SE191323C1 - - Google Patents

Description

Inventors: CJ Cavallito and AP Gray_ Priority requested by Iran on 22 June 1956 (USA) t. It has been found that asymmetric bisquaternary ammonium salts of the formula anion-anion on-RI \ / a1kylene bridge — N + —R3 I / R3, -which constitute solid substances with a relatively high melting point, have valuable therapeutic properties. In this formula, RN represents a pyridyl ring, which may be partially or completely hydrogenated and which is substituted in such a way that its total radical weight amounts to at least 150, each of the symbols 114, R, and R represents a lower alkyl or lower alkenyl group, two of these groups being able to be joined to form a ring, which may additionally contain a heteroatom and wherein the radical R

Total radical radical weight not exceeding 117, the alkylene bridge contains 2-6 carbon atoms and may consist of a straight or branched chain, and the anions consist of halide ions, which may be the same or different.

In particular, these compounds of the formula I have a hypotensive effect, and a ganglion-blocking effect, which had effects unrelated to each other, i.e. vary independently of each other when changing the molecular structure of the framework indicated by the above formula. In the clinical use of these new compounds, it has been shown that such frequently occurring side effects as severe postural hypotension, constipation, dilation and paralysis of the Opts pupil, dry mouth, decrease in sexual activity, etc. are largely eliminated.

The present invention therefore relates to the production of bisquaternary amnionium salts with tetapentic action. wherein cid for this salt -marking in the first run consists in that a cyclic compound of the formula R-N is quaternized with a ca-haloalkylammonium salt of the form. Anion - alkylene bridge — N-I --- R2 I-- \ R3'1 to form an asymmetric bisquaternary ammonium salt of the above formula I, the various symbols having the meanings given above.

The invention comprises Oxen the modification of the above process which involved the preparation of an asymmetric bisquaternary ammonium salt of the formula anion-anj011-R-N + -alkylene bridge-NF-R2 I \ R3, -van in R-N denotes a piperidine ring , which is substituted in such a way that its total radical weight including a possible substituent at the nitrogen atom amounts to at least 150, and the symbols R. ', R3 and R3 as well as the terms "anjom and" alkylene bridge have the meanings given above, the radical radical does not exceed 117, in that a compound of the formula R-N, wherein R-N has (I) 2 - the above meaning, which compound is a ring-substituted piperidine compound which is unsubstituted at the ring nitrogen atom, N-alkylated with a lower dialkylaminoalkyl halide of the formula / R anjone - alkylene bridge —N \ 2 to form a diterriar has of the formula / RR — N alkylene bridge — N, `1:12 in which both the latter formulas Rs, R ,, R — N and the expression * alkyleneb back »have the meanings given above, and that the ditertiary base is subsequently quaternized.

Other bisquaternary pyridinium and piperidinium salts with hypotensive action have been previously known, see Chemical Abstracts, 48 (1954) sp. 8960 !. These compounds have the formula B — R — CH, - —CH s — C11, —CH2 — CH, —RBr, wherein R may denote hi. a. (a) methylpiperidinium or (b) pyridinium. In contrast to the compounds of the present invention, these compounds have a symmetrical structure and thus differ from the new compounds of the invention in this and other respects. For lowering blood pressure, the compound (b) is stated to be less active than the compound (a); flag of the hypotensive effect independent ganglion blocking effect is not mentioned.

In the radicals of the compounds of the invention, the preferred substituents attached to the nitrogen atom are three lower alkyl radicals consisting of methyl, ethyl, n-propyl or isopropyl. Two of these radicals may be joined together to form with the nitrogen atom a small, heterocyclic radical, for example a pyrrolidine radical, methyl-pyrrolidine radical or piperidine radical, and the heterocyclic ring may comprise an oxygen or sulfur atom, as in the morpholine and thiamorpholine radicals.

The rigid part R-N of the molecule should have a radical weight of 175-350. This radical can be substituted with a large number of different radicals.

The lower alkylene bridge (C2-C4) between the ram quaternary ammonite parts may, as mentioned above, be straight or branched. The ophthalmic pharmacological effect should be obtained with compounds, where the bridge comprises three carbon atoms.

The molecular moiety —N — R, the substituent R, R, R, and R 5 may be, for example, three lower alkyl groups or three lower alkenyl groups, which are the same or different, or this moiety may also be an N-heterocyclic radical, which may also comprise an oxygen or sulfur atom, and a lower alkyl or lower alkenyl radical may be attached to the heterocyclic nitrogen atom. The total number of carbon atoms in the substituents attached to the quaternary quaternary atom in this moiety does not reside at about 7 and at least one of these substituents is suitably a methyl radical.

The smaller ammonium moiety preferably consists of: trimethylammonium, methyldiethylammonium, dimethylethylammonium, methyldipropylammonium, dimethylisopropylammonium, methylethylpropylamethonium, N-methylpyrrolidinium, N-ethylpyrrolidinium, N-methylpiperidinium, N-methylmethylmethylphilylmethylmethylfolylmethyl. As further examples of the minor part may be mentioned diethylanunium, N-ethylpiperidinium, N-propylpyrrolidinium and N-ethylmorpholinium.

The major part of the molecule (RN) has a radical weight of at least 150 and consists of a substituted pyridine ring. The pyridine ring itself may be fully or partially hydrogenated. The substituents on the ring may be attached to any of the available ring positions, except for the 2- and 6 positions of the ring when the pyridine ring is not solid or partially hydrogenated, may not have substituents, since the quaternization then. is the answer due to steric obstruction. Although the substituents may comprise various fused rings, they are not fused to the pyridine ring but constitute real substituents in relation thereto. Since the unsubstituted pyridyl radical has a molecular weight of 79, its substituents must have such a weight that a total weight is obtained for the substituted pyridyl radical of at least 150 and suitably 150-350.

As few polar radicals as possible are bound to the hydrogenated or unhydrated pyridine radicals. With this limitation, the substituents can be constituted by arbitrary, organic radicals of sufficient weight, for example various types such as condensed, organic ring structures, aryl, branched chain alkyl, aralkyl, aralkoxy, aralkenyl, aryltioalkyl, diarylaminoalkyl, heterocycloalkyl, cycloalkyl, aralkoalkyl , arylcarboxyalkyl, arylimidoalkyl and heterocyclic ring structures, each of which is attached to the pyridine ring directly or by a bridge, comprising chains containing such various groups as carbonyl, alkane, alkene, ether, thioether, ester, amide and sulfone. At most one ring atom in the substituted CsN ring, i.e. the basic pyridine ring, may form part of another ring system.

The larger anunonium moiety may be, for example, the preferred radicals: 2- and 4- (3-indolylethyl) -pyridinium, 2- and 4- (1-indolylethyl) -pyridinium, 2- and 4- (1-methyl-3-indolylethyl) ) - pyridinium, 2- (3-indolylethyl) -5-ethylpyridinium, 241- - methyl-3-indolylethyl) -5-ethylpyridinium, 2- and 4- (1-naphthylethyl) -pyridinium and 2- and. 4- (14-Indenylethyl) -pyridinium.

Other examples include such large pyriminium moieties as: 2- and 4- (1-naphthylethyl) -pyridinium, and 4- (2-naphthylethyl) -pyridimum, 2-, 3- and 4- (2-indolyl) -pyridinium, 2- And 443-indorylethyl) -pyridinium, 2-, 3- and 4- (3,3'-diindolylmethyl) -pyridinium, 2- and 4- (1-benstriazolylethyl) = pyridinium, 2-, 3- and 4-16- (bicycl-101212.1] -heptenyl)] -pyridinium, 546- (bicycl-12-12.2.11-2-heptinyl) 1-2-picolinium, 2-, 3- and 4-benzylpyridiniurene, 2-, 3 and 4-carboxanilidopyridinium, and 4-benzoxypropyl) -pyridinium, 2-, 3- and 4-benzoylpyridinium, 2- and 4-stilbazolium, 2-, 3- and 4- (phenylthioethyl) -pyridinium, 2-, 3- and 4- (tert -butylthioethyl) -pyridinium, 2-, 3- and 4- (benzylthioethyl) -pyridinium, 3- and 4-carbobenzyloxypyridinium, 2 and 4- (diphenylaminoethyl) -pyridinium, 2- and 4- (phthalimidoethyl) -pyridinium, 2- and 4-hexylpyridinium, 2- and 4Acylpyridinium, 2- and 4- (2-oxocyclohexylethyl) -pyridinium, 2- (3,4-dichlorobenzyl) -pyridinium 2-, 3- and 4- (diphenylmethyl) -pyridinium, and 4 - (triphenylmethyl) -pyridinium, 2-, "3- and 4- (benzyloxyethyl) -pyridinium, 2- and 4- (9-fluorenyloxypropyl) -pyridinium, 2-, 3- and 4- (benzyloxymethyl) -pyridinium, 2-, 3- and 4-diphenylmethoxymethyl) -pyridinium, 2 , 3- and 4- (9-fluorenecarboxypropyl) -pyridinium, 2- and 441- (1-benzyl-3-indolyl) -2-propyl-pyridinium, 2- and 4413- (1-methyl-3-indolyl) -α-cyclohexylethyl-pyridinium, 2- and 4- (1-methyl-3-oxindolylethyl) -pyridinium, 2-, 3- and 4- (2-benzothiazolylthioethyl) -pyridinium, 2- (2-pyridylamino) -pyridinium, 2- [4- (9-Fluorenylethyl) -pyridinium, 2- and 4- (9-fluorophenyl) -pyridinium, 2-orb 4- (3-benzothiophenylethyl) -pyridinium, 2- and 4- (9-carbazolethyl) - pyridinium, 2- and 4- (3,4-dichloro-phenyl-type-pyridinium, 2,4-di-phenyl-pyridinium, 2,5-bis- (phenylthio-type-pyridinium) 2,4-bis- (phenylethyl) -pyridinium, 2- and 4 - (2-thienylethyl) -pyridinium, 2- and 4- (2-furylethyl) -pyridinium, 2,4-bis (2-furylethyl) -pyridinium, 2- and 4- (2-benzofurylethyl) -pyridinium, 2- and 4-phenylpyridinium, 2- and 4- (2-nalthyl) -pyridinium, 2- (2-phthalimidinoethyl) -5-ethylpyridinium, 2- and 4- (2-benzisosulfonazolylethyl-pyridinium, 2-hexyl-5-ethylpyridinium, 2,4-bis- (2-pyrrolylethyl) -pyridinium, 2- and 4- (2-phenyl-1-pyrrolylethyl) -pyridinium, 2- and 4- (1-oxindolylethyl) -pyridinium, 2- and 4- (2-indanyl) -pyridinium, α- (2-indanylidene) -4-picolinium, α- (1-indanylidene) -2-picolinium, α- ( cyclohexylidene) -4-picolinium, 4- (p-methyl-13-phenylethylene) -pyridinium, 2 and 4- (6-phenylbutadienyl) -pyridinium, 2- and 4- (benzoylpropyl) -pyridinium and 5- (cyclohexylthioethyl) -2 -picolinium.

It is also possible to use 1- (lower-alkyl) -piperidinium corresponding to the types indicated above, the pyridine ring here being replaced by a 1- (15-gra-alkyl) -piperidine ring, as well as piperidinium systems, such as: spiro- (1-methyloxindole) - 3,4 '- (1'-methylpiperidinium), spiro- [fluoren-9,4' - (11-methylpiperidinium) 1,1-benzylpiperidinium, 1-phenylethylpiperidinium, 1- (2-hydroxy-2-phenylethyl) -piperidinium , 1-octylpiperidinium, 1-do decylpiperidinium, 1- (2-hydroxydecyl) -piperidinine, 1- (2-hydroxyalkyl) -piperidinium, 1- (2-acetoxyalkyl) -piperldinium. ock, 142-benzoxy-octyl), 4piperidinium.

In carrying out the method of the invention, the reactants have the same components as in equimolar amounts, or, excess of either reagent. used, depending on the possibilities to acquire the starting materials and to rent the product. Examples of quaternization reactions according to the invention are quaternization of a cyclic compound; which contains an indolylalkylpyridine group, and which is obtained by addition reaction between a fig containing an indole nucleus, which is unsubstituted L 3 -constitution, on a vinylpyridine base, and: cyaternization of a cyclic compound, which contains an indenylalkylpyridine group; containing an indene, which is unsubstituted, and a vinylpyridine base.

The quaternization is usually carried out in the presence of. solvents. In the following, lean are given: examples of solvents which can be used to advantage: Solvents. Acetonitrile, aliphatic alcohols, such as ethanol, dimethylformamide, methanol, isopropyl alcohol, methyl alcohol, isoamyl alcohol; nitrobenzene; nitroalkanes, such as nitromethane and nitroethane; mixtures of dioxane and an alcohol, and similar powdered solvents and mixtures thereof. The reaction can then be carried out with a large excess of it as a starting material or other base, which serves as a solvent. For the preparation of compounds of the types described in Examples 16-18, alcohols and alcoholic mixtures are precipitated, but with success some other of the above-mentioned powdered solvents may be used.

Temperature. The reaction can be carried out at room temperature and up to 150 ° C at atmospheric pressure or in a closed reaction vessel, with reflux being preferred at about 80 ° C. The lower temperatures of this range with subsequent longer reaction time are preferred, while over 200 ° C reversal of quaternization constitutes a joke onskvard complication.

The following non-limiting examples illustrate the process of the invention.

Example 1. 1- (4-Benzylpyridinium) -3- (trimethylammonium) -propane dibromide.

A solution of 10.4 g (0.04 mol) of 3-bromopropyltrimethylammonium bromide and 9.0 g (0.06 mol) of 4-benzylpyridine in 35 ml of acetonitrile was boiled for 6 hours under reflux. The resulting formation was collected and recrystallized from n-propanel and ethyl acetate to give 7.6 g (44% of theory) of 1- (4-benzylpyridinium) -3- (trimethylammonium) -propane dibromide. After three more recrystallizations in isopropanol, the product melted at 172-174 ° C.

Analysis: Berdknat: C 50.25% H 6.09% Br 37.15% Found: 50.326.3836.72 4- Example 2. 1- (2-Benzylpyridinium) -3- (trimethylammonium) -propanedibromide.

To 6.8 g (0.026 mol) of 3-bromopropyltrimethylammonium bromide dissolved in isopropanol was added 6.8 g (0.04 mol) of distilled 2-benzylpyridine and the resulting solution was boiled for 30 hours under Aterflode. By diluting the cooled solution with ethyl acetate, 1- (2-benzylpyridinium-3- (trimethylammonium) -propane dibromide precipitated as a hygroscopic solid.

Example 3. 144- (t-Butylthioethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide.

In the same manner as in Example 1, 4- (tert-butylthioethyl) -pyridine was reacted with 3-bromopropyltrimethylammonium bromide to give (tert-butylthioethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide as a hygroscopic solid.

Example 4. 144- (n-propylthioethyl) -pyridinium 3- (trimethylammonium) -propane dibromide.

In the same manner as in Example 1, 144- (n-propylthioethyl) -pyridinium-3- (trimethylammonium) -propane dibromide was obtained in the form of a hygroscopic solid by reacting 4- (n-propylthioethyl) -pyridine with 3-bromopropyltrimethyltrimethylammonium bromide.

Example 5. 144- (Benzoxypropyl) -pyridinium 1-3- (trimethylammonium) -propane dibromide.

In the same manner as in Example 1, 144- (benzoxypropyl) -pyridinium] -3- (trimethylammonium) -propane dibromide was obtained as a solid, which during probe division narrows at 225-226 ° C by reacting 4- (benzoxypropyl) -pyridine with 3-bromopropyltrimethylammonium bromide.

Analysis: Berliknat: C 50.21% H 6.02% Br 31.82% Found: 50.5.9431, Example 6. 144- (Carbobenzyloxy) -pyridinium] -3- (trimethylammonium) -propanedibromide.

In the same manner as in Example 1, 144- (carbobenzyloxy) -pyridinium] -3- (trimethylammonium) -propane dibromide was obtained by reacting benzyl 1-4 picolinate with 3-bromopropyltrimethylammonium bromide.

Example 7. 1- [4- (Phenylthioethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide.

In the same manner as in Example 1, 144- (phenylthioethyl) -pyridinium] -3- (trimethylammonium) -propanedibromide was prepared, which narrowed at 170-172 ° C by reacting 4- (phenylthioethyl) -pyridine with 3- bromopropyltrimethylammonium bromide.

Analysis: Calculated: C 47.91% H 5.92% Br 33.55% Found: 47.5.8334.00 Example 8. 142- (phenylthioethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide.

In the same manner as in Example 1, 1-12- (phenylthioethyl) -pyridinium] -3- (trimethylammonium) —propane dibromide, a hygroscopic solid of 2- (phenylthioethyl) -pyridine and 3-bromopropyltrimethylammonium bromide were prepared.

Analysis: Calculated: Br 33.55% Found: 33, Example 9. 1- (4-Benzylpyridinium) -3- (1-methylpyrrolidinium) -propane dibromide.

In the same manner as in Example 1, 1- (4-benzylpyridinium) -3- (1-methylpyrrolidinium) -propane dibromide, a hygroscopic solid Amu, is obtained by reacting 4-benzylpyridine with 3-bromopropyl-1-methylpyrrolidinium bromide.

Analysis: Calculated: (-I- 1H 2 O): Br 33.70% Found: 33.8 Example 10. 1- (4-Benzylpryridinium) -3- (1-methylpiperidinium) -propane dibromide.

In the same manner as in Example 1, 1- (4-benzylpyridinium) -3- (1-methylpiperidinium) -propane dibromide, melting at 227-230 ° C, is obtained by reacting 4-benzylpyridine with 3-bromopropyl-1-methylpiperidinium bromide Analysis: Calculated (+ 1/2 H 2 O): C 52.61% H 6.53% Br 33.34 H 2 O 1.85% Found: 52.196.12 Br 32.77 H 2 O 1.02 Example 11. 1- ( 4-Benzylpyridinium) -6- (trimethylammonium) -hexanedibromide.

In the same manner as in Example 1, 1- (4-benzylpyridinium) -6- (trimethylammonium) hexane dibromide was obtained by reacting 4-benzylpyridine with 6-bromohexyltrimethylammonium bromide.

Example 12. 144- (Diphenylaminoethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide.

PA the same salt as in Example 1, 144- (diphenylaminoethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide is obtained by reacting 4- (diphenylaminoethyl) -pyridine with 3-bromopropylmethylammonium bromide.

Example 13. 142- (2-Oxocyclohexylethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide.

On the same salt as in Example 1, 2- (2-oxocyclohexylethyl) -pyridine was reacted with 3-bromopropyltrimethylammonium bromide to give 142- (2-oxocyclohexylethyl) -pyridinium1-3- (trimethylammonium) -propane dibromide as a solid amine hygroscopic.

Example 14. 1- (4-Benzoylpyridinium) -3- (trimethylammonium) -propane dibromide.

In the same manner as in Example 1, 4-benzoylpyridine was reacted with 3-bromopropyltrimethylammonium bromide to give 1- (4-benzoylpyridinium) -3- (trimethylammonium) -propane dibromide as a solid which melted at 221-222 ° C with probing. .

Analysis: Calculated (+ 1/2 H 2 O): C 47.69% H 5.57% Br 35.26% H 2 O 1.99%. Found: C 47.97% H 5.63% Br 35.52% H 2 O 2.80% Example115. 144- (4,5,6,7-Tetrachlorophthalimidethyl) -pyridinium 1-3- (trimethylammonium) -propanedibromide, In the same manner as in Example 1, 4- (4,5,6,7-tetrachlorophthalimidethyl) -pyridine and 3 bromopropyltrimethylammonium bromide, wherein erlions 144- (4,5,6,7, -tetrachlorophthalimideethyl) -pyridinium 1-3- (trimethylammonium) -propane dibromide.

Example 16. 1- (4-Benzyl-1-methylpiperidinium) -3- (trimethylammonium) -propane dibromide.

A solution of 7.0 g (0.037 mol) of 4-benzyl-1-methylpiperidine and 10.5 g (0.04 mol) of 3-bromopropyltrimethylammonium bromide in 50 ml of isopropanol was boiled for 24 hours under reflux. The crystallized solution obtained when diluted with ethyl acetate was recrystallized twice from isopropanol and ethyl acetate to give 8.6 g (50% of theory) of 1- (4-benzyl-1-methylpiperidinium) -3- (trimethyl). -ammonium) -propane dibromide, which narrows at 237-238 ° C.

Analysis: Calculated: C 50.67% H 7.61% Br 35.49% Found: 50.587.7335.03 Example 17. 1- (2-Benzyl-1-methylpiperidinium) -3- (trimethylammonium) -propane dibromide. 2-Benzyl-1-methylpiperidine was reacted with 3-bromopropylmethylethylunonium bromide in the same manner as in Example 116 to give 1- (2-benzyl-1-methylpiperidinium) -3- (trimethylammonium) -propane dibromide as a white hygroscopic solid.

Analysis: Calculated: Br 35.49% Found: 35.13 Example 18. 144- (3-hydroxypropyl) -1-methylpiperidinium] -3- (trimethylammonium) -propane dibromide.

In the same manner as in Example 16, 4- (3-hydroxypropyl) -1-methylpiperidine was quaternized with 3-bromopropyltrimethylammonium bromide and recrystallized from ethanol and ethyl acetate. This gives about 43% of the theoretical yield of the product 144- (3-hydroxypropyl) -1-methylpiperidinium] -3- (trimethylammonium) propylene dibr omid, which is obtained at about 2 ° C.

Analysis: Calculated: C 43.07% H 8.19% Br 38.21% Found: 42.938.0237.93 Example 19. 144- (3-Indolylethyl) -pyridinium-3- (trimethylammonium) -propane dibromide.

A% solution of 6.4 g (0.028 mol) of 4- (3-indolylethyl) pyridine and 7.9 g (0.03 mol) of 3-bromopropyltrimethylammonium bromide in 50 ml of acetonitrile was boiled for 28 hours under reflux in a water vapor bath. The crystallized precipitate was collected and recrystallized twice from ethanol and ethyl acetate to give 8.7 g (65% of theory) of 144- (3-indolylethyl) -pyridinium] -3- (trimethylammonium) -propanedibromide, as of light green crystals, which during gas evolution melt at 218 ° C.

Analysis: Calculated: C 52.18% H 6.05% Br 33.07% Found: 52.746.33.0 This compound was tested on laboratory animals and humans with the following results: I. Hypotensive (standard test) Dose (mg / kg, intravenous ) effect on Reduction of blood pressure% anesthetized dogs Duration (I1) 0.01 / 2 0.1 40-6> 3 0.40-64 0.40-6> 4 Note. The hypotensive effect of this association reappears rather slowly.

Acute toxic effect on moss, mg / kg according to B. Behrens and G. Karber, Archives for Experimental Pathology and Pharmacology, 177, 379 (1934).

Intravenous L13 „9.0.

Ganglieblockad - cat, upper cervical ganglia according to G. H. Acheson and S. A. Pereira, Journal of Pharmacology and Experimental Therapeutics, 87, 273, (1946).

Dose, (mg / kg, Degree (0-4 -I-) Complete Ater- intray cheese) hamting after 0.1 <1 h 0.1 h Note. Two cats showed minor blockade after using the compound. However, these cats were less likely than usual for hexamethonium.

Effect on the pupil - anesthetized male cat, (by gentle intraperitoneal injection).

Dose, (mg / kg. Intraperitoneally) 0, partial 0, marked Effect of intravenous injection on an anesthetized monkey.

Monkey - about 5 kg, male Dose = 5 mg total Result: No immediate effects not noted. After 30 minutes there was a slight dilation of the pupils and the animal was calmer. No signs of dry mouth or postural hypotension could be observed to a greater extent.

Samples in 8 hypertensive human patients (by intravenous injection into isotonic saline solution).

Intra-dose average dose Average blood pressure drop% (mg / kg) 0, back position - 20 standing - 33 Example 120, 144- (1-benzotriazolylethyl) -pyridinium] -3- (trimethylammonium) -propanedibromide. In the same manner as described herein in Example 19, 4- (1-benzothiazolylethyl) -pyridine was reacted with 3-Widening Light Reaction Partial Insignificant bromopropyltrimethylammonium bromide in ethanol solution. Orneal crystallization from ethanol and ether and then 1: isopropanol gave 1-14- (1-benzotriazolyltethyl), pyridinium] -3- (trimethylammonium) -propanedione as a white crystallized line.

Analysis:.

Calculated (-1-1 H 2 O): C 45.34% H 5.81%.

Br 31.76% Found: C 45.57% 11 6.03% Br 31.91% • Example 21. 142- (3-indolylethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide.

142- (3-Indolylethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide, melting at 201-203 ° C, was obtained by reacting Example 19 of 2- (3-indolylethyl) -pyridine with 3-bromopropyltrimethylammonium bromide.

Andy & Calculated: C 52.18% H 6.05% Br 33.07% Found: 52,236.1732.51 This compound was tested on laboratory animals and humans with the following results: Hypotensive effect on trained dogs (standard sample).

Dose (mg / kg, intraventist) reduction of blood pressure 1% Duration h 0.02 0.06 0.1 6> 3-1 / 2 1.0 65-70> 4 0.25 * 35-> 3-1 / 2 * Inked in the small intestine.

Acute toxicity - moss, mg / kg according to B. Behrens and G. Karber, Archives for Experimental Pathology and Pharmacology, 177, 379 (1934) Intravenous LD = 13 ± 1 mg / kg.

Ganglieblockad - cat, upper cervical ganglia according to G. H. Acheson and S. A. Pereira, Journal of Pharmacology and Experimental Therapeutics, 87, 273, (1946).

Duration to Degree (0-4 +) recovery 0.000 0.1 + 30 min 0, ± ++ 1 h 0, ++++ Effect on the pupil - anesthetized male cat (by standard intraperitoneal injection).

Dose (mg / kg, intraperitoneally) 0, partial 0, maximal V. Effect on intravenous injection in uncontrolled monkeys.

Monkey - 6.6 kg; lane - Dose = 5 mg (0.75 mg / kg) The immediate effect of the result ... No surface, further effect could not possibly be observed with: -andantag for sVag; Nidning of the pupils after 30 rain: 7 Sasorn kande vantas var animal calmer .

WE. Sample * of four human hypertensive patients (by intravenous injection in isotonic saline). - Intravenils. . gencimsnitSdos - !, Genainsuittlig blood pressure drop 1% (mg / kg) 0.13 backbone - 20 standing Example 22. -1-14- (phthalimidethyl) -pyridinium.] - 31 (trimethylammonium) -: propane dibromide; 144- (Phthalimidethyl) -pyridinium 1-3- (triethylamyl, monium) -propane dibronide, melting at 204 ° C, was prepared by formulating Example 19 of phthalimidethyl-pyridine with 3-bromopropyltrimethylammonium bromide.

Analysis: Calculated: C 49.14% H 5.30% Br 31.14% Found 49.465.3230.89 Example 23. 1-4- (1-Rindenylethyl) -pyridinium-3- (trimethylammonium) -propanedibromide. 144- (1-Findenylethylpyridinium] -3- (trimethylammonium) -propane dibromide, melting at 197 ° C, was prepared by reacting according to Example 19 of 4- (1-indenylethyl) -pyridine with 3-bromopropyltrenethylammonium bromide.

Analysis: Calculated: C 54.78% H 6.27% Br 33.14%.

Found: 54.526, 4833.0 Example 24. 1-12- (2-Benzothiazolthioethyl) -pyridinium] -3- (trinaethylammonium) -propane dibromide.

Following the procedures of Examples 1 and 19, 2- (2-benzothiazolthioethyl) -pyridine was reacted with 34-tromopropyltrimethylammonium bromide to give 1- [2- (2-benzothiazolethioethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide.

Example 25. 1, spiro - [(1-methyloxindole) -3,4 '- (1'-methylpiperidinium)] - 3- (trimethylammonium) -propane dibromide.

A solution of 3.9 g (0.017 mol) of spiro - [(1-methyloxindole) -3,4 '- (1'-methylpiperidine)] [C, Eisleb. Ber. 74, 1433 (1941) 1 and 6.8 g (0.026 mol) of 3-bromopropyltrimethylammonium bromide in 15 ml of ethanol were boiled for 20 hours under a stream of water on a steam bath. The cooled solution was diluted with ethyl acetate, the precipitate was collected and recrystallized twice from n-propanol and ethyl acetate to give 3.6 g (43% of theory) of 1-spiro - [(1-methyloxindole) - 3.4 '- (1'-methylpiperidinium)] - 3- (trimethylammonium) - propane dibromide, which melts at 251 ° C during evolution of gas.

Analysis: Calculated: C 48.89% H 6.77% Br 32.53% Found: 48.777.0432.19 Example 26. 144- (3-Indolylethyl) -1-methyl-piper. = Idinium] -3- ( trimethylammonium) -propanedibromide. During application of the kit according to Example Dose (mg / kg, intravenous cheese) Enlargement Light reaction partial none in ■ a; - 191123 - 4- (3-Indolylethyl) 4-methylpiperidine-Triad 3-bromopropyltrimethylanimonium bphomide was converted to 144- - (3-indolylethyl) -1-Methyl-piperidinium3- (trimethylammonium) -orbpandibioin-ethyl (Ex. 4,414 .14). Ethylpiperidinium, nium] -3- (trimethylarrithlycine) -propanedibromide. While fuming the satellite of Example 25, 4- (3-indolylethyl) -1-ethylpiperidine was reacted with 3-bromopropyltrimethylammonium bromide to give 1-4 (3-indolylethyl) -1- ethylpiperidinium] -3- (trinethylammonium), propane dibromide, in the form of a hygroscopic solid.

Analysis: Calculated: C. 53.39% H 7.60 °. / ,, Found: 7.54 isr a • Example 18. 144-1- (bicycl 10-2.2; 1] -2-hept-ny1) ] -pyridinium) -3- (trimethylammonium) -propane dibromide. While fuming the precipitate of Example 16, 446.7 (bicyclo [2- [2,2,11,2 (heptenyl) j-pyridine) was refluxed in isopropylanol with 3-bromopropyltrimethylammonium bromide to give 1- (4- [6- (bicyclo- {2 , 2,11-2-heptenyl-pyridinium) -3- (trimethylammonium) -propane dibromide as hygroscopic glass after drying in vacuo Over phosphorus pentoxide.

Analysis: Calculated: Br 36.98% Found: 37.14 Example 29. 1, (3, Carbanilide pyridinium) -3- (trimethylammonium) -propanedibromide.

An acetonitrile solution of 5.9 g (0.03 moles) of nicotinic anilide and 7.8 g (0.03 moles) of 3-bromopropyltri,7 methylammonium bromide was boiled for 25 hours in Ater-Side pfi. water finger bath. The precipitate was triturated and recrystallized from ethanol to give 12.0 g (87% of theory) of carbanilidepyridinium (-3- (trimethylammonium) -propandibromide, which narrows at 181 DEG C. Analysis: Calculated: C 47.07% I-1 5.50% Br 34.80 °, / o Found: 46.995.5134.34 Example 30. 1- (3-Carbobenzyloxypyridinium) -3- (trimethylammonium) -propanedibromide While applying the kit of Example 29, 1- (3-Carbobenzyloxypyridinium) -3- (trimethylammonium) -propane dibromide was obtained by saturating benzyl nicotinate with 3-bromopropyltrimethylammonium bromide.

Example 31. 1- (2-Piperidinopyridinium) -3- (trimethylammonium) -propane dibromide.

Applying the procedure of Example 29, 1- (2-piperidinopyridinium) -3- (trimethylammonium) -propane dibromide was obtained by reacting 2-piperidinopyridine with 3-bromopropyltrimethylammonium bromide.

Example 32. 112- (2-Oxo-3-methylpentyl) -pyridinium I-3- (trimethylammononium) -propandibromide, Id. Using the kit of Example 1, 2- (2-oxo-3-methylpeuty1) -pyridine was reacted. with 3, bromopropyltrimethylammonium bromide to 142- 43xo-3-methylpentyl) -pyridinittap3- (trimethylanum * nium) -propane dibromide. Example 33. 142- (2-Oxo-carbethoxypentyl) -pyridinium] -3- (trimethylammonium) -propaneclibromide .; During the addition of the procedure of Example 1, 2- (2-oxo-3-carbethoxypentyl) -pyridia was reacted with 3-bromopropyltrimethylammonium bromide to give 1 to 27-oxo-3-carbethoxypentyl) -pyridiniump- (trimethylammonium) -propane dibromide of a hygrosk, o7 whip, though Annie.

Example 134,144- (dipentylm: ethyl) -pyridinium 14- (trimethylammonium) -propanedibromide.

Using the procedure of Example 1, 4- (diphenylmethyl) -pyridine was reacted with 3-bromotopropyltrimethylammonium bromide to give 1414- (diphenylmyl, 7thyl) -pyridinium] -3- (trimethylamnionium) -propanyl bromide as a solid hygrose. drune. Melting point (separation) 145-160 ° C. Example 35. 144- (1,2-Diphenylethenyl) -pyridine; During application of the kit of Example 1, 4- (1,2-diphenylethenyl) -pyridium was reacted with, Irompropyltrimethylammonium bromide to give 1-14 = (1,2-diphenylethenyl) -pyridinium-3- (trimethylammonium) -propane dibromide • Example 36. 1- [4- (triphenylmethyl) -pyridinium] -3- (trimethylammonium) propane dibromide.

Using the kit of the example, 4- (triphenylmethyl) -pyridine was reacted with 3-bromine prepyltrimethylammonium bromide to give 1- [4- (triphenylmethyl) -pyridinium173- (trimethylammonium) -propanedibromide as a crystallized solid Amne.

Example 37, 1- (2 - [(1-Naphthyl) -ethyl] pyridinium 3- (trimethylammonium) -propane dibromide]. to 1- (2-t (1, naphthyl) -ethyl] -pyridinium) -3r (trimethylammonium) -pro, pandibromide, center (finder division) 170-171 ° C.

Analysis: Calculated: C 55.88% H 6.12% Br 32.33 ° A, Found: 56.15 "6.3631.58 - Example 38. 1- (4-1 (1-naphthyl) -ethyl] -pyridinium) 3- (trimethylammonium) -propanedibromide.

While applying the kit of Example 1, 4 [(1-naphthyl) -ethyl-pyridine was reacted with 3-bromo, -propyltrimethylammonium bromide to give 1- (4 - [(1-naphthyl) ethyl] -pyridinium) -3- (trimethylammonium) - pro'pandibromide.

Example 39. 1- (413- (9-Fluorenecarboxy) -propyl-pyridinium) -3- (trimethylammonium) -propane-dibromide.

During application of the kit of Example 1, 443- (9-fluorenecarbcod) -propyl] -pyridine was reacted with 3-bromopropyltrimethylammonium bromide to give 1- (413- (9-fluorenecarboxy) -propyl] -pyridinium) -3- (trimethylamine ammonium) -propane dibromide .

Example 40. 142- (3-Indolylethyl) -1-methylpiperidinium] -3- (trimethylammonium) -propane dibromide.

While applying the web of Example 1, 2- (3-indolylethyl) -1-methylpiperidine was reacted with 3-bromopropyltrimethylammonium bromide to give 1- [2- (3 "- indolylethyl) -1-methylpiperidinium] -3- (trimethylammonium). ) -propanedibromide.

Example 41. 142- (Phenylethylamino) -pyridinium 1-3- (trimethylammonium) -propane dibromide.

Applying the kit of Example 1, 2- (phenylethylamino) -pyridine was reacted with 3-bromopropyltrimethylammonium bromide to give 1- [2- (phenylethylamino) -pyridinium] -3- (trimethylammonium) -propane dibromide.

Example 42. 142- (2-Pyridylamino) -pyridinium 1-3- (trimethylammonium) -propanedibromide.

Applying the kit of Example 1, 2,2'-dipyridylamine was reacted with 3-bromopropyltrimethylammonium bromide to give 1-12- (2-pyridylamino) -pyridinium] -3- (trimethylammonium) -propane dibromide.

Example 43. 1-spiro- [fluoren-9,4 '- (1'-methylpiperidinium)] - 3- (trimethylammonium) -propanedibromide.

Using the kit of Example 25, spiro- [fluoren-9,4 '- (1'-methylpiperidine)] was reacted with 3-bromopropyltrimethylammonium bromide to form 1-spiro-Ifluoren-9,4'41'-methylpiperidinium)] - 3- (trimethylammonium) -propane dibromide, m.p. 274 ° C (dec.).

Analysis: Calculated: C 56.48% H 6.71% Br 31.32% Found: 56.066.9230.87 Example 44. 144- (1-Methyl-3-indolylethyl) -pyridinium-3- (trimethylammonium) -propane dibromide .

A solution of 12.0 g (0.049 mol) of 4- (1-methyl-3-indolylethyl) -pyridine and 9.15 g (0.035 mol) of 3-bromopropyltrimethylammonium bromide in 50 ml of acetonitrile was boiled for 25 hours under reflux. The solvent was decanted by Iran the oily precipitate, the oil was dissolved in ethanol and reprecipitated with ether, after which the procedure was repeated. The oily product was dried in vacuo at room temperature over phosphorus pentoxide to give 5.65 g (32% of theory) of an orange colored hygroscopic product, 144 - (- methyl-3-indolylmethyl) -pyridinium] -3- (trimethylammonium) - propane dibromide, which was then recrystallized from isopropanol to give yellow, hygroscopic needles.

Analysis: Calculated: C 53.13% H 6.28% Br 32.14% Found: 52.836.4711.98 This compound was tested on laboratory animals and humans with the following results: I. Hypotensive effects on anesthetized dogs (standard sample) Dose (mg (kg) intraventist 0.01 Decrease in blood pressure in% Duration ih 0.02> 3 0.04 0,0> 2 0.1> 3 II Acute toxicity - moss, mg / kg [according to B. Behrens and G. Karber, Archives for Experimental Pathology and Pharmacology, 177, 379, (1934)]. IntravenOs LD. = 9.0.

III. Ganglieblockad - cat, Upper cervical ganglia, [according to G. H. Acheson and S. A. Pereira, Journal of Pharmacology and Experimental Therapeutics, 87, 273, (1946)].

Dose (mg / kg) intraventist 0.0 Degree (0-1 +) - Duration ih - 0.1 + 0.2 0, ++ 0.5-0.7 1.0 ± -FF 2 2.0 ++ ++ '2 IV. Effect on the pupil - anesthetized male cat (by normal intraperitoneal injection).

EnlargementLight reaction 0.1 no normal 0, partial partial 0, complete no Effect on intravenous injection on an anesthetized monkey.

Experimental animals - 6.7 kg.

Dose = 3.0 mg total.

Results: No noticeable acute effects or section 24 h. The animal was examined in more detail for signs of ganglion blockage (eg dilation of the pupils, dry mouth and the like), however, no effects could be observed.

Samples in nine hypertensive human patients (by intravenous injection into isotonic saline).

Intraventis average dose (mg / kg) 0, back position - 20 standing - Example 45. 1- [4- (methyl-3-indolylethyl) -pyridinium] -3- (trimethylanunonium) -propane monochloride, nmn bromide.

The mixed salt 144- (1-methyl-3-indolyl-ethyl) -pyridinium] -3- (trimethylammonium) -propane monochloride, monobromide was prepared by heating equimolar amounts of 4- (1-methyl-3-indolylethyl) -pyridine and chloropropyltrimethylammonium bromide in dimethylformamide solution for 20 hours at 125 ° C (oil bath temperature) and collecting the precipitate from the cooled reaction mixture. The yield was 80% of theory.

Example 46. 144- (1-Methyl-3-indolylethyl) -pyridinium] -3- (trimethylammonium) -propane dichloride.

A solution of 25 g of 144- (1-methyl-3-indolylethyl) -pyridinium] -3- (trimethylammonium) -propanedibromide dissolved in 500 ml of ethanol was passed through a column of Amberlite * anion exchange resin IRA 401 (which had previously been regenerated with a solution of sodium chloride), after which the column was washed with fresh methane. The eluate was concentrated in vacuo and the residue was recrystallized from acetonitrile. 16.5 g (81% of theory) of 144- (1-methyl-3-indolylethylpyridinium] -3- (trimethyl- Dose (mg / kg) intraperitoneally are obtained. Average propellant blood pressure drop - -9 ammonium) -propane dichloride salt , melting point 195 ° C (probe division).

Analysis: Calculated: Cl 17.36% Found: 17, Example 47. 142- (3-Indolylethyl) -5-ethylpyridinium] -3- (trimethylammonium) -propane dibromide.

A mixture of 1 g (0.004 mol) of 2- (3-indolylethyl) -5-ethylpyridine and 5.2 g (0.02 mol) of 3-bromopropylmethylammonium bromide dissolved in 50 ml of acetonitrile was boiled for 24 hours under reflux. The solution was cooled, the precipitate was filtered off and recrystallized twice from isopropanol and ethyl acetate and finally twice from isopropanol alone. The resulting still crude material was dissolved in 25 ml of acetonitrile and refluxed for 5 hours with an additional 4 g of 2- (3-indolylethyl) -5-ethylpyridine. Recrystallization of the resulting product from isopropanol gay 1.4 g (13.5% of theory) of a white hygroscopic product 142- (3-indolylethyl) -5-ethylpyridinium] -3- (trimethylammonium) -propane dibromide.

Analysis: Calculated: ionized Br 31.26% Found: 30.79 Example 48. 142- (1-methyl-3-indolylethyl) -pyridinium] -3- (trimethylammonium) -propanedibromide.

Using the procedure of Example 44, 2- (1-methyl-3-indolylethyl) pyridine was reacted with 3-bromopropyltrimethylammonium bromide (methyl-3-indolylethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide, a solid dime having a melting point of 13 -140 ° C, dec.

Analysis: Calculated: C 53.13% H 6.28% Br 32.14% Found: 53.265.9611.83 Example 49. 142- (1-methyl-3-indolylethyl) -5-ethylpyridinium 1-3- (trimethylammonium prop andibromide .

Applying the kit of Example 44, 2- (1-methyl-3-indolylethyl) -5-ethylpyridine was reacted with 3-bromopropyltrimethylammonium bromide to give 142- (1-methyl-3-indolylethyl) -5-ethylpyridinium] -3- (trimethylammonium ) -propane dibromide, a solid with a melting point of 173-174 ° C (solid division).

Analysis: Calculated: C 54.86% H 6.72% Br 30.42% Found: 54.216.5330.28 This compound was tested on laboratory animals and humans with the following results: I. Hypotensive effect on promised dogs (standard test) Dose (mg / kg) intravenous Blood pressure collection Duration ih 0.01 55 *> 3 0.055 *> 3 0.050-> 3 0.1 50-6> 3 * Slow collection during 30-45 min.

Acute toxicity moss, mg / kg [according to B, Behrens and G. Karber Archives for Experimental Pathology and Pharmacology, 177, 379 (1934)].

Intravenous = 7.5.

Ganglieblockad- cat. Upper cervical ganglia [according to G. H. Acheson and S. A. Pereira, Journal of Pharmacology and Experimental Therapeutics, 87, 273 (1946) 1.

Dose (mg / kg) intraventist 0.1 0.25 0.5 1.0 2.0 IV. An effect on the pupil of an anesthetized male cat (by normal intraperitoneal injection).

Dose (mg / kg) intravenous Expansion Light reaction 0.1 none normal 0, no normal 0, complete * none * Duration ea 2 h.

Effect yid intravenous injection pt obedovad apa.

Hanapa by 7 kg.

Dose = 3.0 mg, total dose (or 0.4 mg / kg).

Result: no detectable effects. The diuretic was carefully studied to detect the ganglion block and dilate the pupils. However, no such signs could be detected.

Test with fern hypertensive humans (by intravenous injection in isotonic saline).

Intravenous average dose Average blood pressure drop (mg / kg) 0.13 spine - 18 standing - 32 Example 50. 114- (1-Benzyl-3-indolylethyl) -pyridinium] -3- (trimethylammonium) -propanedibromide. 4- (1-Benzyl-3-indolylethyl) -pyridine was reacted with 3-bromopropyltrimethylammonium bromide according to Example 19 to give 144- (1-benzyl-3-indolylethyl) -pyridinium1-3- (trimethylammonium) -propanedibromide in in the form of a solid, which melted at 191-194 ° C (probing).

Analysis: Calculated: C 58.64% H 6.15% Br 27.87% Found: 58.365.927.34 Example 51. 1- (241- (1-methyl-3-indolyl) -2-propyl] -pyridinium ) -3- (trimethylammonium) -propane-bromide. 241- (1-Methyl-3-indolyl) -2-propyl-pyridine was reacted according to Example 44 with 3-bromopropyltrinethylammonium bromide to give 1424141-methyl-3-indolyl) -2-propyl-pyridinium) -3- (trimethylammonium) -propanedibromide. 4- (1-Indolylethyl) -pyridine was reacted according to Example 19 with 3-bromopropyltrimethylammonium bridge- Degree (0-4 +) Duration in 0, 0.4 0, - - Mid to 144- (14-indolylethyl) -pyrclinitim1-3- (trimethylammonium ) -propanedrihomide in the form of a solid awe; which melted at, 223-225 ° C under sander Analysis: Calculated: C 52.18% H 6.05% Br 33.07 Found: 51.795.8732.63 Donna compound was tested on laboratory animals and humans with the following results: I. Hypotensive effect on anesthetized dogs (standard test).

Dose (mg / kg) intravenous Blood pressure reduction Duration h 0.000 0 0.0012 1 .0.01 6> 2 0.06> 2 0.1 70> 2: .0.60> 2 Regardless of the injected dose were all the reactions concerning the lowering of the blood pressure are equal in the sense that the lowering occurred during a period ph 20-40 min.

Acute toxicity - moss, mg / kg [according to B. Behrens and G. Karber, Archives for Experimental Pathology and Pharmacology, 177, 279 (1934)]. 1 h intravenous Lam, = 18, .24 + h a = 8, Ganglieblocked, cat, upper cervical ganglia [according to G. H. Acheson ocb. S. A. Pereira, Journal of Pharmacology and Experimental Therapeutics, 87, 273, (1946) 1.

Degree (0-1 +) Duration in h. 0.01-0,000 0.10, 0, +++> 0, Effect on the pupil in non-anesthetized male cat (by normal intraperitoneal injection) Dose (mg / kg) intraperitoneally 0.1 0, Effect in anesthetized monkey.

Hanapa by 7 kg.

Dose = 3.0 mg total (or 0.4 mg / kg).

Result: No noticeable effects acute or Mom 96 hours after injection of the compound. There were jokes some obvious symptoms of ganglion blockage.

Samples of four hypertensive people (by intravenous injection in isotonic saline).

Intraventis average dose Average blood pressure drop (mg / kg) 0.13 spine - 16 standing - 34 Example 53. 142- (1-Benzotriazarlylethyl) -pyridinium-3- (trimethylammonium) -propane dibronide. 2- (1-Benzotriazolylethyl) -pyridine reacted according to Example 119 with 3-bromopropyltrimethylanonium bromide to give 142- (1-benzotriazlylethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide form of a hygroscopic solid. Br 32.88 Found: 32, Example 54. 142- (1-indenylethyl) -pyridinium 1-3- (trimethylammonium) -propane dibromide. 2- (1-indenylethyl) -pyridine was reacted according to Example 44 to give 3-bromopropylthimethylammonium bromide to -112- (1-indenylethyl) -pyridinium 1-3- (trimethylammonium) -propanedibromide in the form of a solid which melts at 188-190 ° C under Decomposition.

Analysis: Calculated: C 54.78% H 6.27% Br 33.13% Num: 54.44-6.4232.68 Example 55. 142- (1-methyl-3-oxindolylethyl) -pyridinium} -3- (trimethylammonium) -propane dibromide. 2- (1-Methyl-3-oxindolylethyl) -pyridine - was reacted according to Example 44 with 3-bromopropyltrimethylammonium bromide to give 142- (1-methyl-3-oxindolylethyl) -pyridinium] -3- (trimethylammoniumpropane dibromide).

Example 50. 144- (Benzyloxyethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide. 4- (Benzyloxyethyl) -pyridine was reacted according to Example 19 with 3-bromopropyltrimethylammonium bromide to give 144- (benzyloxyethyl) -pyridiniumyl-3-trimethyl] trimethyl -propanedibromide.

Example 57. 1- [4- (Benzylthioethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide. 4- (Benzylthioethyl) -pyridine was reacted according to Example 1 with 3-bromopropyltrimethylammonium bromide to give 144- (benzylthioethyl) -pyridinium] -3- (trimethylammonium) -propane dibronide.

Example 58. 144- (9-Fluoro-thioethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide. 4- (9-fluoro-thioethyl) pyridine is reacted according to Example 1 with 3-bromopropyltrimethylammonium bromide to give 14- (9-fluoro-thioethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide, which melts at 202-204 ° C during gas evolution.

Example 59. 1- (246- (Bicyclo-12,2,1] -2-heptenyl) -1-pyridinium) -3- (trimethylammonium) -propane dibromide. 2 {6- (Bicyclo- [2,2,1] -2-heptenyl] -pyridine was reacted according to Example 19 with 3-bromopropyltrimethylammonium bromide to 1- (2-46- (bicyclo- [2,2,1] -2- heptenyl)] - pyridinium) -3- (trimethylammonium propane dibromide as a hygroscopic solid.

Example 60. 1- (546- (Bicyclo- [2,2,1] -2-heptenyl)] - 2-picolinium) -3- (trimethylammonium) -propane dibromide. [6- (Bicyclo- [2,2,1] -2-heptenyl)] - 2-picoline was reacted according to Example 44 with 3-bromopropyltrimethylammonium bromide to 1- (546- (bicyclo- [2,2,1] - 2 -heptenyl (1-2-picolinium) -3-trimethylammonium) - Dose (mg / kg) intravenous Enlargement par tial complete Light reaction partial none by intravenous injection on non--11 propanedibromide as a hygroscopic solid Mune.

Analysis: Berdknat: Br 35.82% Found: 35.58 Example 61. 1- (44beta- (1-methyl-3-indolyl) -alpha-cyclohexylethyl-pyridinium) -3- (trimethylammonium) -propane dibromide. 4-1beta- (1-methyl-3-indolyl) -alpha-cyclohexylethylpyridine was reacted according to Example 19 with 3-bromopropyltrimethylammonium bromide to 1- (44beta (1-methyl-3-indolyl) -alpha-cylohexylethylpyridinium) -3- (trimethylammonium) -propanedibromide, which narrows at 237-239 ° C.

Example 62. 1- (44beta- (1-methyl-3-indolyl) -alpha- (4-ethylcyclohexyl) -ethyl] -pyridinium) -3- (trimethyl-ammonium) -propane dibromide. 4- [beta α- (1-methyl-34-n-ol) -alf α- (4-ethylcyclohexyl) -ethyl)] -pyridine was reacted according to Example 19 with 3-bromopropyltrimethylammonium bromide to 1- (4- [beta- ( 1-methyl-3-indolyl) -alpha α- (4-ethylcyclohexyl) -ethyl-pyridinium) -3- (trimethylammonium) -propane dibromide, which melts at 150 ° C with sonication.

Example 63. 143- (2-Indoly1) -pyridinium 1-3- (trimethylammonium) -propane dibromide. 3- (2-Indoly1) -pyridine was reacted according to Example 19 with 3-bromopropyltrimethylammonium bromide to 1- [3- (2-indolyl) -pyridinium] -3- (trimethylammonium) -propane dibromide, melting at 2462500 ° C.

Analysis: Berdknat: C 50.12% H 5.54% Br 35.11% Found: 50.065.44934.96 Example 64. 114- (2-indoly1) -pyridinium 1-3- (trimethylammonium) -propane dibromide. 4- (2-Indoly1) -pyridine was reacted according to Example 19 with 3-bromopropyltrimethylammonium bromide to give 144- (2-indolyl) -pyridinium] -3- (trimethylammonium) -propane dibromide, which narrows at 236238 ° C.

Analysis: Berdknat: Br 35.11% Found: 34.51 Example 65. 144- (3,3'-diindolylmethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide. 4- (3,3'-Diindolylmethyl) -pyridine was reacted according to Example 1 with 3-bromopropyltrimethylammonium bromide to give 114- (3,3'-diindolylmethyl-pyridinium] -3- (trimethylammonium) -propane dibromide melting at 220 ° C with decomposition.

Analysis: Berdknat: C 57.54% H 5.52% Br 27.35% Found: 57.435.6326.72 Example 66. 143,3'-Diindolylmethyl) -pyridinium-3- (trimethylammonium) -propanedibromide. 3- (3,3'-Diindolylmethyl) -pyridine was reacted according to Example 1 with 3-bromopropyltrimethylammonium bromide to give 143- (3,3'-diindolylmethyl-pyridinium] -3- (trimethylammonium) -propane dibromide.

Example 67. 142- (3,3'-Diindolylmethyl) -pyridinium] -3- (trimethylammonium) -propane dibromide. 2- (3,3'-Diindolylmethyl) -pyridine was reacted according to Example 1 with 3-bromopropyltrimethylammonium bromide to give 112- (3,3'-diindolylmethyl-pyridinium] -3- (trimethylammonium) -propane dibromide.

Example 68. 1- (44bis- (1-methyl-3-indolyl) -methyl] -pyridinium) -3- (trimethylammonium) -pr on andibromide. 4- [Bis- (1-methyl-3-indolyl) methyl-pyridine was reacted according to Example 1 with 3-bromopropyltrimethylammonium bromide to 1- (4-ibis- (1-methyl-3-indolyl) -methyl) -1-pyridinium) - 3- (trimethylammonium) -propane dibromide.

Example 69. 144- (1-Methyl-3-indolylethyl) -1-methyl-piperidinium] -3- (trimethylammonium) -propidibromide. 4- (1-Methyl-3-indolylethyl) -1-methylpiperidine was reacted according to Example 25 with 3-bromopropyltrimethylammonium bromide to give 144- (1-methyl-3-indolylethyl) -1-methylpiperidininium] -3- (trimethylammonium) -propane dibromide.

Example 70. 142- (1-Methyl-3-indolylethyl) -1-methyl-piperidinium] -3- (trimethylammonium) -propane dibromide. 2- (1-Methyl-3-indolylethyl) -1-methylpiperidine was reacted according to Example 25 with 3-bromopropyltrimethylammonium bromide to give 1-12- (1-methyl-3-indolylethyl) -1-methylpiperidinium] -3- (trimethylammonium) propane dibromide .

Example 71, 1- (412- (Bicyclo4,2,2,11-heptyl)] - 1-methylpiperidinium) -3- (trimethylammonium) -propanedibromide. 4- [2- (Bicyclo- [2,2,11-heptyl)] -1-methylpiperidine was reacted according to Example 25 with 3-bromopropyltrimethylammonium bromide to 1- (442- (bicyclo- [2,2,1] -heptyl] )] - 1-methylpiperidinium) -3- (trimethylammonium) propane dibromide which melts at 258-260 ° C during solid division.

Analysis: Berdknat: C 50.22% H 8.43% Br 35.18% Found: 50.2688.4434.58 Example 72. 1- (4-Benzyl-1-methylpiperidinium) -2- (trimethylammonium) ethanedioiodide.

A solution of 5.0 g (0.02 mol) of 1- (dimethylaminoethyl) -4-benzylpiperidine and 7.1 g (0.05 mol) of methyl iodide in 50 ml of ethanol was boiled for 18 hours under reflux. Recrystallization of the precipitate formed from methanol ethyl acetate gay 6.0 g (56% of theory) 1- (4-benzyl-1-methylpiperidinium) -2- (trimethylammonium) ethanedioiodide as white crystals, melting at 216- 218.5 ° G with probe division.

Analysis: Berdknat: C 40.77% H 6.08% J 47.87% Found: 41.05.9647.31 Example 73. 1-11- (2-hydroxy-1-octyl) -piperidinium 1-3- ( trimethylammonium) -propanedibromide. 1- (2-Hydroxy-1-octyl) -piperidine was reacted according to Example 116 with 3-bromopropyltrimethylammonium bromide to give 1414- (2-hydroxy-1-octyl) -piperidinium3- (trimethylammonium) -propane dibromide. Example 74. 1-11- (2-Acetoxy-1-octyl) -piperidinium] -3- (trimethylammonium): propane dibromide. 1- (2-Acetoxy-1-octyl) tiperidite was reacted with Example 3-bromopropyltrimethylammonium bromide to give 141- (2-acetoxy-4-octyl) piperidiniumj3- (trimethylammonium) propanedibromide.

Example 75. 141- (2-Benzoxy-1-octyl) -piperidinium] -3- (trimethylammonium) -propanedibromide. 1- (2-Benzoxy-1-octyl) piperidine was reacted according to Example 116 with 3-bromopropyltrimethylammonium bromide to give 141- (2-benzodyl-1-octyl) -piperidinium] -3- (trimethylammonium) -propanedibromide.

Example 76. 111- (2-Hydroxy-1-decyl) -piperidinium] -3-trimethylammonium) -propanedibromide. 1- (2-Hydroxy-1-decyl) -piperidine was reacted according to Example 16 with 3-bromopropyltrimethylammonium bromide to give 1414- (2-hydroxy-1-decyl) -piperidinium-3- (trimethylammonium) -propane dibromide.

Example 77. 141- (2-Acetozi-1-decyl) -piperidimium] -3- (trimethylammonium) -propane dibromide. 1- (2-Acetoxy-1-decyl) -piperidine was reacted according to Example 116 with 3-bromopropyltrimethylammonium bromide to give 1-11- (2-acetoxy-1-decyl) -piperidinium-3- (trimethylammonium) -propane dibromide.

Example 78. 141- (2-hydroxy-1-dodecyl) = piperddinium] -3- (trimethylammonium) -probandibromide. 1- (2-Hydroxy-1-dodecyl) -piperidine was reacted according to Example 16 with 3-bromopropyltrimethylammonium bromide to give 141- (2-hydroxy-1-dodecyl) -piperidinium] -3- (trimethylla, ammonium) -propane dibromide.

Example 79. 14142-Acetoxy-1-dodecyl) -piperidinium 1-3- (trimethylammonium) -propane dibromide. 1- (2-Acetoxy-1-dodecyl) -piperidine was reacted according to Example 16 with 3-bromopropyl-trimethylammonium bromide to give 141- (2-acetoxy-1-dodecyl) -piperidinium-3- (trimethylammonium) -propane dibromide.

Example 80. 1- [1- (2,11-Dihydroxy-1-undecyl) -piperidinium] -3- (trimethylammonium) -propane dibromide. 1- (2,11-Dihydroxy-1-undecyl) -piperidine was reacted according to Example 16 with 3-bromopropyltrimethylammonium bromide to give 111- (2,11-dihydroxy-1-undecyl) -piperidinium] -3- (triethylammonium) -propane -dibromide.

Example 81. 141- (2,11-Diacetoxy-1-undecyl) -piperidinium] -3- (trimethylammonium) -propane dibromide. 1- (2,11-Diacetoxy-1-undecyl) -piperidine was reacted according to Example 16 with 3-bromopropyltrimethylammonium bromide to give 141- (2,11-diacetoxy-1-undecyl) -piperidinium] -3- (trimethylammonium) -propane -dibromide.

Example 82. 141- (2-Hydroxy-2-benzyl-4-butyl) -piperidinium-3- (trimethylammonium) -propane dibromide. 1- (2-Hydroxy-2-benzyl-4-butyl) -piperidine was reacted according to Example 16 with 3-bromopropyltrimethylammonium bromide t1114-1- (2-hydroxy-2-benzyl-4-butyl) piperidinium] -3- (trimethylammonium) -propanedibromide.

Example 83. 141- (2-Phenyl-2-hydroxyethyl) -piperidinium] -3- (trimethylammonium) -propanedibromide. 1- (2-Phenyl-2-hydroxyethyl) -piperidine was reacted according to Example 16 with 3-bromopropyltrimethylammonium broniumide to 111 (2-phenyl-2-hydroxyethyl) -piperidinium] -3- (trimethylammonium) -propanedibromide.

Example 84. 1- {2- (Benzoxypropyl) -pyridinium] 3- (trimethylammonium) -propidibromide. 2- (Benzoxypropyl) -pyridine was reacted according to Example 1 with 3-bromopropyltrimethylammonium bromide to give 1414- (benzodocopropyl) -pyridine] -3- (trimethylammonium) -propane dibronide.

Example 85. 143 (9-Fluorenecarboxymethyl) -1-methylpiperidinium] -3- (trimethylammonium) -propane bromide. 3- (9-Fluorenecarbamide-methyl) -1-methyl-piperidine was reacted according to Example 16 with 3-bromopropyltrimethylammonium bromide to give 1-13- (9-fluorenecarboxymethyl) -1-methylpiperidinium1-3- (trimethylammonium) -propane dibromide.

Example 86. 143- (Diphenylmethoxymethyl) -1-methyl-1-methylpiperidinium] -3- (trinethylammonium) -propanedibromide. 3- (Cliphenylmethoxymethyl) -1-methylperidine was reacted according to Example 1 with 3-bromopropyltrimethylammonium bromide to give 143- (diphenylmethoxymethyl) -1-methylpiperidinium] -3- (trimethylammonium) propane dibromide.

Claims (6)

Patent claim: A method of preparing asymmetric bisquaternary ammonium salts having a therapeutic effect, characterized in that a cyclic compound of the formula R-N is quaternized with a co-haloalkylammonium salt of the formula anion -anj on- R3.1 alkylene bridge — NE - / - R 2 \\ R3 'in which formulas R-N represent a pyridyl ring, which may be partially or completely hydrogenated and which is substituted on. Thus, its total radical weight is at least 150, each of the symbols R1, R3 and R3 represents a lower alkyl or lower alkenyl group, wherein tvd. of these groups may be joined to form a ring, which may additionally contain a heteroatom and wherein the total radical weight of the radical R 31 exceeds 117, the alkylene bridge contains 2-6 carbon atoms and may be formed by a straight or branched chain, and the anions consists of halide ions, which may be the same or different. 2. A set according to claim 1, characterized in that the quaternization is carried out in the presence of a solvent. 3. A kit according to claim 1 or 2, characterized in that the quaternization is carried out at a temperature between about room temperature and 150 ° C at atmospheric pressure. 4. According to claim 1 or 2, characterized in that the quaternization is carried out at reflux temperature. 5. According to any one of claims 1-4, there is claimed to be quaternizing a cyclic compound containing an indolylalkylpyridine group and obtained by addition reaction Indian an equation containing an indole nucleus which is unsubstituted in 3-position and a vinylpyridine base. 6. A method according to any one of claims 1-4, characterized in that a cyclic compound containing an indenylalkylpyridine group is quaternized and the soul is obtained by addition reaction between an equation containing an indene, which is unsubstituted and a vinylpyridine base. Modification of the process according to claim 1, characterized in that an asymmetric bisquaternary ammonium salt is prepared with the formula anion-anion- / R-N + -alkylene bridge-N + -R 2 j R 2, van in R-N denotes a piperidine ring, which is substituted in such a way that its total radical weight including a possible substituent at the nitrogen atom amounts to at least 150, and the symbols R1, R, and R, as well as the terms "anion" and "alkylene bridge" have the meanings given above, wherein the radical / \ —N — R2 R3! total radical weight does not exceed 117, in that a compound of the formula R-N, wherein R-N has the meaning given above, which compound is a ring-substituted piperidine compound which is unsubstituted at the ring nitrogen atom, The alkyls having a lower dialkylaminoalkyl halide of the formula Alkylene bridge - N, "'R. a to form a ditertiary base of the formula / 111 R — N alkylene bridge — N, \ R2 which both of the latter formulas RI, 112, R — N and the term« alkylene bridge »have the meanings given above, and that the ditertiary base is subsequently quaternized.Read publications: U.S. Patent Nos. 2,113,606, 2,746,96 6. Other publications: Chemical abstracts 40 (1946), sp. 40218, 48 (1954), sp. 8960 f, 49 (1955), sp. 8912 b.