Note: Descriptions are shown in the official language in which they were submitted.
0'~3 45 6
This invention relates to new snd useful piperazine deriva-
tives having antibacterial activities, intermediates thereof, processes
for preparing them, and also to their use.
This invention provides compounts of the following formula
Rl - N4 lN ~ ~ f ~I)
` wherein Rl is a hydrogen atom, an alkyl group having 1 to 4
carbon atoms, 2 to 4 carbon atoms, a benzyl group, a benzyl
group substituted by methoxy, a phenyl group, a propargyl
group or an acyl group; R2 is an alkyl group having 1 to 4
carbon atoms, or a vinyl group, and salts thereof.
The term "acyl group", as used in the present specification
and appended claims, denotes a carbonic or carboxylic acid residue such as
a lower alkanoyl group such as formyl, acetyl, trifluoroacetyl, or propionyl,
a lower alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, and -
a phenyl-substituted lower alkoxycarbonyl group, e.g. benzyloxycarbonyl.
~'
10'73456
In the present specification and appended claims,
the term "lower alkyl group" either in itself or as part of -
other groups denotes an alkyl group containing 1 to 4 carbon
atoms.
Of the compounds of formula I the following
compounds and salts thereof are suitable as antibacterial
agents. o
~I COOH
Rl a~ 3/ L
lQ 2a '~
In this formula Rla is a hydrogen atom, an alkyl
group having 1 to 4 carbon atoms,(a hydroxyalkyl group having
2 to 4 carbon atoms, a phenyl group or a propargyl group;
and R2a is an~alkyl group having 1 to 4 carbon atoms, an
alkyl group having 2 to 4 carbon atoms substituted by
hydroxy or halogen, a vinyl group, an allyl group, or a
benzyl group.
Especially'suitable compounds of this invention
as antibacterial agents are shown below.
5,8-Dihydro-8-ethyl-2-Cl-piperazinyl)-5-oxopyrido
~,3-~ pyrimidine-6- carboxylic acid.
5,8-dihydro-8-ethyl-2-C4-ethyl-1-piperazinyl)-5- oxo-
pyrido ~,3-~ pyrimidine-6-carboxylic acidJ
8-benzyl-5,8-dihydro-2-~1-piperazinyl)-5-
oxopyrido r2,3-~ pyrimidi-ne-6-carboxylic acid.
5,8-dihydro-2-~1-piperazinyl)-8-vinyl-5-oxopyrido
~,3-~ pyrimidine-6-carboxylic acid.
~0'~ 6
8-~2-chloroethyl)-5,8;dihydro-2~ piperazinyl)-5-oxopyrido(2,
3-d)pyrimidine-6-carboxylic acid, and pharmaceutically acceptable acid
addition salts or alkali metal salts of these compounds.
The above-described compounds of this invention are sometimes
obtained as hydrates and they are also within the scope of this invention.
In the present specification, these hydrates will be described as coming
within the scope of the compounds of formula (I) in the free form, other
than the Salts of the compounds of formula (I).
Relatively similar compounds to the compounds of this invention
are disclosed in British Patent Specification No. 1,129,358 (published
October 2, 1968) and Deutsch Offenlegungschrift No. 2,143,369 (published
March 9, 1972) as antibacterial agents.
We have made work in an attempt to prepare antibacterial agents
which are more useful than these known compounds, and found that by intro-
ducing a piperazine into the 2-position of the pyrido(2,3-d)pyrimidine
nucleus, there can be obtained compounds havin~ characteristic antibacterial
activity (especially, against Pseudomonas aeruginosa or Mycobacterium
tuberculosis).
The compounds of formula (I) are synthesized by any of the
following processes.
Process 1
The compounds of formula (I) are prepared by reacting compounds
(a) of the following formula
.~ ~
.
10"~3~1S6
N N
R2
wherein X is a halogen atom, a lower alkylthio group, a lower
alkoxy group, and R2 is the same as defined above, and R3 repre-
sents an alkyl group of 1 to 6 carbon atoms with compounds ~b)
of the following formula ~-
~ ,.
Rl - N NH ~b)
wherein Rl is the same as defined above, followed by a hydrolysis
step to remove the group R3.
The reaction in this process 1) is performed by heating the com-
pounds (a) and (b) at atmospheric pressure in a solvent, if desired, in
the presence of a base such as sodium bicarbonate or triethylamine to
give the compounds of formula [I] in good yield.
Where compounds (a) in which X is a halogen atom are used as
starting material, it is preferred to perform the reaction in the pre-
sence of a base, as a dehydrohalogenating agent, such as sodium bicar-
bonate, sodium carbonate, potassium carbonate, or triethylamine. Usually,
the compounds ~a) and ~b) are used in stoichiometric amounts. Further-
more, the compound (b) may be used in excess to make them serve also as
a dehydrohalogenating agent. The compound (b) may be used in the form
of hydrate or acid addition salt of, for example, hydrochloric acid.
The preferred reaction temperature is in the range of 60C.
~. ,. -, .:
~ 10~34~6
to 120C
The solvent used in this reaction should be selected
according to the properties of the materials to be used.
Examples of the solvent are alcohols such as ethanol or
propanol, aromatic hydrocarbons such as benzene or toluene,
halogenoalkanes such as dichloroethane or chloroform,
ethers such as tetrahydrofuran, dioxane or diphenyl -
ether, acetonitrile, dimethyl sulfoxide, dimethylformamide
and water. They may be used either alone or in mixture,
`10 Process 2) ~.
Of the compounds of formula LI] the following
compounds
Rl- N N ~ a]
R2
~ herein R2' is a hydrogen atom. an alkyl group having
1 to 4 carbon atoms, an alkyl group having 2 to 4 carbon atoms
substituted by halogen, an allIyl group or a benzyl group and
R3' is an alkyl group having 1 to 6 carbon atoms, and Rl is
the same as defined above,
can be obtained by heating compounds of formula Cc) below
,COOR3'
~ ~ CDOR3' cc)
Rl- ~ N N
R2 .,
--6--
-, - - - -.- - -. . - . - --. . -: : .,
10~34S6
wherein Rl, R21 and R31 are the same as defined above,
to induce intramolecular cyclization.
The reaction in process 2) is performed by heating the compounds
(c3 directly or in a high-boiling solvent, such as diphenyl ether, o-
dichlorobenzene, diphenylene oxide, dibutyl phthalate, or mixtures of these.
The suitable heating temperature is 140 to 260C.
It is also possible to perform the cyclization reaction in the
presence of a conventional cyclization agent such as polyphosphoric acid,
a polyphosphoric acid alkyl ester, concentrated sulfuric acid or phosphorus
pentoxide. Where polyphosphoric acid, polyphosphoric acid alkyl ester or
phosphorus pentoxide is used as the cyclization agent, the reaction is
generally carried out in a solvent such as benzene, dioxane or dimethyl-
formamide. When concentrated sulfuric acid is used, the reaction is general-
ly carried out in a solvent such as acetic anhydride or acetic acid. Of
course, depending upon the properties of the cyclization agent, it can be
made to serve also as the solvent. If the cyclization agent is used, the
reaction is carried out at relatively low temperatures.
The cyclization is followed by a hydrolysis step to remove the
group R3.
Closely related compounds can also be prepared by the following
processes, which can be transformed into compounds of the invention by a
hydrolysis step to remove the group R3.
Process 3
Of the compounds of formula (I), those of the following formula
Ri - N N ~ ~ COOR3 (I-b)
/ R2"
- 7 -
~0~3456
wherein Rl and R3 are the same as defined above,
and R2" is an alkyl group having 1 to 4 carbon
atoms, an alkyl group having 2 to ~ carbon atoms
substituted by hydroxy, halogen, a ben~yl
~;roup, or an allyl group; -
are obtained by reacting compounds (d) (the compound of
*ormula (I) in which R2 is a h~drogen atom),
o
R -N ~ ~ (d)
1 ~ H
wherein Rl and R3 are the same as defined above,
with an alkylating agent corresponding to R2".
Known alkylating agents can be used. Specific
examples include alkyl halides such as methyl iodide, ethyl
iodide, allyl bromide, benzyl chloride, 1,2-dibromoethane,
ethyle~e chlorohydrin or ethylene bromohydrin, and iower
alkyl esters such as dimethyl sulfate, diethyl sulfate,
methyl p-toluenesulfonate, or triethyl phosphateO
~he reaction in the process 3) is generally
carried out by reacting the compound (d) with a stoichio-
metric amount of the alkylating agent in an inert solvent
at an elevated temperature. If desired, the alkylating
agent may be used in excess. The solvent may be either non-
aqueous or hydrous. Examples of the solvent are ethanol,
dioxane, dimethylformamidè, dimethyl sulfoxide and water.
The reaction is promoted by adding an acid acceptor, for
example, a base such as an alkali carbonate, an alkali
hydroxide, an alkali metal alkoxide, sodium hydride,
-- 8 --
,~
10~3456
triethylamine, benzyltrimethyl ammonium hydroxide. Where
the alkylating agent is made to act in a hydrous solvent,
the carboxylic acid ester portion sometimes undergoes
hydrolysis depending upon the reaction conditions, and thus
is converted to a free carboxylic acid. Furthermore, when
compounds of formula (d) in ~Ihich Rl is a hydrogen atom are
alkylated, N-alkylated products at the 4-position of the
piperazine nucleus can be obtained together with N-alkylated
products at the 8-position of the pyrido~2,3-d~pyrimidine
nucleus. Accordingly, the desired products can be obtained -
by suitably choosing the starting material, solvent and
alkylating agentO
Where the product of the formula [I-b~ is a com-
pound in which R2" is a hydroxyalkyl group, it may be
further halogenated with a halogenating agent such as
thionyl chloride or phosphorus oxychloride to convert the
hydroxyalkyl group to a halogenoalkyl groupO
Process 4)
Compounds of formula ~I-b~ can also be obtained
by heating compounds of formula (e) below
OR COOR
N ~ll ~ ~ (e)
Rl-N N~-~N ~ ~ N
wherein R is a lower alkyl group and Rl and R~
are as defined above,
either directly or in the presence of an alkylating agent
such as used in process 3) described above.
_ 9 _
: . ,
" lOq3~56
The reaction in process 4) is carried out by directly heating the
compound (e) or in a solvent such as lower alcohols (such as methanol,
ethanol, propanol or diethylene glycol), ethers (such as diethyl ether,
dioxane, tetrahydrof`uran, 1,2-dimethoxyethane, dimethyleneglycol dimethyl
ether or diphenyl ether~, or aromatic hydrocarbons (such as benzene or
toluene). The reaction is promoted by adding a catalyst such as a Lewis
acid (such as boron trifluoride, or aluminum chloride) or a protonic acid
(such as toluenesulfonic acid, sulfuric acid, hydrochloric acid or phos-
phoric acid). The heating temperature is 40 to 250C.
10By reacting the compound (e) with the above described alkylating
agent in a stoichiometric amount or in an excess amount in a solvent, the
compound ~I-b] can be obtained. ~xamples of the solvent are water, dimethyl-
formamide, and dimethyl sulfoxide in addition to the above-exemplified sol-
vents. Whèn alkylating agents are liquid aIkyl halides or alkyl phosphates,
they may be used concurrently as solvents.
Process 5)
Compounds of formula br] wherein R3 is a hydrogen atom,
that is, compounds of formula [I-c] below:
R~ ~ tI-C3 ~.
wherein Rl and R2 are the same as defined anove, can be obtained by hydro-
lyzing compounds of formula [I]
-- 10 _
,~
~0~3456
wherein R3 is an alkyl group having 1 to 6 carbon atoms,
that is, compounds of formula (h) below
COOR3'
Rl-N N 1 ~ N --
R2
wherein P1, R2 and R3' are the same as defined
above.
The hydrolysis reaction in the process 5) is
carried out by contacting the compound (h) with water. `
Generally, in order to promote the reaction, it is performed
in the presence of a catalyst such as an acid or base.
Ex~mples of the acid are inorganic acids such QS
hydrochloric acid, hydrobromic acid, hydroiodic acid,
sulfuric acid or phosphoric acid, a~d organic acids such
as acetic acid, oxalic acid or toluenesulfonic acid.
Examples of the base are alkali metal hydroxides
such as sodium hydroxide or barium~hydroxide, alkali metal
carbonates such as sodium carbonate or potassium carbonate,
and sodium acetate.
This reaction may also be performed by directly -
heating the m~terial in the pre~ence of the above acid,
and then adding water. The solvent is usuall~ water, but
depending upon the properties of the material, a h~drous
solvent such as ethanol, dioxane, ethyleneglycol dimethyl
ether, benzene or acetic acid may also be used. The reaction
temperature may be room temperature, but usually 50 to 200C.,
preferably 70 to 120C o
~ 11 --
lO'Y3~56
Where Rl in the compound (h) is a for~yl or
tri~luoroacetyl group, ~1 is converted to a hydrogen atom
by being hydrolyzed together with the ester portion of this
compound.
5Process 6)
Of the ccmpounds of formula (I), those in which R
is a hydrogen atom, that is, compounds of formula ~I-d~
below
COOR
N ~ ~ /
H-N ~ ~`N ~ ~ N ~ ~I-d~
R2
wherein R2 and R3 are the same as defined above,
can be obtained by hydrolyzing or hydrogenolyzing compounds
of formula (i) below .
- COCR
N~
R ' ~ N'~`N
R2 -,
wherein R2 and R3 are the same as defined above,
and Rl' is an acyl group,an arylsulfonyl group,
: a benzyl group, a vinyl group, a trityl group, or
a group -CH2-CH2-Z in which ~ is a halogen atom,-
a lower alkoxy group, a benzyloxy group, an
alcoholic hydroxy group or its derivative, or a
group which may form a tertiary or quaternary
amine together with the residue;
- 12 -
. .~ . . ~ ,
- ~ . .: .
lOq34S6
according to the nature of R1'.
The acyl group as Rl' means the carboxylic or car-
bonic acid residues as described above.
The derivatives of the alcoholic hydroxyl group
as Z include, for example, acyloxy groups such as acetyloxy
or ethoxycarbonyloxy; aryl sulfonyloxy groups such as
tosyloxy or benzenesulfonyloxy, or lower alkylsulfonyloxy
groups such as methanesulfonyloxy or ethanesulfonyloxy; or
S-aryldithiocarbonyloxy groups such as S-phenyldithio-
carbonyloxy, or lower alkyldithiocarbonyloxy group such as
S-methyldithiocarbonyloxy or S-ethyldithiocarbonyloxy groups.
Specific examples of the group that can form a
tertiary or quaternary amine together with the residue are
-N-`~CH3)2, -N(C2H5~2' ~ 3 3
and -~CH3)2. -~
The hydrolysls reaction in the process 6) is generally
carried out by reacting the compound (i) with a min-
eral acid or an alkali hydroxide. At this time, the ester
portion is also hydrolyzed to form a free carboxylic
a-cid. Where R1' is a formyl, trifluoroacetyl or trityl group
it is split off under mild hydrolysis conditions with-
out affecting the other functional groups. This reac-
tion is carried out at 20 to 150C.
The hydrogenolysis reaction in the process C) is
carried out by hydrogenating the compound ~i) using, for
example, a hydrogen gas stream in a solvent in the presence
of a catalyst such as platinum, palladium or Raney nickel,
or by hydrogenolyzing the compound (i) with metallic sodium
lOq3456
in liquid ammonia. The above catalytic hydrogenolysis reac-
t~on proceeds at room temperature. If desired, however, it
may be carrièd out at an elevated tèmperature up to 60C.
Suita~le solvents are ethyleneglycol, dioxane, dimethyl-
formamide, ethanol, and acetic acid. Especially when R~ sa benzyl, trityl or tosyl group,- such a group can be split
off with metallic sodium in liquid am~onia.
Process 7)
Of the compounds of formula (I), those in which
R2 is a vinyl group, that is, compounds of the formula
tI-e~ below
'I
R ~ J tI_~
CH=CH2 . ' - ', .
,
wherein Rl and R3 are the same as defined above, -
can be obtaineà by heatin~ compounds (j) below
0 COOR
R -N/ N 1`~ ~ N~ ~i)
- 1 ~ HC-CH2
y z
wherein Rl and R3 are the same as defined above;
- and Y and Z are different from each other, and
each represent a hydrogen atom, a halogen atom,
a lower alkoxy group, a benzyloxy ~roup, an
alcoholic hydroxy group or its derivative, or a
group that can form a tertiary or quaternary amine
.
.
1073~S6
together wi~h the residue, with the proviso that
either Y or Z is always a hydrogen atom.
~he derivatives of the alcoholic hydroxy groups
as Y and Z include, for example, acyloxy groups such as
acetyloxy or ethoxycarbonyloxy; arylsulfonyloxy groups such
as tosyloxy or benzenesulfonyloxy, or lower alkylsulfonyloxy
groups such as methanesulfonyloxy or ethanesulfonyloxy; or
S-aryldithiocarbonyloxy groups such as S-tolyldithio-
-~ carbonyloxy or S-phen~ldithiocarbonyloxy, or lower alkyl- - -
; 10 dithiocarbonyloxy such as S-methyldithiocarbonyloxy or S- - --
ethyldithiocarbonyloxy groups. ~ -
~ Specific examples of the group as Y and Z that
` can form a tertiary or quaternary amine with the residue are
:. ~
( 3)2' -N(C2H5)2' -N ~, ~ -N~ H3)3 ~, - ~(C2H5) 0 ~,
., .
( 3)2- ~
~he reaction in process 7) is carried out by ~- -
simply heating the compound (j) or heating it in the -~?e
~ presence of a catal~st such as an acidic substance, an acid ;
-~- anhydride or a base. ExampIes o~ the catalyst are ordinary
acids such as hydrochloric acid, sulfuric acid, poly-
~ phosphoric acid, phosphoric anhydride, formic acid, acetic
`~ ~ acid, toluenesulfonic acid, or potassium bicarbonate, ~ewis
~` acids such as thionyl chloride, phosphorus oxychloride,
~ boron trifluoride or zinc chloride, alkali hydroxides,
-~ 25 alkall carbonates, metal hydrides such as sodium hydride,
alkali metal alkoxide such as sodium ethylate, sodium -~
methoxide or potassium tertO-butoxide, pyridine, collidine,
benzyltrimethylammoni~ hydroxide, acetic anhydride, phthalic
- 15 -
. . . . .. . .
10~3456
anhydride, silver oxide, iodine, and tert.-butyl lithium.
The reaction temperature is usually 50 to 270C. The reaction
proceeds in the absence of solvent, but preferably, it is carried out in
a solvent. Examples of the solvents are water~ alcohol, acetic acid,
dimethylformamide, dimethyl sulfoxide, ether, benzene, dioxane, tetrahydro-
furan, and pyridine.
In this reaction, depending upon the nature of R1 and/or R3 of
the starting compound (j) and the reaction conditions, R1 and/or R3 of the
final product [I-e] may sometimes be replaced with a hydrogen atom.
The starting compound (a) used in process 1) is a known compound
disclosed in Deutsche Offenlegungschrift No. 2,143,369 described above.
The starting compound (b) is a known compound and can be obtained by known
methods.
The starting compound (c) used in process 2) is obtained by react-
ing the corresponding 2-(1-piperazinyl)-6-aminopyrimidine and aIkoxymethyl-
enemalonate in accordance with the method disclosed in British Patent
Specification No. 1,129,358.
The compound (e) used in process 4 is a novel compound which is
obtained by heating a compound (f) below
~ ~COOR~3
wherein R1 and R31 are the same as defined above; together with an excess of
a halogenating agent such as
- 16 -
;~`1
iO~34~6
phosphorus oxychloride in a solvent such as benzene through
intramolecular cyclization to produce a compound of the
following formula (g) below
CGOR3'
~l-N ~ N J (g)
wherein Rl and R~' are the same as described
above, and X is a halogen atom;
and then heating this compound with an alkali metal alkoxide
in a solvent such as dimethyleneglycol dimethyl ether, ~ .
dioxane, benzene or a lower alcohol, or with a lower alcohol :
in the presence of a base such as an alkali metal tertO-
; butoxide or trimethylbenzylammonium hydroxide.
~he starting compound (i) used in the process 6) ~-~
partly covers the compound of formula ~I~ in accordance with .
this invention, and can be prepared in the same manner as ~.
ln process 1) or b~ reacting the compound (d) with an
alkylating agent in the same manner as in the process 3).
~: The starting material (j) used in the process 7)
is a novel compouna, and can be prepared by reacting the -~
starting compound (d) used in the process 3) with a halide
of the formula :
CH2Z-CHY-halogen (k)
wherein Y and Z are the same as defined above;
in the same way as described in the process 3)0
~he compound (d) used as the starting compound
in the process 3) and the compound (h) used as the startin~
lOq3456
compound in the process 5) are part of the compounds [I] of this invention,
and can be prepared by any of the suitable methods described above.
The compounds of the present invention prepared in the above
process can be isolated and purified by u9ual methods. The compounds [I]
can be obtained in the free state or in the form of salt depending upon the
selection of the starting materials and the reaction conditions. Further-
more, the compounds [I] can be converted to pharmaceutically acceptable
amine salts or carboxylic acid salts by treatment with acid or alkali, or
vice versa. The acid may be a variety of organic and inorganic acids, ex-
amples of which are hydrochloric acid, acetic acid, lactic acid, succinic
acid, oxalic acid and methanesulfonic acid.
The antibacterial activities of the typical compounds of this
invention are shown in Tables I to V together with those of the compounds
disclosed in the aforesaid British Patent or German Patent.
In the Tables II to IV, the ED50 and ID50 values were calculated
in accordance with the Behrens-Kaerber method [Arch. Exp Path, Pharm.,
162, 480 (1931)]. The compound numbers are those described in the Examples
and compounds PA and AT-616 are as follows:
Compound PA:
5~8-Dihydro-8-ethyl-2-pyrrolidino-5-oxopyrido [2,3-d]pyrimi-
dine-6_carboxylic acid which is the most valuable compound disclosed in the
British patent.
Compound AT_616
5~8-Dihydro-8-ethyl-2-(3~hydroxy-pyrrolidino)-5-oxopyrido[2,
3_d]pyrimi~;ne-6-carboxylic acid which is the most valuable compound dis~
closed in the German Patent.
- 18 -
lOq34S6
I ~ ~ ~ ~ ~
- ~ - - : ::
~ c
td ~ ,~ ~ N _l ~ : ~" ~ ~ 1_/ ~
~: l.~oY _ _ ~
D ,-~ ¦ U
~. 8~ l ~ ' 1 1 ~ 1~ 1
b4 >=\ ~ ~Y ~ ~ ~ ~ ~ X ~ -.-
~ o ~<z~ _ __ __ _ 3~
,~ ~ Z 1 1~
~o Z,~ _ X sS ~ s~`' s~ s
. ~ ~
_.
-19-
.
1073456
.__~ N~ O-- rO'~ _~_.
.,
Or~\ ~ O O ~ ~
~ _ _ __ ._ ~ ~ .
O ~ h
-~ ----------- ~ h
,D h
O O O O O O
~1 ~1 0~ ~ ~1
_ _ /\ l H o ~ :
j, __ _ _ ~__. __ ._
~--1 ~ ~ X ~ ~ s~
- ---- ----- ----_ ~ 4~ ~
p: V / 5 ~ ,h
~U~ ~ V V / o O ~O ~ h
V-- ~ ~ h o ~ ~3 h o
~ ! 1 ~ .~
s:l ~~ ~. / a) ~ ~ h ~ ~ h ~1
o ~ l ~ a H~ h~ ~
- _* __ __ 3
a) ~ o~ ~ ~D ~ ~ *
E~ _ __._ ._ ._ _ . _ ..
-- 20 --
.`~1 ` , ,
lOq3~6
2) In vivo efficacy against systcmic infcction with l'scudomonas aerugi-
nosa in mice.
TABLE II
Compound Dose (mg/Kg) ED50
No Route200100 50 25 12.5 6.3 3.1 (m~/kQ)
...... _ _ ~,
1 ip - - 8/8 8/8 4/8 2/8 1/8 10.5
po 8/84/8 0/8 - - - - 100
2 ip - - 8/8 - - - ~ C35.4
po 5/8 - - - - _ _ ~200
11* ip _ - - 8/8 - - - < 17.7
po 8/87/8 - - - - - <100 ,
21 ip - 4/8 0/8 - - - - ~100
po 4/8 - - - - _ _ ~200
33 ip _ _ - 8/8 - - ~ < 17.7
ip - 8/8 7/8 1/8 - - - 35
63* ip -' - 8/8 8/8 - - - C 17.7
_ .. .....
PA ip - 0/8 - - - - - >100
po 0/8 - - ~ ~ ~ ~ ~200
AT-616 ip - 3/8 - - _ _ _ >100
po 1/8 - ~ ~ ~ - ~ ~200
. ......... . .
The numerical figures in the Table show the number of the survival
/the total number. 0/8 means that all of 8 mice died. 8/8 means that all
8 mice survived: The survival rate of nontreated control was 0/8.
Experimental Conditions: ,
Organism: Pseudomonas aeruginosa No. 12
Mice: male mice (ddY-S~ weighing 20 g approximately
Infection: intraperitoneal infection with 50 to 100 LD50 f a
bacterial suspension in 4% gastric mucin (about 5 x103,
cells/mouse) .
Medication: twice, about 5 minutes and 6 hours after infection
Dru'g: an allcaline solution for parenteral administration and a
suspension in 0.2% CMC for oral administration
Observation of mortality: 7 days
i.p.: intraperitoneal administration
p.o.: oral administration
-21-
-
lOq3456
3) In vivo efficacy against systemic infection with Salmonella typhimurium
in mice
TABLE III
Comp~o,und _ ~~Dose ~mg/kg) ED50
No. Route 100 50 25 12.5 6.3tmg/kg)
1 ip _ _ 8/8 8/8 4/86.3
po _ 8/8 8/8 4/8 0/812.5
4 ip _ 8/8 _ _ _< 35.4
po _ 8/8 _ _ _< 35.4
11* po _ 8/8 _ _ _< 35.4
21 ip _ _ 8/8 _ _< 17.7
po _ _ 8/8 _ _C 17.7
33 ip _ _ 7/8 4/8 1~812.5
38 po _ 8/8 6/8 0/8 _21.0
54* po _ 8/8 6/8 2/8 _17.7
: _ __
PA ip 9/105/10 3/10 0/10 _ 43.5
po ~ 10/104/10 3/10 0/10 _ 46.7
The nu~èrical figures in the table show the number of the
survival/the total number. 0/8 means that all of 8 mice died. 8/8
means that all 8 mice survived. The survival rate of nontreated control
- was 0/8.
Experimental conditions.
Organism: Salmonella typhimurium S-9
Mice: male mice ~d W-S) weighing 20 g approximately
Infection: Intraperitoneal infection with 50 to 100 LD50 of a
bacterial suspension in nutrient broth (about 105
cells/mouse)
Medication: twice a day for 4 days from the day of infection.
Drug: an alkaline solution for parenteral administration and
suspension in 0.2% CMC for oral administration
Observation: 14 days
i.p.: intraperitoneal administration
p.o.: oral administration
~; , : . . , , . ;, . . :
1073456
4) Antituberculous activity in vitro
Table IV
,
Mycobacterium tuberculosis
Compound , Rl i R2 I R31 H '¦ I H37~V *
37RV Kurono I resistant
6 1~3~ G2~I5- I H- ¦ 6.3 6.3 1 6.3
-. i _~ , -
~ PA ~ ! loo loo i loo I --
_ I
* I~, PAS, SM-resistant strain
~he minimum inhibitory concentration (MIC:~g/ml)
was determined by the well known serial dilution methodO --
hxperimental conditions:
. Medium: Xirchner medium containing 002% bovine
albumin, pH 7.0 (3 ml/tube)
Inoculum: l drop of 1:102 dilution of a culture in
Modified Kirchner medium for 2 weeks
(OD=003) per tube
Incubation temp. and time; 37C for 3 weeks
5) Acute toxicity in mice
~able V
Dose (m~/k~ D50
Compound Route L 40001 2000ll lOOO 15 1 (mg/kg)
l iv ~ 0/6 ~5/6 700
I Po ! 6/6 1 6/6 ~ 4000
y,
~, ~ .,,.., ~
lOq3456
The numerical figures in the table show the number of survival/
the total number. 0/6 means that all of 6 mice died and 6/6 means that
all of mice survived.
The compound was in alkaline solution for intravenous administra-
tion and suspension containing 0.2% CMC for oral administration and ad-
ministered to male mice (ddY5 ) weighing 20 g approximately. After 7 days
the incidence of death was recorded and LD50 value was estimated.
i.v.: intraveneous administration
p.o.: oral administration
- 24 _
, s~ -- , s
., . . ~,~ ,, ~
1073~56
A clinical dosage of the compound ~I~ depends on
body weight, age and administration route but it i8 generally
in the range of 100 mg - 5 g/day, preferably of 200 mg-3g/day.
The compounds [I~ may be used as medicines, for -
5 example, in the form of pharmaceutical preparations contain-
ing the compound in admixture with an organic or inorganic,
solid of liquid pharmaceutical adjuvants suitable for
peroral, parenteral, enteral or local administration.
Pharmaceutically acceptable adjuvants are substances that
do not react with the compounds, for example, water, gelatin,
lactose, starch, cellulosei preferably microcrystalline
cellusose, carboxymethyl cellulosei methyl cellulose
sorbitol, magnesium stearate, talc, vegetable oils, benzyl
alcohol, gums, propylene glycol, polyalkylene glycolsj -
methylparaben and othèr known medicinal adjuvantO The
~ pharmaceutical preparations may be, for example, powderj
-~ tablets, ointments, suppositories, creams or capsules, or
in liquid form as solutions, suspensions or emulsions.
^ Thèy may be sterilized and/or contain assistants such as
preserving, stabilizing, wetting or emulsifying agents,
salts for regulating the osmotic pressure or buffers. They
may further contain other therapeutically valuable substances.
The preparations are prepared by conventional methods.
- 25 -
lOq345
Example A
5,8-dihydro-~-ethyl-2-(1-piperazinyl)-5-oxopyrido
~2,3-d~pyrimidine-6-carboxylic acid 2~0 g
Starch 54 g
Calcium carboxymethyl cellulose 40 g
Ilicrocrystalline cellulose~o g
Magnesium stearate 6 g
The above components are blended, granulated and
made into tablets in a manner known ~ se. This 1000
tablets each wei~hing 400 ~$ are formed.
Exam~le ~
5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido
~2,3-d~pyrimidine-6-carboxylic acid 250 g
Starch 50 g
~actose 35 g
~alc 15 g
~ he above components were blended and granulated
and filled into 1,000 capsules in accordance with tne
conventional methods.
Example C -
-5,8-dihydro-8-eth~1-2-(1-piperazinyl3-~-oxopyrido
~2,3-d~pyrimidine-6-carboxylic acid hydrochloride ~ g
Sorbitol - 3
Sugar 40 g
Methylparaben Small amount
Sodium carboxymethyl cellulose Small amount
~lavour ~mall amount
Water to make 100 ml
- 26 -
- :.~ ,,.
-~ . .
1~3456
The following Examples illustrate the preparation of
the compounds of the present invention. In all of the Example,
percentages are by weight unless otherwise specified.
Examples 1 to 14 illustrate the preparation of the
compounds of this invention in accordance with the process 1).
Example 1
5,8-Dihydro-8-ethy-l-2--~l-pi~erazinyl)-5-oxopyrid~
~2,3-d ~ rimidine-6-carboxylic acid ~compound 1):
A mixture containing 1.33 g of 5,8-dihy~ro-8-ethyl-2-
methylthio-5-oxopyrido [2,3-~ pyrimidine-6-carboxylic acid,
1.94 g of piperazine hexahydrate and 20 ml. of dimethyl sul-
foxide was heated at 110C for one hour with stirring.
The separated solid was collected by filtration, washed with
ethanol, and then dried at such a temperature that did not
rise above 50C to give 1.57 g of the trihydrate of the pro-
- duct as nearly colorless needles, m.p. 253-255C. ;~
Analysis----calcs. for C14H703N5-3H20: C, 47.05;
H, 6.49, N, 19.62; H20, 15.12. Found: C, 46.87; H, 6.41;
N, 19.54; H20, 15.1.
The trihydrate was further dried at 110C to give
1.31 g of the anhydrous product, m.p. 253-255C.
analysis----calcs. for C14H1703N5: C~ 55-43;
H, 5.65; N, 23.09. Found C, 55.48; H, 5.74; N, 22.85.
Example 2
5,8-Dihydro-8-ethyl-2-(4-methyl-1-piperazinyl)-5-
oxopyrido- [2,3-~ pyrimidine-6-carboxylic acid (comPound 3~. -
A mixture containing 1.33 g of 5,8-dihydro-8-ethyl-
2-methylthio-5-oxopyrido ~,3-~ pyrimidine-6-carboxylic acid,
1.30 g of 4-methylpiperazine, and 20 ml of dimethyl sulfoxide
-27-
1073~S6
was heated at 110C for one hour with stirringO ~he separated
solid was collected by filtration, washed with ethanol, and
recrystall zed from dimethylformamide to ~ive 1.86 g of the
product, as nearly colorless needles, m.pO 232 - 233C.
Example ~
5,8-Dihydro-8-ethyl-2-~4-(2-hydroxy-n-propyl)-1-pipera-
.
zinyl~-5-oxop~rido~2,3-d~pyrimidine-6-carboxylic acid
. .
(compound 4)0
Following the procedure described in Example 2 using
in place of 4-methyl piperazine 1044 g of 4-(2-hydroxy-n-
propyl)piperazine, there is obtained 1.40 g of the product,
as colorless needles, m.p. 214 - 216C. ~- -
Example 4
5,S-Dih,ydro-8-ethyl-2-(4-phen;gl-l-piperazin;yl)-5-- -
oxop~rido~ ?,3-d~pyrimidine-6-carbox~lic acid (compound 6)0
~ollowing the procedure described in Example 2 using ~
in place of 4-methyl piperazine 1062 g of 4-phenylpiperazine, ~ - -
there is obtained l.S0 g of the product, as yellowish orange
needles, m.p. 247 - 248C.
Example 5
?-(4-Benz~l-l-piperazinyl)-5~8-dihydro-8-ethyl-5-oxo-
p~rido~2,3-d3Pyrimidine-6-carboxylic acid (compound 7)0
~ ollowing the procedure described in Example 2 using
in place of 4-methyl piperazine 1.75 g of 4-benzylpiperazine,
there is obtained 1.40 g of the product, as colorless scales,
m.pO 204 - 206C.
EXample 6
2-(4-Acet~1-1-piperazillyl)-5,8-dihydro-~-eth~1-5-oxo-
P~ridor2,3-d~p7rrinidine-6-carbox~lic acid (compound 10).
- 2~ -
1073456
Following the procedure described in Example 2 using
in place of 4-methyl piperazine 1.28 g of 4-acetylpipera7,ine,
there is o~tained 1051 g of the product, as yellowish needles,
m.p. 298 - 300Co
ExamPle 7
~ he following compounds were prepared in the same
way as i n Example 2
G
~ COGR3 :~
Rl-M N N / , ~
R2 ,
Compound _ Rl ¦ 2 _ R3 ¦ m.p.CO
17 CH30 ~ -CH2- ¦C2H5 H 198 - 199 I
19 CH3- 1 ~ -CH2- H 251 - 255 ¦
18 HOCH2CH2 ¦C2H5_ ¦ H 226 - 228 j
C2H5C~ IC2H5 H ~ 300
21 C2H5- IC2H5- H 228 - 230 !
22 CH3- ¦C2E5_ C2H5- 146 - 147 !
24 ~CO- ¦C2H5_ H ~ 300
~2 CH3- ~CH2=CH- H 233 - 234 '
53 H ¦CH2=CHCH2_ H 253 - 255 1
33 H I ~ ~ CH2- H 2~0 - 253 ¦
34 II ¦T~OCH2cTI2- H 249 - 251 1
37 CH3 , CH2=CE CH2- H 256 - 258 i
38 ICH-C-CH2- I C2H5- H 254 - 257 ¦
C 3~ ~ CH2I ¦ H 218 - 220
. . , . _ , ., _,
- 29 -
10~3456
Example 8
The following compounds were prepared in the same way
as in Example 2. o
Compound Rl R2 R3
64 C2H5- CH2=CH- H
~ CH2=CH- H
66 ~ 2 C~2=CH- H
67 CH3 ~ ~ 2 ~ H .
Example 9
5,8-Dihydro-2-~l-piperazinyl)-8-n-propyl-5-oxopyrid
2,3-d~ pyrimidine-6-carboxylic acid ~compound 2).
A mixture containing 1.40 g of 5,8-dihydro-2-methyl-
thio-8-n-propyl-5-oxopyrido~2,3-d~ pyrimidine-6-carboxylic
acid, 2.94 g of piperazine hexahydrate, and 20 ml of dimethyl-
- - sulfoxide was heated at 100-110C for 1.5 hours. The pre-
cipitate was collected, washed with ethanol, and then recrystal-
lized from water to yield 1.40 g of the product, as color-
less needlès, m.p. 259-261C.
Example 10
5,8-Dihydro-2-t4-methyl-1-piperazinyl)-8-n-Propyl-5-
oxopyridoL2,3-d~ pyrimidine-6-carboxylic acid tcompound 26).
-30-
in~34s6
Following the procedure described in Example 9 using in place
of piperazine hexahydrate a molar equivalent quantity of 4-methylpiperazine~
there is obtained the product~ m.p, 254 - 25?C.
Exam~le 11
5.8-Dihydro-8-eth~1-5-oxo-2-~l~iperazinyl)-pyrido[2 ~3]pyrimidine-
6-carboxylic acid (compound 1)
A mixture containing 1.0 g of 5,8-dihydro-8-ethyl-2-methoxy-5-
oxopyrido[2,3_d]pyrim;dine-6-carboxylic acid 1.6 g of piperazine hexahydrate
and 50 ml of dimethyl sulfoxide was heated at 100 - llo& for 1.5 hours.
After removal of dimethyl sulfoxide by distillation under reduced pressure, ~ ~;;
the residual solid was rec~ystallized from dimethylformamide to give 1.0 g
of the product, as colorless needles, m.p. 253 - 255C.
Example 12
5,8-Dihydro-8-~2-hydroxyethyl)-2-(4-methyl-l-piperazin~l)-5- ~ -
oxopyrido[2~3-d]pyrimidine-6-carboxylic acid ~compound 31).
Following the procedure described in Example 11, there is obtained
the product, m.p. 232.5 - 233.5.
Example 13
Ethyl 2-(4-acetyl-1-piperazin~1)-5~8-dih~dro-8-eth~1-5-oxopyrido
[2~3-d]pyr;m;dine-6-carboxylate (compound 42).
A mixture containing 1.0 g of ethyl 2-chloro-5,8-dihydro-8-ethyl-
5-oxopyrido[2,3-d]pyrimidine-6-carboxylate, 0.60 g of sodium bicarbonate,
20 ml of dimethyl sulfoxide, and 0.60 g of l-acetylpiperazine was heated at
120C for 1.5 hours with stirring. The dimethylsulfoxide was distilled
- 31 -
0 7 34 56
off in vacuo and the residue was taken up in chloroform. The chloroform
solution was washed with water, dried over anhydrous magnesium sulfate,
and concentrated to dryness. The residual solid was recrystallized from a
mixture of n-hexane and acetone to yield 1.21 of the product, m.p. 208 -
210& with decomposition.
Example 14
5.8-Dihydro-2-(1-piperazinyl)-8-vinyl-5-oxopyrido[2~3_d]
pyrimidine-6-carboxylic acid hydrochloride (compound 54).
To a mixture containing 1.2 g of piperazine hexahydrate and 6 ml.
of dimethylformamide heated at 80C was added a solution of ethyl 5,8-
dihydro-2-methylthio-8-vinyl-5-oxopyrido~2,-3-d3pyrimidine-6-carboxylate -
(0.47 g) in 6 ml of dimethylformamide. The reaction mixture was allowed to
react at the same temperature for 2.5 hours with stirring. After removal -
of the solvent under reduced pressure 30 ml of 15% hydrochloric acid solu-
tion was added to the reaation mixture, which was then heated on a steam
bath for 30 minutes. The solid that precipitated was col~ected, and dis-
solved in 30 ml of water The resulting aqueous solution was treated with --~;
decolorizing charcoal followed by filtration. Addition of 2 ml of concen-
trated hydrochloric acid to tbe filtrate gave, a solid on cooling which was
collected and recrystallized from diluted aqueous ethanol to yield 0.47 g
of the product as colorless prisms, m.p. 298 - 301C with decomposition.
Examples 15 to 19 illustrate the preparation of the salts of the
compounds of this invention~
Example 15
~J - 32 -
1073456
Potassium 5,8_dihydro_8-ethyl-2_(1_piperazinyl)-5_oxo~yrido[2,3_d]
pyrimidine-6-carboxylate (compound 32).
To a solution of potassium carbonate (2.76 g) in 60 ml of water
was added 6.06 g of 5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido[2,3-d]
pyrimidine_6_carboxylic acid. The resulting mixture was heated on a steam
bath until it became a clear solution. Ethanol was added to the solution,
and the mixture was then kept below room temperature by external cooling to
yield the precipitate, wh~ch was collected and washed with ethanol. There
is obtained 4.2 g of the product m.p. above 300& .
Example 16
5,8-Dihydro-8-ethvl-2-(l-piperazinyl)-5-oxopyrido[2~3-d]pyrimi~ine
6-carboxylic acid hydrochloride (compound 11).
To a stirred solution of saturated alcoholic hy~rochloric acid
(20 ml) was added, under ice-cooling, in portions 1.28 g of 5,8-dihydro-8-
ethyl-2-(1-piperazinyl)_5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid.
The reaction mixture was then allowed to stand with continuous
stirring while being maintained below 5C.
The resulting precipitate was collected, and washed with ethanol
to yield 1.40 g of the product, as colorless needles, m.p. above 300C.
Example 17
5~ ~ ro-8-n-propyl-2-(l-pi~erazinyl)-5-oxopyrido~2~3-d]
p~rimidine-6-carboxylic acid h~drochloride (compound 28).
Following the procedure described in Example 16, there is obtained
the product, m.p. 294 - 295C with decomposition.
.
10'~34 56
Example 18
5,8-Dihydro-8-ethyl-2-~1-piPerazinyl)-5-oxopyrido [2,3-d]
pyrimidine-6-carboxylic acid acetate (compound 12~.
To a stirred suspension containing 0.30 g of 5,8-
dihydro-8-ethyl-2- Cl -piperazinyl)-5-oxopyrido[2,3-d] pyrimidine-
6-carboxylic acid and 20 ml of an absolute ethanol was added 2ml. of
glacial acetic acid at room temperature. The reaction mixture
was stirred for an additional two hours. The resulting pre-
cipitate was collected, and washed with ethanol to yield 0.35 g
of the product, as colorless needles, m.p. 257-258C.
Example 19
The following salt were prepared in the same way as in
Example 18.
5,8-Dihydro-8-ethyl-2-(1-piperazinyl~-5-oxopyrido [2,3-d]
pyrim-dine-6-carboxylic acid lactate (compound 13): m.p. 230-
235&
5,8-Dihydro-8-ethyl-2-~1-piperazinyl)-S-oxopyrido [2,3-d]
pyrimidin -6-carboxylic acid succinate (compound 14~: m.p.
202-204& .
S,8-Dihydro-8-ethyl-2-(1-piperazinyl)-5-oxoPyrido [2,3-dl
pyrimidine-6-carboxylic acid oxalate compound 15): m.p.
261-263C.
5,8-Dihydro-8-ethyl-2-~1-piperazinyl)-5-oxopyrido [2,3d]
pyrimidine-6-carboxylic_acid methanesulfonate ~compound 16):
m.p. 294-295C. (dec.)
Examples 20 to 25 illustrate the preparation of the com-
pounds of this invention by the process 2).
- 34 -
10~3456
Example 20
Ethyl 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido
C2~3-3 pyrimidine-6-carboxylate ~compound 59)
To 16 ml of diphenyl ether heated at 250-255C was
added with stirring 2.0 g of diethyl N- C2-C4-acetyl-1-pipera-
zinyl)-4-pyrimidiny~ - aminomethylenemalonate, gentle refluxing
was~ continued for 10 minutes, and then the mixture allowed to
cool to room temperature~ To the mixture was added 12 ml
of n-hexane and the resulting precipitate was collected, washed with
ethanol, and recrystallized from ethanol to yield 1.52 g of
the product, m.p. 300-302C with decomposition.
~xample 21
The following compounds were prepared in the same
way as in Example 20. o
Rl-~l~NJN\~ COOR3'
~2' .,
COMPOUND Rl R2~ - ~ mpCC
42 CH3C0- C2H5- C2H5- 208-210 (dec.)
56 H C2H5- C2H5- 156-158
CF3CO C2H5- C2H5- 244-246
Example 22
Ethyl 5,8-dihydro-8-ethyl-2-~4-methyl-1-piperazinyl)-
5-oxopyrido [2,3-~ pyrimidine-6-carboxylate ~compound 22)
A mixture containing 1.0 g of diethyl N-ethyl-N-
-35-
. .
10734S6
t2-(4-methyl-1-piperazinyl)~ pyrimidinyl~aminomethylene
malonate and 6.0 g of polyphosphoric acid was heated at
140C for 20 minutes, and then poured into ice-water. The
resulting mixture was made alkaline with 28% aqueous ammonia
and extracted with chloroform. ~he extract was washed with
water, and dried over anhydrous magnesium sulfate, and the
solvent was removed by distillation to give a crude product
which was recrystallized from water to ~ive 0~72 g of the
product, m.p. 146 - 147C.
ExamPle 23 -
Eth~l 2-(4-benz~l-1-piperazin~ ,8-dihydro-~-ethyl-
5-oxop~ridot2,~-d~p~rimidine-6-carbox~late (compound 55)
~ ollowing the procedure described in Example 22,
there is obtained the product, m.p. 151 - 153C.
Example 24 `-
Ethyl 5,8-dih~dro-~-eth~1-2-(1-piPerazin~l)-~- --
oxopyrido~2~3-dlp~rimidine-6-carbox~rlate (compound 56)
Diethyl N-ethyl-~ 2-(1-piperazinyl)-~-pyrimidinyl~
-aminomethylenemalonate (1.0 g) ~as heated at 250C for 30
minutes and the resulting solid was recrystallized from
ethanol to give 0.73 g of the product, m.p. 156 - 158C.
Example 25
.
Ethyl 5?~-dih~dro-2-(4-meth~l-1-piperazin~1)-5-
- oxop~ridot2,3-d~p~rimidine-6-carbox~late (compound 70)0
To a 50 ml of diphenyl ether heated at 210 - 220C
was added with stirrin~ 7.0 g of diethyl N-~2-(4-methyl-1-
piperazinyl)-4-pyrimidiny~alqinomethylenemalonate, and heat-
ing was continued for one hour. To the resulting mixture,
after being cooled, was added 50 ml of n-hexane. The
!
6 _
,
~0~3~S~ -
resulting precipitate was collected, washed with ethanol,
and recrystallized from dimethylform~mide to yield 6.3 g of
the product, m~p. 266 - 268C.
Examples 26 to 3~ illustrate the preparation of the
compounds of this invention by the process 3).
Example 26
Et~yl 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-8-ethyl-
5-o~op~rido~2,3-d~pyrimidine-6-carboxylate (compound 42)
To a suspension of ethyl 2-(4-acetyl-1-piperazinyl)-
5,8-dihydro-5-oxopyrido~2,3-d)pyrimidine-6-carbox~ylate (4.0 g),
and 6.0 g of potassium ca~bonate in 100 ml of 5~/0 aqueous
ethanol was added with stirring a total of 5.5 ml diethyl
sulfate in three portions and the mixture was allowed to -
react for 2 hours at room temperature.
15 ~ ~he reaction product was extracted with chloroform,
and the extract dried over anhydrous magnesium sulfate,
followed by evaporation of the solvent to leave a crystalline
residue,-to which n-hexane was added. ~he crystals were
collècted and recrystallized from a mixture of n-hexane and
20- acetone-to give 3O4 g of the product~ m.p. 208 - 210C with
decomposition.
Example 27
2-(4-Acetyl-l-piperazinyl~-5,8-dihydro-8-ethyl-5-
oxoPyrido~2~3-dlp~yrimidine-6-carboxylic acid (compound 10)
To a solution of 0O45 g of 2-(4-acetyl-1-pipera-
zinyl)-5,8-dihydro-5-oxopyrido~2,3-d)pyrimidine-6-carboxylic
acid in 30 ml of sodium carbonate was added two 0.5 ml
portions of diethyl sulfate with stirring at room temperature.
After the completion of the reaction the mixture was
- 37 -
iO734S6
neutralized with acetic acid. The precipitate resulted was
collected and recrystallized from dimethylformamide to yield
0.4 g of the product, m.p~ 298 - 300Co
Exam~le 28
2-(l-piPerazin~yl)- and 2-(4-ethyl-1-Piperazin~ 5,8-
dih,ydro-8-ethyl-5-oxopyrido~2,3-dlp~rimidine-6-carboxylic
~`~ acids (com~ound l and 21) -
~o a solution of 1.5 g of 5,8-dihydro-2-(1-piperazinyl)
- -5-oxopyrido~2,3~d~pyrimidine-6-carboxylic acid in 60 ~1 of --
a lOYo aqueous solution of sodium carbonate was added three
10 ml portions of diethyl sulfateO After completion of the
reaction, the resulting mixture was neutralized with acetic ~-
àcid. ~he precipitate was collected and recrystallized from ~-~
dimethyl~ormamide to- give 0.& g of 2-~1-piperazinyl)-5,8-
dihydro-8-ethyl-5-oxopyrido~2,3-~pyrimidine-6-carboxylic
acid (compound 1) m.p. 253 - 255C.~ Concentration of the ~
mother liquor to about a half volume gave another solid which -~-
was further recrystallized from the same solvent to give
0.6 g of 2-(4-ethyl-1-piperazinyl)-5,8-dihydro-8-ethyl-5-
oxopyridoC2,3-d~pyrimidine-6-carbox~lic acid (compound 21),
m.pn~ 228 - 230C. --
E*amPle 29
5;8-Dihydro-8-ethw1-2-(4-methyl-1-piperazinyl)-5-
oxoP~r1dor2,3-dlP~rimidine-6-carboxylic acid (comPound 3)
~o a mixture containing 1.0 g of 5,8-dihydro-2-
(4-methyl-1-piperazin~l)-5-oxopyrido[2,3-d~pyrimidine-6-
carbox~lic acid, loO g of 65% sodium h~-dride, and 40 ml of
dimethylformamide held at 60C, was added 1.0 ml of ethyl
iodide. The resulting mixture was heated on a steam bath
- 38 -
lOq3456
for 2.S hoursO Dimethylformamide was distilled off in vacuo~
the residue dissolved in 10 ml of water, and the resulting
solution neutralized with acetic acid~ ~he precipitate was
collected and recrystallized from ethanol to yield 0.72 g of
the product, m.p. 232 - 233C.
ExamE~le 30
Eth~1 2-(4-benzyl-1-piperazi~yl)-5-,8-dihydro-8-ethyl-
5-oxQp~rido~2-,3-dlp~rimidine-6-carboxylate (compound--55)
; A mixture of 103 g of ethyl 2-(4-benzyl-1-pipera-
zinyl)-5,8-dihydro-5-oxopyridot2,3-d~pyrimidine-6-carboxylate,
5.0 ml of ethyl iodide, 20 ml of a 12/~ aqueous solution of -~
sodi`um carbonate, ànd 200 ml of dimethylformamide was heated
at 95C for 3 hours. After removal of the solvent and an
excess of the reagent by distillation in vacuo, the resulting
~ i5 residue was taken up in chloroform and filteredO The filtrate
- ~ was dried and then concentrated to dryness to leave a solid
~`- which was collected and recrystallized from ethanol to give
1.0 g of the producti m.pO 151 - 153C.
'ExamPle E31
: 2b ~ 8-Bén~yl~dro-2~ methyl-l-Pi-perazinyl~-5-
oxc~ ido~2,3~alp~rimidine-6-carbox~lic acid (compound 19)
.~ .
A mixture of loO g of 5i8-dihydro-2-(4-methyl-1-
pi~erazinyl)-5-oxopyrido~2,3-d~pyrimidine-6-carboxylic acid,
0.6 ml of ben~yl chloride, 20 ml of a 12% aqueous solution
f potassium carbonate and 150 ml of dimethylformamide was
heated at 95C for 2 hours. After removal of the solvent
and an excess of the reagent, the resulting residue was taken
up in water and the aqueous solution neutralized with acetic
acid. ~he solid that separated was collected and recrystal-
- 39 -
.
i.O73L~56
lized from dimethylformamide to give 0.7 g of the product,
m.p~ 251 - 25~C.
Example 32
~,CCCR3
''
2 -~
~ he following compounds were prepared in the same
way as in Example 26.
: Compound I Rl ¦ R2 ¦ R3 ¦ m.p;~Cv
22 CH3- C2H5- C2H5- ~ 14~ _ 147v
20 2 5_ C2X5- H ~ > 300 .-.
~he followi~g compounds were prepared in same way
as in Example 27. --
¦ Co~ l Rl ¦ R2 ' `¦ R3 ¦ m-p-C- I -
_6 ! ~- ~C2~ 247-248~
The following compounds were prepared in the same
way as in Example 28.
Co~pound Rl ¦ R2 1IR3 I m.p.C.
3 CH3- C2H5- H ~ 232 - 234
56 E C2E~5_ 2 5 !
t
-- 40 --
- . ~ .. - -
lO'Y3~S6
The following compounds were prepared in the same
way as Example 290
. __
Compound Rl R2" R3 mOp.C.
. .... .. _ _
7 ~ ~ -CH2- C2H5- H 204 - 206
17 CI~30 ~ CH2 C2H5- H 198 - 199 ~
21 C2H5 '~2H5- H 228 - 230 1 -
39 CH30\ C2H5 H 218 - 220
39 Cl;~ ,GE"_ ~ C2H5~ 054 _ P~7
.
~he following compounds were prepared in the same
way as in Example 30
. _ .
Compound I Rl R2" R m.p.C.
i 3 .
i ~"e: .~c2~5- n-C3H7_ 15 ~ 5 ~ 158n 5 ¦
Exam~le 33
Rl-~ N N
-- R2 "
The following compounds were prepared in the same
way as in Example 31.
- 41 -
0'~3456
No. ¦ Rl I R2" R3 m.p.C0 l agent
26 CH3- ~n-C3H7- ¦H 254 - 257 ~ n-C3H7Br
31 CH3- IHOCH2CH2- ¦H 23205 - 23305l I~OCH2CH2Cl
37 CH3_ ICH2=CHCH2-lH 256 - 258 ¦ CH2=CHCH2Br I -
CH3- ¦C1CH2CH2_ ¦H 226 - 228
Example 34 -~
Ethyl 5,8-dihydro-8-(2-hydrox~eth~1)-2-(4-methyl-1-
piperazin~l)-5-oxopyrido~2,3-d~pyrimidine-6-carbox~late
(compound 68)o
A mixture containing 5.0 g of ethyl 5,8-dihydro-2-
(4-methyl-1-piperazinyl)-5-oxopyrido~2,3-d~pyrimidine-6-
carboxylate, 70 ml of dimethylformamide, 0.90 g of 50/~ sodium
hydride, and 3.8 g of ethylene chloro_ydrin was heated at
100C for one hour. Dimethylformamide was distilled off in
vacuo, and the residue taken up in chloroform. The chloro-
form solution was washed with water, dried over anhydrous
magnesium sulfate, and the solvent di~tilled offO The re-
sulti~g solid was recrystallized from ethanol to yield 4.6 g
of the product, m.p. 197 - 199C.
Example 35
Ethyl 8-(2-chloroethyl)-5,8-dihydro-2-(4-methyl-1-
razin~ oxop~ridot2,3-d~p~rimidine-6-carbox~late
(compound 69).
To a solution of 8.0 g of ethyl 5,8-dihydro-8-
(2-hydroxyethyl)-2-(4-methyl-1-piperazinyl~-~-oxopyrido-
~2,3-d~pyrimidine-6-carboxylate in 80 ml of chloroform was
- 42 -
" 1073456
added with stirring 6 ml of thionyl chloride, the resulting mixture was
allowed to react at room temperature for 30 minutes and then heated to
reflux for 2 hours. After removal of the solvent and an excess of the re-
agent, the residue was taken up in chloroform. The chloroform solution
was washed with water, dried and the solvent distilled off. The solid
obtained was recrystallized from ethyl acetate to give 6.9 g of the product,
m.p. 154 - 155C.
Examples 36 to 42 illustrate the preparation of the compounds of
this invention by the process 4).
Example 36
Ethyl 5,8-dihydro-8-ethyl-2-(4_methyl-1-piperazinyl)-5-oxopyrido
r~3-d]p~rimidine 6-carboxylate (compound 22)
A mixture containing 1.0 g of ethyl 5-ethoxy-2-(4-methyl-1-
piperazinyl)pyrido[2~3-d]pyrimidine-6-carboxylate and 5.0 ml of dimethylene
glycol dimethyl ether was heated to reflux for 3 hours. The solvent was
removed by distillation in vacuo and the residual solid was recrystallized
from water to yield 0.72 g of the product, m.p. 146 - 147& .
The starting materials used above were prepared as follows:
Ethyl 5-chloro-2-(4-methyl-1-piperazinyl)pyrido[2,3-d]pyrimidine-
6-carboxylate.
A mixture containing 30 g of diethyl N-[2-(4-methyl-1-piperazinyl)-
4-pyrimidinyl]Pm;nomethylene malonate and 150 ml of phosphorus oxychloride
was heated at 95C for 5 hours. An excess ~ the reagent was removed in
vacuo, the residue was made alkaline with 28% aqueous a~monia. The result-
ing mixture was extracted with chloroform, the extract washed -~
- 43 -
.,,~
10~3456
.
.,
with cold water, and dried over anhydrous magnesium sulfate.
The solvent was distilled off to leave a ~lid which was
recrystallized from acetoneO There is obtained 23.5 g of the
above product as yellow needless, m.p. 173 - 175C.
Ethyl 5-ethoxy-2-(4-methyl-1-piperazinyl)~_ido~2,3-d~
p2ri_dine-6-carboxylateO
A mixture containing 300 g of ethyl 5-chloro-2-
~4-methyl-1-piperazinyl)pyrido~2,3-d~pyrimidine-6-carboxylate,
0.7 g of sodium ethoxide, and 50 ml of absolùte ethanol was
heated to reflux for 2 hoursO ~he ethanol was removed by
distillation in vacuo, the residue was extracted with chloro--
form and the extract washed with water, and dried over an- ~-
hydrous magnesium ~Ulfate. After the solvent was distilled
off the residue was crystallized from n-hexane to give 2.8 g
of the product as pale yellow needlés, m.p. 105 - 108C.
ExamPle 37
Ethyl 5,8-di~ydro-8-eth~1-2-~4-methyl-l_piperazi~yl)- - !
'.' :: .
5-oxopyrido~2,3-dlpyrimidine-6-carbox~late (compound 22)o
A mixture containing 1.0 g~of ethyl 5-ethoxy-2-(4- ~ -
methyl-l-piperazinyl)pyrido~2~3-d~pyrimidine-6-carbox,Ylate
and 5.0 ml of ethyl iodide was heated to reflux for one hour.
Aftsr ethyl iodide was recovered by distillation, the re-
sulting solid was crystallized from water to give 0069 g of
the product, m~p. 146 - 147C.
Ex~mPlb 38
Ethyl 5,8-di~ydro-8-ethyl-2-(1-piperazi~yl)-5-
oxop~ridot2,3-dlp~rimidine-6-carboxylate (compound 56)
Following the procedure described in Example 36
using ethYl 5-ethoxy-2-(l-piperazi~Yl)pyrido~2~3-d)
- 44 -
... . . .
10~34~6
pyrimidine-6-c~rboxylate, there is obtained the product,
m.p. 156 - 158C.
Example 39
Ethyl 2-(4-acet~l-1-piperazinyl)-5,8-dihydro-8-ethyl-
5-oxopyrido~2,3-dlp~rimidine-6-carbox~late (compound 42)
Following the procedure described in Example 37
using ethyl 2-(4-acetyl-1-piperazinyl)-5-ethoxypyridoC2,3-d~
pyrimidine-6-carboxylate with ethyl iodide, there is obtained
the product, mOp. 208 - 210C with decompositionO ;
Example 40
Ethyl 2-(4-benz,yl-1-piperazin,yl)-5,8-dihydro-8-eth,yl-
5-oxop~ridot2,3-d~pyrimidine-6-carbox~late (compound 55)
Following the procedure described in Example 37
using ethyl 2-(4-benzyl-1-piperazinyl)-~-ethoxypyridot2,3-d~
pyrimidine-6-carboxylate with ethyl iodide, there is ob-
tained the product, m.p. 151 - 153C.
ExamPle 41
.
Eth,yl 2-(4-acet~ -piperazin~yl)-8-(2-chloroethyl)-5~8
d~Ydro-5-oxopyridot2~3-d~pyrimidine-6-carboxylate (compound
....
61)
A solution of 1.0 g of ethyl 2-(4-acetyl-1-pipera-
z~nyl~-5-ethoxypyridot2~3-d)pyrimidine-6-carboxylate in 10
ml of 1,2-dichloroethane was heated to reflux for 15 hours~
After removal of an excess of the reagent by distillation,
the resulting solid was taken up in chloroform and the
chloroform solution washed with water, and dried over an-
hydrous magnesium sulfate. ~he solvent was distilled off
to leave a solid which was recrystallized from ethyl acetate
to give 0.65 g of the product, mOp. 205 - 206C.
- 45 -
- ~ ..,
456
Ethyl 2-~4-acetyl-l-piperaziny-l-8-(2-bromoethyl)
5,8-dihydro-5-oxopyridor2,3-3 pyrimidine-6---carboxylate
compound 62)
Following the procedure described above and using
1,2-dibromoethane in place of 1,2-dichloroethane, there is
obtained the product, m.p. 202-204C.
Example 42
Ethyl 5,8-dihydro-8-~?-hydroxyethyl)-2-~4-methyl-1-
piperazinyl)-5-oxopyridoC2,3-~ pyrimidine-6-carboxylate ~com-
pound 68)
Following the procedure described in Example 37 using
ethyl 2-~4-methyl-1-piperazinyl)-5-ethoxypyrido{2,3-~ pyrimidine-6-
carboxylate with ethylenebromohydrine, there is obtained the
product, m.p. 197-199C.
Examples 43 to 51 illustrate the preparation of
the compounds of this invention by the process 5).
Example 43
5,8-Dihydro-8-ethyl-2-~1-piperazinyl)-5-oxopyrido
r2,3-~ pyrimidine-6-carboxylic acid (compound 1).
Ethyl 5,8-dihydro-8-ethyl-5-oxo-2-~1-piperazinyl)
pyridoC2,3-~ pyrimidine-6-carboxylate ~5.o g) was dissolved
in 30 ml of a 7~ aqueous solution of sodium hydroxide by
heating at 90C for 20 minutes. After cooling, the resul-
ting solution was neutralized with acetic acid to yield a
precipitate which was collected, and recrystallized from
dimethylformamide. There is obtained 4.3 g of the product
m.p. 253-255C.
Example 44
5,8-Dihydro-8-ethyl-2-~4-methyl-1-piperazinyl)-5-
-46-
-
10'~;~456
ox~pyri_o[2,3-~ pyrimidine-6-carboxylic acid (compound 3)
n-Propyl 5,8-dihydro-8-ethy~-2-(4-methyl-1-piperazinyl)
-5-oxopyrido ~2,3-~ pyrimidine-6-carboxylate (4.5 g) was dis-
solved in 30 ml of a 10% aque0us sol~tion of sodium carbonate
by heating at 95C for 30 minutes.
After being cooled, the resulting solution was
neutralized with acetic acid to give a precipitate which was
collected and recrystallized from dimethylformamide. There
is obtained 3.8 g of the product, m.p. 232-233 C.
Example 45
8-Benzyl-5,8-dihydro-2-(1-piperazinyl)-5-oxopyrido
2,3-~ pyrimidine-6-carboxylic acid (compound 33)
Ethyl 8-benzyl-5,8-dihydro-2-(1-piperazinyl)-5-
oxopyrido~2,3-~ pyrimidine-6-carboxylate (1.5 g) was di-
solved in 20 ml of a 12% aqueous solution of sulfuric acid
by heating at 90C for one hour. The resulting solution
was filtered to remove a small amount of the insoluble
material and the filtrate was neutralized with 28% aqueous
ammonia, to separate a solid which was collected, washed
with water, and recrystallized from dimethylformamide.
There is obtained 1.1 g of the product, m.p. 25~-253C.
Example 46
Using n-propyl ester as a starting material, the
following compounds were prepared in the same way as in
Example 44.
-47-
10734S6
o
~ .COOH
Rl-N N- N ~ ~N
A 2
¦ Compound I Rl I R2 i m.p.C
26iCH3_ ¦n-C~H7 j 254 - 257
31~CH3- ! HCCH2CH2- ¦232.5 - 23305 ¦
¦ ! ~ H2_ ¦C2H5 1 204 - 206
Example 47
Using ethyl ester as a starting material, the
~ollowing co..;polunds were prepared in the same way as in
Example ~
O
,COOH
~ / R
j Compoundl Rl ~ R2 ! mOP co
1 34 ! H ¦HOCH2CH2- ¦ 24~ - 251
! 50 ¦ H ¦CH2=CHCH2-l 253 - 255
37 CH3- CH2=CHCH2-1 256 - 258
18 HOCH2CH2 C2H5- ¦ 226 - 228
38 CH-C-CH2- C2H5- ¦ 254 - 257
i 45 I CII3- ! ClCH2CH2- ! 226 - 228
- 4~ -
.
. ~ . .
10~34S6
E~cample 48
.
Using ~thyl ester as a starting material, the
following compounds were prepared in the same way as in
Example 43.
O
~ ,COOH
N~
J R
Compound Rl ¦ R2 j m.p.G
I
2 . H ¦ n-C3Hj j259 - 261
6 ~ C2H5- ~247 - 248 ¦
7 ~ -CH2 C2H5- ¦204 - 206
17 CH30 ~ CH2C2H5- 198 - 199 : .
19 CH3-~ ~ CH2-1l251 - 255
21 C2H5-¦ G2H5- ¦228 - 230
. 1 39 CH30 ~C2H5- ~218 - 220
. CH3C
ExamPle 49
2-(4-Acet~l-1-piperazi~yl)-5~8-dih~dro-8-et~yl-5-
oxop~ridot2,3~p~rimidine-6-carboxylic acid (compound 10)
Ethyl 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-8-
ethyl-5-oxopyrido~2.3-d)pyrimidine-6-carboxylate (500 g)
- 49 -
, ,,,!
107345~
was dissolved in 35 ml of a 10% aqueous solution of sodium
carbonate by heating at 90C for 30 minutes. ~he resulting
solution was filtered to remove the insoluble material,
and the filtrate was neutralized with acetic acid to give a
precipitate which was collected and recrystallized from a
mixture of benzene and chloroform. There is obtained 4.1 g
of the product, m.pO 298 - 300Co
Example 50
5,8-Dihydro-2-(4-methyl-1-Piperazin,yl)-8-vin;yl-5-
oxoP~ridot2,3-dlpyrimidine-6-carboxylic acid (compound 52)
5,8-Dihydro-2-(4-methyl-1-piperazinyl)-8-vinyl-
5-oxopyrido~2,3-d~pyrimidine-6-carboxylic acid, m.p. 233 -
234C, is obtained by hydrolysis of the corresponding ethyl
ester as in EXample 49O
Exa~æle 51
5,8-Dih~dro-2-(1-piperazinyl)-&-vinyl-5-oxopyrido
t2-3-d~Pyrimidine-6-carboxylic acid hydrochloride (compound
54)
Ethyl 5,8-dihydro-2-(1-piperazinyl)-8-vinyl-5-
20 oxopyridot2,3-~pyrimidine-6-carbo:~late (loO ~5) was dis-
solved in 6 ml of a 10% aqueous solution sodium carbonate by
heating at 95Co ~he resulting solution was filtered to
remove the insoluble material and acidified with concentrated
h~drochloric acid below pH 1~ The resulting precipitate
was collected and recrystallized from diluted aqueous
ethanol to yield 0.78 g of the product, m.p. 298 - ~01C
with decompositionO
Examples 52 to 53 illustrate the preparation of
the compounds of this invention by the process 6).
- 5 -
10~34
Example 52
5,8-Dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido-
~2,3-d~p~rimidine-6-carbox~lic acid (comPound 1)
(A~ 2-(4-Acetyl-l-piperazinyl)-~,8-dihydro-8-ethyl-
5-oxopyridot2,3-d~pyrimidine-6-carboxylic acid (2.0 g) was
dissolved in 40 ml of a 10% aqueous solution of sodium
hydroxide by heating at 90 - 95C,for 1.5 hours. ~he
resulting solution was treated with decolorizing charcoal
and filtered. ~he filtrate was neutralized with acetic
acid to give 1.6 g of the product as a pure state, m.p.
253 - 255C.
(B) Ethyl 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-8-
ethyl-5-oxopyridoc2?3-d~pyrimidine-~i-carboxylate (106 g)
was dissolved in 30 ml of a l~/o aqueous solution of sodium
hydroxide by heating at 90 - 95C for one hour. ~eutraliza-
tion of the reaction mixture with acetic acid under coolin~
yielded a crude solid, which was recrystallized from
dimethylformamide to give 1.1 g of the product as a pure
state. ~-
Example 53
.. . ..
5,8-Dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido
C2,~-d~pyrimidine-6-carboxylic acid ~ydrochloride (compound
.. . .... . . :
)
A mixture containing, 2.0 g of 5,8-dihydro-8-
ethyl-2-(4-formyl-1-piperazinyl)-~-oxopyridoC2,3-d~pyrimidine-
6-carboxylic acid and 30 ml of 10% aqueous hydrochloric acid
was heated at 90 - 95C for one hour. The reaction mixture
was concentrated to dryness and addition of ethanol to the
residue resulted in the separation of a solid, which was
- 51 -
10~3~
collected and washed with ethanol to yield 1.7 g of the
product, m.p. above 300C.
ExamPl-e 54
5,8-Di~ydro-8-ethyl-2-(1-piperazin~1)-5-oxop~rido-
[2,3-d~pyrimidine-6-carboxylic acid (compound 1) and 8-
benzyl-5~8-dihydro-s-oxo-2-(l-piperazinyl)pyrido~2~3-d
pyrimidine-6-carboxylic acid (compound 33)
Following the procedure described in Example 52
(A) using 5,8-dihydro-2-(4-ethoxycarbonyl-1-piperazinyl)-
8-ethyl-5-oxopyrido~2,3-d~pyrimidine-6-carboxylic acid or
2-(4-acetyl-1-piperazinyl)-8-benzyl-5~8-dihydro-5-oxopyrido
C2,3-d~pyrimidine-6-carboxylic acid, there is obtained,
respectively, 5.8-dih~dro-8-ethyl-2-(1-piperazinyl)-5-
oxopyrido~2?3-d~pyrimidine-6-carboxylic acid, m.p. 253 -
255C or 8-benzyl-5,8-dihydro-2-(1-piperazinyl)-5-oxo- ~-
pyrido~2,3-d~pyrimidine-6-carboxylic acid, m.p. 250 - 253C.
Example 55 `~
5~8-Dihydro-8-n-propyl-2-(l-piperazinyl)-5-oxoPyrido
.
r2,3-d~p~rimidine-6-carboxylic acid hydrochloride (compound ~-
28)~and the corresponding free carbox~lic acid (comPound 2)
Following the procedure described in Example 53
using 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-8-n-propyl-5-
oxopyrido[2,3-d~pyrimidine-6-carboxylic acid, there is
obtained 5,8-dihydro-8-n-propyl-2-(1-piperazinyl)-5-oxo-
pyrido[2,3-d~pyrimidine-6-carboxylic acid hydrochloride
m.p. 294 - 295C with decompositionO
The above hydrochloride (1.0 g)was dissolved in
5 ml of water and neutralized with a 5~ aqueous solution of
sodium bicarbonate to yield the corresponding free carboxylic
- 52 -
10~3456
acid m~p. 250-261C.
Example 56
Ethyl 5,8-dihydro-8-ethyl--2-~l-piperazinyl)-5-oxopyrido
r2?3- 1 pyrimidine-6-carboxylate tcompound 56)
~ A) A mixture containing 4.5 g of ethyl 5,8-dihydro-
8-ethyl-2-(4-trifluoroacetyl-1-piperazinyl)-5-oxopyrido
~2,3-~pyrimidine-6- carboxylate, 20 ml of a 7% aqueous solution
of potassium carbonates, 50 ml of methanol, and 15 ml of chloroform
was allowed to react at room temperature for 1.5 hours with
10 stirring. The solvent was then removed by distillation in vacuo,
and the resulting residue was taken up in chlorofonm. The
chloroform solution was dried over anhydrous magnesium sulfate, and
the solvent was distilled off to yield a crude product, which was
recrystallized from acetone to give 2.9 g of the product m.p. 156-
158C.
~ B) A solution of 3.0 g of ethyl 2-~4-benzyl-1-
piperazinyl),5,8-dihydro-8-ethyl-5-oxopyrido C2,3-~ -pyrimidine-6-
carboxylate in 100 ml of ethanol was allowed to consume an equi-
valent amount o hydrogen over 1.5 g of 10% palladium-on-carbon
20 under hydrogen atm~sphere. The reaction mixture was filtered to
remove the catalyst, and the filtrate was concentrated to give a
solid which was collected and recrystallized from acetone. There
is obtained 2.5 g of the product, m.p. 156-158C.
Example 57
n-Propyl 5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-
oxopyridor2,3-dlpyrimidine-6-carboxylate ~compou~d 571.
Following the procedure described in Example 56
~B), n-Propyl 2-~4-benzyl-1-piperazinyl)-5,8-dihydro-8-
lQq3456
ethyl-5-oxopyrido L2,3-d]pyrimidine-6-carboxylate is hydrogenolyzed
to yield the product, m.p. 152-153C.
Example 58
8-~2-Chloroethyl2-5~8-dihydro-2-~l-piperazinyl)-5-oxopyrido
2,3-~ pyrimidine-6-carboxylic acid hydrochloride ~compound 63)
A mixture containing 1.0 g of ethyl 2-~4-acetyl-1-pipera-
zinyl)-8-(2-chloroethyl)-5,8-dihydro-5-oxopyridoL2,3-~ -pyrimidine
-6-carboxylate and 12 ml of 20% aqueous hydrochloric acid was heated
on a steam bath for 2 hours, during which period crystals separated
out. The crystals were collected, after cooling and recrystallized
from diluted aqueous ethanol containing ;a small amount of con-
centrated hydrochloric acid to yield 0.9 g of the product m.p
280C with decomposi~ion.
Examples 59 to 61 illustrate the preparation of the compounds
of this invention by the process 7).
Example 59
:
5,8-Dihydro-2-(4-methyl-1-piperazinyl)-8-vinyl-5-oxopyrido
[2,3-~ pyrimidine-6-carboxylic acid ~compound 52)
~A) To a mixture, containing 60 ml of absolute ethanol and
0.65 g of 65% sodium hydride, which was held at 60C was added with
stirring 1.5 g of ethyl 8-(2-chloroethyl)-5,8-dihydro-2-~4-methyl-1-
piperazinyl)-5-oxopyrido C2,3-~ -pyrimidine-6-carboxylate. The re-
sulting mixture was heated to reflux for one hour and then 30 ml of
water added to it. The mixture was refluxed for an additional 30 min-
utes. The ethanol was distilled off under reduced pressure. The
resulting residue was neutralized with 1 N-hydrochloric acid
-54-
: ,
iO'~3~
and extracted with chloroform. The extract was washed with
water and dried over anhydrous magnesium sulfate. The
solvent distilled off. ~he solid that obtained was recrys-
tallized from a mixture of chloroform and ethanol to give
0.92 g of the product, m.pO 233 - 234C.
(B) A solution of 8-(2-chloroethyl)-~,8-dihydro-2-
(4-methyl-1-piperazinyl)-5-oxopyrido[2,3-d)pyrimidine-6-
carboxylic acid (loO g) in 20 ml of a 10% aqueous solution
of sodium hydroxide was he~te~ at 95C for three
hours~ ~he reaction mixture was then neutralized with
hydrochloric acid under ice-cooling and chilled~ The re-
sulting precipitate was collected to give 0.63 g of the
product. Recrystallization from a mixture of chloroform
and ethanol gave the product as pure state.
Example 60
5, 8-Dih;ydro -2- ( 1-piperazinyl ) -8-vin~y1-5-oxopyrido t2, 3-d~
pyrimidine-6-carboxylic acid hydrochloride (compound $4)
To a mixture, containing 400 ml of absolute ethanol ~-
and 2.0 g of 65% sodium hydride, which was held at 60C was
added with stirring 5.0 g of ethyl 2-(4-acetyl-1-piperazinyl)
-8-(2-chloroethyl)-5,8-dihydro-5-oxopyrido[2,3-d~pyrimidine-
6-carboxylate. The resulting mixture was heated to reflux
for 2 hours and at the end of the period 200 ml of water was
added. ~he mixture was refluxed for an additional 30 minutes~
The ethanol was distilled off under reduced pressùre and the
resulting residue was acidified with concentrated hydrochloric
acid to pH loO~ The resulting precipitate was collected and
recrystallized from water to yield 2.8 g of the product,
m~p. 298 - 301C with decompositionO
1073456
Example 61
5,8-Dih~dro-2-(4-meth,yl-i-~iPerazin~1)-8-vin~1-5-
oxop~idoC2,~-dlp~rimidine-6-carbox~lic acid (compound 52)
Following the prooedure described in Example 59
(A), using ethyl 5,8-dihydro-8-(2-methanesulfonyloxyethyl)-
2-(4-methyl-1-p~perazinyl)-5-oxopyrido~2,3-d)pyrimidine-6-
carboxylate with potassium tert-butoxide in dimethyl -.. ~ -
sulfoxide as a solvent, there is obtained the product, m.p.
~: 23~ - 234C.
-- ' :
:
- 56 -
. . - - . ~ , ,, . ~
