JPS638111B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to quinuclidine-3-carboxylic acid 2,6-xylidide, a compound that has been demonstrated to be an effective antiarrhythmic agent, and its pharmaceutically acceptable salts, or to compounds without antiarrhythmic activity, such as quinuclidine-3-carboxylic acid. It relates to the preparation of related compounds such as 2-carboxylic acid xylidides. In the process of the present invention, the compound is prepared by reacting quinuclidine carboxylic acid with dimethylaniline in anhydrous chloroform and oxalyl chloride. The desired compound is prepared in high yield and purity. Lidocaine and similar compounds have traditionally been used to treat arrhythmia, and are also used as a means of treating coronary heart disease, but their biological half-life is only about 75 minutes, so they have been used to prevent syndromes that can lead to sudden death. It is impossible to use it for. In addition, lidocaine is poorly absorbed from the intestinal tract, exhibits harmful side effects such as hypotension and neurotoxicity, and has a low therapeutic index (the ratio of the drug's tolerated dose to its effective dose). Furthermore, because of its rapid metabolism, lidocaine must be administered by continuous intravenous infusion to maintain adequate plasma concentrations. Therefore, research has been continuously carried out with the aim of developing preparations with improved antiarrhythmic effects. Aktiebolaget Astra
Astra) French patent number 1565045 is based on the formula Discloses a group of compounds represented by: However, R ₁
and R ₂ is hydrogen, halogen or lower alkyl. This patent also discloses a process for the preparation of the above group of compounds, characterized in that quinuclidine carboxylic acid is converted into its methyl ester and then treated with a mixture of methylmagnesium iodide and the appropriate aniline. However, the yield is low and it is contaminated with harmful by-products. The French patent cites 2,6-xylidide of quinuclidine-2-carboxylic acid as a specific example and points out that this compound has antiarrhythmic and local anesthetic effects. However, additional tests conducted by the present inventors revealed that this compound is neurotoxic and has no useful antiarrhythmic effect. Dahlbom and Dolby are published in "Acta Pharma. Suecica" No. 65, p. 277 (1969).
In a paper published in 2013, the compound N-
We have reported on various derivatives of quinuclidine-3-carboxylic acid, including (quinuclidine-3-carbonyl)-2,6-dimethylaniline, and tested these compounds for various pharmacological and microbiological effects, and found that they have weak It is pointed out that there is no pharmacological effect other than local anesthetic effect. According to the above-mentioned paper by Acta Pharma Suecica, quinuclidine carboxylic acid hydrochloride is heated under reflux in the presence of thionyl chloride, for example, 2.6-
The above compound is prepared by reaction with an aniline such as dimethylaniline. However, this reaction significantly discolors the reactants and forms sulfur-containing substances of unknown composition that contaminate the intended product. The yield of incompletely purified product obtained by this process often cannot exceed 60% of theory. Despite the teachings in Acta Pharma Suecica, 2,6-xylidide of quinuclidine-3-carboxylic acid and its pharmaceutically acceptable salts, such as the hydrochloride, are associated with adverse side effects. The present invention has revealed that it exhibits a high degree of antiarrhythmic effect. This is surprising in view of the fact that quinuclidine-2-carboxylic acid 2,6-xylidide disclosed in French Patent No. 1566045 is neurotoxic and lacks useful arrhythmia therapeutic effects. The present invention is based on quinuclidine carboxylic acid and aniline derivatives having the formula A method for preparing amides of the above formula, i.e., by reacting quinuclidine carboxylic acid with a suitable aniline derivative in anhydrous chloroform in the presence of oxalyl chloride. It is related to the characteristic manufacturing method.
However, in the above formula, R ₁ and R ₂ represent hydrogen, halogen or lower alkyl. By applying this method, it is possible to obtain the desired compound in pure form with a yield of over 90% of the theoretical value. SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a process for the preparation of aniline derivatives of quinuclidinecarboxylic acid, particularly 2,6-xylidide of quinuclidine-3-carboxylic acid, which has antiarrhythmia therapeutic effects. Other objects and advantages of the invention will be apparent from the following description and claims. In view of the above and other objects, the present invention comprises reacting quinuclidine carboxylic acid (or its acid addition salt, e.g. hydrochloride) with a suitable aniline under reflux in anhydrous chloroform in the presence of oxalyl chloride. In particular, it is directed to a process for synthesizing 2,6-xylidide of quinuclidine-3-carboxylic acid and compounds related thereto. As already pointed out, the 2,6-xylidide of quinuclidine-2-carboxylic acid is neurotoxic and lacks useful antiarrhythmic effects, but its isomer, i.e. The present invention has revealed the fact that 2,6-xylidide of quinuclidine-3-carboxylic acid represented by the formula exhibits excellent antiarrhythmic effects with almost no side effects. To obtain arrhythmia therapeutic effect, any physiologically compatible salt of 2,6-xylidide of quinuclidine-3-carboxylic acid can be used, but preferably an appropriate amount of hydrochloride is used. This is because hydrochloride is highly soluble and easily available. In order to demonstrate the effective antiarrhythmic action of the drug according to the invention, quinuclidine-3-carboxylic acid 2.
Comparison of 6-xylidide hydrochloride (hereinafter referred to as "compound" for convenience) with known antiarrhythmic agents and 2,6- of quinuclidine-2-carboxylic acid
A comparison was also made with xylidide hydrochloride (referred to below as "compound" for convenience). The following examples are provided to facilitate understanding of the production method of the present invention, and the present invention is not limited to these examples. Example 1 This example relates to the production of 2,6-xylidide hydrochloride (compound) of quinuclidine-3-carboxylic acid using the production method of the present invention. Quinuclidine-3-carboxylic acid hydrochloride 2.5g
(0.013 mol) was dissolved in anhydrous and alcohol-free chloroform (150 c.c.). Oxalyl chloride (10 ml) was added and the mixture was refluxed for 3 hours in a glass apparatus protected from atmospheric moisture before the solvent was evaporated to dryness. Then add 3 g of 2,6-dimethylaniline to 100 ml of anhydrous and alcohol-free chloroform.
(0.025 mol) of the mixture was treated with a solution of
It was refluxed for 6 hours. All volatile solvents were removed by distillation (80°C oil bath) and the residue was treated with 25 ml of a cold 3N aqueous hydrochloric acid solution. Decant the clear acid solution from the small amount of insoluble residue and adjust the pH with 5% aqueous sodium hydroxide.
Adjust to 4.5, extract once with ether (25 ml),
The ether extract was discarded. The pH was raised to 8 and the aqueous solution was extracted again with ether (25ml). The ether extract contained recovered 2,6-dimethylaniline. When the aqueous solution was made strongly alkaline, the desired compound was obtained as a precipitate. This was extracted with chloroform (50 ml), the chloroform solution was evaporated to dryness under reduced pressure, the residue was dissolved in 200 ml of 5% hydrogen chloride methanol solution, and the resulting solution was evaporated to dryness again. The residue was recrystallized from a mixture of methanol and ether (1:1). Yield: Hydrochloride (compound: melting point 234-236℃)
3g. An additional amount (0.5 g) was recovered from the mother liquor by concentration. Total yield of pure compound is 91% of theoretical value
It was hot. However, the implementation of the above process using thionyl chloride instead of oxalyl chloride of the present invention results in significant discoloration of the reaction mixture and the formation of sulfur-containing substances of unknown composition, which may contaminate the desired product. As a result, the yield of partially purified product remained at or below 60% of theory. Example 2 This example relates to the synthesis of 2,6-xylidide hydrochloride (compound) of quinuclidine-2-carboxylic acid using the process of the present invention. Quinuclidine-2-carboxylic acid hydrochloride 1.5g
(0.0078 mol) was dissolved in 100 ml of anhydrous and alcohol-free chloroform. Oxalyl chloride (7 ml) was added and the clear mixture was refluxed for 3 hours in a glass apparatus protected from atmospheric moisture and the solvent was evaporated to dryness. The mixture was treated with a solution of 1.5 g (0.0125 mol) of 2,6-dimethylaniline in 50 ml of anhydrous and alcohol-free chloroform and refluxed for 6 hours. The volatile solvent was removed by distillation in an 80°C oil bath, the residue was dissolved in a cold 3N aqueous hydrochloric acid solution, and the supernatant solution was decanted from the small amount of insoluble residue. The pH of the clear solution was adjusted to 5.5 by adding 5% aqueous sodium hydroxide solution and then extracted with 25 ml of ether. The ether extract contained recovered 2,6-dimethylaniline. The aqueous phase was made strongly alkaline with sodium hydroxide and extracted with 100 ml of chloroform. The chloroform extract solution was evaporated to dryness and the residue was layered on top of a 2 cm diameter, 50 cm long column made of chromatographic grade neutral alumina with an activity coefficient of 1. Approximately 1
Impurities were washed away by elution with benzene. Then add the compound to chloroform (500c.c.)
It was eluted with. The recovered chloroform solution was evaporated to dryness, the residue was dissolved in 5% hydrogen chloride methanol solution (100 c.c.), this solution was evaporated, and the residue was recrystallized from a mixture of methanol and ether (1:1). The hydrochloride (compound) was obtained.
Yield: 1 g (50% of theory), melting point: 216°C. The method for producing the above-mentioned compound is quinuclidine-
converting the 2-carboxylic acid to its methyl ester;
French patent No.
It is much better than the method described in No. 1566045. That is, the production method of the present invention achieves high yield and purity. On the other hand, if one attempts to prepare the compound by substituting thionyl chloride for the oxalyl chloride used in the process of the present invention, significant decomposition of quinuclidine-2-carboxylic acid will occur.
A tar-like sulfur-containing substance of unknown composition is formed.
No measurable yield is obtained. The antiarrhythmic effect, other pharmacological properties, and side effects of the compound were compared with known antiarrhythmic agents, and the results of comparison with the compound are detailed below. The toxicity of the compound was determined by intraperitoneally injecting a 0.5% solution of the drug into ICR albino mice (〓) weighing 20-25 g. The animals were divided into groups of 6 and administered the medication. LD ₅₀ obtained by subject analysis is 60±
It was 5 mg/Kg. The compound showed no interactions with other centrally acting drugs, which is considered evidence that the compound lacks activity on the central nervous system. Administering metrazol 30, 60 and
Intraperitoneal injection of the compound 90 minutes prior resulted in metrazol administration-induced convulsions (metrazol 100
mg/Kg). Oxotremorine administration
Oxotremorine-induced tremor (oxotremorine
(20 μg/Kg intraperitoneal injection) showed no effect. Thirty minutes after intraperitoneal injection of the compound, subjects were inhaled with Indoklon (trade name for hexafluorodiethyl ether ( _CF3CH2 - _O - _CH2CF3 )) or given _a 30-volt electric shock. The results showed that the compound had no effect on seizures caused by indochron or electric shock. 5 mg/g over 15-30 seconds to a conscious, healthy dog.
As a result of intravenous injection of the Kg compound, no significant changes in posture, behavior, or mood were observed compared to controls. The compounds were injected intravenously into conscious, healthy dogs and electrocardiogram leads were monitored for 2 hours after injection to test for effects on the normal heart. A single dose of 3mg/Kg, 3mg/Kg and 2mg/Kg administered over 30-60 minutes to a total of 6 animals.
As a result of observing the case where the dose was divided into 1 mg/Kg and cumulatively added at a total of 6 mg/Kg, no change was observed in the electrocardiogram. In order to obtain a transient high concentration of the compound in the heart, in one case only 5 mg/Kg was administered at once and rapidly. There was a widening of the QRS complex, but no other signs of toxic effects were observed. ECG is 15
It returned to normal within minutes. Nembutal anesthetized dog (Nembutal 25mg/
When a total of 6 mg/Kg of the compound was administered intravenously over 30 minutes divided into 3 mg/Kg, 2 mg/Kg and 1 mg/Kg, no change was observed in the electrocardiogram. Cats anesthetized with Nembutal had a different reaction than dogs. Total 3mg/Kg little by little over 34 minutes
As a result of administering this compound, the QRS wave shifted to the left. In cases where 6 mg/Kg and 10.5 mg/Kg were administered cumulatively, the width of the QRS wave expanded, but sinus rhythm was maintained. For example 16.5
In cases where the dose was increased to mg/Kg (cumulative), a second grade AV block appeared. The atrial conduction velocity decreased, as evidenced by the broadening of the P wave. If the drug is discontinued at this stage, the severe toxic effects will disappear after 40 minutes, and the heart will return to normal sinus rhythm. Even larger amounts, e.g. 7.5mg/
Kg of compound (cumulative dose: 24mg/
Kg), severe AV block appeared, followed by cardiac arrest. The studies conducted on ouabain-induced arrhythmia are described below. 〓 and ♀ cats (1.8-3.4 kg) were anesthetized with Nembutal (40 mg/Kg intraperitoneal injection). A cannula was inserted into the trachea to secure a breathing path. Mechanical ventilation was used only if respiratory distress was observed between the administration of Nembutal and the administration of other drugs (2 out of 10 cases). Cannulae were inserted into the femoral artery and vein for blood pressure measurement and drug administration, respectively. Grass 7 type polyglyph (Grass
Electrocardiogram leads were monitored throughout using a Model 7polygraph. All drug solutions administered were in saline. Arrhythmia was induced by administering ouabain in two ways. That is, small doses were injected every 30 minutes or continuous infusion. Ventricular tachycardia (VT) usually occurs after administering a total dose of 75-80 μg/Kg over at least 1 hour. After inducing arrhythmia, the compound was injected intravenously in an amount of 1 mg/0.2 ml/Kg over 30 seconds. In most cases, the procedure was repeated one more time, but if the arrhythmia recurred within 1 hour, the dose was reduced to 0.5 mg/Kg.
For comparison, lidocaine was administered in the same manner. In another experiment using mongrel dogs, they were anesthetized with an intravenous injection of Nembutal (25 mg/Kg), and then given ouabain in gradually decreasing doses of 40 μg/Kg, 20 μg/Kg, and 10 μg/Kg at 30-minute intervals. administered to induce arrhythmia. Compound treatment was then performed as described below. Cumulative administration of 70-90 μg/Kg of ouabain to cats to achieve a steady arrhythmia state, followed by administration of the compound as a single therapeutic dose 1 mg/Kg 10 minutes later, resulted in a higher incidence than lidocaine administered under the same conditions. Significant improvements in electrocardiograms persisted for a much longer period of time. The results for cats treated with the compound are listed in Table 1 and the results for lidocaine treatment are listed in Table 2. In dogs, a single dose of the compound (1 mg/Kg) restored ventricular tachycardia (VT) to normal sinus beats. 45
When arrhythmia recurred after minutes, normal sinus pulsation could be restored by additional administration of the compound equivalent to 1/2 of the initial dose (Table 3).

【table】

【table】

[Table] Abbreviations are the same as in Table 1.
〓: In cases 11 and 12, lidocaine HCl was injected intravenously at a dose of 4 mg/Kg and in case 13, at a dose of 1.6 mg/Kg.
〓〓: Arrhythmia recurred.

[Table] Abbreviations are the same as in Table 1.
〓: Arrhythmia recurred after this time, but 0.25mg/Kg
It was suppressed by a single intravenous injection of EO-122.
The compound was administered parenterally to obstructive arrhythmia in conscious dogs, and its effects were evaluated. The left anterior descending coronary artery was ligated in five dogs to achieve an occlusive effect. Although arrhythmia appeared, it recovered spontaneously after 3 to 4 days. Compounds were administered once within 24 hours and once within 48 hours after ligation. A single intravenous injection of 3 mg/kg within 24 hours resulted in recovery of full, uninterrupted sinus pulsation for 20 minutes and continued for the next 2-3 hours.
A mixture of SR, VT and VPB appeared. Dosing within the next 24 hours is usually in small doses, e.g.
The same results were obtained with 1.5mg/Kg. The therapeutic blood concentrations were therefore 5 μg/cc and 2.5 μg/cc. Intravenous injections of 3 mg/Kg of lidocaine in the same dog either had no effect or the effect lasted only for a very short time. Lidocaine was administered 2 hours before or 2 hours after compound administration, based on the assumption that this interval would prevent cumulative effects with the compound. A study was also conducted to evaluate the effect of oral administration of the compound on arrhythmia induced by the above-described occlusion procedure in conscious dogs. After ligating the left anterior descending coronary artery and inducing arrhythmia as described above, 15-20 mg/Kg of the compound was administered at 4-
Orally administered in 6 gelatin capsules,
No pretreatments such as pulverization or mixing with diluents or carriers were carried out. All cases showed complete efficacy in restoring normal sinus beats, but with a delay of 11-60 minutes after dosing, depending on the severity of the symptoms. The efficacy parameters of the compound were evaluated in conscious dogs with arrhythmia symptoms due to occlusion. 1
After intravenous injection of the therapeutic dose, venous blood samples were taken at regular time intervals, spiked with heparin, and analyzed for compound content by gas chromatography. The following data were obtained from this analysis. Biological half-life (t _1/2 ) 4-5 hour distribution t _1/2 (t _1/2 for distribution) 5 minute volume of distribution
0.2/Kg (body weight) Effective blood concentration 2.5-5 μg/ml The biological efficacy of orally administered compounds was evaluated by administering 7.5 mg/Kg to conscious healthy dogs. The above 7.5 mg/Kg was divided into 6 gelatin capsules and slipped down the throat. Peak blood concentration occurs 1 hour after digestion and is 1.5−
It was around 2 μg/ml. Approximately 30% of the digested drug was absorbed within 4 hours after digestion. This indicates a combined absorption/excretion trend.
This was confirmed by measuring the AUC (area under the curve) of elimination kinetics. The biological efficacy of the drug appears to be similar in unanesthetized dogs with arrhythmia. Next, the main properties of the compound will be summarized in comparison with lidocaine.

【table】

[Table] As is clear from the above test results, the compound of the present invention not only has the antiarrhythmic effect of lidocaine, but also has many other pharmacological advantages. i.e., long biological half-life eliminates the need for continuous infusion; high biological efficacy after oral administration eliminates the need for repeated injections; side effects such as hypotension and central nervous system stimulation There is no. Also, the compound is not significantly denatured by the liver. Therefore, in the present invention, arrhythmia following acute myocardial infarction can be treated by single or repeated intravenous injections of the compound as the main agent and its pharmacologically effective acid addition salt, and patients can be treated with full-scale treatment. It can be used for emergency purposes before or during transfer to a treatment facility, for the treatment of arrhythmia caused by digitalis poisoning, and for continued treatment in an oral form. As already pointed out, 2,6-quinuclidine-3-carboxylic acid can achieve the above effects.
Only xylidide and its physiologically compatible acid addition salts, its isomer 2,6-xylidide of quinuclidine-2-carboxylic acid, is not only neurotoxic but also lacks effective antiarrhythmia effects. This means that the compound i.e. French Patent No. 1566045
This is demonstrated by tests on the 2,6-xylidide hydrochloride of quinuclidine-2-carboxylic acid prepared both by the process of the present invention and by the process of the present invention. As a result of intraperitoneal administration of the compound to albino mice, the following symptoms appeared. Dose Effect Effect 20-30mg/Kg Excitement, increased locomotion 40-60mg/Kg Neurotoxicity, ataxia, partial paralysis 100mg/Kg Fatal dose. The cause of death appears to be breathing difficulty. Effect of compound on drug-induced arrhythmia. 2.7Kg pre-anesthetized with Nembutal.
Arrhythmia was induced in cats by slow infusion of a total of 70 μg/Kg of ouabain over 1 hour. At this stage, the electrocardiogram showed clear signs of arrhythmia, primarily due to ventricular premature beats (extrasystles) and ventricular tachycardia. Intravenous injection of the compound at a rate of 1.1 mg/Kg resulted in fibrillation and death. Effect of compound on arrhythmia induced by coronary artery occlusion Arrhythmia was induced in a dog weighing 15 kg by ligating the left anterior descending coronary artery with No. 000 silk thread. Twenty-four hours after surgery, clear signs of arrhythmia, primarily ventricular tachycardia, appeared on the electrocardiogram. The compound was injected intravenously at a rate of 3 mg/Kg, but the electrocardiogram showed only slight signs of improvement for a short time. On the other hand, symptoms of neurotoxicity such as abnormal excitement and shaking the head were frequently observed. In light of the above results, it is clear that the compound cannot be used as an antiarrhythmic agent. Although the production method of the present invention has been explained above with particular reference to the compound and the preparation of In the presence of oxalyl chloride in anhydrous chloroform, quinuclidine carboxylic acid of the formula It goes without saying that the method for producing the above-mentioned compound and compounds similar thereto is characterized by producing the corresponding quinuclidine carboxylic acid xylidide by reacting it with aniline represented by the formula, and recovering this. Note that R ₁ and R ₂ in the above formula represent the same contents as described above.

Claims (1)

[Claims] 1 Where R ₁ and R ₂ are selected from the group consisting of hydrogen, halogen and lower alkyl, the formula A method for producing a compound represented by the formula In anhydrous chloroform and in the presence of oxalyl chloride, _{quinuclidinecarboxylic} acid represented by the _formula A method for producing a quinuclidine carboxylic acid derivative, which comprises reacting the quinuclidine carboxylic acid with aniline represented by the following formula and recovering the formed aniline derivative of the quinuclidine carboxylic acid. 2. The manufacturing method according to claim 1, wherein the reaction is carried out by refluxing the reactants. 3. The method of claim 1, wherein the quinuclidine carboxylic acid is selected from the group consisting of quinuclidine-2-carboxylic acid and quinuclidine-3-carboxylic acid, and the aniline is 2,6-dimethylaniline. .