(4-Oxo-4H-1-benzopyran-3-yl)aminooxoacetic acids and their derivatives

The present invention relates to compounds of the formula: ##STR1## wherein R.sub.1 is hydrogen, halogen, hydroxy, lower alkoxy or lower alkyl, R.sub.2 is hydrogen or lower alkyl; R.sub.3 is hydrogen or lower alkyl. These compounds, including their corresponding pharmaceutically acceptable salts, are useful in the management of allergic conditions such as hay fever and as a prophylactic in the treatment of bronchial asthma.

The present invention relates to (4-oxo-4H-1-benzopyran-3-yl)aminooxoacetic 
acids and their derivatives having the following formula: 
##STR2## 
wherein R.sub.1 is hydrogen, halogen, hydroxy, lower alkoxy or lower 
alkyl, R.sub.2 is hydrogen or lower alkyl and R.sub.3 is hydrogen or lower 
alkyl. 
In the above definition for R.sub.1 -R.sub.3 lower alkyl is meant to have 
1-6 carbon atoms and includes, for example, methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl and so on. 
Halogen includes all the four members, i.e., chlorine, bromine, fluorine 
and iodine. 
The present invention also includes within its scope the corresponding 
pharmaceutically acceptable salts of the above compounds as well as 
methods for the treatment of allergic conditions by the administration of 
the aforesaid compound in a pharmaceutical dosage form. 
The compounds of this invention are active in prevention of allergic and 
asthmatic reactions in rats at dose levels of 0.5 mg/kg to 100 mg/kg; thus 
ethyl (6-chloro-4-oxo-4H-1-benzopyran-3-yl)aminooxoacetate shows a 92% 
inhibition of the allergic response at 10 mg/kg when tested 
intraperitoneally in the passive cutaneous anaphalaxis (PCA) screen, which 
is a modification of procedures described by I. Mota, Life Sciences, 7: 
465 (1963) and Z. Ovary and O. Bier, Proc. Soc. Exptl. Biol. Med., 81: 585 
(1952). Similarly, (6-chloro-4-oxo-4H-1-benzopyran-3-yl)aminooxoacetic 
acid shows a 41% inhibition of the allergic response at 0.5 mg/kg when 
tested intravenously in the PCA screen. Consequently, they are indicated 
in the management of asthma, hay fever and other allergic conditions. 
Generally speaking, for the treatment of bronchial asthma, a dose of about 
1-100 mg/kg orally or by parenteral administration is suggested. This 
dosage regimen may be varied depending upon the age, sex, weight of the 
patient and the severity of the condition being treated, by methods 
well-known to the healing arts. 
The compounds of this invention and their salts may also be administered by 
inhalation in which the compounds are inhaled directly in the form of an 
aerosol. 
The pharmaceutical dosage forms for the administration of the instant 
compounds are tablets, capsules and aqueous suspensions. These dosage 
forms are prepared by combining the active ingredient with pharmaceutical 
diluents such as lactose and compounded into tablets by well-known 
tabletting technology. The active ingredient in the finished dosage form 
is from 1-100 mg per unit. 
According to the present invention, Compound I is prepared by the following 
reaction scheme: 
##STR3## 
The starting materials are prepared by the following procedure: 
2-Methyl-3-nitro-4H-1-benzopyran-4-one and 3-aminochromone by the method of 
G. J. P. Beckett and G. P. Ellis, Tetrahedron Letters, 719 (1976); 
3-amino-6-chlorochromone by the method of M. von Strandtmann and S. 
Klutchko, U.S. Pat. No. 3,906,005, and ethyl oxalyl chloride is available 
from Aldrich Chemical Company. 
Briefly, Compound II is prepared by hydrogenating Compound II by a known 
hydrogenation procedure, e.g., palladium on charcoal under an atmosphere 
of hydrogen. Compound IV, in turn, is readily obtained by treatment with 
an alkyl oxalyl halide at ambient temperature. The corresponding acid, V, 
is prepared by hydrolysis in a manner known per se. 
Esters corresponding to Compound V are also prepared in a manner per se. 
For more detailed description of the preparation of the instant compounds, 
please refer to the following examples. The pharmaceutically acceptable 
salts of the present invention are prepared by reacting Compound I 
(wherein R.sub.3 =H) with bases such as sodium, potassium and calcium 
hydroxides or bicarbonates in stoichiometric amounts, and they may also be 
prepared by reacting with organic bases such as amines. The salts thus 
formed are recovered by methods well-known in the art. 
In order to illustrate the practice of the invention, the following 
examples are included. In the examples, temperatures are in degrees 
Centigrade.