JPS6154777B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to primary acylanilides known to be effective as antiarrhythmic agents. A large number of anilides are known that are structurally different from those described herein. Some have been described as having therapeutic utility in the literature, such as Swedish Patent Nos. 147308, 147309 and 153705, Swiss Patent No. 318077.
No. 336815 and No. 464882,
German Patent No. 967642, French Patent No.
Specification No. 1161363, British Patent No. 705460, British Patent No.
Specifications of No. 726080, No. 754413, and No. 809286, Chemical Abstracts Vol. 42, Column 7871d (1948), Vol. 47, Column 1055g (1958), and U.S. Patent No. 3542850 It is described in. Since the introduction of intensive coronary therapy, emphasis has been placed on the treatment of premature ventricular beats and other cardiac arrhythmias. None of the conventional drugs are completely sufficient for the suppression of such arrhythmias. For example, drugs such as quinidine, procainamide, propranolol and diphenylhydantoin (phenytoin, British Pharmacopoeia) have been used, but these exhibit undesirable side effects. Certain phenoxy derivatives of aminopropane have also been studied, but their effects on the central nervous system are similar to those of phenytoin (Procedures of the British Pharmacological Society, Vol. 39, p. 183). (1970)). Besides the above-mentioned compounds other pharmaceutical preparations exhibit antiarrhythmic properties. For example, the local anesthetic xylocaine (lidocaine), whose chemical name is 2-diethylamino-2',6'-acetoxylidide, is an antiarrhythmic drug suitable for intravenous or intramuscular use. (See Medical Journal, Vol. 2, pp. 29-30 (1970) and The Merck Index, Vol. 8, p. 618, published by Merck & Co., Ltd., 1968). However, this drug is not effective orally because the drug level in the blood is low (Lancet 1969, p. 1303 and Clinical and Pharmacological Therapy Vol. 12, No. 1, pp. 105-116). (1971)). When lidocaine is administered orally, there is significant loss of drug, presumably due to hepatic action (most of the drug must immediately pass through the liver for absorption from the intestinal tract). Also, the duration of blood levels achieved with lidocaine is quite short, so it does not provide long-term protection. It is also known that certain 2-aminotetralines exhibit antiarrhythmic properties (Journal of Medicinal Chemistry Vol. 14).
60-62 (1971)). The present invention is based on the general formula (wherein R ₁ is selected from the group consisting of hydrogen, methyl, ethyl and propyl, R ₂ is selected from the group consisting of methyl and ethyl, R ₃ is selected from the group consisting of hydrogen and methyl, and R ₄ is selected from the group consisting of hydrogen and methyl. selected from the group consisting of hydrogen, methyl and C _1-4 alkoxy groups, R ₅ selected from the group consisting of methyl and ethyl, R ₆ selected from the group consisting of hydrogen, methyl and ethyl, R ₇ selected from the group consisting of hydrogen, methyl and ethyl), their therapeutically acceptable salts and their optical isomers. Compounds of this type have been found to be effective long-lasting cardiac antiarrhythmic agents. These compounds are particularly useful when administered orally. Specific examples of the meanings of the above groups R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ include the following. _R1 : H, _CH3 , _C2H5 , _n - _C3H7 , iso _{- C3H7 ,}
Among these, H, CH ₃ , C ₂ H ₅ and n-C ₃ H ₇
is preferred, and H is particularly preferred. _R2 : _CH3 , _{C2H5 .} R ₃ :H, CH ₃ , and among these meanings, H is preferred. R ₄ :H, CH ₃ , OCH ₃ , OC ₂ H ₅ , OCH ₂ CH ₂ CH ₃ ,
OCH( _CH3 ) ₂ , O( _CH2 ) _{3CH3 ,}

【formula】

[Formula] OC(CH ₃ ) ₃ , among these meanings H, CH ₃ ,
OCH ₂ CH ₂ CH ₃ and O(CH ₂ ) ₃ CH ₃ are preferred. _{R5 : CH3} , _C2H5 . R ₆ :H, CH ₃ , C ₂ H ₅ , and among these meanings, H and CH ₃ are preferred. R ₇ :H, CH ₃ , C ₂ H ₅ , and among these meanings, H and CH ₃ are preferred. Examples of preferred group combinations include the following. (a) _R2 = _R5 = _CH3 , _R3 = _R4 =H. (b) R ₁ = H, R ₂ = R ₅ = CH ₃ , R ₃ = R ₄ = R ₆ = R ₇ =
H. (c) R ₁ = H, R ₇ = R ₈ = H, R ₉ = R ₁₀ = CH ₃ . It is clear that for certain combinations of R ₆ and R ₇ compounds of the formula exist in different stereoisomeric forms (optical or enantiomers). Such forms can be obtained by conventional methods; for example, d- to l-optical isomers can be produced by treating the corresponding racemates with l- to d-tartaric acid. The following novel compounds are preferred embodiments of the invention. (3-Amino-2'/6'-propionoxylidide) (3-amino-2'/6'-butyroxylidide) (3-Amino-2'-ethyl-6'-methylpropionanilide) (3-amino-2-methyl-2',6'-propionoxylidide) (3-amino-2', 4', 6'-propionomesidide) (3-Amino-2'/6'-dimethyl-4'-propoxypropionanilide) (3-amino-2', 3', 6'-trimethyl-propionanilide) (3-amino-2'-methyl-6'-ethyl-butylanilide) (3-amino-2', 4', 6'-butyromesidide) (3-amino-2', 3', 6'-trimethylbutyroanilide) (3-amino-2'/6'-valeroxylidide) (3-amino-2-methyl-2',6'-butyloxylidide) (3-amino-4'-methoxy-2',6'-dimethylbutylanilide) (3-Amino-4'-ethoxy-2',6'-dimethylbutylanilide) A particularly preferred compound of the present invention is and and therapeutically acceptable salts thereof. As used herein, the expression "therapeutically acceptable salt" refers to a salt that is physiologically acceptable when administered in dosages and intervals (e.g., frequency of administration) that are effective for the indicated therapeutic use of the parent compound. It is recognized in the art to refer to acid addition salts that are non-toxic. Examples of representative therapeutically acceptable acid addition salts of the compounds include, but are not limited to, salts of mineral acids such as hydrochloric, phosphoric, or sulfuric acid, and salts of mineral acids such as succinic and tartaric acids, and Mention may be made of salts of organic acids such as sulfonic acids such as methanesulfonic acid. Therapeutically, the derivatives of the compounds of this invention are usually prepared as a solid form of the active ingredient in the form of the free base or one of the common therapeutically acceptable salts, such as the hydrochloride salt.
It is administered orally or by injection in the form of a pharmaceutical formulation with a pharmaceutically acceptable carrier which can be a semi-solid or liquid diluent or an ingestible capsule. Usually the active substance accounts for 0.1 to 10% by weight of the preparation when in aqueous solution, for example in the form of a soluble acid salt, but in solid preparations,
For example, when present in the form of a tablet or capsule, the concentration of the compound of the invention may be up to 100% by weight of the tablet or capsule. Pharmaceutical formulations in oral dosage unit form can be produced by mixing either the base or acid salt forms described above with a solid powdered carrier. Examples of carriers include, for example, lactose, sutucarose, sorbitol, mannitol and starches, such as potato starch, corn starch or amylopectin, cellulose derivatives and gelatin. The carrier can also be a lubricant, such as magnesium stearate or calcium stearate, carbo wax or other polyethylene glycol wax, which may be compressed to form the tablet or core; These cores can then be further coated with a concentrated sugar solution which may also contain gum arabic, gelatin, talc and/or titanium dioxide, or alternatively dissolved in a readily volatile organic solvent or mixture of organic solvents. It can be coated with a lacquer. Dyes can be added to these coatings. Sustained sustained release tablets are obtained by using several layers of active drug that are separated by gradual dissolution of the coating. Another method of preparing sustained release tablets is to divide the dose of active drug into granules having coatings of varying thickness and compress the granules together with carrier materials into tablets. The active substance can also be incorporated into slowly dissolving tablets made from fatty or waxy substances, or tablets or physiologically inert plastics such as those described in US Pat. No. 3,317,394. It may also be evenly distributed in an insoluble substance such as a substance. Soft gelatin capsules (sealed pearl capsules) and other sealed capsules consist, for example, of a mixture of gelatin and glycerol and can contain a mixture of active substances and vegetable oils. Hard gelatin capsules may contain active ingredients such as lactose, sutucarose, sorbitol, mannitol or starches such as potato starch, corn starch or amylopectin or cellulose derivatives or gelatin and solid powder carriers such as magnesium stearate or stearic acid. Contains granules of substance. For parenteral use by injection, the formulations of the invention advantageously consist of an aqueous solution of a water-soluble pharmaceutically acceptable acid salt of the active substance and optionally also contain stabilizers and/or buffer substances. It is convenient to do so. These solutions can be made isotonic by the addition of sodium chloride. In clinical use, the amount of active substance to be administered to a patient must be carefully adjusted depending on the individual requirements in each case. However, specific examples of appropriate doses required to treat acute conditions of ventricular arrhythmia include, for example, about 100 mg to about 1000 mg of 3-amino-2',6' by intravenous route for a male weighing 70 to 80 kg. - Administration of butyroxylidide hydrochloride can be mentioned. The daily requirement by oral administration can be from about 0.8 g to about 8 g. The dosage unit of the compounds of the invention is at least 10 mg, preferably from 50 to 500 mg in the case of tablets, capsules and similar solid dosage forms. The above compounds can be prepared in one or both of the following methods. The applicability of each of these methods can be readily determined by those skilled in the art. The definitions of all groups in the formula are the same as above unless otherwise specified. The term "product" refers to a compound of the invention. Addition of ammonia to anilide of unsaturated carboxylic acid [n=1] Reduction or hydrogenation of cyanoacylanilides In the product R ₇ is H. Reduction with a reducing agent or catalytic hydrogenation with hydrogen. The following examples further illustrate the invention. Example 1 Synthesis of 3-amino-2'/6'-butyloxylidide 1 g of ammonium chloride was mixed with 95% alcohol (150%
2′,6′-crotonoxylidide (11.8 ml) in
g, 0.062 mol) and the mixture was saturated with gaseous ammonia at 0°C. The resulting mixture was placed in a pressure vessel and heated to 80°C for 48 hours. When the contents are transferred to a distillation apparatus and the solvent is evaporated under reduced pressure,
A solidifying oil was obtained as a residue. this
Dissolved in 1M HCl (75ml) and extracted with ether. I threw away the ether. The acid solution was made alkaline to PH11 with sodium hydroxide. The liberated oily base was thoroughly extracted into methylene chloride. The combined extracts were dried (K ₂ CO ₃ ), filtered and concentrated in vacuo. An ethereal solution of hydrogen chloride was added and the resulting hydrochloride precipitate (10.0 g) was collected and recrystallized from a mixture of alcohol and ether. Colorless crystals dried at 100°C for 2 hours at 0.1 mmHg melt at 171-173°C. C ₁₂ H ₁₉ ClN ₂₀
Calculated value as C59.4, H7.89, Cl 14.6, N11.5 Actual value C59.3, H8.01, Cl 14.4, N11.4. Example 2 3-amino-2-methyl-2', 6'-propionoxylidide A 2-methyl-2', 6'-acryloxylidide magnesium (29.0 g, 1.2 mol), ethyl bromide (130 g , 1.2 mol) and 400 ml of anhydrous ether. 2,6-xylidine (121 g, 1.0 mole) dissolved in 400 ml of anhydrous ether was added over a period of 45 minutes with effective mechanical stirring. another
Add 400 ml of anhydrous ether, then add methyl methacrylate (100 g,
1.0M) solution was added over 30 minutes under reflux. Reflux was continued for 2 hours. The reaction mixture was cooled and 800 ml of 9N HCl was slowly and carefully added with continuous stirring and cooling. The ether phase was separated, washed with water, 0.2M sodium bicarbonate and water, dried over anhydrous magnesium sulfate,
passed. Evaporation of the ether leaves a solid that can be recrystallized from petroleum ether (boiling point 60-110°C) containing a small amount of isopropyl alcohol or from a mixture of ethyl alcohol and water. Yield 35%, melting point 101-105℃. B 3-Amino-2-methyl-2',6'-propionoxylidide This compound was prepared according to the example except that ammonium bromide was used instead of ammonium chloride and the reaction mixture was heated to 115-120°C for 4 days. 2-methyl-2' (described above) according to the method described in 1.
Obtained in 59% yield from 6'-acryloxylidide. Isolate the final product by IR and NMR
Identified by spectrum. Example 3 Synthesis of 3′-amino-2′·6′-propionoxylidide 2-cyano-2′·6′-acetoxylidide (Acta,
Chem, Scand, 9 , 493-6 (1955)) (5
g, 0.026 mol) in the presence of 1 g of rhodium/alumina in a pearl shaker at 25-40° C. under a pressure of 2.5 atmospheres. After the hydrogenation was completed, the catalyst was removed and the liquid was evaporated to dryness. The residue is dissolved in ethanol and the hydrochloride salt is prepared by addition of gaseous hydrogen chloride. Complete precipitation of the salt is achieved by adding ether. After evaporation, the hydrochloride salt is recrystallized from ethanol-ether and has a melting point of 218-221°C. It was identified as the product described in Reference Example 1 below. Reference example 1 Synthesis of 3-amino-2', 6'-propionoxylidide 3-bromo-2', 6'-propionoxylidide (25.6 g, 0.10 mol), potassium phthalimide (20.3 g, 0.10 mol) and dimethylformamide (85ml) was refluxed for 2 hours. Once cooled, a solution of 30 ml of glacial acetic acid in 75 ml of water was added and the mixture was stirred for 1 hour. The solids were removed, dried, then suspended in 95% alcohol (200ml) and 85%
% aqueous hydrazine hydrate (9 ml, 0.28 mol) was added. The mixture was stirred and heated to reflux for 2 hours.
Concentrated hydrochloric acid (11ml) was added and stirring continued for several hours at room temperature. The solids were removed and washed with 95% alcohol. The liquid was evaporated to 200ml, cooled in an ice bath and diluted to 1000ml with ether. The precipitated hydrochloride salt was filtered, redissolved in 150 ml of absolute alcohol, filtered hot, and the cooled solution was diluted with 550 ml of ether. After cooling to 0°C, the hydrochloride was filtered off, washed with some ether and dried.
Yield 18.2g (80%). Melting point 218-221℃.
Calculated values as C ₁₁ H ₁₇ ClN ₂ O C57.8, H7.49, Cl
15.5, N12.2, actual value C57.7, H7.48, Cl 15.7,
N12.1. Reference Example 2 Synthesis of 3-amino-2'-ethyl-6'-methylpropionanilide A Synthesis of 3-bromo-2'-ethyl-6'-methylpropionanilide In a container with a glass stopper, add glacial acetic acid (95ml). ) in 2-ethyl-6-methyl-aniline (15.0 g,
A solution of 3-bromo-propionyl chloride (21.1 g, 0.122 mol) was cooled to 13°C.
added. Mix the mixture and immediately add water (150ml)
and a cooled (3°C) solution of sodium acetate trihydrate (36.9g) in the solution. The mixture was stirred thoroughly for 30 minutes. The white product formed was filtered off, carefully washed with water and dried. This product i.e. 3-
Bromo-2'-ethyl-6'-methyl-propionanilide (27.4 g, 91%) melts at 149-150°C;
It was pure enough for use in the next step. B Synthesis of 3-amino-2'-ethyl-6'-methylpropionanilide The above-mentioned 3-bromo-2'-ethyl-6'-methylpropionanilide (13.5 g, 0.0500 mol),
Potassium phthalimide (10.2g, 0.0551mol)
and dimethylformamide (50 ml) were stirred under reflux for 2 hours. Glacial acetic acid (20ml) and water (50ml)
ml) mixture until the mixture reaches room temperature.
Added with continuous stirring. The solid phthalimide derivative was filtered, washed with water, and dried. yield
13.8g (82.1%), melting point 208-209.5°C. This product (13.8 g, 0.041 mol) was suspended in 250 ml of alcohol and 85% hydrazine hydrate (4.0 mol) was added. The mixture was refluxed with stirring for 2 hours. Concentrated hydrochloric acid (8ml) was added and stirring continued until the mixture reached room temperature. The solids were filtered, washed with some 95% ethanol, and discarded. The solvent was evaporated and the residue was dissolved in water, filtered, made basic with 7M sodium hydroxide and thoroughly extracted with methylene chloride. The extract was dried (K ₂ CO ₃ ), filtered and gaseous hydrogen chloride was fed into solution. The generated salt was filtered, washed with methylene chloride, and dried (9.5 g).
It was recrystallized from alcohol-ether. Yield 7.35 g of 3-amino-2'-ethyl-6'-methylpropionanilide, melting point 215.5-216°C.
Calculated value as C ₁₂ H ₁₉ ClN ₂ O C59.4, H7.89, Cl
14.6, N11.5, actual value C59.3, H7.80, Cl 14.6,
N11.7. Reference Example 3 Synthesis of 3-amino-2', 4', 6'-propionomesidide This compound was prepared using 13.5 g of 3-bromo-2', 4', 6'-propionomesidide in 50 ml of dimethylformamide. By refluxing mesidide and 10.2 g of potassium phthalimide for 3 hours, the 3-
Prepared as described for amino-2'-ethyl-6'-methylpropionanilide. The intermediate phthalimide derivative was 14.5 g (yield: 90
%). This derivative was decomposed as described in Reference Example 2B to give the desired base, which was converted to the hydrochloride salt by bubbling anhydrous hydrogen chloride into a chloroform solution of the base. When recrystallized from alcohol with a small amount of water added, it becomes 272.5 ~
The melting point was 273.5°C. Its ^pKa23a value is _{approximately} 8.7
It was found to be ~8.8. Calculated value as C ₁₂ H ₁₉ ClN ₂ O C59.4, H7.89, Cl 14.6, N11.5, measured value
C59.2, H7.78, Cl 14.5, N11.6. Reference Example 4 Synthesis A of 3-amino-2',6'-dimethyl-4'-n-propoxypropionanilide Synthesis of 3-bromo-2',6'-dimethyl-4'-propoxypropionanilide This compound is 20g of 4-propoxy-2.
Reference example from 6-xylidine, 95 ml glacial acetic acid, 37 g sodium acetate trihydrate, 150 ml water and 21.2 g 3-bromopropionyl bromide
It was produced in the same manner as 3-bromo-2'-ethyl-6'-methylpropionanilide of 2A. The yield is
93%, and the melting point of the recrystallized product (methanol:water) was 121.5-122.5°C. B Synthesis of 3-amino-2',6'-dimethyl-4'-propoxypropionanilide 15.7 g of 3-bromo-2',6'-dimethyl-
4′-propoxypropionanilide and 10.2
Reference Example 2B-3 from g of potassium phthalimide
-Amino-2'-ethyl-6'-methylpropionanilide. The intermediate phthalimide derivative was obtained in 88% yield. That is 4
It was suspended in 250 ml of 95% alcohol to which was added ml of 64% hydrazine and decomposed by refluxing for 90 minutes. A hydrochloride salt was prepared from the obtained base. Melting point 208-210.5℃. Calculated _{for C14H23ClN2O2} C58.6, H8.08, Cl 12.4, N9.77, found C58.8 _, H8.20, _Cl 12.3, N9.96. Formulation example 1 3-amino-2',6'-butyroxylidide hydrochloride solution for injection

[Table] Dissolve sufficient amount of solid ingredients in 950-975 ml of water for injection. Add hydrochloric acid or sodium hydroxide solution until the PH is within the desired range. This solution is diluted to 1000 ml with water for injection, passed through a Millipore membrane to make it sterile, and aseptically filled into sterile containers. Formulation Example 2 Liquid formulation for oral administration of 3-amino-2',6'-butyroxylidide hydrochloride A liquid formulation containing the following ingredients was prepared. 3-Amino-2',6'-butyroxylidide hydrochloride
Add 30.0g liquid glucose 300g sucrose 250g preservative qs aroma essence qs coloring agent (approved) qs purified water to make 1000ml. Therapeutic uses of the compounds disclosed herein are illustrated in the following examples. Pharmacological Tests 1 The antiarrhythmic effects of many compounds of the invention were demonstrated by observing the protection they confer against chloroform-induced fibrillation in mice. Experiments in mice were carried out by a modification of the method described by J.D.Dubrieux-Lawson (J.Pharm.Exp.
Therap. 160 , 22-31, (1968)). This method is based on the observation that when untreated, unanesthetized mice are exposed to chloroform vapor, their breathing rapidly ceases, and electrocardiograms and macroscopic examination indicate that the ventricles are fibrillating. . This arrest of breathing is not accompanied by ventricular fibrillation if the mice are appropriately treated with known antiarrhythmic agents prior to exposure to chloroform. Groups of 10 female Swiss albino mice (HAM/ICR) weighing 18-25 g each were pretreated with 4 different doses of the best compounds 20 min before standard time, then treated with cotton and 50 ml of Contains chloroform
It was placed in a 2000ml beaker. Immediately after breathing ceased, each mouse was removed from the beaker, its chest opened, and its heart examined for the presence of ventricular fibrillation. The nature of the heart rhythm was then confirmed by electrocardiographic recording. The heart was touched with forceps whenever fibrillation was not evident. The heart was considered fibrillating if slight convulsive movements were present on the ventricular surface and lasted for at least 5 seconds after thoracotomy or mechanical stimulation. In animals in which coordinated ventricular motion was evident following such procedures, ventricular fibrillation was considered absent. Dose response curves were constructed from these values and the ED ₅₀ values thus obtained were compared to the ED ₅₀ values for standard lidocaine. Relative potency is ED ₅₀ of test compound/ED ₅₀ of lidocaine. The route of administration was subcutaneous.

The values in [Table] are confidence limits.
Pharmacological Test 2 Several compounds of the invention were tested to determine the protection they confer against chloroform-induced ventricular fibrillation in guinea pigs. Morimotu (250-350g)
were placed in a series of 4000 ml beakers containing cotton and 100 ml of chloroform. After cessation of breathing, the animal was removed from the beaker, its chest opened, and its heart examined for the presence of ventricular fibrillation. The nature of the heart rhythm was confirmed by electrocardiogram recording. The heart was touched with forceps whenever fibrillation was not evident. Fibrillation was considered present if there was a slight convulsive movement on the surface of the ventricle and it lasted for at least 5 seconds after thoracotomy or mechanical stimulation. In animals in which coordinated ventricular motion was evident after such treatment, ventricular fibrillation was considered absent. Twenty minutes before placing the animals in chloroform, a single dose (approximately 1-5 ml) of each test compound was administered intraperitoneally using a 25 gauge needle. The following table lists the protection observed for various dosages of test compound.

[Table] Anilide Pharmacology Test 3 The compound 3-amino-2',6'-butyroxylidide was tested in dogs according to a modification of the method described by A.S. Harris (Circ. 1 , 1318).
~1328 (1950)). In this method, the dog was anesthetized, its heart was exposed, and the anterior descending branch of the left coronary artery was ligated in two stages. The chest was closed and the dog was allowed to recover from anesthesia. Over the first few days after such surgery, electrocardiograms show the presence of ventricular fibrillation, and these arrhythmias have been shown to be suppressed with known antiarrhythmic drugs (Am. NYAcad.Sci. 65 , 543–551 (1956)
reference). To test the effect of 3-amino-2',6'-butyroxylidide on such arrhythmias, unanesthetized dogs were supported in cloth slings and treated with the drug intravenously or orally. . Electrocardiographic, cardiovascular, and other drug effects were examined. These experiments showed that the intravenous dosage produced a clear suppression of ventricular fibrillation without any observable undesirable reactions. Other dogs were given the dose orally, which also resulted in clear suppression of ventricular fibrillation. The following table summarizes the results of the endovascular procedures. Response of unanesthetized dogs to intravenous dosage of 3-amino-2',6'-butyroxylidide on the first day after coronary artery ligation.

In addition, experiments using isolated cardiac tissue (eg Parkinge fibers) also demonstrated the advantageous properties of the compounds of the invention. The compounds of the invention unexpectedly exhibit antiarrhythmic activity. They have a weak local anesthetic effect compared to lidocaine, a known anesthetic and antiarrhythmic agent. It is generally accepted in the prior art that antiarrhythmic activity and local anesthetic activity are very closely related, and that primary amines are much less active local anesthetics than the corresponding secondary amines. Despite this teaching, the weak local anesthetics of the present invention exhibit strong antiarrhythmic activity (Trount and Tuchman, Local Anesthetics, Drills Pharmacology and Medicine, edited by De Palma, Matsuk-Growhil, 1965). (published in 2010) and Dowerzier, "Local Anesthetics," Textbook of Organic Medicinal and Pharmaceutical Chemistry, 5th edition, pp. 597-598). When administered to animals, the compounds of the invention:
Does not produce methemoglobin in the animal bloodstream.
This is due to the type of substituent these compounds have at the ortho position of the benzene ring.

Claims (1)

[Claims] 1 Ammonia as the formula (wherein R ₁ to _{R 7} are the same as those described below) and optionally converting the obtained compound into an optical isomer and/or a therapeutically acceptable salt thereof. Characterized by the formula (wherein R ₁ is selected from the group consisting of hydrogen, methyl, ethyl and propyl, R ₂ is selected from the group consisting of methyl and ethyl, R ₃ is selected from the group consisting of hydrogen and methyl, and R ₄ is selected from the group consisting of hydrogen and methyl. selected from the group consisting of hydrogen, methyl and C _1-4 alkoxy groups, R ₅ selected from the group consisting of methyl and ethyl, R ₆ selected from the group consisting of hydrogen, methyl and ethyl, R ₇ selected from the group consisting of hydrogen, A method for producing a compound selected from the group consisting of methyl and ethyl. 2 formulas (wherein R ₁ to _{R 6} are the same as those described below) is reduced using a reducing agent or catalytically with hydrogen, and optionally the obtained compound is converted into an optical isomer and/or its treatment. The formula is characterized by converting the above into an acceptable salt. (wherein R ₁ is selected from the group consisting of hydrogen, methyl, ethyl and propyl, R ₂ is selected from the group consisting of methyl and ethyl, R ₃ is selected from the group consisting of hydrogen and methyl, and R ₄ is selected from the group consisting of hydrogen and methyl. selected from the group consisting of hydrogen, methyl and C _1-4 alkoxy groups, R ₅ is selected from the group consisting of methyl and ethyl, R ₆ is selected from the group consisting of hydrogen, methyl and ethyl and R ₇ is hydrogen. A method for producing a compound.