CH618963A5 - Process for the preparation of oxanilic acid derivatives - Google Patents

Abstract

The compounds of formula I - the definition of the symbols is given in Claim 1 - are obtained by the acylation of the 1-amino compound by means of a reactive derivative of the oxalic hemiester. If R<1> = R<2> = H, it is necessary either to protect the amino group -NR<1>R<2> in position 3 or 4 or else a 3- or 4-nitro compound is used for the oxalation, which is then reduced. The 2-cyano group can be formed by taking the corresponding acid amide as the starting compound. The free acid (R = H) or salts (R = alkali metal or NH4<+>) are obtained by saponification of the ester. The compounds of formula I can be used as agents against atopic allergies. <IMAGE>

Description

The present invention relates to the preparation of derivatives of 2-cyano-3 or 4- (substituted amino) oxanilic acids.

Atopic allergic reactions are of the immediate hypersensitivity type, as opposed to delayed hypersensitivity reactions, the latter being involved in conditions such as sensitivity to tuberculin, rejection of transplants, contact dermatitis, etc. Commonly encountered clinical conditions which are known to be at least in part due to immediate atopic hypersensitivity reactions are allergic rhinitis (hay fever) and asthma, seasonal or persistent, anaphylaxis, hives, conjunctivitis, angioedema, eczema, various reactions to food and medication, as well as reactions to insect bites. The substances most frequently responsible for atopic allergic reactions are plant pollen, animal feathers and dandruff, dust, milk and wheat, which are inhaled or ingested. Atopic hypersensitivity is encountered in humans, dogs and other animals,

although its presence is only exceptionally encountered in lower animals.

Atopic reactions (immediate hypersensitivity) are characterized by the immunopathological mechanism, the elements of which are: 1) production of a specific immunoglobin (antibody; immunoglobin E in humans or homocytotropic antibody in rats); 2) binding of this immunoglobin to the surface of a target cell; 3) combination of an antigen or allergin with the antibody attached to the cell, which: 4) causes the release of one or more pharmacological mediators, which, in turn; 5) causes symptoms of clinical disease, such as increased vascular permeability, contraction of smooth muscles, hypersecretion of the mucous glands, leukotaxis (especially eosinophilotaxis), and irritation of sensitive nerve endings.

A compound that will interfere with the antigen / IgE reaction (immunoglobin E) to prevent the release of mediators from the leukocyte or to allow a non-productive antigen / antibody reaction without the release of mediators, will necessarily block the atopic allergic reaction, avoiding so the resulting changes that are symptomatic of the disease.

The presence of antibodies associated with atopic reactions in the serum of the host is established by passive sensitization of the skin of a normal host, after injection into the skin of the latter of a serum from a sensitized host, then injection of the antigen into the same area of skin 24 hours later, which results in a local rash. This reaction is commonly called the Prausnitz-Kustner (P-K) reaction.

The antibody associated with atopic hypersensitivity has particularities since it does not precipitate in all its forms with its antigen, that it does not pass from the mother to the fetus via the placenta, that it has an affinity special for the skin, that it often lacks specificity for a particular antigen in an individual sensitized by various anti-gene factors, and that it is usually labile at around 56 ° C after 2 h.

The homocytotropic antibody whose existence is detected or induced in rats is related by its function and its reaction to

the immunoglobin E (reactin or IgE) found in humans. The correlation between the homocytotropic antibody in rats and human immunoglobin E has been established due to the common effects encountered in chemical reactions, immunological reactions, and drug sensitivities on the two species making these antibodies. In humans, reactin is the antibody responsible for immediate atopic hypersensitivity reactions. In rats, the homocytotropic antibody is responsible for immediate atopic hypersensitivity reactions.

In theory, reactin influences the cell membrane of a leukocyte by reaction with an antigen, which initiates, in the leukocyte, one or more reactions ultimately releasing a mediator, such as bradykinin, SRS-A (or slow-reacting substance) A), histamine and other unknown substances. The mediator causes a change in the permeability of the cell membrane allowing a rapid variation in the flow or exudation of the mediator (s) out of the cells, which results in an allergic attack symptom. The various methods commonly used to relieve symptoms of allergic attack, none of which have been found to be entirely acceptable, include: 1) avoiding attack by the antigen, 2) blocking the production of the antibody by means of an immunosuppressant, 3) to block the effect of mediators on the cell under attack, by administration of anti-histamine agents, anti-5-hydroxytryptamine (5-HT) agents or anti-inflammatory agents, or 4) stimulating the cell under attack so that it opposes the effect of the mediator, by means of bronchodilator agents, such as that sold under the name of Isoprel, or of a xanthine.

The only commercial compound known to date as being able to act as an antiallergic, mainly by blocking the reaction or reactions with leukocytes, thereby preventing the production and release of mediators, is the disodium chromoglycate (Intal, registered trademark) .

Disodium chromoglycate and compounds of this class are preventive in the sense that they must be administered, to be effective, to the sensitized animal before the allergic attack. They are not effective after release of the mediators from the leukocytes. Therefore, their function is to prevent the release of mediators and / or a productive antibody / antigen reaction. The passive skin anaphylaxis test (measuring the effect of mediator release) can be used to establish that a compound is effective for all atopias, as this test establishes the values of decreased mediator release, expressing the decreased allergic sensitivity of the animal. The passive cutaneous anaphylaxis test in rats establishes the mediator release rate from leukocytes located in the skin of the rodent, as a factor of the reduced effect on the skin of the test animal compared to to control animals.

The passive cutaneous anaphylaxis test in rats is a classic method of estimating the efficacy of drugs of the Intal class vis-à-vis the sensitivity of the classic test animal, resulting from 'an antigen / antibody interaction and a release of mediators. Extrapolating from an effect on the rat homocytotropic antibody to an effect on the human reactin antibody (IgE) is well suited because of the well-established relationship between these two antibodies.

Knowledge of the mechanism of activity of Intal in blocking the production of chemical mediators resulting from an antigen / antibody reaction, knowledge also of the variety of confirmed activities of Intal in the control or prevention of reactions of immediate hypersensitivity in humans, as well as knowledge of the close relationship between the rat homocytotropic antibody and immunoglobin E in humans, combined with the fact that Intal is the classic agent currently used in estimating the efficacy of new antiallergic compounds for atopic allergic reactions via the passive skin anaphylaxis test in rats, must lead to the practical conclusion that compounds which are active in the test passive skin anaphylaxis in rats can, with certainty

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very reasonable, to be considered as active antiallergic agents in humans, dogs, etc.

When developing new antiallergic agents, their mechanism of activity is compared to that of Intal as a standard compound, due to its known activity in humans and its activity in the skin anaphylaxis test. passive in rats. We can refer in this connection to Pfister et al., "J. Med. Chem. ”, Vol. 15, No. 10, pp. 1032-1035 (1972); Broughton et al., "Nature", vol. 251, pp. 650-652.18 October 1971, and Assem et al., "British Med. Journal ”, April 13, 1974, pp. 93-95.

According to the invention, a group of interesting chemical compounds is prepared for inhibiting the development of the physical symptoms accompanying an atopic allergic reaction, these compounds corresponding to the formula:

NOT

3 ^ _ CN

- NIICOCO-U

in which:

R represents - H; an alkali metal; NH4; an alkyl of 1 to 6 carbon atoms; an aralkoyl of 7 or 8 carbon atoms, or a cycloalkyl of 5 or 6 carbon atoms;

R1 represents —H or an alkyl of 1 to 9 carbon atoms; R2 represents - H, an alkyl of 1 to 9 carbon atoms or a cycloalkyl of 3 to 6 carbon atoms and

R1 and R2, when considered together with the nitrogen atom to which they are attached, may represent an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 4- (lower alkyl) piperazinyl, morpholino or thiomorpholino group;

this group of new compounds also including the acid addition salts, acceptable in pharmacy, of the compounds corresponding to the above formula.

In the above formula, the alkali metals envisaged for the group R are sodium, potassium or lithium. The expression alkyl of 1 to 6 carbon atoms denotes alkyl groups such as methyl, ethyl, normal propyl, isopropyl, normal butyl, secondary butyl, tertiary butyl, pentyl and hexyl . The expression aralkyl of 7 or 8 carbon atoms designates the benzyl and phenethyl radicals. The expression cycloalkyl of 5 or 6 carbon atoms includes cyclopentyl and cyclohexyl. The groups representing R1 and R2 can be normal or secondary alkyls having from 1 to 9 carbon atoms each. When R1 and R2 represent a cyclic group with the nitrogen atom of the structural formula, they represent dimethylene, trimethylene, tetramethylene, pentamethylene or the radicals 3-oxa, aza or thiapentamethylene (oxy, thio or imino- diethylene). In cases where R1 and R2 represent a heterocyclic group containing nitrogen, it is preferable to prepare the compounds in the form of their acid addition salts, pharmaceutically acceptable, non-toxic, for the purposes of separation. and recovery. Likewise, when R1 and / or R2 represent hydrogen, the amino group is protected during the reaction with the ester of chlorooxalic acid, the protective group then being removed. To this end, any conventional protecting group which is known in the art can be used, the trimethylsilyl group being representative of the type of protecting group which is especially suitable for the intended purpose.

The expression pharmaceutically acceptable acid addition salts includes non-toxic acid addition salts which can be formed with organic or mineral acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric acids, methane-

sulfonic, nitric, p-toluenesulfonic, acetic, citric, maleic, succinic, etc.

The preferred compounds from the point of view of the power exerted are those for which R1 and R2 are hydrogen, or else R1 is a lower alkyl and R2 is hydrogen, and for which the amino group:

is in position 3.

Compounds of 2-cyanooxanilic acid substituted in position 3 or 4 generally occur by condensing an appropriately substituted 2-cyanoaniline with a half ester of activated oxalic acid, in which the substituent in position 3 or 4 is an amino, alkylamino of 1 to 9 carbon atoms in the alkyl moiety, dialkoylamino of 1 to 9 carbon atoms in the alkyl moiety, cycloalkylamino of 3 to 6 carbon atoms, aziridinyl, azetidinyl, pyrrolidinyl , piperidinyl, piperazinyl, 4- (lower alkyl) piperazinyl, morpholino or thiomorpholino. The term half-ester of activated oxalic acid denotes acid halides, mixed anhydrides, azides and the like used in the production of amide linkages.

The 2-cyano group can optionally be formed through the dehydration of a previous derivative correspondingly substituted by a carbamyl group in position 2. In addition, a free amino group can be produced in position 3 or 4 by reduction of a nitro substituent after condensation with the abovementioned half-ester of activated oxalic acid. The free amino group can then be subjected to mono- or dialkylation with groups which can optionally be cyclized. Likewise, the final ester produced is saponified with an appropriate base to give an alkali metal or ammonium salt.

The compounds according to the invention have been shown to relieve allergic manifestations when administered by the peritoneum route and / or orally to sensitized rats.

The technique applied to establish the antiallergic activity of the compounds of the invention is that described in "Immunology", vol. 16, pp. 749 to 760 (1969), according to which we take groups of four male rats, weighing 200 to 250 g, of the Charles River breed, so as to have a control, of an animal receiving a standard antiallergic compound (chromoglycate disodium) and two animals for the test compound. Serum from rats immunized with egg albumin and pertussis vaccine is injected intracutaneously into the shaved back of rats. The test compound is administered via the peritoneum or the oral route at a maximum dose of 200 mg / kg body weight of the animal, 24 hours after the initial injections. After 5 min, 1 ml of a 0.5% solution of Evans blue dye and 8 mg of egg albumin is injected intravenously. After 40 min, the animals are sacrificed and the size of the bulb formed on the back is measured. The mean size of the ampoule is calculated for the animals having received the test compound and the percentage of inhibition is determined in comparison with the control animal.

Although the mechanism by which the compounds of the invention act is not fully understood, the licensee is led to believe that these compounds block, in a manner apparently similar to that by which the Intal product acts, the reaction (s) in leukocytes, leading to the production and release of mediators. The compounds of the invention allow an antigen / antibody reaction which is not productive of mediators, by effectively blocking the immunoglobin E type reaction. The compounds of the invention therefore block the release of mediators commonly resulting from the antigen / antibody reaction, as emerges from the passive cutaneous anaphylaxis test using rat homocytotropic antibodies, which, as is known, has a good correlation with human reactin antibodies.

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It has been established, by analogy with the disodium chromoglycate, the activity correlation of which between conventional test animals, on the one hand, and domestic animals and humans, on the other hand, is known, that the compounds of The present invention are antiallergic agents suitable as inhalation agents or for oral or parenteral administration.

In this way, the compounds according to the present invention are advantageous for suppressing allergic manifestations of immediate atopic sensitivity in humans and homeothermic animals, that is to say domesticated animals, such as mice, rats, the hamster, the gerbil, the dog, the cat, the sheep, the goat, the horse, the cow, etc., and this by administration of an effective amount of one or more of the compounds of the invention by the oral route , topical, intraperitoneal, intramuscular or intravenous. The compounds of the invention can be administered in conjunction with known compounds ensuring an anti-histamine, antihypertensive, analgesic, central nervous system depressant, immunosuppressive, antiserotonin, anti-bradykinin or endocrinological effect. In addition, known conventional adjuvants can be combined with the antiallergic agents of the invention to obtain compositions and solutions suitable for administration, although it is considered advantageous and practicable to use the antiallergic agents as as pure compounds or without additives other than those intended for the formation of solutions or suspensions of suitable pharmaceutical liquids or vapors.

The effective dose range in test animals has been shown to range from approximately 0.01 mg / kg to a dose providing almost 100% prevention of allergic sensitivity to 200 mg / kg of body weight of the receiver, or less.

For inhalation, the dose is 2 mg or less, administered as needed before the attack. The dose envisaged for use by the oral or intraperitoneal route in humans, based on the efficacy of the compounds, ranges from approximately 1 mg to 2 g, preferably from 5 mg to approximately 1.5 g, in the form of unit doses to be administered when needed and up to the desired effect, in one or more doses taken under the supervision of a doctor. With regard to the dose to be used in the treatment of a specific atopic allergic reaction, the subjective observations of the attending physician are decisive. The dose for humans, as well as the dose for dogs, depends on the specific allergy being treated, the importance, the age, the type of sensitivity and the severity of the attack. known allergic in the treated patient. No exceptional experience is necessary to establish the dose volume and the most advantageous regimen for a particular patient, since the loss or suppression of the symptom is apparent to both the patient and the doctor. The effective amount of the antiallergic compound administered should be determined empirically for each subject treated.

As examples of the compounds of the invention which are active orally, there may be mentioned the ethyl ester of 2-cyano-3- (dimethylamino) oxanilic acid, showing an oral activity equivalent to an inhibition of 54% at 5 mg / kg body weight of the host, 67% inhibition at 25 mg / kg body weight, and 73% inhibition at 100 mg / kg body weight, as well as hydrochloride d 2-cyano-3- (4-methyl-1-piperazinyl) oxanilic acid ethyl ester, which shows 77% inhibition when administered orally at 25 mg / kg bodyweight host. As examples of the compounds according to the invention showing antiallergic activity during administration into the peritoneum, mention may be made of ethyl ester of 2-cyano-3- (1-piperi-dinyl) oxanilic acid, which ensures 93% inhibition at 200 mg / kg body weight of the host, the two compounds mentioned in the preceding sentence assuming, for the same purpose, and being used in the same way, a 93% inhibition at 200 mg / kg body weight of the host, and 88% inhibition at 200 mg / kg body weight. As mentioned previously, the preferred compounds are those for which the amino group appears in position 3 in the form of the free amino group or the amino lower alkyl group. These compounds have been found to provide 100% inhibition in a dose as low as 0.10 mg / kg when administered intravenously using the sodium salt of [2-cyano-3- (methylamino) phenylamino acid. ] oxoacetic.

Example 1:

[2-Cyano-3- (dimethylamino) phenyl-amino] oxoacetic acid ethyl ester

To a solution of 9.7 g of 2,6-dinitrobenzonitrile and 6.1 g of dimethylamine hydrochloride in 100 ml of dimethylformamide, 6 g of potassium hydroxide in 20 ml of water are added. The solution is stirred for 4 h, poured into ice water, then filtered and dried the product, namely 2-dimethylamino-6-nitro-benzonitrile, with a melting point of 112-116 ° C.

Analysis for c9h9n3o2:

Calculated: C 56.54 H 4.75 N 21.98 Found: C 56.28 H 4.77 N 21.77.

To a suspension of 5.7 g of 2-dimethylamino-6-nitrobenzo-nitrile in 20 ml of methanol and 17 ml of concentrated hydrochloric acid, 5.3 g of an iron powder is added in portions. The mixture is stirred for 1 h, diluted with 200 ml of water and extracted with methylene chloride, then dried and evaporated in vacuo to obtain the crude 2-amino-6-dimethylaminobenzonitrile.

2.7 g of methylene chloride are added dropwise to a solution of 3.4 g of crude 2-amino-6-dimethylaminobenzo-nitrile and 1.6 g of pyridine in 50 ml of methylene chloride at 0 °. ethyl oxalyl in 25 ml of methylene chloride. The solution is stirred at 0 ° C for 3 h, heated to room temperature and water is added. The organic phase is separated, dried and evaporated to give a yellow solid which is recrystallized from benzene / hexane to obtain 3.2 g of the title compound, with a melting point of 124-126 ° C.

Analysis for Ci 3H15n3o3:

Calculated: C 59.76 H 5.79 N 16.08 Found: C 59.47 H 5.47 N 16.08.

Example 2:

\ 2-Cyano-3- (l-piperidinyl) phenylamino ~ \ -oxoacetic acid ethyl ester

To a solution of 19.3 g of 2,6-dinitrobenzonitrile in 300 ml of dimethylformamide, 25.5 g of piperidine is added and the resulting solution is heated to 85 ° C., then it is kept at this temperature until that the reaction is complete. The reaction mixture is poured into water, and the product, namely 2-nitro-6- (1-piperidinyl) benzonitrile, is filtered and dried, with a melting point of 119-121 ° C.

Analysis for C12H13N3O2:

Calculated: C 62.32 H 5.67 N 18.17 Found: C 62.32 H 5.82 N 18.26.

The 2-nitro-6- (1-piperidinyl) benzonitrile prepared according to the preceding paragraph is converted into 2-amino-6- (1-piperidinyl) -benzonitrile by reduction with iron according to the method of Example 1.

The title compound is obtained by reaction of 2-amino-6- (1-piperidinyl) benzonitrile with ethyloxalyl chloride, the melting point of the compound obtained being 98-100 ° C.

Analysis for C16H19N3O3:

Calculated: C 63.77 H 6.36 N 13.94 Found: C 63.76 H 6.37 N 13.76.

Example 3:

[2-Cyano-3- (4-methyl-1-piperazinyl) phenylamino] oxacetic acid ethyl ester hydrochloride

By following the process presented in the first paragraph of

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Example 2, except that N-methylpiperazine is substituted for piperidine, 2- (4-methyl-1-piperazinyl) -6-nitrobenzo-nitrile is prepared, with a melting point of 126- 129 ° C.

Analysis for C12H14N4O2:

Calculated: C 58.52 H 5.73 N 22.75

Found: C 58.65 H 5.87 N 22.78.

To a solution of 4.92 g of 2- (4-methyl-1-piperazinyl) -6-nitrobenzonitrile in 11 ml of concentrated hydrochloric acid, 3.4 g of an iron powder is added. The mixture is stirred for 30 min, it is poured into ice water and the pH is adjusted to 12. Methylene chloride is added, the total mixture is filtered through celite, the methylene chloride is separated, dried and evaporated to obtain a crude solid product, namely 2-amino-6- (4-methyl-1-piperazinyl) benzonitrile.

A mixture of 3.96 g of crude 2- (4-methyl-1-piperazmyl) -6-aminobenzonitrile and 2.74 g of ethyloxalyl chloride is stirred for 2 h at room temperature, then poured into 1 , 68 g of sodium bicarbonate in 25 ml of water and the mixture is stirred for 5 min. The organic layer is separated, dried and evaporated. The remainder is dissolved in diethyl ether / ethanol, diethyl ether / hydrochloric acid is added and the crystallization of the product is allowed to develop to obtain the title compound, in the pure state, of a melting point of 204-206 ° C (decomposition).

Analysis for C16H20N4O3 .HCl:

s Calculated: C 54.56 H 6.00 N 15.88 Cl 10.05

Found: C 54.53 H 6.31 N 15.90 Cl 10.08.

Following the general preparation methods, described in the previous examples, while modifying the amine reagent (HNR1! * 2) used in the displacement reaction with 2,6-dinitro-10 benzonitrile, also reducing the remaining nitro substituent to give the reactive amino group and finally combining the product with an oxalyl chloride ester, a family of esters of 2-cyano-3- or 4- (substituted amino) oxanilic acids is obtained, which is can saponify directly to give a salt, or which is easily hydrolyzed under moderate conditions to give the corresponding oxanilic acids which, in turn, are readily converted to the corresponding salts by reaction with a desired base.

Various amines, HNR * R2, which are used in the synthesis of the antiallergic compounds of the invention, using in each case ethyloxalyl chloride as a representative element of the oxalyl ester reagents which can be used in a such synthesis, are:

NHR1R2

R1

R2

Ethyl acid ester

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

-h -ch3

-ch3

-H

-ch2ch3 -H

-ch2ch2ch2-CH3 -H -H

-H

-ch3

-ch3

-CH

/

chs ch3 -ch2ch3 -ch2ch2ch2ch3

ch3

I

-chch2ch3 -ch2ch2ch2ch3

heptyl hexyl ch3 I

-ch2ch

I

ch3

2-cyano-3- (methylamino) oxanilic 2-cyano-3- (dimethylamino) oxanilic

2-cyano-3- (isopropylmethylamino) oxanilic

2-cyano-3- (ethylamino) oxanilic

2-cyano-3- (ethylbutylamino) oxanilic

2-cyano-3- (sec-butylamino) oxanilic

2-cyano-3- (dibutylamino) oxanilic

2-cyano-3- (heptylamino) oxanilic 2-cyano-3- (hexylamino) oxanilic

2-cyano-3- (isobutylamino) oxanilic

R1

11. 1-pyrrolidinyl

12. 1-piperidinyl

13. 4-methyl-1-piperazinyl

14. morpholino

15. thiomorpholino

16. 1-Azetidine

17. 1-Aziridine

Ethyl acid ester:

2-cyano-3- (1-pyrrolidinyl) oxanilic

2-cyano-3- (piperidino) oxanilic

2-cyano- (4-methyl-1-piperazinyl) oxanilic

2-cyano-3- (morpholino) oxanilic.

2-cyano-3- (thiomorpholino) oxanilic

2-cyano-3- (l-azetidinyl) oxanilic

2-cyano-3- (l-aziridinyl) oxanilic

Example 4:

[2-Cyano-4- (dimethylamino) phenyl-amino] oxoacetic acid ethyl ester

To a solution of 4.6 g of ethyl ester of [2- (amino-

65 carbonyl) -4- (dimethylamino) phenylamino] oxoacetic in 130 ml of chloroform at 0 ° C., 2 ml of phosphorus oxychloride and 13 ml of triethylamine are added. The reaction mixture is stirred at room temperature until the reaction is complete

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(about 6 days). Water is added, the pH is adjusted to about 5 and the organic layer is separated, dried and evaporated. The product is recrystallized from ethanol, melting point 150-152 ° C.

Analysis for c13h15n3o3:

Calculated: C 59.76 H 5.79 N 16.08 Found: C 59.76 H 6.02 N 15.91.

The ethyl ester of [2- (aminocarbonyl) -4- (dimethyl lamino) pheny lamino] oxacetic acid is prepared by oxalation of 2-amino-5-dimethylaminobenzamide with ethyloxalyl chloride as in the case of the example 2, melting point of 203-205 ° C.

Analysis for CUH17N3O4 .:

Calculated: C 55.90 H 6.14 N 15.05 Found: C 56.12 H 6.23 N 15.08.

2-amino-5-dimethylaminobenzamide is obtained by treatment of 5-dimethylamino-isatoic anhydride hydrochloride with IN ammonium hydroxide in a manner similar to the method of R. P. Staizer and E. C. Wagner, "J. Org. Chem. ”, 13.347 (1948).

5-Dimethylamino-isatoic anhydride hydrochloride is obtained by treatment of the corresponding anthranilic acid with phosgene in a manner identical to that presented by J.H. Sellstedt et al., "J. Med. Chem. ”, 18.926 (1975) for 3,5-dimethylanthranilic acid, m.p. 256-258 ° C (dec.).

Analysis for c10h10n2o3. HCl:

Calculated: C 49.49 H 4.57 N 11.55 Cl 14.61

Found: C 49.15 H 4.54 N 11.10 Cl 14.57.

5-Dimethylaminoanthranilic acid is known, see R. A. Rossi and H. E. Bertorello, "An. Assoc. Quirn. Silver ”, 55.227 (1967).

Example 5:

[3-Amino-2-cyanophenylamino] -oxoacetic acid ethyl ester

The title compound is prepared by reduction of the ethyl ester of [3-nitro-2-cyanophenylamino] oxoacetic acid with a catalyst containing 10% palladium on charcoal and with cyclohexene in ethanol, following the process of ID Entwistle and RAW Johnstone, "J. Chem. Soc. ”, Perkin I, 1300 (1975). The crude product is chromatographed on silica gel with chloroform and recrystallized from ethanol, melting point 133-136 ° C.

Analysis for CHH11N3O3:

Calculated: C 56.64 H 4.76 N 18.02 Found: C 56.58 H 4.64 N 18.20.

The ethyl ester of [3-nitro-2-cyanophenyl-amino] oxoacetic acid is prepared by treatment of 2-amino-6-nitrobenzo-nitrile with ethyloxalyl chloride as in the case of Example 1, point 111-113 ° C.

Analysis for c11h9n3o5:

Calculated: C 50.19 H 3.45 N 15.97

Found: C 50.11 H 3.44 N 15.99.

2-amino-6-nitrobenzonitrile is prepared in the following manner.

19.3 g of 2,6-dinitrobenzonitrile are dissolved in 400 ml of methanol and 250 ml of dioxane at reflux. 60 ml of concentrated hydrochloric acid are added thereto, then 18 g of an iron powder per portion. The mixture is allowed to reflux for 1 h, then evaporated to dryness. Water is added, the resulting solid is separated by filtration, dried and extracted with hot ethyl acetate. After filtration through celite, the product is left to crystallize, melting point 196-198 ° C.

Analysis for c7h5n3o2:

Calculated: C 51.54 H 3.09 N 25.76

Found: C 51.39 H 3.01 N 25.68.

Example 6:

\ _3- (methylamino) -2-cyanophenylamino \ -oxoacetic acid ethyl ester

The oxalation of 2-amino-6-methylaminobenzonitrile as in Example 1 gives the title compound, m.p .: 137-139 ° C.

Analysis for C12H13N3O3:

Calculated: C 58.29 H 5.30 N 17.00 Found: C 58.13 H 5.32 N 16.94.

The 2-amino-6-methylaminobenzonitrile is prepared by reduction with iron of the 2-methylamino-6-nitrobenzonitrile as in Example 1.

2-methylamino-6-nitrobenzonitrile is prepared as follows. To 19.3 g of 2,6-dinitrobenzonitrile in 150 ml of dimethylformamide at 85 ° C., 25 ml of 40% aqueous methylamine are added. The mixture is heated for 1 h, it is poured into ice water and the product is separated by filtration, melting point of 203-206 ° C.

Analysis for C8H7N3O2:

Calculated: C 54.23 H 3.99 N 23.72

Found: C 54.24 H 3.70 N 24.02.

Example 7:

\ 2-Cyano-3- (ethylamino) phenylamino ~ \ -oxoacetic acid ethyl ester

The crude 2-amino-6-ethylaminobenzonitrile is subjected to oxalation, as in the case of Example 1, to obtain the compound cited in the heading, melting point 99-102 ° C.

Analysis for c13h15n3o3:

Calculated: C 59.76 H 4.79 N 16.08 Found: C 59.35 H 5.89 N 15.88.

The crude 2-amino-6-ethylaminobenzonitrile is prepared by reduction of 2-ethylamino-6-nitrobenzonitrile with iron as in Example 1.

The 2-ethylamino-6-nitrobenzonitrile is obtained by displacement on the 2,6-dinitrobenzonitrile with ethylamine as in Example 6, m.p .: 114-116 ° C.

Analysis for c9h9n3o2:

Calculated: C 56.54 H 4.75 N 21.98

Found: C 56.73 H 4.75 N 21.73.

Example 8:

[3- (Butylamino) -2-cyanophenylamino] -oxoacetic acid ethyl ester

This material is prepared by following the method of Example 1, by oxalation of 2-amino-6-butylaminobenzonitrile, with a melting point of 101-105 ° C.

Analysis for c15h19n3o3:

Calculated: C 62.26 H 6.62 N 14.52 Found: C 62.03 H 6.42 N 14.55

2-amino-6-butylaminobenzonitrile is obtained by reduction of iron as in Example 1.

2-Butylamino-6-nitrobenzonitrile is obtained by the usual displacement reaction using butylamine, m.p .: 72-74 ° C.

Analysis for C ^ H ^^ Os:

Calculated: C 60.26 H 5.98 N 19.15 Found: C 60.38 H 6.09 N 19.06.

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Example 9:

[3- (Ethylmethylamino) -2-cyanophenyl-amino] oxoacetic acid ethyl ester

Treatment of 2-amino-6- (ethylmethylamino) benzonitrile with oxalyl chloride as in the case of Example 1 gives the product mentioned in the heading, melting point of 75-78 ° C.

Analysis for C14H16N303:

Calculated: C 61.08 H 6.22 N 15.26 Found: C 60.77 H 6.21 N 15.34.

The amine is obtained by the usual reduction with iron. 2- (ethylmethylamino) -6-nitrobenzonitrile is obtained by displacement with ethylmethylamine, melting point 60-63 ° C.

Analysis for Q0H11N3O2:

Calculated: C 58.53 H 5.40 N 20.48 Found: C 58.84 H 5.48 N 20.81.

Example 10:

Ethyl ester of [2-cyano-3- (methylisopropylamino) -phenylamino] oxoacetic acid

The usual oxalation of 2-amino-6- (methylisopropylamino) -benzonitrile as in the case of Example 1 gives the compound mentioned in the heading, melting point of 64-67 ° C.

Analysis for c15h19n3o3:

Calculated: C 62.26 H 6.62 N 14.52 Found: C 62.30 H 6.65 N 14.53

2-amino-6- (methylisopropylamino) benzonitrile is obtained by iron reduction as in Example 1.

2- (methylisopropylamino) -6-nitrobenzonitrile is obtained by the usual substitution with methylisopropylamine, m.p .: 70-72 ° C.

Analysis for c11h13n3o2:

Calculated: C 60.26 H 5.98 N 19.15 Found: C 60.21 H 5.93 N 19.19.

Example 11:

[2-Cyano-3- (pyrrolidinyl) phenylamino] -oxoacetic acid ethyl ester

The oxalation of 2-amino-6-pyrrolidinylbenzonitrile as in Example 1 gives the title compound, m.p .: 138-141 ° C.

Analysis for c15h17n3o3:

Calculated: C 62.70 H 5.96 N 14.63 Found: C 62.81 H 5.98 N 14.61.

The 2-amino-6-pyrrolidinylbenzonitrile is prepared by iron reduction of the corresponding nitro derivative, as in the case of Example 1, melting point of 112-114 ° C.

Analysis for CuHi3N3:

Calculated: C 70.56 H 7.00 N 22.44

Found: C 70.51 H 6.71 N 22.50.

2-nitro-6-pyrrolidinylbenzonitrile is prepared by the usual displacement (example 6) using Pyrrolidine, melting point 111-113 ° C.

Analysis for c11h11n3o2:

Calculated: C 60.82 H 5.10 N 19.35 Found: C 61.04 H 5.14 N 19.59.

Example 12:

[2-Cyano-3- (morpholinyl) phenylamino] -oxoacetic acid ethyl ester

This compound is prepared from 2-amino-6-morpholinyl-

benzonitrile and oxalyl chloride in the usual manner, m.p .: 115-117 ° C.

Analysis for c15h17n3o4:

Calculated: C 59.39 H 5.65 N 13.86 Found: C 59.21 H 4.76 N 13.69.

2-amino-6-morpholinylbenzonitrile is prepared by reduction of 2- (4-morpholinyl) -6-nitrobenzonitrile as in Example 1, m.p .: 157-160 ° C.

Analysis for c11h13n3o:

Calculated: C 65.00 H 6.45 N 20.68

Found: C 64.81 H 6.35 N 20.79.

2- (4-morpholinyl) -6-nitrobenzonitrile is prepared by displacement with morpholine as in the case of Example 6, melting point 152-155 ° C.

Analysis for c11h11n3o3:

Calculated: C 56.65 H 4.76 N 18.02 Found: C 56.95 H 4.82 N 18.35.

Example 13:

1-methylpropyl ester of [2-cyano-3- (4-morpholinyl) -phenylaminojoxoacetic acid

This material is prepared according to the method of Example 12, using sec-butyloxalyl chloride, instead of ethyloxalyl chloride, melting point 108-111 ° C.

Analysis for c17h21n3o4:

Calculated: C 61.62 H 6.39 N 12.68 Found: C 61.42 H 6.71 N 12.95.

The following sodium salts were all prepared by the same process. The ethyl ester of oxoacetic acid is dissolved in ethanol under reflux, exactly one equivalent of 5.9N sodium hydroxide is added and the solution is allowed to cool. The resulting solid is filtered, washed with ethanol and dried to give the sodium salt.

Example 14:

Sodium salt of [2-cyano-3- (methylamino) phenylamino ~ \ -oxoacetic acid, 2 / d hydrate, Vj ethanolate m.p .: 272-275 ° C. (dec).

Analysis for C10H8N3O3. V5 ETOH. 2 / s HzO:

Calculated: C 48.49 H 3.91 N 16.31 Found: C 48.70 H 3.82 N 16.29.

Example 15:

Sodium salt of 2-cyano-3- (ethylmethylaminó) phenylaminó \ -oxoacetic acid, 7 / d 0 hydrate m.p .: 90-94 ° C.

Analysis for C ^ H ^ NaOsNa. 710 H20:

Calculated: C 51.14 H 4.79 N 14.91 Found: C 51.01 H 4.65 N 14.99.

Example 16:

Sodium salt of acid [3- (butylamino) -2-cyanophenylamino] -

oxoacetic

M.p .: 252-254 ° C.

Analysis for Ci3Ho, 4N303Na:

Calculated: C 55.12 H 4.98 N 14.83 Found: C 54.82 H 4.80 N 14.59.

Example 17:

Sodium salt of acid [2-cyano-3- (4-morpholinyî) phenylamino] -

oxoacetic, 4A 0 hydrate

M.p .: 170 ° C (contraction), 240 ° C (dec.)

5

10

15

20

25

30

35

40

45

50

55

60

65

9

618,963

Analysis for CisHiaNsCUNa. Vio H2O:

Calculated: C 51.28 H 4.24 N 13.80 Found: C 51.35 H 4.28 N 13.91.

Example 18:

(4-amino-2-cyanophenylamino) -oxoacetic acid ethyl ester

5.0 g of ethyl ester of (2-cyano-4-nitro-phenylamino) oxoacetic acid are hydrogenated in 150 ml of ethanol and 0.4 g of a catalyst containing 10% palladium on carbon, up to that the hydrogen fixation ceases. The reaction mixture is filtered through celite, evaporated to dryness and the solid is recrystallized from ethanol, 4.1 g, melting point 137-139 ° C.

Analysis for C11H11N3O3:

Calculated: C 56.65 H 4.76 N 18.02 Found: C 56.49 H 4.94 N 18.09.

The ethyl ester of (2-cyano-4-nitrophenyl) -oxoacetic acid is prepared by the usual oxalation of 2-amino-5-nitrobenzo-nitrile as in the case of Example 1, melting point 137 -139 ° C.

Analysis for c11h9n3o5:

Calculated: C 50.19 H 3.45 N 15.97

Found: C 49.99 H 3.55 N 15.98.

s The oxalyl chloride ester used in the synthesis of the compounds of the invention is preferably the ethyl ester, the secondary butyl ester or the cyclohexyl ester. However, other simple esters are also applicable, giving the corresponding esters with unchanged biological activity, although uptake by the host may vary somewhat. Thus, the esters produced initially can be the lower alkyl esters (for example methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, amyl, secondary amyl, hexyl, etc.), the esters of aralkyls (for example benzy-lique, phenethyl, etc.), or esters of cycloalkyls (for example cyclopentyl, cyclohexyl, etc.). Thus, the esters produced according to the invention include esters in which the hydrocarbon fragment of the alcohol is an alkyl of 1 to 6 carbon atoms, an aralkoyl of 7 or 8 carbon atoms or a cyclo-alkyl of 5 or 6 carbon atoms.

R

Claims (28)

618,963 2 1. Process for the preparation of a compound of formula R 1 H 2 Cl (I) NHCOCOOR and its pharmaceutically acceptable acid addition salts, formula in which: R represents a C1-C6 alkyl, C7 or C8 aralkoy or C 5 or Ce cycloalkyl radical, R1 is hydrogen or a C1-C9 alkyl group, and R2 is hydrogen, a C1-C9 alkyl group or a C1-C9 cycloalkyl group, or R1 and R2 form, together with the nitrogen atom to which they are linked, an aziridinyl, azetidinyl, pyrrolidinyl, piperininyl, piperazinyl, 4- (lower alkyl) piperazinyl, morpholino or thiomorpholino radical, the substituent —NR'R2 being fixed in position 3 or 4, characterized in that an amino compound of formula is reacted 30 (the) 2 (Ib) with a reactive functional derivative of the carboxyl group of the acid of formula HOOC-COOR and dehydrating the compound obtained to form the substituent —CN if a starting material of formula Ib was used. 2. Process for the preparation of a compound of formula I in which R is hydrogen, an alkali metal or a group - nh4, characterized in that the process of claim 1 is first carried out and that saponifies the ester obtained. 3. Process for the preparation of a compound of formula I in which R1 = R2 = H, characterized in that a compound of formula is reacted with a reactive functional derivative of the carboxyl group of the acid of formula HOOC-COOR in which R is a C1 to C6 alkyl, aralkyl to G7 or C8 or cycloalkyl to C5 or C6 radical and then the NO2 group is reduced to form the nh2 group. 4. Process for the preparation of a compound of formula I in which at least one of R1 and R2 is other than hydrogen, characterized in that the process according to claim 3 is carried out and that the primary amine obtained is subjected to a mono- or dialcoylation. 5. Method according to claim 1 for the preparation of a compound having the substituent - NRJR2 in position 3. 6. Method according to claims 1 and 5, characterized in that R1 is hydrogen or a straight chain alkyl radical in Ci to C6, and R2 is hydrogen or a C1 to C6 alkyl radical 7. The method of claim 1 for the preparation of C1 to C6 alkyl esters of 2-cyano-3- (dimethylamino) -oxanilic acid. 8. The method of claim 2 for the preparation of 2-cyano-3- (dimethylamino) oxanilic acid or one of its alkali metal or ammonium salts. 9. The method of claim 1 for the preparation of a 5 C1-C6 alkyl ester of 2-cyano-3- (methylamino) acid - oxanilic. 10. The method of claim 2 for the preparation of 2-cyano-3- (methylamino) oxanilic acid or one of its alkali metal salts, especially the sodium or ammonium salt. 11. 11. Process according to claim 1 for the preparation of a C1-C6 alkyl ester of 2-cyano-3- (1-piperidinyl) -oxanilic acid. 12. The method of claim 2 for the preparation of 2-cyano-3- (1-piperidinyl) oxanilic acid or a salt thereof. 15 alkali or ammonium metal. 13. The method of claim 1 for the preparation of a C1-C6 alkyl ester of 2-cyano-3- (4-methyl-1-piperazinyl) oxanilic acid. 14. The process according to claim 2 for the preparation of 2-cyano-3- (4-methyl-1-piperazinyl) oxanilic acid or one of its alkali metal or ammonium salts. 15. The method of claim 1 for the preparation of a C1-C6 alkyl ester of 2-cyano-4- acid (dimethylamino) - 25 oxanilic. 16. The method of claim 2 for the preparation of 2-cyano-4- (dimethylamino) oxanilic acid or one of its alkali metal or ammonium salts. 17. The method of claim 3 for the preparation of a C1-C6 alkyl ester of 2-cyano-3-aminooxanilic acid. 18. Process for the preparation of 2-cyano-3 aminooxani-lic acid or one of its alkali metal or ammonium salts, characterized in that the process according to claim 17 is carried out and that the saponified ester obtained. 19. The method of claim 1 for the preparation of a C1 to C6 alkyl ester of 2-cyano-3- (ethylamino) -oxanilic acid. 20. The method of claim 2 for the preparation 40 2-cyano-3- (ethylamino) oxanilic acid or one of its alkali metal or ammonium salts. 21. The method of claim 1 for the preparation of a C1-C6 alkyl ester of 2-cyano-3- (butylamino) -oxanilic acid. 22. Method according to claim 2 for the preparation of 2-cyano-3- (butylamino) oxanilic acid or one of its alkali metal salts, in particular the sodium or ammonium salt. 23. The method of claim 1 for the preparation of a C1-C6 alkyl ester of 2-cyano-3- (ethylmethylamino) acid - 50 oxanilic. 24. The method of claim 2 for the preparation of 2-cyano-3- (ethylmethylamino) oxanilic acid or one of its alkali metal salts, in particular the sodium or ammonium salt. 25. The method of claim 1 for the preparation of a 55 C1-C6 alkyl ester of 2-cyano-3- (methylisopropyl-) acid amino) oxanilic. 26. The method of claim 2 for the preparation of a C1-C6 alkyl ester of 2-cyano-3- (methylisopropyl-amino) oxanilic acid or one of its alkali metal or ammonium salts. 27. The process as claimed in claim 1 for the preparation of a C1-C6 alkyl ester of 2-cyano-3- (pyrrolidinyl) -oxanilic acid. 28. The method of claim 2 for the preparation of 2-cyano-3- (pyrrolidinyl) oxanilic acid or one of its alkali metal salts 65 or ammonium. 29. The method of claim 1 for the preparation of a C1 to C6 alkyl ester of 2-cyano-3- (morpholinyl) -oxanilic acid. 35 3 618,963 30. The method of claim 2 for the preparation of 2-cyano-3- (morpholinyl) oxanilic acid or one of its alkali metal or ammonium salts. 31. The method of claim 3 for the preparation of a C1-C6 alkyl ester of 2-cyano-4-aminooxanilic acid. 32. Process for the preparation of 2-cyano-4-aminooxani-lic acid or one of its alkali metal or ammonium salts, characterized in that the process according to claim 31 is carried out and that saponifies l 'ester obtained.