CA1120475A - 7,8-dihydro-2,5,8-trisubstituted-7-oxo-pyrido [2,3-d]-pyrimidine-6-carboxylic acid derivatives - Google Patents
7,8-dihydro-2,5,8-trisubstituted-7-oxo-pyrido [2,3-d]-pyrimidine-6-carboxylic acid derivativesInfo
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- CA1120475A CA1120475A CA000350056A CA350056A CA1120475A CA 1120475 A CA1120475 A CA 1120475A CA 000350056 A CA000350056 A CA 000350056A CA 350056 A CA350056 A CA 350056A CA 1120475 A CA1120475 A CA 1120475A
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- pyrimidine
- carboxylic acid
- oxo
- dihydro
- ethyl ester
- Prior art date
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Abstract
Abstract The pyrido[2,3-d]pyrimidines are of the formula:
wherein R2 is hydrogen, hydroxy, alkyl, alkylthlo, phenyl, 4-me-thoxyphenyl, 4-chlorophenyl, 1-pyrrolidinyl or methylphenylarnino;
R5 is hydroxy, alkylamino, 2-hydroxyethylamino, 2-alkoxyethyl-amino, dialkylamino, 4-methyl-1-piperazinyl, 4-morpholinyl or 1-pyrrolidinyl or amino with the provisos that if R8 is alkyl and R2 is phenyl then R5 is other than amino and if R8 is alkyl and R2 is alkylthio then R5is other than 1-pyrrolidinyl; R6 is al-koxy, amino, mono- or dialkylamino, 2-hydroxyethylamino, 2-al-koxyethylamino or 2 (dialkylamino)-ethylamino; and R8 is hydro-gen, alkyl, 2 alkoxyethyl, allyl, propargyl, phenyl, 4-methoxy-phenyl, 4-chlorophenyl, benzyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-(4-morpholinyl)-phenyl or piperonyl. The compounds are useful as anti-secretory agents. Some also exhibit anti-allergy acti-vity. Processes for preparing the compounds are described and also novel intermediates useful in the processes.
wherein R2 is hydrogen, hydroxy, alkyl, alkylthlo, phenyl, 4-me-thoxyphenyl, 4-chlorophenyl, 1-pyrrolidinyl or methylphenylarnino;
R5 is hydroxy, alkylamino, 2-hydroxyethylamino, 2-alkoxyethyl-amino, dialkylamino, 4-methyl-1-piperazinyl, 4-morpholinyl or 1-pyrrolidinyl or amino with the provisos that if R8 is alkyl and R2 is phenyl then R5 is other than amino and if R8 is alkyl and R2 is alkylthio then R5is other than 1-pyrrolidinyl; R6 is al-koxy, amino, mono- or dialkylamino, 2-hydroxyethylamino, 2-al-koxyethylamino or 2 (dialkylamino)-ethylamino; and R8 is hydro-gen, alkyl, 2 alkoxyethyl, allyl, propargyl, phenyl, 4-methoxy-phenyl, 4-chlorophenyl, benzyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-(4-morpholinyl)-phenyl or piperonyl. The compounds are useful as anti-secretory agents. Some also exhibit anti-allergy acti-vity. Processes for preparing the compounds are described and also novel intermediates useful in the processes.
Description
7,8 _IHYDRO-2,5,8-TRISUBSTITUTED-7~0XO-PYRIDOC223-d]-PYRIMIDINE
This .in~ention relates to pyrido[2~3-d]pyrimidine derivatives and also to intermediates useful in processes for preparing the pyrido~2, 3-d~pyrimidine dPrivatives. :1~ partic-ular the invention relate~ to a group of 7,8-dihydro 5,6-sub-stituted-7-oxo-pyrido~2,3-d~pyrimidine deri~atives which may also ~e substi$uted in the 2 and 8 positions and which act as gastric anti-secretory agents, by virtue of which they may be used in the treatment of peptic ulcer disease. MR~Y o~ the compounds of this invention also exhibit anti-allergy acti~ity, b~ virtue of which they are useful in the prophylactic sup-pression of allergic manifestations in warm-blooded animals.
As ~lti-secretory agents, the compounds of this in vention reduce (1) total gastric volume, (2) hydroge~ io~ se-cretio~, or ~) hydroge~ ion concentration. The reduction of any one o~ these parameters aids in attenuat~ng the general ae-bilitating influen¢e of a peptic ulcer in hwman~. The use o~
compou~ds exhibiting a~ti-secretory activity i~ the curati~e and/or prophylactic treatment o peptic ulcer disease is an established, beneficial procedure.
As anti-allergy agents, the compounds of this inven-tion suppress the manifestations of an allergic respo~se o~ the atopic immediate hypersensitivity type in warm-blooded, sensi-tized animals when administered prior to an allergic attack.
Although the mechanism of action is not known, it is believed that the anti allergy agents o~ this invention function in the same manner as disodium cromogl~cate ~o block reaction(s) within mast cells, thereby preventing the production and release of 4~75 mediators such as Bradykinin, SRS-A (slow reacting substano0-A), histamine and other unk~own substances. The suppression of allergic manifestations is a de~irable treatme~t in both h~man and domestic warm-blooded animals 3uch as the mouse, rat, ham-ster, gerbil, dog, cat, sheep, goat, horse ~nd cow.
me pyrido[2, 3-d]pyrimidine compoumds of the i~vention are tho~e OI the general îormula ~,COR6 . R8 in which R2 is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, phenyl, 4-methoxyphenyl, 4-chlorophe~yl, l-p~rrolidinyl or methylphenylami~o, R5 is hydroxy9 alkylamino of 1 to 6 ~arbon atoms, 2-hydroxyethylamino, 2-alk-oxyethylamino of 3 $o 8 carbon atoms, dialkylamino wherein each alkyl group conta~ns from 1 to 6 carbon atoms~ 4-methyl-1-piper-azinyl, 4-morpholinyl, l-pyrrolidinyl or amino with the provisos that if R8 is alkyl and R~ is phenyl then R~ is other than amino a~d if R8 is alkyl and R2 is alkylthio then R5 is other than 1 pyrroiidinyl; R6 i~ alkoxy OI 1 to 6 carbon atoms9 amino, mono-or di-alkylamino where each alkyl group contains from 1 to 6 carbon atoms, 2-hydroxyethylamino, 2-alkoxyethylamino of 3 to 8 carbon atoms or 2-(dialkylamino)-ethylamino in which each alkyl group contains from 1 to 6 carbon atoms; R8 is hydrogen, alkyl of 1 to 6 carbon atoms~ ~-alkoxyethyl of 3 to 6 carkon atoms, allyl, propargyl, phenyl, 4-methoxyphenyl, 4-chlorophenyl~
benzyl~ 4~methoxybenzyl, 4-chlorobenzyl, 4-(4-morpholinyl)-phenyl or piperonyl, and the pharmaceutically acceptable salts thereof.
The preferred anti-secretory agents bas~d upon their abilit~ to inhibit about fifty percent total acid at a dose of 32 milligrams per kilogram i.d., are of the formula:
~5 ~ COR~
R21 N ~ ~0 in which R is phenyl~ methylthio or l-pyrrolidinyl;
R5 is amino, hydroxy, 2-methoxyethylamino or l-pyrrolidinyl;
R6 is ethoxy and R~ is hydrogen, methyl, ethyl, prop~l, allyl~ 2~methoxy-ethyl, ph~yl, piperonyl, 4-methoxybell~.yl or benzyl., m e compounds of thi~ invention which exhibit anti allergy activity present the structural formula:
F,21`~co~6 ~8 in whioh R2 is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms~
alkylthio of 1 to 6 carbon atoms, phenyl, 4Amethoxy-phenyl, 4 chlorophe~yl9 l-pyrrolidinyl or methylphenyl-~n~no;
R5 is hydroxy~ alkylamino of 1 to 6 carbon atoms, dialk~amino wherein each alkyl group contains from 1 to 6 carbon a~oms, 4-morpholinyl~ 2-alkoxyethyl~m~no of ~ 7 ~
3 to 8 carbon atoms or 2-(diallsylamino)ethylamino in which each alkyl group contains from 1 to 6 carbon atoms~
and R8 is alkyl of 1 to 6 carbon atoms, 2-alkoxyethyl of 3 to 6 carb~n atoms, allyl, propargyl, phenyl, 4-methoxy-phenyl, 4-chloropheny~, benzyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-(4-morpholinyl)phenyl or piperonyl;
or a pharmaceutically acceptable salt thereof.
The compounds of the inve~tion in ~hich R5 is hydroxy or amino and R6 is alkoxy may be prepared by . reacting a pyrimi-dine derivative of general formula:
N ~
R2 ~ N ~ ~R8 where R2 and R~ are as defined above (in connection with the com-po~nds of the inventio~) and X is COOAlkyl or -CN with an alkyl malonyl halide, e.g. ethyl malonyl chloride~ (where X is COOAlkyl or -CN) or with an alkali metal dialkyl malonate, e.g.
a sodio dialkyl malonate, such as sodio diet~ylmalonate, ~where X is -CN). An example of this process where X is COO~lkyl, to-gether with the preparation of the starting material is illus-trated below:
OH
CO~E ~ N ~ l. C~ICOC~L ~ N f ~ coR6 R ~N ~Cl - 1 ~ ~ 2 NaOR6 R2 1 N N38 ~
I II III
An example of the proce~s in which X is -CN to produce com-po~ds in which a primary amino group appears in the 5-positio~
is ill ustrated below: N~2 ~ 2 ) Na~R6 2 ~coR6 R2 N HR~ R N l O
R~
The illustrated proeess involves reactio~ o:f ethyl malon~l chloride with a 4-amino-5-cyaIlo-2-substituted pyrimidine.
Whe~ an alkali metal dialkylmalonate i~ employed as the reac-tant with 4-amino-5-cyano-2-substituted pyrimidine in the pre-ceding equation, the same product is obt~ined directly upon acidification of the reaction mixture~
Compounds of the invention in which R5 is hydroxy and R6 is alkoxy can be prepared by an alternative route in which B pyrido-oxazine-dione of general formula:
where R2 and R8 are as defined above (in connection with the com-pounds of the invention) is reacted with a~ alka~i metal dialkyl malonate e.g. sodio diethylmalon~te. The pyrimido-oxazine-di-one can, for example, be reacted with diethylmalonate and sodium ethoxide. The pyrido-oxazine~dione may be prepar~d by reacting an acid of general formula: r COOH
N~/
R21N ~NHR8 (where R~ and R8 are as defined above) with an alkyl halofor-mate, e.g. ethyl chloroIormate. l~e acid may be prepared by hy-drolysis oî the ester II aboveO An example of thi~ al~ernative route, together with the preparation of the starting material is illustr~ted below:
O
N~co2 OH N ~ ClCO Et i~
R2--~N N~8 H~ R21N NHI~ R2~ ~O
VI V~
' NaC~I(COR6)2 ~ 1 COR6 R N ~ 7 ~ O
III
-Once a compound of the invention is obtained by a method mentioned above it can he converted into another com-pound of the inventio~ by, for example, one or more of the following processeæ:-(a) Halogenation of a compound in which R5 is hydroxy to ~ive a compound in ~hich R5 is halogen and reaction of the halo com-pound wi~h an amine to giYe a compound in which R5 is amino, alkylamino, 2-hydroxyethylamino, 2-alkoxyethylamino, dialkyl-amino, 4-methyl-l-piperazinyl, 4-morpholinyl or l-pyrrolidinyl~
This process is exemplified below:
OH Cl g N ~ coR6 N ~ coR6 R2 l ` N N O R~ l ~ N ~~
III R9~ ~ R10 IV
N ~ coR6 ~2 1 ~ ~ I ~ o ~8 ,,,~9 where -N is an ~mi~o grouping embraced by the description ~ p~10 of R5. The chlorination of III to IV may b~ carried out with, for example, POC13.
(~) Oxidation of a compound in which R2 is alkythio to give a corresponding compound in which R2 is alkysulphonyl and acidifi-cation of the alkysulphonyl compound to ~i~e a compound in ~hich R2 is hydroxy or reaction of the alkysulphonyl compound with an amine to give a compound in which R2 is l~pyrrolidinyl or methyl-phenylamino~ This technique illustrated below N ~ coR6 Rl~S02 `N ~ O R9 R9~ N
~ ~ .
N ~
g ~N~HolN ~'\
where -N is an amino grouping embraced by the definition ~R10 of R2 and R12 is alk~l of 1 to 6 ¢arborl atoms. The oxidation may be oarried out with, for example, 3-chloro-perbenzoic acid.
(c) Reaction of a compound in which R6 is alkoxy (an ester) with ammonia or with an amine to give an amide in which R6 is ami~o, monoalkylamino, dialk~lamino, 2~hydroxyethylamino, 2-alkoxyethyl-amino or 2- (dialkylamino) ethylamino.
(d) Alkylation, allylation or alkynylation of a compound of the invention in which R8 is hydrogen to give a compound in which ~8 is alkyl, allyl or propargyl. The alkylation~ allylation or alkyrlylation may be ef:Eected by, for example, reacting an alkali metal ~alt of the compound with an alkyl, allyl or pro-pargyl halide.
(e) Co~version of a basic compound of the invention i~to its pharmaceutically acceptable salt.
Th~ pyrimido-oxazine-diones of formula VII~ represent a compound intermsdiate aspec~ of this invention in that they are useful in production o the ultimate anti-secretory agents.
The pyrimido-oxazine-dio~es present the structural formula:
o N ~0 R~ N 7~o in which R2 is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon at~ms,~phenyl, 4-methoxyphenyl, 4-chlorophenyl9 l-pyrrolidinyl or methylphenylamino;
and R8 is hydroge~, alkyl of 1 to 6 carbon atoms, 2-alkoxy-~ ethyl of 3 to 6 carbon atoms, allyl, proparg~l, phenylg 4-me~hoxyphenyl, 4-chlorophenyl, benzyl, 4-methoxybe~zyl, 4-chlorobenzyl, 4-(4-morpholinyl)-phenyl or piperonyl.
The 5-chloro-pyrido-pyrimidines of formula IV con-stitute an additional compound intermediate aspect of the in-_ g _ ~ 7 5 vention in that they are useful in the production of anti-secretory agents containing an amino substituent in 5-position~
The 5-chloropyrido-pyrimidine intermediates present the struc-tural formula: Cl N~coR6
This .in~ention relates to pyrido[2~3-d]pyrimidine derivatives and also to intermediates useful in processes for preparing the pyrido~2, 3-d~pyrimidine dPrivatives. :1~ partic-ular the invention relate~ to a group of 7,8-dihydro 5,6-sub-stituted-7-oxo-pyrido~2,3-d~pyrimidine deri~atives which may also ~e substi$uted in the 2 and 8 positions and which act as gastric anti-secretory agents, by virtue of which they may be used in the treatment of peptic ulcer disease. MR~Y o~ the compounds of this invention also exhibit anti-allergy acti~ity, b~ virtue of which they are useful in the prophylactic sup-pression of allergic manifestations in warm-blooded animals.
As ~lti-secretory agents, the compounds of this in vention reduce (1) total gastric volume, (2) hydroge~ io~ se-cretio~, or ~) hydroge~ ion concentration. The reduction of any one o~ these parameters aids in attenuat~ng the general ae-bilitating influen¢e of a peptic ulcer in hwman~. The use o~
compou~ds exhibiting a~ti-secretory activity i~ the curati~e and/or prophylactic treatment o peptic ulcer disease is an established, beneficial procedure.
As anti-allergy agents, the compounds of this inven-tion suppress the manifestations of an allergic respo~se o~ the atopic immediate hypersensitivity type in warm-blooded, sensi-tized animals when administered prior to an allergic attack.
Although the mechanism of action is not known, it is believed that the anti allergy agents o~ this invention function in the same manner as disodium cromogl~cate ~o block reaction(s) within mast cells, thereby preventing the production and release of 4~75 mediators such as Bradykinin, SRS-A (slow reacting substano0-A), histamine and other unk~own substances. The suppression of allergic manifestations is a de~irable treatme~t in both h~man and domestic warm-blooded animals 3uch as the mouse, rat, ham-ster, gerbil, dog, cat, sheep, goat, horse ~nd cow.
me pyrido[2, 3-d]pyrimidine compoumds of the i~vention are tho~e OI the general îormula ~,COR6 . R8 in which R2 is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, phenyl, 4-methoxyphenyl, 4-chlorophe~yl, l-p~rrolidinyl or methylphenylami~o, R5 is hydroxy9 alkylamino of 1 to 6 ~arbon atoms, 2-hydroxyethylamino, 2-alk-oxyethylamino of 3 $o 8 carbon atoms, dialkylamino wherein each alkyl group conta~ns from 1 to 6 carbon atoms~ 4-methyl-1-piper-azinyl, 4-morpholinyl, l-pyrrolidinyl or amino with the provisos that if R8 is alkyl and R~ is phenyl then R~ is other than amino a~d if R8 is alkyl and R2 is alkylthio then R5 is other than 1 pyrroiidinyl; R6 i~ alkoxy OI 1 to 6 carbon atoms9 amino, mono-or di-alkylamino where each alkyl group contains from 1 to 6 carbon atoms, 2-hydroxyethylamino, 2-alkoxyethylamino of 3 to 8 carbon atoms or 2-(dialkylamino)-ethylamino in which each alkyl group contains from 1 to 6 carbon atoms; R8 is hydrogen, alkyl of 1 to 6 carbon atoms~ ~-alkoxyethyl of 3 to 6 carkon atoms, allyl, propargyl, phenyl, 4-methoxyphenyl, 4-chlorophenyl~
benzyl~ 4~methoxybenzyl, 4-chlorobenzyl, 4-(4-morpholinyl)-phenyl or piperonyl, and the pharmaceutically acceptable salts thereof.
The preferred anti-secretory agents bas~d upon their abilit~ to inhibit about fifty percent total acid at a dose of 32 milligrams per kilogram i.d., are of the formula:
~5 ~ COR~
R21 N ~ ~0 in which R is phenyl~ methylthio or l-pyrrolidinyl;
R5 is amino, hydroxy, 2-methoxyethylamino or l-pyrrolidinyl;
R6 is ethoxy and R~ is hydrogen, methyl, ethyl, prop~l, allyl~ 2~methoxy-ethyl, ph~yl, piperonyl, 4-methoxybell~.yl or benzyl., m e compounds of thi~ invention which exhibit anti allergy activity present the structural formula:
F,21`~co~6 ~8 in whioh R2 is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms~
alkylthio of 1 to 6 carbon atoms, phenyl, 4Amethoxy-phenyl, 4 chlorophe~yl9 l-pyrrolidinyl or methylphenyl-~n~no;
R5 is hydroxy~ alkylamino of 1 to 6 carbon atoms, dialk~amino wherein each alkyl group contains from 1 to 6 carbon a~oms, 4-morpholinyl~ 2-alkoxyethyl~m~no of ~ 7 ~
3 to 8 carbon atoms or 2-(diallsylamino)ethylamino in which each alkyl group contains from 1 to 6 carbon atoms~
and R8 is alkyl of 1 to 6 carbon atoms, 2-alkoxyethyl of 3 to 6 carb~n atoms, allyl, propargyl, phenyl, 4-methoxy-phenyl, 4-chloropheny~, benzyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-(4-morpholinyl)phenyl or piperonyl;
or a pharmaceutically acceptable salt thereof.
The compounds of the inve~tion in ~hich R5 is hydroxy or amino and R6 is alkoxy may be prepared by . reacting a pyrimi-dine derivative of general formula:
N ~
R2 ~ N ~ ~R8 where R2 and R~ are as defined above (in connection with the com-po~nds of the inventio~) and X is COOAlkyl or -CN with an alkyl malonyl halide, e.g. ethyl malonyl chloride~ (where X is COOAlkyl or -CN) or with an alkali metal dialkyl malonate, e.g.
a sodio dialkyl malonate, such as sodio diet~ylmalonate, ~where X is -CN). An example of this process where X is COO~lkyl, to-gether with the preparation of the starting material is illus-trated below:
OH
CO~E ~ N ~ l. C~ICOC~L ~ N f ~ coR6 R ~N ~Cl - 1 ~ ~ 2 NaOR6 R2 1 N N38 ~
I II III
An example of the proce~s in which X is -CN to produce com-po~ds in which a primary amino group appears in the 5-positio~
is ill ustrated below: N~2 ~ 2 ) Na~R6 2 ~coR6 R2 N HR~ R N l O
R~
The illustrated proeess involves reactio~ o:f ethyl malon~l chloride with a 4-amino-5-cyaIlo-2-substituted pyrimidine.
Whe~ an alkali metal dialkylmalonate i~ employed as the reac-tant with 4-amino-5-cyano-2-substituted pyrimidine in the pre-ceding equation, the same product is obt~ined directly upon acidification of the reaction mixture~
Compounds of the invention in which R5 is hydroxy and R6 is alkoxy can be prepared by an alternative route in which B pyrido-oxazine-dione of general formula:
where R2 and R8 are as defined above (in connection with the com-pounds of the invention) is reacted with a~ alka~i metal dialkyl malonate e.g. sodio diethylmalon~te. The pyrimido-oxazine-di-one can, for example, be reacted with diethylmalonate and sodium ethoxide. The pyrido-oxazine~dione may be prepar~d by reacting an acid of general formula: r COOH
N~/
R21N ~NHR8 (where R~ and R8 are as defined above) with an alkyl halofor-mate, e.g. ethyl chloroIormate. l~e acid may be prepared by hy-drolysis oî the ester II aboveO An example of thi~ al~ernative route, together with the preparation of the starting material is illustr~ted below:
O
N~co2 OH N ~ ClCO Et i~
R2--~N N~8 H~ R21N NHI~ R2~ ~O
VI V~
' NaC~I(COR6)2 ~ 1 COR6 R N ~ 7 ~ O
III
-Once a compound of the invention is obtained by a method mentioned above it can he converted into another com-pound of the inventio~ by, for example, one or more of the following processeæ:-(a) Halogenation of a compound in which R5 is hydroxy to ~ive a compound in ~hich R5 is halogen and reaction of the halo com-pound wi~h an amine to giYe a compound in which R5 is amino, alkylamino, 2-hydroxyethylamino, 2-alkoxyethylamino, dialkyl-amino, 4-methyl-l-piperazinyl, 4-morpholinyl or l-pyrrolidinyl~
This process is exemplified below:
OH Cl g N ~ coR6 N ~ coR6 R2 l ` N N O R~ l ~ N ~~
III R9~ ~ R10 IV
N ~ coR6 ~2 1 ~ ~ I ~ o ~8 ,,,~9 where -N is an ~mi~o grouping embraced by the description ~ p~10 of R5. The chlorination of III to IV may b~ carried out with, for example, POC13.
(~) Oxidation of a compound in which R2 is alkythio to give a corresponding compound in which R2 is alkysulphonyl and acidifi-cation of the alkysulphonyl compound to ~i~e a compound in ~hich R2 is hydroxy or reaction of the alkysulphonyl compound with an amine to give a compound in which R2 is l~pyrrolidinyl or methyl-phenylamino~ This technique illustrated below N ~ coR6 Rl~S02 `N ~ O R9 R9~ N
~ ~ .
N ~
g ~N~HolN ~'\
where -N is an amino grouping embraced by the definition ~R10 of R2 and R12 is alk~l of 1 to 6 ¢arborl atoms. The oxidation may be oarried out with, for example, 3-chloro-perbenzoic acid.
(c) Reaction of a compound in which R6 is alkoxy (an ester) with ammonia or with an amine to give an amide in which R6 is ami~o, monoalkylamino, dialk~lamino, 2~hydroxyethylamino, 2-alkoxyethyl-amino or 2- (dialkylamino) ethylamino.
(d) Alkylation, allylation or alkynylation of a compound of the invention in which R8 is hydrogen to give a compound in which ~8 is alkyl, allyl or propargyl. The alkylation~ allylation or alkyrlylation may be ef:Eected by, for example, reacting an alkali metal ~alt of the compound with an alkyl, allyl or pro-pargyl halide.
(e) Co~version of a basic compound of the invention i~to its pharmaceutically acceptable salt.
Th~ pyrimido-oxazine-diones of formula VII~ represent a compound intermsdiate aspec~ of this invention in that they are useful in production o the ultimate anti-secretory agents.
The pyrimido-oxazine-dio~es present the structural formula:
o N ~0 R~ N 7~o in which R2 is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon at~ms,~phenyl, 4-methoxyphenyl, 4-chlorophenyl9 l-pyrrolidinyl or methylphenylamino;
and R8 is hydroge~, alkyl of 1 to 6 carbon atoms, 2-alkoxy-~ ethyl of 3 to 6 carbon atoms, allyl, proparg~l, phenylg 4-me~hoxyphenyl, 4-chlorophenyl, benzyl, 4-methoxybe~zyl, 4-chlorobenzyl, 4-(4-morpholinyl)-phenyl or piperonyl.
The 5-chloro-pyrido-pyrimidines of formula IV con-stitute an additional compound intermediate aspect of the in-_ g _ ~ 7 5 vention in that they are useful in the production of anti-secretory agents containing an amino substituent in 5-position~
The 5-chloropyrido-pyrimidine intermediates present the struc-tural formula: Cl N~coR6
2 f ~T ~N ~
in which R is hydrogen, hydroxy, alkyl of 1 to 6 carbon atom~, alkythio of 1 to 6 carbon. atoms, phenyl, 4-methoxy-phenyl, 4-chlorophenyl, pyrrolidinyl or phen~lmethyl-amino;
R6 is alkoxy o~ 1 to 6 carbon atoms;
and R8 is hydrogen, alkyl of 1 to 6 carbon atoms, 2-alkoxy-ethyl of 3 to 6 carbon atoms, allyl, propargyl, phenyl, 4-methoxyphenyl, 4-chlorophenyl, ben~yl, 4-methoxy-benzyl, 4~chlorobenzyl, 4-(4-morpholinyl~-phenyl or piperonylO
An additional compound intermediate aspect of this in-vention resides in the 2-alkylsulpho~yl pyrido~pyrimidines use-~ul in the production of anti-secretory agent~ containing an amino or hydroxy substituent in 2-position~ The 2-alkylsul-phonyl pyrido-pyrimidines present the ~tructural formula:
OH
N ~coR6 R12S02 ~ N ~\\0 ~ 7 5 in which R6 is alkoxy of 1 to 6 carbon atom~, amino, mono- or di-alkylamino ~here each alkyl group contains from 1 to 6 carbon atoms, 2 hydroxyethylamino, 2-alkoxy-ethyl-amino in which each al~yl group contains from 1 to 5 carbon atoms;
s R8 is hydrogen, alk~l of 1 to 6 carbon atoms, 2-alkoxy-eth~l of 3 to 6 carbon atoms, allyl, propargyl, phenyl, 4 methoxyphenyl, 4-chlorophenyl, benzyl, 4-methoxybenzylt 4-chlorobenzyl or pipero~yl;
and R12 is alkyl of 1 to 6 carbon atoms.
me anti-seoretory agent~ of this invention are ac-tive in the ~ollowin:g scienti~ically recogni~ed, standard test for gastric anti-secretory activity:
Male Charles River rats of Sprague-Dawley strain and 190 to 240 grams body weig~t are food deprived for 24 hours with ~ater ad libitum until the test~ Groups of te~ rat~ each are assi~ned to either contro:l or drug treatmentO Pyloric li-gation was performed under ether ane~thesia through a midline laparotomy, and either control vehicle (0.25 methylcellulose3 : or drug i~ control vehi~le was administered intraduodenaIly (i.d.) The rats are sacrificed by C02 asphyxiation four hours after pyloric ligatio~. The stomachs are removed and the gas-tric cvntents emptied into graduated centrifuge tubes. The gas-tri samples are centrifuged for 20 minutes ~nd those ob~iour.ly :
contaminated by food, blood or feces are discarded. ~le volume of gastric fluid is recorded and the acid conce~tration of 1~0 milliliter sample aliquots i~ measured by electrometric titration to p~ 7.0 with Ool N NaOH. The ca~culated product of gastric volume (ml/4 hr) and acid concentration (mEq/L) estimates the total acid output (TAO,mEq/4 hr);o~er the four hour test period.
An analysis of variance is performed on these data to determine statistically significant (p<0.05~ deviation between control ver~
sus drug-treated groups.
4~75 Those compo~ds indicated above to be anti-allergy agents ha~e demonstrated ability to reli~ve allergic manifes~
tations when administered intraperitoneally to sensitiz~d rats~ Several of the compo~nds tested were found to be effee-tive anti-aller~y agents when administered orally to tha sensi-tized animal~.
The technique employed to establish the anti-allergic actîvity of the disclosed compounds is reported in Immunology, vol. 16~ 749-760 (1960) and involves four male Charles River rats (200-250 grams body weight) per group to provide a con-trol9 a host for administration of a standard anti-allergic compound (disodium cromoglycate~ and animals for the test com-pound. The rats were injected intracutaneously on their shaved backs with sera from rats immuni~ed with egg albumin and per-tussis vaccine, Twenty-four hours after the initial i~Jections, the test compound is administered intraperitoneally or orally at a dosage level of 200 milligrams per kilogram host body weight.
Five minutes later (u~les~ otherwise indicated) one milliliter of a 0.5 per ce~t solution of Evans blue dye and 8 milligrams of egg albumin is injected intravenously. After forty minutes, the animal is sacrificed and the bleb si~e on its back is measured.
The mean bleb size for the animals administered the test compound is calculated and the per cent inhibition is determi~ed by com-Farison with the control animal.
Thus, the compounds disclosed herein are useful in the treatment of peptic ulcer disease and/or for symptomatic relief of atopic immediate hypersensitivity reactions. ~here the two conditions occur simultaneously in the same patient, the com-po~ds of this inventîon hold out the decided advarltage of single ~ 7 5 compound tllerapeutic administration for both problems. Where the conditions occur separately, the second acti~ity of the compounds is either ~lconsequential, as treatment of a non-sensitized animal with an anti-allergy agent, or of no deleter-ious effect that would be contradicative of applicability of the treatment, as a decrease in total gastric acid output in an allergic animal does not preclude prophylactic treatment of the allergy~ For either use, the dosage regimen will vary with the mode of administration~ size and ag~ of the subject treated as well as the severity of the dysfunctionO ThuS9 administra-ti~n of the compounds of this invention should be under the guidance and i~struction of a physician, or in the case o~ treat-ment of domestic animals, a veterinarian.
The compounds of this invention may be administered by conventional oral or par~nteral routes as solids, liquids or nubulised suspensions. Conventional adjuvants known to the art may be combined with the anti-secretory, anti allergy agents of this in~ention to provide compositions and solutions for admin-~ istrative purposes, although it is considered desirable an~
; 20 feasible ~o use neat or pure compounds without additives otherthan for the purpose of providing suitable pharmaceutically acceptable solution or liquid or vapour suspensions. Toward that end, those compounds ~hich contain a basic amino substit-uent may~lbe con~erted to pharmaceutically acceptable salts with such acids as hydrochloric, hydrobromic7 sulphuric, phosphoric, methane sulphonic, nitric, p-toluene sulphonic, acetic, citric, maleic, SUCGiniC acid~ and the like.
~ i7~
The following examples are presented -to illustrate the production of representative compounds of this invention.
After each example, the ~nti-~ecretory activit~ expr~ssed as the percent inhibition of gastric total ~cid output at a dose of 32 milligrams per kilogram intraduodenal (i.d.~ i~ presente~
for the exemplified compound~ Likewise, the anti-allergy activ~
ity expressed as the percent inhibition of allergic response at the sta~ed dose and route of administration, either intra-peritoneal (i.p.) or oral (p.o.~, is given for the exemplified lQ compound where applicable~
EXA~LE 1 8 Ethyl-7~8-dihydro-5-hFdroxy-7-oxo-2-phenylpyrido~2,3-d]pyrimi _ dine-6-carb~yxylic acid ethyl ester _ _ A solution of ethylamine gas (3.6 g. - ~04 mole) in cold ethanol was prepared and ~o this was added 2~2 gO (.02 mole) of Na2C03, followed by 10 g. (.04 mole) o 4-chloro-2-phenyl-5-pyrimidine carboxylic acid ethyl ester. This was stirred i~ a stoppered flask overnight at room ~emperature. Then it was re-fluxed for one hour and filtered. The filtrate was strip~ed to dryness and scratched until crude solid began to form~ mis solid was recrystalli~ed from hexane to give 6.0 g. of ~ethyl-amino-2-phenyl-5-pyrimidine carboxylic acid ethyl ester m. p.
4~-48 C.
o C15H1 ~ 32 C, 66.40; ~, 6~32; N~ 15 49 . : Found: C~ 66.24; H, 6.15; N, 15.37.
To 9.2 g. (~034 mole) of 4-ethylamino-2-phenyl-5~
pyrimidine-carboxylic acid ethyl ester in diethyl ether was add-ed to 2~6 g. (0.17 mole) of ethyl malonyl chloride and then ~ '75 stirred 3 hours at room temperature. The reaction was then fil-tered and the filtrate stripped to dryness. Thi8 residue was dissolved in ethanol and added to a solution of 0.78 g, of so-dium (.034 mole) i~ ethanol ~nd stirr~d at room temperature for 10 minutes. Acidification with acetic acid followed by the slow addition of water resulted in th~ formation of a precipitate.
The crude product was removed by filtration ~nd recrystallized from hexa~e m.p~ 175-177 C - to give 1.0 g. of the title productO
Anal. Calcd. for Cl ~ 1 ~ 34: C, 63.71; H, 5.05; N, 12~38 Found: C, 63.49; E, 5.12; N, 12.03 A~ti secretory - 45/0 ~nti-allergy - 99%; 50 mg/kg. p.o.
~ 2 8-Ethyl-7,8-dihydro-5-hydrox~-7-oxo-2-phenylpyrido[2,3-d~pyrimi~
di~e-6-carbox lic acid eth~l ester A solution of 20% NaOH (120 ml.) was added .~..2~.,A g..
(.09 mole) of 4-ethylamino-2-phe~yl-5-pyrimidi~e carboxylic acid ethyl ester ~prepared as in the ~irst paragraph of Example 1) and was heated~ 15 ml. of ethanol was added for solubility and this was refluxed 3 hours. When cooled and acidified with dilute acetic acid, a white solid ormed which was collected on a fil-ter and rinsed with 400~ml. of ethanol to give 18.4 g. of ~-ethyl-ami~o-2-phenyl-5-pyrimidine carboxylic acid. The compound was used directly in the next step without further purification, mOp~ 262-264 C (dec).
AnalO calcd. for C13H13N3~2: C, 64.18 ~ H~ 5. 38; N ~ 17~ 27 Found- C, 63.95; H, 5.05; N, 17.11 4~S
A mixture of 200 ml. of ethyl chloroformate and 50 ml.
of xylene was added tv 18.4 g. (.076 mole) of 4-ethylamino-2-phenyl-5-pyrimidine carboxylic acid and refluxed 27 hours. Th~
reaction was then cooled and yielded 9 gO of l-ethyl-7-phenyl-2H-pyrimido C4,5-d~ ~1,3~ oxazine-2,4(1H)-dione as a pi~k solid-m.p. 206-211 C. The product was used directly in the next step without further purification Anal. calcd. for C14HllN303: C, 62~44; , 4 2;
F~und: C, 62.06; ~I, 4 15; N, 15.32.
To a 40 ml. solution of NaO~t (1.0 g. Na - .042 mole) was added 6.8 g. (.042 mole~ o~. diethyl malonate and this is stirred 10 minutes, then stripped to dryness. Dimethylformamide was added until a solutio~ formed and to this was added 5.7 g.
(.321 mole) of l~eth~1-7-phenyl-2~-pyrimidoC~,5-d]~lq3~oxa-~i~e 2,4(1H)-dione and the mixture heated at reflux for 2 hour~.
The reaction was then cooled and poured into dilute HCl and the resulting precipitate filtered off and rinsed well with water.
Recrystallization with hexane-ethyl acetate gave 501 g. of the title product - m.p. 177~180~ C.
Anal. calcd. ~or C18H1 ~304: C, 63 71; H, 5.05; N, 12.38 Found: C, 63.47; ~, 5~10; N~ 1 44 Anti-secretory - 45/0 Anti-allergy - 9~/o; 50 mg/kg~ p.o.
8-Ethyl-7,8-dihydro-7-oxo-2~phenyl-5~ pyrrolidinyl~pyridoC2,3 _ -d]-~rimidine-6-carbox~lic ac_d eth~l ester 60 ml. of P~C13 was added to 3~1 g. (.009 mole) of 8 ethyl 7,8 dihydro-5-hydroxy-7-oxo-2-phenylpyrido~293-d]pyrimi-dine-6-carboxylic acid ethyl ester (prepared by the method of ~ 7 S
Example 1~ and this was refluxed 5 hours. The POC13 was then removed vi~ a rotary evaporator and the residue was added to ice water. An off-white solid formed and was recrystallized from ethyl acetate to give 3 g. of 5-chloro-8-ethyl-7,8-dihy-droY7-oxo-2-phenyl-p~rido~2,3-d]pyrimidine-6~carboxylic acid ethyl ester - mOp. 165-168 C.
To 0.7 g. (.002 mole) of 5-chloro-8-ethyl-7,8-dihy-dro-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester in ethanol was added 0.14 g. (.002 mole) of pyr-rolidine and 0.21 (.002 mole~ of sodium carbonate and this mixture was reflw~ed 3 hours. At that point, the solid i~-org~nic material was filtered ~nd the filtrate allowed to stand several days. Pale yellow crystals of the title compo~d formed which were removed by ~iltration - m.p~ 149-153 C~
o C24H22~403: C~ 67O33; ~I, 6~16; N, 14 28 Found. C, 66.97j E, 5.93; N, 14~16 Anti-secretory - 71%
7,8-dihydro-8-ethyl-5-morpholino-7-oxo-2-phenylpyrido[2,3-d]-_ _p~r Four grams (.011 mole3 of 5-chloro-7,8-dihydro-8-ethyl-7~oxo-2-phenyl-pyridoC2,3-d]pyrimidine-&-carboxylic acid ethyl ester ~prepared ~y the me-thod of Example 3, first para-graph~ 0.97 g. (.011 mole) of morpholine and 1.2 g. (.011 mole) o Na2C03 were combined in 125 ml. of ethanol and heated at re-flux for 4 hours. After heating, the reaction mixture was fil-tere~ and the filtrate chilled in ice. An orange solid formed ~hich was collected on ~ filter. Recr~stallization from tha~ol gave 3.9 g. o product - m.p. 195-197 C.
9L'75 ~nal. calc,d. ~or C2~24N~04: C, 64.69; H, 5.92; Nq 13.72 Found: C, 64~42; H, 6.21; N, 13.81 Anti-allergy - l~/o; 25 mg/kg. p~o.
EX~LE 5 7,8-dihydro-8-ethyl-5-(4-methyl-1-piperazinyl)-7-oxo-2-phenyl~
pyridoC2,3-d]pyrimi_ine-6-carbo~lic acid eth~l ester To 0.9 g. (.0025 mole) of 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic a¢id ethyl :
ester (prepared by the metho~ of Example 3~ first paragraph) and 0.25 g. (.0025 mole) of N-methyl piperazine in 40 ml. of ethanol was added 0.27 g~ (~0025 mole) of Na2C03. r~he reaction mix~ure wa~ refluxed for 3 hour3 after which time it was fil~
t~red ~nd chilled in ice. The resulting precipitate was re-moved by filtration, and rinsed with diethyl ether, giving 0.7 g. of solid m.p~ 180-185 C0 Anal. cal~d~ for C23H2 ~ 503: C, 6S 3, ` Found: C,. 65.61; H~ 6.58; N9 16.59 Anti-seeretory - 38%
EXAMP~E 6 5-diethylamino-7,8-dihydro-8-~thyl-7-oxo-2-phenylpyrido[2,3-d~-~ lmidine-6-carboxylic acid eth~l ester Two grams (.0056 mole) of 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyridoC2,3-d]pyrimidine-6-carboxylic acid ethyl ester ~prepared by the method of Example 3, first paragraph) and 0.82 g. (.011 mole) of diethylamine were added together in ethanol in an autoclave and heated on a steam bath for 2 hours.
The reaetion mixture was then filtered and the filtrats chilled 4~Si in ice. The precipitate which formed was collected on a suc-tion filter. Recrystallizatio~ from ethyl acetate gave 0.8 g~
of product m.p. 110-115 C.
Anal- calcd- for ~22H26N43 C, 66-9~ 6-64; N~ 14-20 Found: C, 66~69; H~ 6.74; N, 14Olg Anti-secretory 29%
Anti-allergy - 3~%; 10 mg/kg i.p.
7~8-dihydro-5~hydroxy-7-oxo-2-phenyl-8-propylp~rido[2,3-d]pyri _ _ midi e-6-carboxylic acid ethyl ester A mixture of 23.3 g. (0.09 mole) of 4-chloro-2-phenyl-5-pyrimidine carboxylic acid ethyl ester and 10.5 g. (.18 mole) of propylamine in 700 mlc of ethanol was refluxed for 3 hours.
Then the volume wa~ concentrated to 100 ml. and chilled~ A
white solid formed and was filtered off and rinsed wit~ petrol-eum ether to give 22.4 gD of 4-prop~lami~o-2-ph~nyl-5-pyrimi-dine carboxylic acid ethyl ester - m.pO 45-46 C.
To 17~3 g. (oO6 mole) of 4-propylamino-2-phenyl-5-car-boxylic acid ethyl ester in diethyl ether was added 4.6 g.
(O03 mole) of ethyl malonyl chlor~de and then ætirred 3 1/2 hours at room temperature. The reaction wa~ then filtered and the filtrate stripped to dryness. The residue was dissolved in ethanol a~d added to a solution of 1.4 g. (.06 mole) of sod-ium in ethanol and stirred 15 minutes at room temperature.
Water and a little ethanol was added to form a clear solution which was then acidified with ~Cl carefully to precipitate the title compound~ The cr~de prolluct was filtered and recrystal-lized from ethyl acetate to give 0.6 g. of solid with the m.p.
162-1~4~ C.
Anal. calcd. for ClgHl ~ 304: C, 64~58; ~, 5.42; N, 11.89 found: C, 64.57; H~ 5.32; N, 11.97 Anti-secretory - 69Yo.
Anti-allergy - 7~/o; 10 mg/kg p.o.
7,8-dihydro-5-hydroxy-7-oxo-2-phenyl-8-propylpyrido~2,3-d]-_ _ p~r~midine-6-car oxyli~_aeid ethyl ester _ _ _ _ 60 ml. of 2~/o NaOH was added to 908 g. (.0~4 mole) of 4-propylamino-2-phenyl-S-pyrimidine carboxylic acid ethyl ester (prepared as in paragraph 1 of Example 7) and refluxed
in which R is hydrogen, hydroxy, alkyl of 1 to 6 carbon atom~, alkythio of 1 to 6 carbon. atoms, phenyl, 4-methoxy-phenyl, 4-chlorophenyl, pyrrolidinyl or phen~lmethyl-amino;
R6 is alkoxy o~ 1 to 6 carbon atoms;
and R8 is hydrogen, alkyl of 1 to 6 carbon atoms, 2-alkoxy-ethyl of 3 to 6 carbon atoms, allyl, propargyl, phenyl, 4-methoxyphenyl, 4-chlorophenyl, ben~yl, 4-methoxy-benzyl, 4~chlorobenzyl, 4-(4-morpholinyl~-phenyl or piperonylO
An additional compound intermediate aspect of this in-vention resides in the 2-alkylsulpho~yl pyrido~pyrimidines use-~ul in the production of anti-secretory agent~ containing an amino or hydroxy substituent in 2-position~ The 2-alkylsul-phonyl pyrido-pyrimidines present the ~tructural formula:
OH
N ~coR6 R12S02 ~ N ~\\0 ~ 7 5 in which R6 is alkoxy of 1 to 6 carbon atom~, amino, mono- or di-alkylamino ~here each alkyl group contains from 1 to 6 carbon atoms, 2 hydroxyethylamino, 2-alkoxy-ethyl-amino in which each al~yl group contains from 1 to 5 carbon atoms;
s R8 is hydrogen, alk~l of 1 to 6 carbon atoms, 2-alkoxy-eth~l of 3 to 6 carbon atoms, allyl, propargyl, phenyl, 4 methoxyphenyl, 4-chlorophenyl, benzyl, 4-methoxybenzylt 4-chlorobenzyl or pipero~yl;
and R12 is alkyl of 1 to 6 carbon atoms.
me anti-seoretory agent~ of this invention are ac-tive in the ~ollowin:g scienti~ically recogni~ed, standard test for gastric anti-secretory activity:
Male Charles River rats of Sprague-Dawley strain and 190 to 240 grams body weig~t are food deprived for 24 hours with ~ater ad libitum until the test~ Groups of te~ rat~ each are assi~ned to either contro:l or drug treatmentO Pyloric li-gation was performed under ether ane~thesia through a midline laparotomy, and either control vehicle (0.25 methylcellulose3 : or drug i~ control vehi~le was administered intraduodenaIly (i.d.) The rats are sacrificed by C02 asphyxiation four hours after pyloric ligatio~. The stomachs are removed and the gas-tric cvntents emptied into graduated centrifuge tubes. The gas-tri samples are centrifuged for 20 minutes ~nd those ob~iour.ly :
contaminated by food, blood or feces are discarded. ~le volume of gastric fluid is recorded and the acid conce~tration of 1~0 milliliter sample aliquots i~ measured by electrometric titration to p~ 7.0 with Ool N NaOH. The ca~culated product of gastric volume (ml/4 hr) and acid concentration (mEq/L) estimates the total acid output (TAO,mEq/4 hr);o~er the four hour test period.
An analysis of variance is performed on these data to determine statistically significant (p<0.05~ deviation between control ver~
sus drug-treated groups.
4~75 Those compo~ds indicated above to be anti-allergy agents ha~e demonstrated ability to reli~ve allergic manifes~
tations when administered intraperitoneally to sensitiz~d rats~ Several of the compo~nds tested were found to be effee-tive anti-aller~y agents when administered orally to tha sensi-tized animal~.
The technique employed to establish the anti-allergic actîvity of the disclosed compounds is reported in Immunology, vol. 16~ 749-760 (1960) and involves four male Charles River rats (200-250 grams body weight) per group to provide a con-trol9 a host for administration of a standard anti-allergic compound (disodium cromoglycate~ and animals for the test com-pound. The rats were injected intracutaneously on their shaved backs with sera from rats immuni~ed with egg albumin and per-tussis vaccine, Twenty-four hours after the initial i~Jections, the test compound is administered intraperitoneally or orally at a dosage level of 200 milligrams per kilogram host body weight.
Five minutes later (u~les~ otherwise indicated) one milliliter of a 0.5 per ce~t solution of Evans blue dye and 8 milligrams of egg albumin is injected intravenously. After forty minutes, the animal is sacrificed and the bleb si~e on its back is measured.
The mean bleb size for the animals administered the test compound is calculated and the per cent inhibition is determi~ed by com-Farison with the control animal.
Thus, the compounds disclosed herein are useful in the treatment of peptic ulcer disease and/or for symptomatic relief of atopic immediate hypersensitivity reactions. ~here the two conditions occur simultaneously in the same patient, the com-po~ds of this inventîon hold out the decided advarltage of single ~ 7 5 compound tllerapeutic administration for both problems. Where the conditions occur separately, the second acti~ity of the compounds is either ~lconsequential, as treatment of a non-sensitized animal with an anti-allergy agent, or of no deleter-ious effect that would be contradicative of applicability of the treatment, as a decrease in total gastric acid output in an allergic animal does not preclude prophylactic treatment of the allergy~ For either use, the dosage regimen will vary with the mode of administration~ size and ag~ of the subject treated as well as the severity of the dysfunctionO ThuS9 administra-ti~n of the compounds of this invention should be under the guidance and i~struction of a physician, or in the case o~ treat-ment of domestic animals, a veterinarian.
The compounds of this invention may be administered by conventional oral or par~nteral routes as solids, liquids or nubulised suspensions. Conventional adjuvants known to the art may be combined with the anti-secretory, anti allergy agents of this in~ention to provide compositions and solutions for admin-~ istrative purposes, although it is considered desirable an~
; 20 feasible ~o use neat or pure compounds without additives otherthan for the purpose of providing suitable pharmaceutically acceptable solution or liquid or vapour suspensions. Toward that end, those compounds ~hich contain a basic amino substit-uent may~lbe con~erted to pharmaceutically acceptable salts with such acids as hydrochloric, hydrobromic7 sulphuric, phosphoric, methane sulphonic, nitric, p-toluene sulphonic, acetic, citric, maleic, SUCGiniC acid~ and the like.
~ i7~
The following examples are presented -to illustrate the production of representative compounds of this invention.
After each example, the ~nti-~ecretory activit~ expr~ssed as the percent inhibition of gastric total ~cid output at a dose of 32 milligrams per kilogram intraduodenal (i.d.~ i~ presente~
for the exemplified compound~ Likewise, the anti-allergy activ~
ity expressed as the percent inhibition of allergic response at the sta~ed dose and route of administration, either intra-peritoneal (i.p.) or oral (p.o.~, is given for the exemplified lQ compound where applicable~
EXA~LE 1 8 Ethyl-7~8-dihydro-5-hFdroxy-7-oxo-2-phenylpyrido~2,3-d]pyrimi _ dine-6-carb~yxylic acid ethyl ester _ _ A solution of ethylamine gas (3.6 g. - ~04 mole) in cold ethanol was prepared and ~o this was added 2~2 gO (.02 mole) of Na2C03, followed by 10 g. (.04 mole) o 4-chloro-2-phenyl-5-pyrimidine carboxylic acid ethyl ester. This was stirred i~ a stoppered flask overnight at room ~emperature. Then it was re-fluxed for one hour and filtered. The filtrate was strip~ed to dryness and scratched until crude solid began to form~ mis solid was recrystalli~ed from hexane to give 6.0 g. of ~ethyl-amino-2-phenyl-5-pyrimidine carboxylic acid ethyl ester m. p.
4~-48 C.
o C15H1 ~ 32 C, 66.40; ~, 6~32; N~ 15 49 . : Found: C~ 66.24; H, 6.15; N, 15.37.
To 9.2 g. (~034 mole) of 4-ethylamino-2-phenyl-5~
pyrimidine-carboxylic acid ethyl ester in diethyl ether was add-ed to 2~6 g. (0.17 mole) of ethyl malonyl chloride and then ~ '75 stirred 3 hours at room temperature. The reaction was then fil-tered and the filtrate stripped to dryness. Thi8 residue was dissolved in ethanol and added to a solution of 0.78 g, of so-dium (.034 mole) i~ ethanol ~nd stirr~d at room temperature for 10 minutes. Acidification with acetic acid followed by the slow addition of water resulted in th~ formation of a precipitate.
The crude product was removed by filtration ~nd recrystallized from hexa~e m.p~ 175-177 C - to give 1.0 g. of the title productO
Anal. Calcd. for Cl ~ 1 ~ 34: C, 63.71; H, 5.05; N, 12~38 Found: C, 63.49; E, 5.12; N, 12.03 A~ti secretory - 45/0 ~nti-allergy - 99%; 50 mg/kg. p.o.
~ 2 8-Ethyl-7,8-dihydro-5-hydrox~-7-oxo-2-phenylpyrido[2,3-d~pyrimi~
di~e-6-carbox lic acid eth~l ester A solution of 20% NaOH (120 ml.) was added .~..2~.,A g..
(.09 mole) of 4-ethylamino-2-phe~yl-5-pyrimidi~e carboxylic acid ethyl ester ~prepared as in the ~irst paragraph of Example 1) and was heated~ 15 ml. of ethanol was added for solubility and this was refluxed 3 hours. When cooled and acidified with dilute acetic acid, a white solid ormed which was collected on a fil-ter and rinsed with 400~ml. of ethanol to give 18.4 g. of ~-ethyl-ami~o-2-phenyl-5-pyrimidine carboxylic acid. The compound was used directly in the next step without further purification, mOp~ 262-264 C (dec).
AnalO calcd. for C13H13N3~2: C, 64.18 ~ H~ 5. 38; N ~ 17~ 27 Found- C, 63.95; H, 5.05; N, 17.11 4~S
A mixture of 200 ml. of ethyl chloroformate and 50 ml.
of xylene was added tv 18.4 g. (.076 mole) of 4-ethylamino-2-phenyl-5-pyrimidine carboxylic acid and refluxed 27 hours. Th~
reaction was then cooled and yielded 9 gO of l-ethyl-7-phenyl-2H-pyrimido C4,5-d~ ~1,3~ oxazine-2,4(1H)-dione as a pi~k solid-m.p. 206-211 C. The product was used directly in the next step without further purification Anal. calcd. for C14HllN303: C, 62~44; , 4 2;
F~und: C, 62.06; ~I, 4 15; N, 15.32.
To a 40 ml. solution of NaO~t (1.0 g. Na - .042 mole) was added 6.8 g. (.042 mole~ o~. diethyl malonate and this is stirred 10 minutes, then stripped to dryness. Dimethylformamide was added until a solutio~ formed and to this was added 5.7 g.
(.321 mole) of l~eth~1-7-phenyl-2~-pyrimidoC~,5-d]~lq3~oxa-~i~e 2,4(1H)-dione and the mixture heated at reflux for 2 hour~.
The reaction was then cooled and poured into dilute HCl and the resulting precipitate filtered off and rinsed well with water.
Recrystallization with hexane-ethyl acetate gave 501 g. of the title product - m.p. 177~180~ C.
Anal. calcd. ~or C18H1 ~304: C, 63 71; H, 5.05; N, 12.38 Found: C, 63.47; ~, 5~10; N~ 1 44 Anti-secretory - 45/0 Anti-allergy - 9~/o; 50 mg/kg~ p.o.
8-Ethyl-7,8-dihydro-7-oxo-2~phenyl-5~ pyrrolidinyl~pyridoC2,3 _ -d]-~rimidine-6-carbox~lic ac_d eth~l ester 60 ml. of P~C13 was added to 3~1 g. (.009 mole) of 8 ethyl 7,8 dihydro-5-hydroxy-7-oxo-2-phenylpyrido~293-d]pyrimi-dine-6-carboxylic acid ethyl ester (prepared by the method of ~ 7 S
Example 1~ and this was refluxed 5 hours. The POC13 was then removed vi~ a rotary evaporator and the residue was added to ice water. An off-white solid formed and was recrystallized from ethyl acetate to give 3 g. of 5-chloro-8-ethyl-7,8-dihy-droY7-oxo-2-phenyl-p~rido~2,3-d]pyrimidine-6~carboxylic acid ethyl ester - mOp. 165-168 C.
To 0.7 g. (.002 mole) of 5-chloro-8-ethyl-7,8-dihy-dro-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester in ethanol was added 0.14 g. (.002 mole) of pyr-rolidine and 0.21 (.002 mole~ of sodium carbonate and this mixture was reflw~ed 3 hours. At that point, the solid i~-org~nic material was filtered ~nd the filtrate allowed to stand several days. Pale yellow crystals of the title compo~d formed which were removed by ~iltration - m.p~ 149-153 C~
o C24H22~403: C~ 67O33; ~I, 6~16; N, 14 28 Found. C, 66.97j E, 5.93; N, 14~16 Anti-secretory - 71%
7,8-dihydro-8-ethyl-5-morpholino-7-oxo-2-phenylpyrido[2,3-d]-_ _p~r Four grams (.011 mole3 of 5-chloro-7,8-dihydro-8-ethyl-7~oxo-2-phenyl-pyridoC2,3-d]pyrimidine-&-carboxylic acid ethyl ester ~prepared ~y the me-thod of Example 3, first para-graph~ 0.97 g. (.011 mole) of morpholine and 1.2 g. (.011 mole) o Na2C03 were combined in 125 ml. of ethanol and heated at re-flux for 4 hours. After heating, the reaction mixture was fil-tere~ and the filtrate chilled in ice. An orange solid formed ~hich was collected on ~ filter. Recr~stallization from tha~ol gave 3.9 g. o product - m.p. 195-197 C.
9L'75 ~nal. calc,d. ~or C2~24N~04: C, 64.69; H, 5.92; Nq 13.72 Found: C, 64~42; H, 6.21; N, 13.81 Anti-allergy - l~/o; 25 mg/kg. p~o.
EX~LE 5 7,8-dihydro-8-ethyl-5-(4-methyl-1-piperazinyl)-7-oxo-2-phenyl~
pyridoC2,3-d]pyrimi_ine-6-carbo~lic acid eth~l ester To 0.9 g. (.0025 mole) of 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic a¢id ethyl :
ester (prepared by the metho~ of Example 3~ first paragraph) and 0.25 g. (.0025 mole) of N-methyl piperazine in 40 ml. of ethanol was added 0.27 g~ (~0025 mole) of Na2C03. r~he reaction mix~ure wa~ refluxed for 3 hour3 after which time it was fil~
t~red ~nd chilled in ice. The resulting precipitate was re-moved by filtration, and rinsed with diethyl ether, giving 0.7 g. of solid m.p~ 180-185 C0 Anal. cal~d~ for C23H2 ~ 503: C, 6S 3, ` Found: C,. 65.61; H~ 6.58; N9 16.59 Anti-seeretory - 38%
EXAMP~E 6 5-diethylamino-7,8-dihydro-8-~thyl-7-oxo-2-phenylpyrido[2,3-d~-~ lmidine-6-carboxylic acid eth~l ester Two grams (.0056 mole) of 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyridoC2,3-d]pyrimidine-6-carboxylic acid ethyl ester ~prepared by the method of Example 3, first paragraph) and 0.82 g. (.011 mole) of diethylamine were added together in ethanol in an autoclave and heated on a steam bath for 2 hours.
The reaetion mixture was then filtered and the filtrats chilled 4~Si in ice. The precipitate which formed was collected on a suc-tion filter. Recrystallizatio~ from ethyl acetate gave 0.8 g~
of product m.p. 110-115 C.
Anal- calcd- for ~22H26N43 C, 66-9~ 6-64; N~ 14-20 Found: C, 66~69; H~ 6.74; N, 14Olg Anti-secretory 29%
Anti-allergy - 3~%; 10 mg/kg i.p.
7~8-dihydro-5~hydroxy-7-oxo-2-phenyl-8-propylp~rido[2,3-d]pyri _ _ midi e-6-carboxylic acid ethyl ester A mixture of 23.3 g. (0.09 mole) of 4-chloro-2-phenyl-5-pyrimidine carboxylic acid ethyl ester and 10.5 g. (.18 mole) of propylamine in 700 mlc of ethanol was refluxed for 3 hours.
Then the volume wa~ concentrated to 100 ml. and chilled~ A
white solid formed and was filtered off and rinsed wit~ petrol-eum ether to give 22.4 gD of 4-prop~lami~o-2-ph~nyl-5-pyrimi-dine carboxylic acid ethyl ester - m.pO 45-46 C.
To 17~3 g. (oO6 mole) of 4-propylamino-2-phenyl-5-car-boxylic acid ethyl ester in diethyl ether was added 4.6 g.
(O03 mole) of ethyl malonyl chlor~de and then ætirred 3 1/2 hours at room temperature. The reaction wa~ then filtered and the filtrate stripped to dryness. The residue was dissolved in ethanol a~d added to a solution of 1.4 g. (.06 mole) of sod-ium in ethanol and stirred 15 minutes at room temperature.
Water and a little ethanol was added to form a clear solution which was then acidified with ~Cl carefully to precipitate the title compound~ The cr~de prolluct was filtered and recrystal-lized from ethyl acetate to give 0.6 g. of solid with the m.p.
162-1~4~ C.
Anal. calcd. for ClgHl ~ 304: C, 64~58; ~, 5.42; N, 11.89 found: C, 64.57; H~ 5.32; N, 11.97 Anti-secretory - 69Yo.
Anti-allergy - 7~/o; 10 mg/kg p.o.
7,8-dihydro-5-hydroxy-7-oxo-2-phenyl-8-propylpyrido~2,3-d]-_ _ p~r~midine-6-car oxyli~_aeid ethyl ester _ _ _ _ 60 ml. of 2~/o NaOH was added to 908 g. (.0~4 mole) of 4-propylamino-2-phenyl-S-pyrimidine carboxylic acid ethyl ester (prepared as in paragraph 1 of Example 7) and refluxed
3.5 hours. The cooled reaction was acidified with dilute acetic acid and a whit~ solid was iltered off. This product wa~ re-crystallized from ethanol m.p. 228-230C. (dec.). There was obtain~d 6.5 g. of 4-propylamino-2-phenyl-5-pyrlmidine carboxy-lic acid which was used directly in the next step without fur-ther purification.
: To 100 ml. of ethyl chloroformate and 25 ml. of xy-lene was added 6.3 g. (.024 mole) of 4-propylamino-2-phenyl- 5-pyrimidin~ carboxylic acid and refluxed 20 hours. Upon cooling and scra~ching a yel~ow solid formed which was filtered and rinsed with petroleum ether to give 1.15 g. of 1-propyl-7-. phenyl-Z~-pyrimido~4,5-d]~1,3]oxazine-2,4(1H)-dione - m.p. 179-.. 181C. ~he product was used in the next step without further purification.
Anal. calcd. for C15H1 ~ 303: C, 63~60; H, 4.62; N, 14.83 found: C, 63.58; H, 4.64; N, 14.59 50 ml. of NaOEt (0.24 g. - .011 mole) wa~ added to 1.7 g. (.011 mole) to ethyl malonate and stirred 10 minutes, then evaporated to dryness. DMF was added until a solution '7~
formed and 1.5 g~ (.005 mole) of 7-phenyl-1-propyl-2H~pyrimido-[4,5-d]~1,3]o;azine-2~4(1H)-dione was added and the mixture re-fluxed 2 hours. The chilled reaction was poured into dilute HCl and the resul~ing precipitate filtered off and rinsed with water.
Recrystallization from ethyl acetate gave 1.5 g. o the title compound - m.p. 164-167C~
Anal. calcd. for ClgHlgN304: C, 64~58; H, 5.42; N~ 11.89 Found: C, 64.62; H, 5.37; N, 11.94 Anti-secretory -6gYo Anti allergy - 7~/~; 10 mg/kg p.o.
EXAMPLE ~
7~8-dihydro-5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido-C2,3-d]Pyrimidine-6-carboxylic acid ethyl ester A mixture of 15.5 g. (.059 mole) of 4-chloro-2-phenyl~
5-pyrimidine carboxylic aeid ethyl ester and 8.9 g. (.118 mole~
of 2-methoxyethylamine in 500 ml. of ethanol was refluxed 4.5 hours. The solution was then concentrated to 100 ml. and chill-ed. ~ ~lite solid formed and was filtered off and rinsed with ethanol to give 14.2 g. of 4-~2-methoxyethylamino)-2 phenyl-5-pyrimidine carboxylic acid ethyl ester with - m~p. 67-74C.
Product was used in the next step wqthout further purification.
C16HlgN303: C, 63~77; H, 6.36; N, 13 94 Found: C, 63.60; H, 6.44; N, 13.89 To 14. g. (.047 mole) of 4-(2-methoxyethylamino)-2-phenyl-5-xarboxylic acid ethyl ester in ether was added 3.53 g. (.024 mole) of ethyl malonyl chloride and then this mixture was stirred at room temperature for 4 hours. The reaction was filtered and the filtrate stripped to dryness. The residue was dissolved in ethanol and added to a solution of 1,08 g. (,047 mole) of sodium in ethanol and stirred 20 minu-tes at room temperature. A little water and ethanol was added and the mixture was acidified with dilute HCl. After chilling the solution in ice, a white solid was formed which was filtered~
rinsed with water and dried in a vacuum oven to give 045 g, of a solid with the m,p. 166-168C, ClgHl ~ 305: C, 61.78; H, 5-18; N 11 38 Found: C3 61~67; H, ~.40; N, 11~04 An~i-secretory - 75Yo Anti-allergy - 10~/o; 100 mg/kg i.p.
7,8-dihydro-5-hyaroxy-8 (2-methoxyethyl)-7-oxo-2-phenylpyrido-[2,3-d]pyrimidine-6-carboxyl-ic acid ethyl ester 60 ml. of 2~/o NaOH and 10 ml. of ethanol was added to ~.3 g. (,024 mole) 4-(2-methoxyethylamino)-2-phenyl-5-pyrimi-dine carboxylic acid ethyl ester ~prepared as in paragraph 1 of Example 9) and refluxed 3 hours, The reaction was then cooled, acidified with dilute acetic acid and filtered to remove the white solid. Rerrystallization from ethanol gave 5.5 g, of 4-(2-methoxyethylamino)-2-phenyl-5-pyrimidine carboxylic acid with m,p, 220-225C.
~nal, calcd. for cl4Hl5~3o3: C~ 6 Found: C~ 61.37; H, 5~48; Nl 15~25 10~ ml, of ethyl chloroformate and 25 ml. of xylene were added to 5.5 g. ~.02 mole) of 4-(2-methoxyethylamino)-2-phenyl-5-pyrimidine carboxylic acid and refluxed 21 hours.
When chilled, the reaction gave up a white solid which was collected by filtration and rinsed with petroleum ether to give 3.2 g. of 1-(2-methoxyethyl)-7-phenyl-2H-pyrimido[4,5-d][1,3]-2,4tl~-dione - m.p~ 172-174C. This compound was used in the next step without urther purification.
Anal calcd. for C15Hl ~ ~0~: C, 60~20; H, 4.38; N, 1~04 Found: C, 60.05; H~ 4.38; N, 13.90 50 ml. of NaOEt (0~5 g~ Na - ~021 mole~ was added to 3~4 g. (.021 mole3 of ethyl malonate and stirred 10 minutes9 then evaporated to dryness. DMF was added until a solution was achie~ed and then 3~2 g. (~011 mole) o 1-(2-methoxyethyl)-7-phenyl-2H-pyrimido~4,5-d~1,3~oxazine-2,4(1~3-dione was added and this mixture refluxed 2 hours. The chilled reaction was poured into dilute HCl and the ensuing precipitate filt~ered off and rinsed with water. Recrystallization from ethyl ace-tate gave 3.5 g. of the title product - m.p. 178-179C.
Anal. calcd~ for ClgHlgN305 C, 61-78; H~ 5-18; N~ 11-38 Found: C, 61090; H, 5.20; N, 11~35 Anti-secretory - 7~/o Antî-allergy - 10~/o; 100 mgJkg i~p.
7,8-dihydro-5-hydrQxy-7-oxo-2-phenyl-8-(2-propenyl)pyrido-C2,3-d]PYrimidine-6-carboxylic acid ethyl ester A mixture of 5 g. ~.019 mole~ of 4-chloro-2-phenyl-5-pyrimidine carboxylic acid ethyl ester and 2.2 g. (.038 mole) of allylamine ir 150 ml. of ethanol was refluxed 3 hours. At this point, the solution was concentrated to 30 ml. and chilledO
A yellow crystalline solid formed and was filtered off tc gi~e
: To 100 ml. of ethyl chloroformate and 25 ml. of xy-lene was added 6.3 g. (.024 mole) of 4-propylamino-2-phenyl- 5-pyrimidin~ carboxylic acid and refluxed 20 hours. Upon cooling and scra~ching a yel~ow solid formed which was filtered and rinsed with petroleum ether to give 1.15 g. of 1-propyl-7-. phenyl-Z~-pyrimido~4,5-d]~1,3]oxazine-2,4(1H)-dione - m.p. 179-.. 181C. ~he product was used in the next step without further purification.
Anal. calcd. for C15H1 ~ 303: C, 63~60; H, 4.62; N, 14.83 found: C, 63.58; H, 4.64; N, 14.59 50 ml. of NaOEt (0.24 g. - .011 mole) wa~ added to 1.7 g. (.011 mole) to ethyl malonate and stirred 10 minutes, then evaporated to dryness. DMF was added until a solution '7~
formed and 1.5 g~ (.005 mole) of 7-phenyl-1-propyl-2H~pyrimido-[4,5-d]~1,3]o;azine-2~4(1H)-dione was added and the mixture re-fluxed 2 hours. The chilled reaction was poured into dilute HCl and the resul~ing precipitate filtered off and rinsed with water.
Recrystallization from ethyl acetate gave 1.5 g. o the title compound - m.p. 164-167C~
Anal. calcd. for ClgHlgN304: C, 64~58; H, 5.42; N~ 11.89 Found: C, 64.62; H, 5.37; N, 11.94 Anti-secretory -6gYo Anti allergy - 7~/~; 10 mg/kg p.o.
EXAMPLE ~
7~8-dihydro-5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido-C2,3-d]Pyrimidine-6-carboxylic acid ethyl ester A mixture of 15.5 g. (.059 mole) of 4-chloro-2-phenyl~
5-pyrimidine carboxylic aeid ethyl ester and 8.9 g. (.118 mole~
of 2-methoxyethylamine in 500 ml. of ethanol was refluxed 4.5 hours. The solution was then concentrated to 100 ml. and chill-ed. ~ ~lite solid formed and was filtered off and rinsed with ethanol to give 14.2 g. of 4-~2-methoxyethylamino)-2 phenyl-5-pyrimidine carboxylic acid ethyl ester with - m~p. 67-74C.
Product was used in the next step wqthout further purification.
C16HlgN303: C, 63~77; H, 6.36; N, 13 94 Found: C, 63.60; H, 6.44; N, 13.89 To 14. g. (.047 mole) of 4-(2-methoxyethylamino)-2-phenyl-5-xarboxylic acid ethyl ester in ether was added 3.53 g. (.024 mole) of ethyl malonyl chloride and then this mixture was stirred at room temperature for 4 hours. The reaction was filtered and the filtrate stripped to dryness. The residue was dissolved in ethanol and added to a solution of 1,08 g. (,047 mole) of sodium in ethanol and stirred 20 minu-tes at room temperature. A little water and ethanol was added and the mixture was acidified with dilute HCl. After chilling the solution in ice, a white solid was formed which was filtered~
rinsed with water and dried in a vacuum oven to give 045 g, of a solid with the m,p. 166-168C, ClgHl ~ 305: C, 61.78; H, 5-18; N 11 38 Found: C3 61~67; H, ~.40; N, 11~04 An~i-secretory - 75Yo Anti-allergy - 10~/o; 100 mg/kg i.p.
7,8-dihydro-5-hyaroxy-8 (2-methoxyethyl)-7-oxo-2-phenylpyrido-[2,3-d]pyrimidine-6-carboxyl-ic acid ethyl ester 60 ml. of 2~/o NaOH and 10 ml. of ethanol was added to ~.3 g. (,024 mole) 4-(2-methoxyethylamino)-2-phenyl-5-pyrimi-dine carboxylic acid ethyl ester ~prepared as in paragraph 1 of Example 9) and refluxed 3 hours, The reaction was then cooled, acidified with dilute acetic acid and filtered to remove the white solid. Rerrystallization from ethanol gave 5.5 g, of 4-(2-methoxyethylamino)-2-phenyl-5-pyrimidine carboxylic acid with m,p, 220-225C.
~nal, calcd. for cl4Hl5~3o3: C~ 6 Found: C~ 61.37; H, 5~48; Nl 15~25 10~ ml, of ethyl chloroformate and 25 ml. of xylene were added to 5.5 g. ~.02 mole) of 4-(2-methoxyethylamino)-2-phenyl-5-pyrimidine carboxylic acid and refluxed 21 hours.
When chilled, the reaction gave up a white solid which was collected by filtration and rinsed with petroleum ether to give 3.2 g. of 1-(2-methoxyethyl)-7-phenyl-2H-pyrimido[4,5-d][1,3]-2,4tl~-dione - m.p~ 172-174C. This compound was used in the next step without urther purification.
Anal calcd. for C15Hl ~ ~0~: C, 60~20; H, 4.38; N, 1~04 Found: C, 60.05; H~ 4.38; N, 13.90 50 ml. of NaOEt (0~5 g~ Na - ~021 mole~ was added to 3~4 g. (.021 mole3 of ethyl malonate and stirred 10 minutes9 then evaporated to dryness. DMF was added until a solution was achie~ed and then 3~2 g. (~011 mole) o 1-(2-methoxyethyl)-7-phenyl-2H-pyrimido~4,5-d~1,3~oxazine-2,4(1~3-dione was added and this mixture refluxed 2 hours. The chilled reaction was poured into dilute HCl and the ensuing precipitate filt~ered off and rinsed with water. Recrystallization from ethyl ace-tate gave 3.5 g. of the title product - m.p. 178-179C.
Anal. calcd~ for ClgHlgN305 C, 61-78; H~ 5-18; N~ 11-38 Found: C, 61090; H, 5.20; N, 11~35 Anti-secretory - 7~/o Antî-allergy - 10~/o; 100 mgJkg i~p.
7,8-dihydro-5-hydrQxy-7-oxo-2-phenyl-8-(2-propenyl)pyrido-C2,3-d]PYrimidine-6-carboxylic acid ethyl ester A mixture of 5 g. ~.019 mole~ of 4-chloro-2-phenyl-5-pyrimidine carboxylic acid ethyl ester and 2.2 g. (.038 mole) of allylamine ir 150 ml. of ethanol was refluxed 3 hours. At this point, the solution was concentrated to 30 ml. and chilledO
A yellow crystalline solid formed and was filtered off tc gi~e
4-(2-propenylamino)-2-phenyl-5-pyrimidine carboxylic acid ethyl ester - m.p. 49-54C. This compound was ~lsed in the next step directly without fur~her purification.
To 16.3 g. (.V57 mole) of 4-(2-propenylamino)-2-phenyl-5-pyrimidine carboxylic acid ethyl ester in diethyl ether s was added 4.3 g. (.029 mole) of ethyl malonyl chloride and then stirred 3 hours at room temperatureO The reaction was then filtered and stripped to dryness and the residue was added to a solution of 1 a3 g~ ( ~037 mole) of Na in ethanol and stirred at room temperature for 10 minutes. Water was added until the reaction became clear and then acidified wi-th HCl. This solution was chilled in ice and the resulting solid was re-moved by fil~ration. Recrystallization rom ethyl acetate gave 0.55 g" of title product with m.p 174-175C.
Anal- ~alcd- for Cl9H17N341/4H20: C, 64~22; H, ~96; ~, 11.81 Found: C, 64.29; H~ 4.78; N, 11.90 Anti-secretory - 68%
Anti-allergy - 8~/o 50 mg/kg i.p.
7,B-dihydro-5-hydroxy-7-oxo- -phenyl-B-(2-propenyl)pyrido-~233-d~pyrimidine-6-carboxylic acid etKyl ester 60 ml. Of 2~to NaOH was added to 5 g. (~018 mole) o 4-~2 propenylamino)-2-phenyl-5-carboxylic acid ethyl ester and refluxed 4.5 hours. The reac~ion wa~ then cooled~ acidified with dilute ace~ic acld and then filtered to remoYe the white solid that had formed. Recrystallization from 95% ethanol gave 4.1 g. of 4-(2-propenylamino)-2-phenyl-5-pyrimidine car-boxylic acid - m.p. 249C. (dec~.
Anal. calcd. for C14H1 ~ 32 Found: C, 65.49; H, 5.20; N, 16.55 100 ml. of ethyl chloroformate and 25 ml. of xylene ~ere added to 4.1 g. ~.016 mole3 of 4-allylamino-2-phenyl-5-pYrimidine carboxylic acid and refluxed overnight. The in-soluble material was removed by filtration. The filtrate was evaporated to dryness. The residue was recrystallized from ethanol to give 1.85 g~ of 7-phenyl-1-(2-propenyl)-~I pyr-imido[4,$-d][173]0xazine-274(1H~-dione - m~p. 188-190C.
Anal~ calcd for Cl ~ llN303-1/2 H20 Found: C, 61.26; ~[~ 4.60; N, 14.08 To a 50 ml. solution of NaOEt (0~3 g. Na - 4013 mole) was added 2.08 g. (~013 mole) of diethyl malonate and this was stirred 10 minutes, then stripped to dryness. ~MF was added to form a svlution and then 1.~5 g. (.0065 mole) of 1-(2-pro-penyl)-7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione was added and heated at reflux for 1.5 hours. When cool, the reaction was poured into dilute ~Cl and the resulting precipi-tate collected on a filter and rinsed ~th water. Recrystalli-zation from ethyl acetate gave 1~0 g. of product - mOp. 177-1~0C
Anal. calcd. or ClgH17N30~: C, 64.9S; ~ 4- ; ~
Found: C, 64.71; H, 4.92; N, 11.89 Anti-secretory - 68%
Anti-allergy -8~/o; 50 mg/kg i.p.
EXA~LE 13 7,8-dihydro-5~hydroxy 7-oxo-2-phenyl-8~benzyl)pyridoC2~3-d]-pyr-imi-ine-6-carboxylic acid ethyl ester _ _ A mixture of 15 g. (.057 mole) of 4-chloro-2-phenyl-
To 16.3 g. (.V57 mole) of 4-(2-propenylamino)-2-phenyl-5-pyrimidine carboxylic acid ethyl ester in diethyl ether s was added 4.3 g. (.029 mole) of ethyl malonyl chloride and then stirred 3 hours at room temperatureO The reaction was then filtered and stripped to dryness and the residue was added to a solution of 1 a3 g~ ( ~037 mole) of Na in ethanol and stirred at room temperature for 10 minutes. Water was added until the reaction became clear and then acidified wi-th HCl. This solution was chilled in ice and the resulting solid was re-moved by fil~ration. Recrystallization rom ethyl acetate gave 0.55 g" of title product with m.p 174-175C.
Anal- ~alcd- for Cl9H17N341/4H20: C, 64~22; H, ~96; ~, 11.81 Found: C, 64.29; H~ 4.78; N, 11.90 Anti-secretory - 68%
Anti-allergy - 8~/o 50 mg/kg i.p.
7,B-dihydro-5-hydroxy-7-oxo- -phenyl-B-(2-propenyl)pyrido-~233-d~pyrimidine-6-carboxylic acid etKyl ester 60 ml. Of 2~to NaOH was added to 5 g. (~018 mole) o 4-~2 propenylamino)-2-phenyl-5-carboxylic acid ethyl ester and refluxed 4.5 hours. The reac~ion wa~ then cooled~ acidified with dilute ace~ic acld and then filtered to remoYe the white solid that had formed. Recrystallization from 95% ethanol gave 4.1 g. of 4-(2-propenylamino)-2-phenyl-5-pyrimidine car-boxylic acid - m.p. 249C. (dec~.
Anal. calcd. for C14H1 ~ 32 Found: C, 65.49; H, 5.20; N, 16.55 100 ml. of ethyl chloroformate and 25 ml. of xylene ~ere added to 4.1 g. ~.016 mole3 of 4-allylamino-2-phenyl-5-pYrimidine carboxylic acid and refluxed overnight. The in-soluble material was removed by filtration. The filtrate was evaporated to dryness. The residue was recrystallized from ethanol to give 1.85 g~ of 7-phenyl-1-(2-propenyl)-~I pyr-imido[4,$-d][173]0xazine-274(1H~-dione - m~p. 188-190C.
Anal~ calcd for Cl ~ llN303-1/2 H20 Found: C, 61.26; ~[~ 4.60; N, 14.08 To a 50 ml. solution of NaOEt (0~3 g. Na - 4013 mole) was added 2.08 g. (~013 mole) of diethyl malonate and this was stirred 10 minutes, then stripped to dryness. ~MF was added to form a svlution and then 1.~5 g. (.0065 mole) of 1-(2-pro-penyl)-7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione was added and heated at reflux for 1.5 hours. When cool, the reaction was poured into dilute ~Cl and the resulting precipi-tate collected on a filter and rinsed ~th water. Recrystalli-zation from ethyl acetate gave 1~0 g. of product - mOp. 177-1~0C
Anal. calcd. or ClgH17N30~: C, 64.9S; ~ 4- ; ~
Found: C, 64.71; H, 4.92; N, 11.89 Anti-secretory - 68%
Anti-allergy -8~/o; 50 mg/kg i.p.
EXA~LE 13 7,8-dihydro-5~hydroxy 7-oxo-2-phenyl-8~benzyl)pyridoC2~3-d]-pyr-imi-ine-6-carboxylic acid ethyl ester _ _ A mixture of 15 g. (.057 mole) of 4-chloro-2-phenyl-
5-pyrimidine carboxylic acid ethyl ester, 6.12 g. (.057 mole) of benzylamine and 3 g. (.029 mole) of Na2C03 in 200 ml. of ethanol was re1uxed 4.5 hours. Then the reaction was cooled and filtered and a precipitate ormed immediately in the filtrate. This solid was recrystallized from ethanol to give 7~
8.3 g. of 4-benzylamino-2-phenyl-5 pyrimidine carboxylic acid ethyl est~r with m.p. 112-115C.
Anal. calcd- for C20Hl ~ 32 Found: C, 71.74; H, 5,71; N, 12059 To 11.0 g. (.033 mole) o 4-benzyla~ino-2-phenyl-S-carboxylic acid ethyl 0ster in diethyl ether was added 2~5 g.
(.016 mole) of ethyl malonyl chloride and then stirred 3 hours at room temperature. The reaction was then filtered and the filtrate stripped to dryness. This residue was then dissol~ed in ethanol to which was then added a solution of ~7~ g~ of sodium (.033 mole) in ethanol. The reaotion mixture was stirred at room temperature for 15 minutes. Acidification via acetic acid and dilution with water caused the formation of a precipi-tate. The crude product was filtered off and recrystallized from hexane to glve 1.4 g. of the title çompvund - m.p~ 230-231C.
Anal. oalcd. or C23HlgN304 C~ 6~
Found: C~ 68~58; H, 4.83; N, 10.50 Ant i-s ecretory - 6~/o Anti-allergy - 6~/o9 100 mg/kg i.p.
7,8-dihydro-5-hydroxy-8-(p-morpholinophenyl)-7-oxo-2-phe~yl-pyrido~2,3-d]pyrimidine-6-carboxylic acid ethyl ester A mixture of 15 g. ~.057 mole) of 4-chloro-2-phenyl-5-pyrimidine carhoxylic acid ethyl ester, 10.2 g. (.057 mole) of p-morpholinoaniline and 3 ~. (.028 mole) of Na2C03 in 400 ml. of ethanol was refluxed for 3 hours. Then the reac-tion ~olution was filtered and the filtrate immediately pre-cipitated 4-(p-morpholinoanilino)-2-phenyl-5-pyrimidine car-boxylic acid ethyl e~ter - m.p~ 173-176C. No further purifi-- 27 ~
cation was done and th~ product used directly in the next st~p.
Anal- calcd- for C2 ~ 2~N403: C, 68-30; H~ 5-98; N~ 13-85 Found: C, 67.99; H, 6.10, N, 13.67 100 ml. of 2~ NaOH, 65 ml. of ethanol and 50 ml.
of water were added to 17.6 g. (.044 mole) of 4-(p-morpholino-anilino)-2-phenyl-5-pyrimidine carboxylic acid ethyl ester and refluxed 4 hours. The reaction mixture wa~ cooled in iee and acidified ~qth acetic acid. The deep orange solid was filtered off. The crude 4-(p-morpholinoanilino~-~-phenyl-5-pyrimidine carboxylic acid was triturated with 8~/o ho$ ethanol and then filtered. There was obtained 9.0 g. of bright yellow solid - m.p. 295C. (dec.~.
Anal. calcd. for C~lH20N403: C, 670 Found: C, 66.83; N, 5.18; N, 14.91 30 ml. of xylene and 120 ml. of ethyl chloroformate were added to 12 gO (.032 mole) of 4-(p-morpholinoanilino~-2-phenyl-5-pyrimidine carboxylic acid and refluxed 72 hours.
Before the third night of reflux~ an additional 100 ml. of ethyl chloroformate and 25 ml. of xylene were added to the reaction. At the end of 72 hours, the reaction was filtered.
The product was collected on a suction filter and rinsed with petroleum ether to give 7 g. of 1-~p-morpholinophenyl)-7-phenyl-2H-pyrimido~4,5-d][1,3]oxazine-2,4(lH)-dione as a bright yellow product - m.p. 268C. (dec.). This material wa~ used directly in the next step without further purification.
50 ml. of NaOEt (0.8 g. Na - .034 mole) was added to 5.45 g. (.034 mole) of ethyl malonate and stirred 10 minu-tes at room temperature, then evaporated to dryness~ Dimethyl-formamide was added until a solution was achieved and to this - 2~ -4'75 was added 6.95 g. (.017 mole~ o~ p-morpholinophenyl)-7-phenyl-2H-pyrimido ~ 4, 5-d] ~1, 3] oxazine-2, 4(lM~ -dione and this mixture refluxed 1.5 hours. The chilled reaction wa~ poured into dilute HCl and the resulting precipitate removed by filtration, rinse~ with water and dried to give 6 g. of crude product. A sample othis was recrystallized from ethyl acetate to ~ive a hemi-hydrate compound with the m.p.
257C. (dec.) Anal. calc~. for C26H24N405 1/2H20 C, 64~85; H~ 5023; N~ 11 67 Found: C, 65 03; H, 5.49; N, ll.SO
7,8-dihydro-5-hydroxy-8-(4-methoxybenzyl)-7-oxo-2-phenyl-pyr i do [ 2,3-d]pyrimidine-6 carboxylic acid ethyl ester A mixture of 11 gl (.042 mole) of 4-chloro 2-phenyl-5-pyrimidine carboxylic acid ethyl ester, 5 7 g. (.042 mole) of p-methoxybenzylamine and 2.2 g. (.021 mole) of Na2C03 in 250 ml. of ethanol was refluxed 3 hours. The reac-tion was then filtered and the filtrate chilled in ice. A
precipitate formed and was filtered off givin~ 10.7 g. of 4-~p-methoxybenzylamino)-2-phenyl-5-pyrimidine carboxylic acid ethyl ester with m p. 105-110C. This compound was usecl in the next step directly without further purification.
Anal. calcd. for C21H21N303: C, 69-4G; ~ u Found: ~, 68.82; H, 5.84; N, 11.50 80 ml. Of 2~/o NaOH and 10 ml. of ethanol were added to 10.7 g. (.029 mole) of 4-(p-methoxybenzylamino)-2-phenyl-5-pyrimidine carboxylic acid ethyl ester and refluxed 3 hours.
The reaction was cooled and acidified with dilute acetic acid and the ensuing white solid filtered off. Trituration with .
~L~Z~47S
95Yo ethanol yielded 8 g. of 4-(p-methoxybenzylamino)-2-phenyl-5-pyrimidine carboxylic acid - m~p~ 263-?66C. (dec.). This compound was used in the next step without further purification, Anal. calcd. for ClgH17N30~: C,68-05; H~ 5-11; N~ 12-53 Found: C, 67.61; N, 5.44; N~ 12.6g 150 ml. of ethyl chloroormate and 30 ml. of xylene were added to 8 g. (.024 m~le) of 4-(4-methoxybenzylamino)-2-pheny~-S-pyrimidine carboxylic acid and ref:luxed 42 hours.
The insoluble product wa~ filtered and rinsed with petroleum ether to give 4.g g. of 1-(4 methoxybenzyl)-7-phenyl-2H-pyrimido~4,5-d]C1,3]oxazine-2,4(1H)-dione as a yellow so:Lid -m.p. 248-253C. The product was used directly in the next step without further purification.
A 50 ml. solution of NaOEt was prepared (0.6 g.
Na - .028 mole) and 4.34 g. (.028 mole) of ethyl malo~ate w~s added to it and stirred 10 minutesO Then this solution was stripped to dryness, dimethylformamide was added to the residue until a solution was again form~d, and then 409 g~
(.014 mole) of 1-(4-methoxybenzyl~-7-phenyl-2H-pyrimido-[4,5-d~1,3]oxazine-2,4(lH)-dione was added and heated to re-flux for 1 1/4 hours. The reaction was then cooled and poured into dilute HCl. The white solid that formed was filtered off and rinsed with water and then with ethanol. R~crystalli-zation ~rom ethyl acetate gave 1.5 g. of the title compound with the m.p. 228-232C.
Anal. calcd. for C24H21N305: C, 66-81;
Found: C, 66.6V; H, 4.88; N, 9.63 Anti-secretory - 5~/o Anti~allergy - 7~/o; 25 mg/kg i.p.
~ 7 S
E~LE 16 _ 7,8-dihydro-2,8-diphenyl-5-hydroxy-7-oxo-pyrido[2,3-d]pyrimi-dine-6-carbo~ c_acid eth~l _ ster _ _ A mixture of 10 gO (,038 mole) of 4-chloro-2-phenyl-5-pyrimidine carboxylic acid ethyl ester antl 7.1 g. (.076 mole) of aniline in 200 ml. of ethanol was refluxed for 3 hours.
Upon cooling a yellow solid precipitated from the solution.
This was filtered off and rinsed with ethanol to give 4-anili-no-2-phenyl-5-pyrimidine carboxylic acid ethyl ester, m.p, 98~100Ca No further purification was done and the product was used directly in the next step~
~nal. calcd. for Clg~l ~ 32 C, 71~45; H, 5~37; N~ 15.16 Found: C, 71.33; H, 5.2~; N; 13.21 60 ml. of 2~/o NaO~ plu~ 20 ml~ of ethanol were added to 10 g. (.031 mole) of 4-anilino-2-phenyl-5-pyrimidine carboxylic acid ethyl e~ter and re~luxed 3 hours. When cooled, a solid precipitate was obtained. The product was then stirred in water, acidified with acetic acid and filtered. Recrystal-lization from 95% EtOH gave 6.3 g. of 4-anilino-2-phenyl--5-pyrimidine carboxylic acid - m.p~ 277-280C.
Anal. Calcd. for C17H13N30~: C, 70.0~; H, 4.50; N, 14.43 Found: C, 69.~2; H, 4.86; N, 14.28 100 ml. of ethyl chloroformate and 40 ml. of xylene were added to 6.3 g~ (.022 mole) of 4-anilino-2-phen~1-5-pyrimidine carboxylic acid and refluxed 27 hours. The in-soluble material was removed by filtration and the filtrate was chilled in ice. The resulting solid was removed by fil-tration and rinsed with petroleum ether to give 1.2 g. of 1,7-diphenyl-2H-pyrimido[4,5-d]~1,3]ox~zine-2,4(1H)-dione -m.p. 252-254C. The material was used in the next step directl~- ~ithout further purification.
or ~18HllN303: C, 68.13; H, 3~50; N 13 24 Found: C, 68.40; H, 3.84; N, 13~6 A 50 ml. solution of sodium ethoxide was pre-pared (0.2 g. Na - O009 mole) and 1.5 g. (O009 mole) of ethyl malonate was added to it and stirred :L0 minutes. Then this solution ~as stripped to dryness, then dimethylformamide was added to the residue until a solution was formed and then 1.5 g. (~005 mole) of 1,7-diphenyl-2H pyrimido~4,5-d]-~,3]oxazine-~,4(1E)-dione was added to this solution and heated to reflux for 2 hours. At the end of this time, the reaction was cooled and poured into dilute HCl. The white solid that formed was removed by filtration, rinsed with water alld recrystallized from ethyl acetate to give 1.15 g.
of the title compound with the m.p. 252C. (dec.~.
Anal~ calcd. for C2~H1 ~ 304: C, 68-21; H~ 4-4 ;
Found- C, 67.92; H, 4.24; N, 10.70 Anti-secretory-64%
Anti_allergy -10~/o; 25 mg/kg i.p.
~ AMPLE 17 5-amino-7,8-dihydro-2-(methylphenylamino3-7-oxopyrido~2,3-d]-_ _E~rimidine-6-carboxylic acid ethyl ester _ _ Sodium (1.15 g~ - .05 g-atom) was dissolved in 350 ml. of ethanol and 9.3 g, (.05 mole) of a-methyl-a-phenyl guanidine HCl was added to this solution and stirred 10 minu-tes. The reaction was filtered to remove NaCl and then 6.1 g. ~.05 mole) of ethoxymethylenemalononitrile was added to the filtrate and this mixture was refluxed for 3 hours. The reaction was chilled in ice ~nd this caused the formation of a white solid - m.p. 188-194C. This crude material was re-crystallized from ethanol to give 5.4 g. of solid 4-amino-2-~methylphenylami~o)-5-pyrimidine-carbonitrile with m~p.
190-195C.
Anal. calcd. for C12HllN5: C, q3098; H, 4.92; N, 31-09 FOuna: c~ 63.89; H, 5.05; N, 31.10 To 10 g. (.044 mole3 of 4-amino-2-~methylphenyl-amino)-5-pyrimidine-carbonitrile in 200 ml~ of tetrahydrofuran was added 6.7 g~ ~.044 mole) o ethyl malonyl chloride and then this mixture was heated at reflux or 2 hoursO The reac-tion was then filtered and the fil~ercake rinsed with tetra-hydrouran. The filtrate was evaporated to dryness on a rotary evaporator. The viscous liquid residue was treated with 50 ml. of 2~/o NaOH and heated to boiling for 5 minutes~
The re~ulting solid was removed by filtration. This solid was slurried in water, acidified with aeetic acid and filtered.
: The crude produet was recrystallized from 95% ethanol to give 1.05 g. of solid with mOp. 297C~ (dec.).
Anal. cal~d. for C~ 53: C; 60-17; H~ 5.05; N~ 20-64 Found: C, 59.87; H, 4,93; N5 20.71 Anti-secretory-25%
7,8-dihydro-5-hydroxy-8-methyl-2-(methylthio)-7-oxo-pyrido-~2~3-d]-pyrimidine-6-carboxylic acid ethyl ester To a mixture of 23.3 g. (0.1 mol~) of 4-chloro-2-methyl-thio-5-pyrimidine carboxylic acid ethyl ester in 150 ml. of ethanol was added 15.5 g. (0.2 mol~) of 4~/o aqueous methylamine. The mixture was ~tirred in an ice bath for 30 ~inutes and ~as filtered. The filter cake was recrystallized from ethanol to give 11 g. of 4-methylamino 2-methylthio-5-pyrimidine carboxylic acid ethyl ester - m.p. 87~89C. (Ref.
E. Peters, et al., J. Org. Chem., 25, 2137 (1960) - m.p. 93-94C.).
To a solution of 4.54 g. (0.02 mole) of 4-methyl-amino-2-methythio-5-pyrimidine carboxylic acid ethyl ester in 100 ml. of anhydrous diethyl ether was added 1.5 g. (0.01 mole3 of ethyl malonyl chloride. The mixture was stirred at room temperature for 1 hour. The mixture wa~ filtered and the filtrate was evaporated in a rotary evaporatorO The residue was triturated with a few mil~ of diethyl ether and was filtered~
The filtrate was evaporated and the residue was dissolved in 10 ml. of ethanolO This solu~ion was added to a solution of 0.37 gO ~0.015 g-atom) of sodium in 20 ml. of ethanol. T~e mixture was stirred at room temperatur~ for IO minutes. The mixture was diluted with water and was acidified with glacial acetic acid. The preeipitate which formed was collected, air dried and was recrystallized-from ethanol to aord 0.4 g.
of title product - m.p~ 166-168C.
for C12H1 ~ 304S: C, 48.80; H, 4.4~, N, 14 23 Found: C, 48.60; H, 4.64; N, 13.89 Anti-secretory - 44%
Anti-allergy - lO~P/o; 10 mg/kg i.p.
7,8-dihydro-5-hydroxy-8-methyl-7-oxo-2-(1 pyrrolidinyl)pyrido-~2,3-d]pyrimidine-6-carboxylic acid ethyl ester To a solution of 2.95 gO (0.01 mole) of 7,8-di-hydro-5-hydroxy~8-methyl-2-(met~ylthio)-7-oxo-pyrido~2 7 3-d]-pyrimidine-6-carboxylic acid ethyl ester (prepared by the method of Example 18) i~ 100 ml. of dichloromethan~ was added a suspension of 4.0 g~ (0.02 mole) of 85~o m - chloroperoxy-benzoic aci~ in 50 ml. of dichloromethane. The mixture was stirred at room temperature for 1 hour. The solution was ex-tracted with 100 ml. of a 2~/o potassium carbonate solution.
The water layer was acidified with glacial acetic acid and was filtered. The filtrate was extracted with 50 ml. of chloroform.
The chloroform layer was dried over magnesium sulfate 7 ~iltered and was evaporated in a rotary evaporator. The residue was re-crystallized from ethanol to afford 1.0 g. of 7,8-dihydro-5-hy-droxy-8-methyl-2-(methylsulfonyl)-7-oxo-pyrido~2,3-d]pyrimi-dine-6-carboxylic acid e$hyl ester - m.p. 184-185C.
Anal- calcd- for C12H13N33S C~ 44-03; H~ 4-00; N~ 12-84 Found: C, 44~41; H, 3.93; N, 12.72 A stirred mixture of 3.27 g. (0.01 mole) of 7,8-di-hydro-5-hydroxy-8-methyl-2-(methylsulonyl)-7-oxo-pyrido[2,3-d]-pyrimidine-6-carboxylic acid ethyl ester and 0.71 g. (0.01 mole) of pyrrolidine in 50 ml. of ethanol was heated under reflux for 1 hour. The mixture was cooled and was filtered. The filter cake was recrystallized twice from ethyl acetate to afford 1.1 g. of title product - m.p. 174-177Co Anal. calcd. for C15Hl~N404: C9 56.59; H~ 5.70; N~ 17.60 Found: C, 56.63; H~ 5~70; N, 17.55 Anti-secretory - 6~/o Anti-allergy - 96%; 10 mg/kg p.o.
-7,8-dihydto-5-hydrox~-2-(methylthio)-7-oxo-8-propylpyrido[2,3-d]-pyrimidine-6-carbox~lic_acid ethyl ester A stirred mixture of 23.3 g. ~0.1 mole) of 4-chloro-2-methylthio-5-pyrimidine carboxylic aeid ethyl ester, 5~9 g~
(0.1 mole) of prop~lamine and 10.6 g. (0.1 mole) of ~odium car-bonate in 150 ml. of ethanol was heated under re~l~ for 3 hours.
The mixture was ~iltered and the filtrate was evaporated in a rotary evaporator~ Theresidue was ~riturated with 100 ml.. of water and was extracted with 100 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evapor-ated in a rotary e~aporator to give a~out 13 g. of 2-methylthio-4-propylamino-5-pyrim;dine carboxylic acid ethyl ester as an oil which wa~ used directly in the next step without further purifi-cation. A small amount of this oil was dissolved in diethyl ether and was acidified with an ethereal hydrochloric acid 901u-tion. The precipitate which formed was collected and wa~ recry-stallized twice from ethyl acetate to af~ord the analytical sam-ple, m.p~ 132-135 ~.
Anal. calcd. for CllH1~ 302fi.HCl. C~ 45.28; ~, 6.22; N~ ~4.40 Fow~d: C, 45~05; H, 6~31; N, 14.3~
To a solution of 12.8 g. (0.05 mole~ of 2--methylthio-4-propylamino-5-pyrimidine carboxylic acid ethyl ester in 100 ml. of anhydrous diethyl ether was added 0.75 g. (0.025 mole) of ethyl malonyl chloride. The mixture was stirred at room temper-ature for 4 hours and was filtered~ me filt~abe was evapora-ted in a rotary e~aporator and the residue was dissolved in 15 ml. of ethanol and this solution was added to a solution of lo 15 go (0~ 05 g atom) of sodium i~ 100 ml. o~ ethanol. After stirring at room temperature for 5 minutes~ the m~xture was di luted with water to th~ cloudy point and was acidified with conc.
hydrochloric acid~ The precipitate which formed was coll~cted air dried and was recrystallized rom ethyl acetate to give 0~2 g. of title product - m,p~ 130-133 C.
Anal. calcd. for C14H1 ~ 30~S: Cj 52~00; H, 5.30; N, 12.99 Found: C, 51.61; H, 5.32; N, 12.84 Anti-secr~tory - 69%
Anti-allergy 70%; 10 mg/kg i.p.
~XAMPLE 21 7,8-dihydro 5-hydroxy-8-isopropyl-2-(methylthio)-7-oxo pyrido-~2~3-d ~ _ A stirred mixture vf 23.26 g. (0.1 mole) of 4-chloro-2-methylthio-5-pyrimidine carboxylic acid ethyl ester and 11.82 g~ ~0.2 mole) of isoprop~l ami~e in 200 ml. of ethanol was heated under reflux for 3 hours. The reaction mixture was taken to dry-ness ~n a rotary evaporator~ The residue was triturated with water until a ~olid had formed. The solid product 2-methyl-thio-4-isopropylamino-5-pyrimidine carbo~lic acid ethyl ester amounted to 28.1 g. An analytical sample was obtained by recry-stallization from ethanol - H20 m~p. 42-44 C.
Analc calcd. for CllHl ~302S: C, 51.74; E, 6~71; N, 1~.46 Fou~d: C, 51.52; H, 6.70; N, 1~.53 A mixture of 2701 g. of 2-methylthio-4~isopropylamino-5-pyrimidine carboxylic acid ethyl ester, 100 ml. of water, 10 ml. o~ ethanol and 100 mlO of 50% sodium hydroxide solution was stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate neutralized with glacial acetic acid. The 2-methylthio-4-isopropylamino-5-pyrimidine carboxylic acid which precipitated amounted to 15.5 g. An analytica~ sam-ple was obtained by recrystallization from ethanol - m.p~ 201-;
203 C.
_ ~7 -Anal. calcd. for C9H13N302S: C, 47.56; H, ~.76; N, 18.49 Found: C, 47.41; H, 5.76; N, 18~70 A stirred mixture of 14.0 g. of 2-methylthio-4~ o-propylami~o-5-pyrimidine carboxylic acid, 100 ml~ of ethyl chloroformate and 150 ml. of chloroform was he~ted for 24 hour3.
under re1ux. The solvents were removed in a rotary evaporator under ~uction. The IR spectrum of -the r0~idue indicates that cyclization to the anhydrid~ had not occurred. Xylene (200 ml~) was added to the residue and the reaction mixture was heated un-~0 der reflux for 3 hours. The reaction mixture wa~ filtered and the filtrate take~ to dry~ess on a rotary ~vaporator. The solid residue was washed with petroleum ether and amo~ ted to 3,4 g.
of 7-methylthio-1-isopropyl-2H-pyrimido~4,5-d]~1,3]oxa~ine-2, 4(1H)-diorle - m. p. 94-96 C. Ihe product was used i~ the next step without further purification.
To a solution of sodium ethoxide (a. g gJ .039 g. atom of sodium in 7S ml. of ethanol) was added 6,24 g. (0.03 mole) of diethyl malonate, The ethanol was removed in a rotary evapor-ator. To the re~idue was added 100 ml. of dimethyl formaD~de followed by 3~ 3 g. (0. 013 mole~ of 7 methylthio-1-isopropyl-2H~
pyrimido~4,5-d][1,3]oxazine-2,4(1H3-dione s~ The reactioIl mix-ture was heated u~der reflux for 1 hour, cooled in ice and poured into 400 ml. of water. The solution was acidified with conc.
hydrochloric acid and the resulting product was collected by suc-tion filtration. Recrystallization from ethanol gave 2 g~ of product - m.p~ 138--140 C.
Anal. calcd. for C14H1 ~ 304S: C, 52.00; H, 5.30; Nq 12.99 Found~ C, 51.81; H, 5.56; N~ 13.08 Anti-allergy - 84~o 25 mg/kg i.p~
E~ 22 7,8~dihydro-5~hydroxy-8-(2-methoxyethyl)-2-methylthio-7-oxo~
pyrido-[2,3-d~pyrimidine-6-carboxylic acid ethyl ester A mixture of 11.63 g. (.05 mole) of 4-chloro-2-methyl-thio--5-pyrimidine carboxylic acid eth~l este:r and 7~51 g. (0.1 mole~ of 2-metho~yethylamine in 100 ml~ of ethanol was hea$ed under reflux for 2 hours. The reaction mixture was filtered R~d the filtrate was taken to dryness on a rotary ev~porator. The residue ~mounted to 11.9 g. of ~-methylthio-4 (2-methoxy-ethyl-amino)-5-pyrimidine carboxy~ic a~id ethyl ester - m.p. 34~35 Ca Recry~tallization from petroleum ether gave 8.9 g. of prolduct, m.p. 36-37 C.
or CllEl ~ 303S: C~ 48.69; H, 6,31; N 15 49 Found: C, 48.66; H, 6~4D; N, 15.60 To a mixture of 26.4 g. of 2-methylthio--4-( -metho~
ethyl~-5-pyrimidine carboxylic acid ethyl ester in 100 ml~ of ethanol was added 100 ml. of water and 40 ml~ of 5~/o sodium hy-droxide soluti~n. The reaction mixture was allowed to stir at room temperature for 2 hours and then acidified wi~h glacial ace-tic acid. The resu~ting solid amounted to 18~0 g. of 2-methyl-thio-4-(2-methoxyethylamino)-5-pyrimidine carboxylic acid - m.p.
179-185 C. The analytical sample was obtained by recrystalliza-t ion from ethanol - m. p. 190-192 C .
Anal. calcdO for CgH13N303S C, 44.23; H, 5.38; N, 17.27 Found: ~7 44.35; H, 5.53; N, 17.470 A mixture of 17 g. of 2-methylthio-4-~2-methoxyethyl-amino)-5-pyrimidine carboxylic acid and 100 ml. of ethyl chloro-formate was heated under reflux for 5 1/2 hours. The reaction mixture was taken to dryness on a rotary evaporator. The r~si-due was recrystallized from eth~nol giving 4.3 gu of 1-(2-meth-oxyethyl)-7 methylthio-~H-pyrimido[4,5-d][1.3]oxa2ine-2,4~1H)-~,g s dione - m.p. 134-136C.
Analysis Calculated For: CloH21N3O4S
C, 4~.60; H, 4.12; N, 15.60 Found: C, 44.23; El, 4.33; N, 15.63 To a solu-tion of sodilam ethoxide (L.l ~. .04 g. atom of sodium ~n 50 ml. of absolute ethanol) was added 7.69 g. (.048 mole) of diethyl malonate. The ethanol was removed in a rotary evaporator. To the' residue was added 50 ml. of dimethyl formamide followed by 4.4 g. ~.016 mole) of 1-(2~methoxyethyl)-7-methyl-thio-2H-pyrimidol4,5-d] L 1,3~oxazine-2,4(lH)-dione. The reaction mixture was heated under reflux for 1 hour, cooled in ice and poured into 400 ml. of water. Acidification with conc. hydrochlo-ric acid gave 4.5 ~. of product - m.p. 102-104C. Rec'rystalli-zation from ethanol gave 3.9 g. of pure product - m.p. 110-112C.
Anal. calc f r C14 17 3 5 ~Eound: C, 49.62, H, 5.24; , 12.38 Anti-secretory - 47%
; Anti-allergy - 80%; 50mg/kg p.o.
Example 23 2~0 7,8-dihydro-5-hydroxy-2-(methylthio)-7-oxo-8-(2-propenyl)pyrido-[2,3-d~pyrimidine-6-carboxylic acid ethyl ester To a suspension of 9.29 g. (0.04 mole) of 4-chloro-2-methylthio-5-pyrimldine carboxylic acid ethyl ester in 100 ml. of ethanol co~led in an ice bath was added 4~56 g. (0.08 mole) of allylamine dropwise over 5 minutes. The mixture was stirred at room temperature overnlyht. The ethanol was evaporated in a rotary evaporator and the residue was triturated with 50 ml. of ether and was Eiltered. The flltrate was evaporated and the residue was dissolved in ethanol and was diluted with water. The precipitate which formed was collected to give 3.8 g. of 4-allylamino-2-methylthio~5-pyrimidine carboxylic acid ethyl ester - m.p. 41-43C.
- (Ref. E. Peter$ et al., J.Org. Chem., 25, 2137 (1960); m.p. 44-45~C).
-~x~ - 40 -,J,~ '7S
To a solutlon of 25.3 g. (0.1 mole) of 4-allylaminP-2 methylthio~5~p~rimidille carbo~ylic acid ethyl ester in 400 ml.
of anhydrous di:eth~l ether was added 7.5 ~. (0.005 mole) of ethyl m~lonyl chlori.de. The:m~ture was stirred at room tempera-ture for 3 hours. The:mixture was filtered and the filtrate was evap-.
~` - 40a -, ,.~ .
~ i75 orated in a rotary evaporator. The residue was ~issolved in 15 ml. o~ ethanol and this soLution was added to a solu~ion of 2.3 g. (0~ g~ atOm) of sodium in 200 mlO of ethanQl. The m~x-tur~ was stirred at room temperature for 5 minutes and was di-luted with water, acidified with glacial acetic acid and was extracted with 150 ml~ of diethyl etherr The ether layer was dried over magnesium sulfate, filtered and was acidified with gaseous hydrogen chloride. The mixture was filtered and the filtrate was cooled in ice. The preeipitate ~hich formed was collected and was recrystalli~d from ethyl acetate to give n. 2 gO of product - m.p. 134-135~ C.
Anal~ calcd. for Cl~H1 ~ 304S: C~ 52.32; H, 4.71; N, 13-08 Foundo C, 52.10; H, 4.76; N, 12.82 Anti-secretory - 48%
A~ti-allergy - 92%; 50 mg/kg pOo.
EX~MPiE 24 7,8-dihydro-5-hydroxy-2-methylthio-7-oxo-8-pipero~yl-pyrido ~2,3-d]pyrimidine-6-carboxylic acîd ethyl e~ter A mixture of 11.63 g. (0.05 mole) of 4-chloro-2-methyl-thio-5-pyrimidine carboxylic acid ethyl ester, 7.56 g. (.05 mole) of pipero~ylamine and 5.3 g. (0.05 mole) of sodium rarbonate in 100 mln of ethanol was heated under reflux for 2 hours. The re-action mixture was cooled in ice, filtered and the ~il$er cake ~iashed with water to remove inor~anic salts. The product 2 me$hylthio-4-piperonylamino-5-p~rimidine carboxylic acid ethyl ester amounted to 14.7 g. - m.p. 85-88 C~ It was used in the ~ext step without purification.
Anal. calcd. for C16H1 ~ 30~S: C, 55.32; H, 4.93; N~ 12.10 Found: C, 55.38; H, 4~88; N, 12.21 -- ~1 --~L~ 7 ~
To 100 ml. o.f 5~o sodi~ hydroxide solution was added 14.7 g. of 2-methylthio-4-pipero~yla~ino-5-pyrimidine carboxylic acîd ethyl ester~ A few milliliters of ethanol was addedr The reaction mixture wa~ heated on a hot plate for a few minutes un-til a clear ~olution was obtained and then allowed to stir for s~veral hours at rovm temperature. Acidification with CollC.
hydrochloric acid gave 13 g. of 2-methylthio--4-piperonylamino-5-pyrimidiQe carboxylic acid - mOp. 214-217C. The product was used ~n the next step without purifi~ation.
A mixture of 5 g. of 2-methylthio-~-piperonlyam:uno-5-pyrimidine carboxylic acid in ~0 ml. of ethyl chloroforma1te was heat~d under reflux for 2 1/2 hours. The reaction mixture was cool~d i~ ice and filtered under ~uction. The filter cake afte.r washing with ethanol amounted to 4.0 g~ of 7-methylthio-1-piper-onyl-2H-pyrimidoC495-d]~1,3]oxaæine~2,4(1H)-dione, hydrate ~
m.p. 160-164 C~ An analytical sample was obtained b~ recry-stallizing from eth~nol - m.p~ 160-16~ C.
or C15HllN305S H20: C9 49-58; H, 3-60; ~ 11 5~
Found: C, 49.15; H~ 3.49; N, 11.15.
To a solutiQn of sodium ethoxide (1.6 g., .03 g~, atom of sodiwm i~ 50 ml. of absolute ethanol) was added 4.8 g~ (.03 mole) of diethyl maln~ate. The ethanol W2S removed under suc-tiOn in a rotary evaporator. To the residue was added 50 ml.
of dry dimethyl for~amide followed by 3.5 gO (oOl mole~ of 7-methylthio-l-piperonyl-~.H-pyrimido[4,5-d][1,3]oxazi~e-2,4(1H)-dione. The reaction mixture was heated under reflux for 2 hour~
cooled in ice and poured into ~00 ml~ of waterO m e reac~ion mixture was aoidified with cOnc. h~drochloric acid. The result-ing precipitate amo~nted to 5~0 g. - m.p. 173-178 C.
Recrystallization from dimethyl formamide gave 3.4 æ. of pure prOduct - m.p. 187-188 C.
- ~2 -C~ 306S: C, 54.93; H, 4.12; N, 10 11 F'ound: C, 54.69; ~, 4.27; N, 10.13 Anti~secretory - 47~o ~nti-allergy - 67.3%; 100 mg/kg i.p.
34.9/0; 50 m~/kg p.o.
~ XAMPLE 25 8-allyl-~j8-dihydro 5-(2-m0thoxyet~lylamino)-7-oxo-2 phenylpyri-do~2~3-d]pyrimidine-6-c~rbox~lic acid ethyl ester Twenty ml. of phosphorous oxychloride was comb~ned with 0.87 g. (oO025 mole) of 8-allyl-7,8-dihydro-5-hydroxy-7-oxo-2-phe~ylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester and this was heated at reflux for 5 hour~. Then the POC13 was evaporat~d and crushed iee added to the residue and the white solid that appeared was fiItered off, ri~sed with water and pe-troleum ether and dried to gi~e 0~ g. of 8~allyl-5-chloro-7, 8-dihydro-7-oxo-2-phe~ylpyrido[2~3-d]pyrimidine-6-carboxylic acid ethyl e~ter - mLp. 148-152C C~ This product was used in the next step without further purificationO
To O.g g, ~.0024 mole) of 8-allyl-5-ehloro-7,8-dihy-dro-7-oxo-2-phenylpyrido~2,3-d]pyrimidi~e-6-carb~xylic acid ethyl ester in 30 ml. of ethanol waæ added 0.17 g. ~.0024 mole) of 2-methoxyethylamine a~d 0.25 g. (.0024 mole) of Na2CO30 This mixture was heated at reflux for 4 hours, then filtered and the filtrate chilled. Yellow crystals formed and were collected On a filter~ Recrystallization from ethanol gave 0.5 g. of pro-duct - m.p. 155-158 C.
C22H24N404: C, 64.69; H, 5.92; N 13 72 Found: C, 64.43; H, 5.99; N, 13.47 Anti-secretory ~ 58%
7~i 2~
7,8-dihydro-8-(2-methox~ethyl)-5-(2-methoxyethylamino)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl e~ter .
80 ml. of phosphornus oxychloride was combined with 4.0 g. (.011 mole) of 7,8-dihydro-5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-PhenylPyridoC2,3-d]Pyrimidine-6-carbox~lic acid ethyl ester and heated at refl~x for 5 hours9 Then the POC13 was re-mo~ed by evaporation and crushed ice added to the residue~ ~he ensuing white solid was filtered off, rinsed well with water and petroleum ether and dried to gi~e 3.8 g~ of 5-chloro-7,8-dihydro-8 (2-methoxyethyl)-7-oxo-2-phenylpyrido~2,3-d]pyrimidine-6-car-boXylic acid ethyl ester - mOp. 119-121 C. This product was used in the next step without further purificationO
To 2.4 g. (.006 mole) o~ 5-chlorow7,8-dih~dro-8 (2-methoxyethyl)-7~oxo-2-phenyl-pyrido~2~3-d]p~rimidine~6 carboxylic acid ethyl ester in 100 ml. Of etha~ol was added 0O45 g. (.OOS
mole) o 2-meth~xyethylamine and 0.65 g~ ~.006 mole) o Na2CO30 This mixture was refluxed 3 hours, then filtered a~d the filtrate ehilled. A solid formed and was filtered off and rinsed with petroleum ether - m~pn 160-163 C. No further purificati,~n was necessary.
C22H26N405: C, 61.96; H, 6015; N, 13 14 Fo~nd: C, 61D75; H, 6.09; N, L3.33 Anti-secretory - 12%
~nti-allergy - 38%; 25 mg/kg p.o~ 10 min. before antigen 2%; 25 mg/kg p.o. ~0 min. before antig~n -- 4~ ~
47~ .
7,8-dihydro-8-ethyl-N (2-hydroxyethyl~ 5-(2-hydroxyethylamino)-_ 7-ox~-2-phenylp~ o~2t3-d]
To 2 g. (~0056 mole) of 5-chloro-7,8-dihydro-8-ethyl-7-oXo-2-Ph~n~lpyrido[2s 3-d~pyrimidirla-6-carboxylic acid ethyl ester (prepared by the methnd of the first paragraph of Example 3) was added 20 ml. of 2-aminoethanol and this mixture was heated at reflux for 1.5 hours. The reaction mixt~e was chilled in ice and the prOd~ct collected On ~ filter a~d recrys%allized from ethanol to give 1.7 g. of product~ - m.p. ~50-253 C.
Anal. ~.alcd. for C2~H23N56 C~ 59r 84; H~ 5- ; 5 Found: C, 59~95; H, 5085; N9 17.34 E~ ~LE 28 5-aminO-7, 8-dihydro-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido-C2t 3-d]pyrimidine-6-carboxylic acid ethyl ester Cnmbined 11 g. (.051 mole) of 4-chloro-5-cyano-2-phen-ylpyrimidine, 5~4 g. ~7051 mole) ~f Na2C03 aIld 3.8 g. (.OSl mole) of 2-methoxyethylamine in 250 ml. of ethanol and heated this at reflux fOr 3 hours. Then the reactiOn was filtered and the fil-20 trate chilled. me product precipitated ~ut nf solutinn and wascollected On a filter and rinsed with petroleum ether to give 9.3 g. of 4-(2-methoxyethylaminn~-2-phenyl-5-pyrimidinecarboni-trile m.p. 122-126 C. The product was used in the next step without further purificatiOn.
To 903,g~ (.037 mole) of 5-cyanO-4-(2-methoxyethyl-; amino)-2-phenyl p~rimidi~e in 350 ml~ of diethyl ether was added 2.8 g. (.019 mole) of ethyl mal~nyl chlOride and this mixture was stirred at rOOm temperature for 405 hours. Then the solid material was filtered off a~d the filtrate evaporated to dryness.
Ethano~ was added until a sOlution was obtained and this solution :
S
was added to 0.85 g. (.057 mole) of Na ~n ethanol and stirred 20 minutes. A little water was added and the solution was acidified with acetic acid. me solid product was collected ~n a suctio~ filter and recry~tallized from ethanol to give 2.0 g. of prOduct - m.p. 2~5-247~ C., Or C19H20N404: C, 61.94; E, 5.47, N, 15 21 - Fo~d: C, 61.59; H, 5,.49; N, 15.31 E~MPLE 29 7, 8~dihydro-5-hydroxy-N~ 8-bis (2-methoxyethyl) -7-oxo-2-phenyl-pyrido ~2, ~-d] pyrimidine-6-carboxamide T~ 1~0 g. (.0027 mole) of 7,8-dihydro-5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-phen7lpyridoc2~3-d]pyrimidine-6~carboxylic acid ethyl e~ter (prepared as in Example 9) was added 0.4 g.
(,0054 mole) of 2-methoxyethylamine in 25 ml~, of ethanol ~nd this was heated at reflux for 4 hour~. The reactiOn was the~ filter-ed a~d chilled and -the filtrate ga~e up a solid that was collect-ed On a SllCti~ filter ~ rin~ed with petrole-un ether. No fur-ther purification was necessary - m.p. 150-154~ C.
A}lal. calcd- for C20H~2~405 C, 60~29; H~ 5-57; N, 14-06 Found: C, 60.~g; H, 5.72; N, 14.03 EXAMPL~ 30 _ N-~2-(diethylamino)ethyl]-7,8-dihydro-5-hydroxy-8-(2-methoxyeth-yl)-7-oxo-2-phenylpyrid~[2,3-d]pyrimidine-6-carbOx~mide To 1.0 g. (.0027 mole3 o 7,8-dihydrO-5-hydrQxy-8-(2 methoxyethyl)-7-oxo-2-phenylpyridoC2,3-d]pyrimidine-6-car~oxy-lie acid ethyl ester (prepared as in E~ample 9) was added to 0.63 g. (.0054 mole~ of diethylethyle~ediamin~ in 25 ml~ of eth-anol. This mixture was heated to refl~Y for 3.5 hours. Then - ~6 -~ ;75 ice-chill;ng caused the formation of a white snlid tha~ was filtered off and re-crystallized from ethanol to giYe 0.9 g. of prOduct with a mrp~ 115 117 C.
Anal- calcd- for C23H2 ~ 54~ C, 62-85; H~ 6~65; N~ 15~4 Found: C~ 62.91; N, 6.70; N, 15.84 7~8-dihydro-5-hydr~x~-7-oxo-2-phenyL-8-(2-propargyl)pyrido[2l3 -d]-pyrimidine-6-carboxylic ~cid ethyl ester 10 grams (.1 mole) of 95% propargylami~e HCl was added to a solutio~ o~ 2.4 g. ~.1 mole) of Na in 50~ ml~ of ~thanol and stirred 15 mi~utes~ Then the solid wa~ filtered Off and to the filtrate was added 27~3 g~ (.1 mole) of 4-chloro-2-ph~ny~-5~-pyrimidinecarb~xylic acid ethyl ester a~d 11 g. (.1 mole) of Na2C03. This mixture was heated at reflu~ for 3 ho~s7 Then the reactio~ was agai~ filtered and the filtrate chilledq The pro- :
duct precipitated out and was filtered off and rinsed with pe-troleum ether to give 25.8 g. of 2-phenyl-~propargy1~nino-5 pyrimidinecarb~xylic acid ethyl ester - m.p. 110-115 C. The prOduct was used in the subseque~t step without further purifica-tinn.
T~ 11.6 g. of 2-phenyl-4-propargylamino-5-pyrimidine-carb~xylic acid ethyl ester in 200 ml. of ether and 800 ml. nf tetrah~drofuran was added 3.1 g. ~.02 mole) of ethyl malo~yl-chlOride and this was stirred 2~S hours at rOom temperature.
men filtration remo~ed al 1 solid and the filtrate ~as evapOr-ated to dryness and ethanol was added to the residue. A solu-tio~ of 0.95 g. ~.041 mole~ of Na in 50 ml. of ethanol was added to the residue sOlution ~nd stirred 10 minutes a$ roOm tempera_-ture. A little water was added and the soluti~n acidified with - ~7 _ ~Z~7S
acetic acid and the ensuing solid filtered off. Recrystalliz-ation from ethyl acetate gave 1~5 gO of product - m.p. 214-215 C.
Anal- calcd~ for C14H1 ~34 C~ 65.43; H~ 4~33; N~ 12-03 Found: C, 65~25; H, 4.56; N, 12.07 Anti-allergy - 68D/n; 25 m~/k~ p.oO 10 min. before antigen ~/o; 25 mg/kg p.o. 60 min, before antigen EXAMPLE 3~
_ 8-all~1-5-ami~o-7,8-dihydro-7-oxo-2-phenylpyr~doC2,3-d]pyrimi __ _ di~e~6-carbox A mîxt~re of 11.2 g. (.052 mole) of 4-chloro-2-phenyl~
5-pyrimidinccarbonitrile~ 3~0 g. (oO52 mole) o~ allylamine and 5.5 g. (,052 mole~ of Na2C03 in 250 ml~ of ethanol was refluxed : 4 hours. The solid material was then fil~ered off a~d the fil-trate chilled. A solid precipitated out and was rin~ed with petroleum ether to give 7.3 gO of 4-allylamino-2-phenyl-5-pyri-midinecarbonitrile - mOp. 158~181 C. l~liS ma$erial was u~ed in a subseq~ent step without further purification.
Anal. calcd. for C14H12N4: C, 71-16; H~ 5-12; N~ 23-71 Foundo C, 70.96; H, 5.11; N, 23~31 A mixture of 7.3 g, (.031 mole) of 4-allylami~o-2-phenyl-5-pyrimidinecarbonitrile and 2.3 g. (aO15 mole) of ethyl malonyl chloride in 300 ml. o~ ether was s~irred at room temp-erature for 4 hour~. The reaction was then filtered and the fil-trate e~aporated to dryness. Ethanol wa~ added to the residue ~nd the slurry was then poured into a solution of 0.7 g. sodium (.031 mole) in 50 ml. of ethanol and stirred for 20 minutes.
Water was then added and the reaction acidified with acetic acid~
~he white solid was filtered off ~nd recrystallized from ethanol to give 1.4 g. of product - mOp. 234-236 C.
- ~8 4~
~nal~ calcd. for ClgH18N403 C, 6S.13; H, 5.18; N, 15.99 Found: C, 64.74; H, 5.07; N, 16.07 E~A~PLE 33 5-amino-7,8-dihydro-8-ethyl-~methyl-7-oxo-pyrido-~2,3-d]pyrimi-_ _ dine~6-carboxylic acid e~hyl e~ter_ _ _ _ _ To a solution of 3~45 g. (0.15 g. atom) of ~odi~ in 500 ml. of ethanol was added ~4.0 g. (0.15 mole) o diethyl mal-onate followed by 6~7 g~ (0.15 mole) 4-amino--2-methyl-5-pyrimi~
dinecarbonitrile~ ~he reaction mixture wa~ heated under reflux with stirring for 17 hours. The resultiQg filter cake was remov- :
ed by filtrati~n to obtain the sodi~m salt ~f 5-amino 7,8-dihy-dro~2-methyl-7-oxo-p~ridoC2, 3-d~ pyrimidine-6-carboxylic acid ~thyl ester.
To a solutio~ containing 5.4 g. (0.02 mole) of the ~od-dium salt of 5-amino-7,8-dih~dro-2-methyl-7-oxo-pyrido~2,3-d~-pyrimidine-6-carbaxylic acid ethyl ester in 50 ml~ of dimethyl-formamide was added 9.35 g. (0.06 mole~ of ethyl iodide. The reaction mixture was heated to 50 for 4 hours; cooled in ice and then po~red into one liter of water. The reaction mixture was kept in a cold room for 3 days and was then filtered. The product amou~ted ~o ~.4 gO (m. PJ 230~231 ) ~ The analytical ~am-pl~ was obtained by recrystallizatio~ from ethanol.
Anal, calcd. for C13H16N403: Cs 56.51; H~ 5-84;
Fou~d: C, 56.12; H, 5.66; N1 20.09 Percentage inhibition: 60%
~L'~()~7 5-amino-8-ethyl-75 8-dihydro-7-oxo-2-propyl-pyrido~2, 3-d~pyrimi-dine~6-carbox lic acid ethYl ester To a solution of 3.4 g. (0.15 g. atom) o~ sodium in 250 ml. of ethanol was added 2400 g~ (Ol 15 mole) of diethyl mal-onate. After a few minutes 8.1 g~ (0O05 mole) of 4-amino-2-propyl-S-p~rimidine carbonitrile was added. The reaction mix-ture was heated under reflux with stirrillg or 5 hours, during which time the sodium salt o~ S-amino-7,8-dihydro-7-oxo-2-prop-yl pyrido~2,3-d]pyrimidine-6-carboxylic acid ethyl ester precip-itated out of solution. This material amounted to 11.3 g.
To a solution containing 5.96 g. (0.02 mole) of the above sodium salt in 50 ml. of dimethylformamide was added 9.36 g. (0.06 mole) of ethyl iodide. The reaction mixture was heated at 50 for 2 hours and was then cooled i~ ice and poured into 500 ml. o~ waterO m e resulting precipitate was collected and amounted to 4O9 g. (m-p- 192-193). Recrystallization from eth-anol gave 3.0 g. of product9 m.p~ 199-200.
Anal- calc~- for C15H20N43 C~ S9 Fou~d: C, 69.19; H, 6.59; N 5 18~81 Percentage inhibition: 29%
E~AMPLE 35 5-amino-8-butyl-7,8-dihydro-2-methyl 7-oxo-pyrido[2,3 d]pyrimi-dlne-6-carbo~ylic~ l ester _ _ To a solution containing 5.4 g. (0~02 mole) of the sodium salt of 5-amino-7,8-dihydro-2-m~thyl-7-oxo-pyrido[2,3-d]-pyrimidine-6-carboxylic acid ethyl ester in 50 ml~ of dimethyl-formamide was added 4.6 g. of butyl iodide. The reaction mixture was heated to 50 for 3 hours, cooled overnight at room temper-ature ~ d was then poured into 500 ml. of water. The product - 50 ~
was collected on a suction filter giving 5.5 g. o crud~ pro-duct, m.p. 214-216. Recs~y~tallization from ethyl acetate af-forded 2~9 g. of product, m.p. 220-222.
Anal. calcd. for clsH2~N4o3: C~ 5 Found: C, 59.13; H, 6056; N, 18.41 8-all~1-5-amino-7,8-dihydro-2-methyl-7-oxo-p~grido[~,3-d]pyrimi-_ dine-6-carboxylic acid eth~l ester _ _ To a solution r.o~taining 5.96 g. ~0.02 mole) of the sodium salt of 5~amino-7,8-dihydro-2-met~yl-7-oxo-pyrido[2,3-d]-pyrimidine-6-~carboxylic acid ethyl ester in 50 ml. of dime$hyl-formamide was added 4.83 g. (0.04 mole) of allyl bromide. The reaction mixture was heated to 50 for 4 hours, cooled in ice and then added to one liter of water. The reaction mixture was cooled in ice and the r~sulting precipitate was collected on a filter. There was obtai~ed 2.9 g. of product, m.p. 217-219 C.
Recrystallization from ethanol gave 1~89 of pure product, m.pO
223-225 C.
Anal. calcd. for C14H16N~03: C, 5 2;
Found: C, 57.87; H, 5~55; N, 19.66 Percentage inhibition: 68%
EXAMPLF. 37 ~-allyl-5-amino-7,8-dihydro-7-oxo-2-propyl-pyridoC2,3-d]pyrimi-_ dine-6-carboxylic acid ethyl ester_ To a solution of 4. 4 g. (0.15 mole) of the sodium s~lt of 5-amino-7,8-dihydro 7-oxo-2-propyl-pyrido[2,3-d]-pyrimidine~
8.3 g. of 4-benzylamino-2-phenyl-5 pyrimidine carboxylic acid ethyl est~r with m.p. 112-115C.
Anal. calcd- for C20Hl ~ 32 Found: C, 71.74; H, 5,71; N, 12059 To 11.0 g. (.033 mole) o 4-benzyla~ino-2-phenyl-S-carboxylic acid ethyl 0ster in diethyl ether was added 2~5 g.
(.016 mole) of ethyl malonyl chloride and then stirred 3 hours at room temperature. The reaction was then filtered and the filtrate stripped to dryness. This residue was then dissol~ed in ethanol to which was then added a solution of ~7~ g~ of sodium (.033 mole) in ethanol. The reaotion mixture was stirred at room temperature for 15 minutes. Acidification via acetic acid and dilution with water caused the formation of a precipi-tate. The crude product was filtered off and recrystallized from hexane to glve 1.4 g. of the title çompvund - m.p~ 230-231C.
Anal. oalcd. or C23HlgN304 C~ 6~
Found: C~ 68~58; H, 4.83; N, 10.50 Ant i-s ecretory - 6~/o Anti-allergy - 6~/o9 100 mg/kg i.p.
7,8-dihydro-5-hydroxy-8-(p-morpholinophenyl)-7-oxo-2-phe~yl-pyrido~2,3-d]pyrimidine-6-carboxylic acid ethyl ester A mixture of 15 g. ~.057 mole) of 4-chloro-2-phenyl-5-pyrimidine carhoxylic acid ethyl ester, 10.2 g. (.057 mole) of p-morpholinoaniline and 3 ~. (.028 mole) of Na2C03 in 400 ml. of ethanol was refluxed for 3 hours. Then the reac-tion ~olution was filtered and the filtrate immediately pre-cipitated 4-(p-morpholinoanilino)-2-phenyl-5-pyrimidine car-boxylic acid ethyl e~ter - m.p~ 173-176C. No further purifi-- 27 ~
cation was done and th~ product used directly in the next st~p.
Anal- calcd- for C2 ~ 2~N403: C, 68-30; H~ 5-98; N~ 13-85 Found: C, 67.99; H, 6.10, N, 13.67 100 ml. of 2~ NaOH, 65 ml. of ethanol and 50 ml.
of water were added to 17.6 g. (.044 mole) of 4-(p-morpholino-anilino)-2-phenyl-5-pyrimidine carboxylic acid ethyl ester and refluxed 4 hours. The reaction mixture wa~ cooled in iee and acidified ~qth acetic acid. The deep orange solid was filtered off. The crude 4-(p-morpholinoanilino~-~-phenyl-5-pyrimidine carboxylic acid was triturated with 8~/o ho$ ethanol and then filtered. There was obtained 9.0 g. of bright yellow solid - m.p. 295C. (dec.~.
Anal. calcd. for C~lH20N403: C, 670 Found: C, 66.83; N, 5.18; N, 14.91 30 ml. of xylene and 120 ml. of ethyl chloroformate were added to 12 gO (.032 mole) of 4-(p-morpholinoanilino~-2-phenyl-5-pyrimidine carboxylic acid and refluxed 72 hours.
Before the third night of reflux~ an additional 100 ml. of ethyl chloroformate and 25 ml. of xylene were added to the reaction. At the end of 72 hours, the reaction was filtered.
The product was collected on a suction filter and rinsed with petroleum ether to give 7 g. of 1-~p-morpholinophenyl)-7-phenyl-2H-pyrimido~4,5-d][1,3]oxazine-2,4(lH)-dione as a bright yellow product - m.p. 268C. (dec.). This material wa~ used directly in the next step without further purification.
50 ml. of NaOEt (0.8 g. Na - .034 mole) was added to 5.45 g. (.034 mole) of ethyl malonate and stirred 10 minu-tes at room temperature, then evaporated to dryness~ Dimethyl-formamide was added until a solution was achieved and to this - 2~ -4'75 was added 6.95 g. (.017 mole~ o~ p-morpholinophenyl)-7-phenyl-2H-pyrimido ~ 4, 5-d] ~1, 3] oxazine-2, 4(lM~ -dione and this mixture refluxed 1.5 hours. The chilled reaction wa~ poured into dilute HCl and the resulting precipitate removed by filtration, rinse~ with water and dried to give 6 g. of crude product. A sample othis was recrystallized from ethyl acetate to ~ive a hemi-hydrate compound with the m.p.
257C. (dec.) Anal. calc~. for C26H24N405 1/2H20 C, 64~85; H~ 5023; N~ 11 67 Found: C, 65 03; H, 5.49; N, ll.SO
7,8-dihydro-5-hydroxy-8-(4-methoxybenzyl)-7-oxo-2-phenyl-pyr i do [ 2,3-d]pyrimidine-6 carboxylic acid ethyl ester A mixture of 11 gl (.042 mole) of 4-chloro 2-phenyl-5-pyrimidine carboxylic acid ethyl ester, 5 7 g. (.042 mole) of p-methoxybenzylamine and 2.2 g. (.021 mole) of Na2C03 in 250 ml. of ethanol was refluxed 3 hours. The reac-tion was then filtered and the filtrate chilled in ice. A
precipitate formed and was filtered off givin~ 10.7 g. of 4-~p-methoxybenzylamino)-2-phenyl-5-pyrimidine carboxylic acid ethyl ester with m p. 105-110C. This compound was usecl in the next step directly without further purification.
Anal. calcd. for C21H21N303: C, 69-4G; ~ u Found: ~, 68.82; H, 5.84; N, 11.50 80 ml. Of 2~/o NaOH and 10 ml. of ethanol were added to 10.7 g. (.029 mole) of 4-(p-methoxybenzylamino)-2-phenyl-5-pyrimidine carboxylic acid ethyl ester and refluxed 3 hours.
The reaction was cooled and acidified with dilute acetic acid and the ensuing white solid filtered off. Trituration with .
~L~Z~47S
95Yo ethanol yielded 8 g. of 4-(p-methoxybenzylamino)-2-phenyl-5-pyrimidine carboxylic acid - m~p~ 263-?66C. (dec.). This compound was used in the next step without further purification, Anal. calcd. for ClgH17N30~: C,68-05; H~ 5-11; N~ 12-53 Found: C, 67.61; N, 5.44; N~ 12.6g 150 ml. of ethyl chloroormate and 30 ml. of xylene were added to 8 g. (.024 m~le) of 4-(4-methoxybenzylamino)-2-pheny~-S-pyrimidine carboxylic acid and ref:luxed 42 hours.
The insoluble product wa~ filtered and rinsed with petroleum ether to give 4.g g. of 1-(4 methoxybenzyl)-7-phenyl-2H-pyrimido~4,5-d]C1,3]oxazine-2,4(1H)-dione as a yellow so:Lid -m.p. 248-253C. The product was used directly in the next step without further purification.
A 50 ml. solution of NaOEt was prepared (0.6 g.
Na - .028 mole) and 4.34 g. (.028 mole) of ethyl malo~ate w~s added to it and stirred 10 minutesO Then this solution was stripped to dryness, dimethylformamide was added to the residue until a solution was again form~d, and then 409 g~
(.014 mole) of 1-(4-methoxybenzyl~-7-phenyl-2H-pyrimido-[4,5-d~1,3]oxazine-2,4(lH)-dione was added and heated to re-flux for 1 1/4 hours. The reaction was then cooled and poured into dilute HCl. The white solid that formed was filtered off and rinsed with water and then with ethanol. R~crystalli-zation ~rom ethyl acetate gave 1.5 g. of the title compound with the m.p. 228-232C.
Anal. calcd. for C24H21N305: C, 66-81;
Found: C, 66.6V; H, 4.88; N, 9.63 Anti-secretory - 5~/o Anti~allergy - 7~/o; 25 mg/kg i.p.
~ 7 S
E~LE 16 _ 7,8-dihydro-2,8-diphenyl-5-hydroxy-7-oxo-pyrido[2,3-d]pyrimi-dine-6-carbo~ c_acid eth~l _ ster _ _ A mixture of 10 gO (,038 mole) of 4-chloro-2-phenyl-5-pyrimidine carboxylic acid ethyl ester antl 7.1 g. (.076 mole) of aniline in 200 ml. of ethanol was refluxed for 3 hours.
Upon cooling a yellow solid precipitated from the solution.
This was filtered off and rinsed with ethanol to give 4-anili-no-2-phenyl-5-pyrimidine carboxylic acid ethyl ester, m.p, 98~100Ca No further purification was done and the product was used directly in the next step~
~nal. calcd. for Clg~l ~ 32 C, 71~45; H, 5~37; N~ 15.16 Found: C, 71.33; H, 5.2~; N; 13.21 60 ml. of 2~/o NaO~ plu~ 20 ml~ of ethanol were added to 10 g. (.031 mole) of 4-anilino-2-phenyl-5-pyrimidine carboxylic acid ethyl e~ter and re~luxed 3 hours. When cooled, a solid precipitate was obtained. The product was then stirred in water, acidified with acetic acid and filtered. Recrystal-lization from 95% EtOH gave 6.3 g. of 4-anilino-2-phenyl--5-pyrimidine carboxylic acid - m.p~ 277-280C.
Anal. Calcd. for C17H13N30~: C, 70.0~; H, 4.50; N, 14.43 Found: C, 69.~2; H, 4.86; N, 14.28 100 ml. of ethyl chloroformate and 40 ml. of xylene were added to 6.3 g~ (.022 mole) of 4-anilino-2-phen~1-5-pyrimidine carboxylic acid and refluxed 27 hours. The in-soluble material was removed by filtration and the filtrate was chilled in ice. The resulting solid was removed by fil-tration and rinsed with petroleum ether to give 1.2 g. of 1,7-diphenyl-2H-pyrimido[4,5-d]~1,3]ox~zine-2,4(1H)-dione -m.p. 252-254C. The material was used in the next step directl~- ~ithout further purification.
or ~18HllN303: C, 68.13; H, 3~50; N 13 24 Found: C, 68.40; H, 3.84; N, 13~6 A 50 ml. solution of sodium ethoxide was pre-pared (0.2 g. Na - O009 mole) and 1.5 g. (O009 mole) of ethyl malonate was added to it and stirred :L0 minutes. Then this solution ~as stripped to dryness, then dimethylformamide was added to the residue until a solution was formed and then 1.5 g. (~005 mole) of 1,7-diphenyl-2H pyrimido~4,5-d]-~,3]oxazine-~,4(1E)-dione was added to this solution and heated to reflux for 2 hours. At the end of this time, the reaction was cooled and poured into dilute HCl. The white solid that formed was removed by filtration, rinsed with water alld recrystallized from ethyl acetate to give 1.15 g.
of the title compound with the m.p. 252C. (dec.~.
Anal~ calcd. for C2~H1 ~ 304: C, 68-21; H~ 4-4 ;
Found- C, 67.92; H, 4.24; N, 10.70 Anti-secretory-64%
Anti_allergy -10~/o; 25 mg/kg i.p.
~ AMPLE 17 5-amino-7,8-dihydro-2-(methylphenylamino3-7-oxopyrido~2,3-d]-_ _E~rimidine-6-carboxylic acid ethyl ester _ _ Sodium (1.15 g~ - .05 g-atom) was dissolved in 350 ml. of ethanol and 9.3 g, (.05 mole) of a-methyl-a-phenyl guanidine HCl was added to this solution and stirred 10 minu-tes. The reaction was filtered to remove NaCl and then 6.1 g. ~.05 mole) of ethoxymethylenemalononitrile was added to the filtrate and this mixture was refluxed for 3 hours. The reaction was chilled in ice ~nd this caused the formation of a white solid - m.p. 188-194C. This crude material was re-crystallized from ethanol to give 5.4 g. of solid 4-amino-2-~methylphenylami~o)-5-pyrimidine-carbonitrile with m~p.
190-195C.
Anal. calcd. for C12HllN5: C, q3098; H, 4.92; N, 31-09 FOuna: c~ 63.89; H, 5.05; N, 31.10 To 10 g. (.044 mole3 of 4-amino-2-~methylphenyl-amino)-5-pyrimidine-carbonitrile in 200 ml~ of tetrahydrofuran was added 6.7 g~ ~.044 mole) o ethyl malonyl chloride and then this mixture was heated at reflux or 2 hoursO The reac-tion was then filtered and the fil~ercake rinsed with tetra-hydrouran. The filtrate was evaporated to dryness on a rotary evaporator. The viscous liquid residue was treated with 50 ml. of 2~/o NaOH and heated to boiling for 5 minutes~
The re~ulting solid was removed by filtration. This solid was slurried in water, acidified with aeetic acid and filtered.
: The crude produet was recrystallized from 95% ethanol to give 1.05 g. of solid with mOp. 297C~ (dec.).
Anal. cal~d. for C~ 53: C; 60-17; H~ 5.05; N~ 20-64 Found: C, 59.87; H, 4,93; N5 20.71 Anti-secretory-25%
7,8-dihydro-5-hydroxy-8-methyl-2-(methylthio)-7-oxo-pyrido-~2~3-d]-pyrimidine-6-carboxylic acid ethyl ester To a mixture of 23.3 g. (0.1 mol~) of 4-chloro-2-methyl-thio-5-pyrimidine carboxylic acid ethyl ester in 150 ml. of ethanol was added 15.5 g. (0.2 mol~) of 4~/o aqueous methylamine. The mixture was ~tirred in an ice bath for 30 ~inutes and ~as filtered. The filter cake was recrystallized from ethanol to give 11 g. of 4-methylamino 2-methylthio-5-pyrimidine carboxylic acid ethyl ester - m.p. 87~89C. (Ref.
E. Peters, et al., J. Org. Chem., 25, 2137 (1960) - m.p. 93-94C.).
To a solution of 4.54 g. (0.02 mole) of 4-methyl-amino-2-methythio-5-pyrimidine carboxylic acid ethyl ester in 100 ml. of anhydrous diethyl ether was added 1.5 g. (0.01 mole3 of ethyl malonyl chloride. The mixture was stirred at room temperature for 1 hour. The mixture wa~ filtered and the filtrate was evaporated in a rotary evaporatorO The residue was triturated with a few mil~ of diethyl ether and was filtered~
The filtrate was evaporated and the residue was dissolved in 10 ml. of ethanolO This solu~ion was added to a solution of 0.37 gO ~0.015 g-atom) of sodium in 20 ml. of ethanol. T~e mixture was stirred at room temperatur~ for IO minutes. The mixture was diluted with water and was acidified with glacial acetic acid. The preeipitate which formed was collected, air dried and was recrystallized-from ethanol to aord 0.4 g.
of title product - m.p~ 166-168C.
for C12H1 ~ 304S: C, 48.80; H, 4.4~, N, 14 23 Found: C, 48.60; H, 4.64; N, 13.89 Anti-secretory - 44%
Anti-allergy - lO~P/o; 10 mg/kg i.p.
7,8-dihydro-5-hydroxy-8-methyl-7-oxo-2-(1 pyrrolidinyl)pyrido-~2,3-d]pyrimidine-6-carboxylic acid ethyl ester To a solution of 2.95 gO (0.01 mole) of 7,8-di-hydro-5-hydroxy~8-methyl-2-(met~ylthio)-7-oxo-pyrido~2 7 3-d]-pyrimidine-6-carboxylic acid ethyl ester (prepared by the method of Example 18) i~ 100 ml. of dichloromethan~ was added a suspension of 4.0 g~ (0.02 mole) of 85~o m - chloroperoxy-benzoic aci~ in 50 ml. of dichloromethane. The mixture was stirred at room temperature for 1 hour. The solution was ex-tracted with 100 ml. of a 2~/o potassium carbonate solution.
The water layer was acidified with glacial acetic acid and was filtered. The filtrate was extracted with 50 ml. of chloroform.
The chloroform layer was dried over magnesium sulfate 7 ~iltered and was evaporated in a rotary evaporator. The residue was re-crystallized from ethanol to afford 1.0 g. of 7,8-dihydro-5-hy-droxy-8-methyl-2-(methylsulfonyl)-7-oxo-pyrido~2,3-d]pyrimi-dine-6-carboxylic acid e$hyl ester - m.p. 184-185C.
Anal- calcd- for C12H13N33S C~ 44-03; H~ 4-00; N~ 12-84 Found: C, 44~41; H, 3.93; N, 12.72 A stirred mixture of 3.27 g. (0.01 mole) of 7,8-di-hydro-5-hydroxy-8-methyl-2-(methylsulonyl)-7-oxo-pyrido[2,3-d]-pyrimidine-6-carboxylic acid ethyl ester and 0.71 g. (0.01 mole) of pyrrolidine in 50 ml. of ethanol was heated under reflux for 1 hour. The mixture was cooled and was filtered. The filter cake was recrystallized twice from ethyl acetate to afford 1.1 g. of title product - m.p. 174-177Co Anal. calcd. for C15Hl~N404: C9 56.59; H~ 5.70; N~ 17.60 Found: C, 56.63; H~ 5~70; N, 17.55 Anti-secretory - 6~/o Anti-allergy - 96%; 10 mg/kg p.o.
-7,8-dihydto-5-hydrox~-2-(methylthio)-7-oxo-8-propylpyrido[2,3-d]-pyrimidine-6-carbox~lic_acid ethyl ester A stirred mixture of 23.3 g. ~0.1 mole) of 4-chloro-2-methylthio-5-pyrimidine carboxylic aeid ethyl ester, 5~9 g~
(0.1 mole) of prop~lamine and 10.6 g. (0.1 mole) of ~odium car-bonate in 150 ml. of ethanol was heated under re~l~ for 3 hours.
The mixture was ~iltered and the filtrate was evaporated in a rotary evaporator~ Theresidue was ~riturated with 100 ml.. of water and was extracted with 100 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evapor-ated in a rotary e~aporator to give a~out 13 g. of 2-methylthio-4-propylamino-5-pyrim;dine carboxylic acid ethyl ester as an oil which wa~ used directly in the next step without further purifi-cation. A small amount of this oil was dissolved in diethyl ether and was acidified with an ethereal hydrochloric acid 901u-tion. The precipitate which formed was collected and wa~ recry-stallized twice from ethyl acetate to af~ord the analytical sam-ple, m.p~ 132-135 ~.
Anal. calcd. for CllH1~ 302fi.HCl. C~ 45.28; ~, 6.22; N~ ~4.40 Fow~d: C, 45~05; H, 6~31; N, 14.3~
To a solution of 12.8 g. (0.05 mole~ of 2--methylthio-4-propylamino-5-pyrimidine carboxylic acid ethyl ester in 100 ml. of anhydrous diethyl ether was added 0.75 g. (0.025 mole) of ethyl malonyl chloride. The mixture was stirred at room temper-ature for 4 hours and was filtered~ me filt~abe was evapora-ted in a rotary e~aporator and the residue was dissolved in 15 ml. of ethanol and this solution was added to a solution of lo 15 go (0~ 05 g atom) of sodium i~ 100 ml. o~ ethanol. After stirring at room temperature for 5 minutes~ the m~xture was di luted with water to th~ cloudy point and was acidified with conc.
hydrochloric acid~ The precipitate which formed was coll~cted air dried and was recrystallized rom ethyl acetate to give 0~2 g. of title product - m,p~ 130-133 C.
Anal. calcd. for C14H1 ~ 30~S: Cj 52~00; H, 5.30; N, 12.99 Found: C, 51.61; H, 5.32; N, 12.84 Anti-secr~tory - 69%
Anti-allergy 70%; 10 mg/kg i.p.
~XAMPLE 21 7,8-dihydro 5-hydroxy-8-isopropyl-2-(methylthio)-7-oxo pyrido-~2~3-d ~ _ A stirred mixture vf 23.26 g. (0.1 mole) of 4-chloro-2-methylthio-5-pyrimidine carboxylic acid ethyl ester and 11.82 g~ ~0.2 mole) of isoprop~l ami~e in 200 ml. of ethanol was heated under reflux for 3 hours. The reaction mixture was taken to dry-ness ~n a rotary evaporator~ The residue was triturated with water until a ~olid had formed. The solid product 2-methyl-thio-4-isopropylamino-5-pyrimidine carbo~lic acid ethyl ester amounted to 28.1 g. An analytical sample was obtained by recry-stallization from ethanol - H20 m~p. 42-44 C.
Analc calcd. for CllHl ~302S: C, 51.74; E, 6~71; N, 1~.46 Fou~d: C, 51.52; H, 6.70; N, 1~.53 A mixture of 2701 g. of 2-methylthio-4~isopropylamino-5-pyrimidine carboxylic acid ethyl ester, 100 ml. of water, 10 ml. o~ ethanol and 100 mlO of 50% sodium hydroxide solution was stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate neutralized with glacial acetic acid. The 2-methylthio-4-isopropylamino-5-pyrimidine carboxylic acid which precipitated amounted to 15.5 g. An analytica~ sam-ple was obtained by recrystallization from ethanol - m.p~ 201-;
203 C.
_ ~7 -Anal. calcd. for C9H13N302S: C, 47.56; H, ~.76; N, 18.49 Found: C, 47.41; H, 5.76; N, 18~70 A stirred mixture of 14.0 g. of 2-methylthio-4~ o-propylami~o-5-pyrimidine carboxylic acid, 100 ml~ of ethyl chloroformate and 150 ml. of chloroform was he~ted for 24 hour3.
under re1ux. The solvents were removed in a rotary evaporator under ~uction. The IR spectrum of -the r0~idue indicates that cyclization to the anhydrid~ had not occurred. Xylene (200 ml~) was added to the residue and the reaction mixture was heated un-~0 der reflux for 3 hours. The reaction mixture wa~ filtered and the filtrate take~ to dry~ess on a rotary ~vaporator. The solid residue was washed with petroleum ether and amo~ ted to 3,4 g.
of 7-methylthio-1-isopropyl-2H-pyrimido~4,5-d]~1,3]oxa~ine-2, 4(1H)-diorle - m. p. 94-96 C. Ihe product was used i~ the next step without further purification.
To a solution of sodium ethoxide (a. g gJ .039 g. atom of sodium in 7S ml. of ethanol) was added 6,24 g. (0.03 mole) of diethyl malonate, The ethanol was removed in a rotary evapor-ator. To the re~idue was added 100 ml. of dimethyl formaD~de followed by 3~ 3 g. (0. 013 mole~ of 7 methylthio-1-isopropyl-2H~
pyrimido~4,5-d][1,3]oxazine-2,4(1H3-dione s~ The reactioIl mix-ture was heated u~der reflux for 1 hour, cooled in ice and poured into 400 ml. of water. The solution was acidified with conc.
hydrochloric acid and the resulting product was collected by suc-tion filtration. Recrystallization from ethanol gave 2 g~ of product - m.p~ 138--140 C.
Anal. calcd. for C14H1 ~ 304S: C, 52.00; H, 5.30; Nq 12.99 Found~ C, 51.81; H, 5.56; N~ 13.08 Anti-allergy - 84~o 25 mg/kg i.p~
E~ 22 7,8~dihydro-5~hydroxy-8-(2-methoxyethyl)-2-methylthio-7-oxo~
pyrido-[2,3-d~pyrimidine-6-carboxylic acid ethyl ester A mixture of 11.63 g. (.05 mole) of 4-chloro-2-methyl-thio--5-pyrimidine carboxylic acid eth~l este:r and 7~51 g. (0.1 mole~ of 2-metho~yethylamine in 100 ml~ of ethanol was hea$ed under reflux for 2 hours. The reaction mixture was filtered R~d the filtrate was taken to dryness on a rotary ev~porator. The residue ~mounted to 11.9 g. of ~-methylthio-4 (2-methoxy-ethyl-amino)-5-pyrimidine carboxy~ic a~id ethyl ester - m.p. 34~35 Ca Recry~tallization from petroleum ether gave 8.9 g. of prolduct, m.p. 36-37 C.
or CllEl ~ 303S: C~ 48.69; H, 6,31; N 15 49 Found: C, 48.66; H, 6~4D; N, 15.60 To a mixture of 26.4 g. of 2-methylthio--4-( -metho~
ethyl~-5-pyrimidine carboxylic acid ethyl ester in 100 ml~ of ethanol was added 100 ml. of water and 40 ml~ of 5~/o sodium hy-droxide soluti~n. The reaction mixture was allowed to stir at room temperature for 2 hours and then acidified wi~h glacial ace-tic acid. The resu~ting solid amounted to 18~0 g. of 2-methyl-thio-4-(2-methoxyethylamino)-5-pyrimidine carboxylic acid - m.p.
179-185 C. The analytical sample was obtained by recrystalliza-t ion from ethanol - m. p. 190-192 C .
Anal. calcdO for CgH13N303S C, 44.23; H, 5.38; N, 17.27 Found: ~7 44.35; H, 5.53; N, 17.470 A mixture of 17 g. of 2-methylthio-4-~2-methoxyethyl-amino)-5-pyrimidine carboxylic acid and 100 ml. of ethyl chloro-formate was heated under reflux for 5 1/2 hours. The reaction mixture was taken to dryness on a rotary evaporator. The r~si-due was recrystallized from eth~nol giving 4.3 gu of 1-(2-meth-oxyethyl)-7 methylthio-~H-pyrimido[4,5-d][1.3]oxa2ine-2,4~1H)-~,g s dione - m.p. 134-136C.
Analysis Calculated For: CloH21N3O4S
C, 4~.60; H, 4.12; N, 15.60 Found: C, 44.23; El, 4.33; N, 15.63 To a solu-tion of sodilam ethoxide (L.l ~. .04 g. atom of sodium ~n 50 ml. of absolute ethanol) was added 7.69 g. (.048 mole) of diethyl malonate. The ethanol was removed in a rotary evaporator. To the' residue was added 50 ml. of dimethyl formamide followed by 4.4 g. ~.016 mole) of 1-(2~methoxyethyl)-7-methyl-thio-2H-pyrimidol4,5-d] L 1,3~oxazine-2,4(lH)-dione. The reaction mixture was heated under reflux for 1 hour, cooled in ice and poured into 400 ml. of water. Acidification with conc. hydrochlo-ric acid gave 4.5 ~. of product - m.p. 102-104C. Rec'rystalli-zation from ethanol gave 3.9 g. of pure product - m.p. 110-112C.
Anal. calc f r C14 17 3 5 ~Eound: C, 49.62, H, 5.24; , 12.38 Anti-secretory - 47%
; Anti-allergy - 80%; 50mg/kg p.o.
Example 23 2~0 7,8-dihydro-5-hydroxy-2-(methylthio)-7-oxo-8-(2-propenyl)pyrido-[2,3-d~pyrimidine-6-carboxylic acid ethyl ester To a suspension of 9.29 g. (0.04 mole) of 4-chloro-2-methylthio-5-pyrimldine carboxylic acid ethyl ester in 100 ml. of ethanol co~led in an ice bath was added 4~56 g. (0.08 mole) of allylamine dropwise over 5 minutes. The mixture was stirred at room temperature overnlyht. The ethanol was evaporated in a rotary evaporator and the residue was triturated with 50 ml. of ether and was Eiltered. The flltrate was evaporated and the residue was dissolved in ethanol and was diluted with water. The precipitate which formed was collected to give 3.8 g. of 4-allylamino-2-methylthio~5-pyrimidine carboxylic acid ethyl ester - m.p. 41-43C.
- (Ref. E. Peter$ et al., J.Org. Chem., 25, 2137 (1960); m.p. 44-45~C).
-~x~ - 40 -,J,~ '7S
To a solutlon of 25.3 g. (0.1 mole) of 4-allylaminP-2 methylthio~5~p~rimidille carbo~ylic acid ethyl ester in 400 ml.
of anhydrous di:eth~l ether was added 7.5 ~. (0.005 mole) of ethyl m~lonyl chlori.de. The:m~ture was stirred at room tempera-ture for 3 hours. The:mixture was filtered and the filtrate was evap-.
~` - 40a -, ,.~ .
~ i75 orated in a rotary evaporator. The residue was ~issolved in 15 ml. o~ ethanol and this soLution was added to a solu~ion of 2.3 g. (0~ g~ atOm) of sodium in 200 mlO of ethanQl. The m~x-tur~ was stirred at room temperature for 5 minutes and was di-luted with water, acidified with glacial acetic acid and was extracted with 150 ml~ of diethyl etherr The ether layer was dried over magnesium sulfate, filtered and was acidified with gaseous hydrogen chloride. The mixture was filtered and the filtrate was cooled in ice. The preeipitate ~hich formed was collected and was recrystalli~d from ethyl acetate to give n. 2 gO of product - m.p. 134-135~ C.
Anal~ calcd. for Cl~H1 ~ 304S: C~ 52.32; H, 4.71; N, 13-08 Foundo C, 52.10; H, 4.76; N, 12.82 Anti-secretory - 48%
A~ti-allergy - 92%; 50 mg/kg pOo.
EX~MPiE 24 7,8-dihydro-5-hydroxy-2-methylthio-7-oxo-8-pipero~yl-pyrido ~2,3-d]pyrimidine-6-carboxylic acîd ethyl e~ter A mixture of 11.63 g. (0.05 mole) of 4-chloro-2-methyl-thio-5-pyrimidine carboxylic acid ethyl ester, 7.56 g. (.05 mole) of pipero~ylamine and 5.3 g. (0.05 mole) of sodium rarbonate in 100 mln of ethanol was heated under reflux for 2 hours. The re-action mixture was cooled in ice, filtered and the ~il$er cake ~iashed with water to remove inor~anic salts. The product 2 me$hylthio-4-piperonylamino-5-p~rimidine carboxylic acid ethyl ester amounted to 14.7 g. - m.p. 85-88 C~ It was used in the ~ext step without purification.
Anal. calcd. for C16H1 ~ 30~S: C, 55.32; H, 4.93; N~ 12.10 Found: C, 55.38; H, 4~88; N, 12.21 -- ~1 --~L~ 7 ~
To 100 ml. o.f 5~o sodi~ hydroxide solution was added 14.7 g. of 2-methylthio-4-pipero~yla~ino-5-pyrimidine carboxylic acîd ethyl ester~ A few milliliters of ethanol was addedr The reaction mixture wa~ heated on a hot plate for a few minutes un-til a clear ~olution was obtained and then allowed to stir for s~veral hours at rovm temperature. Acidification with CollC.
hydrochloric acid gave 13 g. of 2-methylthio--4-piperonylamino-5-pyrimidiQe carboxylic acid - mOp. 214-217C. The product was used ~n the next step without purifi~ation.
A mixture of 5 g. of 2-methylthio-~-piperonlyam:uno-5-pyrimidine carboxylic acid in ~0 ml. of ethyl chloroforma1te was heat~d under reflux for 2 1/2 hours. The reaction mixture was cool~d i~ ice and filtered under ~uction. The filter cake afte.r washing with ethanol amounted to 4.0 g~ of 7-methylthio-1-piper-onyl-2H-pyrimidoC495-d]~1,3]oxaæine~2,4(1H)-dione, hydrate ~
m.p. 160-164 C~ An analytical sample was obtained b~ recry-stallizing from eth~nol - m.p~ 160-16~ C.
or C15HllN305S H20: C9 49-58; H, 3-60; ~ 11 5~
Found: C, 49.15; H~ 3.49; N, 11.15.
To a solutiQn of sodium ethoxide (1.6 g., .03 g~, atom of sodiwm i~ 50 ml. of absolute ethanol) was added 4.8 g~ (.03 mole) of diethyl maln~ate. The ethanol W2S removed under suc-tiOn in a rotary evaporator. To the residue was added 50 ml.
of dry dimethyl for~amide followed by 3.5 gO (oOl mole~ of 7-methylthio-l-piperonyl-~.H-pyrimido[4,5-d][1,3]oxazi~e-2,4(1H)-dione. The reaction mixture was heated under reflux for 2 hour~
cooled in ice and poured into ~00 ml~ of waterO m e reac~ion mixture was aoidified with cOnc. h~drochloric acid. The result-ing precipitate amo~nted to 5~0 g. - m.p. 173-178 C.
Recrystallization from dimethyl formamide gave 3.4 æ. of pure prOduct - m.p. 187-188 C.
- ~2 -C~ 306S: C, 54.93; H, 4.12; N, 10 11 F'ound: C, 54.69; ~, 4.27; N, 10.13 Anti~secretory - 47~o ~nti-allergy - 67.3%; 100 mg/kg i.p.
34.9/0; 50 m~/kg p.o.
~ XAMPLE 25 8-allyl-~j8-dihydro 5-(2-m0thoxyet~lylamino)-7-oxo-2 phenylpyri-do~2~3-d]pyrimidine-6-c~rbox~lic acid ethyl ester Twenty ml. of phosphorous oxychloride was comb~ned with 0.87 g. (oO025 mole) of 8-allyl-7,8-dihydro-5-hydroxy-7-oxo-2-phe~ylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester and this was heated at reflux for 5 hour~. Then the POC13 was evaporat~d and crushed iee added to the residue and the white solid that appeared was fiItered off, ri~sed with water and pe-troleum ether and dried to gi~e 0~ g. of 8~allyl-5-chloro-7, 8-dihydro-7-oxo-2-phe~ylpyrido[2~3-d]pyrimidine-6-carboxylic acid ethyl e~ter - mLp. 148-152C C~ This product was used in the next step without further purificationO
To O.g g, ~.0024 mole) of 8-allyl-5-ehloro-7,8-dihy-dro-7-oxo-2-phenylpyrido~2,3-d]pyrimidi~e-6-carb~xylic acid ethyl ester in 30 ml. of ethanol waæ added 0.17 g. ~.0024 mole) of 2-methoxyethylamine a~d 0.25 g. (.0024 mole) of Na2CO30 This mixture was heated at reflux for 4 hours, then filtered and the filtrate chilled. Yellow crystals formed and were collected On a filter~ Recrystallization from ethanol gave 0.5 g. of pro-duct - m.p. 155-158 C.
C22H24N404: C, 64.69; H, 5.92; N 13 72 Found: C, 64.43; H, 5.99; N, 13.47 Anti-secretory ~ 58%
7~i 2~
7,8-dihydro-8-(2-methox~ethyl)-5-(2-methoxyethylamino)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl e~ter .
80 ml. of phosphornus oxychloride was combined with 4.0 g. (.011 mole) of 7,8-dihydro-5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-PhenylPyridoC2,3-d]Pyrimidine-6-carbox~lic acid ethyl ester and heated at refl~x for 5 hours9 Then the POC13 was re-mo~ed by evaporation and crushed ice added to the residue~ ~he ensuing white solid was filtered off, rinsed well with water and petroleum ether and dried to gi~e 3.8 g~ of 5-chloro-7,8-dihydro-8 (2-methoxyethyl)-7-oxo-2-phenylpyrido~2,3-d]pyrimidine-6-car-boXylic acid ethyl ester - mOp. 119-121 C. This product was used in the next step without further purificationO
To 2.4 g. (.006 mole) o~ 5-chlorow7,8-dih~dro-8 (2-methoxyethyl)-7~oxo-2-phenyl-pyrido~2~3-d]p~rimidine~6 carboxylic acid ethyl ester in 100 ml. Of etha~ol was added 0O45 g. (.OOS
mole) o 2-meth~xyethylamine and 0.65 g~ ~.006 mole) o Na2CO30 This mixture was refluxed 3 hours, then filtered a~d the filtrate ehilled. A solid formed and was filtered off and rinsed with petroleum ether - m~pn 160-163 C. No further purificati,~n was necessary.
C22H26N405: C, 61.96; H, 6015; N, 13 14 Fo~nd: C, 61D75; H, 6.09; N, L3.33 Anti-secretory - 12%
~nti-allergy - 38%; 25 mg/kg p.o~ 10 min. before antigen 2%; 25 mg/kg p.o. ~0 min. before antig~n -- 4~ ~
47~ .
7,8-dihydro-8-ethyl-N (2-hydroxyethyl~ 5-(2-hydroxyethylamino)-_ 7-ox~-2-phenylp~ o~2t3-d]
To 2 g. (~0056 mole) of 5-chloro-7,8-dihydro-8-ethyl-7-oXo-2-Ph~n~lpyrido[2s 3-d~pyrimidirla-6-carboxylic acid ethyl ester (prepared by the methnd of the first paragraph of Example 3) was added 20 ml. of 2-aminoethanol and this mixture was heated at reflux for 1.5 hours. The reaction mixt~e was chilled in ice and the prOd~ct collected On ~ filter a~d recrys%allized from ethanol to give 1.7 g. of product~ - m.p. ~50-253 C.
Anal. ~.alcd. for C2~H23N56 C~ 59r 84; H~ 5- ; 5 Found: C, 59~95; H, 5085; N9 17.34 E~ ~LE 28 5-aminO-7, 8-dihydro-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido-C2t 3-d]pyrimidine-6-carboxylic acid ethyl ester Cnmbined 11 g. (.051 mole) of 4-chloro-5-cyano-2-phen-ylpyrimidine, 5~4 g. ~7051 mole) ~f Na2C03 aIld 3.8 g. (.OSl mole) of 2-methoxyethylamine in 250 ml. of ethanol and heated this at reflux fOr 3 hours. Then the reactiOn was filtered and the fil-20 trate chilled. me product precipitated ~ut nf solutinn and wascollected On a filter and rinsed with petroleum ether to give 9.3 g. of 4-(2-methoxyethylaminn~-2-phenyl-5-pyrimidinecarboni-trile m.p. 122-126 C. The product was used in the next step without further purificatiOn.
To 903,g~ (.037 mole) of 5-cyanO-4-(2-methoxyethyl-; amino)-2-phenyl p~rimidi~e in 350 ml~ of diethyl ether was added 2.8 g. (.019 mole) of ethyl mal~nyl chlOride and this mixture was stirred at rOOm temperature for 405 hours. Then the solid material was filtered off a~d the filtrate evaporated to dryness.
Ethano~ was added until a sOlution was obtained and this solution :
S
was added to 0.85 g. (.057 mole) of Na ~n ethanol and stirred 20 minutes. A little water was added and the solution was acidified with acetic acid. me solid product was collected ~n a suctio~ filter and recry~tallized from ethanol to give 2.0 g. of prOduct - m.p. 2~5-247~ C., Or C19H20N404: C, 61.94; E, 5.47, N, 15 21 - Fo~d: C, 61.59; H, 5,.49; N, 15.31 E~MPLE 29 7, 8~dihydro-5-hydroxy-N~ 8-bis (2-methoxyethyl) -7-oxo-2-phenyl-pyrido ~2, ~-d] pyrimidine-6-carboxamide T~ 1~0 g. (.0027 mole) of 7,8-dihydro-5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-phen7lpyridoc2~3-d]pyrimidine-6~carboxylic acid ethyl e~ter (prepared as in Example 9) was added 0.4 g.
(,0054 mole) of 2-methoxyethylamine in 25 ml~, of ethanol ~nd this was heated at reflux for 4 hour~. The reactiOn was the~ filter-ed a~d chilled and -the filtrate ga~e up a solid that was collect-ed On a SllCti~ filter ~ rin~ed with petrole-un ether. No fur-ther purification was necessary - m.p. 150-154~ C.
A}lal. calcd- for C20H~2~405 C, 60~29; H~ 5-57; N, 14-06 Found: C, 60.~g; H, 5.72; N, 14.03 EXAMPL~ 30 _ N-~2-(diethylamino)ethyl]-7,8-dihydro-5-hydroxy-8-(2-methoxyeth-yl)-7-oxo-2-phenylpyrid~[2,3-d]pyrimidine-6-carbOx~mide To 1.0 g. (.0027 mole3 o 7,8-dihydrO-5-hydrQxy-8-(2 methoxyethyl)-7-oxo-2-phenylpyridoC2,3-d]pyrimidine-6-car~oxy-lie acid ethyl ester (prepared as in E~ample 9) was added to 0.63 g. (.0054 mole~ of diethylethyle~ediamin~ in 25 ml~ of eth-anol. This mixture was heated to refl~Y for 3.5 hours. Then - ~6 -~ ;75 ice-chill;ng caused the formation of a white snlid tha~ was filtered off and re-crystallized from ethanol to giYe 0.9 g. of prOduct with a mrp~ 115 117 C.
Anal- calcd- for C23H2 ~ 54~ C, 62-85; H~ 6~65; N~ 15~4 Found: C~ 62.91; N, 6.70; N, 15.84 7~8-dihydro-5-hydr~x~-7-oxo-2-phenyL-8-(2-propargyl)pyrido[2l3 -d]-pyrimidine-6-carboxylic ~cid ethyl ester 10 grams (.1 mole) of 95% propargylami~e HCl was added to a solutio~ o~ 2.4 g. ~.1 mole) of Na in 50~ ml~ of ~thanol and stirred 15 mi~utes~ Then the solid wa~ filtered Off and to the filtrate was added 27~3 g~ (.1 mole) of 4-chloro-2-ph~ny~-5~-pyrimidinecarb~xylic acid ethyl ester a~d 11 g. (.1 mole) of Na2C03. This mixture was heated at reflu~ for 3 ho~s7 Then the reactio~ was agai~ filtered and the filtrate chilledq The pro- :
duct precipitated out and was filtered off and rinsed with pe-troleum ether to give 25.8 g. of 2-phenyl-~propargy1~nino-5 pyrimidinecarb~xylic acid ethyl ester - m.p. 110-115 C. The prOduct was used in the subseque~t step without further purifica-tinn.
T~ 11.6 g. of 2-phenyl-4-propargylamino-5-pyrimidine-carb~xylic acid ethyl ester in 200 ml. of ether and 800 ml. nf tetrah~drofuran was added 3.1 g. ~.02 mole) of ethyl malo~yl-chlOride and this was stirred 2~S hours at rOom temperature.
men filtration remo~ed al 1 solid and the filtrate ~as evapOr-ated to dryness and ethanol was added to the residue. A solu-tio~ of 0.95 g. ~.041 mole~ of Na in 50 ml. of ethanol was added to the residue sOlution ~nd stirred 10 minutes a$ roOm tempera_-ture. A little water was added and the soluti~n acidified with - ~7 _ ~Z~7S
acetic acid and the ensuing solid filtered off. Recrystalliz-ation from ethyl acetate gave 1~5 gO of product - m.p. 214-215 C.
Anal- calcd~ for C14H1 ~34 C~ 65.43; H~ 4~33; N~ 12-03 Found: C, 65~25; H, 4.56; N, 12.07 Anti-allergy - 68D/n; 25 m~/k~ p.oO 10 min. before antigen ~/o; 25 mg/kg p.o. 60 min, before antigen EXAMPLE 3~
_ 8-all~1-5-ami~o-7,8-dihydro-7-oxo-2-phenylpyr~doC2,3-d]pyrimi __ _ di~e~6-carbox A mîxt~re of 11.2 g. (.052 mole) of 4-chloro-2-phenyl~
5-pyrimidinccarbonitrile~ 3~0 g. (oO52 mole) o~ allylamine and 5.5 g. (,052 mole~ of Na2C03 in 250 ml~ of ethanol was refluxed : 4 hours. The solid material was then fil~ered off a~d the fil-trate chilled. A solid precipitated out and was rin~ed with petroleum ether to give 7.3 gO of 4-allylamino-2-phenyl-5-pyri-midinecarbonitrile - mOp. 158~181 C. l~liS ma$erial was u~ed in a subseq~ent step without further purification.
Anal. calcd. for C14H12N4: C, 71-16; H~ 5-12; N~ 23-71 Foundo C, 70.96; H, 5.11; N, 23~31 A mixture of 7.3 g, (.031 mole) of 4-allylami~o-2-phenyl-5-pyrimidinecarbonitrile and 2.3 g. (aO15 mole) of ethyl malonyl chloride in 300 ml. o~ ether was s~irred at room temp-erature for 4 hour~. The reaction was then filtered and the fil-trate e~aporated to dryness. Ethanol wa~ added to the residue ~nd the slurry was then poured into a solution of 0.7 g. sodium (.031 mole) in 50 ml. of ethanol and stirred for 20 minutes.
Water was then added and the reaction acidified with acetic acid~
~he white solid was filtered off ~nd recrystallized from ethanol to give 1.4 g. of product - mOp. 234-236 C.
- ~8 4~
~nal~ calcd. for ClgH18N403 C, 6S.13; H, 5.18; N, 15.99 Found: C, 64.74; H, 5.07; N, 16.07 E~A~PLE 33 5-amino-7,8-dihydro-8-ethyl-~methyl-7-oxo-pyrido-~2,3-d]pyrimi-_ _ dine~6-carboxylic acid e~hyl e~ter_ _ _ _ _ To a solution of 3~45 g. (0.15 g. atom) of ~odi~ in 500 ml. of ethanol was added ~4.0 g. (0.15 mole) o diethyl mal-onate followed by 6~7 g~ (0.15 mole) 4-amino--2-methyl-5-pyrimi~
dinecarbonitrile~ ~he reaction mixture wa~ heated under reflux with stirring for 17 hours. The resultiQg filter cake was remov- :
ed by filtrati~n to obtain the sodi~m salt ~f 5-amino 7,8-dihy-dro~2-methyl-7-oxo-p~ridoC2, 3-d~ pyrimidine-6-carboxylic acid ~thyl ester.
To a solutio~ containing 5.4 g. (0.02 mole) of the ~od-dium salt of 5-amino-7,8-dih~dro-2-methyl-7-oxo-pyrido~2,3-d~-pyrimidine-6-carbaxylic acid ethyl ester in 50 ml~ of dimethyl-formamide was added 9.35 g. (0.06 mole~ of ethyl iodide. The reaction mixture was heated to 50 for 4 hours; cooled in ice and then po~red into one liter of water. The reaction mixture was kept in a cold room for 3 days and was then filtered. The product amou~ted ~o ~.4 gO (m. PJ 230~231 ) ~ The analytical ~am-pl~ was obtained by recrystallizatio~ from ethanol.
Anal, calcd. for C13H16N403: Cs 56.51; H~ 5-84;
Fou~d: C, 56.12; H, 5.66; N1 20.09 Percentage inhibition: 60%
~L'~()~7 5-amino-8-ethyl-75 8-dihydro-7-oxo-2-propyl-pyrido~2, 3-d~pyrimi-dine~6-carbox lic acid ethYl ester To a solution of 3.4 g. (0.15 g. atom) o~ sodium in 250 ml. of ethanol was added 2400 g~ (Ol 15 mole) of diethyl mal-onate. After a few minutes 8.1 g~ (0O05 mole) of 4-amino-2-propyl-S-p~rimidine carbonitrile was added. The reaction mix-ture was heated under reflux with stirrillg or 5 hours, during which time the sodium salt o~ S-amino-7,8-dihydro-7-oxo-2-prop-yl pyrido~2,3-d]pyrimidine-6-carboxylic acid ethyl ester precip-itated out of solution. This material amounted to 11.3 g.
To a solution containing 5.96 g. (0.02 mole) of the above sodium salt in 50 ml. of dimethylformamide was added 9.36 g. (0.06 mole) of ethyl iodide. The reaction mixture was heated at 50 for 2 hours and was then cooled i~ ice and poured into 500 ml. o~ waterO m e resulting precipitate was collected and amounted to 4O9 g. (m-p- 192-193). Recrystallization from eth-anol gave 3.0 g. of product9 m.p~ 199-200.
Anal- calc~- for C15H20N43 C~ S9 Fou~d: C, 69.19; H, 6.59; N 5 18~81 Percentage inhibition: 29%
E~AMPLE 35 5-amino-8-butyl-7,8-dihydro-2-methyl 7-oxo-pyrido[2,3 d]pyrimi-dlne-6-carbo~ylic~ l ester _ _ To a solution containing 5.4 g. (0~02 mole) of the sodium salt of 5-amino-7,8-dihydro-2-m~thyl-7-oxo-pyrido[2,3-d]-pyrimidine-6-carboxylic acid ethyl ester in 50 ml~ of dimethyl-formamide was added 4.6 g. of butyl iodide. The reaction mixture was heated to 50 for 3 hours, cooled overnight at room temper-ature ~ d was then poured into 500 ml. of water. The product - 50 ~
was collected on a suction filter giving 5.5 g. o crud~ pro-duct, m.p. 214-216. Recs~y~tallization from ethyl acetate af-forded 2~9 g. of product, m.p. 220-222.
Anal. calcd. for clsH2~N4o3: C~ 5 Found: C, 59.13; H, 6056; N, 18.41 8-all~1-5-amino-7,8-dihydro-2-methyl-7-oxo-p~grido[~,3-d]pyrimi-_ dine-6-carboxylic acid eth~l ester _ _ To a solution r.o~taining 5.96 g. ~0.02 mole) of the sodium salt of 5~amino-7,8-dihydro-2-met~yl-7-oxo-pyrido[2,3-d]-pyrimidine-6-~carboxylic acid ethyl ester in 50 ml. of dime$hyl-formamide was added 4.83 g. (0.04 mole) of allyl bromide. The reaction mixture was heated to 50 for 4 hours, cooled in ice and then added to one liter of water. The reaction mixture was cooled in ice and the r~sulting precipitate was collected on a filter. There was obtai~ed 2.9 g. of product, m.p. 217-219 C.
Recrystallization from ethanol gave 1~89 of pure product, m.pO
223-225 C.
Anal. calcd. for C14H16N~03: C, 5 2;
Found: C, 57.87; H, 5~55; N, 19.66 Percentage inhibition: 68%
EXAMPLF. 37 ~-allyl-5-amino-7,8-dihydro-7-oxo-2-propyl-pyridoC2,3-d]pyrimi-_ dine-6-carboxylic acid ethyl ester_ To a solution of 4. 4 g. (0.15 mole) of the sodium s~lt of 5-amino-7,8-dihydro 7-oxo-2-propyl-pyrido[2,3-d]-pyrimidine~
6-carboxylic acid ethyl ester in 50 ml. of dimethyl-~ormamide was added 5.4 gO (0.045 mole) of allyi bromide. me reaction mixture ~-as heated at 50 for 2 hours and was then cooled in ice ~ 7 ~
and poured into 500 ml. of water. The resulting precipitate amountsd to 3.0 g~, m.p. 185-189 C. Recrys-talliæation from ethanol ~ave 2.5 g.~ m.p. 191~193 C.
Anal- calcd- for C16H2 ~ ~3 C, 60-74; H~ 6-37; N~ 17-71 Found: C, 60.55; E, 6,31; N, 17.68 5-amino~7,8-dihydro-2-methyl-7-oxo~pyrido[2,3-d~pyrimidin~-6-carbo~ylic acid ethyl ester To a solution of 3.45 gO (0.15 g. atom) of sodiwm in 500 mlO of ethanol was added 24~0 g. (0.15 mole) of diethyl mal-onate followed by 6.7 g. (0.15 mole) 4 amino-2-methyl-5-pyrimi dinecarbonitrile9 The reaction mixture was heated uncler reflu~
with stirring for 17 hoursO The resulting filter cake was re-moved by filtratio~ and di~sol~ed in 200 ml. of water/ The solu-tion was acidified with conc. hydrochloric acid. The resulting precipitate was collected and recrystallized from ethanol. There was obtained ~.8 g. of product, m.p. 273-275 C.d~
Anal. calcd. for CllH12N403 _ : C, 51.35; H, 5.09;:~
2 N, 2l~78 Found: C, 51.24; ~, 5.00; N~ 21~25 Percentage inhibitiona 58%
- 5~ -
and poured into 500 ml. of water. The resulting precipitate amountsd to 3.0 g~, m.p. 185-189 C. Recrys-talliæation from ethanol ~ave 2.5 g.~ m.p. 191~193 C.
Anal- calcd- for C16H2 ~ ~3 C, 60-74; H~ 6-37; N~ 17-71 Found: C, 60.55; E, 6,31; N, 17.68 5-amino~7,8-dihydro-2-methyl-7-oxo~pyrido[2,3-d~pyrimidin~-6-carbo~ylic acid ethyl ester To a solution of 3.45 gO (0.15 g. atom) of sodiwm in 500 mlO of ethanol was added 24~0 g. (0.15 mole) of diethyl mal-onate followed by 6.7 g. (0.15 mole) 4 amino-2-methyl-5-pyrimi dinecarbonitrile9 The reaction mixture was heated uncler reflu~
with stirring for 17 hoursO The resulting filter cake was re-moved by filtratio~ and di~sol~ed in 200 ml. of water/ The solu-tion was acidified with conc. hydrochloric acid. The resulting precipitate was collected and recrystallized from ethanol. There was obtained ~.8 g. of product, m.p. 273-275 C.d~
Anal. calcd. for CllH12N403 _ : C, 51.35; H, 5.09;:~
2 N, 2l~78 Found: C, 51.24; ~, 5.00; N~ 21~25 Percentage inhibitiona 58%
- 5~ -
Claims (84)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula:
.I
in which R2 is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, phenyl, 4-methoxyphenul, 4-chlorophenyl, l-pyrrolidinyl or methylphenylamino; R5 is hy-droxy, alkylamino of 1 to 6 carbon atoms, 2-hydroxyethylamino, 2-alkoxyethylamino of 3 to 8 carbon atoms, dialkylamino where-in each alkyl group contains from 1 to 6 carbon atoms, 4-me-thyl-l-piperazinyl, 4-morpholinyl, l-pyrrolidinyl or amino with the provisos that if R8 is alkyl and R2 is phenyl then R5 is other than amino and if R8 is alkyl and R2 is alkylthio, then R5 is other than l-pyrrolidinyl; R6 is alkoxy of 1 to 6 carbon atoms, amino, mono- or di-alkylamino where each alkyl group contains from 1 to 6 carbon atoms, 2-hydroxyethylamino, 2-al-koxyethylamino of 3 to 8 carbon atoms or 2-(dialkylamino)ethyl-amino in which each alkyl group contains from 1 to 6 carbon atoms; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, 2-alkoxy-ethyl of 3 to 6 carbon atoms, allyl, propargyl, phenyl, 4-me-thoxyphenyl, 4-chlorophenyl, benzyl, 4-methoxybenzyl, 4-chlo-robenzyl, 4-(4-morpholinyl)-phenyl or piperonyl, or a pharma-ceutically acceptable salt thereof which comprises:
(a) reacting a pyrimidine derivative of the general formula:
where X is -C02 alkyl or -CN with (i) an alkyl malonyl halide followed by ring closure under basic conditions; or (ii) when X is -CN, an alkali metal dialkyl malonate followed by acid-ification to give a compound of formula I in which R5 is hy-droxy or amino and R6 is alkoxy, or (b) reacting a compound of the formula:
where R2 and R8 are defined supra, with an alkali metal dialkyl malonate to give a compound of formula I in which R5.is hydroxy and R6 is alkoxy and, if desired, (c) halogenating a compound of formula I in which R is hydroxy to give a corresponding compound in which R5 is halogen and reacting the halo compound with an amine to give a compound of formula I in which R5 is amino, alkylamino, 2-hydroxyethyla-mino, 2-alkoxyethylamino, dialkylamino, 4-methyl-1-piperazinyl, 4-morpholinyl or l-pyrrolidinyl and/or d) oxidizing a compound of formula I in which R2 is alkylthio to give a corresponding compound in which R2 is alkyl-sulphonyl and acidifying the alkylsulphonyl compound to give a compound of formula I in which R is hydroxy or reacting the alkylsulphonyl compound with an amine to give a compound of for-mula I in which R2 is l-pyrrolidinyl or methylphenylamino and/or (e) reacting a compound of formula I in which R6 is alkoxy with ammonia or with an amine to give a compound of formula I in which R6 is amino, alkylamino, dialkylamino, 2-hydroxyethylamino, 2-alkoxyethylamino or 2-(dialkylamino)ethylamino, and/or (f) alkylating, allylating or alkynylating a compound of formula I in which R8 is hydrogen to give a compound in which R8 is alkyl, allyl or propargyl, and/or (g) converting a basic compound of formula I into its phar-maceutically acceptable salt.
.I
in which R2 is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, phenyl, 4-methoxyphenul, 4-chlorophenyl, l-pyrrolidinyl or methylphenylamino; R5 is hy-droxy, alkylamino of 1 to 6 carbon atoms, 2-hydroxyethylamino, 2-alkoxyethylamino of 3 to 8 carbon atoms, dialkylamino where-in each alkyl group contains from 1 to 6 carbon atoms, 4-me-thyl-l-piperazinyl, 4-morpholinyl, l-pyrrolidinyl or amino with the provisos that if R8 is alkyl and R2 is phenyl then R5 is other than amino and if R8 is alkyl and R2 is alkylthio, then R5 is other than l-pyrrolidinyl; R6 is alkoxy of 1 to 6 carbon atoms, amino, mono- or di-alkylamino where each alkyl group contains from 1 to 6 carbon atoms, 2-hydroxyethylamino, 2-al-koxyethylamino of 3 to 8 carbon atoms or 2-(dialkylamino)ethyl-amino in which each alkyl group contains from 1 to 6 carbon atoms; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, 2-alkoxy-ethyl of 3 to 6 carbon atoms, allyl, propargyl, phenyl, 4-me-thoxyphenyl, 4-chlorophenyl, benzyl, 4-methoxybenzyl, 4-chlo-robenzyl, 4-(4-morpholinyl)-phenyl or piperonyl, or a pharma-ceutically acceptable salt thereof which comprises:
(a) reacting a pyrimidine derivative of the general formula:
where X is -C02 alkyl or -CN with (i) an alkyl malonyl halide followed by ring closure under basic conditions; or (ii) when X is -CN, an alkali metal dialkyl malonate followed by acid-ification to give a compound of formula I in which R5 is hy-droxy or amino and R6 is alkoxy, or (b) reacting a compound of the formula:
where R2 and R8 are defined supra, with an alkali metal dialkyl malonate to give a compound of formula I in which R5.is hydroxy and R6 is alkoxy and, if desired, (c) halogenating a compound of formula I in which R is hydroxy to give a corresponding compound in which R5 is halogen and reacting the halo compound with an amine to give a compound of formula I in which R5 is amino, alkylamino, 2-hydroxyethyla-mino, 2-alkoxyethylamino, dialkylamino, 4-methyl-1-piperazinyl, 4-morpholinyl or l-pyrrolidinyl and/or d) oxidizing a compound of formula I in which R2 is alkylthio to give a corresponding compound in which R2 is alkyl-sulphonyl and acidifying the alkylsulphonyl compound to give a compound of formula I in which R is hydroxy or reacting the alkylsulphonyl compound with an amine to give a compound of for-mula I in which R2 is l-pyrrolidinyl or methylphenylamino and/or (e) reacting a compound of formula I in which R6 is alkoxy with ammonia or with an amine to give a compound of formula I in which R6 is amino, alkylamino, dialkylamino, 2-hydroxyethylamino, 2-alkoxyethylamino or 2-(dialkylamino)ethylamino, and/or (f) alkylating, allylating or alkynylating a compound of formula I in which R8 is hydrogen to give a compound in which R8 is alkyl, allyl or propargyl, and/or (g) converting a basic compound of formula I into its phar-maceutically acceptable salt.
2. A compound of the formula in which R2 is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, phenyl, 4-methoxyphenyl, 4-chlorophenyl, l-pyrrolidinyl or methylphenylamino; R5 is hy-droxy, alkylamino of 1 to 6 carbon atoms, 2-hydroxyethylamino, 2-alkoxyethylamino of 3 to 8 carbon atoms, dialkylamino where-in each alkyl group contains from 1 to 6 carbon atoms, 4-me-thyl-l-piperazinyl, 4-morpholinyl, l-pyrrolidinyl or amino with the provisos that if R8 is alkyl and R2 is phenyl then R5 is other than amino and if R8 is alkyl and R2 is alkylthio, then R5 is other than l-pyrrolidinyl; R6 is alkoxy of 1 to 6 carbon atoms, amino, mono- or di-alkylamino where each alkyl group contains from l to 6 carbon atoms, 2-hydroxyethylamino, 2-al-koxyethylamino of 3 to 8 carbon atoms or 2-(dialkylamino)ethyl-amino in which each alkyl group contains from l to 6 carbon atoms; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, 2-alkoxy-ethyl of 3 to 6 carbon atoms, allyl, propargyl, phenyl, 4-me-thoxyphenyl, 4-chlorophenyl, benzyl, 4-methoxybenzyl, 4-chlo-robenzyl, 4-(4-morpholinyl)-phenyl or piperonyl, or a pharma-ceutically acceptable salt thereof whenever prepared or produced by the process as claimed in Claim 1 or an obvious chemical equi-valent thereof
3. A process as claimed in Claim l wherein R is phenyl, methylthio or l-pyrroldinyl; R5 is amino, hydroxy, 2-methoxyethylamino or l-pyrrolidinyl; R6 is ethoxy and R8 is hy-drogen, methyl, ethyl, propyl, allyl, 2-methoxyethyl, phenyl, piperonyl, 4-methoxybenzyl or benzyl.
4. A compound of formula I or a pharmaceutically ac-ceptable salt thereof whenever prepared or produced by the process of Claim 3 or an obvious chemical equivalent thereof.
5. A process as claimed in Claim l wherein R2 is hy-drogen, hydroxy, alkyl of l to 6 carbon atoms, alkylthio of l to 6 carbon atoms, phenyl, 4-methoxypbenyl, 4-chlorophenyl, l-pyrro-lidinyl or methylphenylamino; R5 is hydroxy, alkylamino of l to 6 carbon atoms, dialkylamino wherein each alkyl group contains from l to 6 carbon atoms, 4-morpholinyl, 2-alkoxyethylamino of 3 to 8 carbon atoms or 2-(dialkylamino)ethylamino in which each alkyl group contains from l to 6 carbon atoms; and R8 is alkyl of l to 6 carbon atoms, 2-alkoxyethyl of 3 to 6 carbon atoms, allyl, pro pargyl, phenyl, 4-methoxyphenyl, 4-chlorophenyl, benzyl, 4-meth-oxybenzyl, 4-chlorobenzyl, 4-(4-morpholinyl)phenyl or piperonyl.
6. A compound of formula I or a pharmaceutically acceptable salt thereof whenever prepared or produced by the process of Claim 5 or an obvious chemical equivalent thereof.
7. A process as claimed in Claim 1 which comprises reacting 4-ethylamino-2-phenyl-5-pyrimidine carboxylic acid ethyl ester with ethyl malonyl chloride in diethyl ether and treating the product with sodium dissolved in ethanol followed by acidification.
8. 8-ethyl-7,8-dihydro-5-hydroxy-7-oxo-2-pllenylpyri-do[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharma-ceutically acceptable salt thereof whenever prepared or produced by the process as claimed in Claim 7 or an obvious chemical equivalent thereof.
9. A process as claimed in Claim 1 which comprises reacting l-ethyl-7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione with sodio diethyl malonate followed by acidification.
10. 8-Ethyl-7,8-dihydro-5-hydroxy-7-oxo-2-phenylpyrido-[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceu-tically acceptable salt thereof whenever prepared by the process of Claim 9 or an obvious chemical equivalent thereof.
11. A process as claimed in Claim 1 which comprises refluxing an ethanolic solution of 5-chloro-8-ethyl-7,8-aihydro-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester with pyrrolidine in the presence of sodium carbonate.
12. 8-Ethyl-7,8-dihydro-7-oxo-2-phenyl-5-(1-pyrroli-dinyl)pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof whenever prepared by the process of Claim 11 or an obvious chemical equivalent thereof.
.
.
13. A process as claimed in Claim 1 which comprises refluxing an ethanolic solution of 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester with morpholine in the presence of sodium carbonate.
14. 7,8-Dihydro-8-ethyl-5-morpholino-7-oxo-2-pheny]-pyrido[2,3-d]pyrimidine carboxylic acid ethyl ester or a pharma-ceutically acceptable salt thereof whenever prepared by the pro-cess of Claim 13 or an obvious chemical equivalent thereof.
15. A process as claimed in Claim l which comprises refluxing an ethanolic solution of 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester with N-methylpiperazine in the presence of sodium carbonate.
16. 7,8-Dihydro-8-ethyl-5(4-methyl-1-piperazinyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl es-ter or a pharmaceutically acceptable salt thereof whenever pre-pared by the process of Claim 15 or an obvious chemical equivalent thereof.
17. A process as claimed in Claim 1 which comprises heating in an autoclave a mixture of 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester with diethylamine.
18. 5-Diethylamino-7,8-dihydro-8-ethyl-7-oxo-2-phenyl-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharma-ceutically acceptable salt thereof whenever prepared by the pro-cess of Claim 17 or an obvious chemical equivalent thereof.
19. A process as claimed in Claim 1 which comprises reacting 4-propylamino-2-phenyl-5-pyrimidine carboxylic acid ethyl ester in diethyl ether with ethyl malonyl chloride and treating the product with sodium dissolved in ethanol followed by acidification .
20. 7,8-Dihydro-5-hydroxy 7-oxo-2-phenyl-8-propyl-pyrido[2,3 d]pyrimidine-6-carboxylic acid ethyl ester or a phar-maceutically acceptable salt thereof whenever prepared by the process as claimed in Claim 19 or an obvious chemical equivalent thereof.
21. A process as claimed in Claim 1 which comprises reacting 7-phenyl-1-propyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione with sodio diethyl malonate followed by acidification.
22. 7,8-Dihydro-5-hydroxy-7-oxo-2-phenyl-8-propyl-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a phar-maceutilcally acceptable salt thereof whenever prepared by the pro-cess of Claim 21 or an obvious chemical equivalent thereof.
23. A process as claimed in Claim 1 which comprises reacting 4-(2-methoxyethylamino)-2-phenyl-5-pyrimldine carboxylic acid ethyl ester with ethyl malonyl chloride in diethyl ether and treating the product with sodium dissolved in ethanol followed by acidification.
24. 7,8-Dihydro-5-hydroxy-8(2-methoxyethyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof whenever prepared by the process of Claim 23 or an obvious chemical equivalent thereof.
25. A process as claimed in Claim 1 which comprises reacting 1(2-methoxyethyl)-7-phenyl-2H-pyrimido[4,5-d] [1,3]-oxazine-2,4(1H)-dione with sodio diethyl malonate followed by acidification.
26. 7,8-Dihydro-5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof whenever prepared with a process of Claim 25 or an obvious chemical equivalent thereof.
27. A process as claimed in Claim 1 which comprises reacting 4(2-propenylarnino)-2-phenyl-5-pyrimidine carboxylic acid ethyl ester with ethyl malonyl chloride in diethyl ether and treat-ing the product with sodium dissolved in ethanol followed by acid-ification.
28. 7,8-Dihydro-5-hydroxy-7-oxo-2-phenyl-8-(2-propenyl)-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a phar-maceutically acceptable salt thereof whenever produced by the pro-cess of Claim 27 or an obvious chemical equivalent thereof.
29. A process as claimed in Claim 1 which comprises reacting 1-(2-propenyl)-7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2, 4(1H)-dione with sodio diethyl malonate followed by acidification.
30. 7,8-Dihydro-5-hydroxy-7-oxo-2-pherlyl-8-(2-propenyl)-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a phar-maceutically acceptable salt thereof whenever produced by the pro-cess of Claim 29 or an obvious chemical equivalent thereof.
31. A process as claimed in Claim 1 which comprises reacting 4-benzylamino-2-phenyl-5-carboxylic acid ethyl ester with ethyl malonyl chloride and treating the product with sodium dis-solved in ethanol followed by acidification.
32. 7,8-Dihydro-5-hydroxy-7-oxo-2-phenyl-8-(benzyl) pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a phar-maceutically acceptable salt thereof whenever produced by the pro-cess of Claim 31 or an obvious chemical equivalent thereof.
33. A process as claimed in Claim 1 which comprises reacting l-(p-morpholinophenyl)-7-phenyl-2H-pyrirnido[4,5-d][1,3]-oxazine-2,4(1H)-dione with sodio diethyl malonate followed by acid-ification.
34. 7,8-Dihydro-5-hydroxy-8-(p-morpholinophenyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof whenever prepared or produced by the process of Claim 33 or an obvious chemical equivalent thereof.
35. A process as claimed in Claim 1 which comprises reacting 1-(4-methoxybenzyl)-7-phenyl-2H-pyrimido[4,5-d][1,3]-oxazine-2,4(1H)-dione with sodio diethyl malonate followed by acidification.
36. 7,8-Dihydro-5-hydroxy-8-(4-methoxybenzyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable thereof whenever produced by the pro-cess of Claim 35 or an obvious chemical equivalent thereof,
37. A process as claimed in Claim 1 which comprises reacting 1,7-diphenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione with sodio diethyl malonate followed by acidification.
38. 7,8-Dihydro-2,8-diphenyl-5-hydroxy-7-oxo-pyrido-[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceu-tically acceptable salt thereof whenever produced by the process as claimed in Claim 37 or an obvious chemical equivalent thereof.
39. A process as claimed in Claim 1 which comprises reacting 4-amino-2-(methylphenylamino)-5-pyrimidine-carbonitrile with ethyl malonyl chloride in tetrahydrofuran and treating the product with sodium hydroxide followed by acidification.
61 90. 5-Amino 7,8-dihydro-2-(methylphenylamino)-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a phar-maceutically acceptable salt thereof whenever produced by the process as claimed in Claim 39 or an obvious chemical equivalent thereof.
1. A process as claimed in Claim 1 which comprises reacting 4-methylamino-2-methylthio-5-pyrimidine carboxylic acid ethyl ester with ethyl malonyl chloride in anhydrous diethyl ether and treating the product with sodium in ethanol followed by acidification.
42. 7,8-Dihydro-5-hydroxy-8-methyl-2-(methylthio)-7-oxo-pyrido[2,3-d]-pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof whenever produced by the process as claimed in Claim 41 or an obvious chemical equivalent thereof.
43. A process as claimed in Claim 1 which comprises oxidizing 7,8-dihydro-5-hydroxy-8-methyl-2-(methylthio)-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester with meta-chloroperoxy benzoic acid in dichloromethane.
44. 7,8-Dihydro-5-hydroxy-8-methyl-2-(methylsulfonyl)-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester when-ever prepared by the process of Claim 43 or an obvious chemical equivalent thereof.
45. A process as claimed in Claim 1 which comprises reacting 7,8-dihydro-5-hydroxy-8-methyl-2-(methylsulfonyl)-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester with pyr-rolidine in refluxing ethanol.
46. 7,8-Dihydro-5-hydroxy-8--methyl-7-oxo-2-(l-pyr-rolidinyl)pyrido[2.3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaccutically acceptable salt thereof whenever produced by the process as claimed in Claim 45 or an obvious chemical equivalent thereof.
47. A process as claimecl in Claim 1 which comprises reacting 2 methylthio-4-propylamino-5-pyrimidine carboxylic acid ethyl ester with ethyl malonyl chloride and treating the product with sodium dissolved in ethanol followed by acidification.
48. 7,8-Dihydro-5-hydroxy-2-(methylthio)-7-oxo-8-pro-pylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof whenever produced by the process as claimed in Claim 47 or an obvious chemical equiv-alent thereof.
49. A process as claimed in Claim 1 which comprises reacting 7-methylthio-l-isopropyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione with sodio diethyl malonate followed by acidifica-tion.
50. 7,8-Dihydro-5-hydroxy-8-isopropyl-2-(methylthio)-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof whenever prepared by the process of Claim 49 or an obvious chemical equivalent thereof.
51. A process as claimed in Claim 1 which comprises reacting 1-(2-methoxyethyl)-7-methylthio-2H-pyrimido[4,5-d][1,3]-oxazine-2,4(1H)-dione with sodio diethyl malonate under reflux in dimethyl formamide followed by acidification.
52. 7,8-Dihydro-5-hydroxy-8-(2-methoxyethyl)-2-methyl-thio-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof whenever prepared by the process of Claim 51 or an obvious chemical equivalent thereof.
53. A process as claimed in Claim 1 which comprises reacting 4-allylamino-2-methylthio-5-pyrimidine carboxylic acid ethyl ester with ethyl malonyl chloride and treating the product with sodium dissolved in ethanol followed by acidification.
54. 7,8-Dihydro-5-hydroxy-2-(methylthio)-7-oxo-8-(2-propenyl)pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof whenever prepared by the process of Claim 53 or an obvious chemical equivalent thereof.
55. A process as claimed in Claim 1 which comprises reacting 7-methylthio-1-piperonyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(lH)-dione with sodio diethyl malonate and dimethyl formamide followed by acidification.
56. 7,8-Dihydro-5-hydroxy-2-methylthio-7-oxo-8-pip-eronyl-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof whenever prepared by the process as claimed in Claim 55 or an obvious chemical equiv-alent thereof.
57. A process as claimed in Claim 1 which comprises refluxing an ethanolic solution of 8-allyl-5-chloro-7,8-dihydro-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester with 2-methoxyethylamine in the presence of sodium carbon-ate.
58. 8-Allyl-7,8-dihydro-5-(2-methoxyethylamino)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl es-ter or a pharmaceutically acceptable salt thereof whenever pre-pared by the process of Claim 57 or an obvious chemical equiva-lent thereof.
59. A process as claimed in Claim 1 which comprises refluxing an ethanolic solution of 5-chloro-7,8-dihydro-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester with 2-methoxyethylamine in the presence of sodium carbonate.
60. 7,8-Dihydro-8-(2-methoxyethyl)-5-(2-methoxyethyl-amino)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof when-ever prepared by the process of Claim 59 or an obvious chemical equivalent thereof.
61. A process as claimed in Claim 1 which comprises reacting 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]-pyrimidine-6-carboxylic acid ethyl ester with 2-aminoethanol.
62. 7,8-Dihydro-8-ethyl-N-(2-hydroxyethyl)-5-(2-hy-droxyethylamino)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carbox-amide or a pharmaceutically acceptable salt thereof whenever pre-pared by the process of Claim 61 or an obvious chemical equiva-lent thereof.
63. A process as claimed in Claim 1 which comprises reacting 5-cyano-4-(2-methoxyethylamino)-2-phenyl pyrimidine with ethyl malonyl chloride in diethyl ether and treating the product with sodium dissolved in ethanol followed by acidification.
64. 5-Amino-7,8-dihydro-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof whenever prepared by the proccss of Claim 63 or an obvious chemical equivalent thereof.
65. A process as claimed in Claim 1 which comprises refluxing 7,8-dihydro-5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-phenyl-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester with 2-methoxyethylamine in ethanol.
66. 7,8-Dihydro-5-hydroxy-N,8-bis(2-methoxyethyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxamide or a phar-maceutically acceptable salt thereof whenever produced by the process of Claim 65 or an obvious chemical equivalent thereof.
67. A process as claimed in Claim 1 which comprises refluxing 7,8-dihydro-5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-phen-ylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester with di-ethylethylenediamine in ethanol.
68. N-[2-diethylamino)ethyl]-7,8-dihydro-5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-car-boxamide or a pharmaceutically acceptable salt thereof whenever prepared by the process of Claim 67.
69. A process as claimed in Claim 1 which comprises reacting 2-phenyl-4-propargylamino-5-pyrimidine carboxylic acid ethyl ester with ethyl malonyl chloride in diethyl ether and treating the product with sodium dissolved in ethanol followed by acidification.
70. 7,8-Dihydro-5-hydroxy 7-oxo-2-phenyl-8-(2-pro-pargyl)pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof whenever produced by the process of Claim 69 or an obvious chemical equivalent there-of.
71. A process as claimed in Claim 1 which comprises reacting 4-allylamino-2-phenyl-5-pyrimidinecarbonitrile with ethyl malonyl chloride in diethyl ether and treating the product with sodium dissolved in ethanol followed by acidification.
72. 8-Allyl-5-amino-7,8-dihydro-7-oxo-2-phenylpyrido-[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceu-tically acceptable salt thereof whenever produced by the procedure of Claim 71 or an obvious chemical equivalent thereof.
73. A process as claimed in Claim 1 which comprises reacting 5-amino-7,8-dihydro-2-methyl-7-oxo-pyride[2-3-d]pyrimi-dine-6-carboxylic acid ethyl ester sodium salt with ethyl iodide in dimethyl formamide.
74. 5-Amino-7,8-dihydro 8-ethyl-2-methyl-7-oxo-pyrido-[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceu-tically acceptable salt thereof whenever produced by the process of Claim 73 or an obvious chemical equivalent thereof.
75. A process as claimed in Claim 1 which comprises reacting 5-amino-7,8-dihydro-7-oxo-2-propyl pyrido[2,3-d]pyrimi-dine-6-carboxylic acid ethyl ester sodium salt with ethyl iodide in dimethyl formamide.
76. 5-Amino-8-ethyl-7,8-dihydro-7-oxo-2-propyl-pyrido-[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceu-tically acceptable salt thereof whenever produced by the process of Claim 75 or an obvious chemical equivalent thereof.
77. A process as claimed in Claim 1 which comprises reacting 5-amino-7,8-dihydro-2-methyl-7-oxo-pyrido[2,3-d]pyrimi-dine-6-carboxylic acid ethyl ester sodium salt ~ith butyl iodide in dimethyl formamide.
78. 5-Amino-8-butyl-7,8-dihydro-2-methyl-7-oxo-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a pharmaceu-tically acceptable salt thereof whenever produced by the process of Claim 77 or an obvious chemical equivalent thereof.
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79. A process as claimed in Claim 1 which comprises reacting 5-amino-7,8-dihydro-2-methyl-7-oxo-pyrido[2,3-d]pyri-midine-6-carboxylic acid ethyl ester with allyl bromide in di-methyl ormamide.
80. 8-Allyl-5-amino-7,8-dihydro-2-methyl-7-oxo-py-rido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a phar-maceutically acceptable salt thereof whenever produced by the process of Claim 79 or an obvious chemical equivalent thereof.
81. A process as claimed in Claim 1 which comprises reacting 5-amino-7,8-dihydro-7-oxo-2-propyl-pyrido[2,3-d]pyri-midine-6-carboxylic acid ethyl ester sodium salt with allyl bromide in dimethyl formamide.
82. 8-Allyl-5-amino-7,8-dihydro-7-oxo-2-propyl-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester or a phar-maceutically acceptable salt thereof whenever prepared by the process of Claim 81 or an obvious chemical equivalent thereof.
83. A process as claimed in Claim 1 which comprises reacting 4-amino-2-methyl-5-pyrimidinecarbonitrile with sodio-diethyl malonate in ethanol followed by acidification.
84. 5-Amino-7,8-dihydro-2-methyl-7-oxo-pyrido[2,3-d]-pyrimidine-6-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof whenever prepared by the process as claimed in Claim 83 or an obvious chemical equivalent thereof.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US31,256 | 1979-04-18 | ||
| US06/031,256 US4215216A (en) | 1979-04-18 | 1979-04-18 | 7,8-Dihydro-2,5,8-trisubstituted-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid derivatives |
| US06/089,013 US4236004A (en) | 1979-04-18 | 1979-10-29 | 2-Alkylsulphonyl-7,8-dihydro-5-hydroxy-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid derivatives |
| US116,123 | 1980-01-28 | ||
| US06/116,123 US4245094A (en) | 1980-01-28 | 1980-01-28 | 5-Amino-2,8-dialkyl-7,8-dihydro-7-oxo-pyrido-[2,3-d]pyrimidine-6 carboxylic acid derivatives |
| US125,620 | 1980-02-28 | ||
| US06/125,620 US4301281A (en) | 1979-04-18 | 1980-02-28 | 7,8-Dihydro-2,5,8-trisubstituted-7-oxo-pyrido[2,3-d]-pyrimidine-6-carboxylic acid amides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1120475A true CA1120475A (en) | 1982-03-23 |
Family
ID=27487881
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000350056A Expired CA1120475A (en) | 1979-04-18 | 1980-04-17 | 7,8-dihydro-2,5,8-trisubstituted-7-oxo-pyrido [2,3-d]-pyrimidine-6-carboxylic acid derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1120475A (en) |
-
1980
- 1980-04-17 CA CA000350056A patent/CA1120475A/en not_active Expired
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