Note: Descriptions are shown in the official language in which they were submitted.
34V75
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
R5
~,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.
47S
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
R8
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:
R5
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:
R8
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
475
(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
II R8
VI V~
'
NaC~I(COR6)2 ~ 1 COR6
R N ~ 7 ~ O
R8
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 ~~
R8 R8
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
7 --
475
amine to give a compound in which R2 is l~pyrrolidinyl or methyl-
phenylamino~ This technique illustrated below
R5
N ~ coR6
Rl~S02 `N ~ O R9
R12
R9~ N
110
~ ~ .
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.
3475
(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
R8
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 ~
R8
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
R8
-- 10 --
~ 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.
- 12 -
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
- 13 -
~ 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
- 15 -
~ '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
- 16 -
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.
EXAMPLE 3
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%
EXAMPLE 4
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.
- 18 -
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
-- 19 --
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.
EXAMILE 7
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.
- 20 -
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.
EXAMPLE 8
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
- 22 -
3475
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.
EXAMPLE 10
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]-
- 23 -
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.
EXAMPLE 11
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
- 24 -
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.
EXAMPLE 12
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
- 25 -
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
- 26 -
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.
- EXAMPLE 14
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
EXAMPLE 15
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
.
- 29 -
~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.
- 30 -
~ 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 -
31 -
47S
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
- 32 -
0475
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%
EXAMPLE 18
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
9L7S
~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.
EXAMPLE 19
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]-
- 34 -
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.
475
EXAMPLE 20
-
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
- 36 -
47S
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~
--8
475
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
- 45 -
:
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
EXAMPLE 31
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%
- 49 -
~L'~()~7
EXAMPLE 34
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
EXAMPLE 36
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
- 51 -
~ 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
EXAMPLE 38
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~ -
