Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~066701
This invention relates to a method for prep&ring new ar.d useful
piperazine derivatives and pharmaceutically acceptable salts thereo~ as
antibacterial agents, and ~nter~ediates thereof.
The useful piperazine derivatives as antibacterial agents are
expressed by the following formula
COOH
N3~5~
~ I . .
2 5
uherein Rl is a hydrogen atom or lower alkyl group.
The intermediates thereof are expressed by the following formula -
R'l - N ~ 1 N~ (II)
C2 5
wherein R'l is a hydrogen atom, lower alkyl group or acyl group
and R2 is a cyano group, lower alkoxycarbonyl group, or lower alkanoyl
group.
The acyl group as R'l means a group selected from ~ormyl, acetyl,
ethoxycarbonyl, benzyloxycarbonyl and benzoyl groups, and the acetyl group
is especially preferred.
The louer alkyl group in Rl means an alkyl group having 1 to 4
carbon atoms such as a methyl, ethyl or butyl group. The methyl and ethyl
groups are preferred.
The louer alkoxycarbonyl or lower alkanoyl group as R2 respectively -~
means an alkoxycarbonyl or aIkanoyl group having 2 to 5 carbon atoms, such
as ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, acetyl, or propionyl
group,
The compound of this invention is synthesized as follows:
. , . , . ,: : -
1066701
First, æ compound of the formula
~ COO alkyl
R ' 1--N N N 1 2 2 R2 ( :[V )
--/ C2H5
wherein R'l and R2 are the same as defined above, and the aIkyl
is an alkyl group preferably containing 1 to ~ carbon atoms, is sub~ected to
Dieck~ann reaction, and the resulting compound of the formula
N ~ J~ 2
R~ \N,J~N 1~ Nl J ~III)
C2H5
wherein R'l and R2 are the same as defined above, is dehydrogenated
to Por~ a compound of the following formula
~ ~ 2 (Il)
C2H5
wherein R'l and R2 are the same as defined above, that is an
intermediate. ~ -
Hydrolysis o`r oxidation of the resulting intermediate (II) accord- .
ing to the nature of radical R2 gives a useful compound as an antibacterial
agent. Specifically, the useful compound of the invention is prepared by ~ ~ :
hydrolyzing a compound of the formula
2 (Il
C2H5
where~n R'l i8 the same as defined above, and R'2 is a cyano
~j
,
1066701
group or lower alkoxycarbonyl group, or by oxidizing a compound of the
formula
(Il )
C H
R'l i8 the same as defined above, and R"2 is a lower alkanoyl
group, followed, if desired, by hydrolysis, to form a compound of formula (I)
2 5
wherein Rl is a hyarogen atom or lower alkyl group.
The above reactions can be schematically shown as follows:
~ COO alkyl cyclization ~ N ~ ~ 2
R 1 ~ N ~ IN CH2,CH2 R2 1 ~ ~ / t
(IV) (III) : : .
.'~
de dro- N ~ ~ 2 hydrolysis > ~ ~ ~OOH
R~ - ~ ~ N ~ I or oxidation R~ C H
(II) (I)
The reaction route ~ill be specifically described below. .
Pro_ess from comDound (IV)to com~ound (III) : .
(intramolecular cyclization) ~ -
Compound (IY) 18 reacted by heating in a ~olYent in the presence
- 3 ~
,, . "" s
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of a basic catalyst conventionally used for Dieckmann reaction, for example,
metallic sodium or potassium, sodium hydride, or sodium ethoxiae, tbereby
intramolecularly cyclizing the compound to form compound (III). This reac-
tion can be achieved with better resultg if a catalytic amount of methanol
or ethanol or another lower alcohol is added. Aromatic hydrocarbons such
as benzene or toluene or ethers such as dioxane, tetrahydrofuran, 1-2-
dimethoxyethane or diethylene glycol dimethyl ether are suitable as the
solvent for use in this reaction. The heating temperature is not particu-
larly restricted, but usually, it is preferred to employ temperatures in the
range of 60 to 180C.
Process from compound (III) to comPound (II)
Compound (III) and a conventional dehydrogenating aeent, such as
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), tetrachloro-1,4-benzo-
quinone (chloranil), tetracyanoethylene, palladium carbon (Pd-C), N-bromo-
succinimide (NBS), manganese dioxide, or selenium dioxide, are heated for a
short period of time at a temperature near the boiling point of the solvent
used. Or compound (III) is heated in the above solvent without using a
dehydrogenating agent. Or the compound (III) is directly heated to a tem-
perature above its melting point, thereby to form compound (II). The pre-
ferred solvent is an inert solvent, for example, an aromatic hydrocarbon suchas benzene, toluene or xylene, an ether such as dioxane, or an alcohol such
as methanol or ethanol. The heating temperature i8 60 to 260C.
Process from comPound (II') to_compound ~I) (hydrolysis)
Of the compounds (II), compound (II') in which R2 is a cyano or
lower alkoxycarbonyl group is hydrolyzed by a customary method to form com-
pound (I). This reaction can be performed by heating the compound (II')
with a mineral acid, and pouring the reaction product into water; or by
heating (70 to 120C.) or warming this compound in a solvent such as water
or a water-containing high-boiling ether such as dioxane or 1,2-dimethoxy-
ethane or a water-containing alcohol such as ethanol, propanol or ethylene
glycol, in the presence of an organic acid or mineral acid.
Also, this reaction can be performed by heating or warming the
-- 4 --
~066701
compound (II') together with water or a water-containing alcohol in the
presence of a base.
The compound in ~hich ~2 is a lower alkoxycarbonyl group unaergoes
hydrolysis under milder conditions than the compound in which R2 is a cyano
group.
Examples of the acid are inorganic acids such as hydrochloric
acidj hydrobromic acid, hydroiodic acid, sul~uric acid or phosphoric acid,
and organic acids such as acetic acid, oxalic acid or toluenesulfonic acid.
Examples of the base are alkali metal hydroxides such as ~odium
hydroxide or barium h~rdroxide, alkali metal carbonates such as sodium
carbonate or potassium carbonate, snd sodium acetate.
In the compound in which R'l is an acyl group, the acyl group is
hydrolyzed in the above reaction and replaced by a hydrogen atom.
Process from compound ~II") to compound (I) (oxidation)
Of the compounds of formula (II), compounds (II") in which R2 is
a lower alkanoyl group can be oxidized to compounds of formula (I) by a
customary method. This reaction can be performed by dissolving or suspend- --
ing the compound (II") in a solvent, and causing an oxidizing agent to act
on it. ;
Suitable oxidizing agents that can be used in this reaction are, - -
for example, permanganates such as potassium permanganate, hypohalogenites
such as potassium hypochlorite, sodium hypobromite, or sodium hypoiodite,
and nitric acid. In this reaction, there can also be employed an indirect
oxidizing method in which a mixture of iodine and pyridine is ~irst caused
to act on the compound and then the resulting product is treated with alkali.
~he case of reacting the compound (II~ with bromine or iodine in
a sodium hydroxide or potassium hydroxide solution is the same as the oxida-
tion with a hypohalogenous acid.
Ihe solvent and the reaction temperatures should be selected
according to the properties of the oxidizing agent used. Suitable solvents
are water, ethers such as dioxane or 1,2-dimethoxyethane, ketones such as
acetone, pyridines such as pyridine or picoline, haloeenoalkanes such as
- 5 -
,. "-i
, . . .
. . .. .. ..
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chloroform or tetrachloromethane, alcohols such as ethanol or t-butanol, or
mixtures of water with the above organic solvents. Generally, the reaction
proceeds sufficiently at room temperature or with ice cooling.
Compounds (II') in which R'l is an acyl group may be oxidized and
then hyarolyzed, or oxidized under such conditions as to inauce hydrolysis.
In the production of compound (II) or (I) from compound (IV) in
the above series Or reactions, the product in each of the steps may be
isolated and then sub~ected to the subsequent reaction, but may also be
directly sub~ected to the subsequent reaction without isolation and purifica-
tion. If the reaction catalyst, temperature, solvent, etc. are properlychosen, compound (II) or (I) can be obtained in one step from the compound
(IV) or (III). These reactions are also included within the method of the
present invention. However, in the case of a method which covers only the
final step Or obtaining compound (I) by hydrolyzing the isolated compound
(II'), the case of a compound Or (II') in which R'2 is a lower alkoxy- -
carbonyl group is omitted.
The starting material of the formula (IV) is a new compound, and
can be readily obtnined by heating compounds (a) and (b) in the presence of
a base, as shown below.
~ 00 alkyl ~2 2 -HCl ~ compound (I~
R'l- N 1 ~HC2H5
(a) (b)
wherein R'l and R2 are the same as defined above.
The compounds(I) of this invention prepared in the above process
can be isolated and purified by usual methods. The compounds (I) can be
obtn~ned in the free state, as a hydrate or in the form of salt depending
upon the ~election Or the starting materials and the reaction conditions.
Furthermore~ the compounds (I) can be converted to phar~aceutically accept-
able amine ~alts or carboxylic acid salts by treatment with acid or alkali,
or vice versa. The acid may be a variety Or organic and inorganic acids,
-- 6 --
~06670~
examples of which are hydrochloric acid, acetic acid, lactic acid, succinic
acid, oxalic acid and methanesulfonic acid.
A clinical dosage of the compound (I) depends on body wieght, age
and administration route but it is generally in the range of 100 mg -
5 g/day, preferably of 200 mg-3g/day.
The compound (I) may be used as medicines, for example, in the
form of pharmaceutical preparations containing the compound in admixture
with an organic or inorganic, solid of liquid pharmaceutical ad~uvants
suitable for oral, parenteral, enteral or local administration. Pharmaceu-
tically acceptable ad~uvants are substances that do not react with the com-
pounds for example, water, gelatin, lactose, starch, cellulose, preferably
microcrystalline cellulose, carboxymethyl cellulose, methyl cellulose,
sorbitol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums,
propylene glycol, polyalkylene glycols, methylparaben and other known
medicinal ad~uvant. The pharmaceutical preparations may be, for example,
powder, tablets, ointments, suppositories, creams or capsules, or in liquia
form as solutions, suspensions or emulsions. They may be sterilized and/or
contain assistants such as preserving, stabilizing, wetting or emulsifying
agents, salts for regulating the osmetic pressure or buffers. They may
~urther contain other therapeutically valuable substances. The preparations
are prepared by conventional methods.
The compounds (I) and their salts have superior antibacterial
activities, and are applied in various formulations as medicines and
veterinary mediclnes.
The antibacterial activities of the typical compounds of this -
invention are shown in Tables I to IV.
In the Tables II to IV, the ED50 and LD50 values were calculated
in accordance with the Behrens-Kaerber method [Arch. Exp. Path. Pharm., 162,
480 (1931)].
Compounds Nos. 1 to 4 in the following Tables stand for the
~ollowing.
Compound No. 1: 8-Ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)
- .
106~701
pyrido[2,3-d]pyrimidine-6-carboxylic acid
Compound No. 2: ô-Ethyl-2-(4-methyl-1-piperazinyl)-5,8-dihydro-
5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid
Compound No. 3: 8-Ethyl-2-(4-ethyl-1-piperazinyl)-5,8-dihydro-
5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid
Compound No. 4: 8-Ethyl-5,8-dihydro-5-oxo-2-(1-pipera~inyl)
pyrido[2,3-d]pyrimidine-6-carboxylic acid hydrochloride
1) In vitro antibacterial activity
Table 1
Staphylococcus ¦ Escherichia ¦Shigella ¦ Pseudomonas
Compound No. aureus coli flexneri aeru~inosQ
_
M:rC (,ug/ ~)
1 .__ 1 ' - 10 :'-
2 30 1 3 100
~ 33o 1 13
The minimum inhibitory concentration (MIC) was determined by the well known
æerial dilution method.
Experimental conditions: -
Medium: nutrient broth, pH 7.0 (5 ml!tube)
Inoculum: 1 drop of 1 : 105 dilution of an overnight broth - -
culture per tube
Incubation temperature and time: 37C i`or 48 hours
2) In vivo efficacy against systemic infection with Pseudomonas
aeruginosa in mice
Table II
._ .............................................. _ :
Compound Doæe (mg/kg ~_____ ED
No. Route 200 100 5o 25 12.5 6.3 3. (m59kg)
_ . ~ ._ __
1 ip _ _ 8/88/8 4/8 2/8 1/8 10.5
po 8/8 4/8 0/8 _ _ _ _ 100
3 ip _ 4/8 o/8 _ _ _ _ -.100
po 4/8 _ _ _ _ _ _ =.200 ~
4 ip _ _ _ 8/8 _ _ _ ~ 17.7 ~ -
po 8/8 7/8 _ _ _ _ _ < 100
_ _ _ - 8 - _ _ _
,' . ~
.
.
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The numerical figures in the table show the number o~ the survival/
the total number. o/8 means that all of 8 mice died. 8/8 means that all
8 mice survived: The survival rate of non-treated control was o/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
(about 5 x 103 cells/mouse) of a bacterial suspension in 4%
gastric mucin
Medication: twice, about 5 minutes and 6 hours after infection
Drug: an alkaline solution for parenteral administration and a
suspension in 0.2% CMC for oral administration
Observation: 7 days
ip: intraperitoneal administration -
po: oral administration
3) In vivo efficacy against systemic infection with Salmonella
typh~murium in mice
Table III
_ _
Compound Dose (mg/kg) ED
No. Route ~ 100 5o 25 12.56.3 (m~9kg~
.. .~ __ ._ .. __
1 ip _ _ 8/8 8/8 4/8 6.3
po _ ô/8 8/8 4/8 o/812.5
3 ip _ _ 8/8 _ _< 17.7
po _ _ 8/8 _ _< 17.7
4 .Po _ ~ _ _ _~< 35.4
The numerical figures in the table show the number of the survival/
the total number. o/8 means that all of 8 mice died. 8/8 means that all 8
mice survived. The survival rate of non-treated control was o/8.
Experimental conditions.
Organism: ~almonella typhimurium ~-9
Mice: male mice (ddY-S) weighing 20 g approximately
Infection: Intraperitoneal infection with 50 to 100 LD50 -
(about 105 cell~/mouse) of a bacterial suspension in nutrient
9 .. ~: .
~066701
Experimental conditions Cont'd.
broth
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
ip: intraperitoneal administration
po: or~l administration
4) Acute toxicity in mice
Table_IV
.. _ ~ _
Compound _ _ DOBe (D 3lkg) _ LD
No. Route4000 2000 1000500 (mg9kg)
._. . . _ . __ . _ .. ._
iY _ _ o/66/6 700
po 6/6 6/6 _ _ > 4000
_ . __ .. ~ :
The numerical figures in the table show the number Or survival/ ~ -
the total number. o/6 means that all of 6 mice died and 6/6 means that
all of mice survived.
The compound was in alkaline solution for intraveneous administra-
tion and suspension containing 0.2% CMC for oral administration, and admin-
istered to male mice (ddY~S) weighing 20 g approximately. A~ter 7 days, the
lncidence o~ death was recorded and LD50 value was estimated.
iv: intraveneous administration
po: oral administration
The invention will be further illustrated by the following
Examples.
Exam~le A ~ -
5,8-dihydro-ô-ethyl-2-(1-piperazinyl)!5-oxopyrido[2,3-d]pyrimidine-
6-carbo~vlic acid 250 g
Starch 54 g
Calcium carboxymethyl cellulose 40 g -
~icrocrystalline cellulose50 g
Magnesium gtearate 6 g
-- 10 -- ;' :' "
. . ,: ' ' - , ' : ' ' ' . , .
1066701
The above components are blended, granulated and made into tablets
in a manner kno~n Per se. Thus, 1000 tablets each weighing 400 mg are
formed.
Example B
5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-
6-carboxylic acid 250 g
Starch 5 g
Lactose 35 g
Talc 15 g
10 The above components were blended and ~ranulated and filled into
1,000 capsules in accordance with the conventional methods.
Example C Preparation of Suspension
5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido[2,3-d]
pyrimidine-6-carboxylic acid hydrochloride 5 g
Sorbitol 30 g
Sugar 4 g
Methylparaben Small amount
Sodium carboxymethyl cellulose Small amount
Flavour Small amount
Water to mske 100 ml
Example 1
8-Etlurl-2-(4-met~rl-l-PiperazinYl)-5~8-dih~rdro-5-oxopyrido
[2.3-d]Pyrimidine-6-carboxylic acid
A mixture containing 3.0 g of 8-ethyl-2-(4-methyl-1-piperazinyl)-
5,8-di~rdro-5-oxopyrido[2,3-d]pyrimidine-6-carbonitrile, 270 ml of acetic
acid, and 150 ml of concentrated hydrochloric acid was heated at 90C for
25 hours. The mixture was concentrated to dryness in vacuo. The resulting
residue was neutralized by addition of a 5% aqueous solution of sodium
hydroxide, and extracted with chloroform. ~e extract, after drying, was
30 concentrated to leave a crude solid which was recrystallized from ethanol
to give 2,6 g o~ the product, m.p. 232-233 C~
-- 11 -- .
1066701
Example 2
8-Ethyl-2-(4-ethyl-1-piperazin~vl~-5~8-dihydro-~ xoP~rido
[2~3-d]Pyrimidine-6-carboxylic acid
The procedure described in Example 1 was repeated using 8-ethyl-
2-(4-ethyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-
carbonitrile. There was obtained the product, m.p. 228 to 230 C.
Example 3
8-Ethyl-~18-dihydro-5-oxo-2-(l-PiPerazinyl~pyrido
~2,3-d]_~rimidine-6-carboxylic acid ~ydrochloride
A mixture containing 5.0 g Or 2-(4-acetyl-1-piperazinyl)-8-
ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carbonitrile, 200 ml of
acetic acid, and 200 ml of concentrated hydrochloric acid waæ heated at 90C
for 3 hours. The mixture was concentrated to dryness in vacuo. To the
residue was added a small amount of concentrated hydrochloric acid. A
resulting hydrochloride was collected and washed with ethanol to yield
4.7 g of the product, m.p. above 300 C.
ExamPle 4 -- -
^o-Ethyl-5.8-dihydro-2-(4-methyl-1-piperazinyl)-5-oxopyrido
[2.3 d~p~rimidine-~-carboxylic acid
To a solution o~ sodium hypobromite, which was prepared by addi-
tion of 3.ô g oP bromine to a mixture containing dioxane (10 ml) and a 15%
aqueous solution (16 ml) of sodium hydroxide with cooling below 10C, was
sdded 2.0 g of 6-acetyl-^o-ethyl-5,ô-dihydro-2-(4-methyl-1-piperazinyl)-5-
oxopyrido[2,3-d~pyrimidine with stirring. After the mixture was allowed ;~
to stssd at room temperature ~or 2 hours, the br~moPorm Pormed as by-
product was removed by extrsction with chloro~orm. The aIkaline, aqueous
layer was neutralized with acetic acid to separate the solid, which was
collected and recrystallized ~rom diluted ethanol to give the product, m.p.
232-233C.
Exa~ple 5
thYl 8-ethYl-2-(4-methYl-l-PiPerazinyl)-5~l8-dihydro-5-oxo- ~.
imidi~e-6-carboxylate
To a solution oP ethyl o^-ethyl-2-(4-methyl-1-piperazinyl)-5-oxo- ~ -
- 12 _
,; , ., l , , ,, , , , , ., ; . ,
~06670~
5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate (3.0 g) in 100 ml
of dry benzene was added 2.8 g of chloranil, and the mixture was heated
to reflux for 30 minutes. After cooling, the separated solid was collected
and recrystalliæed from dimethylformamide to give 2.8 B of the product,
m.p. 146-147C.
Example 6
8-Ethyl-2-(4-methyl-1-piperazinyl~-5~8-dihydro-5-oxopyrido
~2,3-d]p~rimidine-6-carbonitrile
Two grams of 8-ethyl-2-(4-methyl-1-piperazinyl)-5-oxo-5,6,7,8-
tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile was heated directly at
220C for 7 minutes and, after cooling, recrystallized from methanol to
yield 1.7 g of the product, m.p. 255-258C.
Example 7
Ethyl 8-ethyl-2-(4-methyl-1-pi~erazinyl)-5,8-dih~dro-5-oxo-
~yrido~213-d]pyrimidine-6-carboxylate
To a solution of ethyl 4-(ethyl-2-ethoxycarbonylethyl)amino-2-
(4-methyl-1-piperazinyl)pyrimidine-5-carboxylate (4.0 g) in 10 ml of l,Z-
dimethoxyethane was added 0.75 g of 50% sodium hydride and the mixture was
heated to reflux for one hour. After removal of the solvent the resulting
residue was neutralized with acetic acid and extracted with chloro~orm.
The extract was waæhed with water, dried over anhydrous sodium sulfate, and
the solvent removed by distillation to give an intermediate which, if
desired, was recrystallized from n-hexane-acetone to yield ethyl 8-ethyl-
2-(4-methyl-1-piperazinyl)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine- ~ -
6-carboxylate in a pure form, m.p. 97-100C.
The lntermediate tetrahydro-ester thus obtained was dissolved
ln benzene and the mixture was heated to reflux for 1.5 hours. The solid
separated on cooling was collected and recrystallized from dimethylformamide
to give 2.5 g of the product, m.p. 146-147C.
ExamPle 8
8-Eth~1-2-(4-methY1~ razinyl)-5,8-dihydro-5-oxo~yrido
[2~3~dJpY-rimi~lne-6-carbonitrlle .
To a mixture containing ethyl 4-(ethyl-2-cyanoethyl)amino-2-(4-
- 13 -
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methyl-l-piperazinyl)pyrimidine-5-carboxylate (4.3 g) and 10 ml of dioxane
was added o.8 g of 50% sodium hydride at roo~ temperature with stirring
and the mixture was heated to reflux for 30 minutes. After removal of the
solvent, the resulting residue was neutralized with acetic acid and
extracted with chloroform. The extract was worked up as in Example 7 and
there was obtained an intermediate which, if desired, was recrystallized
from n-hexane-acetone to give 8-ethyl-2-(4-methyl-1-piperazinyl)-5-oxo-
5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile in a pure form,
m.p. 172-174C.
The tetrahydro-carbonitrile was dissolved in 100 ml of dry
benzene and 2.5 g of chloranil was added to it. The mixture was heated to
reflux for 30 minutes. The solid separated on cooling was collected and
recrystallized from methanol to yield 2.9 g of the product, m.p. 255-258C.
Exam~le 9
2-(4-Acetyl-l-piperazinyl)-8-ethyl-5~8-dihydro-5-oxop~rido[?~3-d]
pyrimidine-6-carbonitrile
To a mixture containing 5.0 g of ethyl 2-(4-acetyl-1-piperazinyl)-
4-(ethyl-2-cyanoethyl)aminopyrimidine-5-carboxylate and 50 ml of ethylene-
glycol dimethyl ether was added 2.0 g of 50~ sodium hydride. Then the mix-
ture was heated at 95C for one hour. The mixture was concentrated to
dryness in vacuo and the resulting residue was neutralized with acetic acid,
and extracted with chloro~orm. The solvent was evaporated from the extract
to give an oily intermediate, 2-(4-acetyl-1-piperazinyl)-8-ethyl-5-oxo-
5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile. The nitrile ~ -
without further purification was dissolved in 50 ml of benzene and 2.5 g ~--
of chloranil was added to it. The mixture was heated to reflux for 30
minutes. The solid separated on cooling was collected, washed with benzene,
and recrystallized from methanol to yield 3.4 g of the product, m.p. 317C.
Example 10
Eth~l 2-(4-acetyl-l-piperazin~l)-8-eth~l-5~8-dihyd-ro-5-oxo- ~;
midine-6-carbo~ylate
Following the procedure described in Example 9, using ethyl 2-
- 14 -
1066701
(4-acetyl-1-piperazinyl)~ ethyl-2-ethoxycarbonylethyl)aminopyrimidine-
5-carbo~ylate as a startine material, there was obtained the product, m.p.
208-210C (decomp.)
ExaF~ e 11
6-Acetyl-8-ethyl-5,8-dih~dro-?-(4-methyl-l-piperazinyl)-5
rido[2.3-d ~ rimidine
Following the procedure described in Example 9, using ethyl 2-
(4-methyl-1-piperazinyl)-4-(ethyl-3-oxobutyl)aminopyrimidine-5-carboxylate,
there was obtained the product, m.p. 198-200C.
Example 12
8-Ethy1-5.8-dihydro-5-oxo-2-(1-PiPerazinyl)pyrido[2.3-d]
~rimidine-6-carboxylic acid
Using 5.0 g of ethyl 4-(ethyl-2-ethoxycarbonylethyl)amino-2-(1-
piperazinyl)pyrimidine-5-carboxylate as a starting material, an intermediate
ethyl 5,8-dihydro-8-ethyl-5-oxo-2-(1-piperazinyl)pyrido~2,3-d]pyrimidine-
6-carboxylate was prepared in the same way as in Example 9. The inter-
mediate, if desired, was purified by recrystallization from acetone. m.p. ~ -~
156-158C. The carboxylate was dissolved in 30 ml of a 7% aqueous solution
of sodium hydroxid~ by heating at 90C for 20 minutes. After cooling, the
resulting solution was neutralized with acetic acid to yield a precipitate
which was collected, and recrystallized from dimethylformamide. There was
obtained 4.3 g of the product, m.p. 253-255C. -
Example 13
8-Ethyl-5~8-dih~dro-7-oxo-2-~ 1-pi~erazinYl)P~rido[2~3-d]
pyrimidine-6-carboxylic acid -
Using 10.0 g of ethyl 4-(ethyl-3-oxobutyl)amino-2-(1-piperazinyl)-
pyrimidine-5-carboxylate as a starting material, 6-acetyl-8-ethyl-5,8-
dlhydro-5-oxo-2-(1-piperazinyl)pyrido[2,3-d]pyrimidine was prepared in the
same way as in Example 9. The intermediate (7.3 g), without further puri-
fication, was worked up and oxidized in the same way as in Example 4 toyleld ~.2 g of the product, m.p. 253-255C.
: ' ' ' '.' ' . ' ',~ ' ': ' .
1066701
Example 14
Ethyl 4-(ethyl-2-ethoxycarbonylethyl)amino-2-(4-methy
pi~erazin~rl)pyrimidi~n-e-5-carbox~rlate
To a solution of 3.9 g of ethyl 4-chloro-2-(4-methyl-1-piperazinyl)
pyrimidine-5-carboxylate in 10 ml of diethyleneglycol dimethyl ether was
added 2.4 g of ethyl 3-ethylaminopropionate and 1.3 g of sodium bicarbonate.
The resulting mixture was heated at 140-150C for 2 hours. After removal
of the solvent, the residue was taken up in chloroform. The chloroform
solution was washed with water, dried, and concentrated to leave the oily
product. The oil was chromatographed on silica gel with chloroform as an
eluant, giving the product in a pure form. The structure of the product
was confirmed by its infra-red absorption (IR) spectrum and nuclear magnetic
resonance (NMR) spectrum.
IR 3pectrum (liquid film, cm 1): 1730, 1700, 1678, 1350, and 1230.
NMR spectrum (CDC13, ppm/~): 8.50 (lH, singlet), 4.27 (2H, quartet, J=7
Hz), 3.90-3.83 (4H, multiplet), 2.34 (3H, singlet); 1.33 (3H, triplet,
J=7 Hz), 1.25 (3H, triplet, J=7 Hz), and 1.20 (3H, triplet, J=7 Hz).
Exam~le 15
Ethrl 4-(ethyl-2-cyanoethyl)amino-2-(4-methrl-1-pi~erazinyl)
~yrimidine-5-carboxylate
Following the procedure described in Example 14 using 1.6 g of
3-ethylaminopropionitrile in place of ethyl 3-ethylaminopropionate, ~
there was obtained the oily product. ~- -
IR ~pectrum (liquid film cm 1): 2240, 1698, 1568, and 1578.
NMR spectrum (CDC13, ppm/~): 8.60 (lH, singlet), 3.71 (2H, quartet,
J=7 Hz), 3.40 (2H, quartet, J=7 Hz), 1.35 (3H, triplet, J=7 Hz), and 1.24
(3H, triplet, J=7 Hz). ;
~. .... ...
- 16 -
