SE443787B - PROCEDURE FOR PREPARING SUBSTITUTED QUINOLIZIDINE AND INDOLIZIDINE DERIVATIVES - Google Patents

Description

The dehydration of a starting compound of the formula II is carried out according to the invention in a solvent in the presence of a dehydrating agent under heating at a temperature between 20 and 150 ° C, preferably between 50 and 100 ° C, and most preferably at the boiling point of the solvent used. As a solvent you can use e.g. water, methanol, ethanol, benzene, toluene, etc., provided that the solution undergoes the acid dehydration reaction. As a dehydrating agent, one can e.g. use hydrochloric acid, sulfuric acid, phosphorus oxychloride and p-toluenesulfonic acid.

The compounds of formula I prepared can be converted into the corresponding acid addition salts by reaction with a pharmaceutically acceptable acid, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid and citric acid.

The quaternary salts of the compounds of formula I have the following general formula: H n (VH2) n A X xfå (III) where R represents a lower alkyl group and X represents an acid residue. These hemenuka salts can be prepared by reacting a compound of formula I with a compound of formula: R-x fIV) where R and X have the meanings given above.

The lower alkyl group R can e.g. be methyl. ethyl, propyl, butyl, etc., The acid residue X may be chlorine, bromine, iodine, a sulfur cysteine residue and an alkyl sulphate residue, etc.

The above quaternization reaction can be carried out in a solvent or without the use of any solvent. As a solvent, one can e.g. use ether, acetone or an alcohol, e.g. methanol or ethanol. The reaction is carried out at a temperature between 5 and 100 ° C, preferably at a temperature between 10 and 100 ° C, possibly in a closed tube.

The subnates fi having the salts of formula III comprise stereoisomers (trans and cis isomers). The salts can be recovered in the form of an isomer mixture or in the form of pure isomers after recrystallization. 7805513-4 3 The new compounds of formula I as well as their acid addition salts and their salts have anticholinergic action, antihistamine effect, antitussive action and analgesic action. In particular, the natural salts have a strong effect against acetylcholine and against boils as well as reduced side effects, such as thirst, pupil dilation, etc.

Below are results obtained from pharmacological examinations of the new compounds.

The protective effect (FD50 value) against cramP ° F inducing '7 g / ml) has been determined. The experiments have been carried out according to I below the by acetylcholine (1 x 10 'agagnus method with cut small intestines from marmots. Those compounds in the table>> give the relative strength of the testers to the effect of atropine, whose effect has been set equal to 1 , 0.

Compound: Relative Strength: 2-Phenylmethylenequinolizidine methyl bromide (Ex.2, ii) 1,12 3-Diphenylimecycinquinolizidinemethylbromia (Ex.4, ii) 0.58 5-Diphenylmethylenekinolizidinethyl bromide (Ex.Ä, iii) 0.45 2- (dithien-2 -ylmethylene) quinolizidine methyl bromide (Ex.10, i) 1,16 3- (dithen-2-ylmethylene) quinolizidine methyl bromide (Ex.12, ii) 0.86 Atropine 1.0 Skopolamine-N-butyl bromide 0.02 Difemanil methyl sulfate .11 Prifinium bromide 0.37 Timepidium bromide 0.15 The test results show that the new compounds of formula I show a strong action against acetylcholine. The effect is clearly better than that of scopolamine-N-butyl bromide, difemanil methyl sulphate, prifinium bromide and timepidium bromide.

The compounds of formula I have less side effects in comparison with atropine such as thirst, pupil dilation, etc. The new compounds can therefore be used as antispasmodics and as anti-boils.

Closely related compounds with similar therapeutic properties are described in German Offenlegungsschrift 1 SÄS 561. However, the new compounds of formula I have a better effect against a _ _. ._ _. .. - -. -., ._,., .. 2_ ._ a. A. The ar 'ë'la experimental method ar * r -Q F' »- o-" "^. -, 10 * .e e" __ has been specified above. -C * - ~ - ° ~ ~,. . . .. _ _, _, _ _-,. _ ..: _ -1 a ..-__ värden) nar be: Laïts genc "-n -l -n, _ ann- _strering til- tar -ss _¿ V 19- e 3. -d: 3" 5 af relat: a ärcen "ar ïïrenzrg- 1 _ .. ... aeq 2 ¿...--, -, p- * ^ Dp ew frå: -Ég _ '" "' r * fl: 'f: .c - “f'n ~ _ _ __! _, _ _ ¿(_ _ A UV., _,. V _. CJ .. u- - ~ --_ ~~ .- ~ -... 7805513-4 _, / ^ \ i> f ~ innan., 4 »atj, L.: '\ - \ / \ \ \ _ men / 7 \ cl 1.3 n \ v / ° \ __ 4 / TTT. 1 UI K Ne Eänvf "rie ee 4," .L. ~. T-_ o er ng ~ vv LDDO lerap index, .D30 / ED50. Kv / l. ... g / ml Relativ “kg (X 108) nelativt varde styrka å fi alefelëeißzeïinfaf - 6 A 2.1 X 10 '0.01 19.00 0.05 0.01 f f. - fv,' OD;, o it, _ 3.90 0.07 0.02 .ïö-: eßi-enlía : _ _ -, 8, _ f,. Ni 3;, a -c- -, 00 19,07 3, c7 l, u0 -Q e. 1: 3 ,:: c: 1,75 17,81 5 , 91. 1,62 - _ ß a »ß-Ö Å ff, _ ca ~ (1-;,; -t ¿, 3o 6, 4 3,01 0,82, ~. Le 11) 1 ,: le 3, ü7 10.30 6.57 1.87 The LA results show that the new compounds according to the invention are about 100 times more effective against acetylxline than the known compounds. ra, thus have precursors higher than the therapeutic index of the known compounds.

In clinical use, the compounds of formula I may be administered orally in a dose of 1-100 mg, preferably 3-30 mg, 3 times a day. The compounds can also be injected in corresponding amounts.

The invention is illustrated by the following working examples.

Example 1. 2-Diphenylmethylenequinolizidine hydrochloride.

To 1.39 g of o, o-diphenylquinolizidine-2-methanol was added 10 ml of ethanolic hydrochloric acid, and the resulting solution was refluxed and stirred for 4 hours. After distilling off ethanol, the residue was dissolved in water, and the resulting aqueous solution was made alkaline with an aqueous solution of potassium carbonate and then extracted with chloroform. The chloroform phase was washed with water and dried. After distilling off the solvent, a yellowish liquid was obtained. The hydrochloride was prepared in a known manner and recrystallized from a mixture of acetone and ether. This gave 0.47 g of 2-diphenylmethylenequinolizidine hydrochloride in the form of colorless needles, m.p. 23 DEG-235 DEG. 7805513-4 5 E1em @ ntarana1§š for c22H25N-Hcl: Calculated: C 77.74 H 7.71 N 4:12 munen. c 77.48 H 7.59 N 5.78 Example gel 2. (1) 2- (diphenylmethylene) quinolizidine methyl iodide.

To a solution of 0.1 g of 2- (diphenylmethylene) quinolizidine in 10 ml of acetone was added 1.0 ml of methyl iodide, after which the reaction mixture was stirred at room temperature for 24 hours. The crystals formed were filtered off and recrystallized from methanol. 0.1 g of colorless needles with a melting point of 280-28100 (decomposition) were obtained. Elemental analysis for C 13 H 99 NI: Calculated C 62.05 H 6, §4 N 5.14 Found: C: 61.97 H 6.4} N}, l} ii) 2-Ediphenylmethylene) quinolizidine methyl bromide. (a) 5; g of 2-diphenylmethylenequinolizidine was dissolved in 50 ml of acetone, 5 ml of methyl bromide were added. Ibn the resulting mixture for 48 hours at room temperature in a sealed tube. The resulting reaction mixture was freed from the solvent, and the residue was recrystallized from a mixture of methanol and acetone.

This gave 5, §Ä g colorless prisms with a melting point of 261- -263 ° c.

NMR (δ) δ = 3.33 (N + Me) Elemental analysis for C 23 H 28 NR 6: Calculated C 69.54 H 7.08 N 5.52 Found: C 69.08 H 7.16 N 5.26 (b) The mother liquor obtained after the recrystallization was dried under reduced pressure. The residue was recrystallized twice in a mixture of methiol and acetone. The mother liquors thus obtained were combined and dried under reduced pressure, and the residue thus obtained was recrystallized from a mixture of methanol and acetone.

1.2 g of colorless prisms with a melting point of 235-23603 (ice product) were obtained.

Nm fi (cnc1¿) ¿= 3.67 (N * - me) (iii) 2- (diphenylmethylene) quinolizidine-ethyl bromide.

This compound was prepared in the same manner as described above, and after recrystallization from acetone it had a melting point of 233-234 ° C. 7805513-4 6 Elemental analysis for Ca ^ ä¿ONür: Calculated: C C?, DU H 7.55 N}, ßO Found C tz C 69.58 H 7.42 N 5.26 Excmftl 5. 5-diphenylmethylenequinolizidine. (a) In 20 ml of 60% sulfuric acid, 1.5 g of c, α-diphenylquinolizidine-5-methanol were heated at a temperature between 90 and 9500 with stirring for 30 minutes. The reaction mixture was then poured into water, and the resulting mixture was made alkaline with a 10% sodium hydroxide solution and then extracted with ether. The resulting ether phase was washed with water and dried. After distilling off the solvent, the residue was recrystallized from hexane to give 1.1 g of a colorless precipitate, with a melting point of 118 DEG-120 DEG.

Elemental analysis for C 22 H 25 N: Calculated; c 87.08 H 8.50 N 4.62 Found: C 87.50 H 8.55 N 4.48 The compound prepared was converted in a known manner to the corresponding hydrochloride. After recrystallization of the hydrochloride in methanol, colorless, flat crystals with a melting point of 225-228 ° C were obtained. (b) The starting material used, ie. α, α-diphenylquinolizidine-3-methanol, was prepared as follows.

To a solution of phenyllithium (prepared from 1.23 g of lithium and 16.80 g of bromobenzene) in 50 ml of anhydrous ether was added dropwise a solution of 120 g of 3-benzoylquinolizidine in anhydrous ether. The reaction mixture was then refluxed for 30 minutes. After destroying the excess phenyllithium with water, the reaction mixture was extracted.

The ether phase thus obtained was washed with water and dried. After distilling off the solvent, α, α-diphenylquinolizidine-3-methanol with a melting point of 166-167 ° C were obtained.

Example 4. (i) 5-Diphenylmethylenequinolizidine methyl iodide.

This compound was prepared in the same manner as described in Example 2 (i), except that methanol was used as the reaction solvent instead of acetone. The residue obtained after removal of the solvent was recrystallized from a mixture of methanol and acetone.

The product was obtained in the form of colorless prisms with a melting point of 221- -22 ° C. Elemental analysis for C 25 H 28 NI: Calculated; c 62.05 H 6.34 N 3.14 Funnec; c 6I, 94 H 6.34 N 3.00 (ii) 2; diphenylmethylenequinolizidine methyl bromide. (a) This compound was prepared according to the meaning described in Example 2 (11) (a). The precipitate was obtained in the form of colorless needles, which melted at 259 DEG-261 DEG C. during decomposition.

Nmm (cDcl¿) 6 = 2.97 (N + _ Me) Elemental analysis for C23H28NBr: Calculated: C 69.34 H 7.08 N 3, Found: C 69.60 H 7.29 N 3 (b) By working In the same manner as in Example 2 (ii) (b), an isomer of the above methyl bromide was prepared from the mother liquor obtained after the recrystallization. After recrystallization from a mixture of methanol and ether, this isomer was obtained in the form of colorless crystals with a melting point of 256-259 ° C. mms (cxclej 6; 5.44 (N + - Me)) / Elemental analysis for C 23 H 28 NBr: Calculated: c 69.34 H 7.08 N 3.52 Found: C 69.06 H 7.20 N 3.48 (111) 3 -dylphenylmethylenexindylzidine-ethyl bromide.

This compound was prepared according to the same method as described in Example 2 (ii) (a). After recrystallization from acetone, the product had a melting point of 225-22800.

Elemental analysis for C 24 H 3 ONBr: Calculated: C 69.90 H 7.33 N 3.40 Funnec = c 69.87 H 7.36 N 5.27 Example 5. 1-Diphenylmethylene quinolizidine sulfate.

A mixture of 3.5 g of α, α-diphenylquinolizidine-1-methanol and 35 ml of 60% sulfuric acid is stirred at 100 DEG C. for 20 minutes. The reactant lens mixture was then poured into water. The resulting mixture was made alkaline with 20% sodium hydroxide solution and then extracted with ether. The ether phase was washed with water and dried. The residue obtained after distilling off the solvent (3.1 g) was treated with ethanolic sulfuric acid. The resulting sulfate was recrystallized from ethanol to give colorless, needle-shaped crystals with a melting point of 219 DEG-212 DEG. Elemental Analysis for C 22 H 25 N-HESO 4: Calculated: c 65.81 H 6.5 N 5.49 Found ~ c = c 65.78 H 5.32 N 3.2h Example 6. (i) 1-Diphenylmethylenequinolizidine -methyl iodide.

To a solution of 0.5 g of 1-diphenylmethylenequinolizidine in 20 ml of acetone was added 1.0 ml of methyl iodide, after which the resulting mixture was allowed to stand for 10 minutes. The crystals thus formed were filtered off.

The off-pepadoe crystals (0.5} 5) were crystallized from methanol, whereby colorless, flat crystals with a melting point of 294-296 ° C were obtained (solar purging).

Elemental analysis for CQBHQBNI: Calculated. c 62.05 H 6.3n N 3.14 Found: C 61.92 H 6.41 N 2.82 (ii) 1-diphenylmethylenequinolizidine methyl bromide.

This compound was prepared in the same manner as described in (i) above. After recrystallization from ethanol, the product had a melting point higher than 50 ° C.

Nmm (cDc1¿) ó = 3.19 (N * _ me) Elemental analysis for C2} H28NBr: Calculated: G 69.54 H 7.08 N 3.52 Found: C 59.29 H 7.19 N §, 27 (111) 1-Difegylmethylenequinolizidine ecybromide.

This compound was prepared in the same manner as described above. After recrystallization from ethanol, the product had a melting point higher than 300 ° C.

Elemental analysis for C 21 H 34 ONBr-1/2 H 2 O: Calculated: C 68.40 H 7.41 N 3.32 Found: C 68.61 H 7.31 N}, 2u Example 7. 1- (dithien-2-ylmethylene ) quinolizidine hydrochloride.

A mixture of 1.40 g of α, α-α-thien-2-yl) quinolizidin-1-methanol and 15 ml of ethanolic hydrochloric acid was stirred at 60 ° C for 1 hour. After distilling off the solvent, the residue was dissolved in water. It was obtained alkaline with 10% sodium hydroxide solution and then with ether. The resulting ether phase was washed with water and dried. After distilling off the solvent, a light brown liquid was obtained. This liquid was converted in a known manner into the corresponding hydrochloride. After recrystallization of the hydrochloride in a mixture of isopropanol and isopropyl ether, light brown prisms were obtained with a melting point of 194-197 ° C.

Elemental analysis for Cl8H211.NS2-HCl: Calculated! C 61, Ä § H 6, §O N 5.98 Found: C 61.1) H 6.64 N 5.84 Example 8. (1) 1- (dithen-2-ylmethylene) quinolizidine methyl iodide.

This compound was prepared according to the method described in Example 6 (i). The acetone was used in a dried form, and the product was obtained in high yield. After recrystallization from isopropanol, the product was obtained in the form of light brown needles with a melting point of 284-285 ° C (dec.).

Elemental analysis for Cl9H2¿INS¿: Calculated: C 49.89 H §, 2§ X §, O6 Found C 50.02 F 5, ÅE N 2.99 In an analogous manner, the compounds listed below were also prepared. } 1-fidien-2-ylmethylene) quinolizidine methyl bromide. After crystallization from a mixture of ethanol and isopropyl, this compound had a melting point of 294-297 ° C (dec.).

NMR (cnc13) á '= 3.56 (N * _ Me) O * ”u Elemental analysis for Cl9H24BrNS2: Calculated: C 55.60 H 5.89 N 5.41 Funnêtz C §5, l8 H 6.11 N § (Iii) 1- (dithien-2-ylmethylene) quinolizidine-ethyl bromide.

After recrystallization from a mixture of ethanol and isopropyl ether, this compound had a melting point of 286-28800 (decomposition).

Elemental analysis for C2OH26BrNS2: Calculated: C §6, §9 H 6.17 N}, §O Found: C §6, Z9 H 6, §4 N §, l} Example 3, 2- (dithien-2-ylmethylene) quinolizidine. Penna föfpnïnë was prepared from α, α- (dithien-2-yl) quinolizidine = 2em = tanO1, operating in the same manner as described in ° X ° mp = 1? m x n use xalium hydroxide instead of sodium hydroxide and ° Xtr1herated with chloroform instead of mad etvr. After recrystallization from the propyl ether, the product was obtained in the form of colorless crystals at an emission point of 88-9000. Calculator: C 65.55 H 6.71 N 4.44 Found: C 6 ¥, j4 H 6.72 N 4.26 Example 10. (1) 2- (ditien- 2-ylmethylene) quinolizidine-methyl bromide.

This compound was prepared according to the same procedure as described in Example 2 (i). After recrystallization from ethanol, the product was obtained in the form of colorless crystals, m.p. 246-24800 (dec.).

Nmm (cnclš) 6: 5.42 (N * Me) Elemental analysis for C 19 H 24 BrNS 2: Calculated: c 55.60 H 5.89 N 5.41 Found: C 75.31 H 5.88 N 5.10 (11) 2- (dician-Ephysylylene) quinalizidine acyl bromide This compound was prepared according to the same procedure as described in Example 2 (ii) (a), except that the reaction mixture was heated to 50 ° C. After recrystallization from isopropanol, the product was obtained in the form of colorless crystals, m.p. 217 DEG-218 DEG.

Elemental analysis for C 2 OH 26 BrNS 2: Calculated: C 56.59 H 6.17 N 3.30 Found: C 56.50 H 6.15 N 5.51 Example 11. 3- (ditien-2-ylmethylene) quinolizidine.

This compound was prepared according to the same procedure as described in Example 7. After recrystallization from isopropyl ether, the product was obtained from a colorless medium having an amine point of 128 DEG-150 DEG. Elemental analysis for CIBHAWHS [__ f ~ .i 7805513-4 11 Calculated: c 68.53 H 6.71 N 4.44 Funnec = c 68.35 H 6.74 N 4.36 Example 12. In the same manner as described in Example 6 (i) the compounds listed below were also prepared. (i) 3- (dithen-2-ylmethylene) quinolizidine methyl iodide.

This compound had a melting point of 223-224 ° C after recrystallization from ethanol.

Elemental analysis for C 19 H 21 INS 2: Calculated: C 49.89 H 5.29 N 5.06 Found = C 49.66 H 5.35 N 2.72 (ii) §1 (dithien-2-ylmethylene) quinolizidine methyl bromide.

After recrystallization from ethanol, this compound melted at 278 DEG-288 DEG C. with decomposition.

NMR (cnc1¿) ¿"= 2.92 (N * _ Me) Elemental analysis for C19H2BBrNS2: Calculated: C 55.60 H 5.89 N 3.41 FUnn @ t = C 55.73 H 5.89 N 3.37 (iii) Qf (dithien-2-ylmethylene) quinolizidine ethyl bromide.

After recrystallization from a mixture of isopropanol and acetone, this compound melted at 226-228 ° C with decomposition.

Elemental analysis for C 2 OH 26 BrNS 2 -1 / 2 H 2 O: Calculated: C 56.12, H 6.22 N}, 2T Found: C 56.15 H 6.18 N 3.04 Example 1). 1-diphenylmethyleneindolizidine.

This compound was prepared from α, α-diphenylindolizidine-1-methanol according to the same procedure as described in Example 5. The compound was obtained as a yellowish viscous substance.

Mass spectrum (c 21 H 23 N) = m / e = 289 (M +), 212 The α, α-diphenylindolizidine-1-methanol used as starting material was prepared as follows.

To a phenyllithium solution (prepared from 0.51 g of metallic lithium, 6.32 g of bromobenzene and 50 ml of anhydrous ether) was added a solution of 2.40 g of 1-ethoxycarbonylindolizidine in 20 ml of anhydrous ether. The addition was made dropwise under cooling with water. After boiling under reflux for about 10 minutes, water was added dropwise. The reaction mixture thus obtained was extracted with ether. The ether phase was extracted with a dilute aqueous solution of hydrogen chloride. The resulting aqueous phase was made alkaline with an aqueous solution of sodium hydroxide and then extracted with ether. The ether phase thus obtained was washed with water and dried. Man contained 3.58 g of yellowish, viscous product.

Mass spectrum (c 21 H 25 No) = m / e = 307 (M +), 230, 123 (round top) The product obtained was a mixture of two diastereoisomers, and it could be used as such in the above reaction.

Example Gel 14. In the same manner as described in Example 6 (i), the following compounds were prepared. (1) 1-Diphenymenylene indolizidine megyl bromide.

After recrystallization from a mixture of ethanol and acetone, this compound was obtained in the form of colorless, flat crystals with a melting point of 210-211 ° C.

NMR (cnc13) d '= 5.49 (N + Me) Elemental analysis for C22H26NBr: Calculated: C 68.75 H 6.82 N 3.64 Found = c 68.56 H 6.85 N 5.51 (ii ) 1-diphenylmethyleneindolizidine methyl iodide.

This compound was obtained in the form of colorless needles with a melting point of 189-19 ° C. (iii) 1-diphenylmethyleneindolizidine ethyl bromide.

This compound was obtained in the form of colorless, flat crystals with a melting point of 16 DEG-164 DEG.

Examples lay. 2-diphenylmethyleneindolizidine.

This compound was prepared according to the same method as described in Example 5. After recrystallization from n-hexane, the compound was obtained in the form of colorless needles having a melting point of 76-79 ° C.

Elemental analysis for C 21 H 25 N: Calculated: C 87.15 H 8.01 N 4.84 Found: C 87.08 H 8.14 N 4.76 Example 16. In the same manner as in Example 6 (i), the following compounds were prepared. (i) 2-Diphenylmethyleneindolizidine methyl iodide.

After recrystallization from a mixture of methanol and acetone, this compound was obtained in the form of colorless needles with a melting point of 242-244 ° C. Elemental analysis for C 22 H 26 NI: Calculated: C 61.26 H 6.08 N 5.25 Found C 61.00 H 6.15 N § 1 (ii) 2-diphenylmethyleneindolizidine methyl bromide.

After recrystallization from a mixture of methanol and acetone, this compound melted at 267-269 ° C with decomposition.

NMR (cDci · d) = 3.08 (N + Me) Elemental analysis for C 22 H 16 NBr: Calculated: c 68.75 H 6.82 N 5.64 Found; C 68.57 H 6.82 N 3.53 Exemoel II, 2-(dithien-2-ylmethylene) indolizidine.

In 20 ml of ethanolic hydrochloric acid, 2.66 g of α, α- (dithien-2-yl) indolizidin-2-methanol were heated at 60 ° C with stirring for 1 1/2 hours. After distilling off ethanol, the residue was dissolved in water, and the resulting aqueous solution was made alkaline with 10% sodium hydroxide solution and then extracted with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was distilled to give 1.76 g of a yellow liquid having a boiling point of 195-19700 at 5 mm Hg. The product was converted to the corresponding hydrochloride in a known manner. After recrystallization of the hydrochloride from isopropanol, yellow prisms with a melting point of 197-200 ° C (decomposition) were obtained. In Elemental Analysis for C 17 H 19 NS 2 -HCl: Calculated: C 60.42 H 5.97 N 4.14 Found: C 60.17 H 6.12 N 3.87 Example Gel 18. In the same manner as in Example 2, the compounds listed above were prepared. . (i) 2- (dithen-2-ylmethylene) indolizidine methyl iodide.

After recrystallization from isopropanol, this compound was obtained as yellowish prisms, m.p. 222-22500.

Claims (2)

Elemental analysis for C 18 H 22 INS 2: Calculated: C 48.76 H 5.00 N 3.16 Found C 48.60 H 5.04 N 2.85 (ii) 2- (dithien-2-ylmethylene) indolizidine methyl bromide . After recrystallization from isopropanol, this compound had a melting point of 20 DEG-20 DEG. NMR (CDCl 3): 5.49 (N + - Me) in Elemental analysis for C 18 H 22 BrNS 2/2 H 2 O: Calculated: C 54.05 H 5.64 N 3.50 Found: C 54.02 H 5.59 N 5, 24 (iii) 2- (dithen-2-ylmethylene) indolizidine-ethyl bromide. After recrystallization from a mixture of isopropanol and acetone, this compound had a melting point of 212-214 ° C. Elemental analysis for C 19 H 21 BrNS 2: Calculated: C 55.60 H 5.89 N 5.41 Found: C 55.55 H 5.91 N 5.16. Process for the preparation of substituted quinolizidine and indolizidine derivatives of the general formula: (CH) i \ Lj2-.I1L _ = <^ (I) A where A denotes a phenyl »or 2. -thienyl group and n represents 3 or 4, as well as pharmacologically acceptable acid addition salts and quaternary salts thereof, characterized in that a compound of the general formula is dehydrated: (C) / ÛQLÄ §H <Ä (II) where A and n have the meanings given above, after which the compound obtained is optionally reacted with a pharmaceutically acceptable, inorganic or organic acid or with a quaternizing agent.