DE2413966A1 - OXAMIC ACID DERIVATIVES - Google Patents

Description

PATENTANWÄLTE O / 1 Q Q R R

PROF. DR. DR. J. REITSTÖTTER ZH 103QO

DR.-ING. WOUFRAM BUNTE DR. WERNER KINZEBACH

D-SOOO MUNICH 4O, BAUERSTRASSE 22 · FERNRUF (Οββ) 37 68 β3 ■ TELEX B2J52O8 ISAR D POSTAL ADDRESS! D-βΟΟΟ MUNICH 43. POST BOX 7BO

Munich, March 22, 1974 M / 15092

AMERICAN.HOME PRODUCTS CORPORATION 685 Third Avenue, New York, New York 10017, U.S.A.

Oxamic acid derivatives

Atopic acute sensitivity is in living things that are at Asthma,. Hay fever, allergic rhinitis, urticaria and the like are the main symptom. The substances that are on Plant pollen, and animal feathers are most commonly responsible for clinical hypersensitivity symptoms Dandruff, dust, milk and wheat, whether inhaled or consumed.

Atopic hypersensitivity occurs in humans, in dogs and in other animals. Your appearance will also be exceptional found in the lower animals.

The presence of antibodies in the serum related to de! Atopic reaction can be shown by the passive sensitization of the skin of normal recipients after injection of j

409839/1070

Serum from a sensitizing host in one area of skin and the next Injection of an antigen into the same site 24 hours later, which causes a local rash. this is generally referred to as the Prausnitz-Kustner (P-K) reaction.

The antibody, which is associated with atopic hypersensitivity, has characteristic features insofar as it does not form precipitates with its antigen in all cases, does not pass from the placenta to the fetus, has a special affinity for the skin, and often has no specific activity against a specific antigen has in a sensitized with a variety of factors individual antigen and is usually labile at about 56 ⁰ C after two hours.

The homocytotropic antibody found or elicited in the rat is both in function and in reaction Related to immunoglobulin E (reagin or IgE) found in humans. The agreement between homocytotropic ι Antibodies in rats and IgE in humans is through The same general effects have been proven to be those in chemical reactions, and immunological reactions Drug responses have been obtained in the two species exhibiting these antibodies. In humans there is reagin the antibody responsible for acute atopic hypersensitivity reactions. In the rat it is homocytotropic Antibodies responsible for acute atopic hypersensitivity reactions.

Theoretically, reagin affects the cell membrane of a mast cell by reacting with an antigen and the reaction (s) within initiates the mast cell, which eventually becomes a mediator, such as bradykinin, SRS-A (slow reacting substance A), histamine and other unknowns Releases substances. The mediator causes a change in the

409839/1070

Permeability of the surrounding cell wall and allows a rapid change in flow or secretion of metiator (s) out of the cells, resulting in a symptom of an allergic attack. The various procedures that are general can be used to relieve symptoms of an allergic attack and none of which are considered entirely satisfactory is considered are: (1) the avoidance of a seizure by j the antigen, (2) the blocking of the formation of antibodies j j with an immunosuppressant, (3) blocking the mediators j on the affected cell by the administration of anti-I histaminica, anti-5-hydroxy-tryptamine (5HT) or anti-I inflammatory agents, or (4) stimulating the loading ■ covered cell to the effect of the mediator by the action of j bronchodilatory agents, such as isoprel or a xanthine, ι to suppress.

! The only compound known so far that ϊ works by blocking the reaction (s) within the mast

: cells, which enables them to produce and release j mediators prevent, anti-allergic effect, is disodium-I cromoglycat (INTAL '^').

: Oxamic acid derivatives are so far used as intermediates for

; Polymer formation and as an aid to chemical research

; been used. Any known oxamic acid derivative that

: is used for the new use according to the invention,

j is indicated in the following examples with a literature

I provide a notice.

^! According to the invention a method for suppressing

i created allergic symptoms in warm-blooded animals, according to

• to give an effective amount of a to a sensitive living being

! Compound of the formula administered

ο γ

t! Il

ANHC - C - B

A is selected from 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, a-naphthyl, ß-naphthyl, Phenyl and substituted phenyl radicals with 1 to 3 substituents, which are independently selected from Lower alkyl, lower alkoxy, halogen, sulfamyl, polyhalo lower alkyl, Carbamyl, nitro, phenylazo, carboxy, cyano, carbloweralkoxy, phenoxyloweralkoxy, lower alkoxyoxalamido and lower alkoxyoxalamidophenoxy radicals,

B alone the meanings -OH, lower alkoxy, -NHp, cyclohexyloxy and phenoxy has and

Y is oxygen and, together with B and the carbon atom to which they are attached, the remainder

N-NH

'■■ means.

; According to a preferred embodiment of the invention

! Method is administered to a sensitized animal

j Compound that, in a minimal dose, reduces the allergic

■ 'reaction suppressed, so that the characteristic wheal

j increases the size of sensitized skin tissue by 75% or more

is reduced, these compounds having the following formula

409839/1070

ο γ

Il Il

AKHC - CB

A is a 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, a-naphthyl, ß-naphthyl, phenyl or substituted phenyl radical, the 1 to • Has substituents that independently of one another are low

'alykl, fluorine, lower alkoxy, carbamyl, carblower alkoxy, Trifluoromethyl, nitro, lower alkoxyoxalamido and Can be phenoxy-lower alkoxy radicals,

B alone means lower alkoxy and

Y alone denotes oxygen and together with B and the carbon atom to which they are attached, the remainder

N-NH

I.

N = N forms.

The new aromatic and heterocyclic oxamic acid derivatives are a further subject of the present invention. The aromatic oxamic acid derivatives have the formula

0 0

It H '

. ANHC -C-R

wherein

R is selected from -OH, lower alkoxy and amino radicals, and j

; A means 2-cyanophenyl, 3-fluorophenyl, 4-phenylazophenyl, 4-carbamylphenyl, 2-nitro-4-trifluoromethylphenyl, 2-cyano-3-methoxyphenyl, 4-nitro-3-trifluoromethy! Phenyl, 5-chloro-2-sulfamoylphenyl and

'owns what

R denotes a hydroxy, lower alkoxy and amino radical,

• 2 ''

R is hydrogen, lower alkoxy, halogen or phenoxy-lower alkoxy,

R is hydrogen, lower alkoxy halogen or nitro and

R is hydrogen or lower alkoxy, however

2 3 4 The prerequisite is that one of the radicals R, R and R is not hydrogen.

Aromatic oxamic acid derivatives preferred according to the invention are those new compounds which reduce the wheal and halo appearances in the tissue of a sensitive animal by 75 % or more of the allergic reaction. These compounds have the following structural formula:

0 0

ti Il

ANHC - C - 'R

i
where - 6 -

R means lower alkyl -and

A 'the meanings 3-fluorophenyl, 2-cyano-3-methoxyphenyl,' 4-nitro-3-trifluoromethylphenyl, 5-chloro-2-sulfamoylphenyl

Ii ² COMI ₀ - I

owns what

• 2 i

, R is hydrogen, a lower alkoxy or phenoxy-lower alkoxy,

rest means, and,

¹ · '■ ■ * ■ ί

3 4 · '

• R and R- independently; hydrogen or lower alkoxy-; can mean residues, but this is a prerequisite. that i

: · 2 3 4 οι ι

one of the radicals R, R and R is not hydrogen. ,

I i The invention.-According to new 'heterocyclic oxamic acid derivativeQ

have the formula I.

: oo I

I ANHC - C - R

; wherein

, A has the meanings 3-pyridyl, 2-pyridyl, if R does not

Ethoxy means 4-pyridyl, 2-pyrazinyl and 2-pyrimidinyl
; owns and

' R means lower alkoxy.

4098397Yo'7U

j When describing the present invention in combination

Term used with alkyl, alkoxy and the like ι "Low" includes monovalent aliphatic hydrocarbon

■ residues with 1 to 6 carbon atoms. The one in the description The term "halogen" as used in the present invention includes Chlorine, bromine, iodine and fluorine.

Each of the compounds of the invention relieves allergic symptoms when intraperitoneally abreicht comparable ^one sensitized rats. Several of the tested compounds ^has been found that they are effective anti-allergic agents, when they are orally administered to sensitized animals.

j That to determine the antiallergic effect of the invention! The method used according to the compounds is described in Immunology, Vol. 16, pages 749-760 (1969). One uses ι 4 male Charles River rats (with 200 to 250 g body weight) per control group, one recipient for the administration; Submission of a standard antiallergic compound (disodium, cromoglycate) and animals for the test compound. The rats are injected intracutaneously on their shaved backs with serum from rats which have been immunized with egg albumin and pertussis vaccine. 24 hours after the first injections, the test compound is administered intraperitoneally or orally in a dosage of 200 mg per kg of body weight. 5 minutes later you inject

■ 1 ml of a 0.5% solution of Evans blue dye [and 8 mg of egg albumin intravenously. After 40 minutes the animal is sacrificed ^; and you measure the size of the vesicles on his back. The mean vesicle size in the animals exposed to the test compound! is calculated and the percentage of inhibition is determined in comparison with the control animal.

I A representative number of the compounds were found in dosage ranges well below 200 mg per kg of body

- 8 4 0 9 8 3 9/107 «

j weight tested to determine the activity of the compounds

'Minimum concentrations of only 3 mg per kg of body weight

; to determine.

! Equal to the functional mechanism of the invention
Connections is not yet fully known, it has been
found that the compounds of the invention, presumably
in a similar way to ΙΝΤΑΐΛ-% the reaction (s) in the
Block mast cells that lead to their production and release
lead by mediators.

The compounds of the invention enable this to occur
a non-productive antigen-antibody reaction. she
effectively block the IgE response and have little or
no effect on the other immunoglobulins such as IgG, IgM,
IgA and IgD. ■

Compounds according to the invention do not have a pharmacological response which is similar to that of the known antiallergic agents, since they do not have an anti-hypertensive effect. (no cardiovascular effect, etc.), no analgotic ] effect, no effect on the central nervous system, no j

immunosuppressive effect, no effect against histamines, i serotonin, bradykinin etc. and no endocrinological effects
Have an effect.

The compounds according to the invention block the release!

of mediators, generally resulting from the reaction of j

i antigen with antibody result, as in a passive cutancn

Anaphylaxis attempt (PCA) using homocytotropic
Rat antibody known to be related to human reagent antibody is shown.

409839 /. 1G7U

Because of the analogy to disodium cromoglycate and the Effective correlation between standard test animals, Domestic animals and humans, the compounds according to the invention have proven to be antiallergic agents that are useful for same purposes with analog dosing and the same Administration like ΙΝΤΑΙλ ^ are suitable. Several of the he j inventive compounds have proven themselves when administered orally proven to be effective antiallergic agents. The orally active compounds are the lower alkyl pyridyloxamates (Methyl-, ethyl- and propyl-2-pyridyloxamate, ethyl-4-pyridyloxamate, Ethyl 3-pyridyl oxamate), the lower alkyl pyrazinyloxamates (Ethyl 2-pyrazinyloxamate), methyl-, ethyl- and i-propyloxanilate, 1H-tetrazole-5-carboxanilide, ethyl 3'-methyloxanilate, Ethyl 4'-methoxyanilate, ethyl 2'-carbamoyl-3'-methoxyoxanilate, Ethyl 4'-nitro-3 '- (trifluoromethyl) oxanilate and ethyl 1-naphthyloxamate.

According to the invention, there is thus a method for suppression allergic symptoms of acute atopic sensitivity in humans and in warm-blooded animals, with the latter also Pets, such as mouse, rat, hamster, gerbil, dog, cat, sheep, goat, horse, cow and the like count, created, by adding an effective amount of one or more of the compounds according to the invention orally, topically, intraperitoneally, administered intramuscularly or intravenously. Since the Compounds no pharmacological mode of action which is similar to or antagonistic to conventional antiallergic drugs, they can together j with known compounds, the antihistamine, antihypertensive, anaigetisehe, the central nervous system calming, immune! reactions suppressing, antiserotonin, antibradykinin ι or cause endocrinological reactions. In addition, these are conventional to those skilled in the art known auxiliaries with the anti-

- 10 -

allergica can be combined, with means and solutions

j for administration, although it is desirable and

j would be possible the antiallergica as pure compounds

'without using any additives other than those used for

Creation of suitable pharmaceutical solutions or liquid

! or steam suspensions are necessary.

! The effective dosage range in experimental animals is approximately j 1.5 mg per kg up to a dosage that ensures 100%

j prevent an allergic reaction, namely 5 mg per kg Body weight when given intraperitoneally. The oral dosage range is from about 1.5 mg / kg up to 90% j Prevention of allergic reactions at 200 mg / kg body weight. In the form of an inhalant, the corresponds to Dose that of Intal ^, (about 2. mg) to 1/20 of this amount, as needed before the attack. Thus, based on the strength of the compounds administered, the dosage in humans will be i • between about 100 mg and Γ g, preferably between 250 mg and about, 750 mg in unit dosage form, to be taken in one as necessary and according to the degree of effect desired given single or in divided doses under the guidance of a doctor.

The compounds according to the invention are the standard test animals in mice for toxicity tests of this kind, not at any dose up to and including 2 g per kg body weight toxic. No toxic level is found in other conventional test animals. The antiallergic agents according to the invention seem to have side effects, the other Antiallergics like sedation, dizziness, depression, etc. have to be free.

! ■. - Ii -

4 0 9 8 3 9/1070

The novel aromatic and heterocyclic oxamic acid derivatives described above are prepared by coupling an amine of the formula ANH ₉ , wherein

el.

A is 3-pyridyl, 2-pyridyl, and if R is not ethoxy, 4-pyridyl, 2-pyrazinyl and 2-pyrimidinyl, 2-cyanophenyl, 3-fluorophenyl, 4-phenylazophenyl, 4-carbamylphenyl, 2-nitro-4-trifluoromethylphenyl, 2-cyano-3-methoxyphenyl, 4-nitro-3-trifluoromethylphenyl, 5-chloro-2-sulfamoylphenyl and

'in what
_w R denotes hydroxyl, lower alkoxy and amino radicals,

2
R is hydrogen, lower alkoxy, halogen or phenoxy lower

alkoxy means
R is hydrogen, lower alkoxy, halogen or nitro, and

4th
R denotes hydrogen and lower alkoxy, however

2. 6 4

The prerequisite is that one of the radicals R, R and R must not be hydrogen, represent

with an appropriately substituted oxalic acid derivative or a precursor thereof.

Thus, methods are applicable which are used in the preparation of peptides by dehydrogenative coupling of the mixed anhydride may be used, or azide coupling methods, though a suitably substituted oxalyl chloride is preferred in

- 12 409839 / 107Ο ~

I presence of an acid acceptor , such as pyridine, at ambient,

! temperature to use. i

I ■ ■ ■ ■ i

! If a substituted oxalyl chloride is used, |

j the reaction according to the following equation: = j

0 0 I.

base

ANH ₂ + ClC-C-OR

5
wherein R represents a group such as lower alkyl, cycloalkyl, aralkyl, etc., which is desired or easily converted into one of the desired functional groups around those designated R above.

j desired functional groups can be converted, J

j The processes for converting oxalic acid derivatives with the! free amine ANH ₂ using mixed anhydride and de-I 'hydrogenating coupling processes are from T. Willand and j _% . H "Determan, Angew. Chem. International Edition (1963) j pages 358 to 370 described ·. The amine ANH _Q reacts with the free acid HO ₂ CCO ₂ R ^ using coupling

reagents of the type a-Chlorvinyläthyläther, oc, α-Dichloräthy1-I ethyl ether, dichloromethyl methyl ether, the chloride of; Ν, Ν-dimethyl-iminoformylchloride, a carbodiimide, cyanamide,! N-ethyl-5-phenylisoxazolium-3 ^I -sulfonate, diphenylphosphoryl-

chloride, Phosphdrpentöxyd, Tetraäthylpyrophosphit, Bis-öj Phenylenpyrophosphit, · Diethyläthylenpyrophosphit, Äthylen-PI imidazolylphosphonit, NjN'-Cabonyldiimidazol, N, N ^f -Carbonyl-! bis-l, 2,4-triazole, diethyl pyrocarbonate, cyanuryl chloride,! Ethyl chloroformate, isobutyl chloroformate, diphenylketene,! Epsilon saccharin chloride and the like.

! Analogously, the amine ANH ₂ can be reacted with C1COCH = CHCOC1,

where see ANHCOCh = CHCONHA results, which after treatment with I ozone and subsequent oxidation with hydrogen peroxide j

- 13 40 98 33/1070

ANHCOCO "H gives" which can be easily converted to a desired ester "by reaction with an alcohol in the presence of an acid catalyst. Furthermore, the amine ANH ₂ easily reacts with an acetal (ClCOCH (COR ⁵ ) ₂ ) or an ortho ester (ClCOC (OR K) resulting in the amide which is converted into an aldehyde ANHCOCHO or an acid ANHCOCO ₂ H, after acidification, after which the aldehyde is oxidized to the acid and esterified with a desired alcohol. In addition, oxalyl dichloride reacts (ClCOCOCl) easily with the amine ANH ₂ , resulting in ANHCOCOCl, which reacts with the desired alcohol, resulting in the compounds according to the invention.

Other less desirable methods of making the novel compounds of the invention include the azide coupling method:

ANH ₂
. ". R ⁵ O ₂ CCON,>'ANHCOCO ₂ R ⁵ ,

the diazo salt process:

ANH ₂
[R ⁵ O ₂ CCO ⁺ N = N] Br "> ANHCOCO ₂ R ⁵ ,

and the activated ester process, in which an activating group Z in the compound RO ₂ CCOZ is replaced by the amine ANH ₂ . Such activating groups are cyanomethoxy, p-nitrophenoxy, p-methylsulfonylphenoxy, 2,4,6-trichlorophenoxy, thiophenoxy, vinyloxy, phthalimidoxy and the like.

In addition, an activated phenyl group, which contains an electron withdrawing group, such as -NO ₂ , -CONH ₂ , cyano, sulfamoyl and the like, and a good "leaving group", such as the chlorine group with a salt of NH COCO ₂ ^{R, couple}

_ 14 _
409839/1070

I γ-

J (NaNHCOCOpR), giving the desired products.

j amine insertions by oximation and Beckmann rearrangement ^! take place according to the scheme

I NOH

I -5 "5

I ACOCO ₂ R ^ ■ + NH ₂ OH - ^ AC-CO ₂ R ^

j Beckmann ANHCOCO ₂ R ⁵

I ANH ₂ +

ANi rcoc - cn - co., 11,

OCOCH ₁

- 15 409839/1070

ι An analogous process takes place via the ketimine AN =! CHCO ₂ R, which oxidizes easily and leads to the desired products

! is relocated.

I c

! , The ketone ANHCOCOR is produced by a hypohalide (NaOBr) j oxidized to the acid, which by a suitable alcohol

* ^ ■ ■ ♦

! ' R OH is diffused to give the desired esters.

j more. Processes for obtaining the new compounds described herein lead via oxidized esterified products

. periodate glycol cleavage of type j intermediates

'ι

Oh T

ANHCOCH - CH - CO H produced by the reaction

■ OH

■ CH..CO OCOCH- C1I "COO

^{M / 15092}

also the reaction

Jtb

rr ^ ^co 2 ^u °

NIICOCO ₂ R

wherein R is -OH, NH ₂ or lower alkoxy gives desired products.

This in the preparation of each of the specifically disclosed compounds The procedure used is in the examples below either in detail or by citing the appropriate Literature indicated, the latter being considered to be included in the description.

CA (Chemical Abstracts), Zh. Obshch. Khim (The Journal of General Chemistry, Russia)., Rec. Trav. Chim (Recueil des Traveau Chimiques des Pays-Bas-Netherlands), Heilbron (Dictionary of Organic Compounds), Ber. Deut. Chem. (Reports from the German Chemical Society),

J.Org. Chem. (Journal of Organic Chemistry), J.A.C.S. (Journal of the American Chemical Society) and Farmaco. Ed. May be. (Il Farmaco Scientifica Edition - Italy).

In the working examples, the number after the title compound denotes the intraperitoneal / oral activity values which are obtained at a dosage of 200 mg per kg of body weight. The activity data denote the inhibition in % of the average vesicle size of sensitized rats to which the named compound was administered according to the test procedure described above. The oral data are representative of those compounds.

- 16 409839/107 (J.

which show inhibition of 50 % or more of the total wheal size in the test animals.

The compounds according to the invention can be used in conventional pharmaceutical Use forms are administered in conjunction with conventional carriers and diluents. 2 examples for [■ Tablet formulations are given below:

(1) 50 mg of 2'-carbamoyl-3'-methoxyoxanilic acid ethyl ester j

86 mg sucrose!

15 mg gelatin '

7 mg acacia gum

3 mg magnesium stearate

To be administered 3 to 4 times a day,

j (2) 200 mg (l-naphthyl) -oxamic acid ethyl ester

j 124 mg sucrose,

j 40 mg gelatin. j

ί ■ 16 mg acacia gum

[13 mg of sorbitol

j 13 mg magnesium stearate

To be administered 3 to 4 times a day.

Lower alkyl pyridyloxamates, lower alkyl pyrazinyloxamates, 1H-tetrazole-5-carboxanilide and the compounds according to claim 60 are advantageously administered orally and the compounds according to claim 56 are more advantageous Way for making inhalants.

- 17 409839 / 107U

example 1

(2-Thiazolyl) -oxamic acid ethyl ester. 100

This connection is known from the literature: CA. : 60 (10591c). Zh. ObshchKhim., 34 (1), 28-32 (1964). It is crystallized from ethanol, F 174-177 ⁰ C.

example

Ethyl (2-pyridyl) oxamic acid ster. 100/9 5

This compound is known from the literature: P.A. Petyunin et al., Zh. Obshch. Khim., 32_, 1395-8 (1962). It is crystallized from diethyl ether, F 73 to 75 ° C.

Example 3

Ethyl (2-pyrimidyl) oxamate. '82

2.85 g (0.03 mol) of 2-aminopyrimidine is condensed with 3.7 ml (0.033 mol) Äthyloxalylchlorid in 100 ml of dichloromethane in the presence of 4.83 ml (0.06 mol) of pyridine at 10 ⁰ C under stirring, 2.06 g of the desired compound are obtained, F 96 to 99 ° C, after having crystallized from ethanol.

Analysis C

calculated: found:

- 18 -

C. 23 H 65 N 53 49, 05 4, 68 21 57 49, 4, 21

409839/107 Π

Example 4 (4-Pyridyl) -oxamic acid ethyl ester. 100

2.82 g (0.03 mol) of 4-aminopyridine are condensed with 3.7 ml (0.033 mol) of ethyloxalyl chloride, similar to Example 3, whereby, after crystallization from diethyl ether, 1.2.6 g of the desired compound are obtained, F. 100 to 113 ⁰ C.

j Analysis C ₉ H ₁₀ N ₂ O ₃

! CHN

calculated: 55.66 5.19 14.43%

found: 55.88 5.15 14.64 %

j. Example 5

-oxamic acid ethyl ester. 100/84

2.82 g (0.03 mol) of 3-aminopyridine are condensed with 3.7 ml (0.033 mol) of ethyloxalyl chloride as described in Example 3, and after crystallization from diethyl ether, 2.36 g of the desired compound, F 98 to 100 ⁰ C.

Analysis ^c q ^h io ^N 2 ° 3

C H N ^

calculated: 55.66 5.19 14.43 %

found: 55.40 5.13 14.71 %

- 19 -

409839 / 107U

IO

Example 6 Ethyl (2-pyrazinyl) oxamidsacid ster. 100/83

2.88 g (0.03 mol) of aminopyrazine are condensed with 3.7 ml

; (0.033 mol) ethyl oxalyl chloride as described in Example 3,

whereby, after crystallization from ethanol, 3.63 g of the

^! desired compound is obtained, F 134 to 137 ° C.

j Analysis CqHqN 0:

CHN

calculated: 49.23 4.65 21.53 %

found: 48.99 4.58 21.56 %

Example 7 . (2-Pyridyl) oxamic acid methyl ester. 77/100

2.82 g (0.03 mol) of 2-aminopyridine are condensed with 3.04 ml (0.033 mol) of methyl oxalyl chloride as described in Example 3, 3.18 g of the desired compound being obtained after crystallization from diethyl ether, F 102 to 106 ⁰ C.

Analysis CgHg ^ O ^:

calculated: found:

Example 8

(2-Pyridyl) oxamic acid n-propyl ester. 58/77

2.82 g (0.03 mol) of 2-aminopyridine are condensed with 4.26 ml (0.033 mol) of n-propyloxalyl chloride as described in Example 3

- 20 409839/10711

C. , 33 H 48 N , 76 53 , 54 4, 47 15th 53 4, 15th

Qi i

j where, after crystallization from diethyl ether, 2.2 g of the ί j desired compound are obtained, F 56 to 59 ⁰ C. ι

■ Analysis oi223

j CHN

■ calculated: 57.68 5.81 13.36 %
J found: 57.72 5.84 13.48 %

: Example 9

j (2-Pyridyl) -oxamic acid isopropyl ster. 100

! 2-aminopyridine is condensed with isopropyloxalyl chloride

J as described in Example 3, using the desired Veri bond in the form of a liquid. |

U ". = _LoW,. '·

; C 'H N I

j calculated: 57.68 5.81 13.46 % j

i found: 57.15 6.04 13.51 % '

Example 10 !

i (2-Pyridyl) oxamic acid n-butyl ester. 100

2-aminopyridine is condensed with n-butyloxalyl chloride as in
Example 3 described, with the desired compound
gives F 35 to 37 ° C.

Analysis C ₁ -, H _n / N ₀ O-,

CHN

calculated: 59.45 6.35 12.60%

found: 59.16 '6.72 12.45 %

-ZL- 4D9839 / 1O7U.

PL

Example 11 (2-Pyridyl) oxamidic acid cyclohexyl ester. 53

2-aminopyridine is condensed with cyclohexyloxalyl chloride as described in Example 3, resulting in the desired compound, F 62 to 64 C.

Analysis Cj-zH-ifNJd ^,

calculated: found:

Example 12

(2-Pyridyl) oxamic acid sec-butyl ester. 100

2-aminopyridine is condensed with sec-butyloxalyl chloride according to the method of Example 3, the desired compound being obtained in the form of a liquid, boiling point 112 to 116 ^° C./

C. 89 H 50 N 28 62, 22nd 6, 00 11 08 63, 7, 11

0.05 mm Hg. C. H N Analysis C - .., H, /, ΝρΟ .. 59.45 6.35 12.60 % 59.48 6.62 12.60 % calculated: at game found: 100/64 Ethyl oxanilate

This connection is known from the literature: G. Tiere, Rec. Trav. Chim., 5-2, 420-4 (1933). It is made from ethanol crystallized, mp 64 to 67 ° C.

- 22 409839 / 107U

Example 14 Oxanilic acid methyl ester. 100/52

This connection is known from the literature: Heilbron Diet, of Org. Cpds., IV, p. 32 (1965). It is made from diethyl ether crystallized, mp 113-116 ° C.

Example 15

Oxanilic acid n-propyl ester. 82

This connection is known from the literature: Heilbron

Diet, of Org. Cpds., Vol. IV, p. 32 (1965). She becomes from j

Diethyl ether, crystallized, mp 90 to 92 ° C.

Example 16 i-propyl oxanilate. 100/60

This connection is known from literature: Heilbron! Diet, of Org. Cpds., Vol. IV, p. 32 (1965). She is going out! Pentane crystallizes, F 51 to 53 ⁰ C.

Example 17 Phenyl oxanilate. 59

This connection is known from the literature: R. Stolle et al. Ber. Deut. Chem., 54B , 1213-20 (1921). It is crystallized from ethanol, F 136 to 139 ° C.

- 23 409839/1070

Example 18 1H-Tetrazole-5-carboxanilide 100/100

This compound is known from the literature: BE Fisher, et al., J. Org. Chem., 24, 1650 (1959). It is crystallized from ethanol-water F 216-218 ⁰ C (dec.).

Example 19 2'-Carboxyoxanilic acid 1-ethyl ester, 50

This connection is known from the literature: JACS 32 , 119 (1910). It is crystallized from toluene, temperature 182 to 183 ° CJ

Example 20 2'-Carbamovloxanilic acid ethyl ester. 90

This compound is known from the literature: BR Baker et al., J. Org. Chem., 27, 4672 (1962). It is crystallized from ethanol, F 160 to 161 ⁰ C.

Example 21 2'-Cyanoxanilic acid ethyl ester. 53

5 g (0.021 mol) of 2'-carbamoyloxanilic acid ethyl ester are heated in 50 ml of acetic anhydride to reflux for 2 hours. The solvent is removed in a rotary evaporator and slurries the residue in water and diethyl ether,

- 24 409839/1070

separates and washes the ether layer with saturated NaHCO ,, saline solution and dried with Na ₂ SO. Evaporation of the ether gives 5 g of a residue which is chromatographed on 150 g of silica gel with benzene. Eluting with 10 % diethyl ether in benzene removes 0.68 g of the desired compound, F 90 to 91 ° C after crystallization from ethanol.

analysis

calculated: found:

Example 22

2'-Methyloxanilic acid ethyl ester. 75

. This compound is known from the literature: PE Todesco et al., CA. 6l: 4l9f. It is a liquid, bp 126 ^° C / 0.05 mm Hg.

Example 23

■ 2'-Methoxyoxanilic acid ethyl ester. 100

C. 54 H 62 N , 84 60, 36 4, 50 12th , 67 60, 4, 12th

This connection is known from the literature: CA .: 61 (4192) ;.

It is crystallized from benzene, F 81 to 85 ° C.

Example 24

3'-Methoxyoxanilic acid ethyl ester. 38 !

This compound is known from the literature: P.A. Petyunin öt al., Zh. Obshch. Khim., 21, 1859-61 (1951). It is crystallized from methanol-water, F 95-98 ° C.

"-""409 8 39/1 0 ² "

Example 25

3'-Trifluoromethyloxanilic acid ethyl ester. 64

This connection is known from the literature: A. Buruffini
et al., Farmaco, Ed. Sci., 22 (9), 717-34 (1967). she will
Crystallized from ethanol, F 120-123 ° C.

Example 26 3 '-Fluoroxanilic acid ethyl ester. 78

5.55 g (0.05 mol) of m-fluoroaniline are condensed with 6.16 ml of j (0.055 mol) ethyl oxalyl chloride, as described in Example 3: whereby 9.26 g of the desired compound are obtained, F 85 bis; 89 C after crystallization from ethanol. ·. j

Analysis O _1n KL _n FNO-10 10

C. , 0 H ■ N 64 57 , 45 4, 78 6, 61 56 4, 87 6,

calculated: τ / .ο α. / η h.hü% ι

found:

Example 27 3'-Methyloxanilic acid ethyl ester. 85

This compound is known from the literature: PA Petyunin
et al., Zh. Obshch. Khim., 24, 1078-82 (1954). It is crystallized from J benzene-hexane, F 56 to 60QC. |

- 26 -

40983971070

; Example 28

j ethyl 4'-carbamoyloxanilic acid. 55

4.08 g (0.03 mol) of p-aminobenzamide are condensed with 3.7 ml

ι (0.033 mol) Ethyloxalylchlorid as described in Example 3,

j whereby 2.85 g of the desired compound are obtained, F 259 bis

! ■ 264 C (decomp.) After crystallization from Ν, Ν-dimethylformamide.

analysis

calculated: found:

C. , 93 H 12th N 29 , 86 55 , 01 5, 24 11 , 92 56 e i 5, e 1 11 B. s ρ i

4'-Methoxyoxanilic acid ethyl ester 75/76

This connection is known from the literature: A. Piutti et al., Br. Deut. Chem., J51, 330-336 (1898). It is made from ethanol crystallized, mp 100-104 ° C.

Example 30

4'-Nitrooxanilic acid ethyl ester. 75

This compound is known from the literature: G. Tierie, Rec. Trav. Chim., £ 2., 420-4 (1933). It is crystallized from acetic acid j, F 169 to 172 ⁰ C.

Example 31

4'-Methyloxanilic acid ethyl ester. 100

This connection is known from the literature: CA. 61 (4192g) It is crystallized from benzene-hexane, F 65 to 67 ⁰ C.

- 27 - .. .. 4Ö9839 / 1O7U

C. 63 H 09 N 14th 64, 61 5, 13th 14, 04 64, 5, 14,

Example 32

4'-Phenylazooxanilic acid ethyl ester. 41

5.92 g (0.03 mol) of p-phenylazoaniline are condensed with 3.7 ml (0.033 mol) of ethyloxalyl chloride, as described in Example 3, 7.36 g of the desired compound are obtained, F 157 to 160 C after crystallization from ethanol.

Analysis C-, ^ H-, cN-, 0-,

calculated: found:

Example 33

p-rPhenylenebisoxamic acid ethyl ester. 77

This connection is known from the literature: CA. 60 (P3012b). It is crystallized from ethanol, F 214-217 ⁰ C.

Example 34 2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester. 100/94

8.75 g (0.0527 mol) of 6-amino-o-anisamide are condensed with 6.2 ml (0.0554 mol) of ethyl oxalyl chloride, similar to that in Example 3 described, whereby 8.35 g of the desired compound are obtained, F 170 to 173 ° C after crystallization from ethanol.

Analysis ^c ₁ 2 ^H i ^{4 N} 2 ° 5

AO C. , 13 28 H - 30th N 52 % calculated: 54 , 36 /1 5, 07U 20th 10, 66 % found: 54 - 5, 10, 39 98

B e i s ρ i el 55

2-CarboxY-5 ^I- methoxyoxanilic acid ethyl ester. 54

1.671 g (0.01 mol) of 6-amino-o-anisic acid are condensed with 1.23 ml (0.011 Hol) ethyloxalyl chloride, similar to in Example 3 described, wherein 1 g of the desired compound obtained, F 142 to 144 ° C after crystallization Ethanol.

analysis

calculated: found:

Example 56 2'-Cyano-5 ^f -methoxyanilinsäureäthylester 80/71

4.67 g '(0.0515 mole) of 2-amino-6-methoxybenzonitrile condensed one with 5.88 ml (0.0546 mol) of ethyloxalyl chloride is similar

C. , 95 H , 90 N 24 55 , 21 4th , 99 5, 52 54 4th 5,

Connection received. F 142 to 145 ° C after crystallization

as described in Example 5, whereby 5.0g of the desired \

Connect!

Toluene.

Analysis calculated

C. , 06 H 87 N 29 58 , 21 4, 95 11 02 58 4, 11

found: 58.21 4.93 11.02 96!

4Q9839 / 107Ü

Example 37

2'-carbamoyl-3 * -chloroxanilic acid ethyl ester. 25th

4.26 g (0.025 mol) of 2-amino-6-chlorobenzamide are condensed with 3.1 ml (0.0275 mol) of ethyl oxalyl chloride to similar Way as described in Example 3 ", using 5.28 g of the desired compound is obtained, F 190 to 193 ° C after crystal sation from ethanol.

Analysis C H

calculated: found:

example '5 &

2 * -Carboxy-3'-methoxyoxanilic acid-1-a thy 1-2'-methy

3.62 g "(0.02 mol) of methyl-6-methoxyanthranilic acid is condensed with 2.46 ml (0.022 mol) of ethyloxalyl chloride in the same manner as in Example 3, giving 3.5 and the desired prebond , F 96 to 99 ° C after crystallization from ethanol.

C. ,8th H 10 N SlZ Λ 48 , 08 4, 05 10 49 4, 10

analysis

CHM

calculated: 55.51 5.38 U ₁ 98 fo

found: 55.56 5.43 ^, 18 %

Example "59

2'-carbamoyl-3 '- (2-phenoxyethoxy) -oxanilic acid hylsi ; he·

4.15 ml (0.033 mol) of 2-phenoxyethanol are nan to Dimethylfulfoxylnatriuni consisting of 1.39 g of 57% sodium Eiatr.'iumhydHd and

- 30 - 409839/1070

i 40 ml of dimethyl sulfoxide has been prepared, with one after j a mixture of the solid salt of alcohol for about 20 minutes

receives. This mixture is added to a solution of 5.8 g. (0.030 mol) 2,6-dinitrobenzonitrile in 20 ml dimethyl sulfoxide

¹ O '

I at 30 to 40 C and stir the resulting purple solution ': overnight at room temperature. The solvent is at! 70 C removed in a rotary evaporator and the residue j is triturated with water. A solid is filtered off and dissolved in ethyl acetate. The ethyl acetate solution is washed twice with H _? 0, saline, and dry with calcium sulfate. Evaporation of the ethyl acetate gives 8.5 g of 2-nitro-6-j (2-phenoxyethoxy) benzonitrile, which is crystallized from 200 ml of ethyl alcohol: 6 g are obtained, mp 129 to 137.5 ° C.

¹ The crystallized 2-nitro-6- (2-phenoxyäthoxy) -benzonitrile i (5.82 g, 0.0205 mole) is stirred at 50 ⁰ C in 116 ml of absolute! Ethanol and add 3.62 ml (0.0615 mol) of 85% hydrazine hydrate, ₍ followed by small portions of Raney nickel. While one

the Raney nickel is added, the temperature is kept at 50 to 60 ° C. and after the evolution of gas and the exothermic reaction have ceased, the mixture is filtered through diatomaceous earth. The filter cake is washed with hot ethanol and concentrated; the filtrate, 2.804 g of 2-amino-6- (2-phenoxyethoxy) ~! ¹ benzamide, F 127 to 130 ^° C. is obtained. j

Analysis C-, -

calculated:
found:

^: 2.8 g (0.0103 mol) of 2-amino-6- (2-phenoxyethoxy) benzamide

"is condensed with 1.26 ml (0.0113 mol) of ethyl oxalyl chloride

¹ described in a similar manner as in Example 2 to give 1.612

ί g of the desired compound is obtained, F 142 to 145 C after

\ Crystallization from ethanol.

4 09839/10 7.Ü-

3 C. 16 H , 92 N 29 66 71 5 , 36 10, 13th 66 6th 10,

C. 28 H 41 N 52 % 61, 14th 5, 57 7, 50 % 61, 5, 7,

M / 15092

Analysis C

calculated: found:

Example 40

2'-carbamoyl-3'-methoxyoxanilic acid methyl ester. 96

4.98 g (0.03 mol) of 6-amino-o-anisamide are condensed with 3.04 ml (0.033 mol) of methyl oxalyl chloride in a manner similar to that in Example 3 described, 4.24 g of the desired compound being obtained, F 195 to 198 C after crystallization from methanol.

Analysis CH _? N 0

"calculated: found:

Example 41 2'-carbaniovl-3'-methoxyoxanilic acid n-propyl ester 96

4.98 g (0.03 mol) of 6-amino-o-anisamide are condensed with 4.25 ml (0.033 mol) of n-propyloxalyl chloride, as in Example 3 described, giving 4.81 g of the desired compound, F 158 to 16l ° C after crystallization from acetonitrile.

Analysis ^c i - ^ - i ^ o ° 5

C. 38 H 80 N , 11 52, 30 ' 4, 94 11 , 40 52, 4, 11

\ calculated: C. , 71 32 H 75 N , 00 % found: 55 .92 5, 93 10 .34 % 55 - 5, 10 -

AQ9839 / 107U

Example 42

2'-Carbamoyl-3 * -methoxyoxanilic acid isopropyl ester 57

4.98 g (Q,; 03 mol) of 6-amino-o-anisamide are condensed with 4.25 ml (0.033 mol) isopropyloxalyl chloride as in Example 3 ", where you get 4.74 g of the desired compound obtained, F 128 to 132 ° C, after crystallization from benzene.

analysis

C. , 71 H 75 N 00 % 55 , 66 5, 93 10, 38 % 55 5, 10,

calculated: found:

Example 43 2 * -carbamoyl-3 * -methoxyoxanilic acid 48

1 * 33 g (0.005 mol) of 2 ^ι -carbamoyl-3 ^l -methoxyoxanilic acid-ethyl ester is stirred in 50 ml of water and 5.0 ml of In KaOH are slowly added, which results in a solution. After 1/2 hour the solution is: filtered and the filtrate is acidified to pH 2 with 1 η HCl, which gives 0.71 g of the desired compound, melting point 214 to 215 ° C. after crystallization from ethanol.

Analysis C-, «H, ^ Q ₁ -M ₂ : - ~

C H. ■ N.

calculated: 50.42 4.23 11.76 %

found: 50.60 · 4.35 11.80%

- 33 -

403833 / 107Ü

M / 15092

C. 63 H 67 N 72 Si 50, 45 4, 70 17, 65 % 50, 4, 17,

Example 44 N- (2-Carbamoyl-3-iHet: hoxyphenyl) -oxamide 26

5.0 g (0.0188 mol) of 2 »-carbamoyl-3 * -methoxyoxanilic acid ethyl ester are added to 50 ml of ethanol saturated with ammonia at zero to 5 ° C. and the mixture is stirred for 2 hours in an ice bath and then filtered off. The cake is washed with ethanol, which gives 1.41 g of the desired compound, F 252 to 255 C after crystallization from water.

Analysis ^ irßjj ^^ h ^:

calculated: found:

Example 45 2 * -Carböxy-4 * -methox yoxanilsäureäthy-lester 61

1.6? g (0.01 mol) of 5-methoxyanthranilic acid are condensed j with 1.23 ml (0.011 mol) of ethyl oxalyl chloride in a similar manner | as in Example 3, 1.32 g of the desired compound being obtained, F 238 to 243 ° C. after crystallization from ethanol.

analysis

calculated: found:

e 93 H 90 N 24 53 99 4, 93 5, 99 53 4, 4,

- 34 -

409839/10? Ü

i Example 46

i -

I 2'-carbamoyl-4 ^t -cKLoroxanilic acid ethyl ester 58

I 3.41 g (0.02 mol) of 2-amino-5-chlorobenzamide are condensed with

j 2.46 ml (0.022 mol) of ethyloxalyl chloride, as in Example 3

i wrote, 4.57 g of the desired compound

i holds, F 204 to 210 ⁰ C after crystallization from acetonitrile.

; analysis

C. ,8th H 10 N 35 Cl 10 48 , 65 4, 98 10, 26th 13, 84 48 3, 10, 12,

calculated: found:

I Example 47

; 2'-Carbamoyl-4 ¹ -nitro-oxanilic acid ethyl ester 59

j 5.43 g (0.03 mol) of 2-amino-5-nitrobenzamide are condensed with ι 3.7 ml (0.033 mol) of ethyloxalyl chloride as described in Example 3: using 6.54 g of the desired compound : obtained, F 206 to 209 ° C after crystallization from ethanol.

j analysis

ι calculated:

! found:

C. , 98 H 94 N , 94 46 , 68 3, 96 14th , 12 46 3, 15th

- 35 -

409839/107 U

! Μ / 15092 ο / 1QQC r

ο * 2 4 Ί 3 9 b b

Vo

B e i s ρ i e 1 48

, 4'-Methoxy-2'-nitro-oxanilic acid ethyl ester 84

ι This connection is known from the literature: Zh. Obshch. . Khim. 1, 2471-7 (1937). It is crystallized from ethanol: F 154 to 16O ⁰ C.

Example 49

2'-Nitro-4 '- (trifluoromethyl) oxanilic acid ethyl ester 29

3.21 g (0.03 mol) of 4-amino-4-nitrobenzotrifluoride are condensed with 3.7 ml (0.033 mol) of ethyl oxalyl chloride as described in Example 3, 7.01 g of the desired compound being obtained, F 124 bis 126 ⁰ C after crystallization from ethanol.

analysis

C. ,1 H • N 16 43 , 97 2, 96 9, 28 42 3, 02 9,

calculated: found:

Example 50

2'-Carbamoyl-5'-methoxyoxanilic acid ethyl ester 91

12.8 g of 2-nitro-4-methoxybenzonitrile is reduced similarly as described in Example 40 to give 9.0 g of 2-amino-panisamid receives, F 152-156 ⁰ C after crystallization from water.

Analysis ^c gH-io ^ 2 ^ 2

C .H N

calculated: 57.82 6.07 16.86 %

found: 58.60 5.76. 16.65 %

- 36 409839 / 107U

4.99 g (0.03 mol) of 2-amino-p-anisamide are condensed with 3.68 ml (0.033 mol) of ethyl oxalyl chloride as in Example 3 described, giving 3.84 g of the desired compound, F 186 to 188 C after crystallization from ethanol.

Analysis ^c ₁₂ ^H i4 ^N 2 ° 5

C. 13th H 34 N 52 54, 29 5, 50 10, 89 54, 5, -10,

calculated:
found:

Example 5'-chloro-2 ¹ -sulfamovloxanilic acid ether ester 70 !

4.13 g (0.02 mol) of 2-amino-4-chlorobenzenesulfonamide condensed with 2.46 ml (0.022 mol) of ethyloxalyl chloride as described in Example 3, 3.04 g of the desired ι Compound obtained, F 183 to 1 * 87 ° C after crystallization from 1

Ethanol. I.

^! · Analysis C ₁₀ H ₁₁ ClN ₂ O ₅ S

■ 'C' H N S

! calculated: 39.2 3.65 9.14 10.45 %

; found: 38.95 3.65 9.14 10.86 %

Example 52

; 2'-Carboxy-4'-methoxyoxanilic acid 1-ethyl-2'-methyl ester 58

j 4.7 g (0.0283 mol) 6-amino-m-anisic acid methyl ester condensed j with 3.48 ml (0.0311 mol) of ethyloxalyl chloride as described in Example 3, giving 5.27 g of the desired compound

- 37 -409839/1070

C. , 51 H 38 N 98 55 , 72 5, 38 4, 37 55 5, 5,

obtained, F 129 to 133 ° C after crystallization from ethanol. Analysis C-,, EL c

calculated: found:

Example 53 2 ', 6'-Dichloroxanilic acid ethyl ester 100

This connection is known from the literature: CA. 60 (162Ia] It is crystallized from diethyl ether, F 128 to 130 ° C.

example

ι 4 '■ -'Nitro-3 ^f - (trifluoromethyl) oxanilic acid ether 100/73 I

6.18 g '(0.03 mol) of 5-amino-2-nitrobenzotrifluoride are condensed with 3.7 ml (0.033 mol) of ethyl oxalyl chloride as described in Example 3, 6.07 g of the desired compound being obtained, F 106 bis HO ⁰ C after crystallization from ethanol.

analysis

calculated: found:

C. 1 H 96 N 55 16 43, 26th 2, 95 9, 18th 43, i 2, e 1 9, B e s ρ i

4,4'-Oxydioxanilic acid diethyl ester 34

This connection is known from the literature: CA. 60 (P 3012b) It is crystallized from ethanol, F 159 to 162 ° C.

- 38 -

409839/1070

- "" - ■ · "- ■ ------ - ■ B e 1 s ρ 'ie 1

Cyclohexyl '2'-carbamoyl-3'-methoxyoxanilic acid 91

ι 6-Amino-o-anisamide is condensed with Cyclohexyloxalylclilorid

j siert, resulting in the desired compound, F 166 bis

! 169 ° C.

j Analysis C ₁₅ H ₂₀ N ₂ O ₅ . . .

: CHN

; calculated: 59.99 6.29 8.75 %

\ found: 60.17 6.33 8.69 %

Example ^ 7

C. 13th H , 17th N 52 57, 43 6th , 46 9, 38 57, 6th 9,

Butyl 2'-carbamoyl-3'-methoxyoxanilate 98

6-Amino-o-anisamide is condensed with n-butyloxalylchlorld. resulting in the desired compound, F 126 to 129 C.

analysis

calculated:
found:

Example 58 2'-Carbamoyl-3'-methoxyoxanilic acid sec-butyl ester 100/70

6-Amino-o-anisamide is condensed with sec-butyloxalyl chloride resulting in the desired compound, F 119 to 122 C.

- 39 -

40983971070

Analysis C, ^, GNPOC *

calculated: found:

C. , 13 H , 17-. N 52 57 , 94 6th , 44 9, 50 56 6th 9,

\ Example 59 "

2'-carbamoyl-3'-ethoxyoxanilic acid ethyl ester

'2-Amino-6-ethoxybenzoic acid amide is condensed with ethyl ! oxalyl chloride, resulting in the desired compound, ι F 142 to 145 ° C.

Example 60 . 2'-carbamoyl-3'-propoxyoxanil acid ethyl ester

: 2-Amino-6-propoxy-benzoic acid amide: is condensed with I ethyloxalyl chloride, whereby the desired compound is

! there, F 130 to 133 ° C. ■. = '■

; Example 61

2'-carbamoyl-3 ^T -isopropoxyoxanilsäureäthylester

2-Amino-6-isopropoxy-benzoic acid amide is condensed with '■■ Ethyloxalylchlorid, whereby the desired compound results! there, F 123 to 125 ° C.

--40 -

4098397 1070

HA5092

Example 62

I 2'-carbamoyl-5'-n-butoxyoxanilic acid ethyl ester

2-amino-6-n-butoxy-benzoic acid amide is condensed with Äthyloxalylchlorid wherein gives the desired compound, F 120 to 123 ⁰ C.

i Example 63

ι (2-Naphthyl) -oxamic acid ethyl ester 76

This connection is known from the literature: CA. 43: 697g, j F 118 to 12O ⁰ C

Example 64

Ethyl (l.-naphthyl) -oxamic acid 97

I This connection is known from the literature: CA. 43: 6973 g,

105-107 ° C

I Example 65

j

j 3 '»4', 5'-trimethoxyoxanilic acid ethyl ester 63

j This connection is known from the literature: CA. 68: 9547 y,

! F 132 to 134 ⁰ C

j Analysis C - ,, Η-,

j calculates:

■ found:

- 41 -

C. 12th H 05 N , 95 55, 14th 6, 26th 4th , 87 55, 6, 4th

4.09839 / 1070

Claims (1)

Claims 1. Compounds of the formula 0 0 Ii Ii ANHC - C - R wherein A means 2-cyanophenyl, 3-fluorophenyl, 4-phenylazophenyl, 4-carbamylphenyl, 2-nitro-4-trifluoromethylphenyl, 2-cyano-3-methoxyphenyl, 4-nitro-3-trifluoromethylphenyl, 5-chloro-2-sulfamoylphenyl and owns what R and R independently of one another hydroxyl, lower alkoxy and Amino radicals mean, 2
R is hydrogen, lower alkoxy, halogen and phenoxy lower alkoxy denotes, R denotes hydrogen, lower alkoxy, halogen or nitro, denotes and ^: R is hydrogen or lower alkoxy, however 2 3 L · A prerequisite is that one of the radicals R, R and R is not hydrogen. - 42 - • 4 0 9 8 3 9/1 0 7 (J. .: 2. Compounds of the formula ί "'" Ό ■' "ο ' , II H j ANH - C - C-R j in which 'R lower alkoxy means j A the meanings 3-fluorophenyl, 2-cyano-3-methoxyphenyl, ^! 4 nitro-3-trifluoro-methylphenyl, 5-chloro-2-sulfamoylphenyl ί and. ■. i ■ COMI ₀ ' owns what 2 R is hydrogen, lower alkoxy or phenoxy-lower alkoxy radicals means, 3 R and R independently of one another are hydrogen or lower alkoxy radicals, with the prerequisite, however, that one of the radicals R, Yc and R ^ is not hydrogen. - 43 - 4 0 9 8 3 9/107 M / 15092 3. Compounds of the formula 0 0 11 1! ANHC - C - R wherein A is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl or 2 pyrimidinyl and R denotes lower alkoxy, but it is a prerequisite that if A is 2-pyridyl, R must not be ethoxy, j 4. "(4-Pyridyl) -oxamic acid ethyl ester. . 5 · '(3-Pyridyl) -oxamic acid ethyl ester. 6. "(2-Pyrazinyl) -oxamic acid ethyl ester. 7. (2-Pyridyl) oxamic acid methyl ester. 8. (2-Pyridyl) oxamic acid n-propyl ester, 9. Isopropyl (2-pyridyl) oxamic acid ester. 10. (2-Pyridyl) oxamic acid n-butyl ester. - 44 409839 / 1Q7U 11. (2-Pyridyl) oxamic acid cyclohexyl ester. 12. (2-Pyridyl) oxamic acid sec-butyl ester. 13 · 2'-Cyanoxanilic acid ethyl ester. ί 3'-Fluoroxanilic acid ethyl ester. 15. 4 · -Carbamoyloxanilic acid ethyl ester. 16. Ethyl 4 '- (phenylazo) oxanilic acid. 17. '2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester. 18. 2 ^{I-carboxy-3 t} -methoxyoxanilsäureäthylester. 19 · 2'-cyano-3 ^f- methoxyoxanilic acid ethyl ester. 20. 2'-Carbamoyl-3'-chloroxanilic acid ethyl ester. 21. 2'-Carboxy-3'-methoxyoxanilic acid 1-ethyl-2 ^f -methyl ester - 45 - 409839/107 Ü 22. 2'-Carbamoyl-3 '- (2-phenoxyethoxy) -oxanilic acid ethyl ester. 23. 2'-Carbamoyl-3'-methoxyoxanilic acid methyl ester. 24. 2'-Carbamoyl-3'-methoxyoxanilic acid n-propyl ester. 25. Isopropyl 2'-carbamoyl-3'-methoxyoxanilic ester. 26. 2'-carbamoyl-3'-methoxyoxanilic acid. 27. N- (2-carbamoyl-3-methoxyphenyl) oxamide. j 28. Ethyl 2'-carboxy-4'-methoxyoxanolate. 29. 2'-Carbamoyl-4'-chloroxanilic acid ethyl ester. 30. 2'-Carbamoyl-4'-nitro-oxanilic acid ethyl ester. 31. 2'-Nitro-4 '- (trifluoromethyl) - »ethyl oxanilate. 32. 2'-carbamoyl-5'-methoxyoxanilic acid ethyl ester, 33 · 5 ¹ -chloro-2'-sulfamoyloxanilic acid ethyl ester. j • ι - 46 - 409839 / 107Ü j 34.2'-Carboxy-4'-methoxyoxanilic acid-i-ether-yl-2'-methyl- ester. <■ - 47 - 35 · 4'-Nitro-3 '- (trifluoromethyl) -oxanilic acid ethyl ester. ^{36.2 f} -Carbamoyl-3'-methoxyoxanilic acid cyclohexyl ester. 37. 2'-Garbamoyl-3'-methoxyoxanilic acid butyl ester, j 38. 2'carbamoyl-3'-methoxyoxanilic acid sec-birtyl ester. 39. Ethyl 2'-carbamoyl-3'-ethoxyoxanilic acid. 40. 2'-Carbamoyl-3'-propoxyoxaniic acid ethyl ester. 41. 2 · -Carbamoyl-3'-isopropoxyoxanilic acid ethyl ester. 42. 2 ^Λ -carbamoyl-3'-n-butoxyoxanil acid ethyl ester. j 43. 3 ', 4 *, 5'-trimethoxyoxanilic acid ethyl ester. 409839 / 107Ü 44. Process for the preparation of an oxamic acid derivative the formula O O Il Il ANHC - C ■ - R is lower alkoxy, an amino radical, or -OH, A is 3-pyridyl, 2-pyridyl if R is not ethoxy means 4-pyridyl, 2-pyrazinyl and 2-pyrimidinyl, 2-cyanophenyl, 3-fluorophenyl, 4-phenylazophenyl, 4-carbamylphenyl, 2-nitro-4-trifluoromethylphenyl, 2-cyano-3-methoxyphenyl, 4-nitro-3-trifluoromethylphenyl, 5-chloro-.2-sulfamoylphenyl and owns what. - R is hydroxy, lower alkoxy or amino radicals, 2
R is hydrogen, lower alkoxy, halogen or phenoxy lower alkoxy means. 3
R is hydrogen, lower alkoxy, halogen or nitro, ' and ι - 48 - 4th
R is hydrogen or lower alkoxy, however 2 "5 4 is provided that one of the radicals R, R and R does not mean hydrogen, characterized in that an amine of the formula ANH ₂ with a reactive compound ZCOX, in which Z is a group which is reactive with an amine, such as hydroxyl, the halogens, azido, diazotate and active ester radicals, and X is a group which leads to -CO ₂ H, -CO ₂ R, -CONH ₂ or ^ .N - NH
-C can be converted, selected under -CH = CHCOZ, -C (OR ⁵ ), -CH (COR ⁵ ) ₂ or -COZ, where R ^{5 is} lower alkyl, cycloalkyl or aralkyl. '■ "' ■" ■■ ■! ^! 45. Process for the preparation of an oxamic acid derivative j according to claim 44, characterized in that a ketoxime 'of the formula 5 NOH ! ■. ■■■■ - » 'AC- CO ₂ R ^{5 :} In the presence of an acidic reagent and Beckmann rearrangement j \ rearranges conditions. , i I ! 46 .. Process for the preparation of an oxamic acid derivative ! according to claim 44, characterized in that a ketoxime j of the formula AN = CHCO ₂ R ^{5 is} oxidized and the ketoxime Ubor Umwnnd-! treatment to a sulfonic acid ester or an acyl ester and hydrolysis is then rearranged. - 49 409839/1070 SO 47. A process for the preparation of an oxamic acid derivative according to claim 44, characterized in that 2-cyanochlorobenzene, 4-carbamylchlorobenzene, 2-nitro-4-trifluoromethylchlorobenzene, 2-cyano-3-methoxychlorobenzene, 4-nitro-3-trifluoromethylchlorobenzene or 5- Reacts chlorine-2-sulfamoylchlorobenzene with NaNHCOCO ₂ R ⁵ . 48. Process for the preparation of an oxamic acid derivative according to claim 44, characterized in that a ketone is used the formula ANHCÖCOR oxidized with a hypohalite and the resulting acid esterified with an alcohol of the formula R OH. 49. Process for the preparation of an oxamic acid derivative according to claim 44, characterized in that compounds the formula OH r ANHCOCh-CHCO ₂ H OH oxidatively splits and then the resulting 5
Acid esterified with an alcohol R OH. 50. Process for the preparation of an oxamic acid derivative | according to claim 44, characterized in that a connection the formula 409839/1070 ; reacts with ozone, a compound of the formula ^ NHCOCO ₀ R ⁵ - '*' ■ is obtained in which R has the meanings -OH, -NH ₂ or lower alkoxy; owns. ! 51. Process for the preparation of an oxamic acid derivative i of the formula ; . ο ύ I H ti I ■ ANHC - C - B j worm ! ■ A 'has the meanings 2-thiazolyl, 2-pyridyl if B is not ethoxy ; .means, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, ι a-naphthyl, ß-naphthyl, phenyl and substituted phenyl j radicals which have one to three substituents, J which, independently of one another, are lower alkyl, lower alkoxy, ί; Halogen, sulfamyl, polyhalo-lower alkyl, carbamyl, j Nitro, phenylazo, carboxy, cyano, carbloweralkoxy, phenyl i oxy-lower alkoxy, lower alkoxyoxalamido and lower alkoxy I can be oxalamidophenyloxy radicals, IB alone. Is selected from -OH, lower alkoxy, -NH ₅ , j cyclohexyloxy and phenoxy, and i Y means oxygen and together with B and the carbon atom, to which they are bound, the rest ^, N - NH - C. ] forms, - 51 - A09839 / 1O7O characterized in that a suitably substituted amine with a suitably substituted oxalyl chloride in Reacts the presence of an acid acceptor. 52. The method according to claim 51 / wherein A is 2-thiazolyl, 2-pyridyl when B is not ethoxy means 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, cx-naphthyl, ß-naphthyl, phenyl or substituted phenyl radicals with 1 to 2 substituents, which are independent of one another Lower alkyl, fluorine, lower alkoxy, carbamyl, carb-lower alkoxy, Trifluoromethyl, nitro, lower alkoxyoxalamido and can be phenoxy-lower alkoxy radicals, B alone means lower alkoxy and Y alone denotes oxygen and, together with B and the carbon atom to which they are bonded, the remainder ^ N - NH N = N forms. 53. Process for the preparation of an oxamic acid derivative of the formula O O Il Il ANHC - C - R wherein 409833/107 S3 j R denotes lower alkoxy, amino radicals or -OH ", and A means' 2-cyanophenyl, 3-fluorophenyl, 4-phenylazophenyl, 4-carbamylphenyl, 2-nitro-4-trifluoromethylphonyl, 2-cyano-3-methoxyphenyl, 4-nitro-3-trifluoromethylphenyl, 5-chloro-2-sulfamoylphenyl and owns what I R is hydroxyl, lower alkoxy or amino radicals, 1 ■ '■. 2 I ₁ -R hydrogen, lower alkoxy, halogen and phenoxy-lower; alkoxy means ; 3 j R is hydrogen, lower alkoxy, halogen and nitro, I and I 4 [R is hydrogen or lower alkoxy, but where I 2 3 4 ! provided that one of the radicals R, R and R I is not hydrogen, ! characterized in that a suitably substituted ■ AmIn with a suitably substituted oxalyl chloride in counter 'was implemented by an acid acceptor. - 53 - 409839 / 107U m / 15092 2 A13966 54. The method according to claim 53, wherein R is lower alkoxy and A is 3-fluorophenyl, 2-cyano-3-methoxyphenyl, 4-nitro-3-trifluoromethylphenyl, 5-chloro-2-sulfamoylphenyl and owns what 2
R is hydrogen, lower alkoxy or phenoxy lower alkoxy '' radicals and ■ 5 '4
R and R independently of one another are hydrogen or lower alkoxy radicals, with the prerequisite, however, 2 ^ 4 that one of the radicals R, R ^ and R is not hydrogen . 55 'The method of claim 44 wherein A is 3-pyridyl, 4-pyridyl, 2-pyrazinyl and 2-pyrimidinyl has and R means lower alkoxy. - 54 - 409839 / 107Ü O Y Il Il MHC -C- ! SS " j 56. Pharmaceutical agent, characterized in that j it is an effective amount of a compound of the formula contains where A 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, naphthyl, phenyl and substituted phenyl radicals with 1 to 3 substituents, - which independently of one another ' are selected from lower alkyl, lower alkoxy, halogen, SuIfamyl, polyhalo-lower alkyl, carbamyl, nitro, phenylazo, Carboxy, cyano, carblowalkoxy, phenoxylow- ! alkoxy, lower alkoxyoxalamido and lower alkoxyoxalamidoj phenoxy radicals, means j, B · alone -OH, lower alkoxy, cyclohexyloxy, -NH ₂ and phenoxy: denotes, and j Ύ means oxygen and together with B and the carbon : atom to which you are bound, the rest ■ .N-NH . forms. ! 57 · Means according to claim 56 »characterized in that j that 'they are a compound of the formula 0 Y Il Il ANHC - C - * B Il Il contain, in which - 55_- 409839 / 107U IG A 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, α-naphthyl, β-naphthyl, phenyl and substituted Phenyl radicals with 1 to 3 substituents, which are independent are selected from lower alkyl, fluorine, lower alkoxy, carbamyl, carb-lower alkoxy, trifluoromethyl, Nitro, lower alkoxyoxalimido and phenoxy lower alkoxy radicals, means, B alone means lower alkoxy, and Y alone means oxygen and together with B and the Carbon atom to which they are attached, the rest .N-NH
-C ^ I ^X N = N forms. 58. Composition according to claim 56, characterized in that it is an effective amount of a lower alkyl pyridyl oxamate contains. 59. Means according to claim 56, characterized in that that it contains an effective amount of a lower alkyl pyrazinyloxamate. 60. Composition according to claim 56, characterized in that it contains an effective amount of a compound selected under methyloxanilate, ethyloxanilate, isopropyloxanilate, - 56 -A 0 9 8 3 97 1 0 7 n Contains ethyl a-naphthyloxamate, ethyl 3 ^f- methyloxanilate, ethyl 4-methoxy-oxanilate, ethyl-2'-carbamoyl-3'-methoxyoxanilate and ethyl-4 ^l -nitro-3 ^t - (trifluoromethyl) oxanilate. 61. Means according to claim 56, characterized in that that it contains an effective amount of 1H-tetrazole-5-carboxanilide.