IE42778B1 - (2-cyanophenylamino)oxoacetic acid derivatives, processes for their preparation and compositions containing them - Google Patents

Description

The invention concerns new benzene derivatives useful as anti-allsrgic agents. In particular the invention provides neu oxanilio acid derivatives, a process for thsir preparation and pharmaceutical compositions containing them. The neu oxanilic acid derivatives are useful far inhibiting development of the physical symptotos attending an atopic allergic reaction.

The background of the invention is as follows.

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 and contact dermatitis. 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 mast frequently responsible far 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 uith - 2 4 2778 the call-bound antibody, uhich (4) induces release of one or more pharmacologic mediators, uhich in turn (5) induces symptoms of clinical disease such as increased vascular permeability, smooth muscle contraction, mucous gland hypersecretion, leukotaxis (especially eosinophilotaxis) and irritation of sensory nerve endings.

A compound uhich uill interfere uith the antigen-IgE reaction to prevent the release of mediators from the mast 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 uhich are symptomatic of the disease.

The presence of antibodies associated uith atopicreactions in the host serum is established by the passive sensitization of the skin of a normal recipient, after injection of serum from a sensitized host into a skin site followed by injection of antigen into the same area 24 hours later, resulting in a local hive. This is commonly referred to as the Prausnitz-Kustner (P-K) reaction.

The antibody associated uith atopic hypersensitivity possesses distinctive features in that it does not in all forms precipitate uith its antigen, fails to pass the placenta from mother tc fetus, has special affinity for the skin, frequently lacks specificity toward an individual antigen in an individual sensitized by a variety of antigenic factors and is usually labile at about 56°C. after tuo hours.

The homocytotropic antibody found in or induced in the rat is related in function and reaction to 4-27 7 8 immunoglobulin E (reagin or IgE) found in tha human.

Tha correlation between homocytotropic antibody in the rat and IgE in tha human has been established through the common effects obtained from chemical reactions, immunological reactions and drug responses in the tuo species hasting those antibodies. In ths human, reagin is the antibody responsible for atopic immediate hypersensitive reactions. In ths rat, the homocytotropic antibody is responsible for atopic immediate hypersensitive reactions.

In theory, reagin, influences the cell membrane of a mast cell by reacting uith an antigen, to initiate the reaction(s) within the mast cell which ultimately releases a mediator such as Bradykinin, SRS-A (slow reacting substance-A), histamine, and other unknown substances. The mediator effects a change in surrounding cell wall permeability 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 considered to be quite acceptable, ars to (1) avoid attack by the antigen, (2) block the production of antibody uith an immunosuppressant, (3) black the action of the mediators on the cell under attack by administration of.anti-histaminics, anti-5-hydroxy-tryptamine (5-HT) or antiinflammatories, or (4) stimulate the cell under attack to negate the action of the mediator through the action of bronchodilators such as Isuprsl or a Xanthine.

Isuprel is a trade mark.

The only commercial compound known to date to operate as an anti-allergic primarily by blocking - 4 42778 reaction(s) within the mast calls, thereby preventing the production and release of mediators, is disodium cromoglycate (INTAL). Intal is a trade mark.

Disodium cromoglycate and compounds of that class are preventative in the sense that they must be administered 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 antibodyantigen reaction. As such, the rat PCA test (measuring the effect of mediator release) may ba used to establish a compound as effective for all atopies because it establishes the diminished mediator release values in terms of the decrease 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 control animals.

The rat PCA (passive cutaneous anaphylaxis) teat provides a classic procedure for evaluating the efficacy of drugs of the Intal class relative to the response of the standard test animal resulting from antigen antibody interaction and mediator release. Extrapolation from an affect on the homocytotrapic antibody of the rat to an effect on reaginic antibody (IgE) in the human is proper because of the well established relationship betueen these antibodies.

Uith knowledge of the mechanism of activity of Intal in blocking the production of chemical mediators resulting from an antigen-antibody reaction and the variety of confirmed activities of Intal in controlling or preventing immediate hypersensitivity reactions in man, as uell as the close relationship betueen the rat homocytotropic antibody and IgE in the human, coupled uith the fact that Intal is the standard nou used in the field for evaluating tha efficacy of neu anti-allergies compounds for atopic allergic reactions via the rat PCA test must lead to the practical conclusion that compounds which are active in the rat PCA test can, uith very reasonable assurance, be projected as active anti-allergies in man, dog and similar animals.

As neu anti-allergies are being developed, their activity mechanism is related to that of Intal as the standard because of its knoun activity in man and its activity in the rat PCA test. In this regard see Pfister et al., 3. Ned. Chem., vol. 15, No. 10, pp 10321033 (1972); Broughton st al., Nature, vol. 251 pp 650652, Oct. 18, 1971; and Assam et al., British Ned. Journal, April 13, 1974, pp93-95.

In accordance uith this invention there is provided a group of chemical compounds, useful for inhibiting development of the physical symptoms attending an atopic allergic reaction, and having the formula: in which -NR1r2 is in the designated 3- or 4R is hydrogen; a pharmaceutically acceptable cation; alkyl of 1 tn 6 carbon atoms; aralkyl of 7 or 8 carbon atoms; or eycloalkyl of 3 to 1 2 atoms; R and R ars independently -H; alkyl, position, carbon alkenyl or alkynyl of up to 9 carbon atoms; cycloalkyl of 5 to 6 carbon atoms; aralkyl of 7 to 9 carbon atoms; aryl of 6 to 10 carbon atoms; furfuryl or aromatic heterocyclyl; 1 2 or R and R , together uith the nitrogen atom to which they are attached, are aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, 4-louer alkyl-piperazinyl, morpholino or thiomorpholino; and pharmaceutically acceptable acid addition salts thereof.

The invention includes a first class of compounds uhich S' have formula I, wherein the group -N-< appears in ^R2 the designated 3- or 4- position; R is hydrogen, an alkali metal, an ammonium ion, alkyl of 1 to 6 carbon atoms, aralkyl of 7 or 8 carbon atoms;or cycloalkyl of 5 or 6 carbon atoms; R is hydrogen or alkyl of 1 to 9 carbon atoms; Rz is hydrogen, alkyl of 1 to 9 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; or R 2 and R , together uith the nitrogen atom to uhich they are attached, are azaridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, 4-louer alkyl-piperazinyl, morpholino or thiomorpholino; and the pharmaceutically acceptable acid addition salts thereof.

The invention also includes a second class of compounds uhich have the formula nhcoco2r (la) in uhich R is hydrogen, a pharmaceutically acceptable cation, alkyl of 1 to 6 carbon atoms, aralkyl of 7 or 8 carbon atoms, or cycloalkyl of 5 Or 6 carbon atoms; R and R are independently hydrogen; alkyl, alkenyl or alkynyl of up to 9 carbon atoms; cycloalkyl of 5 or 6 carbon atoms; aralkyl of 7 to 9 carbon atoms; aryl of 6 to 10 carbon atoms; furfuryl or aromatic heterocyclyJ 1 2 or R and R , together uith the nitrogen atom to uhich they are attached, are aziridinyl, azetidinyl, ' pyrrolidinyl,. piperidino, piperazinyl, 4-louer alkylpiperazinyl, morpholino or thiomqrpholino; and the pharmaceutically acceptable acid addition salts thereof.

The invention also includes a third class of compounds which have the formula Ia, in which R is -H; an alkali metal; +NH4; alkyl of 1 to 6 carbon atoms; aralkyl of 7 or 8 carbon atoms; or cycloalkyl of 5 or 6 1 2 carbon atoms; R and R are independently -H; alkyl; alkenyl or alkynyl of up to 9 carbon atoms; cycloalkyl of 5 or 6 carbon atoms; aralkyl of 7 to 9 carbon atoms; aryl of 6 to 10 carbon atoms; furfuryl; 2,3 or 4-pyridyl; 2 or 3-thienyl; 2, 4 or 5-pyrimidinyl; 2 or 1,3,5-triazin-2-yl; or R and R , together, uith the nitrogen atom to uhich they are attached, are aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, 4-louer piperazinyl, morpholino or thiomorpholino; and the pharmaceutically acceptable acid addition salts thereof.

By the term lower alkyl as used herein, therein is intended alkyl of 1 to S, preferably 1 to 4 carbon atoms.

Ths compounds where R is a pharmaceutically acceptable cation are the pharmaceutically acceptable carboxylate salts. Such salts include the alkali metal salts, particularly ths sodium,potassium or lithium salts, the ammonium salts and non-toxic amine salts. Suitable organic amines include the di(louer)alkylamines, the tri(lower) alkylamines, aralkylamines, arylamines and hBterocyclicamines, 2 7 7 8 Examples of such amines include diethylamine, triethylamine, procaine, dibenzylamine, Ν,Ν -dibenzylethylene diamine, 1- ephenamine, N-louer alkyl piperidines and pyrrolidine. Embraced by the expression alkyl of 1 to 6 carbon atoms are such alkyl groups as methyl, ethyl, n-propyl, i-propyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl and n-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 are cyclopentyl and cyclohexyl. The groups representing 2 R and R may be normal or secondary alkyl, alkenyl or alkynyl substituents containing up to 9 carbon atoms 2 each. The cycloalkyl groups contemplated for R and R are cyclopentyl and cyclohexyl radicals. The 2 aralkyl groups representing R and R may be benzyl, phenethyl, or phenpropyl uhile the aryl groups may be phenyl, tolyl, ethylphenyl, or alpha-naphthyl. The aromatic heterocyclyl substituents contemplated for R 2 or R include 2-pyridyl, 3-pyridyl., 4-pyridyl, 2- thienyl, 3-thienyl, 2-pyrimidinyl, 4-pyrimidinyl, 51 2 pyrimidinyl or 1,3,5-triazine-2-yl. Uhere R and R represent a cyclic group uith the nitrogen atom depicted in the structural formula, they are represented as dimethylene, trimethylene, tatramethylene, pentamethylene, or the 3-oxa, aza, or thia-pentamathylene radicals (oxy, thio or imino di-ethylene). In those situations uhere 1 2 R and R represent a heterocyclic group containing nitrogen, it is preferred to prepare the compounds in the form of their pharmaceutically acceptable acid addition salts for the purpose of separation and recovery. Likewise, 2 when R or R is hydrogen, that amino group is protected during reaction uith the chlorooxalio acid ester followed ultimately by removal of the protecting group. For this purpose, any standard protecting group known to the art may be employed, the trimethylsilyl group being representative 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 addition salts which may be formed with either organic or inorganic acids such as hydrochloric, hydrobromic, sulphuric, phosphoric, methane sulphonic, nitric, p-toluene sulphonic, acetic, citric, maleic and succinic acid.

The preferred compounds from the standpoint of 1 2 production simplicity are those in which R and R are taken together with tha nitrogen atoms to which they are attached to form a heterocyclyl group as described above, and those in which R is hydrogen or normal alkyl of ο to 6 carbon atoms and R is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, phenyl, cyclopentyl or cyclohexyl.

The preferred compounds from the standpoint of 1 potency ars those in which R and R are hydrogen or R is 12 lower alkyl and R is hydrogen and the group -NR R is in the 3-position.

Examples of compounds according to the invention include [2-cyano-3- (dimethy lamino) phenylamine] oxoacetic acid,[2-cyano3-( piperidino) phenylaminejoxoacetic acid,[2-cyano-3-(4-methyl-l25 piperazinyl) phenylamino] oxoacetic acid, £2-cyano-4-(dimethylamino)phenylamino]-oxoaoetic acid, [3-amino-2-oyanophenylamino]oxoaoetic acid, [2-cyano-3-(methylamino)phenylamino]oxoacetic acid, [2-cyano-3-(ethylamino)phenylamino]-oxoacetic acid, [3-(butylamino)-2-cyanophenylamino]-oxoaoetic acid, 30 [3-(ethylmsthylamino)-2-cyanaphanylamino]-oxoacatic acid, [2-cyano-3-(methylisopropylamino)phenylamino]-oxoacetic acid, [2-cyano-3-(morpholino)phenylamino]-oxoacetic acid and (4-amino-2-cyanophanylamino)-oxoacatic acid and their alkali metal and ammonium salts and their alkyl asters containing 1 to 6 carbon atoma in the alkoxy moiety and tha acid addition salts of such compounds.

The invention provides a process for the preparation of a compound having formula I or a pharmaceutically acceptable acid addition salt thereof, uherein (a) a compound having the formula X aCN nh2 ω) wherein X is at the designated 3- or 4-position and represents -NR R (uherein R and Rz are as defined above) or a protected form of the group of formula 2 -NHR (uherein R is as defined above) is coupled with 15 a compound having the formula A-B, uherein A represents carboxyl or a reactive derivative thereof and B represents -CBjR (uhere R is as defined above) or a precursor therefor, A and X being chosen as to ba essentially unreactive towards each other under tha process conditions; 20 or (B) a compound having the formula C0NH2 NHCOB (III) uhere X and B ara as defined above, is dehydrated to form a nitrile; and, where necessary, the product is subjected to treatment to remove a protecting group from II 43778 X and/or to convert a precursor for -002R a kncwn method into and, if desired, a compound having formula I is converted into a pharmaceutically acceptable salt thereof or a salt form of a compound of formula I is converted into a compound of formula I.

Tha invention also provides a process for the preparation of a compound having formula I or a pharmaceutically acceptable acid addition salt thereof, uherein a compound having the formula NHCOB (IV) wherein the -NOg substituent is at the designated 3.or 4- position and B is as defined above, is reduced to convert the nitro group into an -NH2 group and, if desired, the resulting primary amine is converted into a secondary or tertiary amine in known manner, and,uhere approp riate, a precursor for -CO2R is converted by a known method into -002R and,i desired, a compound having formula I is converted into a phari ceutically acceptable salt thereof or a salt of a compound having formula I is converted into a compound having formula I.

The invention also includes a process for the preparation of the aforesaid first class of compounds and their pharmaceutically acceptable acid addition salts, in which an appropriately substituted cyanoaniline is reacted with an activated oxalic acid half ester and, if desired, converted into the appropriate oxoacetic acid or -an alkali metal or ammonium salt by a known method, for example, by saponification. These products may also be prepared by a process wherein a corresponding 2-carbamyl compound is dehydrated to form the 2-cyano group or by a process, wherein a corresponding 3- or 4-nitro compound is reduced to form an amino group at the 3- or 4- position and, if desired, the amino group is mono- or dialkylated with a monofunctional alkylating agent to give a secondary or tertiary amino or alkylated with a bifunctional alkylating agent to give a cyclic amine.

The process of the present invention includes a process for the preparation of the aforesaid third class of compounds having formula I and their pharmaceutically acceptable acid addition salts, in which a corresponding 2-cyano-3-(unsubstituted or substituted amino)aniline is reacted with the acid chloride of an oxanilic acid half ester and, if desired, the resulting ester product is hydrolysed.

Starting materials of formula A-B are generally known. Starting materials of formula II are known or may be prepared using known methods. One such method is the base catalyzed nitro group displacement from 2,6-dinitrobenzonitrile by ammonia, a primary amine or a secondary amine and reduction of the remaining nitro group of the product with nascent hydrogen as produced with iron, nickel or zinc in the presence of a mineral acid. Reduction with Pd-C and cyclohexene is a desirable method (Entwistle et al., J.Chem.Soc., Perkin I, 1300 (1975) .

Additional methods for preparing the starting material of formula II involve the production of an amide followed by dehydration, thus - 13 42778 or by displacement of a halo group in: where X is chloro, bromo, iodo or fluoro.

Process (A) of the invention comprises the reaction of the NH2 group uith the moiety represented by A to form an amide linkage. The reaction may be carried out by reacting the compound of formula II uith an acid of formula A-B (uhere A is carboxyl) in the presence of a condensing agent, for instance, a carbodiimide or a carbonyl diimidazole. The compounds of formula A-B uhere A is a reactive derivative of carboxyl may be used, for example, an ester, acyl halide, simple or mixed anhydride or the aoid azide. The acid halides, particularly the acid chlorides, i.s. uhere A is -C0C1, are especially suitable.

It uill be apparent to the skilled reader that the compound of formula II may have tuo reactive sites uhen *1 o R and/or R is hydrogen. Undesired reaction at the site 1 2 -NR R may be prevented in standard manner, particularly by selecting X and A in the starting materials so that X and A do not react together under the process conditions. Where A is a carboxyl derivative that reacts uith amines and R and/or R is hydrogen one should use a compound of formula II uhere X is a protected form of the amino group. The compound of formula II uhere X is a protected form of amino is reacted uith the compound having formula A-B and the protecting group is removed after the reaction. 43778 For this purpose any standard protecting group known to the art may be employed. The trimethylsilyl group is representative of the kind of protecting group especially suitable for the purpose. The trimethylsilyl group may be removed after the main reaction by hydrolysis.

In the compound having formula A-B, B may represent -C02R where R is preferably alkyl of 1 to 6 carbon atoms, aralkyl of 7 to 8 carbon atoms or cycloalkyl of 5 to 6 carbon atoms in the compound of formula I. Alternatively, B may represent a precursor for -CC^R. For example, where COgR is intended to be carboxyl or a pharmaceutically acceptable salt thereof such as an alkali metal, amine or ammonium salt in ths final product of formula I, one may use a protected form of carboxyl as B in the compound of formula A-B. Any standard protecting group may be used for protecting the carboxyl group. In particular one may use an ester derivative, preferably a lower alkyl ester derivative. The ester derivative may be hydrolysed after the main reaction to afford a free or salified carboxyl group.

The compounds having formula III may be prepared in standard manner, in particular, by reaction of compounds having the formula CONH (X) NH (where X is at the 3- or 4- position and is as defined above) uith a compound having formula A-B (where A and B are as defined above). The compounds having formula III may be dehydrated to form a nitrile by treatment uith a suitable dehydrating agent, for example, triphenyl phosphine ditriflate uhich is (CgHgJjPO plus (CF^SOg^O, phosphorus oxychloride, phosphorus pentachloride or thionyl chloride.

Ue prefer to carry out the dehydration in the presence ef an acid acceptor preferably an organic base, for instance, pyridine. However, an acid acceptor is not necessary in all cases, particularly since not all dehydrating agents require the elimination of a hydrogen halide and the group X may be basic, and therefore act as an acid acceptor. The reaction conditions used for the dehydration of the oompound having formula III , for example, the solvent used and the temperature may be in accordance uith standard conditions for the formation of nitriles from amides.

The compounds having formula IV may be prepared in knoun manner, in particular by reaction of 2-eyano-3 or 4-nitroaniline uith a compound having formula A-B (uhere A and B are as defined above). The reduction of the nitro group of the compound having formula IV may be carried out by hydrogenation using a palladium on carbon catalyst.

In the compounds having formulas III and IV, B may represent -COjR uhere R is preferably alkyl of 1 to 6 carbon atoms, aralkyl of 7 to 8 oarbon atoms or cycloalkyl of 5 or 6 carbon atoms in the compound of formula I. Alternatively, B may represent a precursor for -COgR. for example where C02R is intended to be carboxyl or a pharmaceutically acceptable salt thereof in the final product of formula I, one may use a protected form of carboxyl as Θ in the compound having formula III or IV. Any standard protecting group for protecting carboxyl may ba used. In particular □na may use an ester derivative, preferably a lower alkyl ester. The ester may be hydrolysed after the main reaction to afford a free or salified carboxyl group.

Compounds having formula I may'be converted into their acid addition salts by addition of an acid, for example, using ethereal hydrogen chloride uhere the hydrochloride is required. Acids of formula I uhere R is hydrogen may be converted into their pharmaceutically acceptable salts by neutralization uith a suitable base. Salt forms of compounds of formula I may be converted into the compound of formula I in standard manner, for example, an acid addition salt may be converted into a compound of formula I by treatment uith a base.

The compounds of this invention have been demonstrated to relieve allergic manifestations when administered - 17 48778 intraperitoneally and/or orally to sensitized rats.

The technique employed to establish the antiallergic activity of the disclosed compounds is reported in Immunology, vol. 16, pp. 749-760 (1969) and involves four male Charles River rats (200-250 grams body weight) per group to provide a control, a host for administration of a standard anti-allergic compound (disodium cromoglycate) and animals for the test compound. The rats ars Injected intracutanecusly on their shaved backs with sera from rats immunized uith egg albumin and pertussis vaccine. Twenty-four hours after the initial injections, the test compound is administered intrapetitoneally or orally at a maximum dosage level of 200 milligrams per kilogran.host body weight. Five minutes later, one millilitre of a 0.5 percent solution of Evans blue dys and 8 milligrams of egg albumin is injected intravenously. After forty minutes, the animal is sacrificed and the bleb size an its back is measured.

The mean blab size for the animals administered the test compound is calculated and the percent inhibition is determined by comparison uith ths control animal.

Although the mechanism by which the campaundsof this invention function is not absolutely known, the applicants have found-that tha compounds of this invention, in a manner believed to be similar to the function of INTAL, black reaction(s) in the mast cell leading to the production and release of mediators. Intal is a trade mark. The compounds of this invention permit the occurrenc of a non-productive antigen-antibody interaction by effectively blocking the IgE type reaction. In summary, the compounds of this invention block the release of mediators commonly resulting From the antigen anti-body reaction as exemplified in a passive cutaneous anaphylaxis test (PCA) using rat homocytotropic antibody - a known correlate of human raaginio antibody.

By analogy to disodium cromoglycate and its activity correlation between standard test animals, domestic animals and man, the compounds of this invention have been established as anti-allergic agents suitable for use as inhalants or by oral or parenteral administration.

Thus, the compounds of this invention are useful for suppressing allergic manifestations cf atopic immediate sensitivity in warm-blooded human and non-human animals, tha latter including domesticated animals such as the mouse, rat, hamster, gerbil, dog, cat, sheep, goat, horse, cow by administering an effective amount of one or more of the compounds of the invention by oral, topical, intraperitoneal, intramuscular or intravenous routes. The compounds of this invention may be administered in conjunction with known compounds effecting anti-histaminic, anti-hypertsnsive, analgesic, central nervous system depressant, immunosuppressive, anti-saratonin, anti-Bradykinin or endocrinological responses. In addition, those conventional adjuvants known to the art may be combined with the anti-allergies of this invention to provide compositions and solutions for administrative purposes, although it is considered desirable and feasible to employ the anti-allergies as neat or pure compounds without additives other than for purposes of providing suitable pharmaceutical solution or liquid or vapour suspensions.

The effective dose range in test animals may be from about Q.Q1 milligrams par kilogram to a dosage resulting in substantially 100 percent prevention of the allergic response at 200 milligrams par kilogram host body weight.

As an inhalant, the dose may be two milligrams or lass, administered as needed prior to attack. Thus, the dosage contemplated for human oral or intraperitoneal use based upon the potency of the compound administered may lie from about 1 milligram to 2 grams, preferably 5 milligrams to about 1.5 gram in unit dosage form to be administered when necessary and to the degree of the desired response, in single or plural doses under the guidance of a physician.

The dosage to be used in the treatment of a specific atopic allergic reaction is determined by the subjective observations of the attending physician. The human dose, like the dose for the dog, depends upon the specific allergy being treated, the size, age, response pattern and severity of the allergic attack in the specific patient. No unusual skill is involved in establishing the most desirable dose size and regimen for a specific patient because the loss or suppression of the symptom is apparent to both the patient and the physician. The effective amount of the anti-allergic compound administered must be empirically determined subjectively.

Illustrative of the compounds of this invention, which are orally active are [2-cyano-3- (dimethylamino) phenylamino] -oxoacetic acid ethyl ester, demonstrating oral activity equivalent to 54% inhibition at 5 milligrams per kilogram host body weight; 67% inhibition at 25 milligrams per kilogram host body UBight and 73% inhibition at 100 milligrams per kilogram host body weight,as well as[2-cyano-3-(4-methyl-l-piperazinyl)phenylamino]oxoacetic 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 invention possessing anti-allergic activity upon intraperitoneal administration is[2-cyano-3-(1-piperidinyl)phenylaminoj-oxoacetic acid ethyl ester which affords 93% inhibition at 200 milligrams per kilogram host body weight; the two compounds mentioned in the preceding sentence presenting, respectively, 93% inhibition at 200 milligrams per kilogram host body weight and 88% inhibition at 200 milligrams per kilogram host body weight.

As noted supra, the preferred compounds are those in which the amino group appears in the 3-position as the free amino group or lower alkylamino group. These compounds have been found to effect 100% inhibition uith as lou as 0.10 milligrams per kilogram dosage administered intravenously uith the sodium salt of [2-cyano-3-(methylamino)phenylamino]oxoacetic acid.

The following Examples illustrate the invention. 2778 EXAMPLE 1 i2-Cyano-3-(dimethylamino)phenylaminoloxoacstie acid ethyl ester To a solution of 9.7 g. of 2,6-dinitrobenzonitrils and 6.1 g. of dimethylamine hydrochloride in 100 ml. of dimethylformamide is added 6 g; of potassium hydroxide in 20 ml. of water. The solution is stirred for 4 hours, poured into icB water and the product, 2-dimethylamino-6-nitrobsnzonitrile, is filtered and dried, mp. 112-116°C.

Analysis for: Calculated : C, 36,54; Η,'4.75; N, 21.98 10 found : C, 56,28; H, 4.77; N, 21.77 To a suspension of 5.7 g. of 2-dimethylamino-6nitrobanzonitrils in 20 ml. of methanol and 17 ml. of concentrated hydrochloric acid is added 5.3 g of iron powder in portions. The mixture is stirred for 1/2 hour, diluted uith 200 ml. of uater and extracted uith methylene chloride uhich is dried and evaporated • in vacuo to yield crude 2-amino-6-dimethylaminobenzonitrile.

To a solution of 3.4 g. bf crude 2-amino-620 dimsthylaminobenzonitrile and 1.6 g. of pyridine in 50 ml. of methylene chloride at 0° is added dropuise 2.7 g. of ethyl oxalyl chloride in 25 ml. of methylene chloride. · The solution is stirred at 0°C. for 3 hours, uarmsd to room temperature and uater is added. The organic phase is separated, dried and evaporated to give a yellow solid which is recrystallized from benzene-hexane to yield 3.2 g. of the title compound, mp. 124-126°C.

Analysis for : C^jH^gNjOj Calculated : C, 59.76; H, 5.79; N, 16.08 Found : C, 59.47; H, 5.47; N, 16.08 2242778 EXAMPLE 2 r2-Cyano-3-piperidino-phenylamino]oxoacetic acid ethyl aster To a solution of 19.3 g. of 2,6-dinitrobenzonitrile in 300 ml. of dimethylformamide is added 25.5g. of piperidine and the resulting solution is warmed to 85°C. and kept at that temperature until the reaction is complete. The reaction mixture is poured into water, the product, 2-nitro6-(l-piperidinyl)benzonitrile, is filtered and dried, mp. 119-121°C.

Analysis : ^2^13^31½ Calculated : C, 62.32; H, 5.67; N, 18.17 Found i C, 62,32; H, 5.82; N, 18.26 The 2-nitro-6-piperidino-benzonitrile prepared in the preceding paragraph is converted to 2-amino-6-piperidin benzonitrile by iron reduction following the procedure of Example 1.

The title compound is produced by reaction of 2-amino-6-piperidino-benzonitrile uith athyl oxalyl chloride, m.p. 98-100°C.

Analysis for : Calculated ; C, 63.77; H, 6.36; N, 13.94 Found : C, 63,76; H, 6.37; N, 13.76 EXAMPLE 3 r2-Cyano-3-(4-methyl-l-piperazinyl)phenylamino] oxacetic acid ethyl 8star hydrochloride Following the procedure presented in the first paragraph of Example 2, uith the exception that N-methylpiperazine is substituted for piperidine, 2-(4-methyll-piperazinyl)-6-nitrobenzonitrile is prepared, m.p. 126-129°C Analysis for : ci2H14N4°2 Calculated : C, 58.52; H, 5.73; N, 22.75 : C, 58.65; H, 5.87; N, 22.78 _ 23 _ Found To a solution of 4.92 g. of 2-(4-methyl-1-piperazinyl)-£ nitrobenzonitrile in 11 ml. of concentrated hydrochloric acid is added 3.4 g. of iron powder. The mixture is stirrec for 30 minutes, poured into ice water and the pH is adjusted to 12. Methylene chloride is added, tha whole mixture is filtered through celite, tha methylene chloride is separated, dried and evaporated to glue solid, crude product, 2-amino6-(4-methyl-1-piperazinyl)benzonitrile, Celite is a Trade Mark. lo A mixture 3.96 g. of crude 2-amino-6-(4-methyl-1piperazinyl)banzonitrile, 2.74g. of ethyl oxalyl chloride and 1.58 g. of pyridine in 30 ml. of methylene chloride is stirred for 2 hours at room temperature, poured into 1.68 g. of sodium bicarbonate in 25 ml. of water and stiired for minutes. The organic layer is separated, dried and evaporated. The residue is dissolved in diethyl etherethanol, saturated diethyl ether-hydrogen chloride is added and tha product is allowed to crystallize to give the pure title compound, m.p. 204-206°C. (dec).

Analysis for iCjgH2gN^03.HCl Calculated :C, 54.46; H, 6.00; N, 15.88; Cl,10.05. Found :C, 54.53; H, 6.31; N, 15.90; Cl,10.08. EXAMPLE 4 /2-Cyano-3-(methylamino)phenylamlno/oxoacetlc acid ethyl ester 25 Following tha procedure given in the first., paragraph. of example 2 except using aqueous methylamine instead of piperidine, 2-methylamino-6-nitrobenzonitiile is obtained, m.p. 203-206°C.

Analysis for: CgH^N^Oj Calculated : C, 54.23; H, 3.99; N, 23.72. Found : C, 54.24; H, 3.70; N, 24.02.

This material is reduced uith iron powder as In 5 example 3 to afford crude 2-amino-6-methyl-aminobenzonitrile.

The above nitrile is oxalated in the usual manner to afford the pure title compound after chromatography □n silica gel uith chloroform and recrystallization from ethanol, m.p. 136-139°C.

Analysis for; ci2H13N3°3 Calculated ; C, 50.29; H, 5.30; N, 17.00 Found : C, 58.11; H, 5.26; N, 16.93 EXAMPLE 5 /2-Oyano-3-ethylmethylamino phenylamlnq/oxoacetic acid ethyl este Using ethylmethylamine instead of piperidine as in example 2 gives 2-ethylmethylamino-6-nitrobenzonitrile, m.p. 60-63°C.

Analysis for: C10H11N3°2 Calculated : C, 53.53; H, 5.40; N, 20.43.

Found ' : C, 58.84; H, 5.48; N, 20.81.

Reduction of the above nitrobenzonitrile uith iron pouder foiloued by oxalation uith ethyl oxalyl chloride as in example 3 gives pure title compound, m.p. 75-78°C.

Analysis for; Calculated : C, 61.08; H, 6.22; N, 15.26.

Found : C, 60.77; H, 6.21; N, 15,34.

EXAMPLE 6 /2-Cyano-3-(ethylamino)phenylamino/oxoacetic acid ethyl ester 2-ethylamino-6-nitrabenzonitrile is obtained as in the preceedlng Example using ethylamine, m.p. 114-116°C Analysis for: CgHgl^Og Calculated : C, 56.54; H, 4.75; N, 21.98. Found : C, 56.73; H, 4.75; N, 21.73.

Reduction and oxalation as in the proceeding Example by recrystallization from benzene-hexane gives the title compound, m.p. 99-102°C.

Analysis for; C13H15N303 Calculated : C, 59.76; H, 5.79; N, 16.08.

Found ; C, 59.35; H, 5.89; N, 15.88. ' EXAMPLE 7 r2-Cyano-3-(morpholino)phenylaminoloxoacetic acid ethyl ester Tha appropriate benzonitrile is obtained from morpholine and 2,6-dinitrobenzonitrile as in previous examples, m.p. 152-155°C.

Analysis for: C11H11N303 Calculated: : C, 56.65; N, 4.76; N, 13.02.

Found : C, 56.95; H, 4.82; N, 18.35.

The above product is reduced uith iron powder and oxalated lo as in the proceeding example to give the title compound, m.p. 115-116°C.

Analysis for: C15H17N.jO4 Calculated : C, 59.39; H, 5.65; N, 13.86.

Found ; C, 59.74; H, 5.79; N, 14.19.

EXAMPLE 8 Following the general preparative procedure exemplified in the preceding examples, by varying tha amine reactant (HNR R ) employed in the displacement reaction uith 2,6-dinitrobenzonitrile, reducing the remaining nitro substituent to afford the reactive amino group and finally coupling that product uith an oxalyl chloride ester, there is afforded a family off2-oyano-3-(substituted amino)phenylaminojoxoacetic acid esters which may be readily hydrolyzed under mild conditions to yield the corresponding oxoacetic acids which are in turn readily converted to the corresponding salts upon reaction with a desired base. 13778 uith a desired base. 2 •The amines, HNR R , employed in the synthesis of the anti-allergic compound of this invention and the final products, employing ethyl oxalyl chloride in each instance as representative of the simple oxalyl ester reactants employed in the HNR1R2 synthesis, are: Final Product R1 £ Ethyl Ester of 10 1. -H -ch3 [2-oyaho-3-(mBthylamino) -phenylamino] oxoacetic acid 2. -CH3 -ch3 CH- |2-cyano-3-(dimethylamino) -phenylamino] oxoacetic acid 3. -CH3 -CH 3 'ch3 (2-cyano-3-(isopropylmethylamino -phenylamino] oxoacetic acid 15 4. -CH2CH=CH2 -ch3 [2-cyano-3-(allylmethylamino) -phenylamino] Oxoacetic acid 5. -H phenyl f2-cyano-3-(phenylamino) phenylamino] oxoacetic acid 20 6. -CH2CH3 -ch2ch2ch2ch3 (2-oyano-3-(ethylbutylamino) 'phenylamino] oxoacetic acid 7. -CH2CH3 CH_ . I -CHCH2CH3 ]2-cyano-3-(sec-butylethylamino) phenylamino] oxoacetic acid 8. -CH2CH=CH2 -CH2CH=CH2 (2-cyano-3-(diallylamino) phenylamino]oxoacetic acid 25 9. -H benzyl |2-oyano-3-(benzylamino) - phenylamino] oxoacetic acid io.-ch2ch2ch2ch3 -ch2ch2ch2ch l3 |2-cyano-3-(dibutylamino) phenylamino], oxoacetic acid 11.-H cyclohexyl [2-oyano-3-(cyclohexylamino) phenylamino]oxoacetic acid 12.-H furfuryl |2-cyano-3-(furfurylamino)phenylamino]oxoacetic acid 13.-H heptyl [2-cyano-3-(heptylamino)phenylaminqj oxoacetic acid 14.-H hexyl ch3 |2-cyano-3-(hexylamino)phenylaminoj oxoacetic acid 15.-H -CH-CH I CH3 (2-cyano-3-(isobutylarnino) phenylamino)oxoacetic acid HNR1R2 Final Product R1 R2 Ethyl Eater oF 16.-H propynyl f2-cyano-3-(propynylamino)phenylamino} oxoacetic acid 17.-H a-methallyl |2-cyano-3-(a-methallylamino )phenylamino] oxoacetic acid 1S.-H (x-methylpropynyl (2-cyano-3- ( a- methylpropynylamino) -phenylamino]oxoacetic acid 19.-H 2-pyridyl |2-cyano-3-(2-pyridylamino)- phenylamino]oxoacetic acid 20.-H 3-pyridyl [2-cyano-3-(3-pyridylamino)~ phenylamino ] oxoacetic acid 21.-H 4-pyridyl f2-cyano-3-(4-pyridylamino) - phenylamino] oxoacetic acid 22.-H 2-thienyl [2-cyano-3-(2-thienylamino)- phenylamino] oxoacetic acid 23.-H 3-thienyl [2-cyano-3-(3-thienylamino)- Lphenylamino ] oxoacetic acid 24.-H 2-pyrimidinyl j 2—cyana-3-(2-pyrimidinylamino)- phenylamino ] oxoacetic acid 25.-H 1,3, -XR1> HN , ) 5-triazinyl |2-oyano-3-(l,3,5-triazinyl-2-yl -amino) phenylamino]oxoacetic acid 26. pyrrolidine |2-cyana-3-(l-pyrrolidinyl) - phenylamino J oxoacetic acid 27. piperidine |2-cyano-3-(piparidino) - phenylamino] oxoacetic acid 28. N-methylpiperazine f2-cyano-(4-methyl-l-piperazinyi -phenylamino] oxoacof.lc acid 29. morpholine |2-cyano-3-(morpholino)- phenylamino] oxoacetic acid 30. thiomorpholine ]2-cyano-3-(thiamorphalino)phenylamino] oxoacetic acid 31. azetidine [2-cyano-3-(l-azetidinyl) - phenylamino] oxoacetic acid 32. a2iridine [2-cyano-3-(l-aziridinyl)- phenylamino] oxoacetic acid • The oxalyl chloride ester employed in the synthesis of the compounds of the invention is preferably the ethyl ester, the sec-butyl ester or the cyclohexyl ester. However, other simple esters are similarly applicable, producing the corresponding ester products uith unchanged biological activity, although assimilation by the host may vary somewhat. Thus, the esters initially produced may be lower alkyl (e.g. methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, amyl, sec-amyl or hexyl); aralkyl (e.g. benzyl or phenethyl); or cycloalkyl (e.g. cyclopentyl ot- cyclohexyl). Thus, the esters produced as part of this invention are esters in uhich the hydrocarbon moiety of the alcohol is alkyl of 1 to 6 carbon atoms, hydrocarbonic aralkyl of 7 or 8 carbon atoms or cycloalkyl of 5 or 6 carbon atoms.

The following Examples 9 to ll illustrate the dehydration of amides to prepare a new compound of the invention.

EXAMPLE 9 [2-Cyano-3-(dimethylamino)phenylaminoloxoacetic ethyl ester To a cold solution (0°C.) of 2.47 g. of [2-aminooarbonyl-3-(dimethylamino)phenylamino]oxacetic acid ethyl ester in 70 ml. of chloroform and 7 ml of triethylamine is added 1.1 ml. of phosphorus oxychloride. Ths reaction mixture is stirred for 70 hr. at room temperature, poured into water and the pH is adjusted to pH 5.

The organic phase is separated, dried and evaporated to give crude nitrile uhich is recrystallized from benzene-hexane to give the title compound as the pure nitrile, m.p. 124-126°C.

EXAMPLE 10 [2-Cyano-3-(dimethylamino)phenylaminoloxoacetic aclri ethyl ester To 2.7Θ g. of triphenylphosphine oxide in 20 ml. of methylene chloride at O'°C. is added 1.57 ml. of trifluoromethanesulfonic anhydride. After 15 min., 2.79 g. of [2-amino-carbonyl-3-(dimethylamino)phenylaminoloxacetic acid ethyl ester in 50 ml. of methylene chloride is added. The reaction mixture is left stirring at room temperature overnight, poured into uater, and the organic phase is separated, dried and evaporated. The resulting solid is chromatographed on silica gel uith chloroform to give pure title compound, m.p. 124-126°C.

EXAMPLE 11 [2-Cyano-4-(dimethylamino)phenylaminoloxoacetic acid ethyl ester To a solution of 4.6 g. of [2-(aminocarbonyl)-4(dimethylamino)ohenylamino]oxoacetic acid ethyl ester in 130 ml. of chloroform at 0°C. is added 2 ml. of phosphorus oxychloride and 13 ml. of triethylamine. The reaction is stirred at room temperature until complete (approximately 6 days). 12778 Uater is added, the pH is adjusted to about 5 and the organic layer is separated, dried and evaporated. The product is recrystallized from ethanol, m.p. 150-152° C.

Analysis for: Calculated: found: C13H15N3°3 C, 59.76; H, 5.79; N, 16.08 C, 59.76; H, 6.02; N, 15.91 EXAMPLE 12 [3-Amino-2-cyanophenvlamino]oxoacetic acid ethyl ester The title compound is prepared by reduction of [3-nitro-2-cyanophenylamino]oxoac8tic acid ethyl ester uith 10% Pd. on charcoal and uith cyclohexene in ethanol according to the procedure of 1.0. Entuistle and R.A.U. Oohnstone, 3. Chem. Soc., Perkin I, 1300 (1975). The crude product is chromatographed on silica gel uith chloroform and recrystallized from ethanol, m.p. 133»136OC.

Analysis for; CH Calculated: C, 56.64; H, 4.76; N, 18.02 Found: C, 56.58; H, 4.64; N, 18.20 [3-Witro-2-cyanophenylamino]oxoacetic acid ethyl ester is prepared by treatment of 2-amino-6-nitrobenzonitrile uith ethyl oxalyl chloride as in Example 1, m.p. 111-113°C.

Analysis for: 11HgN3^5 Calculated: C, 50.19; H, 3.45; N, 15.97 Found: C, 50.11; H, 3.44; N, 15.99 4377s 2-Amino-6-nitrobenzonitrile is prepared as follows: 2,6-Oinitrobenzonitrile (19.3 g.) is dissolved in methanol (400 ml.) and dioxane (250 ml.) at reflux.· To this is added cone, hydrochloric acid (60 ml.) followed by iron powder (18 g.) in portions. The mixture is left at reflux for 1 hr., and is evaporated to drynass.

Uater is added, the resultant solid is filtered off, dried and extracted uith hot ethyl acetate. After filtration through Calita , tha product is allowed to crystallize, m.p. 196-198°C.Olite is a registered Trade Mark Analysis for: CyH^N^Oj Calculated: found: C, 51.54; H, 3.09; N, 25.76 C, 51.39; H,3.01; N, 25.68 EXAMPLE 13 [3-(Butylamino)-2-cyanophenylamino]oxoacetic acid ethyl aster This material is prepared following the procedure of Example 1, by oxalation of 2-amino-6-butylaminobenzonitrile, m.p. 101-105°C.

Analysis for; Calculated: found: C15H19N3°3 C, 62.26; H, 6.62; N, 14.52 C, 62.03; H, 6.42; N, 14.55 2-amino-6-butylaminobanzonitrile is obtained by iron reduction as in Example 1. 2-butylamino-6-nitrobenzonitrile is obtained by tha usual displacement reaction using butylamine, m.p. 72-74°C.

Analysis for; Calculated: Found: C, 60.26; H, 5.98; N, 19.15 C, 60.38; H, 6.09; N, 19.06 EXAMPLE 14 [2-Cyano-3-(methylisopropylaniino)phenylamino]oxoacetic acid ethyl estBr The usual oxalation as in Example 1 of 2-amino-6(methylisopropylamino)benzonitrile gives the title compound, m.p. 64-67°C.

Analysis for: ^15^19^3^3 Calculated: C, 62.26; H, 6.62; N, 14.52 Found; C, 62.30; H, 6.65; N, 14.53 2-amino-6-(methylisopropylaniino)benzonitrile is obtained by iron reduction as in Example 1. 2-(methylisopropylaniino)-6-nitrobenzonitrile is obtained by the usual substitution using methylisopropylamine, m.p. 7Q-72aC.

Analysis for: Calculated: Found: C11H13N3Q2 C, 60.26; H, 5.98; N, 19.15 C, 60.21; H, 5.93; N, 19.19 EXAMPLE 15 [2-Cyano-3-(l-pyrrolidinyl)phenylamino]oxoacetic acid ethyl eater Oxalation of 2-amino-6-pyrrolidinylbehzonitrile as in Example 1 gives the title oompound, m.p. 138-141°C.

Analysis for:.

Calculated; Found: C15H17N3°3 C, 62.70; H, 5,96; N, 14.63 C, 62.81; H, 5,98; N, 14.61 2-amino-6-pyrrolidinylbenzonitrile is prepared by iron reduction of the corresponding nitro derivative as in Example 1, m.p. 112-114°C.

Analysis for: C11H13N3 C, 70.56; H, 7.00; N, 22.44 C, 70.51; H, 6.71; N, 22.50 2-nitro-6-pyrrolidinylbenzonitrila is prepared by the usual displacement (example 6) using pyrrolidine, m.p. 111-113°C.

Analysis For: c11R11^3θ2 Calculated: C, 60.82; H, 5.10; N, 19.35 Found: C, 61.04; H, 5.14; N, 19.59 Calculated: Found: EXAMPLE 16 [2-Cyano-3-(morpholino)phenylamino]oxoacetic acid1-methylpropyl ester This material is prepared as in Example 7 using sec-butyloxalyl chloride instead of athyl oxalyl chloride, m.p. 108-111°C.

Analysis for: Calculated: Found: Tha following tha same procedure: C17H21N3°4 C, 61.62; H, C, 61.42; H, sodium salts 6.39; N, 12.68 6.71; N, 12.95 are all prepared by Ϊ7 7 8 The oxacetic 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 resulting solid is filtered, washed uith ethanol and dried to give the sodium salt.

EXAMPLE 17 [2-Cyano-3-(methylamino)phenylamino]-oxoacetic acid sodium salt, 2/5 hydrate, 1/5 ethanolate m.p. 272-275°C.(dec) Analysis for: Calculated: Found; C10H3N3°3·1/5 Et0H· 2/5 H2fl C, 48.49; H, 3.91; N, 16.31 C, 48.70; H, 3.82; N, 16.29 EXAMPLE 18 [2-Cyano-3-(ethylm9thylamino)phenylamino]oxoacetic acid, sodium salt, 7/10 hydrate m.p. 90-94°C.

Analysis for: Calculated: Found: C12H12N3°5Na·7/10 H2° C, 51.14; H, 4.79; N, 14.91 C, 51.01; H, 4.65; N, 14.99 EXAMPLE 19 [3-(Butylamino)-2-cvanoohenylamino]oxoacetic acid sodium salt m.p. 252-254°C Analysis for: Calculated: Found: C13^4N3°3Na C, 55.12; H, 4.98; N, 14.83 C, 54.82; H, 4.80; N, 14.59 EXAMPLE 20 [ 2-Cyano-3-(morpholino)phenylaminoloxoacetic acid, sodium salt, 4/10 hydrate m.p. 170°C.(shrink), 240°C.(dec.) Analysis for: ^13H12^3^4^3 4/10 H20 Calculated: C, 51.28; H, 4.24; N, 13.80 Found: C, 51.35; H, 4.28; N, 13.91 EXAMPLE 21 (4-Amino-2-Cyanophenylaiiiino)oxoacetic acid ethyl ester .0 g. of (2-cyano-4-nitrophenylamino)oxoacetic acid ethyl ester in 150 ml. of ethanol and 0.4 g. of % Pd/C is hydrogenated until hydrogen uptake ceases.

The reaction mixture is filtered through Celite, evaporated to dryness and the solid is recystallized from ethanol, 4.1 g., m.p. 137-139°C.Celite is a registered Trade Mark.

Analysis for: C11H11N3^3 Calculated; C, 56.65; H, 4.76; N, 18.02 Found; C, 56.49; H, 4.94; N, 18.09 (2-cyano-4-nitrophenyl)oxoacetic acid ethyl estBr is prepared by the usual ethyl oxalation of 2-amino-5 nitrobenzonitrile as in Example 1, m.p. 137-319°C.

Analysis for: C11H9N3°5 Calculated: C, 50.19; H, 3.45; N, 15.97 Found: C, 49.99; H, 3.5a; N, 15.98

Claims (4)

CLAIMS: A compound having tha formula R 1 R 2 n — CN KA- — nhcdco 2 r (I) in uhiph the group appears in the designated 3- or 4- position; R is hydrogen, a pharmaceutically acceptable cation, alkyl of 1 to 6 carbon atoms, aralkyl of 7 or Θ carbon atoms or cycloalkyl of 3 to 6 oarbon 1 2 atoms; R and R are independently hydrogen; alkyl, alkenyl or alkynyl of up to 9 carbon atoms; cycloalkyl of 5 or 6 carbon atoms; aralkyl of 7 to 9 carbon atoms; aryl of 6 to 10 carbon atoms; furfuryl or aromatic 1 2 hetarocyclyl; or R and R , together uith the nitrogen atom to uhich they are attached, are aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, 4-louar alkylpiperazinyl, morpholino or thiomorpholino; or a pharmaceutically acceptable acid addition salt thereof. 2. A compound having tha formula I as illustrated in r1 claim 1, uherain tha group -N appears in the designated 3- or 4- position; R is hydrogen, an alkali (natal, an ammonium ion, alkyl of 1 to 6 carbon atoms, inclusive, aralkyl of 7 or 8 oarbon atoms or cycloalkyl 1 of 8 or 5 carbon atoms; R is hydrogan or alkyl of 1 to 9 2 carbon atoms; R is hydrogen, alkyl of 1 to 9 carbon atoms 43778 1 2 or cycloalkyl of 3 to 6 carbon atoms; or R and R , together with tha nitrogen atom to which they are attached, are aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, 4-lower alkyl -piperazinyl, morpholino or thiomorpholino, or a pharmaceutically acceptable acid addition salt thereof. 3. A compound having the formula in which R is hydrogen, a pharmaceutically acceptable cation, alkyl of 1 to 5 carbon atoms, inclusive, aralkyl of 7 or 3 carbon atoms, or cycloalkyl of 5 or 6 1 2 carbon atoms; R and R are independently hydrogen; alkyl, alkenyl or alkynyl of up to 9 carbon atoms; cycloalkyl of 5 or 6 carbon atoms; aralkyl of 7 to 9 carbon atoms; aryl of 6 to 10 carbon atoms; furfuryl Ί 2 or aromatic heterocyclyl; or R and R , together with the nitrogen atom to which they are attached, are aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, 4-louer alkyl-piperazinyl, morpholino or thiomorpholino; or a pharmaceutically acceptable acid addition salt thereof. 4. A compound having formula Ia as illustrated in claim 3, in which R is -H; an alkali metal; ®ΝΗ^; alkyl of 1 to 6 carbon atoms) aralkyl of 7 or 8 carbon atoms; or cycloalkyl of 5 or 6 carbon atoms; 39 ,2778 R 1 and R 2 are independently -H; alkyl, alkenyl or alkynyl of up to 9 carbon atoms; cycloalkyl of 5 or 6 carbon atoms; aralkyl of 7 to 9 carbon atoms; aryl c.f 6 to 10 carbon atoms; furfuryl; 2,3 or 4-pyridyl; 2 or 3- thienyl; 2, 4 or 5-pyrimidinyl; or 1,3,5-triaZin-2-yl; or R and R , together, with the nitrogen atom to which they are attached, are aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, 4-lower alkyl-piperazinyl, morpholino or thiomorpholino; or a pharmaceutically acceptable acid addition salt thereof. 5. A compound as claimed m claim 1, in which R is hydrogen or normal alkyl of 1 to 6 carbon atoms and R is hydrogen or alkyl of 1 to 6 carbon atoms. j 6. A compound as claimed in claim 2, in which R is hydrogen or normal alkyl of 1 to 6 oarbon atoms and R is hydrogen or alkyl of 1 to 6 oarbon atoms. i 7. A compound as olaimed in claim 3, in which R is hydrogen or normal alkyl of 1 to 6 oarbon atoms and R is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, phenyl, cyclopentyl or cyclohexyl. 8. A compound as claimed in claim 4, in which R is hydrogen or normal alkyl of 1 to 6 carbon atoms and R is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, phenyl, cyclopentyl or cyclohexyl. 9. A compound as claimed in claim 3, uherein R 2 12 and R are both hydrogen or R is hydrogen and R is lower alkyl. 1 2 10. A compound as claimed in claim 4, wherein R and R 1 2 are both hydrogen or R is hydrogen and R is lower alkyl. 11. A compound as claimed in claim 1, in which R and 2 R taken together uith the nitrogen atom to which they are attached, are aziridinyl, azetidinyl, pyrrolidinyl piperidino, piperazinyl, 4-louer alkyl-piperazinyl, morpholino or thiomorpholino. 12. A compound as claimed in claim 2, uherein R and 2 R are as defined in claim 11. -I 13. A compound as claimed ln claim 3, wherein R and 2 R are as defined in claim 11. 14. A compound as claimed in claim 4, uherein R and 2 R are as defined in claim 11. 15. A compound selected from/2-cyano-3-(dimethylamino)phenylamino/oxoacetic acid and its alkali metal and ammonium salts and its alkyl asters containing 1 to 6 carbon atoms in the alkoxy moiety and their pharmaceutically acceptable acid addition salts. 16. A compound selected from/2-cyano-3-(piperidino)phenylamino_/oxoacetic acid and its alkali metal and ammonium salts and its alkyl esters containing 1 to 6 carbon atoms in the alkoxy moiety and their pharmaceutically acceptable acid addition salts. 17. A oompound selected from/2-cyano-3-(4-methyl-1-piperazinyl)phenylamino/oxoacetic acid and its alkali metal and ammonium salts and its alkyl esters containing 1 to 6 carbon atoms in the alkoxy moiety and their pharmaceutically acceptable acid addition salts. 41 3778 18. A compound selected from [2-cyano-4-(dimethylamino) phenylaminoloxoacetic acid and its alkali metal and ammonium salts and its alkyl esters containing 1 to 6 carbon atoms in the alkoxy moiety and their pharmaceutically acceptable acid addition salts. 19. A compound selected from [3-amino-2-cyanophenylamino]oxoacetic acid and its alkali metal and ammonium salts and its alkyl esters containing 1 to 6 carbon atoms in the alkoxy moiety and their pharmaceutically acceptable acid addition salts. 20. A compound selected from [2-cyano-3-(methylamino) phenylaminoloxoacetic acid and its alkali metal and ammonium salts and its alkyl esters containing 1 to 6 carbon atoms in the alkoxy moiety and their pharmaceutically acceptable acid addition salts. 21. A compound selected frcm [2-cyano-3-(ethylamino) phenylaminoloxoacetic acid and its alkali metal and ammonium salts and its alkyl esters containing 1 to 6 carbon atoms in the alkoxy moiety and their pharmaceutically acceptable acid addition salts. 22. A compound selected from [3-(butylamino)-2cyanophenylaminoloxoacetic acid and its alkali metal and ammonium salts and its alkyl esters containing 1 to 6 oarbon atoms in the alkoxy moiety and their pharmaceutically acceptable acid addition salts. 23. A compound selected from [3-(ethylmethylamino)-2eyanophenylamino]oxoacetic acid and its alkali metal and ammonium salts and its alkyl esters containing 1 to 6 carbon atoms in the alkoxy moiety and their pharmaceutically acceptable acid addition salts. 24. A compound solected from [2-cyano-3-(methylisopropylamino) phenylamino]oxoacetic acid and its alkali metal and ammonium salts and its alkyl esters containing 1 to 6 carbon atoms in the alkoxy moiety and their pharmaceutically acceptable acid addition salts. 25. A compound selected from [2-cyano-3-(l-pyrrolidinyl) phenylamino] oxoacetic acid and its alkali metal and ammonium salts and its alkyl asters containing 1 to 6 carbon atoms in the alkoxy moiety and their pharmaceutically acceptable acid addition salts. 26. A compound selected from [2-cyano-3-(morpholino) phenylamino] oxoacetic acid and its alkali metal and ammonium salts and its alkyl esters containing 1 to 6 carbon atoms in the alkoxy moiety and their pharmaceutically acceptable acid addition salts. 27. A compound selected from (4-amino-2-cyanophenylamino)oxoacetic acid and its alkali metal and ammonium salts and its alkyl esters containing 1 to 6 carbon atoms in the alkoxy moiety and their pharmaceutically acceptable acid addition salts. 28. A [2-cyano-3-(methylamino)phenylaniino]oxoacQUe acid alkali metal salt. 29. [2-Cyano-3-(dimethylamino)phenylamino]oxoacetic acid ethyl ester or a pharmaceutically acceptable acid addition salt thereof. 30. [2-Cyano-3—piperidino phenylaminq/bxoacetic acid ethyl ester Dr a pharmaceutically acceptable acid addition salt thereof. 31. [2-Cyano-3-(4-methyl-1-pipetazinyl)phenylamino] oxoacetic acid ethyl ester or a pharmaceutically acceptable acid addition salt thereof. 32. [2-Cyano-4-(dimethylamino)phenylamino]oxoacetic acid ethyl ester or a pharmaceutically acceptable acid addition salt thereof. 33. [3-Amino-2-cyanophenylamino]oxoacetic acid ethyl ester or a pharmaceutically acceptable acid addition salt thereof. 34. [2-Cyano-3-(methylamino)phenylamino]oXoacetic acid 5 ethyl ester or a pharmaceutically acceptable acid addition salt thereof. 35. [2-Cyano-3-(ethylamino)phenylamino]oxoacetic acid ethyl ester or a pharmaceutically acceptable acid addition salt thereof. Ιθ 36. , [3-(Sutylamino)-2-cyanophenylamino)oxoacetic acid ethyl ester or a pharmaceutically acceptable acid addition salt thereof. 37. [3-(Ethylmethylamino)-2-cyanophenylamino]oxoacetic acid ethyl ester or a pharmaceutically acceptable acid 15 addition salt thereof. 38. [2-Cyano-3-(Msthylisopropylamino)phenylamino] □xoacetic acid ethyl ester or a pharmaceutically acceptable acid addition salt thereof. 39. [2-Cyano-3-(1-pyrrolidinyl)phenylamino] oxoacetic 20 acid ethyl ester or a pharmaceutically acceptable acid addition salt thereof. 40. [2-Cyano-3-(morpholino)phenylamino]oxoacetic acid ethyl ester or a pharmaceutically acceptable acid addition salt thereof. 25 41. [2-Cyano-3-(morpholino)phenylamino]oxoacetic acid

1-mBthylpropyl ester or a pharmaceutically acceptable acid addition salt thereof. 42. [2-Cyano-3-(methylamino)phenylamino] oxoacetic acid sodium salt. LO 43. /2-Cyano-3-(ethy lmethylamino) phenylamino/oxoacetic acid sodium salt. 44. /3-(Butylamino)-2-Cyanophenylamino/oxoacetic acid sodium salt. 45. /2-Cyano-3-(morpholino)phenylamino/oxoacetic acid sodium salt. 46. (4-Amino-2-cyanophenylamino)oxoacetic acid ethyl ester or a pharmaceutically acceptable acid addition salt thereof. 47. A process for the preparation of a compound having the formula in which the group - N and R arc as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, 43778 uherein (A) a compound having the formula X 2 (II) wherein X is at thB designated 3- or 4- position and 12 12 represents -NR R (wherein R and R are as defined above) or a protected form of the group of formula -NHR (wherein R is as defined above) is coupled uith a compound having ths formula A-B, uherein A represents carboxyl or a reactive derivative thereof and B represents -C0 2 R (uhere R is as defined above) or a precursor therefor, A and X being chosen as to be essentially unreactive towards each other under the process conditions; or (B) a compound having the formula (III) 15 uhere X and B are as defined above, is dehydrated to form a nitrile; and, uhere necessary, the product is subjected to treatment to remove a protecting group from X and/or to convert a precursor for-co 2 R by a known method Into 20 -CO,R and, if desired, a compound having formula I is converted into a pharmaceutically acceptable salt thereof or a salt form of a compound of formula I is converted into a compound of formula I. 48. A process as claimed in claim 47, uherein R and 2 R are as defined in claim 5. 49. A process as claimed in claim 47, uherein R and 2 R are as defined in claim 11. 50. A process for the preparation of a compound having the formula -CN nhcoco 2 r (I) 1 2 wherein the -NR R substituent and R are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof uherein a compound having the formula wherein the -N0 2 substituent is at the designated 3- or 4position and B is as defined in claim 47, is reduced to convert the nitro group into an -NH 2 group and, if desired, the resulting primary amine is converted into a 5 secondary or tertiary amine in known manner and, where appropriate, a precursor for -CC> 2 R is converted by a known method into -CO 2 R if desired, a compound having formula I is converted into a pharmaceutically acceptable salt thereof or a salt of a compound having formula I is converted into 10 a compound having formula X. 1 2 51. A process as claimed in claim 50, wherein R and R are as defined in claim 5. 52. A compound as claimed in claim 1, whenever prepared by ci process as claimed in any one of claims 47 to 51. 15 53. A process for the preparation of a compound as claimed in claim 2, wherein an appropriately substituted cyanoaniline is reacted with an activated oxalic acid half ester and, if desired, the ester product is converted into the appropriate oxacetic acid or alkali metal or ammonium 20 salt thereof by a known method. 54. A process for the preparation of a compound as claimed in claim 2, wherein a corresponding 2-carbamyl compound is dehydrated to form the

2-cyano group. 55. A process for the preparation of a compound 25 as claimed in claim 2, wherein a corresponding 3- or 4nitro compound is reduced to form an amino group at the

3- or

4- position and, if desired, the amino group is mono- or di-alkylated with a monofunctional alkylating agent to give a secondary or tertiary amine or alkylated with 30 a bifunctional alkylating agent to give a cyclic amine. 56. A process as claimed in any one of claims 53 to 55, 1 2 wherein R and R are as defined in claim 6. 57. A compound as claimed in claim 2, whenever 142 7 7 8 prepared by a process as claimed in any one of claims 53 to 56. 58. A process for the preparation of a compound as claimed in claim 3, in which (A) a compound having the formula X ! CN ΙΟ NH 2 (Ila) 12 12 uherein X represents -NR R (uherein R and R are as defined in claim 3 or a protected form of the group of formula -NHR (uherein R ia as defined above) is coupled uith a compound having the formula A-B uherein A represents carboxyl or a reactive derivative thereof and B represents -C0 2 R (uhere R is as defined in claim 3)or a precursor therefor, A and X being chosen as to bs essentially unreactive touards aach other under the process conditions; or (B) a compound having the formula X uhere X and B are as defined above is dehydrated to form a nitrile; iO and, uhere necessary, the product is subjected to treatment to remove a protecting group from X and/or to convert a precursor for -COjR by a known method into —COjR and, if desired, a compound having formula Ia is aonvertpd into a pharmaceutically acceptable salt thereof or a salt form of a compound of formula Ia is converted into a compound of formula claimed la. 59. A process as in claim 58, wherein R 1 and R 2 are as defined in claim 7. 60. A process as claimed in claim 58, wherein R 1 and R 2 are as defined in claim 9. 61. A process as claimed in claim 58, uherein R 1 and R 2 are as defined in claim 11 < 62. A compound as claimed in claim 3, whenever prepared by a process as claimed in any one of claims 58 to 61. 63. A process for the preparation of a compound as claimed in claim 4, in uhich a corresponding 2-cyano-3(substituted or unsubstituted .imino) aniline is reacted Willi the acid chloride of an oxalic acid half ester and, if desired, the resulting ester product is hydrolysed. 64. A process as claimed in claim 63, uherein R 1 and R 2 are as defined in claim 8. 65. A process as claimed in claim 63, uherein R 1 and R 2 are as defined in claim 10. 66. A process as claimed in claim 63, wherein R 1 and R 2 are as defined in claim 11. 67. A compound as claimed in claim 4, whenever prepared by a process as claimed in any one of claims 63 to 66. 68. A process for the preparation of a compound claimed in claim .4, carried out substantially as described with reference to any one of Examples 1 to 3 herein or any one of items Nos. 1 to 12 and 16 to 32 of Example 8 herein. 69. A compound as claimed in claim 4, whenever prepared by a process as claimed in claim 68. 70. A process for the preparation of a oompound as claimed in claim 3, carried out substantially as described in any one of Examples 4 to 7, 9 and 10 herein. 71. A compound as claimed in claim 3, whenever prepared by a process as claimed in claim 70. 72. A process for tha preparation of a compound as claimed in claim 2 carried out substantially as described With reference to any one of Examples 11 to 21 herein or any of item nos. 13 to 15 of Example 8 herein. 73. A compound as claimed in claim 2, whenever prepared by a process as claimed in claim 72. 74. A pharmaceutical composition comprising a compound as claimed in any one of claims 1, 5, 11 and 52 and a pharmacologically suitable carrier. 75. A pharmaceutical composition comprising a compound as claimed in any one of claims 2, 6, 12 and 57 and a pharmacologically suitable carrier. 76. A pharmaceutical composition comprising a compound as claimed in any one of claims I, 7, ‘1, I i and 59. 62 and a pharmacologically suitable carrier. 77. A pharmaceutical composition comprising a compound as claimed in any one of claims 4, 8, 10, 14 and 60. 67 and'a pharmacologically suitable carrier. 78. A pharmaceutical composition comprising a compound us claimed in any one of claims 15 to 17 and 29 to 31 and a pharmacologically suitable carrier. 79. A pharmaceutical composition comprising a compound as claimed in any one of claims 20, 21, 23, 34, 35 and 37 and a pharmacologically suitable carrier. 80. A pharmaceutical composition comprising a compound as claimed in any one of claims 18, 19, 22, 24 to 28, 32 to 33, 36 and 38 to 46 and a pharmacologically suitable carrier.