2-Hydroxyoxanilic acid derivatives and salts, their preparation and pharmaceutical compositions containing them

This invention relates to novel 2-hydroxyoxanilic acid derivatives, and provides the 2-hydroxyoxanilic acid derivatives shown by following formula I, and the salts thereof

wherein A represents a hydroxyl group, a lower alkoxy group optionally substituted by hydroxyl, an amino group, a hydrazino group, a mono- or di-lower alkylamino group optionally substituted by amino, or a piperazino group optionally substituted by lower alkyl; R₁ represents halogen, a nitro group, a lower alkyl group having 2 or more carbon atoms, an amino or cyano group, a mono- or di-lower alkylamino group, a hydroxylgroup, a lower alkoxy group, a lower alkoxycarbonyl lower alkoxy group, a carboxy lower alkoxy group, a lower alkanoyloxy group, a lower alkanoyl group, an arylsulfonyloxy group, a group

(wherein R₃ represents hydrogen, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, an amino group, or a mono- or di-lower alkylamino group and R₄ represents hydrogen or a lower alkyl group), or a group

(wherein X represents oxygen and Y represents a hydroxylgroup, a lower alkoxy group, or an amino group optionally substituted bv lower alkyl or phenyl lower alkyl, R₁ being at the 5-position when it is

and at the 4-position or the 5-position when it is cyano or

and R₂ represents hydrogen, halogen, a nitro group, a lower alkyl group, an amino group, a mono- or di-lower alkylamino group, a hydroxylgroup, a lower alkoxy group, a lower alkoxycarbonyl lower alkoxy group, a carboxy lower alkoxy group, a lower alkanoyloxy group, a lower alkanoyl group, or an arylsulfonyloxy group.

In the general formula I described above the term "lower" means a straight or branched carbon chain having 1-5 carbon atoms. Therefore, as the lower alkyl group for "a mono- or di-lower alkylamino group optionally substituted by amino ", "a piperazino group optionally substituted by lower alkyl ", "a mono- or di-lower alkylamino group, "a lower alkyl group", and "an amino group optionally substituted by phenyl lower alkyl" in formula I, there may be a methyl group, ethyl group, propyl group, sec-butyl group, tert-butyl group, etc; as the lower alkoxy group for "a lower alkoxy group optionally substituted by hydroxyl ", a lower alkoxy group "a lower alkoxycarbonyl lower alkoxy group", "a carboxy lower alkoxy group", and a lower alkoxycarbonyl group", there may be a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, etc; and as the lower alkanoyl group for "a lower alkanoyloxy group" and "a lower alkanoyl group", there may be a formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, etc.

As practical examples of "a lower alkyl group having 2 or more carbon atoms", there are ethyl the group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group, n-amyl group, tert-amyl group, etc. Also, as examples of "halogen", there are fluorine, chlorine, bromine and iodine atoms etc., and as examples of "an arylsulfonyloxy group", there are the phenyl- sulfonyloxy group, tolylsulfonyloxy group, naphthylsulfonyloxy group, etc.

The compounds of formula I

form salts, which are also included as compounds of this invention. As pharmaceutically acceptable salts according to the invention. for example, there are the acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., or an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, etc.; the salts with an alkali metal such as sodium, potassium, etc., or an alkaline earth metal such as calcium, etc.; the ammonium salts; and the salts with an organic base such as methylamine, ethylamine, diethylamine, trimethylamine, triethylamine, pyridine, picoline, arginine, lysine, etc.

Although there are known various oxanilic acid derivatives, they have been investigated mainly for use as antiallergic agents(e. g., U. S. Pat. Nos. 3,993,679; 4,017,538;.4,054,591; 4,069,343; 4,087,606; 4,Ob9,973 and 4,095,028). As oxalinic acid derivatives possessing pharmacological activities other than antiallergic known activity, there are known only some compounds which are useful in the prophylactic treatment for gastric ulcers as disclosed in U. S. Pat. No. 4,137,325. No oxanilic acid derivatives have been known to possess strong immunoregulatory action.

Ethyl 2-hydroxyoxanilate, methyl 2-hydroxyoxanilate ("Chem. Abstr.", 57, pl1207b), ethyl 2-hydroxy-5-methyloxanilate ("Chem. Abstr.", 58, p6840b), and 3-carboxy-2-hydroxy-5-nitrooxanilic acid esters (West German Pat. 2,746,385) are known 2-hydroxyoxanilic acid derivatives. However, there are no disclosures in the aforesaid literature about the use of the first three compounds as medicaments. It is disclosed in the German patent that the fourth group of compounds possess an antiallergic action, but the patent does not disclose that they have action on the immune system and a strong immunoregulatory action.

In the compounds

of this invention the 2-position of .oxanilic acid is substituted by hydroxyl, and. such 2-hydroxyoxanilic acid derivatives have immuno- be regulatory action. Furthermore,these compounds can useful as antiallergic agents, antiasthamatics, antirheumatics, carcinostatic agents, therapeutic agents for autoimmune disease, and suppressants of rejection in tissue transplants and skin grafts.

The compounds of this invention which enhance cell- mediated immunity such as delayed type hypersensitivity reaction and lymphocyte blastogenesis, and/or potentiate humoral antibody formationion, are useful as carcinostatic agents, antitumor agents, antirheumatics, and therapeutic agents for chronic hepatitis. Some of the compounds of this invention having immunostimulating action are effective for the protection and prophylaxis of virus or bacterial infection based on reduction in immunity. Moreover, they can be effective in tumour gross inhibition tests. Thus such compounds can be useful as carcinostatic agents and antitumor agents.

The compounds of this invention which inhibit humoral antibody formation such as IgE antibody formation are useful as antiallergic agents and / antiasthmatics since IgE antibody plays a key role in the Type I immediate hypersensitivity reaction.

Some of the compounds of this invention having an immunosuppressive action inhibit the passive cutaneous anaphylaxis (PCA) reaction in rats,suggesting they have an antiallergic action. In particular, the compounds of this invention showing a long lasting inhibitory effect in PCA tests (oral administration)in addition to suppression of IgE antibody formation are useful as antiallergic agents and antiasthmatics.

The compounds of this invention which suppress cell- mediated immunity such as delayed type hypersensitivity reaction are useful as antiallergic agents, antirheumatics, therapeutic agentsfor autoimmune disease and suppressants of rejection in tissue transplants s and skin grafts. In particular, the aforesaid compounds of this invention are useful in the treatment of delayed type hypersensitivity and rheumatoid arthritis.

Furthermore, some of the compounds of this invention inhibit passive cutaneous anaphlaxis (PCA). Therefore, such compounds are useful as antiallergic agente and antiasthmatics.

Since

/the compounds of this invention have weak toxicity, they can be used as medicaments for various uses as described above.

The medical compositions which contain compounds I or pharmaceutically acceptable salts thereof can be formulated conventionally using conventional carriers and excipients. The medicaments may be administered orally as tablets, pills, capsules, granules, etc., or may be administered parenterally as injections such as intraveous injection, intramuscular injection, etc., or as aerosols,suppositories, etc. The doses of the medicaments are appropriately selected according to each case on considering the symptom and age of the patient, sex distinction, etc., but are usually 5-600 mg per day for adults in the case of oral administration and 1-300 mg per day for adults in the case of parenteral administration. The medicaments are usually administered 2 or 3 times a day.

A compound of this invention shown by formula I can be prepared by reacting an aminophenol shown by formula II

(wherein Z represents hydrogen or a protective group for hydroxyl and R₁ and R₂ have the same significance as in formula I) and an oxalylic acid shown by formula III

(wherein A has the same significance as in formula I) or a reactive derivative .thereof in ordinary manner to form an oxalylate and, when Z is a protective group for hydroxyl, removing the protective group in ordinary manner.

As the reactive derivative of oxalylic acid, an oxalyl halide such as oxalyl chloride is usually used and in this case the reaction is performed in a solvent such as benzene, methylene chloride, tetrahydrofuran, etc., preferably in the presence of a base such as pyridine, dimethylaniline, potassium carbonate, sodium carbonate, etc. The reaction temperature is room temperature or lower, preferably lower than 10°C. When a diaminophenol shown by formula II'

wherein R₂ and Z have the same significance as described above is used as the aminophenol of formula IT in this process, these two amino groups are oxalylated. As the protective group for the hydroxyl of the aminophenol of formula II, a benzyl group is usually used and in this case the protective group (benzyl group) is removed by reduction, e. g., catalytic reduction in ordinary manner.

Compounds of this invention can also be obtained by transforming others of formula I. For this purpose, there are illustrated (1) ester hydrolysis, (2) ester interchange, (3) ester amination, (4) nitro group reduction, (5) amino group acylation, and (6) halogenation. These reactions can all be performed in ordinary manner.

• (1) By the hydrolysis of an ester, a compound of formula I wherein A is, for example, an ethoxy group is converted into a compound of formula I wherein A is a hydroxyl group. This reaction is usually performed under alkaline conditions.
• (2) By ester interchange, a compound of formula I wherein A is, for example, an ethoxy group is convertable to a compound of formula I wherein A is a propoxy group, an isopropoxy group, a butoxy group or a 2-hydroxyethoxy group. This reaction is usually performed by heating the former compound in a corresponding alcohol in the presence of an acid catalyst such as p-toluenesulfonic acid.
• (3) By the amination of an ester, a compound of formula I wherein A is, for example, an ethoxy group is convertable to a compound of formula I wherein A is an amino group, a methylamino group, an ethylamino group, a 2-aminoethylamino group, a hydrazino group, or a 4-methylpiperazino group. This reaction is usually performed by reacting the former compound with a corresponding amine in a solvent such as methancl, etc.
• (4) By the reduction of a nitro group, a compound of formula I wherein at least one of R1 and R₂ is a nitro group is converted into a compound of formula I wherein at least one of R₁ and R₂ is an amino group. This reaction is usually performed by catalytically reducing the former compound.
• (5) By the acylation of an amino group, a compound of formula I wherein R₁ is an amino group or a mono-lower alkylamino group is convertable to a compound of formula I wherein R₁ is a group shown by

  (wherein R₃ and R₄ have the same significance as defined above). This acylation is performed by reacting the compound of formula I wherein R₁ is an amino group or a mono-lower alkylamino group with the carboxylic acid shown by R₃COOH or a reactive derivative thereof. As reactive derivatives of the carboxylic acid shown by H₃COOH, there are illustrated an acid anhydride, an acyl halide, etc. Practical examples of them are acetic anhydride, ethyl chlorocarbonate, methyl isocyanate, etc. This reaction can be performed as in the case of the aforesaid oxalylation, and can be performed under the conditions usually employed for acylation. When the free carboxylic acid (R₃COOH) is used, usually the reaction is carried out in the presence of a coupling agent e.g. dicyclohexylcarbodiimide.

• (6) By halogenation, a compound of formula I wherein R₂ is hydrogen atom is convertable to a compound of formula I wherein R₂ is a halogen atom. This reaction is performed by treating with a halogenating agent, such as bromine, chlorine, iodine, etc., in ordinary manner.

The compounds of this invention prepared as described above can be isolated and purified by conventional chemical operations

such as recrystallization, extraction, various kinds of chromatography, etc.

Experimental results indicating the excellent pharmacological effect of. compounds of this invention are given below.

Activity to delayed type hypersensitivity of mice:

• Seven week old ICR-SLC mice (Shizuoka Agric. Coop. Assoc.) were sensitized by painting 0.1 ml of 7% picryl chloride (PC) solution in absolute ethanol on the shaved abdomen. After the 7 day sensitization period, mice were challenged by painting 0.02 ml of 1% picryl chloride solution in olive oil on the inside of each ear. The ear thickness was measured by dial thickness gauge. Increase in ear thickness was calculated as the difference between the value measured before challenge and 24 hours after it. The test compounds were administered orally from day 0 to day 3 after the immunization. The results are shown in Table I.

The above experimental results show that the compounds of this invention increased markedly the delayed type hypersensitivity reaction, which shows clearly that the compounds of this invention possessed strong immunostimulating action.

Example 1

A solution of 2.7 g of ethyl oxalylchloride in 6 ml of benzene was added dropwise to a solution of 3 g of 2-amino-4-chlorophenol and 3 ml of pyridine in 30 ml of tetrahydrofuran with stirring under cooling to 0-10 C. After the addition was finished, the reaction mixture was stirred for one hour at room temperature and then 50 ml of toluene and 100 ml of water were successively added to the reaction mixture. Crystals thus formed were recovered by filtration from the reaction mixture, washed with water, and recrystallized from ethanol to provide 2.8 g of the white crystals of ethyl 5-chloro-2-hydroxyoxanilate.

Elemental analysis for C₁₀H₁₀NO₄Cl:

Nuclear magnetic resonance spectra (DMSO-d₆)

• δ :1.31 (3H, t, -CH₃)
• ₄._{29 (2H}, q, -C^H2^-)
• 6.91 (1H, d, H at the 6-position of benzene ring)
• 7.05 (1H, dd, H at the 4-position of benzene ring)
• 8.01 (lH, d, H at the 3-position of benzene ring).

Example 2

By following the same procedure as in Example 1 using 3 g of 2-amino-4-nitrophenol and 2.7 g of ethyl oxalyl chloride as the raw materials, 4.0 g of the white crystals of 2-hydroxy-5-nitrooxanilate were obtained.

Melting point: 280°C (decomd.) Nuclear magnetic resonance spectra (DMSO-d₆)

• δ : 1.32 (3H, t, -CH₃)
• 4.31 (2H, q, -CH2^-)
• 7.05 (lH, d, H at the 6-position of benzene ring)
• 7.95 (lH, dd, H at the 4-position of benzene ring)
• 8.87 (1H, d, H at the 3-position of benzene ring)

Example 3

To a mixture of 60 ml cf methylene chloride and 3 ml of pyridine was added 3 g of 2-amino-4-ethylphenol hydrochloride and then a solution of 2.3 g of ethyloxalyl chloride in 30 ml of methylene chloride was added thereto at temperatures below 10°C. After stirring the reaction mixture for 3 hours, the reaction mixture was washed with water, 5% hydrochloric acid, and then water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Crystals thus formed were recovered and recrystallized from ethanol to provide 1.9 g of ethyl 5-ethyl-2-hydroxyoxanilate.

Elemental analysis for C₁₂H₁₅NO₄:

Nuclear magnetic resonance spectra (CDCl₃)

• δ : 1.20 (3H, t, -CH₂^CH₃)
• ₁.₄₁ (3H, t, -COOCH₂CH₃)
• 2.56 (2H, ^q, -CH₂^CH₃)
• 4.42 (2H, q, -COOCH2CH3)
• 6.90 (2H, m, H at the 3- and 4-positions of benzene ring)
• 7.2b (1H, d, H at the 6-position of benzene ring)

Example 4

By following the same procedure as in Example 1 using 2 g of 2-amino-5-methoxyphenol and 2.7 g of ethyl oxalyl chloride, 2.13 g of ethyl 2-hydroxy-4-methoxyoxanilate was obtained.

Elemental analysis for C₁₁H₁₃NO₅:

Mass spectrum:

• m/e: 239(M⁺)

Example 5

A solution of 2.5 g of ethyl oxalyl chloride in 15 ml of methylene chloride was added dropwise to a solution of 3.4 g of 2-amino-4-(n-propyl)phenol hydrochloride and 3 ml of pyridine in a mixture of b0 ml of methylene chloride and 30 ml of tetrahydrofuran with stirring under cooling to 0-10°C. After the addition was finished, the reaction mixture was stirred for 3 hours at room temperature, washed with water, 5% hydrochloric acid, and then water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Crystals formed were recovered and recrystallized from ethanol to provide 3.4 g of ethyl 2-hydroxy-5-n-propyloxanilate.

Melting point: 155-160°C Elemental analysis for C₁₃H₁₇NO₄:

Mass spectrum:

• m/e: 251(M⁺)

By following the same procedure as example 5, compounds of following examples 6 - 15 were prepared.

Example 6

Ethyl 2-hydroxy-4-nitrooxanilate Melting point: 269-271°_C (decomposed) Elemental analysis for C₁₀H₁₀N₂O₆:

Example 7

Ethyl 2-hydroxy-5-methoxyoxanilate Mass spectrum m/e: 239 (M⁺) Elemental analysis for C₁₁H₁₃NO₅:

Example 8

Ethyl 3-chloro-2-hydroxyoxanilate Melting point: 161-163°C Elemental analysis for C₁₀H₁₀NO₄Cl:

Example 9

Ethyl 4-chloro-2-hydroxyoxanilate Melting point: above 300°C Elemental analysis for C₁₀H₁₀NO₄Cl:

Example 10

Methyl 5-chloro-2-hydroxyoxanilate Melting point: above 300°C Elemental analysis for C₉H₈NO₄Cl:

Example 11

Ethyl 2-hydroxy-5-isopropyloxanilate Melting point: 150-155°C Elemental analysis for C₁₃H₁₇NO₄:

Example 12

Ethyl 5-n-butyl-2-hydroxyoxanilate Melting point: 135-140°C Elemental analysis for C₁₄H₁₉NO₄:

Example 13

Ethyl 5-n-amyl-2-hydroxyoxanilate Melting point: 135-138°C Elemental analysis for C₁₅H₂₁NO₄:

Example 14

Ethyl 5-fluoro-2-hydroxyoxanilate Melting point: 262-265°C Elemental analysis for C₁₀H₁₀NO₄F:

Example 15

Ethyl 5-bromo-2-hydroxyoxanilate Melting point: above 300°C Elemental analysis for C₁₀H₁₀NO₄Br:

Example 16

A mixture of 2 g of ethyl 5-chloro-2-hydroxyoxanilate, 50 ml of ethanol, and b.2 ml of a 1 normal sodium hydroxide solution was stirred for one hour at 60°C. The reaction mixture was concentrated under reduced pressure and the crystals formed were recovered and dissolved in 100 ml of water. Activated carbon was added to the solution and after filtering the mixture, the filtrate was concentrated under reduced pressure to 10 ml. After adding 10 ml of water to the concentrate, the mixture was allowed to stand overnight and the crystals formed were recovered by filtration to provide 1.1 g of sodium 5-chloro-2-hydroxyoxanilate.

Melting point: > 300°C

Elemental analysis for C₆H₅NO₄ClNa:

Example 17

A mixture of 2 g oi ethyl 5-chloro-2-hydroxyoxanilate, 100 ml of isopropyl alcohol, and 100 mg of p-toluenesulfonic acid was refluxed for 24 hours. The reaction mixture was allowed to cool to room temperature and then allowed to stand overnight. Crystals formed were recovered by filtration and recrystallized from isopropyl alcohol to provide 1.1 g of isopropyl 5-chloro-2-hydroxyoxanilate.

Melting point: >300°C

Elemental analysis for C₁₁H₁₂NO₄Cl:

Example 18

A mixture of 2.5 g of ethyl 5-chloro-2-hydroxyoxanilate, 200 mg of p-toluenesulfonic acid, and 100 ml of n-propanol was stirred for 2 days at 100°C. The reaction mixture was concentrated under reduced pressure and the residue was washed with ether and recrystallized from n-propanol to provide 0.9 g of n-propyl 5-chloro-2-hydroxyoxanilate.

Mass spectrum: m/e: 257(M⁺)

Elemental analysis for C₁₁H₁₂NO₄Cl:

By following the same procedure as example 18, compounds of following examples 19 and 20 were prepared.

Example 19

n-Butyl 5-chloro-2-hydroxyoxanilate Mass spectrum m/e: 271 (M⁺) Elemental analysis for C₁₂H₁₄NO₄Cl:

Example 20

2-Hydroxyethyl 5-chloro-2-hydroxyoxanilate Melting point: above 300°C Elemental analysis for C₁₀H₁₀NO₅Cl:

Example 21

A solution of 1.25 g of ethyl oxalyl chloride in 10 ml of methylene chloride was added dropwise to a solution of 1.4 g of 4-acetoxy-2-aminophenol and 1.1 ml of pyridine in 30 ml of

tetrahydrofuran at a temperature below 10°C. After the addition was finished, the reaction mixture was allowed to rise to room temperature and stirred for 3 hours. The reaction mixture was concentrated under'reduced pressure and the residue was washed with diluted hydrochloric acid, washed with water, and recrystallized from a mixture of tetrahydrofuran and n-hexane to provide 1.7 g of ethyl 5-acetoxy-2-hydroxyoxanilate.

Mass spectrum: m/e: 267(M⁺)

Elemental analysis for C₁₂H₁₃NO₆:

By following the same procedure as example 21, compounds of following examples 22 - 25 were prepared.

Example 22

Ethyl 5-acetyl-2-hydroxyoxanilate Melting point: 263-265°C (decomposed) Elemental analysis for C₁₂H₁₃NO₅:

Example 23

Ethyl 3,5-dichloro-4-hydroxyoxanilate Mass spectrum m/e: 277 (M⁺) Elemental analysis for C₁₀H₉NO₄Cl:

Example 24

Ethyl 5-ethoxycarbonylmethoxy-2-hydroxyoxanilate Melting point: 191-193⁰C Elemental analysis for C₁₄H₁₇NO₇:

Example 25

Ethyl 2-hydroxy-5-phenylsulfonyloxyoxanilate Melting point: 196-199°C Elemental analysis for C₁₆H₁₅NO₇S:

Example 26

A mixture of 2 g of ethyl 5-chloro--2-hydroxyoxanilate, 150 ml of methanol and 20 ml of concentrated aqueous ammonia was stirred for one hour at room temperature. The reaction mixture formed was concentrated under reduced pressure and crystals were recrystallized from 50% ethanol to provide 1.2 g of 5-chloro-2-hydroxyoxanylamide.

Melting point: 247°C

Elemental analysis for C₈H₇N₂O₃Cl:

By following the same procedure as example 26, compounds of following examples 27 - 30 were prepared.

Example 27

5-Chloro-2-hydroxy-N-methyloxanilamide Melting point: 280-283°C Elemental analysis for C₉H₉N₂O₃Cl:

Example 28

5-Chloro-2-hydroxy-N,N-dimethyloxanylamide Melting point: 193-196°C Elemental analysis for C₁₀H₁₁N₂O₃Cl:

Example 29

5-Chloro-2-hydroxyoxanilohydrazide Melting point: above 300°C Elemental analysis for C₈H₈N₃O₃Cl:

Example 30

5-Chloro-2-hydroxy-N-(2-aminoethyl)oxanilamide Mass spectrum m/e: 257 (M⁺) Elemental analysis for C₁₀H₁₂N₃O₃Cl:

Example 31

A solution of 3 g of ethyl 2-hydroxy-5-nitrooxanilate in 50 ml of ethanol was catalytically hydrogenated in the presence of 0.5 g of 10% palladium carbon. After the absorption of hydrogen stopped, the catalyst was filtered off and 6 ml of a mixture of 2N-HCl ethanol was added to the filtrate. After concentrating the mixture under reduced pressure, the solids formed were washed with a small amount of ethanol and dried to provide 2.2 g of ethyl 5-amino-2-hydroxyoxanilate hydrochloride.

Melting point: 250-260°C (decompd.)

Elemental analysis for C₁₀H₁₃N₂O₄Cl:

Example 32

After catalytically reducing 2.5 g of 2-nitroquinol in 50 ml of tetrahydrofuran in the presence of 10% palladium-carbon until the absorption of hydrogen stopped, the catalyst was filtered off and 3 ml of pyridine was added to the filtrate. To the solution was added dropwise a solution of 2.5 g of ethyl oxalyl chloride in 10 ml of methylene chloride at a temperature below 15°C. Thereafter, the reaction mixture was stirred for 3 hours at room temperature. After removing insoluble matters

by filtration, the filtrate was concentrated under reduced pressure and the residue was mixed with 50 ml of diluted hydrochloric acid followed by stirring for one hour at room temperature. Crystals formed were recovered by filtration, washed with water and then ethanol, and recrystallized from ethanol to provide 0.7 g of ethyl 2,5-dihydroxy- oxanilate.

Melting point: > 300°C

Elemental analysis for C₁₀H₁₁NO₅:

Example 33

A solution of 2.3 g of ethyl 2-hydroxy-5-nitrooxanilate in 40 ml of tetrahydrofuran was catalytically hydrogenated in the presence of 0.3 g of 10% palladium carbon until the absorption of hydrogen stopped. After the reaction was over, the catalyst was filtered off and to the filtrate was added 3.5 ml of acetic anhydride under cooling below -20°C.

The mixture was further stirred for 30 minutes at room temperature and crystals formed were recovered by filtration, washed with tetrahydrofuran, and dried to provide 2.2 g of ethyl 5-acetamido-2-hydroxyoxanilate.

Melting point: >300°C (decompd.)

Elemental analysis for C₁₂H₁₄N₂O₅:

By following the same procedure as in Example 33, the compounds in following Examples 34-36 were produced.

Example 34

By following the above-described procedure using a mixture of acetic anhydride and formic acid (5:3 V/V) in place of acetic anhydride in Example 33, 2.1 g of ethyl 5-formamido-2-hydroxyoxanilate was obtained.

Melting point: >300°C (decompd.)

Elemental analysis for C₁₁H₁₂N₂O₅:

Example 35

By following the above-described procedure using methyl isocyanate in place of acetic anhydride in Example 33, ethyl 2-hydroxy-5-(3-methylureido)oxanilate was obtained.

Melting point: 235-236°C (decompd.)

Elemental analysis for ^C₁₂^H₁₅^N₃⁰₅^:

Example 36

By following the above-described procedure using ethyl chlorocarbonate and pyridine in place of acetic anhydride in Example 33, 5-ethoxycarbonylacido-2-hydroxyoxanilate was obtained.

Melting point: 257-259⁰C (decompd.)

Elemental analysis for C₁₂H₁₄N₂O₆:

Example 37

To a mixture of 1 g of 4,6-diaminoresorcinol monomethyl ether dihydrochloride, 2 ml of pyridine, and 10 ml of methylene chloride was added dropwise a mixture of 1.5 g of ethyl oxalyl chloride and 10 ml of methylene chloride at a temperature below 5°C. After the addition was finished, the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to provide 0.9 g of ethyl 5-ethoxyoxalylamido-2-hydroxy-4-methoxyoxanilate.

Melting point: 274-277°C

Elemental analysis for C₁₅H₁₈N₂O₈:

Example 38

In 25 ml of tetrahydrofuran was dissolved 2.5 g of 4-cyano-2-nitrophenol and then catalytic reduction was performed using 0.25 g of 10% palladium carbon as a catalyst until the absorption of hydrogen stopped. After the reaction was over, the catalyst was filtered off and to the filtrate containing 2-amino-4-cyanophenol was added dropwise a mixture of 2.5 g of ethyl oxalyl chloride and 4 ml of toluene with stirring under cooling below -10°C. After the addition was finished, the reaction mixture was stirred for 2 hours at room temperature and crystals formed were recovered by filtration, washed with water and then propanol, and recrystallized from methyl cellosolve to provide 2.1 g of ethyl 5-cyano-2-hydroxyoxanilate,

Melting point: 295°C (decompd.)

Elemental analysis for C₁₁H₁₀N₂O₄:

By following the same procedure as example 38, compounds of following

/examples 39 and 40 were prepared.

Example 39

Ethyl 4-cyano-2-hydroxyoxanilate Melting point: above 300°C Elemental analysis for C₁₁H₁₀N₂O₄:

Example 40

Ethyl 5-ethoxycarbonyl-2-hydroxyoxanilate Melting point: 245-246°C (ethanol-toluene) Elemental analysis for C₁₃H₁₅NO₆:

Example 41

By reducing N,N-dibenzyl-4-benzyloxy-3-nitrobenzamide (melting point 131-132°C) in water-containing methanol with reduced iron powder-hydrochloric acid, 3-amino-N,N-dibenzyl-4-benzyloxybenzamide (melting point 81°C) was obtained. Then, by reacting 3-amino-N,N-dibenzyl-4-benzyloxybenzamide with ethyl oxalyl chloride in the presence of pyridine in tetrahydrofuran, ethyl 2-benzyloxy-5-(N,N-dibenzylcarbamoyl)-oxanilate (melting point 132-133°C) was obtained. A solution of 3.6 g of ethyl 2-benzyloxy-5-(N,N-dibenzylcarbamoyl)-oxanilate thus obtained in 100 ml of ethanol was catalytically hydrogenated in the presence of 0.8 g of 10% palladium carbon of hydrogen stopped. until the absorption/After the reaction was over, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to provide 2.7 g of ethyl 5-(N,N-dibenzyl- carbamoyl)-2-hydroxyoxanilate , a gum.

Nuclear magnetic resonance spectra (CDC1₃)

• δ : 1.40 (3H, t,-CH₃)
• 4.36 (2H, q., -CH₂^CH₃)
• 4.57 (4H, S,

• 6.64 (1H, d, H at the 3-position of benzene ring)
• 7.04 (lH, d, d, H at the 4-position of benzene ring)
• 7.1-7.5 (10H, 2

• 8.38 (1H, d, H at the 6-position of benzene ring)
• 9.42 and 9.90 (each 1H, -OH and -NH-)

The N,N-dibenzyl-4-benzyloxy-3-nitrobenzamide which was used as the raw material in this example was obtained by the reaction of 4-benzyloxy-3-nitrobenzoyl chloride with N,N'-dibenzylamine.

Example 42

By reducing 4-benzyloxy-3-nitrobeznoic acid benzyl ester (melting point 68-70°C) with reduced iron powder-hydrochloric acid in 90% methanol, 3-amino-4-benzyloxybenzoic acid benzyl ester (melting point 79-81°C) was obtained and further by reacting the product with ethyl oxalyl chloride in the presence of pyridine in tetrahydrofuran, 2-benzyloxy-5-benzyloxycarbonyl oxanilate (melting point 136-138⁰C) was obtained.

1.8 g of ethyl 2-benzyloxy-5-benzyloxycarbonyl oxanilate thus obtained was dissolved in 50 ml of ethanol and in the presence of catalytically hydrogenated/0.3 g of 10% palladium carbon until the absorption of hydrogen stopped. After the reaction was over, the catalyst was filtered off and the filtrate was concentrated under reduced.pressure. Crystals formed were washed with isopropanol and dried to provide 0.9 g of ethyl 5-carboxy-2-hydroxyoxanilate.

Melting point: >300°C Elemental analysis for C₁₁H₁₁NO₆:

The 4-benzyloxy-3-nitrobenzoic acid benzyl ester which was used as the raw material in this example was obtained through the steps of benzylation, hydrolysis and benzylation of 4-hydroxy-3-nitrobenzoic acid ethyl ester.

Example 43

To a mixture of 30 ml of 4% potassium hydroxide solution ethyl and 30 ml of methanol was added 2 g of/5-cyano-2-hydroxyoxanilate and the mixture was stirred overnight at room temperature. To the reaction mixture was added 15 ml of 10% hydrochloric acid solution and white crystals formed were recovered by filtration and recrystallized from water to provide 1.2 g of 5-cyano-2-hydroxyoxanilic acid.

Melting point: >300°C

Mass spectrum (FD): m/e: 206(M⁺)

Example 44

To a mixture of 1.2 g of N-methylpiperazine and 20 ml of methanol was added gradually 2 g of ethyl 5-cyano-2-hydroxyoxanilate and after stirring the mixture for 3 hours at room temperature, crystals formed were recovered by filtration, washed successively with isopropanol and ether, and dried to provide 2 g of l-(5-cyano-2-hydroxyoxanilyl)-4-methylpiperazine.

Melting point: 256°C

Elemental analysis for C₁₄H₁₆N₄O₃:

Example 45

A mixture of 1.1 g of bromine and .5 ml of acetic acid was added dropwise to a solution of 1.5 g of ethyl 5-cyano-2-hydroxyoxanilate and 1 g of sodium acetate in a mixed solution of 10 ml of dimethyl sulfoxide, 10 ml of methanol and 20 ml of acetic acid. After stirring the mixture for 30 minutes at room temperature, 6 ml of 2 normal hydrochloric acid and 200 ml of water were added to the reaction mixture and the product was extracted with a mixture of 30 ml of toluene and 40 ml of ethyl acetate. The extract was washed with water, dried, and then concentrated under reduced pressure. Crystals formed were washed with a mixture of ether and n-hexane to provide 1.5 g of ethyl 3-bromo-5-cyano-2-hydroxyoxanilate.

Mleting point: 163-165°C

Elemental analysis for C₁₁H₉N₂O₄Br:

Example 46

2 g of 2-nitroso-5-dimethylaminophenol hydrochloride was dissolved in 40 ml of methanol and catalytically hydrogenated in of the presence of 0.15 g of 10% palladium carbon as a catalyst until the absorption of hydrogen stopped. After the reaction was over, the catalyst was filtered away and the filtrate was concentrated under reduced pressure. After dissolving 1.9 g of the amorphous powder of 2-amino-5-dimethylaminophenol hydrochloride thus obtained in 30 ml of pyridine, a mixture of 1.5 g of ethyl oxalyl chloride and 5 ml of toluene was added dropwise to the solution under cooling to temperatures below 0°C. After the addition was finished, the reaction mixture was stirred overnight at room temperature and crystals thus formed were recovered by filtration, washed successively with water and isopropanol, and dried to provide 1.3 g of ethyl 4-dimethylamino-2-hydroxyoxanilate.

Melting point: 259-260°C (decompd.)

Elemental analysis for C₁₂H₁₆N₂O₄:

Example 47

2.1 g of 4-benzyloxy-N-methyl-3-nitroacetanilide, obtained by benzylating and then methylating 4-hydroxy-3-nitro- acetanilide, was dissolved in 30 ml of tctrahydrofuran and in the presence of . catalytically hydrogenated/ 0.2 g of 10% palladium carbon as a catalyst until the absorption of hydrogen stopped. After the reaction was over, the reaction mixture was filtered to remove the catalyst and 2 ml of pyridine was added to the filtrate. Then, to the mixture was gradually added a mixture of 1.2 g of ethyl oxalyl chloride and 5 ml of toluene under cooling below -10°C and the resultant mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with 50 ml of a mixture of toluene and ethyl acetate (1 : 1). After washing the extract with water followed by drying, the solvent was distilled off. To the residue formed was added isopropanol and crystals thus formed were recovered by filtration, washed with isopropanol, and dried to provide 0.6 g of ethyl 5-(N-acetylmethylamino)-2-hydroxyoxanilate.

Melting point: 190-192°C.

Elemental analysis for C₁₃H₁₆N₂O₅: