PL121492B1 - Process for preparing novel salts of bis-tetrahydroisoquinolinium-alkyl m-or p-phenylene-dialkanocarboxylatessilanov bis-tetragidroizokhinolino-alkilovykh solejj - Google Patents

Description

The invention relates to a method for preparing new salts of m- or p-phenylene-alkyl bis-tetrahydroisoquinolinium dialkanoate carboxylates that induce neuromuscular blockade. Neuromuscular blocking agents are used to relax skeletal muscles during surgical procedures and during tracheal intubation. Two types of neuromuscular blocking agents are generally used: nondepolarizing and depolarizing. Nondepolarizing agents include d-tubocurarine, pancuronium, gallamine, diallyloxyferrine, and toxiferine. Depolarizing agents include succinylcholine and decamstonium. All conventional nondepolarizing agents used in surgery to relax skeletal muscles have a long duration of action, e.g., 60 to 180 minutes in humans. However, depolarizing agents, at doses normally used in surgery, produce muscle relaxation that is shorter in duration than nondepolarizing agents. For example, succinylcholine has a short-acting effect of about 5 to 15 minutes, whereas decamstonium has a muscle relaxant effect of about 20 to 40 minutes. Currently, there are no short-acting nondepolarizing agents suitable for clinical use. A short duration of action is defined here as less than about 10 minutes in a monkey. Long-term action of nondepolarizing agents is unacceptable in many surgical procedures lasting less than one hour because their effects on the patient do not completely subside after the procedure; for example, the patient may be unable to breathe adequately on their own. Every nondepolarizing agent has inherent side effects. For example, gallamine and pancuronium may cause tachycardia, and d-tubocurarine and diallyloxyferrine may cause hypotension. Because such drugs can be pharmacologically antagonistic to anticholinesterase agents, this leads to the need to administer a second drug, which in turn can cause other side effects, such as bradycardia, intestinal spasm, and bronchial hemorrhage. Therefore, to avoid these side effects of anticholinesterase agents, a third drug, an anticholinergic drug such as atropine, must be administered. Depolarizing agents do not have pharmacological antagonists. Although in most cases it is not necessary to counteract the effects of depolarizing agents, in some patients the effects of succinylcholine administration last longer due to abnormal metabolism of the agent in the body. Depolarizing agents, whose action initially causes skeletal muscle contraction and smooth muscle excitation, are also known to cause side effects in some cases such as increased intraocular and intragastric pressure, cardiac arrhythmias, potassium secretion, and myalgia. These side effects caused by depolarizing agents are not seen with nondepolarizing agents. It is therefore obvious that there is a need for a new neuromuscular blocking agent that would possess the short duration of action of depolarizing agents and the relatively few side effects and reversibility of action of nondepolarizing agents. It should be understood, however, that although nondepolarizing agents generally have few side effects, gellamine and pancuronium may cause tachycardia and d-tubocurarine and diallyloxyferrine may lower blood pressure. Based on the studies conducted so far, it has surprisingly been found that the compounds of the present invention do not exhibit such side effects when used in the doses intended for clinical use. Further description of the neuromuscular blocking agents Neuromuscular blockade can be found in "The Pharmacological Basis of Therapeutics", 5th edition, edited by Louis S. Goodman and Alfred Gilman, published by McMillan Co., 1975, chapter 28, author George B. Koelle. Agents inducing neuromuscular blockade are also described in the following articles: "Neuromuscular Blocking Activity of a New Series of Quaternary N-substituted Choline Esters" - British Journal of Pharmacology, September 1971, vol. 43, no. 1, p. 107, "The Pharmacology of New Short Acting Nondepolarizing Ester Neuromuscular Blocking Agents - Clinical Implications" - published in Anesthesia and Analgesia Current Researches, vol. 52, no. 6, p. 982, November-December 1974, "Potential Clinical Uses of Short-Acting Nondepolarizing Neuromuscular-Biocking Agents as Predicted from Animal Experiments" — published in Anesthesia and Analgesia .... Current Researches, vol. 54, no. 5, p. 669, September-October 1974 and U.S. Pat. The invention provides new and improved neuromuscular blocking agents, sometimes called muscle relaxants, which combine a non-depolarizing mechanism of action with the short-acting and reversible action necessary for meeting the ideal clinical requirements for use during surgical procedures. The novel neuromuscular blocking agents are represented by the general formula I, wherein most preferably C is meta to B as in formula II, or C is para to B as in formula III, and B and C represent p-groups in the general formula IV, wherein m is 2, 3 or 4, preferably 2, n is 2, 3 or 4, most preferably 3, R1, R2, R2, R3, R4, R5, R6 and R7 are the same or different and represent hydrogen atoms or alkoxy groups with 1-4 carbon atoms (i.e. methoxy, ethoxy, propoxy or butoxy), Y represents an alkyl radical with 1-4 carbon atoms (methyl, ethyl, propyl or butyl), and X represents an equivalent of a pharmacologically acceptable anion, where at least one of the substituents R1-R4 is always a lower alkoxy group and at least one of the substituents R5-R7 is always a lower alkoxy group. Most preferred are compounds of Formulae 2 and 3, in which Y represents a methyl group, m represents 2, n represents 3, 4 R5, R6 and R7 represent methoxy groups in In positions 3, 4, and 5 of the phenyl ring of the benzyl group, R1 and R2 are hydrogen atoms, and R2 and R3 are methoxy groups, since these compounds hydrolyze much slower than the dimethoxybenzyl compounds, the meta compound (Formula 2) being even more preferred than the corresponding para compound, since its action is much shorter. These most preferred compounds also show the fewest side effects and high potency. Examples of suitable anions are: iodide, methanesulfonate, toluene-4-sulfonate, bromide, chloride, sulfate, phosphate, hydrogenphosphate, acetate, benzenesulfonate, nitrobenzenesulfonate, naphthalenesulfonate, and propionate. The most preferred anions are methanesulfonate and chloride due to the low solubility of their salts in water. Since the activity of the compound is related to its cationic part, the nature of the anion is unimportant, provided that it is a pharmacologically acceptable anion. A process for the preparation of compounds of the general formula I, wherein B and C have the above-mentioned meanings, according to the invention consists in reacting a salt of the general formula V with a compound of the formula VI, wherein n, m, Y, R1-R7 and X- have the above-mentioned meanings, one of the substituents Q and Q' represents a halogen atom and the other a carboxylic acid salt group, or one of the substituents Q and Q' represents a hydroxyl group and the other an acid halide group, and optionally rearranging the obtained salt into a salt of the formula I. In the case where, for example, a suitable salt of a dicarboxylic acid of the formula VI, e.g. a silver salt, is reacted with a suitable N-alkyl-N-alkyl halide, the reaction proceeds as follows: (-haloalkyl)-1-benzyltetraisoquinolinium compound of formula 5, wherein Q is a halogen atom such as chlorine, bromine or iodine, then the obtained salt of formula 7 is rearranged into a salt of formula 1, for example by heating, preferably at a temperature of from 90 to 140° C. Preferably, the salt of formula 7 is prepared by reacting a silver salt of the anion with a halide of a cation, especially bromide. The reactions of the compound of formula 5 with the compound of formula 6 are carried out in an inert solvent, preferably using an acid chloride as the substrate. Benzyltetrahydroquinolines are prepared in a conventional manner from appropriately substituted phenylethylamines and phenylacetic acid by the Bischler-Napierulski reaction. The tertiary benzylisoquinoline is quaternized with the appropriate α-bromo-ω-chloroalkane, d-iodo-ω-chloroalkane, or α-iodo-ω-bromoalkane. The resulting N-methyl-N-(ω-haloalkyl)-1-benzyltetrahydroisoquinolinium halide is boiled in water with the silver salt of the appropriate dicarboxylic acid to give silver bromide and the benzylisoquinolinium salt of the acid. This salt is rearranged to the corresponding ester by heating. For example, the general reaction using an α-bromo-00-chloroalkane is shown in Scheme 1, where Z is a (C1-thymg) group and R1-R7 are as defined above. Other salts are prepared by the known ion exchange reaction from the dichloride salt using a suitable salt containing the desired anion, e.g., silver methylsulfonate. The rearrangement reaction temperature is preferably from 90°C to 140°C. The corresponding 1-benzyltetrahydroisoquinoline obtained as described above is quaternized with the appropriate α-halo-α-hydroxyalkane. This process can be carried out in a wide variety of solvents (e.g., acetonitrile, lower alcohols, DMF, aromatic hydrocarbons, etc.) ranging from a temperature of 100°C to 140°C. The reaction is shown in Scheme 2. The bis-acid chloride of the corresponding meta- or para-phenylene dicarboxylic acid is obtained in a conventional manner by treatment with a reagent such as thionyl chloride. The bis-acid chloride is then esterified, for example, with two moles of the appropriate quaternary salt containing an o-hydroxyalkyl chain. The desired salts are prepared by ion exchange using known methods, such as the double exchange reaction with a silver salt, exchange on an anion exchange resin, etc. m- and p-phenylene diacetic acids are commercially available (Aldrich). m- and p-phenylene diacrylic acids are obtained by condensation of isophthalic aldehyde and terephthalic aldehyde with malonic acid by the method Knoevenagel-Doebner. Terephthalaldehyde (150 mmol) and malonic acid (18 mmol) are mixed with pyridine (45 ml) and piperidine (1.5 ml). The mixture is heated on a steam bath (85-95°C) for 3 hours. The solution is cooled to room temperature and distilled in vacuo to remove pyridine. The solid residue is washed with hot isopropanol (70°C) to remove any pyridine residues. The product, p-phenylene diacrylic acid, is filtered off and dried (m.p. below 275°C). In the same way, m-phenylene diacrylic acid (m.p. above 275°C) is obtained from isophthalaldehyde. 275°). m- and p-phenylene dipropionic acids can be obtained by catalytic reduction in known methods, e.g. by reacting the corresponding phenylene diacrylic acid with hydrogen at a pressure of 275790 to 372417 Pa in the presence of 5% palladium on charcoal in dilute methanol or dimethylformamide at a temperature from room temperature to 55°C. Another method is given in Synthetic Organic Chemistry by C. Wagner and Zook, 1973, method 26 on page 431. The compounds prepared by the method of the present invention may sometimes contain water of hydration in various amounts, e.g. 1-5 or more water molecules per quaternary moiety, wherein Compounds containing water of hydration are also within the scope of this invention. The compounds of formula 1, 2 or 3 are used as agents inducing neuromuscular blockade during surgery or tracheal intubation by conventional parenteral administration, e.g. intramuscularly or intravenously, in solution. The compounds of formula 1, 2 or 3 are administered to patients such as monkeys, humans and other mammals to produce neuromuscular blockade. The dose varies depending on the species of patient, with a suitable dose of a compound of formula 1, 2 or 3 when administered intravenously for a monkey being 1.0 to 4.0 mg/kg body weight and for a human being 0.2 to 3.0 mg/kg body weight, and most preferably 0.5 to 4.0 mg/kg body weight. 1.5 mg/kg of body weight. These amounts are based on the weight of the cation, which constitutes the active ingredient. The dose for intramuscular administration is two to four times the intravenous dose. Compounds of formula I are usually re-administered every 5 to 20 minutes, preferably 5 to 15 minutes, after the initial administration or 6, a continuous infusion is administered depending on the desired duration of muscle blockade, as determined by the anaesthesiologist and surgeon treating the patient. The action of the compounds can be reversed by the use of known anticholinesterase agents, such as neostigmine and edroformium, without the side effects associated with agents with a depolarizing mechanism of action. Thus, compounds of formula I, II, or III are useful as agents producing short-acting neuromuscular blockade, suitable for use in mammals, e.g., humans or monkeys, at an intravenous dose of 0.05 to 4.0 mg/kg of the mammal's body weight. The compounds can be formulated as pharmacological preparations for parenteral administration. The preparation can be an aqueous or non-aqueous solution or an aqueous or non-aqueous emulsion in a pharmacologically acceptable liquid or mixture of liquids, which may contain bacteriostatic agents, antioxidants, buffers, thickening agents, suspending agents and other pharmacologically acceptable auxiliaries. Such preparations are generally in the form of unit doses, e.g., ampoules or disposable injection devices, or multiple doses, e.g., in bottles from which withdraw the appropriate amount of the agent. All such preparations should be prepared sterilely. The compounds of the invention may be in powder form, e.g., a unit dose in a sealed vial into which sterile water or another pharmacologically acceptable sterile liquid carrier may be introduced by means of a needle. A unit dose suitable for producing neuromuscular blockade in mammals, e.g., humans or monkeys, is about 10 mg to 400 mg, most preferably about 10 mg to 400 mg. The compounds of the invention, if appropriate, may also be administered in combination with other non-depolarizing agents, such as those mentioned above. Thus, a suitable pharmacological preparation for parenteral administration preferably contains 10 to 400 mg of a compound of the formula 1, 2 or 3 in this solution. A simple and preferred preparation is a solution of compound 1, 2 or 3 in water, which can be obtained by simply dissolving the compound in previously sterilized pure water, i.e., free of pyrogens, under aseptic conditions and sterilizing the solution. Compounds of formula 1, 2 or 3 can also be administered by infusion in dextrose or saline solution, e.g., Ringers' solution. These compounds can also be administered in other solvents, such as alcohol, polyethylene glycol, and dimethyl sulfoxide. They can also be administered intramuscularly in the form of a suspension. Pharmacological studies. Compounds HH HO, HH 177, HH 121, and HH 35 are dissolved separately in 0.9% saline to a concentration of 2 mg/ml. Cynomolgus monkeys were anesthetized with halothane, nitrous oxide, and oxygen, maintaining a halothane concentration of 1.0%. To administer the drug and record blood pressure, arterial and venous catheters were placed in the femoral vessels. Oxygen was delivered to the lungs via an endotracheal tube. Convulsive and tetanic contractions of the tibialis muscle were induced indirectly via the sciatic nerve. Simultaneously, electrocardiographic recordings of blood pressure (lead I), heart rate, and muscle activity were made. As shown in the table, individual compounds were administered to 4-6 animals. Four additional animals received succinylcholine chloride or d-Tubocurarine chloride was used as a control compound. The table shows the dose range required to achieve 95% blockade of the twitch response of the tibialis anterior muscle under the above-mentioned anesthetic conditions for each group of animals receiving each drug. The table also shows the duration of action of each compound for each group of animals. The duration of action is defined as the period from drug injection to full recovery of the twitch response of the tibialis anterior muscle. The duration of action of these compounds in monkeys is more indicative of the expected duration of action in humans than data obtained in studies on other animal species, such as cats and dogs, for the following reason: The compounds are believed to be degraded (hydrolyzed) by an enzyme (plasma cholinesterase) present in humans, monkeys, cats, and dogs. It is also assumed that the rate of The degradation of the compound by this enzyme is the main factor determining the duration of action of the compound in the body. The action of monkey plasma cholinesterase is known to be most similar to the analogous action in humans (see Hobbiger and Peck, British Journal of Pharmacology 37: 258—271, 1969). Table Potency of selected compounds causing neuromuscular blockade in cynomolgus monkeys Compound | HH 110 | HH 177 | HH121 HH 35 1 succinylcholine rin Number of animals tested 6 4 6 4 4 4 ED95*) (mg cation/kg) 0.5—1.0 0.5-1.0 2.0—4.0 2.0—4.0 1.0—2.0 0.2—0.4 Time range of action (minutes from injection to return of reaction) | 5—8 1 8—12 | 4—6 | 3—5 4—6 1 30—50 | *) ED95 is the dose necessary to produce 95% blockade of the twitch response of the tibialis anterior muscle induced indirectly via the sciatic nerve at a frequency of 0.15 Hz. The invention is illustrated by the following examples, in which the temperature is given in degrees Celsius. Example 1. Preparation of bis-3-[N-methyl-1-(3,4,5-trimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinium]propyl m-phenylenedipropionate dichloride (HH 110). 1. Preparation of silver m-phenylene dipropionate. A mixture of 4.4 g (40 milliequivalents) of m-phenylene dipropionic acid, 60 ml of water, and 40 ml of 1 N KOH is heated to boiling and, if necessary, adjusted to pH 7.0 with the same acid. To the hot yellow solution is added 6.8 g (40 millimoles) of AgNO3, as a result of which a heavy precipitate immediately forms. The mixture is cooled and filtered, the filtered precipitate is washed with water, filtered again, and dried. Quantitative yield. The product is a slightly colored amorphous powder. This powder is ground before use in the next step. 2. Preparation of 5'-methoxylaudanosine (compound 8). 3,4-Dimethoxyphenylethylamine and 3,4,5-trimethoxyphenylacetic acid are heated together in a flask at 165°-190°C until water bubbles cease. The product, 3,4,5-trimethoxybenzylacetylhomoveratrilamine, is recrystallized from methanol. Yield: 80%. Melting point: 94°C. 3.9 g (10 mmol) of 3,4,5-trimethoxyphenylacetylhomoveratrilamine in 15 ml of toluene and 5 ml of POCl3 is heated at reflux for 2 hours. The semi-solids that settled to the bottom were carefully separated (excess POCl3) and the free base was isolated by adding excess NaOH and extracting with benzene. The product, 1-(3',4',5'-trimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline, was boiled under reflux with excess methyl iodide and acetone or benzene. The quaternary salt, 1-(3',4',5'-trimethoxybenzyl)-2-methyl-6,7-dimethoxy-3,4-dihydroisoquinolinium iodide, melting at 224°C, precipitated. 26 5.1 g (10 mmol) of 1-(3,4,5,-trimethoxybenzyl)-2-methyl-6,7-dimethoxy-3,4-dihydroisoquinolinium iodide are dissolved in 80 ml of H2O and 16 ml of concentrated HCl. To the boiling, stirred solution is added in small portions 1.1 g of Zn dust. The yellow color disappears (reaction time 15-20 minutes). The mixture is filtered hot to remove unreacted zinc and made alkaline with concentrated NaOH. Filtration of the partially precipitated zinc hydroxide is impractical, so to avoid emulsion formation the entire mixture is carefully shaken with chloroform. The remaining chloroform solution is redissolved in ether, and the ether-insoluble materials are filtered off. The ether residue does not crystallize on standing. This amine is a resinous substance that hardens on standing. The crude amine is used in the next step. 3. Preparation of N-(S-chloropropyl)-methoxylaudanosinium bromide (compound of formula 9). 1.4 g (4 mmol) of 5'-methoxylaudanosine is dissolved in 8 ml of dimethylformamide with gentle heating, 1.2 g of 1-bromo-3-chloropropane (approximately 100% excess) is added to the mixture and then it is left for 5 days at room temperature (sometimes some of the unreacted 5'-methoxylaudanosine crystallizes but eventually redissolves). The reddish-orange solution is treated with a large amount of ether and the precipitated resinous quaternary salt is decanted and made into a slurry in fresh ether. After After 1 day of standing in ether, a low-melting solid is obtained. Yield: 1.6 g, about 80% of theory. 4. Preparation of N-propyl-5'-methoxylaudanosine m-phenylenedipropionate (HH 110) (compound of formula 10). (Horenstein-Pahlicke ester formation reaction). A mixture of 2.1 g (4 mmol) of N-(3-chloropropyl-5'-methoxylaudanosinium bromide, 0.85 g (4 milliequivalents) of silver m-phenylenedipropionate and about 150 ml of water is brought to the boil in an open beaker for about 10-15 minutes, stirring occasionally by hand. stirring. At boiling point, the silver salt dissolves slightly and reacts with the quaternary bromide. The mixture is cooled to room temperature, filtered, and the aqueous solution is evaporated to dryness in a large vessel on a steam bath. The residue is heated further on a steam bath (90°C) for about 2 hours, after which complete rearrangement to the ester occurs. The reaction is shown in Scheme 3. The amorphous residue is boiled with isopropanol (about 40 ml) and then filtered hot to remove traces of mechanical impurities. Resinous substances precipitate from the filtrate at room temperature, the precipitation of which is completed when the filtrate is allowed to stand. overnight at about -3°C. The supernatant is decanted and the precipitate is triturated twice in ethyl acetate. The resin then takes on a semi-solid form which can be filtered off. After thorough drying at 75°C, the resin solidifies. In this state, it probably still retains water in a variable amount. Yield 1 g (approximately 40%). Yields vary for different product batches. Melting point (with decomposition) 80-90°C. Analysis % Calculated % Found % C 52.99 53.22 H 6.46 5.94 N 1.99 2.00 J 18.06 19.38 The calculations take into account 2 H2O per quaternary group. Example n. Preparation of p-phenylene dichloride Bis-3-[N-methyl-1-(3,4,5-trimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinio]propyl dipropionate (HH 177). 1. Preparation of silver p-phenylene dipropionate. A mixture of 4.4 g (40 milliequivalents) p-phenylene dipropionic acid (Aldrich), 60 ml of water and 40 ml of 1 N KOH is heated to boiling and, if necessary, adjusted to pH 7.0 with the same acid. 6.8 g (40 mmol) of AgNO3 is added to the hot yellow solution, as a result of which a heavy precipitate immediately precipitates. The mixture is cooled and filtered, and the filtered precipitate is removed. washed with water, filtered again and dried. Quantitative yield. The product is an amorphous, slightly colored powder which is ground before use in the next step. 2. Preparation of 5'-metholcylaudanosine (compound of formula 8). 3,4-Dimethyloxyphenylethylamine and 3,4,5-trimethoxyphenylacetic acid are heated together in a flask at 165°-190°C until water bubbles cease. The product, 3,4,5-trimethoxybenzylacetylhomoveratrilamine, is recrystallized from methanol. Yield: 80%. Melting point: 94°C. 3.9 g (10 mmol) of 3,4,5-trimethoxyphenylacetyl- Homoveratrylamine in 15 ml of toluene and 5 ml of POCl2 is refluxed for 2 hours. The semi-solids that have settled to the bottom are carefully separated (excess POCl2) and the free base is isolated by adding excess NaOH and extracting with benzene. The product, 1-(3',4',5'-trimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline, is refluxed with acetone or benzene and excess methyl iodide. The quaternary salt, 1-(3',4',5'-trimethoxybenzyl)-2-methyl-3'-dimethyl-3,4-dihydroisoquinolinium iodide, melting at 224°C, precipitates. 5.1 g 1-(3.4% 5,-trimethoxybenzyl)-2-methyl-6,7-dimethoxy-3,4-dihydroisoquinolinium iodide is dissolved in 80 ml of H2O and 16 ml of concentrated HCl. To the boiling, stirred solution is added in small portions 1.1 g of Zn dust. The yellow color disappears (reaction time 15-20 minutes). The mixture is filtered hot to remove unreacted zinc and made alkaline with concentrated NaOH. Filtration of the partially precipitated zinc hydroxide is impractical, so the entire mixture is shaken with chloroform to avoid the formation of an emulsion. The remaining chloroform solution is redissolved in ether, and the ether-insoluble substances are filtered off. The ether residue does not crystallize on standing. This amine is a resinous substance that hardens on standing. The crude amine is used in the next step. 3. Preparation of N-(3-chloropropyl)-5'-methoxylaudanosinium bromide (compound of formula 9). 1.4 g (4 mmol) of 5'-methoxylaudanosine is dissolved in 8 ml of dimethylformamide with gentle heating. 1.2 g of 1-bromo-3-chloropropane (approximately 100% excess) is added to the mixture, and then 25 IU is allowed to stand for 5 days at room temperature (sometimes some unreacted laudanosine crystallizes but eventually redissolves). The reddish-orange solution is treated with a large amount of ether, and the precipitated resinous quaternary salt is decanted and slurried in fresh ether. After 1 day in ether, a low-melting solid is obtained. Yield: 1.6 g, about 80% of theory. 4. Preparation of N-propyl-5'-methoxylaudanosinium p-phenylene dipropionate (HH 177) (compound of Formula 11) (Horenstein-Pahlicke ester formation reaction). A mixture of 2.1 g (4 mmol) of N-(3-chloropropyl)-5'-methoxylaudanosinium bromide, 0.85 g (4 milliequivalents) of silver p-phenylene dipropionate and about 150 ml water is boiled in an open beaker for about 10-15 minutes, with occasional hand stirring. At boiling temperature, the silver salt dissolves slightly and reacts with the quaternary bromide. The mixture is cooled to room temperature, filtered, and the aqueous solution is evaporated to dryness in a large vessel on a steam bath. The residue is continued to be heated on a steam bath (90°C) for about 2 hours, after which complete rearrangement to the ester takes place. The reaction is shown in Scheme 4. The amorphous residue is boiled with isopropanol (about 40 ml) and then filtered hot to remove traces of mechanical impurities. The filtrate resinous substances precipitate at room temperature, the precipitation of which is completed after the filtrate is left overnight at about -3°C. The supernatant is decanted and the precipitate is triturated twice in ethyl acetate. The resin then takes on the form of a semi-solid substance which can be filtered off. After thorough drying at 75°C, the resinous substance solidifies. In this state, it probably still retains water in a variable amount. Yield 1 g (about 40%). Yields vary for different batches of the product. Melting point 65 (with decomposition) 80-90°C. 121 492 11 Example III. Preparation of bis-3-[N-methyl-1-(3,4-dimethoxy-]-p-phenylene dipropionate dichloride 1. Preparation of silver p-phenylenedipropionate. A mixture of 4.4 g (40 milliequivalents) of p-phenylenedipropionic acid (Aldrich), 60 ml of water and 40 ml of 1 N KOH is heated to boiling and, if necessary, adjusted to pH 7.0 with the same acid. 6.8 g (40 mmol) of AgNO3 is added to the hot yellow solution, as a result of which a heavy precipitate immediately precipitates. The mixture is cooled and filtered, the filtered precipitate is washed with water, filtered again and dried. Quantitative yield. The product is an amorphous, slightly colored powder, which is ground before use in the next step. 2. Preparation of N-(3-chloropropyl)laudanosinium bromide (compound of formula 12). 1.4 g (4 mmol) of laudanosine (from Aldrich) is dissolved in 8 ml of dimethylformamide with gentle heating. 1.2 g of 1-bromo-3-chloropropane (approximately 100% excess) is added to the mixture and then allowed to stand for 5 days at room temperature (sometimes some of the unreacted laudanosine crystallizes but eventually redissolves). The reddish-orange solution is treated with a large amount of ether, and the precipitated resinous quaternary salt is decanted and made into a slurry in fresh ether. After 1 day in ether, a low-melting solid is obtained. Yield: 1.6 g, about 80% of theory. 3. Preparation of N-propyl-laudanosine p-phenylenedipropionate (HH 121) (compound of Formula 13) (Horenstein-Pahlick ester formation reaction)* A mixture of 2.1 g (4 mmol) of N-(3-chloropropyl-laudanosinium bromide, 0.85 g (4 milliequivalents) of silver p-phenylenedipropionate and about 150 ml of water is brought to boiling in an open beaker for about 10-15 minutes, with occasional manual stirring. At boiling temperature, the silver salt dissolves slightly and reacts with quaternary bromine. The mixture is cooled to room temperature, filtered, and the aqueous solution is evaporated to dryness in a large vessel on a steam bath. The residue is heated on a steam bath for about 2 hours, after which complete rearrangement to the ester takes place. The reaction is shown in Scheme 5. The amorphous residue is boiled with isopropanol (about 40 ml) and then filtered hot to remove traces of mechanical impurities. Resinous substances precipitate from the filtrate at room temperature, the precipitation of which is complete after the filtrate has been left overnight at about -3°C. The supernatant is decanted, and the precipitate is triturated twice in ethyl acetate. The resin takes on a then a semi-solid substance, which can be filtered off. After thorough drying at 75°C, the resinous substance solidifies. In this state, it probably still retains water in a variable amount. Yield 1 g (approximately 40%). Yields vary for different batches of the product. Melting point (with decomposition) 80-90°C. 12 Analysis Calculated % Found % C 53.57 53.62 H 6.44 6.06 5 N 2.08 2.10 J 18.87 18.87 The calculations take into account 2H2O per quaternary group. Example IV. Preparation of bis-3-[N-methyl-1-(3,4-dimethoxybenzyl)]-m-phenylenedipropionate dichloride -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinio]propyl (HH35). 1. Preparation of silver m-phenylene dipropionate. A mixture of 4.4 g (40 milliequivalents) of m-15-phenylene dipropionic acid (Aldrich), 60 ml of water and 40 ml of 1 N KOH is heated to boiling and, if necessary, adjusted to pH 7.0 with the same acid. To the hot yellow solution is added 6.8 g (40 mmol) of AgNO3, as a result of which a heavy precipitate immediately precipitates. The mixture is cooled and filtered, and the filtered precipitate is washed with water, filtered again and dried. Quantitative yield. The product is an amorphous, slightly colored powder. This powder is ground before use in the next step. 2. Preparation of 3-chloropropyllaudanosinium bromide (compound of Formula 12). 1.4 g (4 mmol) of laudanosine (from Aldrich) is dissolved in 8 ml of dimethylformamide with gentle heating. 1.2 g of 1-bromo-3-chloropropane (approximately 100% excess) is added to the mixture and then allowed to stand for 5 days at room temperature (sometimes some unreacted laudanosine crystallizes but eventually redissolves). The reddish-orange solution is treated with a large amount of ether, and the precipitated gummy quaternary salt is decanted and It is made into a slurry in fresh ether. After standing in ether for 1 day, a low-melting solid is obtained. Yield: 1.6 g, about 80% of theory. 3. Preparation of N-propyl laudanosine m-phenylenedipropionate (HH 35) (compound of formula 14) (Horenstein-Pahlicke ester formation reaction). A mixture of 2.1 g (4 milliliters) of N-(3-chloropropyl)laudanosinium bromide, 0.85 g (4 milliequivalents) of silver m-phenylenedipropionate and about 150 ml of water is brought to boiling in an open beaker for about 10-15 minutes, with occasional manual stirring. At boiling temperature The silver salt 50 dissolves slightly and reacts with the quaternary bromide. The mixture is cooled to room temperature, filtered, and the aqueous solution is evaporated to dryness in a large vessel on a steam bath. The residue is heated further on a steam bath at 90°C for about 2 hours, after which complete rearrangement to the ester takes place. The reaction is shown in Scheme 6. The amorphous residue is boiled with isopropanol (about 40 ml) and then filtered hot to remove traces of mechanical impurities. Resinous substances precipitate from the filtrate at room temperature, the precipitation of which is complete after the filtrate has been left overnight at about -3°C. The supernatant liquid The resin is decanted, the ester is removed, and the precipitate is triturated twice in ethyl acetate. The resin then becomes a semi-solid substance which can be filtered off. After thorough drying at 75°C, the resin solidifies. In this state, it probably retains a variable amount of water. Yield: 1 g (approximately 40%). Yields vary for different batches of the product. Melting point (with decomposition): 80-90°C. Example 5. Preparation of p-phenylenedipropionatebis-3-[N-methyl-1-(3,4-dimethoxybenzyl)-5,6,7-trimethoxy-1,3,4-tetrahydroisoquinoline]propyl dichloride (LL 37). 1. Preparation Silver p-phenylene dipropionate. A mixture of 4.4 g (40 milliequivalents) p-phenylene dipropionic acid, 60 ml water, and 40 ml 1 N KOH is heated to boiling and, if necessary, adjusted to pH 7.0 with the same acid. To the hot yellow solution, 6.8 g (40 mmol) AgNO3 is added, as a result of which a heavy precipitate immediately precipitates. The mixture is cooled and filtered, the filtered precipitate is washed with water, filtered again, and dried. Quantitative yield. The product is a slightly colored amorphous powder. This powder is ground before use in the next step. 2. Preparation of 5-methoxylaudanosine [N-methyl-1- (3,4-Dimethoxybenzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline] (compound of formula XV). 2,3,4-Trimethoxyphenylethylamine and 3,4-dimethoxyphenylacetic acid are heated together in a flask at 165°-190°C until water bubbles cease. The product, N-(3,4-dimethoxyphenylacetyl)-2,3,4-trimethoxyphenylethylamine, is recrystallized from methanol. Yield: 80%. Melting point: 101°C. 3.9 g (10 mmol) of N-(3,4-dimethoxyphenylacetyl)-2,3,4-trimethoxyphenylethylamine in 15 ml toluene and 5 ml of POCl3 are refluxed for 2 hours. The semisolids that have settled to the bottom are carefully separated (excess POCl3) and the free base is isolated by adding excess NaOH and extracting with benzene. The product, 1-(3',4'-dimethoxybenzyl)-5,6,7-trimethoxy-3,4-dihydroquinoline, is refluxed with excess methyl iodide and acetone or benzene. The quaternary salt, 1-(3',4'-dimethoxybenzyl)-2-methyl-5,6,7-trimethoxy-3,4-dihydroisodiinolinium iodide, melting at 165°C, is precipitated. 5.1 g (10 mmol) of 1-(3',4'-dimethoxybenzyl)-2-methyl-5,6,7-trimethoxy-3,4-dihydroisodiinolinium iodide, melting at 165°C, is obtained. (3'4'-Dimethoxybenzylmethyl-5,6,7-trimethyloxy-3,4-dimethylbenzyl) is dissolved in 80 ml of H2O and 16 ml of concentrated HCl. 1.1 g of Zn dust is added in small portions to the boiling, stirred solution. The yellow color disappears (reaction time 15-20 minutes). The mixture is filtered hot to remove unreacted zinc and made alkaline with concentrated NaOH. Filtration of the partially precipitated zinc hydroxide is impractical, so to avoid the formation of an emulsion, the entire mixture is shaken carefully with chloroform. The remaining chloroform solution is redissolved in ether and the ether-insoluble substances are filtered off. The residue The ether amine does not crystallize on standing. This amine is a resinous substance that hardens on standing. The crude amine is used in the next step. 3. Preparation of N-(3-chloropropyl)-5'-methoxylaudanosinium bromide (compound of formula 9). 1.4 g (4 mmol) of 5'-methoxylaudanosine is dissolved in 8 ml of dimethylformamide with gentle heating, 1.2 g of 1-bromo-3-chloropropane (approximately 100% excess) is added to the mixture, and then it is allowed to stand for 5 days at room temperature (sometimes some unreacted 5'-methoxylaudanosine crystallizes but eventually redissolves). The reddish-orange solution is treated with a large amount of ether, and the precipitated The resinous quaternary salt is decanted and made into a slurry in fresh ether. After 1 day in ether, a low-melting solid is obtained. Yield: 1.6 g, about 80% of theory. 4. Preparation of N-propyl-5'-methoxylaudanosine p-phenylenedipropionate (LL 37) (compound of formula 16) (Horenstein-Pahlicke ester formation reaction). A mixture of 2.1 g (4 mmol) of N-(3-chloropropyl)-5-methoxylaudanosinium bromide, 0.85 g (4 milliequivalents) of silver diproprionate and about 150 ml of water is heated at boiling in an open beaker for about 10-15 minutes, stirring occasionally by hand. At boiling temperature, the silver salt dissolves slightly and reacts with the quaternary bromide. The mixture is cooled to room temperature, filtered, and the aqueous solution is evaporated to spirit in a large vessel on a steam bath. The residue is heated further on a steam bath (90°C) for about 2 hours, after which complete rearrangement to the ester takes place. The reaction is shown in Scheme 7. The amorphous residue is boiled with isopropanol (about 40 ml) and then filtered hot to remove traces of mechanical impurities. Resinous substances precipitate from the filtrate at room temperature, the precipitation of which continues to complete. The remaining filtrate is left to stand overnight at about -3°C. The supernatant is decanted and the precipitate is triturated twice in ethyl acetate. The resin then becomes a semi-solid substance which can be filtered off. After thorough drying at 75°C, the resin solidifies. In this state, it probably still retains water in a variable amount. Yield: 1 g (approximately 40%). Yields vary for different batches of the product. Melting point (with decomposition): 80-90°C. Example 5: Preparation of bis-3-[N-methyl-1-(3,4,5-trimethoxybenzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinone]-p-phenylenedipropionate dichloride nolinio] propyl (KK 194). 1. Preparation of silver p-phenylenepropionate. 50 A mixture of 4.4 g (40 milliequivalents) p-phenylenedipropionic acid, 60 ml of water and 40 ml of 1 N KOH is heated to boiling and, if necessary, adjusted to pH 7.0 with the same acid. To the hot yellow solution is added 6.8 g (40 mmol) AgNO3, as a result of which a heavy precipitate immediately precipitates. The mixture is cooled and filtered, the filtered precipitate is washed with water, filtered again and dried. Quantitative yield. The product is a slightly colored amorphous powder. This powder is ground before use in the next step. 2. Preparation of 5,5'-dimethoxylaudanosine (compound of formula 17). 2,3,4-Trimethoxyphenylerylamine and 3,4,5-trimethoxyphenylacetic acid are heated together in a flask at 165°-190°C until no more water bubbles are formed. The product, N-(3,4,5-trimethoxyphenylacetylamine)-2,3,4-trimethoxyphenylethylamine, is recrystallized from methanol. Yield: 80%. Melting point: 85°C. 3.9 g (10 mmol) of N-(3,4,5-trimethoxyphenylacetyl)-2,3,4-trimethoxyphenylethylamine in 15 ml of toluene and 5 ml of POCl2 is boiled under reflux for 2 hours. The semisolids that have settled to the bottom are carefully separated (excess POCl2) and the free base is isolated by adding excess NaOH and extracting with benzene. The product, 1-(3*,4*,5,-trimethoxybenzyl)-5,6,7-trimethoxy-3,4-dihydroisoquinoline, is boiled under reflux together with excess methyl iodide and acetone or benzene. The quaternary salt, 1-(S,S-trimethoxybenzyl)-2-methyl-5,6,7-trimethoxy-3,4-dihydroisoquinolinium iodide, melting at 181°C, is precipitated. 5.1 g (10 moles) of 1-(3',4,,5-trimethoxybenzyl)-2-methyl-5,6,7-trimethoxy-3,4-dihydroisoquinolinium iodide are dissolved in 80 ml of H2O and 16 ml of concentrated HCl. To the boiling, stirred solution is added in small portions 1.1 g of Zn dust. The yellow color disappears (reaction time 15-20 minutes). The mixture is filtered hot to remove unreacted zinc and made alkaline with concentrated NaOH. Filtering off the partially precipitated zinc hydroxide is impractical, so to avoid emulsion formation, the entire mixture is shaken carefully with chloroform. The remaining chloroform solution is redissolved in ether, and the ether-insoluble materials are filtered off. The ether residue does not crystallize on standing. This amine is a resinous substance that hardens on standing. The crude amine is used in the next step. 3. Preparation of N-(3-chloropropyl)-5,5'-dimethoxylaudanosinium bromide. 1.4 g (4 mmol) of 5,5'-dimethoxylaudanosine is dissolved in 8 ml of dimethylformamide with gentle heating. 1.2 g of 1-bromo-2-chloropropane (approximately 100% excess) was added to the mixture, and it was allowed to stand at room temperature for 5 days (sometimes some of the unreacted 5,5'-dimethoxylaudanosine crystallized but eventually redissolved). The red-orange solution was treated with a large amount of ether, and the precipitated resinous quaternary salt was decanted and slurried in fresh ether. After 1 day in the ether, a low-melting solid was obtained. Yield: 1.6 g, approximately 80% of theory. 4. Preparation of N-propyl-5'-methoxylaudanosine p-phenylene dipropionate (KK 194) (compound of formula 18) (Horenstein-Pahlicke ester formation reaction). A mixture of 2.1 g (4 mmol) of N-(3-chloropropyl)-5'-dimethoxylaudanosinium bromide, 0.85 g (4 milliequivalents) of silver p-phenylene dipropionate and about 150 ml of water is boiled in an open beaker for about 10-15 minutes, with occasional manual stirring. At the boiling point, the silver salt dissolves slightly and reacts with the quaternary bromide. The mixture is cooled to room temperature, filtered and the aqueous solution is evaporated to dryness in a The residue is heated in a large vessel on a steam bath. The residue is heated on a steam bath (90°C) for about 2 hours, after which complete rearrangement to the ester takes place. The reaction is shown in Scheme 8. Example VII. In an ion-exchange process, HH 110 reacts with silver methylsulfonate to produce bis-3-[N-methyl-1-(3,4,5-trimethoxybenzyl)-6,7-5-dimethoxy-1,2,3,4-tetrahyavinisocriinolinio]propyl m-phenylenedipropionate dimethylsulfonate. HH 110 dichloride and silver methylsulfonate are dissolved in acetonitrile. The reaction mixture was stirred at room temperature for 30 minutes until a precipitate of silver chloride was obtained. The mixture was filtered through a filter paper to separate the silver chloride, leaving the methylsulfonate salt in solution. The acetonitrile was then evaporated. The product was dissolved in ethanol and filtered to remove residual silver chloride, and the ethanol was then evaporated. Example 8. Preparation of bis-3-[N-methyl-1-(3,4,5-trimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinio]propyl m-phenylenedipropionate diiodide tetrahydrate. 3.2 g of N-(3-hydroxypropyl)-5'-methoxylaudanosinium iodide are dissolved in anhydrous acetonitrile and 4 g of No. 4' molecular sieve are added. The mixture is stirred for 24 hours at room temperature and then 0.78 g of m-phenylene dipropionyl dichloride (prepared by the reaction of thionyl chloride with the known m-phenylene dipropionic acid, F.S. Kipping, J. Chem. Soc., 53, 21 (1888)) and another 4 g of No. 4' molecular sieve are added. The mixture was stirred for 24-48 hours at room temperature, filtered, and evaporated to dryness to give a dark brown oil, which dissolved in hot methanol and reprecipitated on cooling as a light brown oil. The oil, on drying, solidified to an amorphous light brown solid. Yield: 60%. This procedure was also used to prepare related compounds, using p-phenylenedipropynyl dichloride instead of the meta isomer and N-(3-hydroxypropyl)laudanosinium iodide instead of 5'-methoxylaudanosinium iodide. Example 9. Preparation of N-(3-hydroxypropyl)-5'-methoxylaudanosinium iodide. 1 g of 5'-methoxylaudanosine (J. Russell Flack, L.L. Miller and F.R. Stermits — Tetrahedron, 30, 931 (1974) in 20 ml of anhydrous acetonitrile and 1.2 g of 1-iodopropanol-3t (S. Wawzonek, J.Org.Chem., 25, 2068 (1968)) was boiled under reflux for 24 hours. The mixture was filtered, the solvent was evaporated under reduced pressure, and ether was added to the residue, as a result of which an oily yellow solid precipitated. After decanting the ether and drying the residue at 60°C, the following was obtained: Quantitative yield: yellow powder. The same procedure is used to prepare N-(3-hydroxypropyl)laudazinium iodide. Patent Claims 1. A method for preparing new salts of bis-tetrahydroisoquinolinium-alkyl n- or p-phenylene-dialkanoate carboxylates of the general formula I, wherein the substituents B and C represent groups of the general formula IV, wherein m represents 2, 3 or 4, n represents 2, 3 or 4, R1, R2, R3, R4, R5, R6 and R7 are the same or different and represent hydrogen atoms or alkoxy groups with 1-4 carbon atoms, Y represents an alkyl radical with 1-4 carbon atoms, and X- represents an equivalent a pharmacologically acceptable anion, wherein at least one of the substituents R1-1U represents an alkoxy group and at least one of the substituents R5-R' represents an alkoxy group, characterized in that the salt of general formula 5 is reacted with a compound of general formula 6, wherein n, m, Y, R1-R7 and X- are as defined above, and one of the substituents Q and Q* represents a halogen atom and the other a carboxylic acid salt group or one of the substituents Q and Q* represents a hydroxyl group and the other an acid halide group, and optionally the obtained salt is rearranged into a salt of formula 1. 2. A method according to claim 1, characterized in that the salt of formula 7 is rearranged, wherein m, n, Y, R1-R' are as defined in claim 1 and Q represents a halogen atom. 3. A process according to claim 2, wherein the salt is heated. 5. A process according to claim 4, wherein the salt is heated at a temperature of from 90°C to 140°C. 6. A process according to claim 2, wherein the salt of formula 7 is prepared by reacting a silver salt of an anion with a halide of a cation. 7. A process according to claim 6, wherein the halide is bromide. 8. A process according to claim 1, wherein the substrate is an acid chloride. 9. A process according to claim 1, wherein the reaction is carried out in 10. A method according to claim 1, characterized in that the substrate is a compound of formula 5, wherein X is an iodide, methanesulfonate, toluene-4-sulfonate, bromide, chloride, sulfate, phosphate, hydrogenphosphate, acetate or propionate anion, and Q, n, Y and R 1 - R 7 have the meanings given in claim 1. 11. A method according to claim 1, characterized in that the substrates are compounds of formulae 5 and 6, wherein m is 2, n is 3, Y is a methyl group, one or two of the substituents R 1 - R 4 are hydrogen atoms and the remaining ones are methoxy groups, and two or three of the substituents R 1 - R 7 are methoxy groups, wherein two of them are methoxy groups, the remaining one is a hydrogen atom, and Q, Q' and X have the meaning given in claim 1. 12. A method according to claim 1, characterized in that the starting materials used are compounds of formulae 5 and 6, wherein m is the number 2, n is the number 3, Y is a methyl group, R1 and R4 are hydrogen atoms, R2 and R3 are methoxy groups, and Rs1, R1 and R7 are methoxy groups located in position 3, 4, 5 of the phenyl ring, and Q, Q' and X have the meaning given in claim 1. B^Q,C-2X" B^Q .2X" Hl Formula C Formula Z B^C'2X~ - Formula 3 o -(CH^-C-O-CCH^-j^^ Q(CH,), /TrR, Formula 5 Formula 4121 492 Q*(CH2) m (CH2)m Formula 6 -|2' OOCCCH,), 2m^O-(CH^COO Formula 7 qCch2), Y I I lx3 R JpH, R.S£o$s*k*°*o£ ^ OCH3 CHS CH£ OCH, 0CH3 „«,, s^^OCH3121 492 ^ CH.CH ^ CH3O' «2 onj OCH, OCH, H, CHo i c c=o ó CH3P^V^ m CKO A^rK, CH CH3O CH£H2Ofea CH, «H)3hCCCoch CH, Br" OCH, Formula 3 CHp OCH, •2CI •AHP OCH, /Ifear // «, r.AA^-CHeiOWHCH CH,1-^ H, OCH, CHpA^TKaW!CHp OCH3 0CH3 Formula fZ OCH3 OCH, 2 er 4H20 flfc PMf/A^ WtC)C-CH2CH2- 3 CH?CH3 OCH, 0CH3 CH3O CHp^A, CH3O N-CH3 CH; Formula 15 OCH3 OCH3 OCH, OCH, 2Cf Formula H n..« OCH CH^^^-^-OC-ChtCH,-^^^ CHaO CHO Ofe0^ OCH, OCH, Formula W CH3°^XH3 OUT T 0CH3 OCH3 Formula 17 CH3 CH2 ^ 2 2CI OCH: AHgO OCH,121 492 OCHj O &P ~ ^CH» C=0 OCH5 0*3 QHZ CH3° XH3 OCHj [¦Y Formula 18 * OCH OCHj COOAg Z + COOAg+ aOUnik R* .. Br y' ch2R4 "3 J + - —2/igBr R.Cl(Mn R, R'R6 R Y CH,R4 1' ^T~ ¦*5 rearrangement l Y SH.R, ? rT heating rearrangement ! Z R 7 o -2Q Ri R, iR= RJR5 ' Re R' R, Scheme f121 492 X-CH2)r7OH ^ '1 R R-CHl -Yor "(CHjnOH R5 R7 Rfc Scheme 2 R, CH2CH2 COOAg CH2CH2C0CAg ch3o CKp ^ ^^Hp^Cl CHp axXoch3 COO °*CHZ CH,CH* " -Br OCH3 OCHa CH, H2 CHtfT ^OCH3 ' ^ OCH3 CH2 + 2 Ag Br CH 6ooXjCXXi aCH2pH£HPH2 OCH, °W OCH?0"3 ' compound of formula 10 Scheme 3121 492 COOAg O-U i L CH2 V +2 CH2 I C COOAg L CH, CHrf^^OCH, OCH, Br- CICHZCH£H COO a °* CH^ 0CH3 CH, COO.ClCH£H2Ot ^CH 0CH3 OCH3 OCH3 + 2A§Br OCH, w OCH a w^^/- ^ 0 formula / / Scheme 4 rH£rV^0CH3 OCH3121 492 COO Ag+ r CH, i t- CH2 ^ + 2 z COO Ag CH2 CHLl ^tfWPW CH^Hs ii ^ oH3 OCH, BF- aCH^CH-CH* COO 7N^U.0CH ^/^/0CH3 CH, CH CH2 CH, 3CH, + _- 0CH3 +2AgBr OCH3 Srfrr0CH3^ [JXW^AoCHz »"«*' n ru ru n-r ' A.. ^ cowshed 13 Scheme 5 OCH3 OCH3121 492 COOAg and CH2 CH2 CH2 COO~Ag CH30 ^CHA^CHp CH ^H, OCH, OCH, ClCH2pH2CH2. 9H2 O^CH, CH2 f% V^0CH3 )CH3 CH2 CH3/ COO OCH OCH, •Br— + 2Ag Br zmazek 13 o *zor /+ CICH2CH2CH2 CH -^ Scheme 6 /-OCH3 OCH3121 492 CH2 CH^COÓ Ag L^ +2 CH2CH£00Ag Cl CH2 OCH3 CHp CH2CH3 OH, COO" CH2 CH2 ch3ch; OCH3 OCH3 OCH3 a ^ CH2 I 0CH3 0CH3 ^2 CH* XH3 9H2_ %rrV0CH3 COO /M^OCH, CH '* CH, 2 Ag Br" compound of formula f€ Scheme 7 OCH3 0CH3121 492 CHjCH^COOAg + 2 CHpHgOOOAg Cc^rCHs CH CH^O-^ •Br CWTf^OCHj OCH, CICHYCH 0CH3 C00" /,NY^^0CH3 CHZ CH3 C^2 ?Hl run-C^OCH^ 2Ag+ Br CH£l 1 —-o * OCH, Ct CR* ,XoCH, CH30^f^uv-n3 OCH3 compound formula 18 Scheme 8 PL PL PL PL PL PL PL

Claims (12)

Patent claims 1. A method for preparing new salts of n- or p-phenylene-dialkanoate bis-tetrahydroisoquinolinium-alkylates of the general formula I, wherein the substituents B and C represent groups of the general formula IV, wherein m represents 2, 3 or 4, n represents 2, 3 or 4, R1, R2, R3, R4, R5, R6 and R7 are the same or different and represent hydrogen atoms or alkoxy groups with 1-4 carbon atoms, Y represents an alkyl radical with 1-4 carbon atoms, and X- represents an equivalent of a pharmacologically acceptable anion, wherein at least one of the substituents R1-17 represents an alkoxy group and at least one of the substituents R5-R8 is denotes an alkoxy group, characterized in that the salt of general formula 5 is reacted with a compound of general formula 6, where n, m, Y, R1—R7 and X— have the above-mentioned meanings, and one of the substituents Q and Q* denotes a halogen atom and the other one a carboxylic acid salt group or one of the substituents Q and Q* denotes a hydroxyl group and the other one an acid halide group, and optionally the obtained salt is rearranged into a salt of formula 1. 2. A method according to claim 1, characterized in that the rearrangement comprises a salt of formula 7, wherein m, n, Y, R 1 - R 2 are as defined in claim 1, and Q is a halogen atom. 3. A method according to claim 2, characterized in that the salt used is in which Q is a chlorine, bromine or iodine atom. 4. The method according to claim 2, characterized in that the salt is heated. 5. The method according to claim 4, characterized in that the salt is heated at a temperature of 90°C to 140°C. 6. The method according to claim 2, characterized in that the salt of formula 7 is prepared by reacting a silver salt of the anion with a halide of the cation. 7. The method according to claim 6, characterized in that bromide is used as the halide. 8. The method according to claim 1, characterized in that an acid chloride is used as the substrate. 9. The method according to claim 1, characterized in that the reaction is carried out in an inert solvent. 10. The method according to claim 1, characterized in that the substrate is a compound of formula 5, wherein X denotes an iodide, methanesulfonate, toluene-4-sulfonate, bromide, chloride, sulfate, phosphate, hydrogenphosphate, acetate or propionate anion, and Q, 10 n, Y and Ri—R7 have the meaning given in claim 1. 11. A method according to claim 1, characterized in that the starting materials used are compounds of formulae 5 and 6, where m is 2, n is 3, Y is a methyl group, one or two of the substituents R1-R4 are hydrogen atoms and the remaining ones are methoxy groups, and two or three of the substituents R5-R7 are methoxy groups, two of them are methoxy groups and the remaining one is a hydrogen atom, and Q, Q' and X have the meaning given in claim 1. 12. A method according to claim 1, characterized in that the starting materials used are compounds of formulae 5 and 6, where m is 2, n is 3, Y is a methyl group, R1 and R4 are hydrogen atoms, R2 and R3 are methoxy groups, and R5, R6 and R7 are methoxy groups located in position 3, 4, 5 of the phenyl ring, and Q, Q' and X have the meaning given in claim 1. 1. B^Q,C-2X" B^Q> .2X" Hlformula C Formula Z B^>C'2X~ - Hformula3 o -(CH^-C-O-CCH^-j^^ Q(CH,), /TrR, Formula 5 Formula 4121 492 Q*(CH2) m (CH2)m Formula 6 -|2' OOCCCH,), 2m^O-(CH^COO Formula 7 qCch2), Y I I lx3 R JpH, R. S£o$s*k*°*o£ ^ OCH3 CHS CH£> OCH, 0CH3 „«,, s^^OCH3121 492 ^ CH.CH ^ CH3O' «2 onj OCH, OCH, H, CHo i c c=o ó CH3P^V^ m CKO A^rK, CH CH3O CH£H2Ofea CH, «H)3hCCCoch CH, Br" OCH, Formula 3 CHp OCH, •2CI •AHP OCH, /Ifear // «, r.AA^-CHeiOWHCH CH,1-^ H, OCH, CHpA^TKaW!CHp OCH3 0CH3 Formula fZ OCH3 OCH, 2 er 4H20 flfc PMf/A^ WtC)C-CH2CH2- 3 CH?CH3 OCH, 0CH3 CH3O CHp^A, CH3O N-CH3 CH; Formula 15 OCH3 OCH3 OCH, OCH, 2Cf Formula H n..« OCH CH^^^-^-OC-ChtCH,-^^^ CHaO CHO Ofe0^ OCH, OCH, Formula W CH3°^XH3 OUT T 0CH3 OCH3 Formula 17 CH3 CH2 ^ 2 2CI OCH: AHgO OCH,121 492 OCHj O &P ~ ^CH» C=0 OCH5 0*3 QHZ CH3° XH3 OCHj [¦Y Formula 18 * OCH OCHj COOAg Z + COOAg+ aOUnik R* .. Br y' ch2R4 "3 J> + - —2/igBr R. Cl(Mn R, R'R6 R Y CH,R4 1' ^T~ ¦*5 rearrangement l Y SH.R, ? rT heating rearrangement ! Z R 7 o -2Q Ri R, i>R= RJ>R5 ' Re R' R, Scheme f121 492 X-CH2)r7OH ^ '1 R R-CHl -Yor "(CHjnOH R5 R7 Rfc Scheme 2 R, CH2CH2 COOAg CH2CH2C0CAg ch3o CKp ^ ^^Hp^Cl CHp axXoch3 COO °*CHZ CH,CH* " -Br OCH3 OCHa CH, H2 CHtfT ^OCH3 ' ^ OCH3 CH2 + 2 Ag Br CH 6ooXjCXXi aCH2pH£HPH2 OCH, °W OCH?0"3 ' compound of formula 10 Scheme 3121 492 COOAg O-U i L CH2 V +2 CH2 I C COOAg L CH, CHrf^^OCH, OCH, Br- CICHZCH£H COO a °* CH^ 0CH3 CH, COO. ClCH£H2Ot ^CH 0CH3 OCH3 OCH3 + 2A§Br OCH, in OCH and in^^/- ^ 0 formula / / Scheme 4 rH£rV^0CH3 OCH3121 492 COO Ag+ r CH, i t- CH2 ^ + 2 z COO Ag CH2 CHLl ^tfWPW CH^Hs ii ^ oH3 OCH, BF- aCH^CH-CH* COO 7N^U.0CH ^/^/0CH3 CH, CH CH2 CH, 3CH, + _- 0CH3 +2AgBr OCH3 Srfrr0CH3^ [JXW^AoCHz »"«*' n ru ru n-r ' A.. ^ barn 13 Scheme 5 OCH3 OCH3121 492 COOAg and CH2 CH2 CH2 COO~Ag CH30 ^CHA^CHp CH ^H, OCH, OCH, ClCH2pH2CH2. 9H2 O^CH, CH2 f% V^0CH3 )CH3 CH2 CH3/ COO OCH OCH, •Br— + 2Ag Br zmazek 13 o *zor /+ CICH2CH2CH2 CH -^ Scheme 6 /-OCH3 OCH3121 492 CH2 CH^COÓ Ag L^ +2 CH2CH£00Ag Cl CH2 OCH3 CHp CH2CH3 OH, COO" CH2 CH2 ch3ch; OCH3 OCH3 OCH3 a ^ CH2 I 0CH3 0CH3 ^2 CH* XH3 9H2_ %rrV0CH3 COO /M^OCH, CH '* CH, 2 Ag Br" compound of formula f€ Scheme 7 OCH3 0CH3121 492 CHjCH^COOAg + 2 CHpHgOOOAg Cc^rCHs CH CH^O-^ •Br CWTf^OCHj OCH, CICHYCH 0CH3 C00" /,NY^^0CH3 CHZ CH3 C^2 ?Hl run-C^OCH^ 2Ag+ Br CH£l 1 —-o * OCH, Ct CR* ,XoCH, CH30^f^uv-n3 OCH3 compound on formula 18 Scheme 8