CA1061356A - 2-cyano-3- or 4-(substituted amino) oxanilic acid derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The 2-cyano-3-or 4-(substituted amino) oxanilic acid derivatives of the formula:
in which the group appears in the designated 3- or 4- position and R is -H; and alkali metal; +NH4; alkyl of 1 to 6 carbon atoms, inclusive; aralkyl of 7 or 8 carbon atoms; or cycloalkyl of 5 or 6 carbon atoms;
R1 is -H or alkyl of 1 to 9 carbon atoms;
R2 is -H, alkyl of 1 to 9 carbon atoms or cycloalkyl of 3 to 6 carbon atoms;
R1 and R3, together, with the nitrogen atom to which they are attached, are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-lower alkyl-piperazinyl, morpholino or thiomorpholino;
and pharmaceutically acceptable acid addition salts thereof are anti-allergic agents.

Description

` ~06~3~G

The presen-t invention relates to 2-cyano-3 or 4 (sub-stituted amino) oxanilic acid derivatives having pharmacological activity.

Atopic allergic reactions are of the immediate hypersensitivity type as opposed to delayed hypersensitivity reactions, the latter being involved in such things as tuberculin sensitivity, transplant rejection, contact dermatitis and the like. Commonly recognized clinical conditions known to be at least in part due to atopic immediate hypersensitivity reactions, include seasonal and perennial allergic rhinitis (hay fever) .... .
and asthma, anaphylaxis, urticaria, conjunctivitis, angioaedema, eczema, various food and drug reactions and insect sting reactions. The substances most frequently responsible for atopic allergic reactions are plant pollen, animal feathers and danders, dust, milk and wheat, whether inhaled or injested. Atopic hypersensitivity is found in man, dog and other animals although its occurrence is exceptionally found in the lower animals.
Atopic (immediate hypersensitivity) reactions are characterized by the immunopathologic mechanism, the elements of which are: (1) a specific immunoglobulin ~antibody: IgE in man, or homocytotropic antibody in the rat) is produced; (2) it is fixed to the surface of a target cell; (3) an antigen or allergin combines with the cell-bound antibody, which(~) induces release of one or more , ~ , ~ 1 -2- i pharmacologic mediators, which in turn (5) induces symp-toms of clinical disease such as increased vascular perme-ability, smooth muscle contraction, mucous gland hyper- ;
secretion, leukotaxis (especially eosinophilotaxis) and irritation of sensory nerve endings~
A compound which will interfere with the antigen-IgE reaction to prevent the release of medialtors from the .: .. . . .
ma~t cell, or permit a non-productive antigen-antibody reaction without release of mediators, of necessity blocks the atopic allergic reaction thereby avoiding the resultant changes which are symptomatic of the disease.
The presence of antibodies associated with atopic reaction~ in the host serum is established by the passive sensitization of the skin of a normal recipient, after in-jection of serum from a sensitized host into a skin ~ite followed by injection of antigen into the same area 2~ hours later, resulting in a local hive. This is commonly referred to as the Prausnitz-Kustner (P-K) reaction.
The antibody associated with atopic hypersensiti-vity possesses distinctive features in that it does not in all forms precipitate with its antigen, fails to pass the placenta from mother to fetus, has special affinity for the skin, frequently lacks specificity toward an individual antigen in an ~ndividual sensiti~ed by a variety of antigenic factors and is usually labile at about 56 C. after two hours.
The homocytotropic antibody found in or induced in the rat is related in function and reaction to immuno-globulin E (reagin or IgE) found in the human. The cor-relation between homocytotropic antibody in the rat and IgE

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. .

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in the human has been established through the common effects obtained from chemical reactions, immunological reactions and drug responses in the two species hosting those antibodies. In the human, reagin is the antibody responsible for atopic immediate hypersensitive reactions.
In the rat, the homocytotropic antibody is responsible for atopic immediate hypersensitive reactions.
In theory, reagin influences the cell membrane `
of a mast cell by reacting with an antigen, to initiate the reaction(s) within the mast cell which ultimately releases a mediator such as Bradykinin, SRS-A (slow reacting sub- ;
stance-A), histamine, and other unknown substances. The mediator effects a change in surrounding cell wall permea-bility permitting a rapid change in flow or exudance of mediator(s) from the cells, resulting in an allergic attack symptom. The various methods commonly employed to relieve the symptoms of allergic attack, none of which are consi-dered to be quite acceptable, are to (1) avoid attack by ~'!
the antigen, (2) block the production of antibody with an immunosuppressant, (3) block the action of the mediators on the cell under attack b~ administration of anti-hista-mines, anti-5-hydroxy-tryptamine (5-HT) or anti-inflamma-tories, or (4) stimulate and cell under attack to negate the action of the mediator through the action of bronchodi-lators such as Isoprel~ or a Xanthine.
The only commercial compound known to date to op- ;
erate as an anti-allergic primarily by blocking reaction(s) within the mast cells, thereby preventing the production and release of mediators, is disodium cromoglycate (INTAr~
Disodium cromoglycate and compounds of that class are preventative in the sense that they must be adminis-,'' .

~!~613~6 tered to the sensitized animal prior to the allergic attack to ,," : ., be effective. They are not effective after the mediators have ;, been released from the mast cells. Hence, their function is in preventing the release of mediators and/or a productive antibody-antigen reaction. As such, the rat PCA test ~measur-ing the effect of mediator release) may be used to establish a compound as effective for all atopies because it establishes the diminished mediator release values in terms of the de-crease in allergic response of the animal. The rat PCA test establishes the extent of mediator release from mast cells located in the rodent skin as a factor of the diminished effect on the skin of the test animal in relationship to the con-trol animals.
The rat PCA (passive cutaneous anaphylaxis) test provides a classic procedure for e~aluating the efficacy of drugs of the INTAL class relative to the response of the standard test animal resulting from antigen antibody inter-action and mediator release. Extrapolation from an effect on the homocytotropic antibody of the rat to an effect on ;~
reaginic antibody (IgE) in the human is proper because of ;
the well established relationship between these antibodiesO
With knowledge of the mechanism of activity of `~
INTAL in blocking the production of chemical mediators re- `
sulting from an antigen~antibody reaction and the variety of confirmed activities of INTAL in controlling or prevent-ing immediate hypersensitivity reactions in man, as well as the close relationship between the rat homocytotropic anti-body and IgE in the human, coupled with the fact that INTAL
is the standard now used in the field for evaluating the efficacy of new anti-allergic compounds for atopic allergic _ 5 -' reaetions via the rat P~A test must lead to the practical conclusion that compounds which are active in the rat PCA
test can, with very reasonable assurance, be projected as active anti-allergie agents in ma~, dog, etc.
As new anti-allergics are being developed, their activity mechanism is related to that of INTAL as the stan-dard because of its known activity in man and its activity in the rat PCA test. In this regard see Pfister et al., JO Med. Chem., vol. 15, No. 10, pp. 1032-1035 (1972);
Broughton et al., Nature, vol. 251, pp. 650-652, October 18, 1971; and Assem et al., British Med. Journal, April 13, 197~, pp. 93-95.
DESCRIPTION OF THE INVENTION
In aeeordance with this invention, there i~ pro-vidod a group of ehemieal eompounds, useful for inhibiting development of the physieal symptoms attending an atopic allergie reaetion, presenting the formula: -' Rl R2 ..

N

CN
~ N~ICOC02R

in which -R is -H; an alkali metal; +NH4; alkyl of 1 to 6 carbon atoms, inclusive; aralkyl of 7 or 8 carbon atoms; or cyeloalkyl of 5 or 6 earbon atoms;
R is -H or alkyl of 1 to 9 carbon atoms;
R is -H, alkyl of 1 to 9 carbon atoms or eycloalk~l of 3 to 6 carbon atoms;
'` ~ ' . '~ ~' ' - 6 - ~

and -`
Rl and *, together with the nitrogen atom to which they are attached, are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperaz;inyl, 4-lower alkyl-pipera~inyl, morpholino or thiomorpholino~
and pharmaceutically acceptable acid addition salts thereof.
In the preeeeding formula, the alkali metals co~- ;
templated for the group "~", ~re sodium, potassium or lith~
iumO Embraced by the expression "alkyl o 1 to 6 carbon atoms" are such alkyl groups as methyl, ethyl, n=propyl, i-propyl, n-butyl, secondary bu~yl, tertiary butyl, pentyl ;
and hexyl. The expression "aralkyl of 7 or 8 carbon atoms"
is intended to embrace the benzyl and phenethyl radicals.
The contemplated cycloalkyl groups of 5 or 6 carbon atoms embrace cyclopentyl as well as cyclohexyl. The groups representing R~ and R2 may be normal or secondary alkyl ~;
containing from 1 to 9 carbon atoms each. Where Rl and R2 represent a cyclic group with the nitrogen atom depicted in the structwral formula, they are represented as dimethylene, trimethylene, tetramethylene, pentamethylene, or the 3-oxa, aza, or thia-pentamethyle~e radicals (oxy, thio or imino di-ethylene). In those situations where Rl and R2 repre-sent a heterocyclic group containing ni$rogen, it is pre-ferred to prepare the compounds in the form of their non- ~ -toxic pharmaceutically acceptable acid addition salts for the purpose of separation and recoveryO Likewise, when Rl and/or R2 is hydrogen, that amino group is proteeted during reaction with the chloro oxalic acid ester follolwed ~0 ultimately by removal of the protecting group. For this purpose, any standard protecti~g group known to the art ,. . .

- 7 - ~

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may be employed, the trimethylsilyl group being represen-~ative of the type of protecting group especially suitable for the purpose stated.
The expression, pharmaceutically acceptable acid addition salts, is used to include the non-toxic acid ad-dition salts which may be formed with either organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, nitric~ p-toluene sulfonic, acetic, citric, maleic, succinic acid and the like.
The pref~rred compounds from the sta~dpoint of potency are those in which Rl a~d R2 are hydrogen or Rl is lower alkyl and R2 is hydrogen and the amino group ~ 1 -N

~, is in the 3-position.
The 3- or 4-substituted-2-cyanooxanilic acid com-pounds o this invention are generally produced by condens- ` i ing an appropriately substituted 2-cyanoaniline w~th an ac-tivated oxalic acid half ester in which the substituent in .
3- or 4-position is amino, alkylamino of 1 to 9 carbon `~
atoms, dialkylamino of 1 to 9 carbon atoms in either alkyl moiety, cycloalkylamino of 3 to 6 carbon atoms, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-lower alkyl-piperazinyl, morpho:Lino or thiomorpholino.
;, , By an activated oxalic acid half ester, applicants embrace the acid halides, mixed anhydrides, azide, and the like ~ -groups employed in the production of amidic linkages. -The 2-cyano group may be formed optionally via f;. . ;~
dehydration of a correspondingly 2-carbamyl ~ubstituted precursor. Further more, a free amino group in 3- or 4-position may be produced ~y reduction of a nitro substi- ;
tue~t after condensation with said activated oxalic acid ''" '" ':~.
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.. , ,.. , .... . , ~ . .. . ~ ,, .. , ... . ., ............. ,,, . .. :, :.

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half ester. The free amino group may be then mono- ~`
or dialkylated with groups which are optionally cyclizable. `
Likewise, the final product ester is saponified with an appropriate base to afford an alkali metal or ammonium salt.
:.~. - .
The compounds of this invention have been demonstrated to relieve allergic manifestations when administered intraperitoneally and/or orallg to sensitized rats.
,. . .
The technique employed to establish the anti~
allergic activity of the disclosed compounds is reported in Immunology, vol. 16, pp. (749-760 (1969) and invol~es -four male Charles River rats (200-250 g. body weight) per group to provide a control, a host for adminis~ration of a standard anti-allergic compound (disodium cromoglycate) and animals for the test compound. The rats are injected intracutaneously or their shaved backs with sera from rats immunized with egg albumin and pertussis vaccine. Twenty-four hours after the initial injections, the test compound is administered intraperitoneally or orally at a m~ximum dosage level of 200 milligrams per kilogram host body weight. Five minutes later one milliliter of a 0.5 percent solution of Evans blue dye and 8 milligrams of egg albumin is injected intravenously. Ater forty minutes, the animal is sacrificed and the bleb size on its back is measured.
The mean bl!ëb size for the animals administered the test compound is calculated and the percent inhibition is deter-miIled by comparison with the control animal.
Although the mechanism by which the compounds of this invention function is not absolutely known, applicants have found that the compounds of this invention, in a man- `

_ 9 _ , ner believed to be similar to the function of INTAL, block ~`
reaction(s) in the mast cell leading to the production and release of media~ors. The compounds of this inventio~ per-mit the occurrence oL a non-productive antigen-antibody interaction by effectively blocking the Ig~ type reaction.
In sum, the compounds of this invention block the release of mediators commonly resulting from the a~tigen antibody ,. i reaction as exemplified in a passive cutaneous anaphylaxis test ~PCA) using rat homocytotropic antibody--a known cor-relate of human reaginic antibody.
By analogy to disodium cromoglycate and its acti-vity correlation between standard tes-t animals, domestic animals and man, the compounds of this invention have been established as anti-allergic agents suitable for use as in-halants or by oral or parenteral administration.
Thus, the compounds of this invention are useful for suppressing allergic manifestations of atopic immediate sensitivity in warm-blooded human and non-human animals, the latter including domesticated animals such as the mouse, rat, hamster, gerbil, dog, cat, sheep, goat, horse, cow, and the like, by administering an effective amount of one or more of the compounds disclosed in this application i by oral, topical, intraperitoneal, intramuscular or intra- `
venous routes. The compounds of this invention may be ad-ministered in coniunction with known compounds effecting antihistaminic, anti-hypertensive, analgesic, central ner-vous s~stem depressant, immunosuppressive, anti-serotonin, anti-Bradykinin or endocrinological responses. In addition, those conventional adjuvants known to the art may be com-bined with the anti-allergios of this invention to provide eompositions and solutions for admi~istrative purposes, :
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-~06~L356 although it is considered desirable and feasible to employ the anti-allergics as neat or pure compounds without addi-tives other than for purposes of pro~iding suitable pharma-ceutical solution or liquid or vapor suspensions.
The effective dose range in test animals has been established to be from about 0-01 mîlligrams per kilogram r to a dosage resulting in substantially 100 percent preven-tion of the allergic response at 200 milligrams per kilo-gram host body wei~ht, or less.
As an inhalant, the dose is two milligrams or less, administered as needed prior to attack. Thus, the ~-dosage contemplated for human oral or intraperitoneal use based upon the potency of the compound administered lies from about 1 milligram to 2 grams, preferably 5 milligrams to about 1.5 grams in unit dosage form to be administered when necessary and to the degree of the desired response, in single or plural doses ~nder the guidance of a p~ysician.
Regarding the dosage to be used in the treatment o~ a specific atopic allergic reaction, the subjective 2Q observations of the attending physician are determinative.
The human dose, like the dose for the dog, depends upon the speci~ic allerg~ being treated, the size, age, response pattern and severity of the known allergic attack in the specific patient. No unusual skill is involved in estab-lishing the most desirable dose size and regimen for a spe-;: .
cific patient because the loss or supp~ession of the symp-tom is apparent to both the patient and the physician.
The effective amount of the anti-allergic compound admin-istered must be empirically determined subjectively.
Illustrative of the compounds of this invention, which are orally active are 2-cyano-3-(dimethylamino)o~a-, ~L~96~35~; `

nilic acid ethyl ester, demonstrating oral activity equi-valent to 5~% inhibition at 5 milligrams per kilogram host body weight; 67% inhibition at 2~ milligrams per kilogram host body weight and 73% inhibition at 100 milligrams per kilogram host body weight, as well as 2-cyarlo-3-(4-methyl-l-piperazinyl)oxanilic acid ethyl ester hydrochloride which effects a 77% inhibition upon oral administration of 25 milligrams per kilogram host body weight. Illustrative of the compounds of this in~ention possessing anti-allergic activity upon intraperitoneal administration is 2-cyano-3-(l-piperidinyl)oxanilic acid ethyl ester which affords 93% ;
inhibit~on at 200 milligrams per kilogram host body weight;
the two compounds mentioned in the preceding sentence pre-senting, respectively, 93% inhibition at 200 milligrams per -kilogram host body weight and 88% inhibition at 200 milli-grams per kilogram host body weight. hs noted suPra, the ,. . .
preferred compounds as those in which the amino group ap~
pears in 3-position as the free amino group or lower alkyl-amino group. These compounds have been found to effect 100% inhibition with as low as 0.10 milligrams per kilo-gram dosage administered intravenously with the sodium salt of ~2-cyano-3-(methylamino)phenylamino~oxoacetic acid.

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Example 1 [2-Cyano-3-(Dimethylamino)Phenylamino]-_ Oxoacetic Acid Eth~l Ester To a solution of 9.7 g. of 2,6-dinitrobenzoni-trile and 6.1 g. of dimethylamine hydrochloride in 100 ml.
of dimethylformamide is added 6 g. of potassium hydroxide in 20 ml. of water. me solution is stirred for 4 hours, poured into ice water and the product, 2-dimethylami~o-6-nitrobenzonitrile, is filtered and dried, m.p. 112-116C.
Analysis for: CgHgN302 Calculated: C, 56.54; H7 4.75; N, 21.98 Found: C, 56.28; H, 4.77; N, 21.77 ,`
To a suspension oP 5.7 g. of 2-dimethylamino-6-nitrobenzonitrile in 20 ml. of meth~ol and 17 ml. of con-"A'~
centrated hydrochloric acid is added 5.3 g. of iron powder -in portions. The mixture is stirred for 1/2 hour, diluted -with 200 ml. of water and extracted with methylene chloride which is dried and evaporated in vacuo to yield crude 2- `
amino-6-dimethylaminobenzonitrile.
To a solution of 3~4 g. of crude 2-amino-6-di-methylaminoben~onitrile and 1.6 g. of pyridine in 50 ml. of m¢thylene chloride at 0 is added dropwis¢ 2.7 g. of ethyl oxalyl chloride in 25 ml. of methylene chloride. The solu-tion is stirred at 0 C. for 3 hours, warmed to room tem- --perature a~d water is added. The organic phase is separated, -dried a~d evaporated to give a yellow solid which is re-crystallized~r-o~ benzene hexane to yield 3~2 g. of the ti-tle compound, m.p. 124-126Co ~. . .
, ~; . .
Analysis for: C13~15N303 Calculated: C, 59.76; H, 5.79; H, 16.08 ~ ' Found: C, 59,47; H, 5.47; N, 16.08 :
- ~3 -' ~LQ6~356 ~ i Example 2 [2-Cyano-3~ Piperidinyl)Phenylamino~-_ Oxoacetic Acid_Ethyl Ester To a solution of 19.3 g. of 2,6-dinitrobenzoni-trile in 300 ml. of dimethylformamide is adlded 25.5 g. of piperidine and the resulting solution is warmed to 85 C.
and kept at that temperature until the reaction is complete.
The reaction mi~ture is poured into water, the product, 2- ;~
nitro-6-(1-piperidinyl)benzonitrile, is filtered and dried, m.p. 119-121C.
,~.. . ..
Analysis for: C12H13N30 Calculated: C, 62.32; ~I, 5.67; N, 18.17 Found: C, 62.32; H, 5.82; N, 18.26 The 2-nitro-6-(1-piperidinyl)benzonitrile pre- ;;
~... : .
pared in the preceding paragraph is converted to 2-amino-6-(l-piperidinyl)benzonitrile by iron reduction following the -procedure of Example 1. `;
The title compound is produced by reaction of 2-amino-6-(1-piperidinyl)benzonitrile with ethyl o~alyl chlo-ride, m.p. 98-100C.
Analysis for: C16HlgN303 Calculated: C, 63.77; H, 6.36; N, 13.94 Found: C, 63.76; H, 6.37; N, 13.76 ~`
~.
E~ample 3 C2-Cyano-3-(4-Methyl-l-Piperazinyl)Phenyl~mino]Oxacetic ;~
_ _ Acid Eth~l Ester H~drochloride ~
Following the procedure presented in the first paragraph of Example 2, with the e~ception that N-meth~l-. . .
piperazine is substituted for piperidine, 2-(~-methyl-]L-piperazinyl)-6-nitrobenzonitrile is prepared, m.p. 126 129 C. ',,' .

' ~. . ' .

~6~3~
Analysis for: C12H14N402 Calculated: C, 58052; H, 5.73; N, 22.75 Found: C, 58.65; H, 5.87; N, 22.78 To a solution of ~.92 g. of 2-(4-methyl-1-piper-azinyl)-6-nitrobenzonitrile in 11 ml~ of concentrated hydro-chloric acid is added 3.4 g. of iron powder~ The mixture is stirred for 30 minutes, poured into ice water and the p~ `r ~`
is adjusted to 12~ Methylene chloride is added, the whole mixture is filtered through celite, the methylene chloridle is separated, dried and evaporated to give solid, crude `- `
product, 2-amino-6-(4-methyl-1-piperaæinyl~benzonitrile.
A mixture 3.96 g. of crude 2-(4-methyl-1-pipera- ;
zinyl)-6-aminobenzonitrile, 2.74 g. of eth~l oxalyl chlo-ride is ~tirred for 2 hours at room temperature, poured into 1.68 g. of sodium bicarbonate in 25 ml. of water and stirred for 5 minutes. The organic layer is separated, :: .
dried and evaporated. The residue is dissolved in diethyl ether-ethanol, saturated diethyl ether-hydrogen chloride is added and the product is allowed to crystallize to give the pure title compou~d, m.p. 204-206C. (dec.).
Analysi9 for: Cl6H20N4o3 HCl Calculated: C, 54.56; ~I, 6.00; N, 15.88; Cl, 10.05 Found: C, 54.53; H, 6.31; N, 15.90; Cl7 10.08 Following the general preparative procedures ;-.. . .
exemplified in the preceding examples, by var~ing the amine reactant (HNRlR2) employed in the displacement reaction with 2,6-dinitrobenzonitrile, reducing the remaining nitro ~.
substituent to afford the reactive amino group ~nd finally coupling that produc$ with ~n oxalyl chloride ester~ there is afforded a family of 2-cyano-3- or 4-~substituted amino)-oxanilic acid esters which may be directly saponified to ,h, - 15 - ~>~
., afford a salt, or readily hydrolyzed under mild conditions to yi~ld the c~rresponding oxanilic acids which are in turn readily converted to the corresponding salts upon reaction with a desired base.
Vario~s amines, HNRlR27 employed in the ~yn~hesis of the anti-allergic compounds of this in~e:ntion and the final products, employing ethyl oxalyl chloride in each instance as representative of the simple oxalyl ester reac- :~
tants employed in the synthesis, are: ~;

N~lR2 - :
Rl R2 ~ 1 Ester of 1. -H -C~I3 2-cyanow3-~methylamino) oxanilic acid

2. -OEI3 -CH3 2-cyano-3-(dimethyl amino)oxanilic acid .i

3. -CH -CH ~ C~I3 2-cyano-3-(isopropyl- ~ :.
3 ~ methylamino)oxanilic ~ CH3 acid .~

4. -~I CH2C 3 2-cyano-3-(ethylamino) :~ : oxanilic acid :

5. -CH CH -CH CH CH2C~I3 2-cyano-3-(eth~lbutyl- :
2 3 2 2 amino)oxanilic acid

6. -H OEI 2-cyano-3-(sec-butyl-1 3 amino)oxanilic acid . :
-~HOEI2CH3 ',``: ' ' .

7- CH~CH2CH2~I3 -CH2C~I2CH2C~l3 2-cyano-3-(dibutyl- . .: .
~ amino)oxanilic acid .. :

8. -~I heptyl 2-cyano-3-(heptyl- ::
amino)oxanilic acid

9. -H hexyl 2-cyano-3-(hexyl~ -C~I3 amino~oxanilic acid

10. -H c~2~ 2-cyano-3-(isobutyl- ..
CH amino)oxanilic acid 3 i~ :
' :

.... .....
. J

.

~ 6~356 R~
/ ~ Final Produet R2 Ethyl Ester of

11. l-pyrrolidinyl 2-cyano-3~ pyrrolidi-nyl)oxanilic acid -

12. l-piperidinyl 2-eyano-3-~(piperidirlo)-o~anilie aeid

13. 4-methyl-1-piperazinyl 2-cyano-(4-methyl- 1-piperazinyl)oxanilic acid -

14. morpholino 2-eya~o-3-(morpholino)- ~`
oxanilie aeid

15. thiomorpholino 2-cyano-3-~thiomorpho- ;-lino)oxanilic aeid

16. l-azetidine 2-cyano-3-(l~azetidi-nyl~oxanilie aeid ;

17. l-aziridine 2-eyano-3-(1-aziridi-nyl)oxanilie aeid Example 4 ~2-Cyano-4-(Dimethylamino)Phenylamino]
Oxoacetie Acid Ethyl Ester To a solution of 4.6 g. of ~2-(aminocarbonyl)-4- S~
..~. . . ..
(dimethylamino)phenylamino]oxoaeetic aeid ethyl ester in ~; ' f 130 ml. of ehloroform at 0C. is added 2 ml. of phos~
phorus oxychloride and 13 ml. of triethylamine. The reac-tion is stirred at room tempera~ure until eomplete (ap-proximately 6 days). Water is added, the p~I is adjusted to about 5 and the organic layer is separated, dried and eva porated. The produet i~ reerystallized from ethanol, m.p.
150-15~C.
Analysis for: C13HlsN303 Caleulated: C, 59.76; H, 5.79; N, 16.08 Found: C, 59.76, H, 6.02, N, 15.91 , - 17 - ~.
.

~6~356 ;`: :

[2-(Aminocarbonyl)-4-(dimethylamirlo)phenylamino]
oxacetic acid ethyl ester is prepared by oxalation OI 2-amino-5-dimethylaminobenzamide with ethyl oxalyl chloride as in Example 1, m.p. 203-205VC.
Analysis for: C13H17N304 Calculated: C, 55.90; H, 6.14; N, 15.05 ;`
Found: C, 56.12; ~I, 6.23; N, 15.08 2--Amino-5-dimethylaminobenzamide is obtained b~
treatment of 5-dimethylaminoisatoic anhydride hydrochloride with lN ammonium hydroxide in a manner similar to the pro-cedure OI R. P. Staizer and E. C. Wagner, J. Org. Chem., 3, 347 (19~8).
5-Dimethylaminoisatoic anhydride hydrochloride is obtained by treatment of the corresponding anthranilic acid with pho~gene in a manner identical to that given in J. H.
Sell~tedt et al., J. Med. Chem., 18 926 (1975) for 3,5-dimethyl anthranilic acid, m.p. 256-258 C. (dec).
Analysis f~r: CloHloN203 HCl Calculated: C, 49.49; H, 4.57; N, 11.55; Cl, 14.61 Folmd: C, 49315; ~I, 4.54; N, 11.10; Cl, 14.57 5-Dimethylaminoanthranilic acid is known, R. A.
Rossi alld H. E. Bertorello, An. Assoc. Quim. Argent., 55, 227 (1967).
E~ample 5 [3-Amino-2-Cyanophenylamino]-(~xoacetic Acid Ethyl Ester _ The title compound is prepared by reduction of i [3-nitro-2-cyanophe~ylamino]oxoacetic acid ethyl ester with 10% Pd. on charcoal and with cyclohexene in ethanol accord~
ing to the procedure of I. D. Entwistle alld R. A. W.

- 18 -~06~356 ~:

Johnstone, J. Chem. Soc., Perkin I, 1300 (1975). The crude product is chromatographed on silica gel with chloro~orm and recrystallized fr-~m ethanol, m.p. 133-136 C.
Analysis for: CllHllN303 Calculated: C, 56.64; H, 4.76; N, 18.02 Found: C, 56.58; H, 4.64; N, 18.20 [3-Nitro-2-cyanophenylamino]oxoac0tic acid ethyl ester is prepared by treatment of 2-amino-6--nitrobenzoni-trile with ethyl oxalyl chloride as in Example 1, m.p.
111-113C. ~ -Analysis for: CllHgN305 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 as follows: i ~
2,6-Dinitrobenzonitrile (19.3 6 ) is dissolved in i ;
methanol (400 ml.) and dioxane (250 ml.) at reflu~. To this is added conc. hydrochlorio acid (60 ml.) follo~ed by iron ~! , powder (18 g.) in portions. The mi~ture is left at reflux for 1 hr., and is evaporated to drynes~. Water is added, the resultant solid is filtered off, dried and extracted with hot ethyl acetate. After filtration through Celit~ , the product i9 allowed to crystallize, m.p. 196~198C.
~nalysis for: C7H5N302 Calculated: C, 51.54; H, 3.09; N, 25.76 Found: C, 51.39 7 H, 3.01; N, 25.68 Example 6 [3-(Methylamino)-2-Cyanophenyl~mino]-_ Oxoacetic Acid Et~l Ester Oxalation of 2-amino-6-methylaminobenzonitrile as in Example 1 gi~es the title compound, m p. 137-139C.

- 19 -;
, ".
. . .~

~ \ ~;

~6~L3S6 :- -Analysis for: C12~I13N303 Calculated: C, 58.29; H, 5.30; N, 17.00 Found: C, 58.13; Hs 5.32; N, 16.94 2-Amino-6-methylaminobenzonitrile is prepared by iron reduction of 2-methylamino-6-nitrobenzonitrile as in Example 1.
2-Meth~lamino-6-nitrobenzonitrile is prepared as follows:
to 19.3 g. of 2,6-dinitrnbenzonitrile in 150 ml. of dimethylform~mide at 85C. is added 25 ml. of 40% aqueous methylamine. The mixture is heated for 1 hour, poured into ice water and the product is removed by filtration~ m.p. 203-206C.
,. .
Analysis for: C8H7N302 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 E~ter Crude 2-amino-6-ethylaminobenzonitrile is , :.:
oxalated as in Example 1 to give the title compound, m.p. 99-102C.
Analysi~ for: C13~ll5N303 Calculated: C, 59.76; H, 4.79; N, 16.08 Found: C, 59.35; H, 5.89; N, 15.88 Crude 2-amino-6-ethylaminobenzonitrile is pre-pared by iron reduction of 2-ethylamino-6-nitro-benzo-nitrile as in Example 1.
2-ethylamino 6-nitrobenzonitrile is obtained by displacement on 2,6-dinitrobenzonitrile with ethylamine ..;. , as in E~ample 6, m.p. 114-116Co ;; ... :. '

- 20 - ~
.. . . . .

~L~6~3~6 Analysis for: C9HgN30~
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-Cyanophenylami3no]-Oxoacetic Acid Ethyl Ester This material is prepared following the procedure of Example 1, by oxalation of 2-amino-6-butylaminoben~onitrile, `j -m.p. 101-105C.
Analysis for: Cls~lgN303 Calculated: C, 62.26; H, 6.62, N, 14.52 Found: C, 62.03; H, 6.~2; N, 1~.55 2-amino-6-butylaminobenzonitrile is obtained b~
iron reduction a~ in Example 1.
2-butylamino-6-nitrobenzonitrile is o~tained by the usual displacement reaction using butylamine, m.p.
72-74C.
Analysis for: CllH13N
Calculated: C, 60.26; H, 5.98; N, 19.15 Found:C, 60~38; H, 6.09; N, 19.06 Example 9 C3-(Ethylmethylamino)~-2-Cyanophenylamino~-_ Oxoacetic Acid Ethyl E~ter Treatment of 2-amino-6-(ethylmethylamino)benzo-nitrile with ethyl oxalyl chloride as in Example 1 gives the product, m.p. 75-78C. ~ -AnalySis for: C14H17N303 Calculated. C, 61.08; H, 6.22; N9 15.26 Found: C9 60.77; H, 6.21; N, 15.34 l~e amine is obtained by the usual iron reduction.
:

- 21 -1C~6~356 2-(ethylmethylamLne)-6-nitrobenzonitrile is obtained by displacement with ethylmethylamine, m.p. 60~63C. ~ ;
Analysis or: CloHllN302 Calculat0d: C, 58.53; H, 5 ~0; N, 20.~8 -~
Found:C, 58.84; H, 5.48; N, 20.81 E~ample 10 ., .
[2-Cyano-3-(Methylisopropylamino)Phenylamino]- -Oxoa¢etic Acid Eth~l Ester ~
v -- :
The usual oxalation as in Example 1 of 2-amino 6-(methylisopropylamino)benzonitrile gives the title compound, m.p~ 64-67C.
Analysis for: ClsH19N303 ~`
Calculated: C, 62.26; H, 6.62; N, 14.52 Found: C, 62.30; ~, 6.65; N, 14.53 2-ami~o~6-(methylisopropylamino)benzonitrile is obtained by iron reduction as in Example 1.
2-(methylisopropylamino)-6-nitrobenzonitrile is obtained by the usual substitution using methylisopropylamine, m.p. 70-72C.
Analysis for: CllH13N30 Caleulated: C, 60.26; H, 5.98; N, 19.15 Found: C, 60.21; ~I, 5.93; N, 19.19 Exam~le 11 C2-Cyano-3-~Pyrrolidinyl)Phenylamino:l- , -'~
Oxoacetic Acid Eth~l Ester O~alation of 2-amino-6-pyrrolidinylbenzonitrile as in Example 1 gives the title compound, m.p. 138-141C.
:, .
Analysis for: C15H17N
Calculated: C, 62.70; H, 5.96; N, 14.63 Fou~d: C, 62.81; H, 5.98, N, 14.61 "'" :.
; ., .

- 22 `` 1~6~356 :`
"
2-amino-6-pyrrolidinylbenzonitrile is prepared by iron reduction of the corresponding nitro deri~ative as in Example 1, m~p. 112-114C. !`,i' .
Analysis for: CllH13N3 Calculated: C, 70.56; H, 7.00; N, 22.44 Found: C, 70.51; H, 6.71; N, 22.50 2-nitro-6-pyrrolidinylbenæonitrile is prepared by the usual displacement (example 6) using pyrrolidine, ..
m.p.lll-113C.
. ~ , Analysis for: CllHllN30 Calculated:C, 60.83; H, 5010; N, 19.35 Found:C, 61.04; H, 5.14; N, 19.59 E~am~le 12 ;
~2-C~ano-3-(Morpholinyl)Phenylamino~-i Oxoacetic ~cid Ethyl Estsr `~
,;
This is prepared from ~-amino-6-morpholinyl-benzonitrile and ethyloxalyl chloride in the usual manner, m.p. 115-117C.
Analysis for: ClsH17N304 Calculated: C, 59.39; H, 5.65; N, 13.86 Found: C, 59.21; H, 4.7~; N, 13.69 ~ `
2-amino-6-morpholinylbenzonitrile is prepared b~
reduction of 2-(4-morpholin~1)-6-nitrobenzonitrile as in Example 1, m.p. 157-160C.
Analysis for~ CllH13N30 Calculated: C, 65.00; H, 6.45; N, 20.68 Found: C, 64.81; H, 6035; N, 20.79 -~
2-(4-morpholinyl)-6-nitrobenzonitrile is pnepa~ed by displacement with morpholine as in Example 6, m.p.
152-155C.

, ., ..

- 23 -~6~L3~;6 ` ~
Analysis for: CllHllN303 Calculated: C, 56.65; H, 4.76; N, 18.02 ; -Found:Cg 56.95; H, 4.82; N, 18.35 ~ ,; , Exam~le 13 '!'.`
[2-Cyano-3-(4-Morpholinyl)Phenyl~ino~- ~
Oxoacetic Aci~ l-Methylpropyl Ester ~ -This material is prepared as in Example 12 using sec-butyloxalyl chloride instead of ethyl oxalyl chloride, m.p. 108-111C.
Analysis ~or C17II21N34 ~ ~ -Calculated: C, 61.62; H, 6.39; N, 12.68 Found: C, 61.42; H, 6.71; N, 12.95 The following sodium salts are all prepared by ;
the same procedure: -The o~oacetic acid ethyl ester is dissolved in ethanol at reflux, exactly one equivalent of 5.9 N sodium hydroxide is added and the solution is allowed to cool.
The resul~ing solid is filtered, washed with e~hanol and dried to gi~e the sodium salt.

Example 14 [2-Cyano-3-(Methylamino)phenylamino]- ;
Oxoacetic Acid Sodium Salt, 2/5 hydrate1 1/5 Ethanola~e i m.p. 272-~75C.(dec) Analysis ~or: CloH8N303 1/5 EtoH 2/5 H20 ;
Calculated: C, 48.49; H, 3.91; N, 16.31 `~
Found: ~, 48.70; H, 3.82; N, 16.29 Example 15 `~' C2-Cyano-3-~EthylmethylamiIlo)Ph~ylamino]- ,, ::, ,.
Oxoacetic Aci~ Sodium Salt, 7/10 Eydrate m.p. 90-94C.

- 2~ -, ,.
::

, . . . . . . . . .. .. . ... . . .. ...

~(~6~356 ; .
Analysis for C12~12N35Na 7/10 H20 Calculated: C, 51.14; H, 4.79; N, 14.91 Foun~: ~, 51.01; H, 4.65; N, 14~99 Exam~le 16 ~3 (Butylamino)-2-Cyanophenylamino]- ;;
Oxoacetic Acid, Sodium Salt m.p. 252-254C.
Analysis for: C13H14N303Na Calculated: C, 55.12; H, ~.98; N, 1~.83 -~
Found: C, 54.82; H, 4.8~-; N, 14.59 !:

Example l?
C2 Cyano-3-(4-Morpholinyl)Phenylamino~-Oxoacetic Acid, Sodium Salt, ~/lQ H~drate m.p. 170C.(shrink), 240C.(dec.) Analysis for: C13H12N30~Na ~/10 H20 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-Cyanophen~l~mino)Oxoacetic Acid Ethyl Ester 5.0 g. of (2-cyano-~-nitrophenylamino)oxoacetic ; acid ethyl ester in 150 ml. of ethanol and 0.4 g. of 10%
Pd/C is hydrogenated until hydrogen uptake ceases. The reaction mixture is filtered through Celit~ , evaporated to dryness and the solid is recrystalli~ed from ethanol, 4.1 g., m.p. 137-139C.
nalysiS or: c~ N3o3 I Calculated: C, 56 65; ~I, 4 76; N, 18.02 ;~ Found: C, 56.49; H, 4.94; N, 18.09 ., , , .,.~ , ; - 25 -... .
.;.~. . ~ ... , . :

. . , . ~ - ~ :
.; .

~ 61356 ~2-cyano-4 nitrophenyl)oxoacetic acid ethyl ester is prepared by the usual ethyl oxalation of 2-amino-5-nitrobenzonitrile as in Example 1, m.p. 137-319C.
Analysis for: CllHgN305 Calculated: C, 50~19; H, 3.45; N, 1~.97 ~ ~
Found: C, 49.99; H, 3.55; N, 15.98 - -The oxalyl chloride ester employed i~ the synthesis of the compounds of this invention is preferable the ethyl ester, the sec-butyl ester or the cyclohexyl esterO Ho~~
ever, other simple esters are similarly applicable, producing the corresponding ester products with unchanged biological activity, although assimilation by the host may vary some-what. Thus, the esters initially produced may be lower alkyl (e.g. methyl, ethyl~ propyl, i-propyl, butyl, sec-butyl, amyl, sec-amyl, hexyl, etc.); aralk~l (e.g. benzyl, phenethyl, etc~); or cycloalkyl (e.g. cyclopantyl, cyclo-hexyl, etc.). Thus, the esters produced as part of this invention embrace esters in which the hydrocarbon moiety of the alcohol is alkyl of 1 to 5 carbon atoms, hydro- ;;
carbonic aralkyl of 7)c~ 8 carbon atoms or cycloalkyl of S to 6 carbon atomY.

,' , ." . .

. .
.'~ .~, _ 26 -... .

Claims (62)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the production of a 3- or 4-substituted 2 cyano oxanilic acid derivative of the formula I.

(I) in which R is -H; an alkali metal; +NH4; alkyl of 1 to 6 carbon atoms, inclusive; aralkyl of 7 or 8 carbon atoms; or cycloalkyl of 5 or 6 carbon atoms; R1 is -H or alkyl of 1 to 9 carbon atoms; R2 is -H, alkyl or 1 to 9 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; and R1 and R2 together, with the nitrogen atom to which they are attached, are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-lower alkyl-piperazinyl, morpholino or thiomorpholino; or a pharmaceutically acceptable acid addition salt thereof, which comprises (a) condensing a compound of the formula II

(II) wherein R1 and R2 are as above with a reactive derivative of an oxalic acid half ester of the formula III

R?CO2?COOH (III) or (b) condensing a compound of the formula IV

(IV) with the reactive derivative of the oxilic acid half ester of formula III and subsequently reducing the nitro group to a amino group and when R1 and R2 is required to be alkyl, alkylating the product obtained. Or (c) dehydrating of a compound of the formula:
wherein R1, R2 and R are as above, and when R is alkyl and R is required to be hydrogen or an alkali metal or NH4+ saponifying the product obtained and if required reacting the product with an alkali metal or amonium base.

2. A process as claimed in Claim 1, in which the reactant cyano compound is produced by the dehydration of the corresponding 2-carbanyl compound.

3. A process as claimed in Claim 1, in which the reactive derivative is an acid halide, mixed anhydride or azide.

4. A compound of the formula:

(L) in which R is -H; an alkali metal; +NH4; alkyl of 1 to 6 carbon atoms, inclusive; aralkyl of 7 or 8 carbon atoms; or cycloalkyl of 5 or 6 carbon atoms; R1 is -H or alkyl of 1 to 9 carbon atoms;
R2 is -H, alkyl of 1 to 9 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; and R1 and R2 together, with the nitrogen atom to which they are attached, are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-lower alkyl-piperazinyl, morpholino or thiomorpholino; or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of Claim 1, 2 or 3 or an obvious chemical equivalent thereof.

5. A process as claimed in Claim 1, in which the group is in 3-position.

6. A compound of formula I given in Claim 1, in which the group is in 3-position, and R, R1 and R2 are as in Claim 1 or a pharmaceutically accept-able acid addition salt thereof whenever prepared or produced by the process of claim 5, or an obvious chemical equivalent thereof.

7. A process as claimed in Claim 1, in which: R1 is hydrogen or normal alkyl of 1 to 6 carbon atoms; and R2 is hydrogen or alkyl of 1 to 6 carbon atoms.

8. A compound of formula I given in Claim 1 in which:
R1 is hydrogen or normal alkyl of 1 to 6 carbon atoms; and R2 is hydrogen or alkyl of 1 to 6 carbon atoms; and R is as in Claim 1 or a pharmaceutically acceptable acid addition salt;
thereof, whenever prepared or produced by the process of Claim 7, or an obvious chemical equivalent thereof.

9. A process as claimed in Claim 1, in which R1 and R2 taken together with the nitrogen atom to which they are attached, present one of the groups aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-lower alkyl-piperazinyl, morpholino or thiomorpholino.

10. A compound of formula I given in Claim 1 in which R1 and R2 taken together with the nitrogen atom to which they are attached, present one of the groups aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-lower alkyl-piperazinyl, morpholino or thiomorpholino and R is as in Claim 1, or a phar-maceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of Claim 9 or an obvious chemical equivalent thereof.

11. A process as claimed in Claim 5 in which R1 and R2 are methyl and R is hydrogen, NH4+ or alkyl of 1 to 6 carbon atoms.

12. The compound which is 2-cyano-3-(dimethylamino) oxamilic acid, an alkali metal salt, the ammonium salt, or an alkyl ester containing from 1 to 6 carbon atoms in the alkoxy moiety whenever prepared or produced by the process of Claim 11 or an obvious chemical equivalent thereof.

13. A process as claimed in Claim 5 in which R1 and R2 together with the nitrogen atom to which they are attached formal-piperidinyl group and R is hydrogen, NH4+ or alkyl of 1 to 6 carbon atoms.

14. The compound which is 2-cyano-3-(1-piperidinyl) oxanilic acid, an alkali metal salt, the ammonium salt, or an alkyl ester containing from 1 to 6 carbon atoms in the alkoxy moiety whenever prepared or produced by the process of claim 13 or an obvious chemical equivalent thereof.

15. A process as claimed in Claim 5, in which R1 and R2 together with the nitrogen atom to which they are attached form a 4-methyl-1-piperazinyl group and R is hydrogen, NH4+ or alkyl of 1 to 6 carbon atoms.

16. The compound which is 2-cyano-3-(4-methyl-1-piperazinyl)oxanilic acid, an alkali metal salt, the ammonium salt, or an alkyl ester containing from 1 to 6 carbon atoms in the alkoxy moiety whenever prepared or produced by the process of claim 15 or an obvious chemical equivalent thereof.

17. A process as claimed in Claim 1 in which the group is in the 4-position R1 and R2 are methyl and R is hydrogen, NH4+ or alkyl of 1 to 6 carbon atoms.

18. The compound which is 2-cyano-4-(dimethylamino-phenylamino] oxoacetic acid, an alkali metal salt, the ammonium salt, or an alkyl ester containing from 1 to 6 carbon atoms in the alkoxy moiety whenever prepared or produced by the process of claim 17 or an obvious chemical equivalent thereof.

19. A process as claimed in Claim 5, in which R1 and R2 are hydrogen and R is hydrogen, NH4+ or alkyl of 1 to 6 carbon atoms.

20. The compound which is [3-amino-2-cyanophenylamino]
oxoacetic acid, an alkali metal salt, the ammonium salt, or an alkyl ester containing from 1 to 6 carbon atoms in the alkoxy moiety whenever prepared or produced by the process of claim 19 or an obvious chemical equivalent thereof.

21. A process as claimed in Claim 5 in which R1 is hydrogen R2 is methyl and R is hydrogen, NH4+ or alkyl of 1 to 6 carbon atoms.

22. The compound which is [3-(methylamino)-2-cyano-phenylamino]oxoacetic acid, an alkali metal salt, the ammonium salt, or an alkyl ester containing from 1 to 6 carbon atoms in the alkoxy moiety whenever prepared or produced by the process of claim 21 or an obvious chemical equivalent thereof.

23. A process as claimed in Claim 5 in which R1 is hydrogen and R2 is ethyl and R is hydrogen, NH4+ or alkyl of 1 to 6 carbon atoms.

24. A compound which is [2-cyano-3-(ethylamino)phenyl-amino]oxoacetic acid, an alkali metal salt, the ammonium salt, or an alkyl ester containing from 1 to 6 carbon atoms in the alkoxy moiety whenever prepared or produced by the process of claim 23 or an obvious chemical equivalent thereof.

25. A process as claimed in Claim 5 in which R1 is n-butyl and R2 is hydrogen and R is hydrogen, NH4+ or alkyl of 1 to 6 carbon atoms.

26. The compound which is [3-(butylamino)-2-cyano-phenylamino]oxoacetic acid, an alkali metal salt, the ammonium salt, or an alkyl ester containing from 1 to 6 carbon atoms in the alkoxy moiety whenever prepared or produced by the process of claim 25 or an obvious chemical equivalent thereof.

27. A process as claimed in Claim 5 in which R1 is ethyl, R2 is methyl and R is hydrogen, NH4+ or alkyl of 1 to 6 carbon atoms.

28. The compound which is [3-(ethyl-methylamino)-2-cyanophenylamino]oxoacetic acid, an alkali metal salt, the ammonium salt, or an alkyl ester containing from 1 to 6 carbon atoms in the alkoxy moiety whenever prepared or produced by the process of claim 27 or an obvious chemical equivalent thereof.

29. A process as claimed in Claim 5 in which R1 is methyl and R2 is isopropyl and R is hydrogen, NH4+ or alkyl of 1 to 6 carbon atoms.

30. The compound which is [2-cyano-3-(methylisopropyl-amino)phenylamino]oxoacetic acid, an alkali metal salt, the ammonium salt, or an alkyl ester containing from 1 to 6 carbon atoms in the alkoxy moiety whenever prepared or produced by the process of claim 29 or an obvious chemical equivalent thereof.

31. A process as claimed in Claim 5 in which R1 and R2 together with the nitrogen atom to which they are attached form a 1-piperidinyl group and R is hydrogen, NH4+ or alkyl of 1 to 6 carbon atoms.

32. The compound which is [2-cyano-3-(pyrrolidinyl) phenylamino]oxoacetic asid, an alkali metal salt, the ammonium salt, or an alkyl ester containing from 1 to 6 carbon atoms in the alkoxy moiety whenever prepared or produced by the process of claim 31 or an obvious chemical equivalent thereof.

33. A process as claimed in Claim 5 in which R1 and R2 together with the nitrogen atom to which the are attached form a morpholinyl group and R is hrdrogen, NH4+ or alkyl of 1 to 6 carbon atoms.

34. The compound which is [2-cyano-3-(morpholinyl) phenylamino]oxoacetic acid, an alkali metal salt, the ammonium salt, or an alkyl ester containing from 1 to 6 carbon atoms in the alkoxy moiety whenever prepared or produced by the process of claim 33 or an obvious chemical equivalent thereof.

35. A process as claimed in Claim 1 in which the group is in the 4-position R1 and R2 are hydrogen and R is hydrogen, NH4+ or alkyl of 1 to 6 carbon atoms.

36. The compound which is (4-amino-2-cyanophenylamino) oxoacetic acid, an alkali metal salt, the ammonium salt, or an alkyl ester containing from 1 to 6 carbon atoms in the alkoxy moiety whenever prepared or produced by the process of claim 35 or an obvious chemical equivalent thereof.

37. A process as claimed in Claim 1 which comprises reacting 2-amino-6-dimethylaminobenzonitrile in methylene chloride with ethyl oxalyl chloride in the presence of pyridine.

38. [2-cyano-3-(dimethylamino)phenylamino]-oxoacetic acid ethyl ester whenever prepared or produced by the process of claim 37 or an obvious chemical equivalent thereof.

39. A process as claimed in Claim 1, which comprises reacting 2-amino-6-(1-piperidinyl)benzonitrile in methylene chloride with ethyl oxalyl chloride in the presence of pyridine.

40. [2-cyano-3-(1-piperidinyl)phenylamino]-oxoacetic acid ethyl ester whenever prepared or produced by the process of claim 39 or an obvious chemical equivalent thereof.

41. A process as claimed in Claim 1, which comprises reacting 2-(4-methyl-1-piperazinyl)-6-aminobenzonitrile with ethyl oxalyl chloride in aqueous sodium solution.

42. [2-cyano-3-(4-methyl-1-piperazinyl)phenylamino]
oxacetic acid ethyl ester hydrochloride whenever prepared or produced by the process of claim 41 or an obvious chemical equivalent thereof.

43. A process as claimed in Claim ? which comprises reacting 2-amino-5-dimethylaminobenzamide with ethyl oxalyl chloride in methylene chloride in the presence of pyridine and dehydrating the [2-(aminocarbonyl)-4-(dimethylamino)phenylamino]
oxoacetic acid ethyl ester so obtained inc hloroform and in the presence of triethyl amine with phosphorus oxychloride.

44. [2-cyano-4-(dimethylamino)phenylamino]oxoacetic acid ethyl ester whenever prepared or produced by the process of claim 43 or an obvious chemical equivalent thereof.

45. A process as claimed in Claim 1 which comprises reacting 2-amino-6-nitrobenzonitrile in methylene chloride with ethyl oxalyl chloride in the presence of pyridine and reducing the [3-nitro-2-cyanophenylamino]oxoacetic acid ethyl ester so obtained.

46. [3-amino-2-cyanophenylamino]-oxoacetic acid ethyl ester whenever prepared or produced by the process of claim 45 or an obvious chemical equivalent thereof.

47. A process as claimed in Claim 1, which comprises acting 2-amino-6-methylaminobenzonitrile in methylene chloride with ethyl oxalyl chloride in the presence of pyridine.

48. [3-(methylamino)-2-cyanophenylamino]-oxoacetic acid ethyl ester whenever prepared or produced by the process of claim 47 or an obvious chemical equivalent thereof.

49. A process as claimed in Claim 1, which comprises reactihg 2-amino-6-ethylaminobenzonitrile in methylene chloride with ethyl oxalyl chloride in the presence of pyridine.

50. [2-cyano-3-tethylamino)phenylamino]-oxoacetic acid ethyl ester whenever prepared or produced by the process of claim 49 or an obvious chemical equivalent thereof.

51. A process as claimed in Claim 1, which comprises reacting 2-amino-6-butylaminobenzonitrile in methylene chloride with ethyl oxalyl chloride in the presence of pyridine.

52. [3-(butylamino)-2-cyanophenylamino]-oxoacetic acid ethyl ester whenever prepared or produced by the process of claim 51 or an obvious chemical equivalent thereof.

53. A process as claimed in Claim 1, which comprises reacting 2-amino-6-(ethylmethylamino)benzonitrile in methylene chloride with ethyl oxalyl chloride in the presence of pyridine.

54. [3-(ethylmethylamino)-2-cyanophenylamino]-oxoacetic acid ethyl ester whenever prepared or produced by the process of claim 53 or an obvious chemical equivalent thereof.

55. A process as claimed in Claim 1 which comprises reacting 2-amino-6-(methylisopropylamino)benzonitrile in methyl-ene chloride with ethyl oxalyl chloride in the presence o pyridine.

56. [2-cyano-3-(methylisopropylamino)phenylamino]-oxoacetic acid ethyl ester whenever prepared or produced by the process of claim 55 or an obvious chemical equivalent thereof.

57. A process as claimed in Claim 1, which comprises reacting 2-amino-6-pyrrolidinylbenzonitrile in methylene chloride with ethyl oxalyl chloride in the presence of pyridine.

58. [2-cyano-3-(pyrrolidinyl)phenylamino]-oxoacetic acid ethyl ester whenever prepared or produced by the process of claim 57 or an obvious chemical equivalent thereof.

59. A process as claimed in Claim 1, which comprises reacting 2-amino-6-morpholinyl-benzonitrile in methylene chloride with ethyl oxalyl chloride in the presence of pyridine.

60. [2-cyano-3-(morpholinyl)phenylamino]-oxoacetic acid ethyl ester whenever prepared or produced by the process of claim 59 or an obvious chemical equivalent thereof.

61. A process as claimed in Claim 1, which comprises reacting 2-amino-6-morpholinyl-benzonitrile in methylene chloride with sec-butyloxalyl chloride in the presence of pyridine.

62. [2-cyano-3-(4-morpholinyl)phenylamino]-oxoacetic acid 1-methylpropyl ester whenever prepared or produced by the process of claim 61 or an obvious chemical equivalent thereof.