JPS6244550B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides substituted 2H-pyran- useful for suppressing the symptoms of allergic reactions caused by antigen-antibody reactions.
This invention relates to 2,6(3H)-dione derivatives. More specifically, the compounds of the present invention contain slow-reacting substances (histamine, serotonin and anaphylaxis) produced and/or released by the interaction of antigens with specific antibodies immobilized on the surface of affected cells (allergic reactions). It is thought that the effect is exerted by suppressing the release and/or formation or release of pharmacological transmitters such as SRS-A) from the cells. These properties make the compounds useful in various allergic diseases such as asthma, rhinitis and urticaria. Compounds of the invention have the formula: [In the formula, R ₁ is lower alkyl succinamoyl (-NHCOCH ₂ CH ₂ COOR ₃ ), ketomalonamoyl (-NHCOCOCOOH) or glyceramoyl

[Formula]; R ₂ is hydrogen or, if R ₁ is glyceramoyl, R ₂ may also be amino or glyceramoyl; R ₃ is lower alkyl, preferably lower alkyl having 1 or 2 carbon atoms. ]. Particularly preferred compounds according to the invention of the formula [] are 3-methylsuccinamoyl, 3-ketomalonamoyl, 3-glyceramoyl, 3,5-bisglyceramoyl and 3-glyceramoyl-5-amino derivatives. Compounds of formula [ ] where R ₂ is hydrogen or glyceramoyl are conveniently prepared according to the following reaction scheme. [In the formula, R ₁ is the same as above. ] That is, 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and a suitably substituted aniline are mixed in an inert organic solvent such as benzene, toluene, ethanol or methanol for 1-3 hours.
The product is obtained by heating at reflux for an hour. Formula where R ₁ is glyceramoyl and R ₂ is amino []
The compound is conveniently prepared by reacting 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one with a suitably substituted nitroaniline followed by hydrogenation, preferably using a palladium-carbon catalyst. Manufactured. Mono- and dialkali metal salts of compounds of formula [ ], such as mono- and disodium salts or mono- and dipotassium salts, are readily prepared by treatment with a suitable alkali metal alkoxide, e.g. methoxide, in an alkanol solvent such as methanol. can be obtained. The pyran-2-one starting material is obtained by reacting acetone dicarboxylic acid with acetic anhydride in sulfuric acid at elevated temperature. For convenience, this reaction product is shown as 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in this specification, but it actually has the tautomerism shown by the following formula [A]. Has a structure. Therefore, the product obtained by reacting this product with aniline as described above also has the following formula [B]
It has a tautomeric structure shown in [In the formula, R ₁ and R ₂ are the same as in the above formula []. ] In this specification, for convenience, the formula []
All compounds produced by the reaction of a compound of formula [A] with aniline using one tautomeric form, i.e., the intermediate enamine, pyran-2,6-dione structure, as shown in I will express it. The substituted aniline starting materials used in the present invention are conveniently prepared by known methods. RHWiley et al.
al., J.Org.Chem., 21:686-688 (1956)] is a reaction product of acetone dicarboxylic acid and acetic anhydride (named 5-carboxydehydroacetic acid).
reported the reaction between Similarly, A.K. Kiang et al., J.
Chem. Soc. (C) 2721-2726 (1971)] also discloses reaction products with such amines. However, there is no disclosure regarding the product of formula []. The ability of the compounds of the invention to suppress transmitter release in sensitized tissues (thereby suppressing the effects of allergic reactions) is determined by the ability of the test compounds to suppress passive cutaneous anaphylaxis (PCA) reactions in rats. . In this test system, titrated and suitably diluted serum containing reaginous antibodies against ovalbumin (previously administered by intraperitoneal injection of ovalbumin aluminum hydroxide or ovalbumin intramuscularly) is prepared from Bordatella pertussis. U.
SP intraperitoneal - N. brasiliensis (N.
brasiliensis) from rats immunized by intraperitoneal injection] are injected intradermally at four sites on the shaved back of normal adult male rats. After 48 hours, the rats were treated with an isotonic salt solution containing 5 mg of ovalbumin antigen and 5 mg of Evans blue dye.
Inject 0.5 ml intravenously. Due to local cellular anaphylaxis, transmitters such as histamine and serotonin released at the site of sensitization increase capillary permeability, causing plasma leakage and wheal formation. This wheal is caused by the presence of Evans, which binds to plasma proteins.
Visualized by blue dye. Under this test condition, the control wheals average approximately 12 x 12 mm. Thirty minutes after challenge, rats are sacrificed, the skin on the back is examined with a reflector, and the diameter of the wheal is recorded. Test compounds are administered intravenously 0.5 min before challenge (longer pretreatment times and other routes of administration, i.e.
orally or intraperitoneally). Percent inhibition is calculated from the difference in mean wheal between the treated group and the control group administered saline or appropriate diluent. Inhibition by the test compound of conditions caused by reaginic antibody-antigen interactions on the surface of sensitized cells indicates that the compound is useful in suppressing symptoms caused by immediate allergic reactions. The compound of formula [] significantly suppresses the PCA reaction when administered intravenously to rats at doses of 0.001 to 10 mg/Kg. For example, 5-acetyl-3-[1-(3
-Methylsuccinamoylphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6
(3H)-dione inhibits rat PCA wheal by 58% when administered intravenously at 0.25 mg/Kg. Other compounds, 5-
Acetyl-3-[1-(3-ketomalonamoylphenylamino)ethylidene]-4-hydroxy-
2H-pyran-2,6(3H)-dione is 0.0312
Intravenous administration of mg/Kg reduced rat PCA wheal by 55%,
5-acetyl-3-[1-(3-glyceramoylphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione is 0.0312
Intravenous administration of mg/Kg inhibits rat PCA wheal by 63%. In addition, 5-acetyl-3-[1-(3,
5-bis-glyceramoylphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,
Intravenous administration of 0.001mg/Kg of 6(3H)-dione reduced rat PCA wheal by 53% and 5-acetyl-3-
[1-(3-glyceramoyl-5-aminophenylamino)ethylidene]-4-hydroxy-2H
-Pyran-2,6(3H)-dione is 0.062mg/Kg
Intravenous administration suppresses rat PCA wheal by 77%. In testing the mechanism of action, the rats were tested for 48 hours.
When administered intravenously at the same dose and pretreatment time showing significant inhibition of the PCA response, the compound of formula [ ] produced wheals of comparable intensity produced by intradermal administration of histamine and serotonin. is not suppressed. In oral administration, 5-acetyl-3-[1
-(3-glyceramoylphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6
(3H)-dione increased by 55% in rat 48-hour PCA reactions at a dose of 25 mg/Kg and a pretreatment time of 15 minutes.
showed suppression of Similarly, 5-acetyl-3-
[1-(3,5-bis-glyceramoylphenylamino)ethylidene-4-hydroxy-2H-pyran-2,6(3H)-dione showed 83% inhibition at oral administration of 3.12 mg/Kg; ,5-acetyl-3
-[1-(3-glyceramoyl-5-aminophenylamino)ethylidene]-4-hydroxy-
2H-pyran-2,6(3H)-dione is 25mg/Kg
showed 61% inhibition by oral administration (pretreatment time 15 minutes in both cases). The toxicity of the compound of formula [] is that the pyran-2-one starting material used for its production has an LD ₅₀ of 1525 mg/Kg when administered orally in mice;
Oral administration of various substituted phenylamino derivatives similar to the [] compound in mice.
Since the LD ₅₀ is 2000 mg/Kg or more, it is considered to be equivalent to these. The compounds of the present invention can be administered as conventional pharmaceutical compositions comprising a suitable amount of a compound of formula [] in combination with a pharmaceutical carrier or diluent. The nature of the composition and pharmaceutical carrier or diluent will, of course, depend on the desired route of administration, ie oral, parenteral or inhalation. Typically, the compound will be administered in a composition containing an amount sufficient to suppress allergic symptoms.
In this case, compositions containing from 0.5 to 500 mg of active ingredient are administered per dose. Advantageously, the daily dose of about
0.5 to about 2000 mg, administered in equal doses 1 to 4 times a day. For the prevention of asthma, the composition is generally in a dosage form suitable for administration by inhalation. That is, the composition is an aqueous suspension or solution of the active ingredient so that it can be administered with a conventional nebulizer. Alternatively, the composition may be a suspension or solution of the active ingredient in a conventional liquefying propellant such as dichlorodifluoromethane or chlorotrifluoroethane so that it can be administered from a pressurized container. The composition may also be a solid active ingredient diluted with a solid diluent, such as lactose, for administration from a powder inhalation device. In these compositions, the amount of carrier or diluent can vary, but preferably
Make up the bulk of the active ingredient suspension or solution. If the diluent is a solid, it may be less, equal to, or more than the solid active ingredient. Various other dosage forms can also be employed. For example, if a solid carrier is used, it can be in the form of tablets, powders or granules in hard gelatin capsules, or troches or lozenges for oral administration. The amount of solid carrier can vary widely, but approximately 25 mg
~1 g is preferred. If a liquid carrier is used, it can be a sterile injectable solution such as a syrup, emulsion, soft gelatin capsule, ampoule, or aqueous or non-aqueous suspension. Examples of solid carriers include lactose, china clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Examples of liquid carriers include syrup, peanut oil, olive oil, water, and the like. Similarly, carriers or diluents include any known delay substances, such as glyceryl monostearate or glyceryl distearate alone or in combination with waxes. These pharmaceutical compositions are manufactured by conventional pharmaceutical methods, including mixing, granulating, and optionally tabletting or various mixing and dissolving the ingredients appropriate to the desired end product. The present invention also includes a method for suppressing allergic symptoms resulting from antigen-antibody reactions, which comprises administering an amount of the compound of formula [ ], preferably in the form of a pharmaceutical composition, effective for suppressing the allergic symptoms. Administration may be in unit dosage form at appropriate intervals or once as needed. Generally, the methods of the present invention are carried out when alleviation of allergic symptoms is specifically needed, but they are also useful as chronic or prophylactic treatments. Particular methods include administering effective amounts at appropriate intervals to reduce or prevent allergic airway obstruction. The actual dosage can be determined based on daily experience from the above dosages, taking into account the severity of the allergic symptoms to be treated. Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto. Example 1 To a solution of 6.31 g (0.045 mol) of m-nitroaniline in 10 ml of dry pyridine (5° C.) is added dropwise, with stirring, 6.8 g (0.045 mol) of methylsuccinoyl chloride. This mixture was left at 25°C for 30 minutes, and then poured into a mixture of 100 ml of 3N hydrochloric acid and 100 g of ice. The precipitate is collected to obtain 3-nitro-N-methylsuccinoylaniline. Melting point 120-126℃ 3-nitro-N-methylsuccinoylaniline
A solution of 1.0 g (0.0028 mol) in 50 ml of methanol
10% palladium-hydrogenated over 100 mg of carbon at 50 psi. The reduction will be completed in 45 minutes. remove the catalyst,
Add 06 g (0.003 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one to this solution containing 3-methylsuccinamoylaniline.
Add. This mixture was heated under reflux for 1 hour, cooled, and the product was collected and 5-acetyl-4-hydroxy-3-[1-(3-methylsuccinamoylphenylamino)ethylidene]-2H-pyran-
2,6(3H)-dione is obtained. Melting point 208-210℃ Elemental analysis value, calculated value (%): C, 57.69; H, 4.84; N, 6.73 Actual value (%): C, 57.39: H, 4.92; N, 6.86 Similarly, ethyl succinoyl chloride and reacted with substituted aniline as described above to give the corresponding product, 5-acetyl-4-hydroxy-3
-[1-(3-ethylsuccinamoylphenylamino)ethylidene]-2H-pyran-2,6
(3H) - Obtain dione. Example 2 A solution of 13.8 g (0.10 mol) of m-nitroaniline in 100 ml of diethyl ether and 30 ml of ethyl acetate contains 9.0 g (0.10 mol) of acryloyl chloride and 4.0 g (0.10 mol) of sodium hydroxide in 20 ml of water.
Add solution in ml. Leave this mixture overnight (18 hours)
Stir at room temperature and collect the precipitate to obtain N-propenoyl-3-nitroaniline. Add 400ml of water and 250g of ice to N-propenoyl-3.
-Add to a solution of 10.0 g (0.055 mol) of nitroaniline in 500 ml of t-butyl alcohol. While maintaining this mixture at 5° C. and stirring vigorously, a solution of 12 g (0.075 mol) of potassium permanganate and 5.0 g (0.125 mol) of sodium hydroxide in 400 ml of water is added. After stirring for 5 minutes, carbon disulfide was added to the mixture until the color of the mixture turned pale yellow to stop the reaction. Cool and precipitate crude N-(2-carboxy-2-oxoacetyl)-3-nitroaniline. Through this, a liquid containing N-(2,3-dihydroxypropionyl)-3-nitroaniline is separated. The crude N-(2-carboxy-2-oxoacetyl)-3-nitroaniline is purified by dissolving it in diethyl ether saturated with hydrogen chloride, filtering and evaporating the liquid. The residue was slurried with 10 times the volume of isopropyl alcohol, filtered, and washed with dilute hydrochloric acid (3N hydrochloric acid) to obtain pure N-(2-carboxylic acid).
2-oxoacetyl)-3-nitroaniline is obtained. Melting point 110℃ N-(2-carboxy-2-oxoacetyl)
-3- Add a solution of 1.2 g (0.005 mol) of nitroaniline in 60 ml of methanol to 200 mg of 10% palladium-carbon.
Top, hydrogenated at 50 psi. Once the theoretical amount of hydrogen has been absorbed, the reduction is stopped and 40 ml of 5% aqueous sodium bicarbonate solution are added to remove the catalyst. Evaporate the liquid to about 50ml and acidify it to PH2 with 3N hydrochloric acid.
Collect the resulting precipitate, wash it with water, dry it, and
(2-carboxy-2-oxoacetyl)-1,
3-phenylenediamine is obtained. Melting point 246℃ 3,5-diacetyl-4,6-dihydroxy-
A mixture of 0.65 g (0.003 mol) of 2H-pyran-2-one, 0.6 g (0.003 mol) of the phenylenediamine obtained above, and 30 ml of methanol is heated under reflux for 1.5 hours. The reaction mixture was cooled and filtered, and the residue was washed with methanol to give 5-acetyl-4-hydroxy-3-[1-(3-ketomalonamoylphenylamino)ethylidene]-2H-pyran-
2,6(3H)-dione is obtained. Melting point 218°C Elemental analysis, calculated value (%): C, 53.74; H, 3.51; N, 6.96 Actual value (%): C, 53.76; H, 3.85; N, 7.21 Example 3 N in Example 2 above The aqueous solution containing -(2,3-dihydroxypropionyl)-3-nitroaniline is extracted three times with 250 ml of ethyl acetate.
The organic layers are combined, dried over magnesium sulphate and evaporated. The residue is stirred with 75 ml of isopropyl alcohol and filtered to obtain pure N-(2,3-dihydroxypropionyl)-3-nitroaniline.
Melting point: 143-144℃ 1.13g (0.005mol) of this 3-nitroaniline
10% palladium-carbon solution in 60 ml of methanol
Hydrogenate 200 mg at 50 psi. Reduction is complete in 30 minutes, the catalyst is removed and the solvent is evaporated to about half its volume. Add 3,5-diacetyl-4,6- to this solution.
Dihydroxy-2H-pyran-2-one 1.06g
(0.005 mol) is added and the mixture is heated to reflux for 1.5 hours. The reaction mixture was cooled, the precipitate was collected, the solid was washed with methanol, dried and the 5-
Acetyl-4-hydroxy-3-[1-(3-glyceramoylphenylamino)ethylidene]-
2H-pyran-2,6(3H)-dione is obtained. Melting point 218°C Elemental analysis, calculated value (%): C, 55.39; H, 4.65; N, 7.18 Actual value (%): C, 55.04; H, 4.79; N, 7.08 Example 4 The above Examples 1 to 3 According to the method, o-nitroaniline or p-nitroaniline is used as the starting material and reacted with 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one to obtain the corresponding isomeric product. A specific example of the pharmaceutical composition of the present invention is 5-acetyl-4-hydroxy-3-[1-(3-methylsuccinamoylphenylamino)ethylidene]
-2H-pyran-2,6(3H)-dione dissolved in sterile water at a concentration of 0.5%, which allows for the administration of the desired amount of aerosolized drug. It is administered as an aerosol from a nebulizer with a controlled flow rate. For oral administration, the following compositions can be prepared. Ingredients mg/tablet 5-acetyl-4-hydroxy-3-[1-
(3-Glyceramoylphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione
10 Calcium Sulfate Dihydrate 150 Sucrose 25 Starch 15 Talc 5 Stearic Acid 3 Sucrose, calcium sulfate and the active ingredient are mixed together and granulated with hot 10% gelatin solution. The wet mass is passed through a #6 mesh sieve and received directly onto a drying tray. The granules are dried at 120°C, passed through a #20 mesh sieve, mixed with starch, talc and stearic acid, and tableted. Example 5 2,2-dimethyl-1,3-dioxolane-4
- A solution of 0.5 g (2.9 mmol) of carboxylic acid in 2 ml of methylene chloride (0° C.), followed by a solution of 0.216 g (1.3 mmol) of 3,5-diaminonitrobenzene in 2 ml of methylene chloride and 1 ml of pyridine, followed by 0.61 g of dicyclohexylcarbodiimide. (3.0 mmol) is added. The mixture is stirred for 72 hours, diluted with ethyl acetate, filtered and the liquid is evaporated to dryness under high vacuum. The residue is chromatographed on silica gel, eluting with chloroform-ethyl acetate (9:1) to give two fractions. The first fraction is a bis-acylated substance
Contains 170mg. Evaporation of the second fraction to dryness gives 250 mg of N-(3-amino-5-nitrophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxamide. N-(3-amino-5-nitrophenyl)-
2,2-dimethyl-1,3-dioxolane-4-
50% of carboxamide 0.915g (3.3mmol)
Heat the mixture in 20 ml of acetic acid over a steam oven for 1 hour and hold over the weekend. Removal of the solvent under high vacuum yields an oily product, N-(2,3-dihydroxypropionyl)-3-amino-5-nitroaniline, which is used in the next step without further purification. N-(2,3-dihydroxypropionyl)-
A mixture of 785 mg (3.3 mmol) of 3-amino-5-nitroaniline and 690 mg (3.3 mmol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 30 ml of methanol is heated to reflux for 30 minutes. . After cooling, the crystalline product was collected and dried under vacuum to give 5-acetyl-4-hydroxy-3.
-[1-(3-glyceramoyl-5-nitrophelamino)ethylidene]-2H-pyran-2,6
Obtain 616 mg of (3H)-dione. This nitro-substituted product is 580 mg (1.3 mmol)
100 mg of 10% palladium-carbon in 150 ml of acetic acid
Top, hydrogenate for 15 minutes under 40 psi hydrogen pressure. The catalyst is removed and the liquid is evaporated to dryness. The residue was titrated with cold acetone-methanol and then crystallized from methanol-ether to give 5-acetyl-3-
[1-(5-amino-3-glyceramoylphenylamino)ethylidene]-4-hydroxy-2H
Obtain 148 mg of crystals of pyran-2,6(3H)-dione. Melting point: 163°C (decomposition) Example 6 N,N′-(5-nitro-1,3-phenylene)-bis-2,2-dimethyl-1,3-dioxolane-4-carboxamide (prepared from Example 5) 50 of 1.0 g (2.4 mmol) of bis-acylated substance)
The solution in 20 ml of % acetic acid is heated on a steam bath for 30 minutes and then stirred at room temperature for 72 hours. The mixture is evaporated to dryness and the residue is tritiated with acetonitrile to obtain 700 mg of crystals of 3,5-bis-(2,3-dihydroxypropionylamino)nitrobenzene. Melting point 224-230°C. A 10% solution of 3.5 g (10.6 mmol) of nitrobenzene in 200 ml of methanol containing 5 ml of water.
Palladium-on 470 mg carbon, under 50 psi hydrogen pressure,
Hydrogenate for 1.5 hours. The catalyst is removed and the residue is evaporated to dryness to obtain 3.95 g of 3,5-bis-(2,3-dihydroxypropionylamino)aniline. This is used directly in the next step. 3,5-Diacetyl-4,6-dihydroxy-
2H-pyran-2-one 0.578g (2.73 mmol)
A mixture of 0.816 g (2.73 mmol) of the aniline obtained above in 20 ml of methanol is refluxed for 1 hour under an argon atmosphere. The reaction mixture was cooled, the precipitate was collected, the solid was washed with methanol, and the 5-acetyl-4-hydroxy-
3-[1-(3,5-bis-glyceramoylphenylamino)ethylidene]-2H-pyran-2,
6(3H)-dione is obtained. Melting point 231℃.

Claims (1)

[Claims] 1 Formula: [In the formula, R ₁ is lower alkyl succinamoyl,
Ketomalonamoyl or glyceramoyl; R ₂ is hydrogen or, when R ₁ is glyceramoyl, R ₂ may also be amino or glyceramoyl; or an alkali metal salt thereof. 2. The compound of item 1 above, wherein R ₁ is in the 3-position. 3. The compound of item 2 above, wherein R ₂ is hydrogen. 4 said third wherein R ₁ is methylsuccinamoyl
compound of term. 5. The compound of item 3 above, wherein R ₁ is ketomalonamoyl. 6. The compound of item 3 above, wherein R ₁ is glyceramoyl. 7. The compound according to item 2 above, wherein R ₁ is glyceramoyl and R ₂ is amino. 8. The compound of item 2 above, wherein R ₁ and R ₂ are glyceramoyl. 9 Effective amount formula: [In the formula, R ₁ is lower alkyl succinamoyl,
ketomalonamoyl or glyceramoyl; R ₂ is hydrogen or, if R ₁ is glyceramoyl, R ₂ may also be amino or glyceramoyl] or an alkali metal salt thereof; and a non-toxic pharmaceutical carrier or diluent. A pharmaceutical composition for suppressing symptoms of an immediate allergic reaction, characterized by: 10. The pharmaceutical composition of item 9 above, which is in a dosage form for inhalation administration. 11. The pharmaceutical composition of item 9 above, which is a solution or suspension of the active ingredient in sterile water. 12. The pharmaceutical composition of item 9 above, which is in the form of an aerosol formulation. 13. The pharmaceutical composition of item 9 above, wherein the pharmaceutical carrier or diluent is a solid. 14. The pharmaceutical composition of item 9 above, wherein R ₁ is 3-methylsuccinamoyl. 15. The pharmaceutical composition of item 9 above, wherein R ₁ is 3-ketomalonamoyl. 16. The pharmaceutical composition of item 9 above, wherein R ₁ is 3-glyceramoyl and R ₂ is hydrogen. 17. The pharmaceutical composition of item 9 above, wherein R ₁ is 3-glyceramoyl and R ₂ is amino. 18. The pharmaceutical composition of item 9 above, wherein R ₁ is 3-glyceramoyl and R ₂ is glyceramoyl. 19. The pharmaceutical composition of paragraph 9, which is in dosage unit form containing from about 0.5 mg to about 500 mg of the active ingredient per unit. 20. The pharmaceutical composition according to item 9 above, which suppresses symptoms of asthma. 21 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one with the formula: [In the formula, R ₁ and R ₂ are the same as described below. ] A formula characterized by reacting with aniline represented by: [In the formula, R ₁ is lower alkyl succinamoyl,
Ketomalonamoyl or glyceramoyl; R ₂ means hydrogen or glyceramoyl] A method for producing a compound represented by the following or an alkali metal salt thereof. 22 The process of item 21 above, wherein the reactants are heated under reflux for 1 to 3 hours in an inert organic solvent. 23 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one with the formula: [In the formula, R ₁ means glyceramoyl] A formula characterized by reacting with aniline represented by: [In the formula, R ₁ is glyceramoyl; R ₂ means amino] A method for producing a compound represented by the following or an alkali metal salt thereof. 24 Incubate the first reactants in an inert organic solvent for 30 minutes to 3
The method of item 23 above, wherein the method is heated under reflux for a period of time. 25. The production method according to item 23 or 24, wherein catalytic hydrogenation is carried out using a palladium-carbon catalyst.