DE2404308C3 - Thieno or furo [3,2-c] pyridinium derivatives and their 43,6,7-tetrahydro derivatives, processes for their preparation and pharmaceuticals containing them - Google Patents

Description

(CHR ¹ J _n -R

have, with a halide of the general formula Z- (CHR ₁ J _n -R (III)

in which Z is a halogen atom and n, R and Ri are the have the abovementioned meaning to a pyridinium salt of the general formula

(CHR ¹ I-RZ

reacted and, if appropriate, the pyridinium salt then hydrogenated

10. Medicaments containing at least one compound according to Claims 1 to 8.

in which

whole number from 1 to 15,

Phenyl or benzoyl radical, optionally with at least one OH group, one Halogen atom, Ci-CV alkyl radical, Ci-Cb alkoxy radical or at least one nitro group is substituted,

H-; HO-; Ci — Cb-alkyl, where if n> \, the radicals R ^; in each group -CHR'-can have different meanings,
H-; Halogen atom and
Halogen atom

as well as the acid addition salts and quaternary ammonium derivatives of the 4,5,6,7-tetrahydro derivatives.

2. 5- (2-chlorobenzyl) -4,5,6,7-tetrahydrothieno- [3,2-c] pyridine and its acid addition salts.

3. S-p -chlorobenzylAS.öy-tetrahydrothieno- [3,2-c] pyridine and its acid addition salts.

4. 5- (2-methylbenzyl) -4,5,6,7-tetrahydrothieno- [3,2-c] pyridine hydrochloride and its acid addition salts.

5. 5- (2,6-chlorobenzyl) -4,5,6,7-tetrahydrothieno- [3,2-c] pyridine hydrochloride and its acid addition salts.

6. 5- (2-Nitrobenzyl) -4,5,6,7-tetrahydrothieno- [3,2-c] pyridine hydrochloride and its acid addition salts.

7. 5-Phenacylthieno [3,2-c] pyridinium bromide
and its acid addition salts.

8. 5- (o-Methoxyphenacyl) -thieno [3,2-c] pyridinium-

broinid and and its acid addition salts.

9. Process for the preparation of derivatives according to claim 1, characterized in that one is in on known manner compounds of the general formula

R ²

(II)

The invention relates to thieno or furo [3,2-c] pyridinium derivatives of the general formula

(CHR ¹ I _n -R

and their 4,5,6,7-tetrahydro derivatives of the general formula

(CHR ¹ J ₁₁ -R

in which

η = integer from 1 to 15,

X O -; - S-;

R = phenyl or benzoyl radical, which is optionally substituted with at least one OH group, a halogen atom, Ci-Cb-alkyl radical, Ci-Cb-alkoxy radical or at least one nitro group,
so R ¹ = H-; HO-; Ci-Cb-alkyl, where if n> 1, the radicals R ¹ in each group —CHR ¹ - can have different meanings,
R ² = II -; Halogen atom and
Z = halogen atom
ss

as well as the acid addition salts and quaternary ammonium derivatives of the 4,5,6,7-tetrahydro derivatives.

The invention also relates to a method for the preparation of derivatives, which is characterized is that in a known manner compounds of the general formula

R ²

in which X and R> have the meaning given above in which X and R2 have the meaning given above,

with a halide of the general formula

Z- (CHR,) ,, - R (III)

in which Z is a halogen atom and n, R and Ri are as defined above, to a pyridinium salt of the general formula

R ²

iCHR ') _n —R

converts and optionally the pyridinium salt then hydrogenated

The derivatives of the formula (I) prepared in this way can be in free form or in the form of Salts .be isolated.

The condensation reaction is preferably carried out in a medium consisting of an inert solvent, z. B. acetonitrile, is carried out.

A reducing derivative, e.g. B. an alkali borohydride, for example sodium borohydride, used. This reduction is carried out in particular at ambient temperature.

The thieno- [3,2-c] pyridines and furo [3,2-c] pyridines of the formula (III) used as starting compounds are known compounds described in the literature.

The products produced by the process according to the invention are preferably obtained by extraction with an organic solvent, e.g. B. ether, after adding a base (e.g. ammonia), evaporation of the solvent and taking up the residue in an acid (e.g. HCl), the product in Is precipitated in the form of crystals, which are filtered off and recrystallized from ethanol.

The salts and quaternary ammonium derivatives of the compounds of the general form! (I) will be after known processes.

The pyridinium derivatives represented by the general formula (1) are particularly effective as an anti-arrhythmic agent.

The examples illustrate the invention.

example 1

Production of 5- (2-chlorobenzyl) -4,5,6,7-tetra-

hydrothieno [3,2-c] pyridine

in the form of the hydrochloride

(Derivative no.1)

A solution of 13.5 g of thieno [3,2-c] pyridine (0.1 mol) and 17.7 g of 2-chlorobenzyl chloride in 150 ml of acetonitrile is allowed to boil for 4 hours. After evaporation of the solvent a solid residue 5- (2-chlorobenzyl) thieno [3,2-c] pyridinium chloride of melting point 166 ⁰ C (derivative no. 30). This compound is taken up in a solution consisting of 300 ml of ethanol and 100 ml of water. 20 g of sodium borohydride (NaBH, i) are added in small portions to the solution, which is kept at room temperature. The reaction mixture is stirred for 12 hours and then evaporated. The residue is taken up in water and acidified with concentrated hydrochloric acid in order to destroy the excess of the reducing agent. The mixture is then made alkaline with ammonia and then extracted with ether. The ethereal solution is washed with water and dried

and evaporated. The oily residue is dissolved in 50 ml of isopropanol and then with a solution of Hydrochloric acid is added to ethanol

After filtration and recrystallization from ethanol, crystals of 5- (2-chlorobenzyl) -4,5,6,7-tetrahydrothieno [3,? - c] pyridine hydrochloride (yield 60%) with a melting point of 19O ⁰ C (determined on the Kofler block) receive.

ic example 2

Production of 5- (4-methoxybenzyl) -

4,5,6,7-tetrahydrothieno [3,2-c] pyridine

in the form of the hydrochloride

(Derivative no.2)

By reacting 13.5 g (0.1 thieno- [3.2-c]

pyridine with 17.2 g (0.11 mol) of 4-methoxybenzyl chloride in the manner described in Example 1 are in a yield of 71% crystals of the hydrochloride from Melting point 214 to 216 ° C (Kofler block) obtained.

Example 3

Production of 5- (3,4,5-trimethoxybenzyl) -

4,5,6,7-tetrahydrothieno [3,2-c] pyridine

in the form of the hydrochloride

(Derivative no.3)

By reacting 13.5 g (0.1 mol) of thieno [3.2-c] -} o pyridine with 23.8 g (0.11 mol) 3,4,5-trimethoxybenzyl chloride in the manner described in Example 1, crystals of the hydrochloride are obtained in a yield of 79% obtained from melting point 200 to 205 ° C (Kofler block).

Example 4

Preparation of 5- (2-hydroxy-2-phenylethyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine in the form of the hydrochloride (derivative no.4)

By reacting 13.5 g of thieno [3,2-c] pyridine with 19.9 g of phenacyl bromide to that described in Example 1 Way (the amount of sodium borohydride is sufficient to simultaneously remove the pyridine ring and the group —CO— des Hydrogenating phenacyl bromides and converting them to -CHOH-) crystals of the hydrochloride are obtained in a yield of 61%. The one on the Koflerblock's specific melting point is 164 to 166 ° C.

The following connections are established in an analogous manner:

Derivative 5:

5-p -chlorobenzyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (Melting point 240 ° C)

Derivative 6:

S-p-ChlorbenzyM.S.ö ^ -tetrahydrofurop ^ -clpyridinfto hydrochloride (melting point 210 ° C)

Derivative 7:

5- (3,5-Dimethoxybenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (melting point 195 ° C)

DerivatS:

5- (3,4,5-trimethoxybenzyl) -4,5,6,7-tetrahydrofuro- [3,2-c] pyridine hydrochloride (Melting point 175 ° C)

Derivative 9:

5- (3-Methoxybenzyl) -4,5,6,7-tetrahydrothieno- [3,2-c] pyridine hydrochloride (melting point 20O ⁰ C)

Derivative 10:

5- (3-methylbenzyl) -4,5,6,7-tetrahydrofuro [3,2-c] pyridine hydrochloride (melting point 210 to 220 ⁰ C)

Derivative 11:

5- (4-methylbenzyl) -4,5,6,7-tetrahydrofuro [3,2-c] pyridine hydrochloride (Melting point 220 to 240 ° C)

Derivative 12:

5- (2-fluorobenzyl) -4,5,6,7-tetrahydrothieno- [3,2-c] pyridine maleate (melting point 197 to 198 ° C)

Derivative 13:

[3,2-c] pyridine hydrochloride (m.p. 210 ⁰ C) derivative 14:

5- (2-phenylethyl) -4,5,6,7-tetrahydrothieno- [3,2-c] pyridine hydrochloride (Melting point 226 ° C)

Derivative 15:

5- (2-phenylethyl) -4,5,6,7-tetrahydrofuro [3,2-c] pyridine hydrochloride (Melting point 235 to 240 ° C)

Derivative 16:

5 - [(1-methyl-2-hydroxy-2-phenyl) ethyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (m.p. 230 ⁰ C)

Derivative 17:

(2-p-hydroxyphenyl-2-hydroxy) -5-ethyl-4,5,6,7-tetrahydrofuro [3,2-c] pyridine (m.p. 179 ⁰ C)

Derivative 18:

5- (2-methylbenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (melting point 208 to 21O ⁰ C)

Derivative 19:

5- (3-methylbenzyl) -4,5,6,7-tetrahydrothieno- [3,2-c] pyridine hydrochloride (Melting point 215 ° C)

Derivative 20:

5- (4-methylbenzyl) -4,5,6,7-tetrahydrothieno- [3,2-c] pyridine hydrochloride (Melting point 260 ° C)

Derivative 21:

5- (4-fluorobenzyl) -4,5,6,7-tetrahydrothienc- [3,2-c] pyridine hydrochloride (Melting point 215 ° C)

Derivative 22:

5- (2,6-chlorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (m.p. 200 ⁰ C)

Derivative 23:

5- (2-nitrobenzyl) -4,5,6,7-tetrahydrothieno- [3,2-c] pyridine hydrochloride (Melting point 180 ° C)

Derivative 24:

5- (4-hydroxybenzyl) 4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (m.p. 240 ⁰ C) derivative 25:

(2-p-Hydroxyphenyl-2-hydroxy) -5-ethyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (melting point 216 to 2i 8 ° C)

Derivative 26:

(2-p-Methoxyphenyl-2-hydroxy) -5-ethyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (Melting point 206 to 208 ° C)

Derivative 27:

(2-p-Chlorophenyl-2-hydroxy) -5-ethyl-4,5,6,7-tetrahydrolhieno [3,2-c] pyridine hydro-
j chloride (melting point 194 to 196 ^ϋ C)

Derivative 28:

5- (2-Hydroxy-2-o-methoxyphenylethyl) -4,5,6,7-telrahydrothieno [3,2-c] pyridine hydrochloride
(Melting point 224 ° C)

Derivative 29:

5- (2-Hydroxy-2-m-methoxyphenylethyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride
2s (melting point 170 ⁰ C)

Example 5

Synthesis of 5-phenacylthicno [3,2-c] -
- ^ ⁰ pyridinium bromide

(Derivative no.31)

A mixture of 13.5 g of thieno [3,2-c] pyridine (0.10 is mol) and 19.9 g of phenacyl bromide (0.10 mol) in 200 ml Acetone is stirred for 2 hours at room temperature. A colorless precipitate is formed, which is filtered off, washed with acetone and dried. This gives 29.7 g of crude product (yield 89%). After recrystallization from 50 ml of water and drying, 26.6 g (yield of recrystallization 89.5%) very hygroscopic, colorless crystals with a melting point of 206 to 207 ° C. (Kofler's block) were obtained.

Example 6

Synthesis of 5- (o-methoxyphenacyl) thieno- [3,2-c] pyridinium bromide

(Derivative no.32)

In the manner described in Example 5, 13.5 g of thieno [3,2-c] pyridine are mixed with 21.3 g of o-methoxyphenacyl bromide implemented, whereby 27.34 g of colorless crystals with a melting point of 258 to 260 ° C (Kofler block) can be obtained.

Example 7

Synthesis of 2-chloro-5-phenacylthieno- [3,2-c] pyridinium bromide

(Derivative no.33)

hS in the manner described in example 5 by reaction of 17 g of 2-chlorothieno [3,2-c] pyridine with 20 g of phenacyl bromide 29.60 g of colorless crystals vom Melting point 239 ° C (Kofler block) obtained.

Example 8

Synthesis of N-p-Chlorophenacylthieno- [3,2-c] pyridinium bromide

(Derivative no. 34) _s

13.5 g of thieno [3,2-c] pyridine with 22.5 g of p-chlorophenacyl reacted in the same manner in Example 5, whereby 25.80 g of colorless crystals of melting point 208-210 ⁰ C (Kofler block) are obtained . ι ο

The following derivatives are prepared in an analogous manner:

Derivative 35:

5- {3,4-D: hydroxyphenacy!) - thieno [3.2-c] pyridir !! - if, umchlorid (yellowish crystals, melting point over 260 ⁰ C)

Derivative 36:

Sp-Fluorophenacylthieno ^^ - cJpyridiniumchlorid (colorless crystals, melting point 166 ⁰ C)

Derivative 37:

S ^ p-HydroxyphenacylJ-thienofS ^ -cJpyridiniumehlorid (brown powder, melting point 260 ⁰ C)

Derivative 38:

S-ip-MethoxyphenacylJ-thienofS ^ -cJpyridiniumbromid (white-yellowish crystals, melting point over 260 ° C)

Derivative 39: '°

S-im-Methoxyphenacyl ^ thienol ^ -cjpyridiniumbromid (yellow powder, melting point 24O ⁰ C)

The derivatives 31 to 39 become the corresponding ones in the manner described in Example 1 Derivatives of formula (I) prepared.

The results of toxicological and pharmacological tests given below illustrate the interesting effects of the derivatives according to the invention, especially the anti-arrhythmic ones Effect of pyridinium derivatives and the anti-inflammatory, vasodilator and agglomeration the platelet preventing effects of 4,5,6,7-tetrahydro derivatives.

I. Toxicological investigation

This investigation, focusing on the acute toxicity, the subacute toxicity, the chronic toxicity, the Tolerability and the development of malformations provided evidence of low toxicity and the good compatibility of the compounds according to the invention.

II. Pharmacological examination

1. The pyridinium derivatives according to the invention are powerful agents against arrhythmia, which by Experiments on animals had been demonstrated in which arythms were caused by the administration of Barium chloride, calcium chloride, K-strophantine, aconif *> tin, isoprenaline, adrenaline and ouabain had been. In these experiments, the pyridinium derivatives according to the invention showed the ajmaline, superior to quinidine and lidocaine.

2. Using the classic method of localized edema caused by fts carrageenin, it was shown that the 4,5,6,7-tetrahydro derivatives according to the invention have anti-inflammatory properties.

55 shafts that are better than those of aspirin and practically identical to those of indomethacine. These results were confirmed by the tests carried out according to the classical method of generalized edema induced with egg white.

3. Both when trying with adenosine diphosphate and when trying with collagen and thrombin showed the 4,5,6,7-tetrahydro derivatives according to the invention a higher effect on the inhibition of Aggregation of platelets as acetylsalicylic acid.

4. Experiments carried out with rabbits showed evidence of a strong peripheral !! and cerebral vasodilatory effect of the 4,5,6,7-tetrahydro derivatives according to the invention, the effect of the des Papaverine is the same at very low doses and is superior at stronger doses, with the duration of the Effect that is strongly superior to that of papaverine.

The pharmaceutical preparations according to the invention can be in the form of tablets, coated tablets, capsules, Drops, syrup, suppositories or injection solutions can be applied.

Each dosage unit advantageously contains 0.005 to 0.1 g of the pyridinium derivative or 0.025 to 0.5 g of the 4,5,6,7-tetrahydro derivative, the daily dose being 0.005 to 0.3 g for the former compounds and 0.025 to 1 g for the latter compounds can.

The pyridinium derivatives are indicated in the case of heart disease in tachycardia of the ventricle, Extrasystoles of the ventricle and cardiac arrhythmias caused by over-excitability of the myocardium Digitalis treatment as well as anesthesia in preparation for surgical interventions on the heart and at general surgical interventions in the elderly.

The 4,5,6,7-tetrahydro derivatives according to the invention are indicated in the treatment of post-traumatic diseases or postoperative edema, in plastic or reparative surgery, in stomatological disorders, in affections that are accompanied by inflammatory reactions such as angina and bronchitis, in inflammatory or degenerative rheumatism and in acute abarticular affections.

In addition, they are due to their inhibitory effect on the agglomeration of blood platelets and their vasodilatory effects beneficial for the treatment of disorders of the cerebral and peripheral Circulatory system and prevent thrombosing complications of atheroma.

Pharmaceutical preparations
Tablets

Derivative no.

talc

Levilite

strength

glucose

Derivative No. 1

Magnesium stearate

Stearic acid

Cornstarch

Lactose

Dragoes

0.100 g
0.003 g
0.010 g
0.010 g
0.025 g

0.080 g
0.010 g 0.005 g 0.020 g 0.015 g

ceiling Capsules Derivative No. 2 drops Derivative No. 5 Derivative No. 8 Derivative No. 8 core 24 0.003 g 04 308 10 ceiling Tablets Derivative # 36 Capsules Derivative No. 33 drops Derivative No. 37 Derivative No. 31 Derivative No. 31 0.003 g 9 rosin Magnesium stearate Flavored excipient, ad Semi-synthetic triglycerides, ad Isotonic saline solution, ad Derivative No. 31
talc 0.001 g kaolin Magnesium hydrocarbonate Corn starch
talc Flavored excipient, ad Semi-synthetic triglycerides Isotonic saline solution, ad 0.005 g turpentine talc Lactose 0.002 g strength Cornstarch Lactose Suppositories 0.002 g Rubber lacquer Suppositories Solution for injection Coated tablets Magnesium stearate 0.005 g Titanium dioxide Calcium carboxymethyl cellulose 0.010 g gelatin 0.010 g strength Magnesium stearate 0.005 g talc 0.002 g Gum arabic Stearic acid Injection solutions 0.001 g White wax 0.001 g 5 White rubber lacquer talc 0.002 g Titanium dioxide White wax for 1 dragee Erythrosine for 1 dragee sugar syrup required White official sugar required crowd crowd IO 0.075 g 0.150 g 0.020 g 0.005 g 0.010 g 0.005 g 0.005 g <5 0.003 g 0.003 g 0.003 g 2.5 g 30 ml 20th 0.100 g 0.025 g
0.010 g 0.100 g 0.010 g 1 suppo
sitorium 1 p 5.00 g 100 ml 0.075 g 3 ml 0.025 g 30th for 1 suppo sitorium required crowd 0.025 g
0.010 g 35 0.005 g 0.010 g 0.005 g 3 ml - (C

Claims (1)

Patent claims: 1. Thieno or furo [3,2-c] pyridinium derivatives of general formula (CHR ¹ J _n -R and their 4,5,6,7-tetrahydro derivatives of the general formula