The 2-cyano-3-or 4-(substituted amino) oxanilic acid derivatives of the formula: ##STR1## in which the group ##STR2## appears in the designated 3- or 4- position and R is --H; an alkali metal; .sup.+ NH.sub.4 ; alkyl of 1 to 6 carbon atoms, inclusive; aralkyl of 7 or 8 carbon atoms; or cycloalkyl of 5 or 6 carbon atoms; PA1 R.sup.1 is --H or alkyl of 1 to 9 carbon atoms; PA1 R.sup.2 is --H, alkyl of 1 to 9 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; PA1 R.sup.1 and R.sup.2, 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.

BACKGROUND OF THE INVENTION 
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 
injected. 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 (4) 
induces release or one or more pharmacologic mediators, which 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 which will interfere with 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 
which are symptomatic of the disease. 
The presence of antibodies associated with atopic reactions 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 with atopic hypersensitivity 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 
individual sensitized by a variety of antigenic factors and is usually 
labile at about 56.degree. C. after 2 hours. 
The homocytotropic antibody found in or induced in the rat is related in 
function and reaction to immunoglobulin E (reagin or IgE) found in the 
human. The correlation between homocytotropic antibody in the rat and IgE 
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 
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, 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 by administration of 
anti-histamines, anti-5-hydroxy-tryptamine (5-HT) or anti-inflammatories, 
or (4) stimulate and cell under attack to negate the action of the 
mediator through the action of bronchodilators such as Isoprel.RTM. or a 
Xanthine. 
The only commercial compound known to date to operate as an anti-allergic 
primarily by blocking reaction(s) within the mast cells, thereby 
preventing the production and release of mediators, is disodium 
cromoglycate (INTAL.RTM.). 
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 
antibody-antigen reaction. As such, the rat PCA test (measuring 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 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) test 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 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 antibodies. 
With 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 well as the 
close relationship between the rat homocytotropic antibody 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 reactions via the rat PCA 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-allergic agents in 
man, dog, etc. 
As new anti-allergics are being developed, their activity mechanism is 
related to that of INTAL as the standard because of its known activity in 
man and its activity in the rat PCA test. In this regard see Pfister et 
al., J. Med. Chem., vol. 15, No. 10, pp. 1032-1035 (1972); Broughton et 
al., Nature, vol. 251, pp. 650-652, Oct. 18, 1971; and Assem et al., 
British Med. Journal, Apr. 13, 1974, pp. 93-95. 
DESCRIPTION OF THE INVENTION 
In accordance with this invention, there is provided a group of chemical 
compounds, useful for inhibiting development of the physical symptoms 
attending an atopic allergic reaction, presenting the formula: 
##STR3## 
in which R is --H; an alkali metal; .sup.+ NH.sub.4 ; alkyl of 1 to 6 
carbon atoms, inclusive; aralkyl of 7 or 8 carbon atoms; or cycloalkyl of 
5 or 6 carbon atoms; 
R.sup.1 is --H or alkyl of 1 to 9 carbon atoms; 
R.sup.2 is --H, alkyl of 1 to 9 carbon atoms or cycloalkyl of 3 to 6 carbon 
atoms; and 
R.sup.1 and R.sup.2, 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. 
In the preceeding formula, the alkali metals contemplated for the group 
"R", are sodium, potassium or lithium. Embraced by the expression "alkyl 
of 1 to 6 carbon atoms" are such alkyl groups as methyl, ethyl, n-propyl, 
i-proyl, n-butyl, secondary butyl, tertiary butyl, pentyl and hexyl. The 
expression "aralkyl of 7 or 8 carbon atoms" is intended to embrace the 
benzyl and phenethyl radicals. The comtemplated cycloalkyl groups of 5 or 
6 carbon atoms embrace cyclopentyl as well as cyclohexyl. The groups 
representing R.sup.1 and R.sup.2 may be normal or secondary alkyl 
containing from 1 to 9 carbon atoms each. Where R.sup.1 and R.sup.2 
represent a cyclic group with the nitrogen atom depicted in the structural 
formula, they are represented as dimethylene, trimethylene, 
tetramethylene, pentamethylene, or the 3-oxa, aza, or thia-pentamethylene 
radicals (oxy, thio or imino di-ethylene). In those situations where 
R.sup.1 and R.sup.2 represent a heterocyclic group containing nitrogen, it 
is preferred to prepare the compounds in the form of their non-toxic 
pharmaceutically acceptable acid addition salts for the purpose of 
separation and recovery. Likewise, when R.sup.1 and/or R.sup.2 is 
hydrogen, that amino group is protected during reaction with the chloro 
oxalic 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, sulfuric, 
phosphoric, methane sulfonic, nitric, p-toluene sulfonic, acetic, citric, 
maleic, succinic acid and the like. 
The preferred compounds from the standpoint of potency are those in which 
R.sup.1 and R.sup.2 are hydrogen or R.sup.1 is lower alkyl and R.sup.2 is 
hydrogen and the amino group 
##STR4## 
is in the 3-position. 
The 3- or 4-substituted-2-cyanooxanilic acid compounds of this invention 
are generally produced by condensing an appropriately substituted 
2-cyanoaniline with an activated 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 5 to 6 carbon atoms, aziridinyl, azetidinyl, 
pyrrolidinyl, piperidinyl piperazinyl, 4-lower alkyl-piperazinyl, 
morpholino 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 dehydration of a 
correspondingly 2-carbamyl substituted precursor. Furthermore, a free 
amino group in 3- or 4-position may be produced by reduction of a nitro 
substituent after condensation with said activated oxalic acid 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 orally 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 involves four male Charles River rats (200-250 g. 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 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 maximum dosage level of 200 
milligrams per kilogram host body weight. Five minutes later 1 milliliter 
of a 0.5 percent solution of Evans blue dye and 8 milligrams of egg 
albumin is injected intravenously. After 40 minutes, the animal is 
sacrificed and the bleb size on its back is measured. The mean bleb size 
for the animals administered the test compound is calculated and the 
percent inhibition is determined 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 manner believed to be similar to the function of INTAL, 
block reaction(s) in the mast cell leading to the production and release 
of mediators. The compounds of this invention permit the occurrence of a 
non-productive antigen-antibody interaction by effectively blocking the 
IgE type reaction. In sum, the compounds of this invention block the 
release of mediators commonly resulting from the antigen antibody reaction 
as exemplified in a passive cutaneous anaphylaxis test (PCA) using rat 
homocytotropic antibody--a known correlate of human reaginic 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 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 ths application by oral, topical, intraperitoneal, 
intramuscular or intravenous routes. The compounds of this invention may 
be administered in conjunction with known compounds effecting 
antihistaminic, anti-hypertensive, analgesic, central nervous system 
depressant, immunosuppressive, anti-serotonin, anti-Bradykinin or 
endocrinological responses. In addition, those conventional adjuvants 
known to the art may be combined with the anti-allergics of this invention 
to provide compositions and solutions for administrative purposes, 
although it is considered desirable and feasible to employ the 
anti-allergics as neat or pure compounds without additives other than for 
purposes of providing suitable pharmaceutical solution or liquid or vapor 
suspensions. 
The effective dose range in test animals has been established to be from 
about 0.01 milligrams per kilogram to a dosage resulting in substantially 
100 percent prevention of the allergic response at 200 milligrams per 
kilogram host body weight, or less. 
As an inhalant, the dose is 2 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 under the 
guidance of a physician. 
Regarding the dosage to be used in the treatment of a specific atopic 
allergic reaction, the subjective observations of the attending physician 
are determinative. 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 known 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)oxanilic 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 weight 
and 73% inhibition at 100 milligrams per kilogram host body weight, as 
well as 2 -cyano-3-(4-methyl-1-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 invention possessing anti-allergic activity upon intraperitoneal 
administration is 2-cyano-3-(1-piperidinyl)oxanilic 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 as those in which the amino group 
appears in 3-position as the free amino group or lower alkylamino group. 
These compounds have been found to effect 100% inhibition with as low as 
0.10 milligrams per kilogram dosage administered intravenously with the 
sodium salt of [2-cyano-3-(methylamino)phenylamino]oxoacetic acid.