JPS5920664B2 - Method for producing new oxamic acid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Atopic direct sensitivity is a major symptom observed in animals suffering from asthma, hay fever, allergic rhinitis, hives, etc.

Substances that are inhaled or ingested and often cause clinical sensitivities include pollen, animal feathers and dander, dust,
Milk and wheat. Atopic hypersensitivity is found in humans, dogs, and other animals, and exceptionally in lower animals.

A patient's serum containing antibodies with an atopic reaction is injected intradermally into a healthy person to provide passive sensitization, and 24 hours later, when the antigen is injected at the same site, localized hives occur. This is generally called Prausnit2-Ku-stne reaction, P
– in response). Antibodies in atopic hypersensitivity have unique properties: they do not precipitate antigens in any form, are not passed from mother to fetus through the placenta, have a particular affinity for the skin, and are highly sensitive to various antigenic factors. They often lack specificity for the individual antigen of the sensitized individual and are usually unstable at about 5°C for 2 hours.

Allotropic antibodies found in rats have a mechanism of action similar to that of human immunoglobulin E (Reagin or IgE).

The correlation between rat allotropic antibodies and human IgE is evidenced by the common effects of chemical, immunological, and drug reactions on both of these antibodies. In humans, the reactants are antibodies that cause atopic direct hypersensitivity;
In rats, allocytotropic antibodies cause atopic direct hypersensitivity. Theoretically, the reactants influence the cell membrane of mast cells through the action of antigens, initiate a reaction in mast cells, and finally produce Bradykinin (Bradykinin).
Me-Diat (In), slow-acting substance-A (SRS-A), histamine and other unknown substances.
Or) is released.

This medicinal substance changes the permeability of the surrounding cell walls, allowing rapid changes in the efflux or secretion of medicinal substances from the cells, causing allergic symptoms. The methods commonly used to relieve allergic symptoms are (1) eliminating antigen attack, (2) blocking antibody production with immunosuppressants, and (3)
) Antihistamines, anti-5-hydroxytryptamine (
(4) administration of bronchodilators such as IsOprel® or xanthines to block the action of Medieta on the attacked cells by administering 5-HT or anti-inflammatory agents; The action stimulates the cells being attacked and counteracts the action of Medieta, but neither is completely acceptable. The only compound currently known that exhibits anti-allergic properties by blocking its action on mast cells and thereby preventing the production and release of methane is disodalium cromoglylate [DisO].
diumcr-0m0g1ycate (registered trademark 1N
TAL)] Derivatives of oxamidic acid have been used in the past as intermediates in polymer formation and have been chemically refined.

The present invention provides a method for producing a novel aromatic oxamic acid derivative useful for suppressing allergic symptoms in warm-blooded animals, and the novel aromatic oxamic acid derivative is represented by the following formula: [wherein R is lower alkoxy or cycloalkyloxy; A is (wherein R1 is one of hydroxy, lower alkoxy and amino; R2 is one of hydrogen, lower alkoxy, halogen and phenoxy(lower) alkoxy) ; R3 means one of hydrogen, lower alkoxy, halogen and nitro; R4 means one of hydrogen and lower alkoxy, and one of R2, R8 and R4 is a group other than hydrogen) ] refers to the group represented by the above aromatic oxamic acid derivative. Preferred aromatic compounds in the practice of this invention include novel compounds that reduce allergic symptoms such as papules and redness and expansion of skin tissue in sensitized animals by 75% or more.

This compound has the following structural formula: Todoroki & Todoroki 1 Crystal VV
▲ [In the formula, R is lower alkoxy; A is the formula (wherein R2 is hydrogen, lower alkoxy, and phenoxy (
(lower) alkoxy group; R3 and R4 are arbitrarily selected from hydrogen and lower alkoxy groups, and one of R2, R3 and R4 is a group other than hydrogen) The term "lower" used herein to modify alkyl, alkoxy, etc. includes monovalent fatty acid hydrocarbon groups having 1 to 6 carbon atoms, and the term "halogen" refers to chlorine. , bromine, iodine and fluorine.

Intraperitoneal administration of each of the compounds disclosed herein to sensitized rats alleviates allergic symptoms. Several of the compounds tested were found to be effective anti-allergic agents when administered orally to sensitized animals. The method used to examine the anti-allergic activity of the compound was based on immunology (ImmunolOg).
y), vol. 16, pp. 749-760 (1969), which was reported in the four-tailed male rat (Charie
A control group, a group administered with a standard anti-allergy compound (disodium cromoglylate), and a group administered with a test compound were used. The rats were injected with serum from rats immunized with albumin and pertussis vaccine, and 24 hours after this injection, the test compound was administered at 1 Kp of body weight.
Administer intraperitoneally or orally at a dose of 200a/day.
5 minutes later, 1! nl! 0.5% Evans blue dye solution and 8 ml of egg albumin are injected intravenously.

After 40 minutes, the rats are sacrificed and the size of the phlegm on their backs is measured.

The average size of the pouches of the rats administered with the test compound is calculated and compared with that of the control group to determine the percent inhibition. 2001 n1 per 1 Kp of body weight of the representative compounds.
Tested at doses significantly lower than 1, this compound was tested at doses significantly lower than 3
It was found that it is active at a concentration of Soko/Kf. Although the mechanism of action of the compounds of the present invention is not completely understood, the inventors believe that the compounds have an effect that inhibits the production and release of mediacetate in mast cells, which is believed to be similar to the effect of INTAL. I found out something. This compound allows non-productive antigen-antibody interactions to occur, effectively blocking IgE-type reactions, and having little effect on other immunoglobulins such as IgG, IgM, IgA and IgD.

The compounds of the present invention differ in pharmacological action from known anti-allergic agents.

Known anti-allergic drugs have no antihypertensive activity (no cardiovascular effect, etc.), no analgesic activity, no central nervous system activity, no immunosuppressive activity, no activity against histamine, serotonin, bradykinin, etc., and no endocrinological activity. . Overall, the compounds of the present invention typically exhibit antigen-antibody responses as exemplified in passive cutaneous anaphylaxis assays (PCA) using rat allogeneic cytotoxic antibodies with known correlations with human reactant antibodies. Prevents the release of Medieta from occurring.

Due to its similarity to disodium cromogliate and its activity correlated with standard test animals, livestock and humans, the compounds of the present invention can be administered at the same dosage as INTAL.
It has been demonstrated that they are suitable anti-allergic agents for administration by the same route, and several compounds of the present invention have been found to be effective anti-allergic agents by oral administration.

Thus, the present invention provides methods for administering locally, intraperitoneally, intramuscularly, or intravenously an effective amount of one or more of the compounds to humans, mice, rats, hamsters, carnivores, dogs, cats, sheep, etc. The present invention provides a method for suppressing allergic symptoms of atopic direct sensitivities in domestic animals such as goats, horses, and cattle.

Since the compound does not have the same pharmacological response or antagonistic effect as common anti-allergic agents, it is not suitable for use with known antihistamines, antihypertensives, analgesics, central nervous system analgesics, immunosuppressants, and antiserotonin agents. , can be administered in combination with anti-bradykinin agents or endocrine-reactive agents. Furthermore, the anti-allergy agent of the present invention can be combined with a conventional auxiliary liquid known in the art to form a composition or solution for administration, but for purposes other than forming a suitable pharmaceutical solution or liquid or gas suspension. It is desirable and appropriate to use the compound as it is or as a pure compound without using any additives. The effective dosage range in test animals is from about 1.5 kp/Kp to 1 kp by i.p.
57!1fi that can achieve 00% allergic reaction prevention
/ weight up to 1Kf.

Oral administration ranges from approximately 1.5 W//Kf to 200 mfi/1K body weight, which can achieve 90% prevention of allergic reactions.
up to f. For inhalation, the dose of INTAL (approximately 2 times) up to 1/20 of the above dose. If this dose is applied to Iruma, the dose of the compound will be approximately 10
0 to 19, preferably 250mfi to about 750WI/
It is in unit dose form and, if necessary, can be taken in one or more divided doses under the guidance of a physician, depending on the degree of desired reaction. It was found that the compound was not toxic to mice, which are the standard laboratory animals for toxicity studies, at any dosage below 29 and above 29 Kf/Kf body weight.

No toxicity was observed in other standard laboratory animals. The anti-allergic agent of the present invention does not exhibit side effects such as depression, dizziness, depression, etc. unlike other general anti-allergic agents.
The above novel aromatic oxamic acid derivative has the formula: ANH2 [
In the formula, A is the formula (wherein R1 is hydroxy, lower alkoxy or amino group; R2 is hydrogen, lower alkoxy, halogen or phenoxy (lower) alkoxy group; R3 is hydrogen, lower alkoxy, halogen or nitro group R4 is hydrogen or a lower alkoxy group, and one of R2, R3 and R4 is a group other than hydrogen)] Prepared by coupling an amine represented by the following with an appropriate substituted oxalic acid derivative or its precursor. do.

It is appropriate to use methods for preparing peptides by mixed anhydride dehydration coupling or azide coupling methods, preferably by preparing a suitable substituted oxalyl chloride at room temperature in the presence of an acid acceptor such as pyridine. use

By using substituted oxalyl chloride, the reaction proceeds as follows: [wherein R5 means lower alkyl or cycloalkyl] The free amine ANH, and the oxalic acid derivative are reacted by a mixed anhydride and dehydration coupling method. The method was developed by T. Wieland and H. Determan.
lland and H Jeterman. Angew. Ch
-Em. International Edition, 1963, pp. 358-370).

Thus, α-monovinyl ethyl ether, α,α-dichloroethyl ethyl ether, dichloromethyl methyl ether, N,N-dimethyliminoformyl chloride, carbodiimide, cyanamide, N-ethyl-5-phenylisoxazolium -3'-sulfonate, diphenylphosphoryl chloride, phosphorus pentoxide, 4-ethyl pyrophosphite, bis-0-phenylene pyrophosphite, diethylethylene pyrophosphite, p-imidazolyl ethylene phosphite, N, Coupling of N'-carbonyldiimidazole, N,N'-carbonylrubis-1,2,4-triazole, pyrocarboxylic acid diethyl ester, cyanuryl chloride, chloroformic acid ethyl ester, chloroformic acid isobutyl ester, diphenyl ketene, ε-saccharin chloride, etc. Free acid HO2CCO2R5 and amine ANH using agent
2 to react. Similarly, the amine ANH2 was converted to CtC
Reacts with OCH=CHCOCt to form ANHCOCH:CH
CONHA is obtained, treated with ozone, and then oxidized with hydrogen peroxide to yield ANHCOCO2H, which is easily converted to the desired ester by reaction with alcohol in the presence of an acid catalyst.

Furthermore, the amine ANH2 is an acetal (CtCOCH(C
OR5)2) or orthoester (CtcOc(0R5
) readily reacts with 3) to give an amide, which is converted to the aldehyde ANHCOCHO or the acid ANHCOCO2H, respectively, acidified to oxidize the aldehyde to the acid and esterified with the desired alcohol. Furthermore, oxalyl dichloride (
CtcOcOct) easily reacts with the amine ANH2 to form A
NHCOCOCt is produced which is reacted with the desired alcohol to give the compound of the invention. Other methods for producing the novel compounds of the present invention include the azide coupling method, which proceeds as follows: Also, the diazo salt method proceeds as follows:
There is also an active ester method in which the active group Z of the compound R5O2CCOZ is replaced by the amine ANH2.

This active group is cyanomethoxy, p-nitrophenoxy,
p-methylsulfonylphenoxy, 2,4,6-trichlorophenoxy, thiophenoxy, vinyloxy, phthalimidoxy and the like. Furthermore, active phenyl groups containing electron-withdrawing groups such as -CONH2 and easily leaving groups such as chloro groups and salts of NH2COCO2R5 (NaNHCO
The desired compound is obtained by coupling with CO2R5).

Insertion of the amine via oxime formation and Beckmann rearrangement follows the formula: NOH Similarly, the easily oxidized and rearranged ketoimine ketone A
NHCOCOR5 is oxidized with hypohalous acid (NaOBr) to give an acid, which is esterified with a suitable alcohol R5OH to yield the desired compound.

Furthermore, as another method for producing the novel compound of the present invention, an intermediate periodoglycol cleavage compound of the formula type prepared by the reaction represented by the formula is oxidized,
It also includes a method of esterification, and similarly includes a method of esterifying the formula: [wherein R6
means -0RNH2 or lower alkoxy] to obtain the desired compound.

The preparation of each of the compounds is detailed in the Examples below or appropriate references are provided.

The following examples are published in Chemical Abstracts (C.A., hereinafter the same), Journal of General Chemistry (
Russia, Zh. Obshch. Khim, hereinafter the same),
Rec. Tra. Chim.
, HeilbrOn Dictionary of Organic Compounds, Ber.Deut.Chem., Journal of Organic Chemistry (J.Org.Chem., same below) ), Journal of the American Chemical Society (J
．． A. C. S. , hereinafter the same) and Farmaco Scientifica Edition (Italy, FarmacO
．． Ed. Sci. , hereinafter the same). In the examples, the next number for the listed compound is 2007n per 1Kf of body weight.
Intraperitoneal/oral activity data at doses of f1, which represent the percent inhibition of the average size of the phlegm when the indicated compound was administered to sensitized rats according to the test method described above. .

Oral activity data are based on the average size of the test animals' collapses.
It is added only to compounds that show inhibition of 0% or more. Reference example 1 (2-pyrimidyl)oxamidic acid ethyl ester 8
22.85f! (0.03 mol) of 2-aminopyrimidine in 100 ml of dichloromethane with 3.7! ! Ll(
0.033 mol) of oxalylethyl chloride and 4.83 m
1 (0.06 mol) of pyridine at 10° C. with stirring to obtain the title compound 2.069.

Melting point of crystallized from ethanol: 96-99°C o Elemental analysis, calculated value as C8H, N3O3; C, 49.
23; H, 4.65; N, 2l. 53, Actual value: C, 4
9. O5:H, 4.68; N, 2l. 57 Example 12
'1-carbamoyl-3'-methoxyoxanilic acid ethyl ester 100/94 In the same manner as in Reference Example 1 above, 8.759 (0.0527 mol) of 6-amino-0
- Condensation of anisamide with 6.2a (0.0554 mol) of oxalylethyl chloride gives the title compound 8.359.

Melting point of crystallized from ethanol: 170-173℃
o Elemental analysis, calculated value as Cl2Hl4N2O5: C
, 54, l3; H, 5.3O; N, lO. 52, actual value: C, 54. 36: H, 5.2O; N, lO. 66 Example 22'-1-carboxy-3'-methoxyoxanilic acid ethyl ester 54 In the same manner as in Reference Example 1 above, 1,6719 (0.01 mol) of 6-amino-0-anisic acid was added to 1. Condensation of 23a (0.011 mol) with oxalylethyl chloride gives the title compound 1f1.

Melting point of crystallized from ethanol: 142-144℃
. Elemental analysis, calculated value as Cl2Hl3NO6: C,
53.93:H, 4.9O:N, 5.24, actual value: C
, 54.2l; H, 4.99; N, 5.32 Reference Example 2 2'-cyano-3'-methoxyoxanilic acid ethyl ester 80/71 In the same manner as in Reference Example 1 above, 4
．． 679 (0.0315 mol) of 2-amino-6-methoxybenzonitrile and 3.88! ! Le(0.0346
molar) of oxalylethyl chloride to give 5.09 of the title compound.

Crystallized from toluene, melting point 142-145°C.
Elemental analysis, calculated value as Cl2Hl2N2O4: C,
58. O6; H, 4.87; N, ll. 29, Actual measurement value:
C, 58.2l; H, 4.93; N, ll. O2 Example 3 2'-carbamoyl-3'-chlorooxanilic acid ethyl ester 25 4. In the same manner as in Reference Example 1 above.
269 (0.025 mol) of 2-amino-6-chlorobenzamide and 3.11n1 (0.0275 mono(ha)) of oxalylethyl chloride are condensed to give 5.28f! of the title compound.

Melting point of crystallized from ethanol: 190-193℃
. Elemental analysis, C, Hl, CtN2O4, calculated value: C, 48.8; H, 4. lO; N, lO. 35. Actual value: C, 49. O8; H, 4. O5; N, lO. Example 72 1-ethyl 2'-methyl 1-carboxy-3'-methoxyoxanilate 2'-methyl ester 3.629 (0.02 mol) of methyl 6-methoxyanthranilate was prepared in the same manner as in Reference Example 1 above. And 2.46! ILI! (0.
022 mol) of oxalylethyl chloride are condensed to form 3.5
The title compound No. 19 is obtained.

Crystallized from ethanol, melting point 96-99°C. Elemental analysis, C,,H,,calculated value as NO6: C,55
．． 5l; H, 5.38; N, 4.98, actual value: C, 5
5.56; H, 5.43; N, 5. l8 Example 5 2'-Carbamoyl-3'-(2-phenoxyethoxy)oxanilic acid ethyl ester 4,15a (
0.033 mol) of 2-phenoxyethanol was added,
After about 20 minutes a mixture of solid salts of alcohol is obtained.

This mixture is added to a solution of 5.89 (0.030 mol) of 2,6-dinitrobenzonitrile in 20!111 dimethyl sulfoxide at 30-40°C and the resulting purple solution is stirred overnight at room temperature. . The solvent is removed on a rotary evaporator at 70° C. and the residue is triturated with water. The solids are separated and dissolved in ethyl acetate. This ethyl acetate solution is washed twice with water and acupuncture water, and dried with calcium sulfate. Evaporate the ethyl acetate and add 8.59 2-
Nitro-6-(2-phenoxyethoxy)benzonitrile is obtained. 6f1 crystallized from 200a of ethanol
Obtain the crystals.

Crystals of 2-nitro-6-(2-phenoxyethoxy)benzonitrile having a melting point of 129-137.5°C and 5.829 (0.0205 mol) were dissolved in 116a of absolute ethanol at 5.829 (0.0205 mol).
Stir at 0C, 3.62! nl (0.0615 mol)
of 85% hydrazine hydrate and then a small amount of Raney nickel.

While adding Raney nickel, the temperature is maintained at 50 to 60°C, and after gas generation and heat generation have stopped, the mixture is filtered through diatomaceous earth. Wash the cake with hot ethanol and concentrate the bottom solution to obtain 2.8049 2-amino-6-(2-phenoxyethoxy)benzamide. Melting point 127-130
℃. Elemental analysis, C, 5Hl6N2O3, calculated value:
C, 66. l6; H, 5.92; N, lO. 29, Actual value: C, 66.7l; H, 6.36; N, lO. l3 In the same manner as in Reference Example 1, 2.89 (0.010
3 mol) of 2-amino-6-(2-phenoxyethoxy)benzamide is condensed with 1.26a (0.0113 mol) of oxalylethyl chloride to give the title compound 1.621. Melting point of crystallized from ethanol: 142~
145℃. Elemental analysis, Cl, H2ON2O6, calculated value: C, 6l. 28; H, 5.4 "; ° N, 7.52
, Actual value: C, 6l. l4; H, 5.57: N, 7.5
O Example 6 2'-carbamoyl-3'-methoxyoxanilic acid methyl ester 96 In the same manner as in Reference Example 1 above, 4
．． 989 (0.03 mol) of 6-amino-0-anisamide is 3.04! Condensation with nl (0.033 mol) of oxalylmethyl chloride yields 4.24f! The title compound is obtained.

Melting point of crystallized from methanol: 195-198℃
. Elemental analysis, C,,H,2N2O5, calculated value: C
, 52.38; H, 4.8O; N, ll. ll, actual value: C, 52.3O; H, 4.94; N, ll. 4O Example 72'-Carbamoyl-3'-methoxyoxanilic acid n-propyl ester 96 In the same manner as in Reference Example 1 above, 4.98f! 1 (0.03 mol) of 6-amino-0-anisamide.

Condensation with 25a (0.033 mol) of oxalyl n-propyl chloride gives 4.81 g of the title compound.

Melting point of crystallized product from acetonitrile: 158-16
Elemental analysis at 1°C, calculated values as Cl3H, 6N2O5: C, 55.7l; H, 5.75: N, lO. OO, actual value: C, 55.92; H, 5.93; N, lO. 34
Example 8 2'-carbamoyl-3'-methoxyoxanilic acid 1-
Propyl ester 57 In the same manner as in Reference Example 1, 4.989 (0.03 mono(c)) of 6-amino-0
- Anisamide is condensed with 4.25 ml (0.033 mol) of oxalyl i-propyl chloride to give 4.74 f1 of the title compound.

Crystallized from benzene, melting point 128-132°C.
Elemental analysis, Cl3H, 6N2O5, calculated value: C,
55.7l; H, 5.75; N, lO. OO, actual measurement value:
C, 55.66; H, 5.93: N, lO. 38 Reference example 32'-carbamoyl-3'-methoxyoxanilic acid 4850! Stir 1.339 (0.005 mol) of 2'-carbamoyl-3'-methoxyoxanilic acid ethyl ester in water of ILe and add 5.0a of 1N NaOH.
Add to make a solution.

After 0.5 hours, the solution is filtered and the effluent is acidified to pH 2 with 1N HCI to give the title compound, 0.719.

Melting point of crystallized from ethanol: 214-215℃
. Elemental analysis, calculated value as ClOHlOO5N2: C
,5O. 42; H, 4.23; N, ll. 76, actual value: C, 5O. 6.0; H, 4.35; N, ll. 8 Reference Example 4 N-(2-carbamoyl-3-methoxyphenyl)oxamide 265.09 (0.0188 mol) of 2'-carbamoyl-3'-methoxyoxanilic acid ethyl ester was added to 50 ml of N-(2-carbamoyl-3-methoxyphenyl)oxamide at 0 to 5°C. Ammonia is added to saturated ethanol, and the mixture is stirred in an ice bath for 2 hours, then filtered.

Wash the cake with ethanol to obtain 1.419 of the title compound. Melting point of crystallized from water: 252-255℃
. Elemental analysis, calculated value as ClOHllN3O4: C
,5O. 63; H, 4.67; N, l7.72, actual value: C, 5O. 45; H, 4.7O; N, 17.65 Example 9 2'-1-carboxy-4'-methoxyoxanilic acid ethyl ester 61 In the same manner as in Reference Example 1 above, 1.
679 (0.01 mol) of 5-methoxyanthranilic acid is condensed with 1.23 ml (0.011 mol) of oxalylethyl chloride to give 1.329 of the title compound.

Melting point of crystallized from ethanol: 238-243℃
o Elemental analysis, calculated value as Cl2Hl3NO6; C,
53.93; H, 4.9O; N, 5.24, actual value; C
,53.99;H,4.93:N,4.99Example 1
0 2'-carbamoyl-4'-chlorooxanilic acid ethyl ester 58 3. In the same manner as in Reference Example 1 above.
41f! (0.02 mol) of 2-amino-5-chlorobenzamide is condensed with 2.46 ml (0.022 mol) of oxalylethyl chloride to give 4.579 of the title compound.

Crystallized from acetonitrile, melting point 204-210
℃. Elemental analysis. Calculated value for Cl, HllctN2O4: C, 48.8; H, 4. lO; N, lO. 35;C
t, l3. lO, actual value: C, 48.65: H, 3.9
8; N, lO. 26; Ct, l2.84 Example 112
'-Carbamoyl-4'-nitrooxanilic acid ethyl ester 59 5.4 in the same manner as in Reference Example 1 above.
39 (0.03 mol) of 2-amino-5-nitrobenzamide are condensed with 3.7 ml (0.033 mol) of oxalylethyl chloride to give 6.549 of the title compound.

Melting point of crystallized from ethanol: 206-209℃
o Elemental analysis, C, lHllN3O6, calculated value: C
, 46.98; H, 3.94; N, 14.94, actual value: C, 46.68; H, 3.96; N, 15. 12 Example 122'Monocarbamoyl-5'-methoxyoxanilic acid ethyl ester 91 In the same manner as in Example 6 above, 2-nitro-4-methoxybenzonitrile of 12,89 was reduced, and 2-nitro-4-methoxybenzonitrile of 9,09 was reduced. 2-amino-p-anisamide is obtained.

Melting point 152-156°C when crystallized from water. Elemental analysis, calculated value as C8HlON2O2: C, 57.8
2; H, 6. O7; N, l6.86, actual value: C, 58
．． 6O; H, 5.76: N, l 6.65 In the same manner as in Reference Example 1 above, 4.99 g (0.03 mol) of 2
-Amino-p-anisamide at 3.68" (0.0
33 mol) of oxalylethyl chloride to give 3.84
The title compound of g is obtained.

Melting point of crystallized from ethanol: 186-188℃
.

Elemental analysis, C, 2H, 4N2O, calculated value: C,
54. l3: H, 5.34; N, lO. 52, Actual value;
C, 54.29; H, 5.5O; N, lO. 89 Examples 13. 2'-1-carboxy-4'-methoxyoxanilic acid 1-ethyl 2'-methyl ester 58 4.7 g (0.0283 mol) of 6-amino-m-anisic acid was prepared in the same manner as in Reference Example 1 above. The methyl ester was added to 3.48" (0.
0311 mol) of oxalylethyl chloride,5.
27 g of the title compound are obtained.

Melting point of crystallized from ethanol: 129-133℃
. Elemental analysis, C,, Calculated value as HlSNO6: C,
55.5l; H, 5.38; N, 4.98, actual value: C
,55.72;H,5.38:N5.37Example 14 2'-monocarbamoyl-3'-methoxyoxanilic acid cyclohexyl ester 916-amino-o
- Condensation of anisamide with oxalylcyclohexyl chloride to give the title compound.

Melting point 166-169°C.

Elemental analysis, C, 6H2ON2O, calculated value: C,
59.99: H, 6.29; N, 8.75, actual value: C
, 6O. l7; H, 6.33; N, 8.69 Example 1
5 2'-Carbamoyl-3'-methoxyoxanilic acid butyl ester 986-Amino-o-anisamide is condensed with oxalyl n-butyl chloride to give the title compound.

Melting point 126-129°C.

Elemental analysis, C, 4H, 8N2O, calculated value: C,
57. l3:H, 6. l7; N, 9.52, actual value:
C, 57.43:H, 6.46:N, 9.38 Examples
16 2'-carbamoyl-3'-methoxyoxanilic acid Sec-butyl ester 100/706-amino-
Condensation of o-anisamide with oxalyl Sec-butyl chloride gives the title compound.

Melting point: 119-122°C.

Elemental analysis, Cl4Hl8N2O, calculated value: C,
57. l3; H, 6. l7; N, 9.52, actual value: C
, 56.94; H, 6.44; N, 9.5O Example
17 2'-1carbamoyl-3'-1ethoxyoxanilic acid ethyl ester 802-Amino-6-ethoxybenzoic acid amide is condensed with oxalylethyl chloride to give the title compound.

Melting point 142-145°C o Example 18 2'-Carbamoyl-3'-propoxyoxanilic acid ethyl ester 522-Amino-6-propoxybenzoic acid amide is condensed with oxalylethyl chloride to obtain the title compound.

Melting point 130 DEG -133 DEG C. Example 19 2'-carbamoyl-3'-i-propoxyoxanilic acid ethyl ester 602-Amino-6-i-propoxybenzoic acid amide is condensed with oxalylethyl chloride to give the title compound.

Melting point 123-125°C. Example 20 2'-carbamoyl-3'-n-butoxyoxanilic acid ethyl ester 752-amino-6-n-
Condensation of butoxybenzoic acid amide with oxalylethyl chloride provides the title compound.

Claims (1)

[Claims] 1 Formula ANH_2 [In the formula, A is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is hydroxy, lower alkoxy, or amino group; R^2 is hydrogen, lower alkoxy , halogen or phenoxy (lower) alkoxy group; R^3 is hydrogen, lower alkoxy, halogen or nitro group; R^4 means hydrogen or lower alkoxy group; R^2, R^3 and R^4
one of which means a group other than hydrogen)] and an amine of the formula ZCOX [wherein Z is a halogen; ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R ^2, R^3 and R^
4 has the same meaning as above; R means lower alkoxy or cycloalkyloxy] A method for producing a novel oxamic acid derivative.