JPH053868B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention provides the following formula [] which is useful as a medicine. The present invention relates to a 4-isobutylaminobutanol derivative represented by: and its pharmacologically acceptable salts. The above-mentioned compounds according to the present invention are novel and have strong antiarrhythmic effects as described later, and are useful as cardiovascular agents. (Prior Art) Several drugs have been used as antiarrhythmia agents, but few are still satisfactory in terms of efficacy and side effects. On the other hand, as aminobutanol derivatives, for example, 4-
Although (N,N-di-n-butylamino)-1,1-diphenyl-1-butanol is disclosed, there is no description regarding pharmacological action. (Problems to be Solved by the Invention) The present inventors have conducted research with the aim of developing a therapeutic agent for arrhythmia that is more effective than existing pharmaceuticals and more useful in terms of safety. As we progressed, we discovered that there was a series of new substances that were completely unrelated in chemical structure to existing antiarrhythmia drugs, and which were superior in terms of efficacy and safety, and we have already applied for a patent. (Gan Sho 58-220342).
In the process of continuing research on the compound related to the above-mentioned application, the present inventors arrived at a compound that surpasses the above-mentioned compound and completed the present invention. Therefore, an object of the present invention is to develop a new drug having a stronger antiarrhythmic effect based on the existence of existing compounds. (Means for Solving the Problems) The compound according to the present invention is a compound that has not been described in any literature, and can be produced, for example, as follows. Each step will be explained in detail below. 1st step Benzoylpropionate compound []
is reacted with a Grignard reagent [ ] or a lithium compound [ ] to produce a compound [ ]. Compound [] is usually used in an amount of 1.0 to 0.8 equivalents relative to the Grignard reagent or lithium compound. As the reaction solvent, anhydrous ether solvents (eg, diethyl ether, tetrahydrofuran, isopropyl ether, dioxane, dimethoxyethane, diethylene glycol, dimethyl ether, etc.) are preferred. The reaction temperature is between -78°C and 100°C, preferably between -20 and 50°C. Reaction time is 30 minutes to 5 hours. After the reaction is completed, the reaction solution may be treated according to a conventional method, but in the case of a reaction with a Grignard reagent, after the reaction is completed, it is generally washed with an aqueous ammonium chloride solution, then with an aqueous sodium bicarbonate solution, and then with water. It is true. The raw material compound [] can be produced by a conventional method. Grignard reagent [ ] and lithium compounds [ ] can be easily prepared by common preparation methods. 2nd step Compound [] is reacted with isobutylamine to produce compound []. Compound [] can be produced by reacting excess isobutylamine in a suitable solvent (e.g., high boiling point solvent such as xylene, toluene, N,N-dimethylformamide, dioxane, etc.) or without using a solvent. can. The reaction is carried out at 80-150°C, preferably 100-110°C.
It is best to do this for ~10 hours. Third step Compound [] is reduced to produce compound []. Compound [] in a suitable solvent (e.g., tetrahydrofuran, dioxane, ether, etc.),
Using 1 to 1.2 equivalents of metal hydride, such as lithium aluminum hydride,
The compound of the present invention [] can be produced by reduction at °C. A reaction time of 1 to 15 hours is sufficient. The target compound thus produced can be isolated in the form of a free base or in the form of an acid addition salt by means known per se. For example, the free base can be purified and collected by distillation, and the acid addition salt can be purified and collected by recrystallization. Acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, acetic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid, lactic acid, malic acid, gluconic acid,
Examples include methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, and pamoic acid. Next, the results of the antiarrhythmia effect of the compound according to the present invention will be shown. 1 Effect of aconitine on arrhythmia in mice The method of Nwangwu et al. (PUNwangwu, TL
Holcslow & SJStohs, Arch, Int.
Pharmacodyn, 229.219-226 (1977)) with some modifications. ddY mice (female) weighing 25 to 30 g were used in groups of four. The animals were anesthetized with Nembutal, and aconitine (5 μg/ml) dissolved in physiological saline was injected into the tail vein at a rate of 0.25 ml/min using a continuous infusion pump to induce arrhythmia. Injection of aconitine was started as the test drug.
It was administered orally or intraperitoneally 30 minutes before. (still,
Lidocaine was administered intraperitoneally 15 minutes before the start of aconitine infusion. ) Arrhythmia was determined by electrocardiogram recording using the standard limb lead method, and cases in which the onset time of arrhythmia was longer than the mean value of the untreated group + 2SD were judged to have antiarrhythmia effects. Based on the efficacy rate in each dose group,
The ED ₅₀ value was determined by Weil's method. The results are shown in Table 1. 2. Dog digitalis arrhythmia Beagle dogs weighing 10 to 14 kg were used. The animals were anesthetized with Nembutal, and arrhythmia was induced by intravenous administration of digoxin (0.10-0.15 mg/Kg). Arrhythmia was determined as ventricular arrhythmia based on the appearance of a large descending or upward QRS complex using electrocardiogram recording using the standard second-limb lead method. After administration of digoxin, when ventricular arrhythmia began to appear continuously, the test drug was administered intravenously, and the efficacy rate and duration of action were examined. The results are shown in Table 2. 3 Effect on canine crown ligation arrhythmia Beagle dogs weighing 8 to 12 kg were used. Under morphine-Nembutal anesthesia, a thoracotomy was performed in the left fifth chamber.
The left anterior descending artery of the coronary artery was examined using the Harris method (Harris S
A two-stage ligation was performed using A Circulation 1 1318 (1950)). Approximately 24 hours after ligation, the limbs were lightly immobilized with a canine immobilizer under no anesthesia, and an electrocardiogram was recorded in a standing position using the standard limb lead method for approximately 1 hour. The test drug was administered to most of the patients. 1,1-diphenyl-4-isobutylamino-1-butanol of the compound of the present invention (example compound)
At 30mg/Kg, marked suppression of ventricular premature contractions was observed in 2 out of 3 cases (suppression rate of 80% or more), and this effect was almost the same as that of Disopyramide at the same dose, but the effect The duration tended to be much longer than that of Disopyramide.

【table】

[Table] From the above results, it is clear that the compound of the present invention has superior antiarrhythmic effects and is less toxic and useful as a pharmaceutical compared to conventionally known antiarrhythmic agents. . When the compound of the present invention is administered as a medicament, the compound of the present invention may be administered as is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, 0.1 to 99.5%.
As a pharmaceutical composition preferably containing 0.5 to 90%,
Administered to animals including humans. As carriers, one or more solid, semisolid, or liquid diluents, fillers, and other formulation auxiliaries are used. Preferably, the pharmaceutical composition is administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intracellularly, locally, transdermally, or rectally. Of course, it is administered in a dosage form suitable for these administration methods (eg, tablets, granules, powders, capsules, injections, suppositories, etc.). It is desirable to adjust the dose as a therapeutic agent for arrhythmia, taking into account the patient's condition such as age and weight, the route of administration, the nature and extent of the disease, etc.
The amount of active ingredient of the compound of the present invention for adults is 1
A range of 1 to 3000 mg per day is common, preferably a range of 1 to 1000 mg. In some cases, a lower dose than this may be sufficient, and in other cases, a higher dose may be required. When administering a large amount, it is desirable to divide the dose into two or three times a day. (Example) The present invention will be explained in more detail with reference to Examples regarding the production of the compounds of the present invention. Example (1) Production of ethyl 4-hydroxy-4,4-diphenylbutyrate Magnesium in 10 ml of dry tetrahydrofuran
Add 7.2 g of iodine and 1 piece of iodine, and add dropwise a solution of 38.8 g of bromobenzene dissolved in 200 ml of dry tetrahydrofuran under reflux and stirring. After the addition, the mixture is stirred for about 1 hour to prepare a Grignard reagent. 34.0 g of ethyl 3-benzoylpropionate is added to 100 ml of dry tetrahydrofuran, and the previously prepared Grignard reagent is added dropwise while stirring at 0° C. in an ice solution. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour, and further stirred at room temperature for 1 hour.
After the reaction, ice and ammonium chloride solution are added and extracted with ether. The ether solution is washed with water and dried over magnesium sulfate. The ether was distilled off under reduced pressure to obtain 47 g of a pale orange oil. IR (Neat) cm ^-1 :
3500, 1780, 1735, 1695 (2) 1,1-diphenyl-3-(N-isobutyl)
Production of carbamoyl-1-propanol 37g of the crude product obtained in (1) above and isobutylamine
Add 15ml to 300ml of xylene and heat on oil bath for 100-110
Heat and stir at ℃ for 8 hours. After the reaction is completed, xylene is distilled off under reduced pressure. The residual oil is purified by silica gel column chromatography (150 g of silica gel, eluted with chloroform) to obtain 9.0 g of crystals. 6.5g of colorless crystals recrystallized from isopropyl ether
I got it. Melting point 107.0℃ Elemental analysis value (as C ₂₀ H ₂₅ NO ₂ ) Theoretical value (%) C: 77.14 H: 8.09 N: 4.50 Actual value (%) C: 77.16 H: 8.50 N: 4.43 IR (KBr) cm ^-1 :3310, 3080, 1635, 1570,
1450, 1275, 1235, 1065, 1022, 765, 760,
705NMR (CDCl ₃ ) δ: 0.87 (6H, d, J = 6.0
Hz), 1.61 to 1.81 (1H, m), 2.22 (2H, t, J =
6.4Hz), 2.63 (2H, t, J = 6.4Hz), 3.02 (2H,
t, J=6.4Hz), 5.44~5.62 (1H, bm), 7.13~
7.38 (6H, m), 7.38-7.50 (4H, m) (3) Production of 1,1-diphenyl-4-isobutylamino-1-butanol (maleate) Add 3.27 g of lithium aluminum hydride to 100 ml of dry tetrahydrofuran. While stirring at room temperature, a solution of 13.4 g of the amide compound obtained in the same manner as in (2) dissolved in 50 ml of dry tetrahydrofuran was added dropwise. After the addition is complete, the mixture is heated under reflux for 14 hours while stirring.
After cooling, add 4 ml of ethyl acetate and 2 g of ice to the reaction solution.
Add 300ml of ether and stir for about 30 minutes. The ether solution is separated by decantation and dried over magnesium sulfate. The ether was distilled off under reduced pressure to obtain 12.6 g of a colorless oil. Add 12.6g of this oil to acetone.
Dissolve in 200 ml, add 4.2 g of maleic acid, and leave to stand. Maleate of 1,1-diphenyl-4-isobutylamino-1-butanol will precipitate. Collect this by filtration and add it to a mixed solvent of methanol and ether. Recrystallization from gives 12.2 g of colorless crystals. Melting point 173-175℃ Elemental analysis value (as _C20H27NO・_C4H4O4 ) Theoretical value (%) C: _69.71 H _{: 7.56} N: 3.39 Actual value (%) C: 69.89 H: 7.57 N: 3.38 IR (KBr) cm ^-1 : 3270, 3065, 2700~1740,
1490, 1370, 1220, 1180, 1065, 990, 870, 755,
700 NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 8Hz),
1.79 (2H, m), 1.90-2.22 (1H, m), 2.53 (2H,
t, J = 6Hz), 2.68 (2H, d, t, J = 8Hz),
3.04 (2H, t, J=6Hz), 6.16 (2H, s), 7.16
~7.46 (10H, m)

Claims (1)

[Claims] 1. The following formula [] A 4-isobutylaminobutanol derivative represented by: and its pharmacologically acceptable salts.