A series of 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-N-(1H-tetrazol-5-yl)carboxamides is provided for use as inhibitors of allergic reactions. The compounds show antiallergy activity by both oral and parenteral routes of administration.

BACKGROUND OF THE INVENTION 
1. Field of the Invention: 
This invention relates to optionally substituted 
1,6-dihydro-6-oxo-2-phenylpyrimidine-5-N-(1H-tetrazol-5-yl)-carboxamide 
derivatives and to their use as inhibitors of allergic reactions. 
2. Description of the Prior Art: 
Various medicinal agents have been employed in the treatment of allergic 
reactions such as bronchial asthma and allergic rhinitis which are 
believed to result mainly from antigenantibody interaction. With respect 
to bronchial asthma, one of the most serious of these 
allergically-mediated diseases, bronchodilators such as theophylline, 
isoproterenol, epinephrine and atropine are used primarily in providing 
symptomatic relief. These agents, however, have undesirable side effects, 
e.g. cardiac stimulation and gastrointestinal distress. 
With the recent introduction of disodium cromoglycate described by J. S. G. 
Cox, et al. in Adv. in Drug Res., 5, 115-196 (1970), the physician has 
been provided with an agent which, when administered to asthmatic patients 
prior to inhalation of specific antigens, inhibits the release of 
mediators, e.g. histamine and SRS-A (slow-reacting-substance of 
anaphylaxis), believed to be responsible for the asthmatic response. While 
making possible a prophylactic treatment for bronchial asthma without 
cardiovascular side effects and thus representing a significant advance, 
disodium cromoglycate suffers from a major disadvantage in that it is not 
orally absorbed and must be administered by inhalation. 
With respect to the compounds of the present invention, no examples of 
1,6-dihydro-6-oxo-2-phenylpyrimidine-5-N-(1H-tetrazol-5-yl)carboxamides 
have been found in the literature. Numerous examples of 
1,6-dihydro-6-oxo-2-phenylpyrimidine-5-carboxylic acid derivatives are 
known, however. Illustrative of such compounds are the following: 
1. Preparation of the unsubstituted acid and ester of the formula 
##STR1## 
where R is hydrogen or ethyl is disclosed by S. Ruhemann in Ber., 30, 821 
(1897). 
2. The p-methylphenyl and p-methoxyphenyl substituted esters and acids of 
the formula 
##STR2## 
where R is hydrogen or ethyl and X is methyl or methoxy are disclosed by 
Mitter, et al. in J. Chem. Soc., 123, 2179 (1923) and Quart. J. Indian 
Chem. Soc., 2, 61 (1925). 
3. Shen, et al. in U.S. Pat. Nos. 3,660,403 and 3,745,161 disclose 
compounds of the general formula 
##STR3## 
where R--Ar-- may inter alia be substituted phenyl, Y may be hydrogen and 
X is any of various substituents including hydroxy, alkoxy or 
N-heterocyclo. The reference compounds are disclosed as having 
antiinflammatory, antipyretic and analgesic activity, and no mention is 
made of any utility as antiallergy agents. 
4. U.S. Pat. No. 3,883,653 discloses antiallergy compounds of the formula 
##STR4## 
where m is an integer of 0 or 1 and Ar is pyridyl, thienyl, furyl, phenyl 
or phenyl substituted by hydroxy, methyl, methoxy, nitro, chloro, fluoro, 
3,4-dimethoxy, 3,4,5-trimethoxy or alkanoylamino. 
5. U.S. Pat. No. 3,448,107 discloses lipid regulating agents of the formula 
##STR5## 
where X.sup.1 and X.sup.2 may be various substituents including hydroxy, 
phenyl, p-chlorophenyl, p-methylphenyl and p-aminophenyl and n may be 0 to 
4. 
6. U.S. Pat. No. 4,031,093 discloses 1,6-dihydro-6-oxo-2(ortho-substituted 
phenyl)pyrimidine-5-carboxylic acid derivatives of the formula 
##STR6## 
wherein Z.sup.a is --O--C.sub.1 --C.sub.6 alkyl, --O--C.sub.2 --C.sub.6 
alkenyl, --O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n in which m is 0 or an 
integer from 1 to 6 and n is an integer from 2 to 7, --OCH.sub.2 
(CH.sub.2).sub.x O(CH.sub.2).sub.y CH.sub.3 in which x and y are each 
independently either 0 or an integer from 1 to 6, --OCF.sub.3, --OCH.sub.2 
CF.sub.3, --O(CH.sub.2).sub.u CO.sub.2 R.sup.a in which u is an integer 
from 1 to 6 and R.sup.a is hydrogen or C.sub.1 -C.sub.6 alkyl, R.sup.c 
--COO-- in which R.sup.c is C.sub.1 -C.sub.6 alkyl, --O--CONHR.sup.b in 
which R.sup.b is C.sub.1 -C.sub.6 alkyl, --O(CH.sub.2).sub.k OH in which k 
is an integer from 2 to 6, 
##STR7## 
Z.sup.b has the meaning stated above for Z.sup.a and in addition may be 
hydrogen, halogen, amino, C.sub.1 -C.sub.6 alkylamino, di(C.sub.1 
-C.sub.6)-alkylamino, --N(CH.sub.2).sub.r in which r is 4 or 5, 
##STR8## 
carb(C.sub.1 -C.sub.6)alkoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 
alkenyl, CF.sub.3, hydroxy, C.sub.1 -C.sub.6 alkylthio, R.sup.c --CO-- in 
which R.sup.c is C.sub.1 -C.sub.6 alkyl or R.sup.c --CONH-- in which 
R.sup.c is C.sub.1 -C.sub.6 alkyl, Z.sup.c is hydrogen or C.sub.1 -C.sub.6 
alkoxy and R is hydrogen or the residue of an easily cleavable ester group 
or a pharmaceutically acceptable salt thereof, provided that when Z.sup.a 
is methoxy, Z.sup.b and Z.sup.c are not hydrogen and when Z.sup.c is 
C.sub.1 -C.sub.6 alkoxy, Z.sup.a and Z.sup.b are both C.sub.1 -C.sub.6 
alkoxy. 
7. U.S. Pat. No. 4,082,751 discloses 
2-phenyl-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one derivatives of the formula 
##STR9## 
wherein R.sup.1, R.sup.2 and R.sup.3 which may be the same or different 
are each hydrogen, halogen, (lower)alkyl, (lower)alkenyl, (lower)alkoxy, 
--O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n in which m is 0 or an integer 
from 1 to 6 and n is an integer from 2 to 7, --OCH.sub.2 (CH.sub.2).sub.x 
O(CH.sub.2).sub.y CH.sub.3 in which x is 0 or an integer from 1 to 6 and 
y is 0 or an integer from 1 to 6, CF.sub.3, --OCF.sub.3, --OCH.sub.2 
CF.sub.3, hydroxy, (lower)alkylthio, amino, nitro, --N(CH.sub.2).sub.r in 
which r is 4 or 5, 
##STR10## 
(lower)alkylamino, di(lower)alkylamino, carboxyl, --CO.sub.2 
--(lower)alkyl, --O(CH.sub.2).sub.u CO.sub.2 R.sup.a in which u is an 
integer from 1 to 6 and R.sup.a is hydrogen or (lower)alkyl, acyl, 
acylamino, acyloxy, 
##STR11## 
in which R.sup.b is (lower)alkyl, --O(CH.sub.2).sub.k OH in which k is an 
integer from 2 to 6, 
##STR12## 
and pharmaceutically acceptable salts thereof, with the proviso that 
R.sup.1, R.sup.2 and R.sup.3 may not all be alike except in the case where 
they represent (lower)alkoxy. 
SUMMARY OF THE INVENTION 
This invention relates to new therapeutically useful 
1,6-dihydro-6-oxo-2-phenylpyrimidine-5-N-(1H-tetrazol-5-yl)-carboxamide 
derivatives, to processes for their preparation, to pharamaceutical 
compositions containing them and to methods for treating 
allergically-mediated diseases in mammals by administration of such 
derivatives or pharmaceutical compositions. 
The compounds of the present invention are useful in the prophylactic 
treatment of allergic conditions such as bronchial asthma, allergic 
rhinitis, urticaria, systemic anaphylaxis, conjunctivitis, atopic 
dermatitis and food allergies. They are of particular value in both 
reagin-mediated type I hypersensitivity asthma (extrinsic asthma) and the 
so-called intrinsic asthma in which no sensitivity to any extrinsic 
antigen can be demonstrated. 
The antiallergy agents of the present invention may be represented by the 
formula 
##STR13## 
wherein R.sup.1, R.sup.2 and R.sup.3 which may be the same or different 
are each hydrogen, halogen, (lower)alkyl, (lower)alkenyl, (lower)-alkoxy, 
--O--(lower)alkenyl, --O--(lower)alkynyl, --O--(CH.sub.2).sub.m 
--CH(CH.sub.2).sub.n in which m is 0 or an integer from 1 to 6 and n is an 
integer from 2 to 7, --OCH.sub.2 (CH.sub.2).sub.x O(CH.sub.2).sub.y 
CH.sub.3 in which x is 0 or an integer from 1 to 6 and y is 0 or an 
integer from 1 to 6, CF.sub.3, --OCF.sub.3, --OCH.sub.2 CF.sub.3, hydroxy, 
(lower)alkylthio, amino, nitro, --N(CH.sub.2).sub.r in which r is 4 or 5, 
(lower)alkylamino, di(lower)alkylamino, carboxyl, --CO.sub.2 
--(lower)alkyl, --O(CH.sub.2).sub.u CO.sub.2 R.sup.a in which u is an 
integer from 1 to 6 and R.sup.a is hydrogen or (lower)alkyl, R.sup. c 
--CO-- in which R.sup.c is (lower)alkyl, R.sup.c --CONH-- in which R.sup.c 
is (lower)alkyl, R.sup.c --COO-- in which R.sup.c is (lower)alkyl, 
##STR14## 
in which R.sup.b is (lower)alkyl, --O(CH.sub.2).sub.k OH in which k is an 
integer from 2 to 6, 
##STR15## 
or --OCH.sub.2 C.sub.6 H.sub.5, or a pharmaceutically acceptable salt 
thereof, with the provisos that (1) no more than two of R.sup.1, R.sup.2 
and R.sup.3 are tertiary alkyl or tertiary alkoxy groups, and when two of 
said R.sup.1, R.sup.2 and R.sup.3 are tertiary alkyl or tertiary alkoxy, 
they are located on non-adjacent positions and (2) R.sup.1, R.sup.2 and 
R.sup.3 may not all be alike except in the case where they represent 
hydrogen or (lower)alkoxy. 
DETAILED DESCRIPTION 
The R.sup.1, R.sup.2 and R.sup.3 substituents mentioned above may be 
located at any of the available positions of the phenyl ring, i.e. at the 
2-6 positions. The substituents groups may be further defined as follows: 
(a) Halogen includes chlorine, bromine, fluorine and iodine; 
(b) (Lower)alkyl includes both straight and branched chain saturated 
aliphatic hydrocarbon radicals having from 1-6 carbon atoms inclusive, 
e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 
tert-butyl, n-pentyl, isopentyl, n-hexyl, etc.; 
(c) (Lower)alkenyl includes straight or branched unsaturated aliphatic 
hydrocarbon radicals containing one double bond and having from 2-6 carbon 
atoms inclusive, e.g. vinyl, allyl, isopropenyl, 2- or 3-methallyl or 
3-butenyl; 
(d) (Lower)alkoxy includes C.sub.1 -C.sub.6 alkoxy radicals, the alkyl 
portion of such radicals being defined as in (b) above. Examples include 
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 
n-pentyloxy, isopentyloxy, n-hexyloxy, etc.; 
(e) --O--(Lower)alkenyl groups include radicals in which the alkenyl 
portion is as defined above in (c), e.g. vinyloxy, allyloxy or 
isopropenyloxy; 
(f) --O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n includes 
cyclo(lower)-alkyloxy and cyclo(lower)alkyl-(C.sub.1 -C.sub.6)alkyloxy 
groups in which the cycloalkyl ring contains from 3 to 8 carbon atoms, 
preferably 3-6 carbon atoms. Examples of such groups are cyclopropyloxy, 
cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, 
cyclopropylmethyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, 
cyclobutylethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, 
cyclohexylethyloxy and cyclohexylpropyloxy; 
(g) --O--CH.sub.2 (CH.sub.2).sub.x O(CH.sub.2).sub.y CH.sub.3 includes 
radicals such as --OCH.sub.2 OCH.sub.3, --OCH.sub.2 CH.sub.2 OCH.sub.3, 
--OCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3, --OCH.sub.2 OCH.sub.2 CH.sub.3 
and --OCH.sub.2 CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3 ; 
(h) (lower)alkylthio includes C.sub.1 -C.sub.6 alkylthio radicals in which 
the alkyl portion is as defined above in (b). Examples of such groups are 
methylthio, ethylthio, n-propylthio and n-butylthio; 
(i) (Lower)alkylamino includes C.sub.1 -C.sub.6 alkylamino radicals in 
which alkyl is as defined in (b). Examples of such groups as methylamino, 
ethylamino, propylamino and butylamino; 
(j) Di(lower)alkylamino includes di C.sub.1 -C.sub.6 alkylamino radicals in 
which alkyl is as defined above in (b). Examples of such groups are 
dimethylamino and diethylamino; 
(k) --CO--(Lower)alkyl includes ester radicals in which the alkyl moiety is 
as defined above in (b), e.g. carbomethoxy, carbethoxy, carbopropoxy and 
carbobutoxy; 
(l) --O(CH.sub.2).sub.u CO.sub.2 R.sup.a represents radicals such as 
--OCH.sub.2 CO.sub.2 H, --OCH.sub.2 CH.sub.2 CO.sub.2 H, --OCH.sub.2 
CH.sub.2 CH.sub.2 CO.sub.2 H, --OCH.sub.2 CO.sub.2 CH.sub.3, --OCH.sub.2 
CO.sub.2 C.sub.2 H.sub.5, --OCH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3 and 
--OCH.sub.2 CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 ; 
(m) --N(CH.sub.2)r includes pyrrolidino and piperidino; 
(n) 
##STR16## 
includes (lower)alkyl carbamoyloxy radicals in which the (lower)alkyl 
portion is as defined above in (b). Examples of such substituents include 
--OCONHCH.sub.3, --OCONHC.sub.2 H.sub.5 and --OCONHC.sub.3 H.sub.7 ; and 
(o) --O--(Lower)alkynyl includes groups in which the alkynyl moiety is a 
straight or branched unsaturated aliphatic hydrocarbon radical containing 
one triple bond and having from 2 to 6 carbon atoms inclusive, e.g. 
ethynyloxy, propargyloxy, butynyloxy, pentynyloxy or hexynyloxy. 
A preferred embodiment of the present invention comprises the compounds of 
formula I as defined above wherein R.sup.1, R.sup.2 and R.sup.3 are each 
independently selected from hydrogen, (lower)alkoxy, --O--(lower)alkenyl, 
--O--(lower)-alkynyl, --O--(CH.sub.2)-CH(CH.sub.2).sub.n in which m is 0 
or an integer from 1 to 6 and n is an integer from 2 to 7, --OCH.sub.2 
C.sub.6 H.sub.5, halogen, CF.sub.3, (lower)alkyl, amino, 
(lower)alkylamino, di(lower)alkylamino, hydroxy, carboxy and 
(lower)alkylthio. Within this group of compounds, a more preferred 
embodiment comprises those compounds wherein R.sup.1, R.sup.2 and R.sup.3 
are each independently selected from hydrogen, (lower)alkoxy, 
--O--(lower)alkenyl, --O--(lower)alkynyl, --O--(CH.sub.2).sub.m 
--CH(CH.sub.2).sub.n in which m is 0 or an integer from 1 to 6 and n is an 
integer from 2 to 7 and --OCH.sub.2 C.sub.6 H.sub.5. 
A more preferred embodiment of the present invention comprises the 
compounds of the formula 
##STR17## 
wherein R.sup.1 and R.sup.2 which may be the same or different are as 
defined above in connection with the compounds of general formula I, and 
the pharmaceutically acceptable salts thereof, with the proviso that when 
both R.sup.1 and R.sup.2 are tertiary alkyl or tertiary alkoxy groups, 
they are located on non-adjacent positions. 
A preferred subgroup within the compounds defined by formula I' comprises 
the compounds wherein R.sup.1 and R.sup.2 are each independently selected 
from hydrogen, (lower)alkoxy, --O--(lower)alkenyl, --O--(lower)alkynyl, 
--O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n in which m is 0 or an integer 
from 1 to 6 and n is an integer from 2 to 7, --OCH.sub.2 C.sub.6 H.sub.5, 
halogen, CF.sub.3, (lower)alkyl, amino, (lower)alkylamino, 
di(lower)alkylamino, hydroxy, carboxy and (lower)alkylthio. Within this 
subgroup, the preferred compounds are those in which R.sup.1 and R.sup.2 
are each independently selected from hydrogen, (lower)alkoxy, 
--O--(lower)alkenyl, --O--(lower)alkynyl, --O--(CH.sub.2).sub.m 
--CH(CH.sub.2).sub.n in which m is 0 or an integer from 1 to 6 and n is an 
integer from 2 to 7 and --OCH.sub.2 C.sub.6 H.sub.5. The most preferred 
compounds within this latter group are those in which R.sup.1 is a 
non-hydrogen substituent. 
A most preferred subgroup within the compounds defined by formula I' 
comprises the compounds wherein R.sup.1 is (lower)alkoxy, 
--O--(lower)alkenyl, --O--(lower)alkynyl, --O--(CH.sub.2).sub.m 
--CH(CH.sub.2).sub.n in which m is 0 or an integer from 1 to 6 and n is an 
integer from 2 to 7 or --OCH.sub.2 C.sub.6 H.sub.5 and R.sup.2 is 
hydrogen, (lower)alkoxy, --O--(lower)alkenyl, --O--(lower)-alkynyl, 
--O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n in which m is 0 or an integer 
from 1 to 6 and n is an integer from 2 to 7, --OCH.sub.2 C.sub.6 H.sub.5, 
amino, di(lower)alkylamino or (lower)alkylthio. 
Another more preferred embodiment of the present invention comprises the 
compounds of the formula 
##STR18## 
wherein R.sup.1 and R.sup.2 which may be the same or different are as 
defined above in connection with the compounds of general formula I, and 
the pharmaceutically acceptable salts thereof. 
A preferred subgroup within the compounds defined by formula I" comprises 
the compounds wherein R.sup.1 and R.sup.2 are each independently selected 
from hydrogen, (lower)-alkoxy, --O--(lower)alkenyl, --O--(lower)alkynyl, 
--O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n in which m is 0 or an integer 
from 1 to 6 and n is an integer from 2 to 7, --OCH.sub.2 C.sub.6 H.sub.5, 
halogen, CF.sub.3, (lower)alkyl, amino, (lower)alkylamino, 
di(lower)alkylamino, hydroxy, carboxy and (lower)alkylthio. Within this 
subgroup, the preferred compounds are those in which R.sup.1 and R.sup.2 
are each independently selected from hydrogen, (lower)alkoxy, 
--O--(lower)alkenyl, --O--(lower)alkynyl, --O--(CH.sub.2).sub.m 
--CH(CH.sub.2).sub.n in which m is 0 or an integer from 1 to 6 and n is an 
integer from 2 to 7 and --OCH.sub.2 C.sub.6 H.sub.5. The most preferred 
compounds within this latter group are those in which R.sup.1 is a 
nonhydrogen substituent. 
A most preferred subgroup within the compounds defined by formula I" 
comprises the compounds wherein R.sup.1 is (lower)alkoxy, 
--O--(lower)alkenyl, --O--(lower)alkynyl, --O--(CH.sub.2).sub.m 
--CH(CH.sub.2).sub.n in which m is 0 or an integer from 1 to 6 and n is an 
integer from 2 to 7 or --OCH.sub.2 C.sub.6 H.sub.5 and R.sup.2 is 
hydrogen, (lower)alkoxy, --O--(lower)alkenyl, --O--(lower)-alkynyl, 
--O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n in which m is 0 or an integer 
from 1 to 6 and n is an integer from 2 to 7, --OCH.sub.2 C.sub.6 H.sub.5, 
amino, di(lower)alkylamino or (lower)alkylthio. 
Other most preferred subgroups within the compounds defined by formula I" 
are as follows: 
(a) compounds where R.sup.1 is (lower)alkoxy, most preferably methoxy, 
ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or 
t-butoxy; 
(b) compounds where R.sup.1 is --O--(lower)alkenyl, most preferably 
allyloxy; 
(c) compounds where R.sup.1 is --O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n 
in which m is 0 or an integer from 1 to 6 and n is an integer from 2 to 7, 
most preferably cyclopropylmethoxy; and 
(d) compounds where R.sup.1 is methoxy, ethoxy, n-propoxy, isopropoxy, 
n-butoxy, isobutoxy, sec-butoxy, t-butoxy, allyloxy or cyclopropylmethoxy 
and R.sup.2 is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 
isobutoxy, sec-butoxy, t-butoxy, allyloxy, cyclopropylmethoxy, amino or 
dimethylamino. 
Another more preferred embodiment of the present invention comprises the 
compounds of the formula 
##STR19## 
wherein R.sup.1 is hydrogen, halogen, (lower)alkyl, (lower)-alkenyl, 
(lower)alkoxy, --O--(lower)alkenyl, --O--(lower)-alkynyl, 
--O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n in which m is 0 or an integer 
from 1 to 6 and n is an integer from 2 to 7, --OCH.sub.2 (CH.sub.2).sub.x 
O(CH.sub.2).sub.y CH.sub.3 in which x is 0 or an integer from 1 to 6 and y 
is 0 or an integer from 1 to 6, CF.sub.3, --OCF.sub.3, --OCH.sub.2 
CF.sub.3, hydroxy, (lower)alkylthio, amino, nitro, --N(CH.sub.2).sub.r in 
which r is 4 or 5, (lower)alkylamino, di(lower)alkylamino, carboxyl, 
--CO.sub.2 --(lower)alkyl, --O(CH.sub.2).sub.u CO.sub.2 R.sup.a in which u 
is an integer from 1 to 6 and R.sup.a is hydrogen or (lower)alkyl, R.sup.c 
--CO-- in which R.sup.c is (lower)alkyl, R.sup.c --CONH-- in which 
R.sup.c is (lower)-alkyl, R.sup.c --COO-- in which R.sup.c is 
(lower)alkyl, 
##STR20## 
in which R.sup.b is (lower)alkyl, --O(CH.sub.2).sub.k OH in which k is an 
integer from 2 to 6, 
##STR21## 
or --OCH.sub.2 C.sub.6 H.sub.5, or a pharmaceutically acceptable salt 
thereof. 
A preferred subgroup within the compounds defined by formula I'" comprises 
the compounds wherein R.sup.1 is hydrogen, (lower)alkoxy, 
--O--(lower)alkenyl, --O--(lower)-alkynyl, --O--(CH.sub.2).sub.m 
--CH(CH.sub.2).sub.n in which m is 0 or an integer from 1 to 6 and n is an 
integer from 2 to 7, --OCH.sub.2 C.sub.6 H.sub.5, halogen, CF.sub.3, 
(lower)alkyl, amino, (lower)alkylamino, di(lower)alkylamino, hydroxy, 
carboxy or (lower)alkylthio. Within this subgroup, the preferred compounds 
are those in which R.sup.1 is (lower)alkoxy, --O--(lower)alkenyl, 
--O--(lower)-alkynyl, --O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n in which 
m is 0 or an integer from 1 to 6 and n is an integer from 2 to 7 or 
--OCH.sub.2 C.sub.6 H.sub.5. 
Other preferred subgroups within the compounds defined by formula I'" are 
as follows: 
(a) compounds where R.sup.1 is (lower)alkoxy, most preferably methoxy, 
ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or 
t-butoxy; 
(b) compounds where R.sup.1 is --O--(lower)alkenyl, most preferably 
allyloxy; 
(c) compounds where R.sup.1 is --O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n 
in which m is 0 or an integer from 1 to 6 and n is an integer from 2 to 7, 
most preferably cyclopropylmethoxy; 
(d) compounds where R.sup.1 is --O--(lower)alkynyl; and 
(e) compounds where R.sup.1 is --OCH.sub.2 C.sub.6 H.sub.5. 
The term "pharmaceutically acceptable salt" as used herein is intended to 
include non-toxic cationic salts such as the alkali metal salts, e.g. 
sodium and potassium, alkaline earth metal salts such as calcium, 
magnesium or barium, aluminum salts, ammonium salts, and salts with 
organic bases, e.g. amines such as triethylamine, n-propylamine, 
tri-n-butylamine, piperidine, ethanolamine, diethanolamine, 
triethanolamine, diethylaminoethylamine, ethylenediamine, 
N,N'-dibenzylethylenediamine, benzylamine, tris(hydroxymethyl)aminomethane 
or pyrrolidine. Salt formation is accomplished by reacting the appropriate 
pyrimidine-5-N-(1H-tetrazol-5-yl)carboxamide with a substantially 
equimolar amount of the appropriate base in an aqueous solution or in a 
suitable organic solvent such as methanol or ethanol. The salts are 
recovered by standard methods such as filtration if they are insoluble in 
the reaction medium, or if they are soluble in the medium, by evaporation 
or by precipitation by addition of a non-solvent for the salt. 
Those skilled in the art will appreciate that the compounds represented by 
structural formulae I-I'" are capable of also existing in the tautomeric 
forms shown below. All of the forms may be present to a greater or lesser 
degree and may co-exist in a dynamic equilibrium mixture. While all of the 
various tautomeric forms are included within the scope of the present 
invention, the form represented by formula 1 below has been arbitrarily 
used herein for the sake of convenience to describe the present compounds. 
##STR22## 
The compounds of formula I may be prepared by coupling of the appropriate 
pyrimidine-5-carboxylic acid of the formula 
##STR23## 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above with 
5-aminotetrazole of the formula 
##STR24## 
The coupling of the acid II with the amino-tetrazole III may be 
accomplished with the aid of a variety of reagents commonly used, for 
example, in peptide synthesis. Examples of these reagents are described by 
Schroder and Lubke in "The Peptides", Vol. I, Academic Press, N.Y., 1965, 
pp. 77-128. The general principle of the synthesis is activation of the 
carboxyl group by either formation, for example, of the corresponding acid 
azide, acid halide (preferably the acid chloride), mixed anhydride (e.g. 
with carbonic acid monoesters), activated ester (e.g. p-nitrophenyl), or 
heterocyclic amide (e.g. imidazolide), or by treatment with a carbodiimide 
(e.g. N,N'-dicyclohexylcarbodiimide). Treatment of the activated carboxyl 
group with 5-aminotetrazole results in amide formation. The coupling 
reaction is carried out in a reaction-inert solvent system. The variety of 
coupling reagents which can be used allows a wide choice of solvents. 
Representative solvents are N,N-dimethylformamide, tetrahydrofuran, 
dioxane, methylene chloride, nitromethane, acetonitrile, 
dimethylsulfoxide, N,N-dimethylacetamide and hexamethylphosphoramide. 
Reaction times and temperatures are not critical. For good yields of 
products within a reasonable length of time, convenient temperatures are 
in the range of about 20.degree.-100.degree. C. for both steps, i.e. 
reaction of the acid with the coupling agent the reaction of the activated 
intermediate with the 5-aminotetrazole. The coupling reaction may be 
carried out either in stepwise fashion, i.e. by isolating the activated 
intermediate before addition of the 5-aminotetrazole, or by adding all 
reactants at once. 
A preferred method of coupling utilizes N,N'-carbonyldiimidazole and is 
illustrated by the following scheme: 
##STR25## 
This reaction scheme may be carried out using the reaction-inert solvents 
mentioned above in both the imidazolide formation step and the step in 
which the imidazolide (either in situ or isolated) is reacted with the 
aminotetrazole. Preferred solvents are tetrahydrofuran and 
N,N-dimethylformamide. The reaction temperature is not critical, but a 
convenient temperature range for both steps has been found to be about 
20.degree.-100.degree. C. 
The pyrimidine-5-carboxylic acids of formula II may be prepared as 
described in U.S. Pat. No. 4,031,093 or by hydrolysis of the 
pyrimidine-5-carboxylate esters disclosed in U.S. Pat. No. 4,082,751. The 
5-aminotetrazole starting material is commercially available. 
In preparing compounds of formula I which contain free hydroxy, amino or 
carboxyl groups, it is of course understood that such groups will be 
protected by conventional protecting groups during the coupling reaction 
of II with III. The protecting group(s) may then be removed by methods 
known per se to give the desired end-products having the unprotected 
substituent groups. Amino-substituted compounds may be prepared from the 
corresponding nitro-substituted product by catalytic hydrogenation. In 
preparing compounds of formula I where R.sup.1, R.sup.2 or R.sup.3 are 
(lower)alkylamino or di(lower)alkylamino, the corresponding 
amino-substituted compound may first be prepared and then alkylated. 
Alternatively, the dialkylamino-substituted compounds can be prepared 
directly from the appropriate starting material of formula II. 
In another aspect, the present invention provides a method of inhibiting or 
preventing the symptoms of an allergic reaction such as bronchial asthma, 
allergic rhinitis, urticaria, allergic conjunctivitis, systemic 
anaphylaxis, atopic dermatitis and food allergy in a mammal susceptible to 
such a reaction which comprises administering to said mammal a 
prophylactically effective dose of a compound of formula I or a 
pharmaceutically acceptable salt thereof. 
The compounds of the present invention may be administered either as 
individual therapeutic agents or as mixtures with other therapeutic 
agents. They may be administered alone but are generally administered in 
the form of pharmaceutical compositions, i.e. mixtures of the active 
agents with suitable pharmaceutical carriers or diluents. Examples of such 
compositions include tablets, lozenges, capsules, powders, aerosol sprays, 
aqueous or oily suspensions, syrups, elixirs and aqueous solutions. The 
compounds are preferably administered orally, but may also be administered 
by inhalation, injection, instillation or by implantation for controlled 
drug release from a solid carrier reservoir. 
The nature of the pharmaceutical composition and the pharmaceutical carrier 
or diluent will, of course, depend on the desired route of administration. 
For example, oral compositions may be in the form of tablets or capsules 
and may contain conventional excipients such as binding agents (e.g. 
syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), 
fillers (e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol or 
glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol, 
or silica), disintegrants (e.g. starch) or wetting agents (e.g. sodium 
lauryl sulfate). Oral liquid preparations may be in the form of aqueous or 
oily suspensions, solutions, emulsions, syrups, elixirs, etc. or may be 
presented as a dry product for reconstitution with water or other suitable 
vehicle before use. Such liquid preparations may contain conventional 
additives such as suspending agents, flavoring agents, diluents or 
emulsifying agents. For parenteral administration, inhalation or 
instillation, solutions or suspensions of a compound of formula I with 
conventional pharmaceutical vehicles may be employed, e.g. as an aerosol 
spray for inhalation, as an aqueous solution for intravenous injection or 
instillation, or as an oily suspension for intramuscular injection. The 
compounds may also be administered by means of inhalers or other devices 
which permit the active compounds in the form of dry powders to come into 
direct contact with the lungs. 
The compounds of the present invention or pharmaceutical compositions 
thereof may be administered to human allergic patients in single oral 
doses of approximately 0.5--500 mg. of active ingredient and multiple oral 
doses totalling up to about 1000 mg./day of active ingredient. When 
administered by inhalation or instillation, lower doses are generally 
given, i.e. on the order of about 0.1 of the normal oral dosage for the 
particular compound in question. These values are illustrative only, 
however, and the physician of course will ultimately determine the dosage 
most suitable for a particular patient on the basis of factors such as 
age, weight, severity of the symptoms and the particular agent to be 
administered. 
The in vivo animal model studies described below indicate that the 
compounds of formula I are highly potent antiallergy agents. 
BIOLOGICAL ACTIVITY DATA 
The reagin-mediated rat Passive Cutaneous Anaphylaxis (PCA) screening test 
used to evaluate the present compounds is generally regarded as one of the 
best animal models for use in predicting the antiallergy activity of test 
compounds in man. This screen provides a measure of the effectiveness of 
test compounds in either inhibiting the release or antagonizing the action 
of mediators arising from the interaction of reaginic antibodies with 
specific antigen, mediators which are causative factors in allergic 
disorders. The details of the test are fully described in U.S. Pat. No. 
4,031,093. 
The test compounds were solubilized in aqueous sodium bicarbonate and 
administered intravenously (i.v.) or per os (p.o.) either one or ten 
minutes, respectively, prior to antigen callenge. Disodium cromoglycate 
(DSCG), solubilized in saline, was administered i.v. at the time of 
challenge and p.o. 30 minutes prior to challenge. Test results were 
recorded in terms of the ID.sub.50 value, i.e. the dose of compound that 
inhibits 50% of the response. To illustrate the relative potency of the 
present compounds, the compound of Example 1 in the rat PCA test was found 
to have an ID.sub.50 of .about.0.051 mg./kg. (i.v.) and .about.0.56 
mg./kg. (p.o.) as compared to 0.6 mg./kg. (i.v.) and &gt;&gt;30 mg./kg. (p.o.) 
for DSCG.