CA1086729A - Tetrazole-5-carboxamide derivatives - Google Patents
Tetrazole-5-carboxamide derivativesInfo
- Publication number
- CA1086729A CA1086729A CA259,451A CA259451A CA1086729A CA 1086729 A CA1086729 A CA 1086729A CA 259451 A CA259451 A CA 259451A CA 1086729 A CA1086729 A CA 1086729A
- Authority
- CA
- Canada
- Prior art keywords
- tetrazole
- acid
- chloride
- pyridine
- methoxy benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D247/00—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Abstract of the Disclosure Anti-allergic agents of N-aromatic 1H-(or 2H)tetrazole-5-carboxamide derivation present the following structural formula:
in which R1 is -CN or -CONH2 R2 is lower alkoxy, hydroxy(lower)alkoxy, or 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.
in which R1 is -CN or -CONH2 R2 is lower alkoxy, hydroxy(lower)alkoxy, or 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.
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 .. . . .
': .
.. . .
.. ' , . .
' 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 ' R H
in which Rl is -CN or -CONH2 R2 is lower alkoxy, hydroxy(lower)alkoxy, or . -_ a, _ ,~, ~.
. ` .~ . `
, ~
"'~ ' ~,:
.,, . ., , ,,, :,,, : , . ... ... . . .. .
~MP-5971-?~ C2/6662 :t -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; ; ;-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,
, .
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 .. . . .
': .
.. . .
.. ' , . .
' 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 ' R H
in which Rl is -CN or -CONH2 R2 is lower alkoxy, hydroxy(lower)alkoxy, or . -_ a, _ ,~, ~.
. ` .~ . `
, ~
"'~ ' ~,:
.,, . ., , ,,, :,,, : , . ... ... . . .. .
~MP-5971-?~ C2/6662 :t -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; ; ;-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
:~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 -
~ 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
- - ~
~-: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~.
' . : ~ ,.~, ~IP-597L-2-C2/6662 ~
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~.
' . : ~ ,.~, ~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 : , .. :
. .
: :.
~.
~IIP-5971-'~-C2/6ffff2 f 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.
', ~ ., ~:
.
~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 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.).
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. `
. -.
~ '; ' "
~ . ,.
. . .
: " ':' . '.' , ' , . ~ . ... . . . ~, . . .. .. . .
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
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 : , .. :
. .
: :.
~.
~IIP-5971-'~-C2/6ffff2 f 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.
', ~ ., ~:
.
~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 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.).
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. `
. -.
~ '; ' "
~ . ,.
. . .
: " ':' . '.' , ' , . ~ . ... . . . ~, . . .. .. . .
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 ~
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
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-:
-- -'. ~ '.: ' .- .. , , , ... .. , .,. . .. - : . , . . :
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. :
.. - .': ' .;' .. '' .
'`.''~ ': ' "
. ~ .. . .
~. ~'' ' . ~
':' . " '~
.: .
- ' '' ~:
, ;
.
,- :, .
~ ,.. ..
. ,.
. . :
:
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~ " ,.: , -:
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 . , :
:
. ~
. ~ ~ ;` ~ ! -- ~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 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.
:
;
~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).
. ~ :
. .
! ` :
- ~ 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 . .
:, ,
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 ~
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
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-:
-- -'. ~ '.: ' .- .. , , , ... .. , .,. . .. - : . , . . :
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. :
.. - .': ' .;' .. '' .
'`.''~ ': ' "
. ~ .. . .
~. ~'' ' . ~
':' . " '~
.: .
- ' '' ~:
, ;
.
,- :, .
~ ,.. ..
. ,.
. . :
:
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~ " ,.: , -:
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 . , :
:
. ~
. ~ ~ ;` ~ ! -- ~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 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.
:
;
~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).
. ~ :
. .
! ` :
- ~ 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 . .
:, ,
Claims (35)
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 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 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 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 in which R1 is -CN or -CONH2, R2 is lower alkoxy, hydroxy(lower) alkoxy, or 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 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 where R9 is lower alkyl;
and R4 is hydrogen or lower alkyl.
and R4 is hydrogen or lower alkyl.
4. The process of claim 1 in which said aromatic amine is of the formula 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 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:
in which R1 is -CN or -CONH2, R2 is lower alkoxy, mono-lower alkylamino, di-lower alkylamino, or a group of the formula where X is -CH2-, -O- or 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.
in which R1 is -CN or -CONH2, R2 is lower alkoxy, mono-lower alkylamino, di-lower alkylamino, or a group of the formula where X is -CH2-, -O- or 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.
CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE
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 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 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 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.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/669,562 US4044144A (en) | 1973-03-23 | 1976-03-23 | 1H-tetrazole-5-carboxamides |
| US05/669,570 US4013647A (en) | 1976-03-23 | 1976-03-23 | Morpholine containing tetrazole-5-carboxamide derivatives |
| US669,570 | 1976-03-23 | ||
| US05/726,374 US4116960A (en) | 1976-03-23 | 1976-09-24 | Tetrazole-5-carboxamide derivatives |
| US669,562 | 1984-11-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1086729A true CA1086729A (en) | 1980-09-30 |
Family
ID=27418192
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA259,451A Expired CA1086729A (en) | 1976-03-23 | 1976-08-19 | Tetrazole-5-carboxamide derivatives |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS52116470A (en) |
| AU (1) | AU510030B2 (en) |
| CA (1) | CA1086729A (en) |
| CH (1) | CH619939A5 (en) |
| DE (1) | DE2641290A1 (en) |
| FR (2) | FR2345149A1 (en) |
| GB (1) | GB1523527A (en) |
| NL (1) | NL7609455A (en) |
-
1976
- 1976-08-19 CA CA259,451A patent/CA1086729A/en not_active Expired
- 1976-08-25 NL NL7609455A patent/NL7609455A/en not_active Application Discontinuation
- 1976-09-10 FR FR7627364A patent/FR2345149A1/en active Granted
- 1976-09-14 DE DE19762641290 patent/DE2641290A1/en not_active Withdrawn
- 1976-09-28 JP JP11791176A patent/JPS52116470A/en active Pending
- 1976-10-06 GB GB41484/76A patent/GB1523527A/en not_active Expired
- 1976-10-13 AU AU18617/76A patent/AU510030B2/en not_active Expired
- 1976-12-10 CH CH1559676A patent/CH619939A5/fr not_active IP Right Cessation
-
1977
- 1977-03-30 FR FR7709517A patent/FR2345438A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| FR2345438A1 (en) | 1977-10-21 |
| GB1523527A (en) | 1978-09-06 |
| FR2345438B1 (en) | 1981-07-03 |
| CH619939A5 (en) | 1980-10-31 |
| AU1861776A (en) | 1978-04-20 |
| AU510030B2 (en) | 1980-06-05 |
| JPS52116470A (en) | 1977-09-29 |
| NL7609455A (en) | 1977-09-27 |
| DE2641290A1 (en) | 1977-10-06 |
| FR2345149B1 (en) | 1980-04-18 |
| FR2345149A1 (en) | 1977-10-21 |
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