to claim 22, namely 1,2,5,6,11,11b-hexahydro-11b-methyl-3H-pyrido / 3 ^f , 2 ·: 4,57pyrrolo / 3,2-g7indolizin-3-one. 24. Compound according to claim 22, namely 1,2,5,6,11,11b-hexahydro-11,11b-dimethyl-3H-pyrido / 3 ', 2': 4,57pyrrolo / 3,2-g7-indolizine- 3-on. 25. The compound of claim 22 which is 11b-ethyl-1,2, -5,6,11,11b-hexahydro-3H-pyrido / 3 ^l , 2 ': 4,57 pyrrolo / 3,2-gjindolizin-3-one . " ⁵⁷ " 309846/1152 AHP-5740 26. The compound of claim 22 which is 11b-ethyl-1,2,5,6,11,11 b-hexahydro-11 -methyl-SH-pyrido / ^ ', 2': 4,57pyrrolo- i. / 3,2-g_7indolizin-3-one. 27. Compound according to claim 22, namely 2,3,6,7,12,12b-Hexahydro-12b-methylpyridoZ "3 ' , 2 ': 4,57 pyrrolo / 2,3- $ 7-quinolizin-4 (1H) -one. . ' 28. Compound according to claim 22, namely 2,3,6,7 _f 12,12b-hexahydro- ^ j ^ b-dimethylpyrido / ^ ¹ , 2 ': 4,57pyrrolo / 2,3-a / quinolizine-4 ( 1H) -one. 29. The compound of claim 22, namely. 1,2,5,6,11,11b-Hexahydro-11b-propyl-3H-pyridoZ3 ' , 2 ': 4,57pyrrolo / ^,% gjindolizi 3-on. '. 30. Compound according to claim 22, namely 1,2,5,6,11,11b- Hexahydro-11 -methyl-11 b-propyl-3H-pyrido / 3 ·, 2 ·: 4,57pyrrolo-! / 3 _f 2-g7indolizin-3-one. ; 31. Compounds according to claim 1 of the general formula: wherein R is methyl, ethyl or n-propyl and R is alkyl with 1-5 Mean carbon atoms and η stands for 1 or 2, as well as their pharmacologically acceptable acid addition salts. 32. Compound according to claim 31, namely 2,3,5,6,11,11b- Hexahydro-11,11 b-dimethyl-iH-pyrido / 3 ', 2': 4,57pyrrolo / 3,2-gJZ-indolizine-4-oxide. " ⁵⁸ " 309846/115 2 S3 AHP-5740 33. Contains: fen * sWrcp A connection of the lOrmulas: and (ok ₂ ) _n .0 2'n wherein R is hydrogen, alkyl with 1-5 carbon atoms or Allyl means R is methyl, ethyl or n-propyl, R represents alkyl with 1-5 carbon atoms or allyl and η represents 1 or 2, or their pharmacologically acceptable Acid addition salts and a pharmaceutically acceptable carrier. 34. Means according to claim 33, containing 2,3,5,6,11,11b- Hexahydro-11,1ib-dimethyl-iH-pyrido / 3 ^1, 2 ': 4,5 / pyrrolo / 3,2-g J- indolizine. Agent according to claim 34 in the form of dosage units. 36. Process for the preparation of compounds of the general formulas: 2'n wherein X represents two hydrogen atoms or an oxo group; R is hydrogen, alkyl with 1-5 carbon atoms or allyl means; - 59 - 3 0: ■ - ■■ H / 1 1 5 2 R is methyl, ethyl or n-propyl; - R denotes alkyl with 1-5 carbon atoms or allyl and η stands for 1 or 2, as well as their pharmacologically acceptable ones Acid addition salts, characterized in that (a) a compound of the general formula: * ¹ H Χ) 2'n wherein R is hydrogen or alkyl having 1-5 carbon atoms means; R is methyl, ethyl or n-propyl; η stands for 1 or 2 and Z and W are independently oxygen, sulfur, or two Mean hydrogen atoms, but one of the radicals Z or W must always mean oxo or sulfur, is reduced and, if desired, a connection in which R is hydrogen, is alkylated on the indole nitrogen, either before or after the reduction stage to "the alkyl or to introduce allyl group (R); or (b) a compound of the general formula: where R is methyl, ethyl or n-propyl and Z and W are each independently oxo, sulfur or two Hydrogen atoms mean and η stands for 1 or 2, - 60 - 30 ^ - iß / 1152- is alkylated on the indole nitrogen to form the alkyl or allyl group (R) to be introduced and, if desired, either before or after the alkylation, a compound in which Z or W is oxo or sulfur is reduced; or (c) a compound of the general formula: wherein R is hydrogen or alkyl with 1-5 carbon atoms, with a compound of the general formula: wherein R is methyl, ethyl or n-propyl,. X is oxo or two hydrogen atoms and η is 1 or 2, is reacted by the Fischer indole method, optionally in the presence of an acidic catalyst, and if desired a product where X is oxo, is reduced and, if desired, a product where R is hydrogen, is alkylated on the indole nitrogen, either before or after the optional reduction step in order to introduce the alkyl or allyl group (R) ; or · '. .. (d) "a compound of the general formula: ι
R. - 61 - 309846/1152 wherein R is hydrogen or alkyl having 1-5 carbon atoms means with a keto acid of the general formula: 0 0. R ¹ -C-GH ₂ (CH ₂ ) _n -G-OH 1 ··
where R is methyl, ethyl or n-propyl and η is 1 or, or a functional derivative thereof, for example an enol lactone derivative of the general formula: ^r n is reacted and an open-chain intermediate product is cyclized, if desired, the product is reduced and if desired a product where R is hydrogen on the indole nitrogen is alkylated, either before or after the liberated reduction stage, to form the alkyl or allyl group (R) introduce; '. . (e). a compound of the general formula: wherein Y is a halide anion, η is 1 or 2 and R denotes hydrogen, alkyl with 1 - 5 carbon atoms or allyl, with a methyl, ethyl or n-propyl-G-rignard reagent (R MgX) or a methyl, ethyl or n-propyllithium reagent (R Li) is reacted to introduce the methyl, ethyl or n-propyl group (R); (f) a compound of the general formula: _ V. t - 62 - 3 0 9 8 "U 6/1152 ι ν (ΟΗ ₂ ) _η .1 where R denotes methyl, ethyl or n-propyl ", η denotes 1 or 2 and R is an unsaturated alkyl group having 2-4 carbon atoms represents, is reduced; or a compound of the general formula: wherein R is alkyl of 1-5 carbon atoms or allyl; R represents methyl, ethyl or n-propyl and η represents 1 or 2, is oxidized with a peroxy acid; or (h) a racemic mixture of a compound of the general formula! wherein R is hydrogen, alkyl of 1-5 carbon atoms or allyl; R represents methyl, ethyl or n-propyl and η represents 1 or 2, is separated; or (i) any product of the above processes (a) to (h) in the form of the free base with a pharmacologically acceptable - 63 - 3 0 '■! ■ ->. >) / 1152 ■ AHP-5740 Union acid is treated so that the pharmacologically acceptable Acid addition salt is formed thereof. 37. The method according to claim 36 for the preparation of a compound of the general formula: wherein R is hydrogen, alkyl having 1-5 carbon atoms or ^; Allyl "means; · · R represents methyl, ethyl or n.-propyl and η represents 1 or 2, characterized in that a combination of the general formula: where R, R and η have the meanings given above and .W is oxo or sulfur, is reduced and if desired a compound where R is hydrogen on indole nitrogen is alkylated, either before or after the reduction step, to introduce the alkyl or allyl group (R). 38. · The method according to claim 36 for producing a Compound of the general formula: * - 64 - .; · ■ .- ι ι ς 7 wherein W is two hydrogen atoms or oxo; R is alkyl of 1-5 carbon atoms or allyl; R represents methyl, ethyl or n-propyl and η stands for 1 or 2, characterized in that a compound of the general formula: ■ where ¥ stands for two hydrogen atoms, oxo or sulfur and R and η have the meanings given above, on the indole nitrogen atom is alkylated to introduce the alkyl or allyl group (R) and, if desired, a compound where X represents oxo or sulfur, either before or after the alkylation step is reduced. 39. The method according to claim 36 for the preparation of a compound of the general formula: 2'n wherein R is hydrogen or alkyl having 1-5 carbon atoms or allyl; R is methyl, ethyl or n-propyl and η is 1 or 2, characterized in that a connection of the. general Formula: ⁵ "3 0 9846/1152 where R is hydrogen or alkyl having 1 - 5 carbon atoms, with a compound of the general formula: wherein R and η have the meanings given above, implemented is, optionally in the presence of an acidic catalyst, and, if desired, a product where R is hydrogen, is alkylated on the indole nitrogen to form the alkyl or allyl group (R) to introduce. 40. The method according to claim 36 for producing a Compound of the formula: (CJH ₉ ) 2'n where X is two hydrogen atoms or oxo, R is hydrogen, alkyl with 1-5 carbon atoms or allyl, R represents ethyl, methyl or n-propyl and η stands for 1 or 2, characterized in that a compound of the general formula: wherein R is hydrogen or alkyl having 1-5 carbon atoms, with a keto acid of the general formula:. - 66 - 3 0 9 8 4 6/1152 AHP-5740 R ¹ -C0CH ₂ (CH ₂ ) _n -C00H wherein R and η have the meanings given above or with the enol lactone of the general formula: wherein R and η have the meanings given above, implemented is, an open-chain intermediate is cyclized, if desired the product is reduced and, if desired, the product where R is hydrogen on the indole nitrogen is alkylated, either before or after the optional reduction, to introduce the alkyl or allyi group (R). 41. The method according to .einem of claims 37 to 40, characterized characterized in that R and R each represent methyl and η represents 1. 42. The method according to any one of claims 37 to 40, characterized 1
characterized in that R and R each represent methyl and η represents 2. 43. The method according to any one of claims 37 to 40, characterized in that R is methyl and R is ethyl and η is 1 stands. 44. The method according to any one of claims 37 to 40, characterized ••1
characterized in that R is ethyl and R is methyl and η is 1. ' 45. The method according to any one of claims 37 to 40, characterized in that R is allyl and R is methyl and η is 1 stands. / 115? AHP-b740 46. The method according to claim 36 for the preparation of a compound of the general formula: 2'n wherein R is alkyl with 1-5 carbon atoms or allyl, R is methyl, ethyl or n-propyl and η stands for 1 or 2, characterized in that a compound of the general formula: ■ <0H ₂ ) _n is oxidized with a peroxy acid. 47.; "Method according to claim 46, characterized in that that R and R each represent methyl and η represents 1. 48. The method according to claim 36, characterized in that that the racemic mixture of a compound of the general formula j. wherein R is hydrogen, alkyl with 1-5 carbon atoms or Allyl means R represents methyl, ethyl or n-propyl and · η represents 1 or 2, is separated. - 68 - 30 9 8 46 Π 152