TETRAZOLE-5-CARBOXAMIDE DERIVATIVES

DERIVES DE 5-CARBOXAMIDE DE TETRAZOLE

English Abstract

Abstract of the Disclosure
Anti-allergic agents of N-aromatic 1H-(or
2H)tetrazole-5-carboxamide derivation present the following
structural formula:
<IMG>
in which
R1 is -CN or -CONH2
R2 is lower alkoxy, hydroxy(lower)alkoxy, or
<IMG>
wherein
R7 and R8 are independently hydrogen, lower
alkyl, or cycloalkyl of 5 to 6 carbon atoms, or
R7 and R8, when taken together with the
nitrogen atom to which they are attached form
a heterocyclic group selected from aziridiayl,
azetidinyl, pyrrolidinyl, piperidino, pipera-
zinyl, 4-lower alkyl piperazinyl, morpholino,

thiomorpholino and ring substituted lower
alkyl analogues of said heterocyclic groups;
R3 is hydrogen, lower alkyl, lower alkoxy\,
halo, polyhalo(lower)alkyl, lower alkyl-
carbonyl or carb(lower)alkoxy;
or a pharmaceutically acceptable salt thereof.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of a 1H-tetrazole-5-
carboxamide which comprises (a) reacting an N-protected oxamic
acid lower alkyl ester with PCl5 in the presence of an acid
acceptor to obtain the imidochloride <IMG> in which R6 is
lower alkyl and R5 is a member selected from the group consisting
of benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 2,6-dimethoxy-
benzyl, 2,4,6-trimethoxybenzyl and trichloroethyl; (b) cyclizing
said imido-chloride with hydrazoic acid to produce the ester
1-R5-5-carbo(lower)-alkoxy-1H-tetrazole; (c) saponifying said
ester to obtain an alkali metal salt of said tetrazole; (d) con-
verting said tetrazole salt to the 5-chloro-carbonyl-1-R5-1H-
tetrazole by reaction with a chlorinating agent; (e) reacting
said 5-chlorocarbonyl-1-R5-1H-tetrazole with an aromatic amine
of the formula ANH2; (f) removing the 1-R5 group from the product
of step (e); wherein A is a member selected from the group con-
sisting of 2-thiazolyl, 2-pyridyl, 6-(lower)alkyl-2-pyridyl, 3-
cyano-2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl,
.alpha.-naphthyl, .beta.-naphthyl, phenyl, 2,6-dichloro-phenyl, and substi-
tuted phenyl moieties having from one to three substituents in
any of the 2,3,4 and 5 positions of the phenyl ring, independently
selected from the group consisting of lower alkyl, lower alkyl-
sulfinyl, lower alkoxy, hydroxy(lower)alkoxy, 2-(lower alkoxy
oxalyloxy)ethoxy, N-mono- and di-lower alkyl amino(lower)alkoxy,
halo, sulfamyl, polyhalo(lower)alkyl, carbamyl, N-lower alkyl-
carbamyl, carboxy, lower alkyl-carbonyl, cyano, carb(lower)alkoxy,
phenoxy(lower)alkoxy, lower alkoxyoxalamine, lower alkoxyoxal-
amidophenoxy and <IMG> where R8 and R7, independently represent
hydrogen, lower alkyl, or cycloalkyl of 5 to 6 carbon atoms, or
R8 and R7, taken together with the nitrogen atom to which they are
38

attached form a heterocyclic group selected from aziridinyl,
azetidinyl, pyrrolidinyl, piperidino, piperazinyl, 4-lower alkyl-
piperazinyl, morpholino, thio morpholino and a ring substituted
lower alkyl analogue of said heterocyclic group.
2. A process as claimed in claim 1 in which in the
reactants A is a group of the formula
<IMG>
in which R1 is -CN or -CONH2, R2 is lower alkoxy, hydroxy(lower)
alkoxy, or
<IMG>
wherein R7 and R8 are independently hydrogen, lower alkyl, or
cycloalkyl of 5 to 6 carbon atoms, or R7 and R8, when taken
together with the nitrogen atom to which they are attached form
a heterocyclic group selected from aziridinyl, azetidinyl,
pyrrolidinyl, piperidino, piperazinyl, 4-lower alkyl piperazinyl,
morpholino, thiomorpholino and ring substituted lower alkyl
analogues of said heterocyclic groups; R3 is hydrogen, lower
alkyl, lower alkoxy, halo, polyhalo(lower)alkyl, lower alkyl-
carbonyl or carb(lower)alkoxy.
3. The process of claim 1 in which said aromatic amine
is of the formula
<IMG>
39

in which R1 is -CN or -CONH2, R3 is hydrogen, lower alkyl, lower
alkoxy, halo, polyhalo(lower)alkyl, lower alkyl carbonyl or carb
(lower)alkoxy; X is -CH?, -O-, or <IMG> where R9 is lower alkyl;
and R4 is hydrogen or lower alkyl.
4. The process of claim 1 in which said aromatic amine
is of the formula
<IMG>
in which R1 is -CN or -CONH2; R2 is lower alkoxy, hydroxy lower
alkoxy, lower alkylamino or di(lower)alkyl amino; R3 is hydrogen,
lower alkyl, lower alkoxy, halo, polyhalo(lower)alkyl, lower
alkyl carbonyl or carb(lower)alkoxy.
5. A process as claimed in claim 2 in which R3 is
hydrogen and R2 is lower alkoxy, mono-lower alkylamino, di-lower
alkylamino, or a group of the formula
<IMG>
where X is -CH2-, -O- or -N- where R9 is lower alkyl.
6. A process as claimed in claim 3 in which in the
reactants X is -O- and R4 is hydrogen or methyl in the 2-position
or X is -CH2- and R4 is hydrogen or methyl in the 4-position and
R3 is hydrogen.
7. A process as claimed in claim 4 in which in the
reactants R2 is methoxy, R3 is hydrogen.
8. A process as claimed in claim 4 in which in the
reactants R1 is carbamoyl, R3 is hydrogen and R2 is methoxy.
9. A process as claimed in claim 4 which comprises
reacting methoxy benzyl oxamic acid ethyl ester in the presence
of pyridine in methylene chloride with PCl5, refluxing the

product obtained with hydrazoic acid, mixing the ethyl ester of
1-(4-methoxy benzyl)-1H-tetrazole-5-carboxylic acid so obtained
dissolved in absolute ethanol with potassium hydroxide, reacting
the potassium salt so obtained in benzene and in the presence of
pyridine with oxalyl chloride, mixing the chloride so obtained
in methylene chloride with 2-amino-6-methoxy benzamide and remov-
ing the 4-methoxy benzyl group from the product carboxamide by
refluxing in the presence of anisole and trifluoro acetic acid.
10. A process as claimed in claim 3 in which in the
reactants R1 is cyano, R3 is hydrogen, X is oxygen and R4 is
hydrogen.
11. A process as claimed in claim 3 which comprises
reacting benzyl oxamic acid ethyl ester in methylene chloride and
in the presence of pyridine with PCl5 refluxing the product obtained with
hydrazoic acid in benzene, treating the ethyl ester so obtained
with potassium hydroxide in absolute ethanol, reacting the potas-
sium salts so obtained with oxalyl chloride in benzene and in the
presence of pyridine, reacting the chloride so obtained with 2-
amino-6-(4-morpholinyl)benzonitrile in methylene chloride and
removing the N-benzyl group from the product carboxamide by
hydrogenation in acetic acid in the presence of a Pd/C catalyst.
12. A compound of the formula:
<IMG>
in which R1 is -CN or -CONH2, R2 is lower alkoxy, mono-lower
alkylamino, di-lower alkylamino, or a group of the formula
<IMG>
41

where X is -CH2-, -O- or <IMG> where R9 is lower alkyl or a phar-
maceutically acceptable salt thereof when prepared by the pro-
cess as claimed in claim 5 or an obvious chemical equivalent
thereof.
13. A compound of the formula given in claim 12
wherein R1 is as in claim 4 and R2 and R3 are as in claim 7
when prepared by the process as claimed in claim 7 or an
obvious chemical equivalent thereof.
14. The compound N-[2-carbamoyl-3-methoxyphenyl]-1H-
tetrazole-5-carboxamide or a pharmaceutically acceptable salt
thereof when prepared by the process as claimed in claim 8 or 9
or an obvious chemical equivalent thereof.
15. The compound N-[2-cyano-3-(4-morpholinyl)phenyl]-
1H-tetrazole-5-carboxamide or a pharmaceutically acceptable salt
thereof when prepared by a process as claimed in claim 10 or 11
or an obvious chemical equivalent thereof.
42

CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE
16. A process as claimed in claim 1 which comprises
reacting methoxy benzyl oxamic acid ethyl ester in the presence
of pyridine in methylene chloride with PCl5, refluxing the pro-
duct obtained with hydrazoic acid, mixing the ethyl ester of
1-(4-methoxy benzyl)-1H-tetrazole-5-carboxylic acid so obtained
dissolved in absolute ethanol with potassium hydroxide, reacting
the potassium salt so obtained in benzene and in the presence
of pyridine with oxalyl chloride, mixing the chloride so obtained
in methylene chloride with 2-aminopyridine and removing the 4-
methoxy benzyl group from the product carboxyamide by refluxing
in the presence of anisole and trifluoroacetic acid.
17. N-(2-pyridinyl)-1H-tetrazole-5-carboxamide or a
pharmaceutically acceptable salt whenever prepared or produced
by the process as claimed in claim 16 or an obvious chemical
equivalent thereof.
18. A process as claimed in claim 1 which comprises
reacting methoxy benzyl oxamic acid ethyl ester in the presence
of pyridine in methylene chloride with PCl5, refluxing the pro-
duct obtained with hydrazoic acid, mixing the ethyl ester of
1-(4-methoxy benzyl)-1H-tetrazole-5-carboxylic acid so obtained
dissolved in absolute ethanol with potassium hydroxide, reacting
the potassium salt so obtained in benzene and in the presence
of pyridine with oxalyl chloride, mixing the chloride so obtained
in methylene chloride with 2-amino-6-ethylaminobenzonitrile and
removing the 4-methoxy benzyl group from the product carboxyamide
by refluxing in the presence of anisole and trifluoroacetic acid.
19. N-[2-cyano-3(ethylamino)phenyl]-1H-tetrazole-5-
carboxamide or a pharmaceutically acceptable salt thereof when-
ever prepared or produced by the process as claimed in claim 18
or an obvious chemical equivalent thereof.
20. A process as claimed in claim 1 which comprises
43

reacting methoxy benzyl oxamic acid ethyl ester in the presence
of pyridine in methylene chloride With PCl5, refluxing the pro-
duct obtained with hydrazoic acid, mixing the ethyl ester of
1-(4-methoxy benzyl)-1H-tetrazole-5-carboxylic acid so obtained
dissolved in absolute ethanol with potassium hydroxide, reacting
the potassium salt so obtained in benzene and in the presence of
pyridine with oxalyl chloride, mixing the chloride so obtained in
methylene chloride with 2-amino-6-piperidinylbenzamide and remov-
ing the 4-methoxy benzyl group from the product carboxyamide by
refluxing in the presence of anisole and trifluoroacetic acid.
21. N-[2-(aminocarbonyl)-3-(1-piperidinyl)phenyl]-1H-
tetrazole-5-carboxamide or a pharmaceutically acceptable salt
thereof whenever prepared or produced by the process as claimed
in claim 20 or an obvious chemical equivalent thereof.
22. A process as claimed in claim 1 which comprises
reacting methoxy benzyl oxamic acid ethyl ester in the presence
of pyridine in methylene chloride with PCl5, refluxing -the pro-
duct obtained with hydrazoic acid, mixing the ethyl ester of
1-(4-methoxy benzyl)-1H-tetrazole-5-carboxylic acid so obtained
dissolved in absolute ethanol with potassium hydroxide, reacting
the potassium salt so obtained in benzene and in the presence
of pyridine with oxalyl chloride, mixing the chloride so obtained
in methylene chloride with 2-amino-6-(1-morpholinyl)benzamide
and removing the 4-methoxy benzyl group from the product carboxy-
amide by refluxing in the presence of anisole and trifluoroacetic
acid.
23. N-[2-(aminocarbonyl)-3-(4-morpholinyl)phenyl]-
1H-tetrazole-5-carboxyamide sodium salt or a pharmaceutically
acceptable salt thereof whenever prepared or produced by the
process as claimed in claim 22 or an obvious chemical equivalent
thereof.
24. A process as claimed in claim 1 which comprises
44

reacting methoxy benzyl oxamic acid ethyl ester in the presence
of pyridine in methylene chloride With PCl5, refluxing the pro-
duct obtained with hydrazoic acid, mixing the ethyl ester of
1-(4-methoxy benzyl)-1H-tetrazole-5-carboxylic acid so obtained
dissolved in absolute ethanol with potassium hydroxide, reacting
the potassium salt so obtained in benzene and in the presence of
pyridine with oxalyl chloride, mixing the chloride so obtained in
methylene chloride with 2-amino-6-dimethylaminobenzamide and
removing the 4-methoxy benzyl group from the product carboxyamide
by refluxing in the presence of anisole and trifluoroacetic acid.
25. N-[2-(aminocarbonyl)-3-(dimethylamino)phenyl]-1H-
tetrazole-5-carboxamide or a pharmaceutically acceptable salt
thereof whenever prepared or produced by the process as claimed
in claim 24 or an obvious chemical equivalent thereof.
26. A process as claimed in claim 1 which comprises
reacting methoxy benzyl oxamic acid ethyl ester in the presence
of pyridine in methylene chloride with PCl5, refluxing the pro-
duct obtained with hydrazoic acid, mixing the ethyl ester of
1-(4-methoxy benzyl)-1H-tetrazole-5-carboxylic acid so obtained
dissolved in absolute ethanol with potassium hydroxide, reacting
the potassium salt so obtained in benzene and in the presence of
pyridine with oxalyl chloride, mixing the chloride so obtained
in methylene chloride with 2-amino-6-dimethylamino benzonitrile
and removing the 4-methoxy benzyl group from the product carboxy-
amide by refluxing in the presence of anisole and trifluoroacetic
acid.
27. N-[2-cyano-3-(dimethylamino)phenyl]-1H-tetrazole-
5-carboxamide or a pharmaceutically acceptable salt thereof when-
ever prepared or produced by the process as claimed in claim 26
or an obvious chemical equivalent thereof.
28. A process as claimed in claim 1 which comprises
reacting methoxy benzyl oxamic acid ethyl ester in the presence

of pyridine in methylene chloride with PCl5, refluxing the pro-
duct obtained with hydrazoic acid, mixing the ethyl ester of
1-(4-methoxy benzyl)-1H-tetrazole-5-carboxylic acid so obtained
dissolved in absolute ethanol with potassium hydroxide, reacting
the potassium salt so obtained in benzene and in the presence
of pyridine with oxalyl chloride, mixing the chloride so obtained
in methylene chloride with 2-amino-6-(4-methylpiperazinyl)benzo-
nitrile and removing the 4-methoxy benzyl group from the product
carboxyamide by refluxing in the presence of anisole and tri-
fluoroacetic acid.
29. N-[2-cyano-3-(4-methyl-1-piperazinyl)phenyl]-1H-
tetrazole-5-carboxamide or a pharmaceutically acceptable salt
thereof whenever prepared or produced by the process as claimed
in claim 28 or an obvious chemical equivalent thereof.
30. A process as claimed in claim 1 which comprises
reacting methoxy benzyl oxamic acid ethyl ester in the presence
of pyridine in methylene chloride with PCl5, refluxing the pro-
duct obtained with hydrazoic acid, mixing the ethyl ester of
1-(4-methoxy benzyl)-1H-tetrazole-5-carboxylic acid so obtained
dissolved in absolute ethanol with potassium hydroxide, reacting
the potassium salt so obtained in benzene and in the presence of
pyridine with oxalyl chloride, mixing the chloride so obtained
in methylene chloride with 2-amino-6-(1-piperidinyl)benzonitrile
and removing the 4-methoxy benzyl group from the product carboxy-
amide by refluxing in the presence of anisole and trifluoroacetic
acid.
31. N-[2-cyano-3-(1-piperidinyl)phenyl]-1H-tetrazole-
S-carboxamide or a pharmaceutically acceptable salt thereof when-
ever prepared or produced by the process as claimed in claim 30
or an obvious chemical equivalent thereof.
32. A process as claimed in claim 1 which comprises
reacting methoxy benzyl oxamic acid ethyl ester in the presence
46

of pyridine in methylene chloride with PCl5, refluxing the pro-
duct obtained with hydrazoic acid, mixing the ethyl ester of
1-(4-methoxy benzyl)-1H-tetrazole-5-carboxylic acid so obtained
dissolved in absolute ethanol with potassium hydroxide, reacting
the potassium salt so obtained in benzene and in the presence
of pyridine with oxalyl chloride, mixing the chloride so obtained
in methylene chloride with 2-amino-6-(4-methyl piperazinyl)benz-
amide and removing the 4-methoxy benzyl group from the product
carboxyamide by refluxing in the presence of anisole and tri-
fluoroacetic acid.
33. N-[2-aminocarbonyl)-3-(4-methyl-1-piperazinyl)
phenyl]-1H-tetrazole-1-carboxamide or a pharmaceutically accept-
able salt thereof whenever prepared or produced by the process
as claimed in claim 32 or an obvious chemical equivalent thereof.
34. A process as claimed in claim 1 which comprises
reacting methoxy benzyl oxamic acid ethyl ester in the presence
of pyridine in methylene chloride with PCl5, refluxing the pro-
duct obtained with hydrazoic acid, mixing the ethyl ester of
1-(4-methoxy benzyl)-1H-tetrazole-5-carboxylic acid so obtained
dissolved in absolute ethanol with potassium hydroxide, reacting
the potassium salt so obtained in benzene and in the presence
of pyridine with oxalyl chloride, mixing the chloride so obtained
in methylene chloride with 3-amino-5-nitrobenzonitrile, refluxing
the product obtained in cyclohexene and ethanol in the presence
of Pd/C, reacting the product obtained with ethyl oxalyl chloride
in methylene chloride and in the presence of pyridine and remov-
ing the 4-methoxybenzyl group from the product obtained by reflux-
ing in the presence of anisole and trifluoro acetic acid.
35. [3-cyano-5(1H-tetrazol-5-ylcarbonyl)amino]phenyl-
amino]-oxoacetic acid ethyl ester whenever prepared or produced
by the process as claimed in claim 34 or an obvious chemical
equivalent thereof.
47

Description

~867Z9
..
,
.
Background of the Invention
Atopic immediate sensitivity is the chief manifes-
tation found in animals suffering from bronchial asthma,
seasonal pollinosis (e.gO hay fever), allergic rhinitis,
urticaria, allergic conjunctivitis, food allergies and ana-
phylactoid reactions. The substances most frequently re-
sponsible for clinically manifest sensitivities are plant ~`
pollen, animal feathers and danders, dust, milk and ~heat,
,
whether inhaled or ingested. Atopic hypersensitivity is
found in man, dog, and other animals. Its occurrence is ~ `
exceptionally found in the lower animals. ~-
The presence of antibodies associated with atopic
hypersensitivity reactions in the host serum is established
by the passive sensitizat ion of the skin of a normal recip-
ient, a~ter injection of~serum from a sensitized host into `
a s};in~si~e follo~ed by injectIon of antigen into the same
ar~a 24 hours later, resulting in a local hive. This is
commonl~ referred to as the Prausnitz-Kustner (P-K) reaction.
,
:
~ ~ - 2 -
: .
,

A~IP-5971-2-C2/6662 f
' ` ',
~867;i~9 : ::
The antibody associated with atopic hypersensi-
tivity possesses distinctive features in that it does not
in all forms precipitate with i$s antigen, fails to pass
the placenta from mother to fetus, has special affinity
for the skin, frequently lacks specificity toward an in-
dividual antigenic factor and is usually labile at about ~ -
56C. after two hours. ~;-
The homocytotropic antibody found in or induced
in the rat is related in function and reaction to immuno- ;-
globulin E (reagin or IgE) found in the human. The
-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) wlthin the mast cell which ultimately releases
a mediator such as Bradykinin, SRS-A (slow reacting sub-
stance-A), histamine and other unknown substances. me
mediator effects a change in surrounding cell wall per-
meability 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 con-
sidered to be quite acceptable, are to (l) avoid attack by
.. . . .
': .
.. . .
- 3 -
.. '
, . .
'

AHP-597:L/2-C2/6662 f
~8G72~
the antigen, (2) block the production of antibody ~ith an
immuno-suppressant, (3) block the action of the mediators
on the cell under attack by administration of anti-
histaminics~ anti-5-hydroxy-typtamines(5-HT) or anti-
inflammatories, or (4) stimulate the cell under attack
to negate the action of the mediator through the action `
of bronchodilators such as Isuprel~ or a Xanthine.
A compound typifying anti-allergic activity by
blocking reaction(s) within the mast cells, thereby prevent~
ing the production and release of mediators, is disodium
cromoglycate.~INTAL~
Description Of The Invention ;~
In accordance with this invention there is
provided a group of novel anti-allergic compounds of the ~.
formula~
, -
R2 Rl
~ N N
$ ~co_C~ 11 '
3 N - N -
R H
in which
Rl is -CN or -CONH2
R2 is lower alkoxy, hydroxy(lower)alkoxy, or . -
_ a, _ ,~, ~.
. ` .~ . `
, ~
"'~ '
~,:
.,, . ., , ,,, :,,, : , . ... ... . . .. .

~MP-5971-?~ C2/6662 :t
729
R7
-N :
\ R8
',.' :'
. ': -' :
wherein . .
R7 and R8 are independently hydrogen, lower alkyl,
~r cycloalkyl of 5 to 6 carbon atoms, or :~
R7 and R8, when taken together with the nitrogen,
atom to which they are attached form a hetero- :
. . . . .
cyclic group selected from aziridinyl, azet
dinyl, pyrrolidlnyl, piperidino, piperazinyl, -
4-lower alkyl piperazinyl, morpholino, thio-
:i?~
morpholino and ring substituted lower alkyl
analogues of said heterocyclic groups;
: R3 is hydrogen, lower alkyl, lower alkoxy, halo, ::
: polyhalo(lower)alkyl, lower alkylcarbonyl,
or~carb(lower)alkoxy;
or a;pharmaceutically aceeptable salt thereof.
The compounds of this lnvention, where R7 and
R8~ $orm a preferred six-membered heterocyclic moiety with
the nitrogen atom to which they are attached, may be
deplcted as~follows.
. .
~ ~: _ _ ~4
: ~ ~ ~ N~ ~ Rl ... .:
N N
R3~
: ~ : . . ~ .,
i: ~
' :

AtlP-5971-'~.-C2/6662 f
~8672~ . :
:-- -
in which
Rl is -CN or -CONH2;
R3 is hydrogen, lower alkyl, lower alkoxy,
halo, polyhalo(lower)alkyl, lower alkyl-
carbonyl or carb(lower)alkoxy; ; ;-
R9
g '~:
X is -CH~-, -0-, or -N- where R is lower
alkyl; and ~:
R4 is hydrogen or lower alkyl;
or a pharmaceutically acceptable salt thereof.
The N-substituted tetrazole-5-carboxamide pro-
ducts of this invention may appear in either the lH or 2H ~ .
tautomeric forms. It is applicants intention, throughout ~.
this specification and in the~appended claims, to embrace
th:~2_-tautomer as well as the 1_ tautomer, both by the :
structural deplctation of the~lH tautomer and by naming
the lHlderlYatives.~ The rela~tionship between the tautomers
is~as follows~
,. :
,:
~ ~ 8 ~ :N - N B ~ N ~
ANHC - C 1¦ _ ANHC ~
: \ N - N . N - N
~ H : H : :
lH ~ 2H .
-- .
: ~ '': '
In~addltion,a novel p~ocess is provided for the - -
preparation:~of~lE~-(or;2H) tetrazole-5-carboxamide deri- :
:~ 20~ vatives~which complises reacting~an amine ANH2, where A :~
~: : . .. .
~: : . :
.:
:
. . .

~I[P-5971-2-C2,/ff6fi2 f
67~9
represents an aromatic or heterocyclic mo:iety, with a
l-protected-lH-tetrazole-5-carbonyl chloride followed
by deprotection (e.g. hydrogenolysis~ etc.) and conver-
sion to a pharmaceutically acceptable non-toxic salt as
desired.
More specifically, the process involved in
producing the N-aromatic and N-heterocyclic lH-(or 2H)
tetrazole-5-carboxamide derivati~es may be described as
a process which comprises:
(a) reacting an N-protected oxamic acid ester
with PC15 ln the presence of an acid
accep~r to obtain the imido-chloride
~C~NHR5 in which R6 is lower alkyl
and R5 is a protecting group;
(b) cyclizing the imido-chloride with hydrazoic
acid to produce the lower alkyl ester of
l-R5-S-carboxy-lH-tetrazole;
(c) saponifying said ester to obtain an alkali
metal salt of said tetrazole;
(d) converting said tetrazole salt to the 5-
chlorocarbonyl-l-R5-lH-tetrazole by reaction
with a chlorinating agent;
(e) reacting said 5-chlorocarbonyl-1-R5-lH-
tetrazole with an amine of the formula ANH2;
(f) removing the l-R5 group from the product
of step(e) to obtain the N-substituted-lH-
(or 2H) tetrazole-5-carboxamide of the
formula~
.. . ...
~.",' . '
,:,,
. , .

.~tlP-~71-~-C2/ff66~ t
i72~
N - N
~ li
ANHC0-C ll
N N :
H
in which -
A is a member selected from the group con-
sisting of 2-thiazolyl, 2-pyridyl, 6-(lower)- ;~
alkyl-2-pyrid~l, 3-cyano-2-pyridyl, 3-
pyridyl, 4-pyridyl, 2-pyrimidiny~, 2-pyrazinyl, ~
a-naphthyl, ~-naphthyl~phenyl, 2,6-dichloro- ~ .
phenyl, and substituted ~ phenyl mo:ieties . ~ .
having~from;one to~three substltuents in any
: :: of the;2,~;3,~4,~and 5 posltions of the phenyl
10 :~ ring, lndependently selected from the group
consisting of lower alkyl,:lower alkylsul- . :
finyl, lower alkoxy,~hydroxy(lower)alkoxy,
2-(lower alkoxy oxalyloxy)ethoxy, N-mono-~
:~and~di-lower alkyl amino~(lowerjalkoxy, halo,
~sulfamyl,~polyhalo(lower)alkyl, carbamyl, :
: ~N-lower alkylcarbamyl, carboxy, lower alkyl-
~carbonyl, cyano, carb(lower3alkoxy, phenoxy- .
~ ower)alkoxy, lower alkoxyoxalamidb, lower
; alkoxyoxalamidophenoxy and -N ,R7 where R8. .
~20~ and~R , independently represent hydrogen,
lower alkyl, or cycloalkyl of 5 or 6 carbon
: - 8 -

AIIP-597l-2-C2~66?l f
7Zg
" .. ..... ..
atomS, or R~ and R7~ taken to~ether With the
nitrogen atom to which they are attached form
a heterocyclic group selected from aziridinyl,
azetidinyl~ pyrrolidinyl~ piperidino, pipera-
" .
zinyl, 4-lower alkylpiperazinyl, morpholino, -
thio morpholino and a ring substituted lower
alkyl analogue of said heterocyclic group.
In the preceding paragraph, the definition of
R8 or R~-asa eycloa1kyl groUp of 5 or 6 carbon atoms embraces
cyclopentyl: and cyclohexyl. Where either R8 or R7 iS
: . . .
hydrogen, undesired acylation of the amino group -NHR7 is
pre:v~n~e~], ~ conventionally by protecting that group with - -
~ !- -
a standard protecting group such aS the trimethylsilyl~ `
. . .
group, which 16 readily removed upon completion of the
reaction between the amlne~ ANH2 :and; the tetrazole-5-
carbonyl chloride.~
~ The chlorlnating agent~employed in~step (d)~of
the~procesS~may be any conventlonal ag;ent employed in the ~-
production~of a carboxylic~acid chloride such as SOC12, : ; :
PC15~ PC13,;oxalyl chlorlde, and the like. ~
The term~"lower'i used throughout this applica-
~tion to modlfy alkyl~ alkoxy,~and the llke, is intended
: t o embrace those univalent aliphatic hydrocarbon radicals
having l to 6 carbon atoms. The term "halo" is used to
embrace~ch~orine~7~bromine~iodlnc~, and fluorlne. The
eXpression "pharmaceutically acceptable salts" is intended
t~o embrace acid~;~addi~tion salts,~where applicable as well
ay~}~=~o~2~)~t~trazoI- Ikali etal o~ amine salts.

~IIP-597L-2-~2/6~62 ~
._ ,
7Z~
Examples of acids wi-th which pharmaceutically acceptable
non-toxic salts may be produced include both organic and
inorganic acids such as hydrochloric, hydrobromic, sulluric,
phosphoric, methane sulfonic, nitric, p-toluene sulfonic,
acetic, citric, maleic, succinic acid, and the like. The
alkali metal or amine sal$s of the lH-(or 2H) tetrazoles
include salts of sodium, potassium, lower alkylamine,
di(lower alkyl) amine, tri(lower alkyl)amine and the
corresponding omega-hydroxy analogues (e.g. methylamine,
ethylamine, propylamine, dimethylamine diethylamine,
dipropylamine, trimethylamine, triethylamine, tripropyl-
amine, di(hydroxyethyl~amine, and the like~ as well as
more complex amines which are empIoyed in depot administra-
.~ ' . .
tion, such as N,N -dibenzylethylenediamine, and the like. -
Furthermore, applicants intend throughout this application, -
by either structural presentation or by compound name
referring to either the lH- or 2H-tetrazole configuration ~-
....
of~the final products, to embrace both of those tautomeric
forms of the unsubstituted tetrazole nucleus.
The~protecting group -R5- employed in preparation
of the lH-tetrazole-5-carbonyl chloride intermediate is
.. ..
sele~cted for lts stability during reaction of the lower
alkyl oximidoyl chloride with hydrazoic acid while possess-
~ , . ~ . -: .
ing the attribute of easy removal after formation of the ~ - -
carboxamide product. Examples of such protecting groups
are benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 2,6-
dlmethoxybenzyl, 2,4,6-trim thoxybenzyl, trichloroethyl,
~ : ; . .
and the like. ~
.:
-
~ . . -
~ . .': - , . ~,: .

~IIP-597L-~-C2/6662 ~
-
': :
~OB~;'729
The preparation o~ the lH-tetrazole-5-carboxylic
acid lower alkyl es-ters is quike unique in itself and
forms an additional aspect of this invention. Thus,
applicants have discovered, unexpectedly, that a N-protected
lower alkyl ester of oximidoyl chloride reacts with hydra-
zoic acid to afford the l~-tetrazole-5-carboxylic acid
lower alkyl esters and that the combination of the N-
.. . .
protecting group with the presence of a lower alkyl ester
functional group in the intermediate imido-chloride, -
cooperate in such manner as to direct the attack of hydra- ~-~
zoic acid in the desired fashion without interference by
the ester function.
In that sense, applicants provide a process for -
producing lE-tetrazole-5-carboxylic acid lower alkyl
.. . ..
esters which comprises reacting a N-protected oxamic acid
, , ,:
lower alkyl ester such as N-benzyloxamic acid ethyl ester
with PC15 in the presence of an acid acceptor $o afford
the correspondlng imidoyl chloride intermediate, which
reacts with hydrazoic acid to yield the desired N-protected-
lH-tetrazole-5-carboxylic acid esters.
In the formation of the l_-tetrazole-5-carboxylic
acid ester ~rom the imido-chloride precursor, the reactant
hydrazoic acid may be produced in situ from, ~or example,
a metal azide, trimethylsilylazide or ammonium azide. It
is intended, throughout this specification that the ex- ~ -
pression hydrazoic acid should be interpreted as encompass-
ing the~metal azides, trimethylsilylazide and ammonium -
azide.
-- 11 -- .
, -
:. ~ : :.
. ::'-
: :.;'.
.: ~ ',::' .
: ~ . , - , , ,.,, : ~ . . - -

AllP-597:L-2-C2/666~ f
6~Z9
The amine reactants ANH2 are generally known
compounds or they may be readily produced by known methods.
Examples of various amine reactants as listed
below, readily enter into reaction with an N-protected-l~
tetrazole-5-carbonyl chloride to yield the final products -
listed below:
,'.''~:.'~ .' '
2 FinaI Product
2-aminothiazole N-[2-thiazolyl]-lH-tetrazole- ~ -
5-carboxamide
2-aminopyridine N-[2-pyridyl]-lH-tetrazole-5-
carboxamide ~:-
2-aminonicotinonitrile N [3~cyano-2-pyridyl]-lH-
tetrazole-5-carboxamide
2-aminopyrimidine N-C2-pyrimidinyl]-lH-tetrazole-
S-carboxamide
~-aminopyridine : :N-[4-pyridyl]-lH-tetrazole-5- ~. .
carboxamide
3-aminopyridine N-[3-pyridyl]-lH-tetrazole-5-
carboxamide .~;
~ 2-amino.i~6.-picoline N-[2-(6-methyl)pyridyl-lH-
. .
tetrazoIe-5-carboxamide ~ .
2-aminopyrazlne : N-[2-pyrazinyl]-1_-tetrazole- ~: -
; 5-carboxamide
aniline N-[phen$1~ -te-~azole-
: 5-carboxamide
: : 2-amLnobenzoio~acid N-~2-carboxyphenyl]-lH- .. ~: :
. ..
~ : tetrazole-5_carboxamide
' . -
: :- ,
~ : ~ : ` .'..... .

~tlP-5971-2-C2/6662 ~
.
~0i8~7~9
,-
ANH2 inal Product
2-aminobenzamide N-[2-carbamoylphenyl]-lH-
tetrazole-5-carboxamide
2-cyanoaniline N-[2-cyanophenyl]-lH-tetrazole- -~-
5-carboxamide
2-methylaniline N-[2-methylphenyl]-lH-tetrazole-
5-carboxamide :.
3-methoxyaniline N-[3-methoxyphenyl~-lH-tetrazole-
5-carboxamide .
10 3-trifluoromethylaniline N-[3-trifluoromethylphenyl]-lH
tetrazole-5-carboxamide : .'
3-fluoroaniline N-[3-fluorophenyl]-lH-tetrazole-
5-carboxamide ~ :.
3-methylaniline N-[3-methylphenyl]-lH-tetrazole-
5-carb~x~mide -
4-aminobenzamide N-~4-carbamoylphenyl]-lH-
t~trazole-5-carboxamide
4-~ethoxyaniline N-[4-methoxyphenyl]-lH-tetrazole-
5-c:arboxamide
~ 2-amino-6-methoxy- ~ N-[2-carbamoyl-3-methoxyphenyl]-
benzamide lH-tetrazole-S-carboxamide
2-amino-6-methoxy _-[2-carboxy-3-methoxyphenyl]-
benæoic acid~ ~ : lH-tetrazole-5-carboxamide
2-cyano-3-methoxyaniline N-~2-cyano-3-methoxyphenyl]-
~ lH-tetrazole-5-carboxamide : ~:
- - ~
~-:amino-6-chloro- N-[2-carbamoyl-3-chlorophenyl]-lH-
benzamide tetrazole-5-carboxamide
. :: :
2-amino-6-phenoxyethoxy- ~-[2 carbamoyl-3-phenoxyethoxy~
..
~ ` benzamide phenyl3-lH-tetrazole-5-carboxamide :~
: ~
~ : - 13 - ~
.. . .
!.
`' ~ ' ' ~' .

~IP-597:L~~-C2/6662 ~
-
ANH2 ~inal Product
2-amino-5-methoxy N-[2-carboxy-4-methoxyphenyl]-
benzoic acid lH-tetrazole-5-carboxamide
2-amino-5-chloro- N-[2-carbamoyl-4-chlorophenyl~-
benzamide lH-tetrazole-5-carboxamide
2-amino-4-methoxy- N-[2-carbamoyl-5 methoxyphenyl]-
benzamide lH-tetrazole-5-carboxamide
5-chloro-2-sulfamoyl- N-[5-chloro-2-sulfamoylphenyl]-
aniline lH-tetrazole-5-carboxamide .
102,6-dichloroaniline N-[2,S-dichlorophenyl]-IH- .~.
tetrazole-5-carboxamide :
4-(4-ethoxycarbamido- N-~4-(4-ethoxycarbamidophenoxy)-
phenoxy)aniline phenyl]-lH-tetrazole-5- ~:
carboxamide ..
2-amino-6~ethoxy- N-[2-carbamoyl-3-ethoxyphenyl]-
benzamide lH-tetrazole-5-carboxamide
2-amino-6-propoxy- N-[2-carbamoyl-3-propoxyphenyl]- :~
benzamide lH-tetrazole-5-carboxamide
2-amino-6-isopropoxy- N-~2-carbamoyl-3-isopropoxy- -~
20benzamide phenyl~-lH-tetrazole-5-carbox-.
amide i .
. . - .
2-amino-6-n-butoxy- N-[2-carbamoyl-3-n-butoxyphenyl]-
benzamide lH-tetrazole-5-carboxamide ;
2-naphthylamine N-[2-naphthyl]-lH-tetrazole_5- ~
: carboxamide ~ .:
l-naphthylamine N-[l-naphthyl]-lH-tetrazole-5-
: carboxamide
: .: . .
. ~ . .~,,
: - 14 -
:: ~ , : - ~
' ' ' ' "~

A~IP-5971-?,-C2/666?1 .~
~86~2~ :
ANH~ Final Product
3,4,5-trimethoxyaniline N-[3,4,5-trimethoxyphenyl]-lH-
tetrazole-5-carboxamide ~ .
2-amino-6-methoxy-N- N-[2-N-methylcarbamoyl-3-
methylbenzamide methoxyphenyl]-lH-tetrazole-
5-carboxamide ~ ,.
2-amino-6-(2-dimethyl- N-[2-carbamoyl-3-(2-dimethyl- .
aminoethoxy)benzamide aminoethoxy)phenyl]-lH-tetra-
zole-5-carboxamide
104,5-dimethylanthranilic N-[2-carboxy-4,5-dimethylphenyl]- ..
acld lH-tetrazole-5-carboxamide
2-amino-4,5-dimethyl- N-[2-carbamoyl-4,5-dimethyl-
benzamide phenyl]-lH-tetrazole-5-
carboxamide
2-acetyl-3-methoxy- : N-2-acetyl-3-methoxyphenyl]-
aniline : lH-tetrazole-5-carboxamide
2-amino-6-(2-hydroxy- N-[2-carbamoyl-3-(2-hydroxy-
propoxy)-benzamide propoxy)phenyl]-lH-tetrazole- . :
5-carboxamide .
202-amino-4,6-dimethoxy- N-C2-carbamoyl-3,5-dimethoxy-
benzamide phenyl]-lEI-tetrazoIe-5- ..
carboxamide -
.. .. .
2-amino-6-(2-hydroxy- N-C2-carbamoyl-~-(2-hydroxy-
ethoxy)-benzamide ethoxy)phenyl]-lH-tetrazole-
5-carboxamide :~: .
2-amino-6-benzyloxy- N-c2-carbamoyl-3-benzyloxyphen-
:
benzamide: yl]-lH-tetrazole-5-carboxamide ~
.::,
4-chloroaniline N-~4-chlorophenyl)-lH-tetrazole-
5-car.boxamide .-
.
.. . . .
: , .... .
:~ : ','-'~

~IP-597~-2-C7./6662 f
~8~
ANH2 Final Product
4-dimethylaminoaniline N-[4~dimethylaminophenyl]-lH-
tetrazole-5-carboxamide
2-amino-6-dimethyl- N-C2-carbamoyl-3-dimethyl-
aminobenzamide aminophenyl]-lH-tetrazole-
5-carboxamide
:
` " '~ '
The compounds of this invention relieve atopic ~ - -
.
allergic manifestations, when administered orally and
parenterally to sensitized rats~ ~
The technique employed to establish the anti- ~-
allergic activity of the~lH-tetrazole-5-carboxamide
,
derivatives of th1s~ln~ention is reported ln ImmunoIogy,
vol. 16, pp. 749-760 (1969)~and lnvolves four male
Charles Rlver~rats (200-250 grams body weight) per~group
to provide a~control~ a host for administration of a ;~ -
stan~dard anti-allerglc compound (disodium cromoglycate)
and~anlmals for the test compound. The rats were
` injected intracutaneously on their shaved backs with
sera;~rom~rats immunized with egg albumin and pertussis
~0 vaccine. Twenty-fQur hours after the inltial in~ections,
.
the test compound is adminlstered intraperitone~ally or
orally at a do~sage~level of 200 milligrams per kilogram
~hast~;body~weight~or less.~ Five minutes later one milli- - -
r;o~a~0.5~per cent s;olution of Evans blue dye and 8
:; :.
-:

~IIP 5971~2~C2/6Gfi2 f
6~2~
milligrams of egg albumin is injected intravenously.
After forty 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 calcu-
lated and the per cent 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 inven-
tion, 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 inter-
action. They effectively block the IgE type reactlon
and have little or no effect on the other immunoglobulins
such as IgG, IgM, IgA, and IgD. ~-
In other words, 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 know correlate of human re~inic 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
the;same uses at analogous doses and through the same
routes of administration as INTAL~.
- I7 -
'
. : ~ ,.~,

~IP-597L-2-C2/6662 ~
7:~9
Thus, the novel compounds of this invention
provide a means 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 administer-
ing an effective amount of one or more of the compounds
disclosed in this application by oral, topical, parenteral,
.: ,
rectal, vaginal, or inhalation routes. The compounds
of this invention may be administered in conjunction with
known compounds effecting anti-histaminic, anti-hyperten-
sive, analgesic, central nervous system depressant, immuno- ;
suppressive, anti-serotonin, anti-Bradykinin or endocrino- ;
logical 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 -~
20purposes of providing suitable pharmaceutical solution or ; ~;
liquid or vapor suspensions, the latter for use as
-.:
inhalants.
The oral dose range lies from below 0.1 milli- ;
gram per kilogram to about 50 milligrams per kilogram
: . - . -
host body weight. As an inhalant the dose is from that ~-
of INTAL~, (about 20 milligrams) to 1/20th that quantity
administered as needed prior to attack. Thus the dosage
contemplated for human use based upon the potency of the
: , .. :
- 18 -
. .
: :.
~.

~IIP-5971-'~-C2/6ffff2 f
7Z9
compounds administered lies from about 5 milligrams to
1 gram, preferably 50 milligrams to about 750 milligrams
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.
', ~ .,
- 19
~:
.

~tlP-574L-2-C2/~)ff~ f
. ~
7;29
.,,,, , -
EX~MIIE I
N-[2-Cyano-3-(4-morpholinyl)- ~ -
phenyl]-lH-tetrazole-5-carboxamide
To a solution of 20.72 g. (0.1 mol.) of benzyl-
oxamic acid ethyl ester and 9.89 g. (0.125 mol.) of
pyridine in 95 ml. of methylene chloride is added 26.03 g.
(0.125 mol.) of PC15 slowly through a Gooch tube at
30G. or less. Stir l hour at room temperature, add 112
ml. of 1.78 molar hydrazoic acid in benzene, stir 1 hour
at room temperature, and slowly bring to reflux. After
4 1/2 hour of reflux, keep the reaction mixture over
night ~t room temperature. The reaction mixture is poured
into a cold NaHC03 solution, diethyl~ether is added and .~r~."~,~
separate the~layers. The~organlc layer is washed again ~;
wl~th a NaHC05 solution, with N HCl, with brine and drled
with~CaC12. Evaporation of the solvent gives 22.46 g. of
.
oil which is~distilled in a falling film moIecular still
at 135C. and 0.15 mm., giving 11.12 g.~o~ product. The
~ oil is crystallized from diethyl ether-pentane to give ~-
6.88 g. of l-benzyl-lH-tetrazole-5-carboxylic acid ethyl
ester, m.p. 51-55C.
An~lysis for CllH12N402
Calculated: ; C, 56~89; H, 5.21; N, 24.13 -
Found: C, 56.58; H, 5.11, N, 24.13
~:
:: ~ ., . :.

Altl'-597L-2-C2/6662 f
The ethyl ester (11.61 g., 0.05 mol.) is
dissolved in 60 ml. of warm absolute ethyl alcohol.
Addition of 3~96 g. (0.06 mol.) of KOH in 7 ml. of water
causes crystallization of the potassium salt. The
mixture is kept at room temperature over night, filtered,
and the filter cake is washed with cold absolute ethyl
alcohol and diethyl ether, giving 11 g. of l-benzyl-lH-
tetrazole-5-carboxylic acid potassium salt.
Analysis for: CgH7KN402
Calculated: C, 4~.61; H, 2.91; N, 23.13
Found: C, 44.26; H, 2.91; N, 23.~7
The potassium salt (7.27 g., 0.03 mol.) and
1.5 ml. of pyridine are stirred at 6C. in 135 ml. of
benzene, and 25 ml. of oxalyl chloride is rapidly added.
After stirring l/2 hour at 15C. the mixture is stripped
at 15C., and scrubbed with two portions of 130 ml. of `~
benzene at 15C. giving a crude mixture of l-benzyl-lH-
tetrazole-5-carbonyl chloride. This preparation of the
acid chloride is kept cold and used immediately for
acylation.
me crude acid chloride (0.03 mol.) from above
is dissolved in 130 ml. CH2Cl2 and poured into a solution
of 2-ami~o-6-(4-morpholinyl)benzonitrile (6.10 g., 0.03
mol.) and 2.73 g~ of pyridine in 130 ml. of CH2Cl at
~.: . ,
at 5-10C. The solution is allowed to come to room
temperature during 2 hours, and then wash twice with -~
wate~r, with~br-~ne, and dry with CaC12. The solution is
evaporated to dryness giving 10.7 g. (m.p. 176-180C.)
,.
~ - 21 -
, - .

~llp-597l-2-c2/6662 f
g
of a white solid which is crystallized from 100 ml. of
acetonitrile, giving 7.65 g. of 1--benzyl-N-[2-cyano-3-
(4-morpholinyl)phenyl]-lH-tetrazole-5-carboxamide as
white crystals, m.p. 184-187C.
Analysis for: C H N 0
20 19 7
Calculated: C, 61.68; ~, 4.92; N, 25.18
Found: C, 61.57; H, 4.78; N, 25.11
The N benzyl derivative above (1.95 g., 0.005 ,~
mol.) is dissolved in warm acetic acid and 0.9 g. of
10 10% Pd/C is added. The mixture is hydrogenated at 35
lbs. over night, and the-mixture is filtered and the cake ~ -~
is washed with hot acetic acid. The filtrate is stripped
to dryness and the residue is triturated with a warm `
solution of 10 ml. concentrated ammonium hydroxide in --
60 ml. of water. The mixture is filtered and the filtrate
is acidified to pH 2 with concentrated HCl~ The acidified
mixture is kept in ice for two hours, filtered, and the
white product is dried. Crystallization of the product
from acetonitrile gives 0.42 g. of N-[2-cyano-3-(4-
morpholinyllphenyl]-lH-tetrazole-5-carboxamide, m.pO
2S3-256C. (dec.).
C H N 0
13 13 7 2
Calculated: C, 52.17; H, 4~38; N, 32.76
Found: C, S2.04; H, 4.34; N, 32.76
''": ~' '
. .
The title compound exhibited 60 per cent
inhibition of the mean bleb size when administered orally `
: .:
at 0.1 milligrams per kilogram and 97% inhibition when ;
: ' ' ,
- 22 - ~
"'--'. :; ''

AtlP-r)971-2-C2/6662 f
;729
administered orally at 50 milligrams/kilogram host body
weight in accordance with the rat PCA test described,
supra.
EXAMPLE II --
N-C2-Cyano-3-( l-piperi dinyl)-
phenyl]-lH-tetrazole-5-carboxamide
In a manner similar to Example I, l-benzyl-lH-
tetrazole-5-carbonyl chloride is condensed with 2-amino-6-
(l-piperidinyl)-benzonitrile to give l-benzyl-N-[2-cyano-
3~ piperidinyl)phenyl]-lH-tetrazole-5-carboxamide. --
In a manner similar to Example I the benzyl
group is hydrogenolyzed from the above tetrazole giving
the title compound. - -
' " '.'
EXAMPLE III
. .. :
.: : .,:
N-[Z-Cyano-3-(4-methyl-1-
piperazinyl)phenyl]-lH-tetrazole-5-carboxamide ~ -
In a manner similar to Example I, l-benzyl-lH- ~ -
tetrazole-5-carbonyl chloride is sondensed with 2 amino-6- ;;
(4-methyl-1-piperazinyl)benzonitrile to give l-benzyl-N-
~2-cyano-3-(4-methyl-1-piperazinyl)phenyl]-lH-tetrazole-5- ~-~
,... . .
carboxamide. `
. -.
~ '; ' "
~ . ,.
- 23 -
. . .
: " ':'
. '.' , '
, . ~ . ... . . . ~, . . .. .. . .

AtlP-597L-2-C2/f~662 f
~67;i~9
In a manner similar to Example I the benzyl
group is hydrogenolyzed from the above tetrazole giving
the title compound.
EXAMPLE IV
: ,
N-[2-carbamoyl-3-~4-morpholinyl)-
phenyl]-lH-tetrazole-5-carboxamide -
~ . . ~. . ,
In a manner similar to Example I, l-benzyl-lH-
tetrazole-5-carbonyl chloride is condensed with 2-amino-6-
(4-morpholinyl)benzamide to give l-benzyl-N-[~-carbamoyl-
3-(4-morpholinyl)phenyl]-lH-tetrazole-5-carboxamide.
In a manner similar to Example I the benzyl i
group is hydrogenolyzed from the above tetrazole giving
the title compound~
:. - . .: .
EX~MPIE V
N-[2-Carbamoyl-5-methoxy~
phenyl]-lH-tetrazole-5-carboxamide
.: :
': . '. ,
To a solution of 23.72 g. (0.1 mol.) of 4- ; -
methoxybenzyloxamic~acid ethyl ester and 8.70 g. (0.11
mol.) of pyridine in 95 ml. of methylene chloride is
added 22.91 g. (0.11 mol.) of PC15 slowly through a
Gooch tube at 30C. or less. Stir 2 hours at room
. .
,~
~:

~IP-5971-2-C2/~)66~ f
- i(3i~3iEi7~9
temperature, add 120 ml. oL 1.79 molar hydrazoic acid in
benzene, stir 1 hour at room temperature, and slowly
bring to reflux. After 3 hours of reflux, keep the reaction
mixture over night at 5C. The reaction mixture is poured
into a cold NaHC03 solution, diethyl ether is added and
separate the layers. The organic layer is washed again
with a NaHC03 solution, with cold 1/2 N HCl, with water,
with NaHC03, with brine and dried with CaC12. Evaporation
of the solvent gives 22 g. of oil which is chromatographed
on silica gel with benzene, giving 10.79 g. of product. -
The oil is crystallized from diethyl ether by cooling in
Acetone-Dry Ice to give 1-(4-methoxybenzyl)-lH-tetrazole- -
5~carboxylic acid ethyl ester, m.p. 51-55C.
Analysis for: Cl~H14N403
Calculated: C, 54.95; H, 5.38; N, 21.36
.:. :, .
Found: C, 54.90; H, 5.19; N, 21.21
`' ' ':
The ethyl ester (10.45 g., 0.0398 mol.) is -
dissolved in 44 ml. of warm absolute ethyl alcohol.
Addition of 3.15 g. (0.048 mol.) of KOE in 5.9 ml. of
water causes crystallization of the potassium salt. The
mixture is kept at room temperature over night, filtered
and the filter cake is washed with cold absolute ethyl
: . :
alcohol and diethyI ether, giving 9.9 g. of 1-(4-methoxy-
benæyl)-lE-tetrazole-5-carboxylic acid potassium salt.
Analysis ~or:~ CloEgKN40
Calculated- ~C,~ 44.10; H, 3.33; N~ 20.58
Found: ~ C, 43.81; ~1, 3.33;~N, 20.61
. ',~ ': .

~ 697L-2~C2/6662 ~
7~9
The potassium salt (9.15 ~., 0.0336 mol.) and
1.68 ml. of pyridine are stirred at 6C. in 150 ml. of
benzene, and 28 ml. of oxalyl chloride is rapidly add~d.
After stirring 3/4 hour at 15C. the mixture is stripped
at 15C., and scrubbed with two portions of 150 ml. of
benzene at 15C., giving a crude mixture of 1-(4-methoxy-
benzyl)-lH-tetrazole-5-carbonyl chloride. This prepara-
tion of the acid chloride is kept cold and used immediately
for acylation.
1-(4-methoxybenzyl)-lH-tetrazole-5-carbonyl
chloride (0.336 moL) is dissolved in 150 ml. methylene
chloride, and added to a 5-10C. solution of 2-amino-6-
methoxybenzamide (5.58 g., 0.0336 mol.) and 2.8 ml. of
pyridine in 150 ml. of methylene chloride. The reaction
solution is stirred for 2 hours at room temperature, add ~ -~
100 ml. of water, stir for 10 minutes, fllter off the
white solid, and wash with water and methylene chloride.
The filter cake is crystallized from acetonitrile giving
8.68 g. of 1-(4 methoxybenzyl)-N [2-carbamoyl-3-methoxy- ~;~
phenyl]-IH-tetrazole-5-carbvxamide, m.p. 190-192C.
Analysis for; C18H18N64
Calcu~ated: ~ C, 56.54; H, 4.75; N, 21.98
Found: C, 56.22; H, 4.55; N, 22.05
~: ' .
The 4-methoxybenzyl group is removed from 52.7
g. (0.138 mol.) of the above tetrazole by adding 74.5 g.
~0.689 mol.) of anisole under nitrogen, adding 890 ml. of
trifluoroacetic a¢id, and refluxing vigorously for 1/2
:
hour. The trifluoroacetic acid is removed on a rotary
- 26 ~
..

~IP-5971-2-C~/6~62 ~
729
evaporator at 70C., the residue is cooled in an ice-
bath and water and ethyl ether is added. The mixture
is stirred for 1 hour, filtered, and the filter cake
is washed with ether and water. The filter cake is stirred
in 1200 ml. of acetonitrile, filtered, and the cake is
washed with acetonitrile, giving 35 g. (94%) of the
title compound, m.p. (252~C~ dec.)
Analysis for: C H N O .1/2 H O
10 10 6 3 2 -
Calculated: C, 44.28; H, 4 09; N, 30.99
Found: C, 44.05; H, 4.22; N, 30 90 ~-
. .
'' .
EXAMPLE VI
: ' . . -
N-[2-Cyano-3-(2-methyl-4-morpholinyl)-
phenyl]-lH -tetrazole-5-carboxamide
- ; ,.
In a manner similar to Example V, 1-(4-methoxy-
benzyl)-lH-tetrazole-5-carbonyl chloride is condensed
with 2-amino-6-(2-methyl-4-morpholinyl)benzonitrile to ~-
give 1-(4-methoxybenzyl)-N-[2-cyano-3-(2-methyl-4-
morpholinyl)phenyl3-lH-tetrazole-5-carboxamide.
By a process similar to those revealed in
Example V and by D. L. Lee and H. Rappaport in J. Org.
Chem., 40, 3491 (1975) and F. Weygan~, et al., in
Chem. Ber.~ 101, 3623 (1968) the 4-methoxybenzyl group -~
. . . .
is removed from the above tetrazole.
; ~ The corresponding thio morpholino analogue is
prepared by the method of Example V employing the 4-
:
-- -
- 27 -
'. ~ '.: '
.- .. , , , ... .. , .,. . .. - : . , . . :

A~IP-5971~2-C2/6662 f'
2~
methoxybenzyl protecting group to ultimately obtain N-
[2-Cyano-3~(thio morpholine)-phenyl-lH-tetrazole-5- :
carboxamide. :
.. - .': '
.;' .. '' .
'`.''~ ': ' "
. ~ .. . .
~. ~'' '
. ~
':' . " '~
.: .
- ' '' ~:
, ;
.
,- :, .
~ ,.. ..
. ,.
. . :
:

67Z9
SUPPLEMENTA~Y DISC~OS~UE
Example VII
N-(2 Pyridinyl)-lH-tetrazole-5-carboxamide sodium salt
As in example V, 4.7 g. (0.05 mole) of 2-amino-
pyridine in 200 ml of methylene chloride and 4.18 g. of
pyridine is treated with l-p-methoxybenzyl-lH-tetrazole-5- -
carbonyl chloride (prepared from 15 g~ of l-p-methoxybenzyl-
lH-tetrazole-5-carboxylic acid potassium salt a~d oxalyl --~
chloride) in 300 ml. of methylene chloride at 0. After 2 --~
hours the reaction mixture is poured into water, the organic
phase is separated, dried and evaporated. The residue is re-
crystallized from acetonitrile, yield: 8.47 g., m.p. 111- -
112 C. ~ -
Analysis for: ClsH14N62
Calculated: C, 58.05; H, 4.35; N, 27.09
Found: C, 57.98; H, 4.40; N, 27.32
A mixture of 8.2 g. (0.027 mole) of the above pro- `~;~
,
duct is dissolved in 150 ml. ~rifluoroa~e~icacid (TFA) and
14.5 ml. (14.4 g., 0.133 moIe) of anisole is added. After
heating at reflux for ~1/2 hour the reaction mixture is evap-
orated to dryness,~the residue is washed well with diethyl
ether and dried, yield: 500 g., m.p. 265-270 C.
~nalysis or: C7H6N60
Calculated: C, 44.21; H~ 3.18; N, 44.20
Found: C, 43.98; ~, 3.26; N, 42.36
To~a~suspension of 3.66 g. (0.016 mole) of the
above tetrazole in 10 ml. of water is added 16.1 ml. of 1.00
~N NaOH. ~The resulting solution is reeze dried and the resi-
due is~dried over P205 to give the desired tetrazole sodium
~ :. .
salt as the monohydrate~ yield: 3.3 g. -
jj~ " ,.: , -:
- 29 -

1~86729
Analysis for: C7H5N60Na H20
Calculated: C, 36.53; H, 3.07; N, 36.52
Found: C, 36.21; H, 3.18; N, 36.21
EXAMPLE VIII
N-[2-Cyano-3-(ethylamino)phenyl]-lH-tetrazole-5- -
_ _ carboxamide sodium salt__
As in the previous example, 80 06 g. (O.OS mol.)
of 2-amino-6-ethylaminobenzonitrile is treated with the
protected tetrazole carbon~l chloride to give 12.4 g. of the
desired product, after recrystallization from acetonitrile,
m.p. lS2-154C.
Analysis for: ClgHlgN702
Calculated: C, 60,46; H, 5.07; N, 25.98
Found: C, 60.64; H, 4.92j N, 26.22
Removal of the protecting group is identical to
the previous example, 12.2 g. of the starting material yielding
7.7 g. of product, m.;p. 244C. (decomp.)
Analysis for: CllHllN
- .
Calculated: C,`51.3S; H, 4.31; N, 38.12
. .
Found: C, 51.45; H, 4.22; N, 35.83
To 7.67 g.(O.03 mol.) of the above product in SOO
ml~ of ethanol is added 5.05 ml. of 5.89 N NaOH.~ This is
followed by the addition of 2 l. of ether. ~ The product is
filtered off a~d dried extensively over P205, yielding
4.2 g.
Analysis for: ~CllHloN7~Ng l l~N2
Calculated~ C,~ ~4.~18;~ H~ 4.;11; N, 32.79
~Fou~d.~ C,~44.78j d, 3.89; N, 32. e
30 -
. ,
:
:
. ~
. ~ ~ ;` ~ ! -

- ~867;~9
EXAMPLE IX
N-C2-(Aminocarbon~1)-3~ piperidinyl)phenyl~-lH-tetrazole-
5-carboxamide sodium salt
.... _ _ _ . _
As in previous examples, 10. 96 g. (O. 05 mol. ) of
2-amino-6-piperidinylbenzamide is acylated to give, after
recrystallization from ethanol, 14.1 g. of the desired ~ - -
product, m.p. 175-177C~ - -
Analysis for: C~2H25N70~
Calculated: C, 60.68; H, 5.79, N, 22.52 ~ -
Found: C, 60.74; H, 5.68; N, 22.77.
The deprotection is as above. Recrystallization from
ethanol gives the tetrazole 7.16 g. , m.p. 234~C. (decomp.).
Analysis for: C14H17N702
Calculated: C,53.32; H, 5.43; N, 31.09
Found: C,52.70; H, 6.42; N, 27.34
The sodium salt is prepared in ethanol, as in example
2. Then 6.5 g. of th~ tetrazole is con~erted to 5.0 g. of
the sodium salt as an ethanol-water complex, m.p. 291C.(decomp). ;~-~
Analysis for: C14H16N702Na 0-4 EtOH 0-6 H20
Calculated: C, 48.30; H, 5~41; N, 26~64
Found: C7 48.30; H, 4.98; N, 26.92
N-C2-(Aminocarbonyl)-3-(4-morpholinyl)phenyl]-lH-tetrazole~
_ 5-carboxamide sodi~m salt
The usual acylation of 2-amino-6-(1-morpholinyl) ~;~
benzamide (8.57 g~. 0.04 mol.) gives the desired product.
Recrystallization~from ethanol yields 10.9 g., m.p. 181-184
.
C.
~nalysis for:~ C21~ 3N704
Calcula~ed: ~ C, 57.65; H, 5.29; N, 22.4
Found: C, 57.57; H, 5.33; N, 22.16
~ - 31 -
'.

~1~)867Z9
Deprotection of 10.8 g. (0.025 mol.) of the abo~e
product in TFA gives 7.8 g. of product.
Analysis for- Cl3~IlsN703
Calculated: C, 49.~0; H, 4.76; N, 30.90
Found: C, 50.29; H, 4.77; N, 30.30
7.4 g. o~ the tetrazole is con~erted to the sodium
salt (6.5 g.3 as in Example 1, m.p. 293C. (decomp.).
Analysis 9r: C13H14N703Na 0.6 H20
Calculated: C, 44~52; H, 4.38; N, 27.96 -
Found: C, 44.92; H, 4.02; N, 27.62
EXAMPLE XI
N-~2-(Aminocarbonyl)-3-(dlmethylamino3phenyl]-lH-tetrazole-
_ 5-carboxamide sodium salt
Treatment of 7.17 g. (0~04 mol.) of 2-amino-6-
dimethylami~obenzamide with the tetrazole oarbonyl chloride
gives, after recr~stalliæation from eth~l acetate-
hexane, 9.5 g. of the~product, m.p. 130-132C.
Analysis for: Clg~I21N703
Calculated: C,~57.71; H, 5.35j N, 2~.80
Found: C, 57.79; H, 5.Z2; N, 24.78 ` -~
The above product~, 9.3 g. (0.023 mol.j is
deproteeted in T~A and recrystallized from~ethanol,
. .
m.p~ 175-178C.~ 6.1 g.
Analy~is ~or: CllH13N702~
Calculated: C,~ 51.35; H, 4.09; N, 38.11
Found: ~ ~C, Sl~.llj ~I, 4.95; N, 37.65
The above~tetrazole~(5.08 g. 0.02 mol.) is converted
to~the sodium~salt a~in example 1, 4.63 g. , m.p. 193C.
~ ~AnalySi9~for~ GllHl2N7o2Na
Calculated; ~C, 44.44i ~? 4.07; N, 32.99
Found~ C, 44.05; H, 4.00; N, 32.45
- 32 -

108G729
EX~MPLE XII
N-~2-Cyano-3-(dimethylamino)phenyl]~ tetrazole-5- -
_ carboxamide sodium salt
2-amino-6-dimethylamino benzanitrile (4.4 g.,
0.027 mol.) is converted $o the protected tetrazole amide
as in ex~mple ~ 5.8 g., m.p. 171-173C. (from acetonitrile).
C j Analysis for: C19HlgN702
Calculated: C, 60~46; H, 5.Q7; N, 25.98
Found: - C, 60.61; H, 5.05; N, 25.92
Deprotection of the above tetrazole is as in the
previous examples, m.p. 198-205C.
AnalysiS for: CllHllN7
Calculated: C, 51.35; H, 4.31; N, 38.12
Found: C, 51.96; H, 4.20; N, 38.22
The sodium salt is prepared as usual with 1.4 g.
(0.005 mo1.) of the above tetrazole being treated with 1.000 N
NaOH in water ns in ex~mple 1. The resultant product (1.0 g.)
was slightly contaminated with sodium~trifluoroacetate, m.p.
155-158C.
~nalysis for: CllHlON70Na 1/8 NaO2CCF
Calculated: C, 45.61; H, 3.40; N~ 33.10
Found: C,;45.30; H, 3.15; N, 33.39
.,., ~ .
EX~MPLE XIII
N-C2-Cyano-3-(4-metllyl-1-piperaz;inyl)phenyl]-lH-tetrazole~
5-carboxamide
To 3.51 g. (0~016 mol.) of 2-amino-6-(4-methyl-
piperazinyl)benzon1tri1e~in 150 ml. of methylene chloride is
added exactly 1 equivalént of 1-p-metho~ybenzyl-5-carbonyl
chloride in methylene chloride at 0C. After 1~ hours
~30 ~the~reaotion~mixture~is treated with water, the pH is adjusted
; ~
~ 33 ~
.
. .
'E~, ~ : . - :.

)867~:9
to 10 with N NaOEI. The organic phase is separated, dried
and evaporated. The residue is recrystallized from
acetonitrile, 4.5 gO
Analysis for: C22H24N802
Calculated: C,61.09, ~, 5~59; N, 25.91
Found: C,60.94; H, 5.49; N, 25.85
The above tetrazole, 4.3 g. (0.01 mol.) is treated
with TFA anisole as before. me residue is recrystallized
from water to give 1.8 g. , m.p.>290C.
AnalySiS for: C14H16N8 0 44 H20
Calculated: C, 52.49; ~, 5.51; N, 34.98
Found: C, 52.89; Hj 5.21; N, 34.52
EXAMPLE XIV
N-[2-Cyano-3-(1-piperidinyljphenyl~-lH-tetrazole-5-carboxamide
__ _ sodium salt
2-amino-6-(1-piperidinyl)benzonitrile (10.06 g.,
0.05 mol.) is treated with 1 equivalent of the usual tetrazole
carbonyl chloride in 600 ml. of methylene chloride and 4.2 ml. ~ -
of pyridine. The product is recrystallized from acetonitrile
after the usual aqueous work-up, yield 12.7 g.9 m.p. 166-168C.
Analysis for: C22H23N702
Calculated: C, 63.29; H, 5.55; N, 23.49
Found: C, 63.15; H, 5. 48; N, 23.54
The above tetrazole, 12.45 g. (0.0298 mol.), is
.
treated with 16.2 ml. of` anisole in 193 ml. of TFA. After
evaporation~of~solvents the residue is washed with ether and
is recr~stallized~frQm ethanol,~yield 7.27 g.
ADalysi8~for: ~ C14H15N70 ~ ;
~alculated: ~ C, 56~55; H,~ 5.08; N, 32.98
30~ Found: ~ C, 56.44; H, 5.03; N, 32.54.
:
34 -
;
~3 ;:

~" ~Ol~7:~9
me above tetrazole is converted to the sodium
salt with 1.000 N NaOH as in example 1. The product
is not completely dried, m.p. 164-167~C.
EXAMPLE XV
N-[2-(Aminocarbonyl)-3-(~ methyl-l-piperazinyl)phenyl]- l~
lH-tetrazole-l-carboxamide : .
2-amino 6-(4-methyl piperazinyl)benzamide (11.71 gO~
0.05 mol.) is acylated with ~he usual acid chloride in methylene
C ohloride as in example ~ The product is recrystallized from
acetonitrile, 15.6 g~
Analysis for: C22H26N803
Calculated: C, 58.65; H, 5.82; N, 24.87
Found: C, 58.20; H, 5.69; N, 24.64 ~
This protected tetrazole (15.3 g., 0.034 mol.) is 11,,,.. ~: '
treated with TFA anisole as in example 7. The resultant
product after work-up is recrystallized from water, 7.7 g., ~: :
m~p.>300C.: ! `
AnalySiS for: Cl ~18N82
Calculated: C, 50.49~ H, 5.54; N, 33.65
Found: C, 50.89; H, 5.31; N, 33.20
: .
. ,
.
, , .
: , : : ;
- 35 - ~
j~ '
- '

6~2~
EX~MPLE XVI
[3-Cyano-5~(1H-tetrazol-5-ylcarbonyl)amino]phenylamino]-
oxoacetic acid ethyl ester
8.15 (0.05 mol.) of 3-amino-5-nitrobenzonitrile
is acylated under the usual conditions to give the crude
desired product, which is crystallized from ethyl acetate-
hexane to yield 13.2 g. This material is not quite pure
and is dissolved in acetonitrile and cooled to -30C. me
crystals are filtered off to give 10.2 g. of product, m.p.
159-162C.
Analysis for: C17H13N704
Calculated: C, 53.82; H, 3.45; N, 25.85
Found: C, 53.36; H, 3.37; N, Z5.52
A mixture of 7.07 g. of the above product, 11.3 ml.
of cyclohexene and 7 g. of 10% Pd/C is heated in 525 ml. of
ethanol at reflux for 1/2 hour. The mixture is filtered
. .
hot through Celite , the filtrate is evaporated to dryness
and the residue is dissolved in 250 ml. of methyle~e chloride.
To this is added 1.6 ml. of pyridine and then 2.3 ml. of
ethyl oxalyl chloride in 10 ml. of methylene chloride. After
18 hours, the mixture is treated with saturated sodium
bicarbonate and then lime. The dried organic layer is
evaporated and the residue is crystallized from ethanol,
5~8 g.
~nalysis~for: C21ElgN705
Caleulated: C, 56.12; H, 4~26; N, 21.82
- ~
Found: ~ C~, 56.10; H, 4~29; N, 20.80
~ ~ The~abov~ tetrazole derivative is deprotected with
TFA-anisole~as in the previous examples to give the desired
materiàl~,~m.p.~244 ;~deo), 5.9 g. (from acetonitrile).
6 - -
. ~ :
. .
! ` :

- ~ g67Z9
Analysis for: C13HllN70~L ~ ~ 3 CH3CN
Calculated: C, 47. 82; H, 3. 51; N, 29. 94
Found: C, 47004; H, 3.41; N, 29.29
'~5.''' ~
''' '~' "' ' "~
, "
.:'' ':~
~. " :'
. -
. ' ' " -:
.. .
; ' -, -':
: `: ,',', ;,'', .
:
,
: ~ ' :, ".'
:: . ~ ~ 1 . .
:,
,