FI64368C - PROCEDURE FOR THE PRODUCTION OF PHARMACOLOGICAL PROPERTIES OF SUBSTITUTES OF QUINOLIZIDES AND INDOLIZIDINDERIVAT - Google Patents

Description

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National Board of Patents and Registration of Finland / 441 Nihtivlk »lp» oun and moon.Date of publication. -

Patent · OCh regi * terstyre! Ser Ansöka · -! utiagd och utl.skrlften p <jb! icerad 20.07.0 '(32) (33) (31) Requested Privilege — Begird prlorltet] _h.C7 "t 09.11.77, 21-12-77, CS.09.77, 03.12. ^ 7, 27.02.Ty

Japan- Japan (JP) Sho52-55266, She> 2-173526, 3ηο5Γ - 1 “2? · Ί1, 3ho52-10727C, Sho52-l * -» 66l3, Sho53-21531 (71) Hokvriku Pharmaceutical Co., ltd ., 1-cnome 3-ll Tatekav & cho, Kavrixvnr.ashi Fukux, Jap & n 1 -Japan (JP; C72) Hideo Kato, Motomachi Katsuyanashi, Fukui, Eiichi Koshinaka, Asahichc Kat-suyamashx, Fukux, liobuo Ogawa, Honmachi Sakae Kurata,

Asahicho .Katsuyamashi, Jukui, Kagari Yamagishi, Asahichc Katsuyamashi,

Fukux, Miyoko Ishizuka, Aradocho Katsuyamashi, Fukux, Japan-Janan (J?) (R'l) Leitzii.gar Oy (51) Method for the preparation of pharmacologically valuable substituted kinclicidin and indolizidine derivatives suhstituerade quinolizidine- and indoli zi di n de ri vat

The invention relates to a process for the preparation of pharmacologically valuable substituted quinolizidine and indolizidine derivatives of the formula I

tCH2! n A

A (I) wherein A is phenyl or 2-thienyl and n is an integer of 3 or 4, and pharmacologically acceptable acid addition salts thereof. and for the preparation of quaternary salts of derivatives.

The process according to the invention is characterized in that the compound of general formula (II): 64368 2 C

OH

wherein A and n are as defined above, are dehydrated and optionally reacted with a quaternizing agent of a pharmaceutically acceptable inorganic or organic acid or of formula R-X, wherein R is lower alkyl and X is an acid residue.

The starting materials of the general formula (II) are known by methods known per se, such as those described by Karl Winterfeld and Joachim Augstein, Chem. Ber. 9J), 863-867 (1957).

The hydration of the starting material of general formula (II) is carried out according to the invention in a solvent in the presence of a dehydrating agent by heating at a temperature of 20 to 150 ° C, preferably 50 to 100 ° C, at the boiling point of the solvent most preferably used. Suitable solvents are various substances, for example water, methanol, ethanol, benzene, toluene, etc., provided that they do not interfere with dehydration. Suitable dehydrating agents are hydrochloric acid, sulfuric acid, phosphorus oxychloride and p-toluenesulfonic acid, etc.

The compounds of general formula (I) thus obtained can be converted into the corresponding acid addition salts with pharmaceutically acceptable acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid and citric acid, etc.

The quaternary salts of the compounds of formula (I) prepared according to the invention may be represented by general formula (III); r ^ f (CH2, n x © I '© (III)

R

wherein R is a lower alkyl group and X is an acid group. They are prepared by reacting a compound of formula (V) with a compound of formula (TV).

11 3 64368 R - X (IV) wherein R and X are as defined above.

Suitable alkyl groups R include methyl, ethyl, propyl, butyl, etc. As the acid group, there may be mentioned a chlorine, bromine and iodine atom, a sulfuric acid group, an alkyl sulfate group, and the like.

The above quaternization reaction can be carried out in the presence or absence of a solvent. As the solvent, for example, ether, acetone and an alcohol such as methanol or ethanol are used. The reaction is carried out at a temperature of 5 to 100 ° C, preferably 10 to 40 ° C, optionally in a molten tube.

The quaternary salts of formula (III) contain stereoisomers (trans and cis isomers) which can be obtained as a mixture or as pure isomers after recrystallization.

Atropine has a potent anti-acetylcholine effect and has long been used as an antispasmodic. However, the clinical use of atropine has been limited due to its strong side effects such as thirst, dilation of the pupils, increase in blood pressure, etc. Therefore, a number of synthetic spasmolytes such as diphemanyl methyl sulfate (cf. U.S.A.) have been proposed and used to date. patent 2,739,696; Merck Index, 9th edition, 3309) Prifinium bromide (cf. Merck Index, 9th edition, 7540) and Thymidium bromide (cf. J. Med Chem. 15, 914 £ 19721) · However, these compounds are not satisfactory because the strong main anti-acetylcholine effect is associated with strong side effects.

It is therefore an object of the invention to provide an impeccable medicament which has the strongest possible anti-acetylcholine effect and yet the lowest possible side effects.

The compounds of formula (I) according to the invention and their acid addition salts and their quaternary salts have anticholinergic, antihistamine, antitussive and analgesic activity. In particular, the quaternary salt has a strong anti-lineage effect and anti-ulcer effect, as well as minor side effects such as thirst, dilation of the pupils, etc.

The following are the results of pharmacological studies of the compounds of the invention.

Method

The ED50 values of the protective effects of the seizures of the compounds induced by acetylcholine _ * 7 (1x10 'g / ml) are determined by the method of Magnus in the truncated ileum of the marmot and the relative potency is calculated when the ED50 value of atropine is 1.0.

Compound Relative _ potency___ 2-Diphenylmethylene-quinolizidine Methyl bromide (e.g. 2 ii) 1,12 3-Diphenylmethylene-quinolizidine Methyl bromide (e.g. 4 ii) 0.58 3-Diphenylmethylene-quinolizidine Ethyl bromide (e.g. 4 iii) 0.45 2 - (dithien-2-ylmethylene) -quinolizidine Methyl bromide (e.g. 10 i) 1,16 3- (dithien-2-ylmethylene) -quinolizidine Methyl bromide (e.g. 12 ii) 0.86

Atropine 1.0

Scopolamine - N - butyl bromide 0.02 4- (diphenylmethylene) -1,1-dimethylpiperidinium methyl sulfate 0.11 3- (diphenylmethylene) -1,1-dimethyl-2-methylpyrrolidinium bromide 0.3? 3- (di-2-phenylmethylene) -5-methoxy-1,1-dimethylpiperidinium bromide 0.15

The table shows that the compounds according to the invention have a strong anti-acetylcholine activity which is much better than that of scopolamine-N-butyl bromide, diphenylmethyl sulphate, proline bromide and thymidium bromide.

At the same time, the compounds according to the invention have lower side effects such as thirst, dilation of the pupils, etc., compared with atropine and can therefore be used in practice as antispasmodics and as antiulcer agents.

In clinical use, the dose of the compounds may be 1 to 100 mc, preferably 3 to 30 mg, three times a day, orally or by injection in an equivalent amount.

In the following, the invention will be explained in more detail with reference to exemplary embodiments.

Example 1 2-Diphenylmethylenequinolizidine hydrochloride 1.39 g of β, α-diphenylquinol zidine-2-methanol α are added dropwise to 10 ml of ethanolic hydrochloric acid and the solution thus obtained is stirred at reflux for 4 hours. The ethanol is distilled off, after which the residue is dissolved in water, and the aqueous solution is made alkaline with an aqueous solution of carbonic acid and then extracted with chloroform. The chloroform phase is washed with water and dried. The solvent is distilled off to form a yellowish liquid. The hydrochloride, which is prepared by a known method and recrystallized from acetone / ether as colorless needles, has a melting point of 233-235 ° C.

Glossary: 0.47 g of 2-diphenylmethylenequinolizide and 1-hydrochloride Elemental analysis: H N HCl C. i-

C H N

Calculated 77.74 7.71 4.12

Found 77.48 7.59 3.78

Example 2 i) 2-Ciphenylmethylene) quinolizidine-methyl iodide.

To a solution of 0.1 g of 2- (diphenylmethylene) quinolizidine in 10 ml of acetone is added 1.0 ml of methyl iodine and stirred for 24 hours at room temperature. The formed crystals are filtered off and recrystallized from methanol to give 0.1 g of colorless needles, m.p. 280-282 ° C (decomposes).

64368 6

Elemental analysis C__, H_0 NI

2 5 2 p

c H N

Calculated 62.03 6.34 3.14

Obtained 61.97 6.43 3.13 ii) 2- (Diphenylmethylene) quinolizidine methyl bromide a) 5.5 g of 2-diphenylmethylenequinolizidine are dissolved in 50 ml of acetone, 5 ml of methyl bromide are added and allowed to stand in a molten tube at room temperature for 48 hours. The solvent thus obtained is removed from the reaction mixture and the residue is crystallized from a mixture of methanol and acetone. 5.34 g of colorless prisms are thus obtained, melting point 261-263 ° C.

NMR (CDCl 3) δ: 3.33 (N + - Me)

Elemental analysis: C ^ 2 H ^ g NBr

C H N

Calculated 69.34 7.08 3.52

Obtained 69.08 7.16 3.26 b) The mother liquor obtained from recrystallization is dried under reduced pressure. The residue is crystallized twice from a mixture of methanol and acetone. The combined mother liquors are dried under reduced pressure and then the residue is recrystallized from a mixture of methanol and acetone to give 1.12 g of colorless prisms, m.p. 235-236 ° C (second isomer).

NMR (CDCl 3) δ: 3.67 (N + - Me) i) 2- (Diphenylmethylene) quinolizidine ethyl bromide This compound is prepared by the method described above.

Melting point 233-234 ° C (from acetone)

Elemental analysis: C24 NBr

C H N

Calculated 69.90 7.33 3.40

Found 69.58 7.42 3.26 64368 7

Example 3 3-Diphenylmethylenequinolizidine a) 1.5 g of α, α-diphenylquinolizidine-3-methanol are heated with stirring for 30 minutes at 90-95 ° C in 20 ml of 60% sulfuric acid. The reaction mixture is then poured into water, basified with 10% sodium hydroxide and extracted with ether. The resulting ether phase is washed with water and dried. The solvent is distilled off, after which the residue is recrystallized from hexane to give 1.1 g of colorless needles, m.p. 118-120 ° C.

Elemental analysis: H _, _ N

22 2o

C H N

Calculated 87.08 8.30 4.62

Found 87.30 8.33 4.48

The compound obtained is converted into the hydrochloride in a known manner. Recrystallization of the hydrochloride from methanol gives colorless, plate-like crystals, m.p. 225-228 ° C.

(b) α, α-Diphenylquinolizidine-3-methanol used as starting material is prepared by the following method:

To a solution of phenyllithium (1.23 g of lithium and 16.80 g of bromobenzene used in the preparation) in 50 ml of anhydrous ether is added dropwise a solution of 120 g of 3-benzoylquinozidine in anhydrous ether, followed by stirring at reflux for 30 minutes. Excess phenyllithium is decomposed with water, after which the reaction mixture is extracted. The ether phase thus obtained is washed with water and dried. The solvent is distilled off to give ex, α-diphenylquinolizoline-3-methanol, m.p. 166-167 ° C.

Example 4 i) 3-Diphenylmethylenequinolizidine methyl iodide

The compound is prepared in the same manner as described in Example 2 i).

However, methanol is used instead of acetone as the reaction solvent.

64368

After removal of the solvent, the residue obtained is crystallized from a mixture of methanol and acetone.

Melting point 221 - 22t ° C (colorless prisms)

Elemental analysis: H 2 g NI

C H N

Calculated 62.03 6.34 3.14

Obtained 61.94 6.34 3.00 1 i) 3-Diphenylmethylenequinolizidine methyl bromide a) The compound is prepared by the method of Example 2 (ii) a).

Melting point 259-26 ° C (decomposes: colorless from nails) NMR (CDCl 3) δ: 2.97 (N - Me)

Elemental analysis: C ^., H_0 NBr z J z o

C H N

Calculated 69.34 7.08 3.52

Obtained 69.60 7.29 3.26 b) The isomer of the above m.ethyl bromide is prepared as described in Example 2 ii b) from the mother liquor of the recrystallization by the same procedure.

o Colorless crystals with a melting point of 256-259 ° C (from methanol / ether) NMR (CDCl 3) o: 3.40 (N + - Me)

Elemental analysis: H NBr

4) j O

C H N

Calculated 69.34 7.08 3.52

Obtained 69.06 7.20 3.48 (3i) 3-Diphenylmethylenequinolizide and ethyl bromide

The compound is prepared in the same manner as described in Example 2 ii a):

Melting point 225-228 ° C (acetone) il 6 4 3 6 8

Elemental analysis: K ^ q NBr 9

C H N

Calculated 69.90 7.33 3.40

Found 69.87 7.36 3.27

Example 5 1-Diphenylmethylenequinolizidine sulfate 3.5 g of α, β-phenylmethylenequinolizidine-1-netanel and 35 ml of 50% sulfuric acid are stirred for 20 minutes at about 100 ° C. The reaction mixture is poured into water, basified with 2C sodium hydroxide solution and extracted with ether. Hotter ’is washed with water and dried. The solvent is distilled off and the resulting residue (3.1 g) is treated with ethanolic sulfuric acid. The sulfate thus obtained is recrystallized from ethanol to give a color tower of crystal needles, melting point 219-221 ° C.

Elemental analysis: C ^ 2 ^ 25 ^ * H2 ^ 4

C H N

Calculated 65.81 6.78 3.49

Found 65.78 6.92 3.24

Example 6 i) 1-Diphenyl.1 methylenequinolizidine methyl iodide

To a solution of 0.5 g of 1-diphenylmethylenequinoline syrup in 20 other acetones is added 1.0 ml of methyl iodide and allowed to stand for 10 minutes. The separated crystals are separated by filtration. The filtered crystals (0.33 g) are recrystallized from methanol to give colorless, plate-like crystals, m.p. 294-296 ° C (dec.).

Elemental analysis: NI

C H N

Calculated 62.03 6.34 3.14

Obtained 61.92 6.41 2.82 10 64368 ii) 1-Diphenylmethylenequinolizidine methyl bromide

The compound is prepared by the method described in i) above.

Melting point> 300 ° C (from ethanol) NMR (CDCl 3) δ: 3.19 (N + - Me)

Elemental analysis: C23 H NBr

C H N

Calculated 69.34 7.08 3.52

Obtained 69.29 7.19 3.27 iii) 1-Diphenylmethylenequinolizidine ethyl bromide

The compound is prepared in the same manner as above.

Melting point> 300 ° C (from ethanol)

Elemental analysis: C24 H3Q NBr * 1/2 H20

C H N

Calculated 69.40 7.41 3.32

Found 68.61 7.31 3.24

Example 7 1- (Dithien-2-ylmethylene) quinolizidine hydrochloride To 1.40 g of α, α- (dithien-2-yl) quinolizidine-1-methanol is added 15 ml of ethanolic hydrochloric acid and stirred for 1 hour at 60 ° C. The solvent is distilled off and the residue is dissolved in water. The resulting solution is made alkaline with 10% sodium hydroxide solution and then extracted with ether. The ether phase is washed with water and dried. The solvent is distilled off to give 1.29 g of a light brown liquid. The liquid is converted to the hydrochloride in a known manner. The hydrochloride is recrystallized from isopropanol / isopropyl ether to give light brown prisms, m.p. 194-197 ° C.

11 64368

Elemental analysis: CH 2 NS 2 · HCl

C H N

Calculated 61.43 6.30 3.98

Found 61.13 6.64 3.84

Example 8 i) 1- (Dithien-2-ylmethylene) quinolizidine methyl iodide

The compound is obtained in good yield by the method of Example 6 i) using acetone dried.

Light brown needles with a melting point of 284-285 ° C (from isopropanol; decomposes)

Elemental analysis: Cig H24 INS2

C H N

Calculated 48.89 5.29 3.06

Found 50.02 5.48 2.99

The following compounds are prepared in an analogous manner: ϋ) 1-dithien-2-ylmethylene) quinolizidine-methyl bromide

Melting point 294-297 ° C

(ethanol / isopropyl from ether; decomposes) NMR (CDCl 3) δ: 3.36 (N + - Me)

Elemental analysis: ciQ H „. Br NSn 19 24 2

C H N

Calculated 55.60 5.89 3.41

Obtained 55.18 6.11 3.51 N - (1- [2-ylmethylene) quinolizidine ethyl bromide

Melting point 286-288 ° C

(from ethanol / isopropyl ether; decomposes)

Elemental analysis: c2Q H26 Br NS2

C H N

Calculated 56.59 6.17 3.30

Found 56.79 6.54 3.13 64368 12

Example 9 2- (Dithien-2-ylmethyl ether) quinolizidine

The compound is prepared by the method described in Example 7 from e, α-maternal-2-yl) -quinolizidine-2-ethanol, using sodium hydroxide instead of sodium hydroxide and chloroform instead of ether.

Colorless crystals with a melting point of 88 to 90 ° C (from ether)

Elemental analysis: C, 8 H χ NS2

C K N

calculated 68.53 6.71 4.44

Found 68.34 6.72 4.26

Example 10 i) 2- (Dithien-2-ylmethylene) Quinolizidine N-methyl bromide

The following compounds are prepared by the method described in Example 2 i):

Colorless crystals with a melting point of 246-248 ° C

'Ethanol; decomposes) MMR (CDCl 3) δ: 3.42 (N + - Me)

Elemental analysis: C, _ H-, BrNS_ i 7 24 2

C H N

Calculated 55.60 5.89 3.41

Obtained 55.31 5.88 3.10 ii) 2- (Dithien-2-ylmethylene) quinolizidine ethyl bromide

The compound is prepared by the method described in Example 2 ii a), however, the reaction mixture is heated to 50 ° C.

Colorless crystals with a melting point of 217-218 ° C

II

64368 (isopropanc list)

Element Ivvsi: C „,, 3r NS

20 Z b 2

C H N

Calculated 56.59 6.17 3.30

Obtained 56.30 6.15 3.31 ::: · · · kk: ii 3- (Dithien-2-ylmethylene) quinolizidine This compound is prepared by a method similar to Example 7.

O

Colorless needles with a melting point of 123 to 130'C

(Isoorouvvlieetteristä)

Elemental naive: C, D H_, NS „" 1o 21 2

C H N

Calculated 68.53 6.71 4.44

Found 68.35 6.74 4.36

Example 12

By a method similar to that described in Example 6 i), the following compounds are prepared: i) 3- (di-en-2-ylmethylene)

Melting point 223-224 ° C (ethanol)

Elemental analysis: ^ INS ,,

C H N

Calculated 49.89 5.29 3.06

Quality 49.66 5.35 2.72 i i) 3- (dithi e n-2-yl limeylene) quinol zididine methyl b ront idi_

Melting point 278-280 ° C (from ethanol; decomposes) NMP (CDCl 3) 6: 2.9 2 (N + - Me)

Elemental analysis: Cig H24 Br NS2 14 64368

C H N

Calculated 55.60 5.89 3.41

Obtained 55.78 5.89 3.37 iii) 3- (Maternal-2-ylmethylene) quinolizidine ethyl bromide

Melting point 226-228 ° C (isopropanol / acetone; decomposes)

Elemental analysis: C2q H Br NS2 · 1/5 H20

C H N

Calculated 56.12 6.22 3.27

Found 56.13 6.18 3.04

Example 13 1-Diphenylmethylene-indolizidine

The compound is prepared by a method similar to that described in Example 5 from α, α-diphenylindolizidine-1-methanol.

Yellowish viscous substance

Mass spectrum ^ 21 ^ 23 ^: m / e: 289 (M +), 212 The α, α-diphenylindolizidine-1-methanol used as starting material is prepared as follows:

To a solution of phenyllithium prepared using 0.51 g of lithium metal, 6.32 g of bromobenzene and 50 ml of anhydrous ether are added dropwise, while cooling with water, a solution of 2.40 g of 1-ethoxycarbonylindolizidine in 20 ml of anhydrous ether. Reflux for about 10 minutes, then add dropwise water. The reaction mixture thus obtained is extracted with ether. The ether phase is then extracted with aqueous dilute hydrochloric acid. The aqueous phase is made alkaline with aqueous sodium hydroxide solution and re-extracted with ether. The ether phase is washed with water, dried to give 3.58 g of a yellowish, viscous substance.

15 64368

Mass spectrum (c 21 H 25 NO 2 m / e: 307 (M +), 230, 123 (base peak)

The compound is a mixture of two diastereoisomers and can be used as such in the above reaction.

Example 14

By the same method as described in Example 6 i), the following compounds are prepared: i) 1-Diphenylmethylene-indolizidine-methyl bromide

Colorless, plate-like crystals with a melting point of 210-211 ° C

(ethanol / acetone) NMR (CDCl 3) δ: 3.49 (N + - Me)

Elemental analysis: H- ,, NBr 22 2b

C H N

Calculated 68.75 6.82 3.64

Obtained 68.56 6.85 3.51 ii) 1-Diphenylmethylene-indolizidine-methyl iodide Melting point 189-190 ° C (colorless needles) i i i) 1-Diphenylmethylene-indolizidine-ethyl bromide

Melting point 163-164 ° C (colorless, plate-like crystals)

Example 15 2-Diphenylmethylene-indolizidine

The compound is prepared by a method as described in Example 5:

Melting point 76-79 ° C (from n-hexane; colorless needles)

Elemental analysis: C, H 2 N

16 6 ^ 368 n ιτ

Calculation: 87.15 3.01 4, 84

Obtained 87.08 8.14 4.76 E symbol 16

By the same method as described in Example 6 i), the following compounds are prepared: '2-11

Melting point 1 42 - 2 4 4 ~ 72 (met ane li / ase uo.nl s ta: colors of the tower needles}

Elemental analysis: C „LI

2 2 2 6

C H N

Calculated 61, 26-6.08 3.25

Obtained 61.00 6.15 3.13 ii) 2-Diphenylimethylene-indolizidine-methyl bromide

Melting point 267 - 2G7 '"C

(raethanol / acetuni s ta; haj oaa) N MR (CDCi-v::?, 08 (Ν '' - Me) A1 ku -ai rear a 1 yvsi: C ~ „li ^ r NEr 2 / ·. a. b

C H N

Calculated 68.75 6.82 3.64

Found 68.57 6.82 3.53

Example 2- 2- (Dithien-2-ylmethylene) indolizidine 2.66 g of u- (dithien-2-yl) indolizidine-2-methane are stirred at 60 ° C with heating for 1 1/2 hours at 20 ° C. hydrochloric acid. The ethanol is distilled off, after which the residue is dissolved in water, made alkaline with 10% sodium hydroxide and extracted with ethyl acetate. Eotte mkorres is washed with water and dried. The solution is distilled off, after which the residue is distilled to give 1.76 q 17 6 4 3 6 3 ..... o vou tior. td πρ ':: 3 ° t t / -i, k i oh ui7'i s o t c> h ° 13 3 - 19 7 ^ C'. '· tvlt 13c,'. 'credit u \ new.0' - p ^; v / e- ^ o '<' o rt lu 'rs L ^ u kt Ίον to t' iön uucolloor ts oo rou uo o tJ sto, "ol - luen saaca. ; " lolaaasae pr is.T.ojc., sulemi -oi s - · .: 197 - 200 ~ C 'decomposes).

Alkua 1 rear ..?. Iyvsi: Cd _ w.r. NS ". HC;

: / j. t Z

C H N

la ^ ketAaa 60.4 2 5.9 7 4.14

Found 60.17 6.12 3.87 '1? i.ne e 7 1 s aa ä 2 ke vatur. la,. e ui 1 a nenc: e Ime '117 v ?. 2η 2 ste laa / ·: 'c’ara3 ’, Tat

i) 2- (di-thi-2-ylin liner le.i) indo 111s 1 diin 1 -: ^ e ty

(i s ocrooano 11 s ta: vä r 1 At omi s t.ä ke 11 er or v 1 in o oi smoa) Λ Ruai ^ o-yy:. :: ’[. O? IKS2

C H N

Calculated 48.76 5.00 3.16

Obtained 43.60 5.04 2.85 1: 0 2 '-.

Q

Odud suiste 200 - 202 0 i isoproparol.er ta '\ MR f; C0C.lo; (': 3, 4 S f O - Me)

Elemental analysis: C, g BBrN39 · 1/5 H 2 O.

C H N

Calculated 54.05 5, C4 3.50 S aaiu 54, 02 5.39 3.24 i i i) 2- (dll un -2-yy 1 ime tv leeni) indo li ts id iin i - e ty?. i_b r naii di

Sulamien; see 212 - 214'J (1 (isopropanol / acetone)

Elemental analysis: CO ,, H ,,. BrNS

.1.9 2 4 2

C H M

Calculated 55.60 5.89 3.4l S a n uv 55.33 5.91 3.16

Claims (8)

18 64368 A process for the preparation of pharmacologically valuable substituted quinolizidine and indolizidine derivatives of the formula I in which A is phenyl or 2-thienyl and n is an integer of 3 or 4, and their pharmacologically acceptable acid addition salts and quaternary salts of derivatives, characterized in that Compound of formula (II): rr <c "2> c / A · OH wherein A and n are as defined above, dehydrating the compound obtained is optionally reacted with a pharmaceutically acceptable, inorganic or organic acid or of formula RX, wherein R is lower alkyl and X is an acid residue, with a corresponding quaternary ringing agent. Process according to Claim 1, characterized in that the compound of the formula I prepared is 2-diphenylmethylenequinolizidine methyl bromide. Process according to Claim 1, characterized in that the compound of the formula I prepared is 3-diphenylmethylenequinolizidine methyl bromide. n 19 64368 Process according to Claim 1, characterized in that the compound of the formula I prepared is 1-diphenylmethylene quinolide and ethyl bromide. Process according to Claim 1, characterized in that the compound of the formula I prepared is 2- (dithien-2-ylmethylene) quinolizidine methyl bromide. Process according to Claim 1, characterized in that the compound of the formula I prepared is 3- (dithien-2-ylmethylene) quinolizidine methyl bromide. 1. A pharmaceutical composition comprising a quinolizidine and an indolizide derivative of formula (I); II ^ 3: C (I) MA for phenyl or 2-thienyl and 3 or 4 or 4, for example pharmacologically acceptable sugar and quaternary quaternary salt, for the purposes of formula (II) ) rv ^ L, ^ | \ (II) OH där A och n avser decamma som ovan, dehydrateriser och denna föreningen eventuting bringas att reagera med en farmaceutiskt god-