NO149432B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE SUBSTITUTED QUINOLIZIDINE AND INDOLIZIDINE DERIVATIVES - Google Patents

Description

The present invention relates to an analogue process for the production of substituted quinolizidine and indolizidine derivatives

vates, which exhibit anticholinergic activity, antihistamine-

activity, antitussive effect and analgesic activity.

Atropine exhibits a powerful effect against acetylcholine and has long been used as a spasmolytic. Atropine has imi-

lertime a limited clinical applicability as this compound exhibits strong side effects such as thirst, pupil dilation, blood pressure elevation etc. A number of synthetic spasmolytics have therefore been produced, such as difemanil methylsulfate (see US patent 2 739 969 and Merck Index, 9th edition, 3309), prifinium bromide (see Merck Index, 9th edition, 7540) and time-

pidium bromide (see J. Med. Chem. 15, 914 [1972]). These compounds are not entirely satisfactory either, as in addition to a strong main effect against acetylcholine, they also exhibit strong side effects.

The purpose of the present invention is to produce

compounds that show the strongest possible effect against acetylcholine in combination with the least possible side effects.

The invention thus relates to an analogue method for

preparation of therapeutically active substituted quinolizidine-

and indolizidine derivatives of general formula:

where A denotes a phenyl or 2-thienyl group and n denotes 3 or 4, as well as pharmacologically acceptable acid addition salts and quaternary salts thereof with formula III:

wherein R denotes a lower alkyl group and X denotes an acid residue.

These new compounds exhibit a powerful effect against acetylcholine with greatly reduced side effects.

The analog method according to the invention is characterized by the fact that a compound with the general formula: where A and n have the above-mentioned meanings, is dehydrated, after which the compound obtained is optionally reacted with a pharmaceutically acceptable, inorganic or organic acid to form acid addition salts or with a quaternizing agent of formula IV:

wherein R and X have the meanings given above, to salts of formula III.

The lower alkyl group R can e.g. be methyl, ethyl, propyl or butyl. The acid residue X can be chlorine, bromine, iodine,

a sulfuric acid residue or an alkyl sulfate residue.

The starting materials with formula II are partly known and partly new compounds, and they can be prepared according to well-known methods, e.g. the method described by Karl Winterfield and Joachim Augstein in Chem. Pray. 90, 863-867 (1957).

The dehydration of a starting compound of formula II

is carried out in a solvent in the presence of a dehydrating agent while heating to a temperature between 20 and 150°C, preferably between 50 and 100°C, and 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 solvent does not interfere with the dehydration reaction. As a dehydrating agent, you can e.g. use hydrochloric acid, sulfuric acid, phos-

foroxychloride and p-toluenesulfonic acid.

The prepared compounds of formula I can be converted into 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 quaternization reaction indicated above can be carried out

in a solvent or without the use of any solvent. As a solvent, you 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 40°C, possibly in a closed tube.

The quaternary salts of formula III comprise stereoisomers (trans- and cis-isomers). The salts can be recovered in the form of a mixture of isomers or in the form of pure isomers or recrystallization.

The new compounds with formula. I as well as their acid addition salts and their quaternary salts exhibit anticholinergic activity, antihistaminic activity, antitussive activity and analgesic activity. In particular, the quaternary salts have a powerful effect against acetylcholine and boils, as well as reduced side effects such as thirst, pupil dilation, etc.

In what follows, results obtained from pharmacological investigations of the new compounds are given.

The protective effect (ED^Q value) has been determined

against convulsions induced by means of acetylcholine (1 x 10 7 g/ml). The experiments were carried out according to the Magnus method with cut small intestines from marmots. In the following table, the relative strength of the tested compounds is indicated in relation to the activity of atropine, whose activity is set equal to 1.0.

From the test results, it appears that the new compounds of formula I exhibit a strong effect against acetylcholine.

The effect is clearly better than the effect of scopolamine-N-butylbromide, diphemanil methylsulphate, prifinium bromide and thymidium bromide.

The compounds of formula I exhibit in comparison

with atropine less such side effects as thirst, pupil dilation etc. The new compounds can therefore be used as spasmolytics and as a remedy for boils.

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

The invention is illustrated by the following design examples.

Example 1 2-diphenylmethylenequinolizidine hydrochloride

10 ml of ethanolic hydrochloric acid was added to 1.39 g of α,α-diphenylquinolizidine-2-methanol and the resulting solution was boiled under reflux and with stirring for 4 hours. After distillation of 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 in a mixture of acetone and ether. 0.47 g of 2-diphenylmethylenequinolizidine hydrochloride was thereby obtained in the form of colorless needles with a melting point of 233 - 235°C.

Elemental analysis for C22H25N"HC"':

Example 2

(i) 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 formed crystals were filtered off and recrystallized in methanol. Thereby, 0.1 g of colorless needles with a melting point of 280 - 281° C (decomposition) were obtained.

Elemental analysis for C23H2gNI:

(ii) 2-(diphenylmethylene)-quinolizidine-methylbromide (a) 5.5 g of 2-diphenylmethylenequinolizidine was dissolved in 50 ml of acetone after which 5 ml of methyl bromide was added. The resulting mixture was allowed to stand for 48 hours at room temperature in a closed tube. The resulting reaction mixture was freed from the solvent and the residue was recrystallized in a mixture of methanol and acetone. 5.34 g of colorless prisms with a melting point of 261 - 263° C were obtained.

NMR (CDCl 3 ) 6 : 3.33 (N<+> - Me)

Elemental analysis for C23H2gNBr:

(b) The mother liquor obtained after recrystallization was dried under reduced pressure. The residue was recrystallized two

times in a mixture of methanol and acetone. The resulting mother liquors were combined and dried under reduced pressure, and the resulting residue was recrystallized in a mixture of methanol and acetone. 1.12 g of colorless prisms with melting point 235 - 236° C (isomer product) were obtained.

NMR (CDCl 3 ) 6 : 3.67 (N+ - Me)

(iii) 2-(diphenylmethylene)-quinolizidine-ethyl bromide

This compound was prepared in the same way as described above and after recrystallization in acetone had a melting point of 233 - 234°C.

Elemental analysis for C^H^NBr:

Example 3 3-Diphenylmethylenequinolizidine

(a) In 20 ml of 60% sulfuric acid, 1.5 g of a,a-diphenylquino-lizidine-3-methanol was heated to a temperature between 90 and 95° C. 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 ether phase obtained was washed with water and dried. After distilling off the solvent, the residue was recrystallized in hexane, whereby 1.1 g of colorless needles with a melting point of 118 - 120° C were obtained.

Elemental analysis for C22<H>2<5N:>

The compound produced was converted in a known manner to the corresponding hydrochloride. After recrystallization of the hydrochlorides in methanol, colourless, plate-shaped crystals with a melting point of 225 - 228° C were obtained.

(b) The starting material used, i.e. α,α-diphenylquino-lizidine-3-methanol, was prepared as follows;'

A solution of 120 g of 3-benzoylquinolizidine in anhydrous ether was added dropwise to a solution of phenyllithium (prepared from 1.23 g of lithium and 16.80 g of bromobenzene) in 50 ml of anhydrous ether. The reaction mixture was then boiled under reflux for 30 minutes. After destroying the excess of 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 was obtained.

Example 4

(i) 3- Diphenylmethylenequinolizidine— methyl iodide

This compound was prepared in the same way as described in example 2(1), whereby, however, methanol was used as the reaction solvent instead of acetone. The residue obtained after removal of the solvent was recrystallized in a mixture of methanol and acetone. The product was obtained in the form of colorless prisms with a melting point of 221 - 224°C.

Elemental analysis for C23H2gNI:

(ii) 3-diphenylmethylenejcinolizidine methyl bromide

(a) This compound was prepared according to the method described in Example 2(ii)(a). The product was obtained in the form of colorless needles which melted at 259 - 261° C during cleavage.

NMR (CDCl 3 ) 5 : 2.97 (N<+> - Me)

Elemental analysis for C^H^NBr:

(b) By proceeding in the same way as described in example 2(ii)(b), an isomer of the above-mentioned methyl bromide was prepared from the mother liquor obtained after the recrystallization. After recrystallization in a mixture of methanol and ether, this isomer was obtained in the form of colorless crystals with a melting point of 256 - 259°C.

NMR (CDCl 3 ) 6 : 3.40 (N+ - Me)

Elemental analysis for C23H2gNBr:

(iii) 3-diphenylmethylenequinolizidine ethyl bromide.

This compound was prepared in the same manner as described in Example 2(ii)(a). After recrystallization in acetone, the product showed a melting point of 225 - 228°C.

Elemental analysis for C -^H^øNBr:

Example 5 1-diphenylmethylenequinolizidine sulfate

A mixture of 3.5 g of α,α-diphenylquinolizidine methanol and 35 ml of 60% sulfuric acid was stirred at 100° C. for 20 minutes. The reaction mixture was then poured into water. The resulting mixture was made alkaline with 20% sodium hydroxide solution and 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 sulfate thus obtained was recrystallized in ethanol, whereby colorless, needle-shaped crystals with a melting point of 219 - 221° C were obtained.

Elemental analysis for C22<H>25N"<H>2S04:

Example 6

(i) 1-diphenylmethylenequinolizidine methyl iodide,

To a solution of 0.5 g of 1-diphenylmethylenequinolizidine

in 20 ml of acetone, 1.0 ml of methyl iodide was added, after which the resulting mixture was allowed to stand for 10 minutes. The crystals thus formed were filtered off. The filtered off crystals (0.53 g) were recrystallized in methanol, whereby colorless, plate-shaped crystals with a melting point of 294 - 296° C (decomposition) were obtained.

Elemental analysis for C^H^gNI:

(ii) 1-Diphenylmethylenecholinezidinemethyiodide This compound was prepared in the same manner as described under item (i) above. After recrystallization in ethanol, the product had a melting point higher than 300°C.

NMR (CDCl 3 ) 6 : 3.19 (N<+> - Me)

Elemental analysis for <C>23H2gNBr:

(iii) 1-diphenylmethylenequinolizidine— methyl bromide

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

Elemental analysis for C24H30NBr•1/2 H20:

Example 7 1-(dithien-2-ylmethylene) — quinolizidine hydrochloride

A mixture of 1.40 g of α,α-(dithien-2-yl)-quinolizi-din-1-methanol and 15 ml of ethanolic hydrochloric acid was stirred at 60° C. during 1 hour. After distilling off the solvent, the residue was dissolved in water. The resulting solution was made alkaline with 10% sodium hydroxide solution and then extracted with ether. The ether phase obtained was washed with water and dried. After distilling off the solvent, 1.29 g of a light brown liquid was obtained. This liquid was converted in a known manner to the corresponding hydrochloride. After recrystallization of the hydrochloride in a mixture of isopropanol and isopropyl ether, light brown prisms with a melting point of 194 - 197° C were obtained.

Elemental analysis for C^gH2^NS2'HC1:

Example 8

(i) 1-(dithien-2-ylmethylene) — k inolizidin- methyl iodide

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

Elemental analysis for C,<nH_.I>NS~:

J 19 24 2

In a similar way, the compounds listed below were also prepared.

(ii) 1-(dithien-2-ylmethylene)-quinolizidine methyl bromide

After recrystallization in a mixture of ethanol and isopropyl ether, this compound had a melting point of 294 - 297° C (decomposition).

NMR (CDCl 3 ) 6 : 3.36 (N+ - Me)

Elemental analysis for C^H^BrNS^:

(iii) 1-(dithien-2-ylmethylene) — quinolizidine-ethyl bromide

After recrystallization in a mixture of ethanol and isopropyl ether, this compound had a melting point of 286 - 288° C (decomposition).

Elemental analysis for C2QH2gBrNS2:

Example 9 2-(dithien-2-ylmethylene) — quinolizidine

This compound was prepared from α,α-(dithien-2-yl)-quinolizidin-2-methanol, whereby one proceeded in the same way as described in example 7, but used potassium hydroxide instead of sodium hydroxide and extracted with chloroform in instead of with ether. After recrystallization in isopropyl ether, the product was obtained in the form of colorless crystals with a melting point of 88 - 90°C.

Elemental analysis for C,„H2iN<S>2<:>

Example 10

(i) 2-(dithien-2-ylmethylene)-quinolizidin- methyl bromide This compound was prepared according to the same procedure as described in example 2 (i). After recrystallization in ethanol, the product was obtained in the form of colorless crystals with a melting point of 246 - 248° C (decomposition).

NMR (CDCl 3 ) δ: 3.42 (N<+> - Me)

Elemental analysis for C-^H^BrNS,,:

(ii) 2-(dithien-2-ylmethylene)—quinolizidin-ethyl bromide This compound was prepared by the same procedure as described in example 2(ii)(a), whereby, however, the reaction mixture was heated to 50° C. After recrystallization in isopropanol, the product obtained in the form of colorless crystals with a melting point of 217 - 218° C.

Elemental analysis for C-,AH„ ,BrNSn :

20 26 2

Example 11 3-(dithien-2-ylmethylene)- quinolizidine

This compound was prepared by the same method as described in example 7. After recrystallization in isopropyl ether, the product was obtained in the form of colorless needles with a melting point of 128 - 130°C.

Elemental analysis for C^gH^NS.-,:

Example 12

In the same way as described in example 6(i), the compounds indicated below were prepared.

(i) 3-(dithien-2-ylmethylene) — quinolizidine methyl iodide

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

Elemental analysis for C^gH2^<I>NS2:

(ii) 3-(dithien-2-ylmethylene)-k. inolizidin-methyl bromide After recrystallization in ethanol, this compound melted at 278 - 280° C with decomposition.

NMR (CDCl 3 ) δ: 2.92 (N+ - Me)

Elemental analysis for C-^gH2^BrNS2:

(iii) 3-(dithien-2-ylmethylene)-quinolizidin-ethyl bromide After recrystallization in a mixture of isopropanol and acetone, this compound melted at 226 - 228° C with decomposition.

Elemental analysis for C H BrNS2"l/2 H20:

Example 13 1-Diphenylmethyleneindolizidine

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

Mass spectrum<m> (C21H23N): m/e : 289 (M<+>), 212

The α,α-diphenylindoli-2idin-1-methanol used as starting material was prepared in the following way: 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 while cooling with water. After boiling under reflux cooling for approx. 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 aqueous phase obtained 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 to give 3.58 g of yellowish viscous product.

Mass spectrum (C^H^NO) : m/e : 307 (M+), 230, 123 (Basic peak)

The product obtained was a mixture of two diastereoisomers, and it could be used as such in the reaction indicated above.

Example 14 In the same way as described in example 6(i), the compounds indicated below were prepared.

(i) 1-Diphenylmethyleneindolizidine methyl bromide

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

NMR (CDCl 3 ) δ: 3.49 (N<+> - Me)

Elemental analysis for C22H26NBr:

(ii) 1-Diphenylmethyleneindolizidine methyl iodide

This compound was obtained in the form of colorless needles with a melting point of 189 - 190° C.

(iii) 1- diphenylmethylene indolizidine ethyl bromide

This compound was obtained in the form of colorless, plate-shaped crystals with a melting point of 163 - 164° C.

Example 15 2-Diphenylmethyleneindolizidine

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

Elemental analysis for C2iH23N:

Example 16 In the same way as described in example 6(i), the compounds indicated below were prepared.

(i) 2- dif eny l methylene indole i z id in- methyl iodide

After recrystallization in 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 C22Il26NI:

(ii) 2- diphenylmethylene indolizidine methyl bromide

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

NMR (CDCl 3 ) δ: 3.08 (N+ - Me)

Elemental analysis for C^f^gNBr:

Example 17 2-(dithien-2-ylmethylene)-indolizidine

In 20 ml of ethanolic hydrochloric acid, 2.66 g of α,α-(dithien-2-yl)-indolizidine-2-methanol were heated to 60° C. with stirring for 1 1/2 minutes. After distilling off the 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, whereby 1.76 g of a yellow liquid with a boiling point of 195 - 197° C at 3 mm Hg was obtained. The product was converted to the corresponding hydrochloride in a known manner. After recrystallization of the hydrochloride in isopropanol, yellow prisms with a melting point of 197 - 200° C (decomposition) were obtained.

Elemental analysis for C,_H,gNS^'HC1:

Example 18 In the same way as described in example 2, the compounds listed below were prepared. (i) 2-(dithien-2-ylmethylene)-indolizide in-methyl iodide After recrystallization in isopropanol, this compound was obtained as yellowish prisms with a melting point of 222 - 225°C. Elemental analysis for C-^gH22INS2: (ii) 2-(dithien-2-ylmethylene)-indolizidine-methylbromide After recrystallization in isopropanol, this compound had a melting point of 200 - 202°C.

NMR (CDCl 3 ) 6 : 3.49 (N+ - Me)

Elemental analysis for C-^I^B1^^ "1/2 t^O:

(iii) 2-(dithien-2"-ylmethylene)-indolizidine-ethyl bromide

After recrystallization in a mixture of isopropanol and acetone, this compound had a melting point of 212 - 214°C.

Elemental analysis for CigH24BrNS2:

Claims (1)

Analogous process for the preparation of therapeutically active substituted quinolizidine and indolizidine derivatives of general formula: where A denotes a phenyl or 2-thienyl group and n denotes 3 or 4, as well as pharmacologically acceptable acid addition salts and quaternary salts thereof with formula III: in which R denotes a lower alkyl group and X denotes an acid residue, characterized in that a compound of general formula: where A and n have the meanings given above, is dehydrated, after which the compound obtained is optionally reacted with a pharmaceutically acceptable, inorganic or organic acid to acid addition salts or with a quaternizing agent of formula IV: wherein R and X have the meanings given above, to salts of • formula III.